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Proposal to change Part B drug WAC-based reimbursement draws criticism
Some physician groups are pushing back on a proposal to lower the add-on percentage for reimbursement of new Part B drugs paid using the wholesale acquisition cost (WAC) when an average sales price (ASP) has not yet been established.
Under current regulation, physicians are reimbursed at WAC plus 6% for newly approved drugs. The Centers for Medicare & Medicaid Services is looking to reduce the add-on to 3% in the proposed update to the physician fee schedule for 2019.
In Sept. 6 comments to the agency, the American College of Rheumatology took on a neutral stance to the proposal as a whole, stating only that it appreciates “that the proposed rule does clarify that the change in reimbursement would not apply to new biosimilars, whose reimbursement would remain at the drug’s WAC plus 6% of the reference drug’s ASP.”
The American Society of Clinical Oncology took a more hard-line stance.
“CMS should not finalize the proposed reduction in the add-on rate for Part B drugs subject to payment through the wholesale acquisition cost methodology and should instead focus on pursuing comprehensive solutions that drive value-based cancer care,” ASCO said in Sept. 10 comments to the agency. It acknowledged CMS’ pursuit to lower drug spending, but suggested this will not have any meaningful impact “since most drugs are paid through a WAC-based methodology on a temporary basis only.”
The American Medical Association argued in Sept. 10 comments to the agency that, when accounting for the budget sequester that is in effect, physicians would only be getting reimbursed with a 1.4% add-on and that enactment of this proposal “would trigger reimbursement cuts for new drugs that will preclude their use in most physician offices and hinder Medicare patients’ access to new and innovated therapies that are more effective and/or less debilitating than existing drugs. AMA strongly believes that this proposal should not be finalized.”
Some physician groups are pushing back on a proposal to lower the add-on percentage for reimbursement of new Part B drugs paid using the wholesale acquisition cost (WAC) when an average sales price (ASP) has not yet been established.
Under current regulation, physicians are reimbursed at WAC plus 6% for newly approved drugs. The Centers for Medicare & Medicaid Services is looking to reduce the add-on to 3% in the proposed update to the physician fee schedule for 2019.
In Sept. 6 comments to the agency, the American College of Rheumatology took on a neutral stance to the proposal as a whole, stating only that it appreciates “that the proposed rule does clarify that the change in reimbursement would not apply to new biosimilars, whose reimbursement would remain at the drug’s WAC plus 6% of the reference drug’s ASP.”
The American Society of Clinical Oncology took a more hard-line stance.
“CMS should not finalize the proposed reduction in the add-on rate for Part B drugs subject to payment through the wholesale acquisition cost methodology and should instead focus on pursuing comprehensive solutions that drive value-based cancer care,” ASCO said in Sept. 10 comments to the agency. It acknowledged CMS’ pursuit to lower drug spending, but suggested this will not have any meaningful impact “since most drugs are paid through a WAC-based methodology on a temporary basis only.”
The American Medical Association argued in Sept. 10 comments to the agency that, when accounting for the budget sequester that is in effect, physicians would only be getting reimbursed with a 1.4% add-on and that enactment of this proposal “would trigger reimbursement cuts for new drugs that will preclude their use in most physician offices and hinder Medicare patients’ access to new and innovated therapies that are more effective and/or less debilitating than existing drugs. AMA strongly believes that this proposal should not be finalized.”
Some physician groups are pushing back on a proposal to lower the add-on percentage for reimbursement of new Part B drugs paid using the wholesale acquisition cost (WAC) when an average sales price (ASP) has not yet been established.
Under current regulation, physicians are reimbursed at WAC plus 6% for newly approved drugs. The Centers for Medicare & Medicaid Services is looking to reduce the add-on to 3% in the proposed update to the physician fee schedule for 2019.
In Sept. 6 comments to the agency, the American College of Rheumatology took on a neutral stance to the proposal as a whole, stating only that it appreciates “that the proposed rule does clarify that the change in reimbursement would not apply to new biosimilars, whose reimbursement would remain at the drug’s WAC plus 6% of the reference drug’s ASP.”
The American Society of Clinical Oncology took a more hard-line stance.
“CMS should not finalize the proposed reduction in the add-on rate for Part B drugs subject to payment through the wholesale acquisition cost methodology and should instead focus on pursuing comprehensive solutions that drive value-based cancer care,” ASCO said in Sept. 10 comments to the agency. It acknowledged CMS’ pursuit to lower drug spending, but suggested this will not have any meaningful impact “since most drugs are paid through a WAC-based methodology on a temporary basis only.”
The American Medical Association argued in Sept. 10 comments to the agency that, when accounting for the budget sequester that is in effect, physicians would only be getting reimbursed with a 1.4% add-on and that enactment of this proposal “would trigger reimbursement cuts for new drugs that will preclude their use in most physician offices and hinder Medicare patients’ access to new and innovated therapies that are more effective and/or less debilitating than existing drugs. AMA strongly believes that this proposal should not be finalized.”
Peripheral opioid blocker eases opioid-induced constipation without inducing withdrawal
LAS VEGAS – .
In three placebo-controlled randomized studies, the drug increased the number of spontaneous bowel movements and improved stool consistency without inducing opioid withdrawal symptoms.
Naldemedine (Symproic) received FDA approval last year based on COMPOSE 1 and COMPOSE 2, which were published in Lancet Gastroenterology and Hepatology last year (2017 Aug 2[8]:555-64). James E. Wild, MD, of Upstate Clinical Research Associates, in Williamsville, N.Y., reported these in a poster presented at the annual PAINWeek.
The year-long COMPOSE 3 trial was not presented at the meeting, but appeared in the journal Pain (2018 May;5:987-94).
Opioids not only affect the central nervous system but also bind to mu-opioid receptors in the gut, decreasing intestinal motility. Naldemedine blocks these receptors from opioid binding but cannot cross the blood-brain barrier. Its peripheral action blocks gut opioid binding, side-stepping the motility problem without inducing any opioid withdrawal symptoms.
COMPOSE 1 (C1) and COMPOSE 2 (C2) comprised a total of 1,095 subjects with chronic, noncancer pain. They were randomized to either naldemedine 0.2 mg daily or placebo for 12 weeks.
Patients were a median of 53 years with a mean opioid use of 61 months. About 60% had a mean daily morphine equivalent of 30-100 mg, and 40% a mean dose of more than 100 mg. At baseline, they had a mean of one spontaneous bowel movement (BM) per week, with a mean of 0.4 deemed “complete.” All the BMs were accompanied by straining.
Response was defined as a patient who had at least three spontaneous BMs per week and an increase of at least one for that week, for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the trial.
In both studies, the responder rate was significantly higher in the naldemedine group than in the placebo group (C1 48% vs. 34%; C2 53% vs. 33%). Those taking naldemedine had a mean of two more spontaneous BMs per week than did those taking placebo, and significantly more of those were accomplished without straining.
The most common treatment-emergent adverse effects were diarrhea (about 8% vs. 3%) and abdominal pain (about 6% vs. 1%).
Three patients in C1 experienced at least one event of opioid withdrawal (two taking the study drug and one taking placebo). There were no confirmed withdrawal events in C2, but seven patients (five taking the study drug and two taking placebo) experienced possible gastrointestinal withdrawal symptoms.
COMPOSE 3 demonstrated naldemedine’s lasting benefit in this population. It randomized 1,246 patients to 52 weeks of placebo or the 0.2 mg/day dose. Patient demographics were similar to the earlier COMPOSE studies.
The primary endpoint was treatment-emergent adverse events. Additional endpoints included opioid withdrawal, pain intensity, frequency of bowel movements, and constipation-related symptoms.
There was a significant and sustained increase from baseline in the frequency of bowel movements with naldemedine, increasing from about two to four each week. Constipation symptoms and quality of life scores both improved significantly, relative to placebo.
Again, the most common adverse event was diarrhea (11% naldemedine vs. 5% placebo). The drug was not associated with any opioid withdrawal symptoms, nor did it interfere with a patient’s pain control.
LAS VEGAS – .
In three placebo-controlled randomized studies, the drug increased the number of spontaneous bowel movements and improved stool consistency without inducing opioid withdrawal symptoms.
Naldemedine (Symproic) received FDA approval last year based on COMPOSE 1 and COMPOSE 2, which were published in Lancet Gastroenterology and Hepatology last year (2017 Aug 2[8]:555-64). James E. Wild, MD, of Upstate Clinical Research Associates, in Williamsville, N.Y., reported these in a poster presented at the annual PAINWeek.
The year-long COMPOSE 3 trial was not presented at the meeting, but appeared in the journal Pain (2018 May;5:987-94).
Opioids not only affect the central nervous system but also bind to mu-opioid receptors in the gut, decreasing intestinal motility. Naldemedine blocks these receptors from opioid binding but cannot cross the blood-brain barrier. Its peripheral action blocks gut opioid binding, side-stepping the motility problem without inducing any opioid withdrawal symptoms.
COMPOSE 1 (C1) and COMPOSE 2 (C2) comprised a total of 1,095 subjects with chronic, noncancer pain. They were randomized to either naldemedine 0.2 mg daily or placebo for 12 weeks.
Patients were a median of 53 years with a mean opioid use of 61 months. About 60% had a mean daily morphine equivalent of 30-100 mg, and 40% a mean dose of more than 100 mg. At baseline, they had a mean of one spontaneous bowel movement (BM) per week, with a mean of 0.4 deemed “complete.” All the BMs were accompanied by straining.
Response was defined as a patient who had at least three spontaneous BMs per week and an increase of at least one for that week, for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the trial.
In both studies, the responder rate was significantly higher in the naldemedine group than in the placebo group (C1 48% vs. 34%; C2 53% vs. 33%). Those taking naldemedine had a mean of two more spontaneous BMs per week than did those taking placebo, and significantly more of those were accomplished without straining.
The most common treatment-emergent adverse effects were diarrhea (about 8% vs. 3%) and abdominal pain (about 6% vs. 1%).
Three patients in C1 experienced at least one event of opioid withdrawal (two taking the study drug and one taking placebo). There were no confirmed withdrawal events in C2, but seven patients (five taking the study drug and two taking placebo) experienced possible gastrointestinal withdrawal symptoms.
COMPOSE 3 demonstrated naldemedine’s lasting benefit in this population. It randomized 1,246 patients to 52 weeks of placebo or the 0.2 mg/day dose. Patient demographics were similar to the earlier COMPOSE studies.
The primary endpoint was treatment-emergent adverse events. Additional endpoints included opioid withdrawal, pain intensity, frequency of bowel movements, and constipation-related symptoms.
There was a significant and sustained increase from baseline in the frequency of bowel movements with naldemedine, increasing from about two to four each week. Constipation symptoms and quality of life scores both improved significantly, relative to placebo.
Again, the most common adverse event was diarrhea (11% naldemedine vs. 5% placebo). The drug was not associated with any opioid withdrawal symptoms, nor did it interfere with a patient’s pain control.
LAS VEGAS – .
In three placebo-controlled randomized studies, the drug increased the number of spontaneous bowel movements and improved stool consistency without inducing opioid withdrawal symptoms.
Naldemedine (Symproic) received FDA approval last year based on COMPOSE 1 and COMPOSE 2, which were published in Lancet Gastroenterology and Hepatology last year (2017 Aug 2[8]:555-64). James E. Wild, MD, of Upstate Clinical Research Associates, in Williamsville, N.Y., reported these in a poster presented at the annual PAINWeek.
The year-long COMPOSE 3 trial was not presented at the meeting, but appeared in the journal Pain (2018 May;5:987-94).
Opioids not only affect the central nervous system but also bind to mu-opioid receptors in the gut, decreasing intestinal motility. Naldemedine blocks these receptors from opioid binding but cannot cross the blood-brain barrier. Its peripheral action blocks gut opioid binding, side-stepping the motility problem without inducing any opioid withdrawal symptoms.
COMPOSE 1 (C1) and COMPOSE 2 (C2) comprised a total of 1,095 subjects with chronic, noncancer pain. They were randomized to either naldemedine 0.2 mg daily or placebo for 12 weeks.
Patients were a median of 53 years with a mean opioid use of 61 months. About 60% had a mean daily morphine equivalent of 30-100 mg, and 40% a mean dose of more than 100 mg. At baseline, they had a mean of one spontaneous bowel movement (BM) per week, with a mean of 0.4 deemed “complete.” All the BMs were accompanied by straining.
Response was defined as a patient who had at least three spontaneous BMs per week and an increase of at least one for that week, for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the trial.
In both studies, the responder rate was significantly higher in the naldemedine group than in the placebo group (C1 48% vs. 34%; C2 53% vs. 33%). Those taking naldemedine had a mean of two more spontaneous BMs per week than did those taking placebo, and significantly more of those were accomplished without straining.
The most common treatment-emergent adverse effects were diarrhea (about 8% vs. 3%) and abdominal pain (about 6% vs. 1%).
Three patients in C1 experienced at least one event of opioid withdrawal (two taking the study drug and one taking placebo). There were no confirmed withdrawal events in C2, but seven patients (five taking the study drug and two taking placebo) experienced possible gastrointestinal withdrawal symptoms.
COMPOSE 3 demonstrated naldemedine’s lasting benefit in this population. It randomized 1,246 patients to 52 weeks of placebo or the 0.2 mg/day dose. Patient demographics were similar to the earlier COMPOSE studies.
The primary endpoint was treatment-emergent adverse events. Additional endpoints included opioid withdrawal, pain intensity, frequency of bowel movements, and constipation-related symptoms.
There was a significant and sustained increase from baseline in the frequency of bowel movements with naldemedine, increasing from about two to four each week. Constipation symptoms and quality of life scores both improved significantly, relative to placebo.
Again, the most common adverse event was diarrhea (11% naldemedine vs. 5% placebo). The drug was not associated with any opioid withdrawal symptoms, nor did it interfere with a patient’s pain control.
AT PAINWEEK 2018
Key clinical point: Naldemedine improves symptoms of opioid-induced constipation over 12 and 52 weeks.
Major finding: The drug doubled the frequency of bowel movements in both 12- and 52-week studies.
Study details: Altogether, COMPOSE 1, 2, and 3 randomized 2,300 patients to placebo or 0.2 mg/day naldemedine.
Disclosures: The studies were sponsored by Shionogi. Dr. Wild is a clinical trialist with Upstate Clinical Research Associates, Williamsville, N.Y.
Source: Wild JE et al. PAINWeek 2018, Abstract 34
New Edition of the ‘Go-To’ Book on Diabetes Available
“Diabetes in America was written to serve as the go-to book for anything you ever wanted to know about diabetes,” says Catherine Cowie, PhD, editor and senior advisor for the National Institute of Diabetes and Digestive and Kidney Diseases’ Diabetes Epidemiology Program. “It’s a resource for everyone, because diabetes affects just about everyone.”
Written by recognized experts who “represent every facet of diabetes,” the book covers relevant research, data and trends, complications and related conditions, and prevention and medical care. It is “rich in data,” says Dr. Cowie, and includes cross-sectional national data, as well as smaller geographic community and longitudinal studies. This edition includes both published and unpublished data that were specifically analyzed for the book.
Clinical trial data are summarized to show the strongest evidence available for the effectiveness of interventions, but the book also emphasizes “points of hope” found through research: For example, people at high risk can prevent or delay type 2 diabetes by losing a modest amount of weight, and rates of some complications, such as lower extremity amputations, are on the decline.
Cowie says Diabetes in America is designed to be useful to a variety of readers. Patients can use it to better understand their condition or risk factors; practitioners can use it to assess patients’ risk of diabetes and associated complications; health policy makers who need “sound quantitative knowledge” can use it to guide decision making; scientists can use it to help identify areas of needed research.
To download, visit: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition.
“Diabetes in America was written to serve as the go-to book for anything you ever wanted to know about diabetes,” says Catherine Cowie, PhD, editor and senior advisor for the National Institute of Diabetes and Digestive and Kidney Diseases’ Diabetes Epidemiology Program. “It’s a resource for everyone, because diabetes affects just about everyone.”
Written by recognized experts who “represent every facet of diabetes,” the book covers relevant research, data and trends, complications and related conditions, and prevention and medical care. It is “rich in data,” says Dr. Cowie, and includes cross-sectional national data, as well as smaller geographic community and longitudinal studies. This edition includes both published and unpublished data that were specifically analyzed for the book.
Clinical trial data are summarized to show the strongest evidence available for the effectiveness of interventions, but the book also emphasizes “points of hope” found through research: For example, people at high risk can prevent or delay type 2 diabetes by losing a modest amount of weight, and rates of some complications, such as lower extremity amputations, are on the decline.
Cowie says Diabetes in America is designed to be useful to a variety of readers. Patients can use it to better understand their condition or risk factors; practitioners can use it to assess patients’ risk of diabetes and associated complications; health policy makers who need “sound quantitative knowledge” can use it to guide decision making; scientists can use it to help identify areas of needed research.
To download, visit: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition.
“Diabetes in America was written to serve as the go-to book for anything you ever wanted to know about diabetes,” says Catherine Cowie, PhD, editor and senior advisor for the National Institute of Diabetes and Digestive and Kidney Diseases’ Diabetes Epidemiology Program. “It’s a resource for everyone, because diabetes affects just about everyone.”
Written by recognized experts who “represent every facet of diabetes,” the book covers relevant research, data and trends, complications and related conditions, and prevention and medical care. It is “rich in data,” says Dr. Cowie, and includes cross-sectional national data, as well as smaller geographic community and longitudinal studies. This edition includes both published and unpublished data that were specifically analyzed for the book.
Clinical trial data are summarized to show the strongest evidence available for the effectiveness of interventions, but the book also emphasizes “points of hope” found through research: For example, people at high risk can prevent or delay type 2 diabetes by losing a modest amount of weight, and rates of some complications, such as lower extremity amputations, are on the decline.
Cowie says Diabetes in America is designed to be useful to a variety of readers. Patients can use it to better understand their condition or risk factors; practitioners can use it to assess patients’ risk of diabetes and associated complications; health policy makers who need “sound quantitative knowledge” can use it to guide decision making; scientists can use it to help identify areas of needed research.
To download, visit: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition.
Novel agents changing treatment algorithm in AML
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
Current management of AML patients
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
FLT3 inhibitor approved for rel/ref AML in Japan
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
Drug approved as part of frontline therapy for HL
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).
The approval was based on the phase 3 ECHELON-1 trial.
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).
The approval was based on the phase 3 ECHELON-1 trial.
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).
The approval was based on the phase 3 ECHELON-1 trial.
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
Product approved to treat hemophilia A in Japan
The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.
Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.
Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.
As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.
The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.
PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.
In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.
In part B, researchers evaluated Jivi for perioperative management.
Efficacy
In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.
Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.
Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).
The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).
The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).
The median ABR for patients treated on demand was 24.1.
There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”
There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.
Safety
Safety data are available for 148 patients age 12 and older.
Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).
A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.
One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.
The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.
Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.
Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.
As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.
The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.
PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.
In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.
In part B, researchers evaluated Jivi for perioperative management.
Efficacy
In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.
Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.
Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).
The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).
The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).
The median ABR for patients treated on demand was 24.1.
There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”
There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.
Safety
Safety data are available for 148 patients age 12 and older.
Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).
A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.
One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.
The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.
Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.
Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.
As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.
The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.
PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.
In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.
In part B, researchers evaluated Jivi for perioperative management.
Efficacy
In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.
Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.
Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).
The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).
The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).
The median ABR for patients treated on demand was 24.1.
There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”
There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.
Safety
Safety data are available for 148 patients age 12 and older.
Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).
A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.
One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.
Polycythemia Vera and Essential Thrombocythemia
From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
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From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
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70. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552–5.
71. Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia 2014;28:2300–3.
72. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123:1544–51.
73. Palandri F, Latagliata R, Polverelli N, et al. Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. Leukemia 2015;29:1344–9.
74. Fu R, Xuan M, Zhou Y, et al. Analysis of calreticulin mutations in Chinese patients with essential thrombocythemia: clinical implications in diagnosis, prognosis and treatment. Leukemia 2014;28:1912–4.
75. Tefferi A, Wassie EA, Guglielmelli P, et al. Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 2014;89:E121–4.
76. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia 2016;30: 431–8.
77. Rumi E, Pietra D, Guglielmelli P, et al. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood 2013;121:4388–95.
78. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008;112:141–9.
79. Gangat N, Wassie EA, Lasho TL, et al. Mutations and thrombosis in essential thrombocythemia: prognostic interaction with age and thrombosis history. Eur J Haematol 2015;94:31–6.
80. Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013;162:730–47.
81. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymph 2013;54:1989–95.
82. Landolfi R, Di Gennaro L, Nicolazzi MA, et al. Polycythemia vera: gender-related phenotypic differences. Intern Emerg Med 2012;7:509–15.
83. Winslow ER, Brunt LM, Drebin JA, et al. Portal vein thrombosis after splenectomy. Am J Surg 2002;184:631–6.
84. Smalberg JH, Arends LR, Valla DC, et al. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012;120:4921–8.
85. Dentali F, Squizzato A, Brivio L, et al. JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009;113:5617–23.
86. Pardanani A, Lasho TL, Hussein K, et al. JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients. Mayo Clin Proc 2008;83:457–9.
87. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29:761–70.
88. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114–24.
89. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013;368:22–33.
90. Kiladjian JJ, Chevret S, Dosquet C, et al. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol 2011;29:3907–13.
91. Kaplan ME, Mack K, Goldberg JD, et al. Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 1986;23:167–71.
92. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997;34:17–23.
93. Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105: 2664–70.
94. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 2013;121:4778–81.
95. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012;119:1363–9.
96. Stein BL, Tiu RV. Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. J Interferon Cytokine Res 2013;33: 145–53.
97. Ludwig H, Cortelezzi A, Van Camp BG, et al. Treatment with recombinant interferon-alpha-2C: multiple myeloma and thrombocythaemia in myeloproliferative diseases. Oncology 1985;42 Suppl 1:19–25.
98. Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 2006;107:451–8.
99. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 2011;117:4706–15.
100. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs 2008;22:315–29.
101. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065–72.
102. Turlure P, Cambier N, Roussel M, et al. Complete hematological, molecular and histological remissions without cytoreductive treatment lasting after pegylated-interferon {alpha}-2a (peg-IFN{alpha}-2a) therapy in polycythemia vera (PV): long term results of a phase 2 trial [abstract]. Blood 2011;118(21). Abstract 280.
103. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27:5418–24.
104. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon a-2a. Blood 2013;122:893–901.
105. Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer 2006;106:2397–405.
106. Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer 2007; 110:2012–18.
107. Them NC, Bagienski K, Berg T, et al. Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b. Am J Hematol 2015;90:288–94.
108. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients [abstract]. Blood 2016;128(suppl 22). Abstract 475.
109. van Genderen PJ, van Vliet HH, Prins FJ, et al. Excessive prolongation of the bleeding time by aspirin in essential thrombocythemia is related to a decrease of large von Willebrand factor multimers in plasma. Ann Hematol 1997;75:215–20.
110. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132–7.
111. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45.
112. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720–8.
113. Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol 2003;51:81–6.
114. Barosi G, Tefferi A, Barbui T, ad hoc committee ‘Definition of clinically relevant outcomes for contemporarily clinical trials in Ph-neg M. Do current response criteria in classical Ph-negative myeloproliferative neoplasms capture benefit for patients? Leukemia 2012;26:1148–9.
115. Bjorkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 2011;29:2410–5.
116. Alvarez-Larran A, Martinez-Aviles L, Hernandez-Boluda JC, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol 2014;93:2037–43.
117. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014;120: 513–20.
118. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib in polycythemia vera resistant to or intolerant of hydroxyurea. N Engl J Med 2015; 372:426–35.
119. Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial. Haematologica 2016;101:821–9.
120. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 2017;18:88–99.
121. Verstovsek S, Passamonti F, Rambaldi A, et al. Long-term results from a phase II open-label study of ruxolitinib in patients with essential thrombocythemia refractory to or intolerant of hydroxyurea [abstract]. Blood 2014;124. Abstract 1847.
122. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib versus best available therapy for ET intolerant or resistant to hydroxycarbamide in a randomized trial. Blood 2017 Aug 9. pii: blood-2017-05-785790 .
123. Bose P, Verstovsek S. Drug development pipeline for myeloproliferative neoplasms: potential future impact on guidelines and management. J Natl Compr Canc Netw 2016;14:1613–24.
124. Cerquozzi S, Teffieri A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J 2015;Nov 13;5:e366.
125. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood 2008;111:3383–7.
126. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post- PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007;31:737–40.
127. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol 2014;21:65–71.
128. Chihara D, Kantarjian HM, Newberry KJ, et al. Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms [abstract]. Blood 2016;128. Abstract 1940.
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130. Kundranda MN, Tibes R, Mesa RA. Transformation of a chronic myeloproliferative neoplasm to acute myelogenous leukemia: does anything work? Curr Hematol Malig Rep 2012;7:78–86.
131. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res 2015;39:950–6.
132. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010;116:3735–42.
133. Pemmaraju N, Kantarjian H, Kadia T, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15:171–6.
134. Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in patients with blast-phase MPN and post-MPN AML: results of a phase I study (Myeloproliferative Disorders Research Consortium 109 trial) [abstract]. Blood 2016;128. Abstract 1124.
135. Bose P, Verstovsek S, Gasior Y, et al. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results [abstract]. Blood 2016;128. Abstract 4262.
Sustainability of Ambulatory Safety Event Reporting Improvement After Intervention Discontinuation
From Novant Health and Novant Health Medical Group, Winston-Salem, NC (Dr. C
Abstract
- Objective: An educational intervention stressing anonymous, voluntary safety event reporting together with monthly regular audit and feedback led to significantly increased reporting of safety events in a nonacademic, community practice setting during a 15-month intervention period. We assessed whether these increased reporting rates would be sustained during the 30-month period after the intervention was discontinued.
- Methods: We reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016, and selected 6 clinics that comprised the intervention collaborative and 18 specialty- and size-matched clinics (1:3 match) that comprised the comparator group. To test the changes in safety event reporting (SER) rates between the intervention and postintervention periods for the intervention collaborative, interrupted time series analysis with a control group was performed.
- Results: The SER rate peaked in the first month following the start of the intervention. Following discontinuation of regular auditing and feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention.
- Conclusion: It is likely that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Keywords: patient safety; safety event reporting; voluntary reporting system; risk management; ambulatory clinic.
We have previously shown that patient safety reporting rates for a 6-practice collaborative group in our non-academic community clinics increased 10-fold after we implemented an improvement initiative consisting of an initial education session followed by provision of monthly audit and written and in-person feedback [1]. The intervention was implemented for 15 months, and after discontinuation of the intervention we have continued to monitor reporting rates. Our objective was to assess whether the increased reporting rates observed in this collaborative during the intervention period would be sustained for 30 months following the intervention.
Methods
This study’s methods have been described in detail previously [1]. For this improvement initiative, we reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016. We identified 6 clinics, the intervention collaborative, in family medicine (n = 3), pediatrics (n = 2), and general surgery (n = 1), and 18 specialty- and size-matched clinics (1:3 match), the comparator group [1]. For the intervention collaborative only, we provided an initial 1-hour educational session on safety events with a listing of all safety event types, along with a 1-page reporting form for voluntary, anonymous submission, with use of the term “safety event” rather than “ error,” to support a nonpunitive culture. After the educational session, we provided monthly audit and written and in-person feedback with peer comparison data by clinic. Monthly audit and feedback continued throughout the intervention and was discontinued postintervention. For event reporting, in our inpatient and outpatient facilities we used VIncident (Verge Solutions, Mt. Pleasant, SC) for the period 2012–2015 and RL6: Risk (RL Solutions, Toronto, ON) for 2016.
The baseline period was 15 months (January 2012–March 2013), the intervention period was 15 months (April 2013–June 2014), and the postintervention period was 30 months (July 2014–December 2016). All 24 clinics were monitored for the 60-month period.
To test the changes in the rate of safety event reporting (SER) between the pre-intervention and postintervention periods and between the intervention and the postintervention periods, interrupted time series (ITS) analysis with a control group was performed using PROC AUTOREG in SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC). Because SER rates are reported monthly, ITS analysis was used to control for autocorrelation, nonstationary variance, seasonality, and trends [2,3].
Results
The SER rate was assessed monthly, so the number of SER rates for each group (intervention and comparator) was 15 during the pre-intervention and intervention periods, respectively, and 30 during the postintervention period. During the pre-intervention period, the intervention collaborative’s baseline median rate of safety events reported was 1.5 per 10,000 patient encounters (Figure). Also, for the intervention collaborative, the pre-intervention baseline mean (standard deviation, SD) SER rate (per 10,000 patient encounters by month) was 1.3 (1.2), the intervention mean SER rate was 12.0 (7.3), and the postintervention rate was 3.2 (1.8). Based on the ITS analysis, there was a significant change in the SER rate between the intervention and postintervention periods for the intervention collaborative (P = 0.01).
The SER rate peaked in the first month following the start of the intervention. After discontinuation of feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention (Figure). The postintervention SER rate was also significantly higher than the pre-intervention rate (P = 0.001).
For the comparator clinics, no significant change in SER rates occurred for the 3 time periods.
Discussion
In this initiative with a 5-year reporting window, we had previously shown that with education and prospective audit and feedback, we could achieve a 10-fold increase in patient SER rates among a multi-practice collaborative while the intervention was maintained [1]. Even though there was a modest but significant increase in the SER rate in the postintervention period for the 6-clinic intervention collaborative compared to baseline, the substantial gains seen during the course of the intervention were not maintained when monthly audit and feedback ceased and monitoring continued for 30 months.
Limitations of this study include possible selection bias resulting from including clinics felt likely to participate rather than identifying clinics in a random fashion. In addition, we did not attempt to determine the specific reasons for the decrease in reporting among these clinics.
The few studies of ambulatory SER do not adequately address the effect of intervention cessation, but researchers who implemented other ambulatory quality improvement efforts have reported that gains often deteriorate or revert to baseline without consistent, ongoing feedback [4]. Likewise, in hospital-based residency programs, a multifaceted approach that includes feedback can increase SER rates, but it is uncertain if the success of this approach can be maintained long-term without continuing feedback of some type [5–7].
There are likely many factors influencing SER in ambulatory clinics, many of which are also applicable in the hospital setting. These include ease of reporting, knowing what events to report, confidentiality of reporting, and the belief that reporting makes a difference in enhancing patient safety [8]. A strong culture of safety in ambulatory clinics may lead to enhanced voluntary SER [9], and a nonpunitive, team-based approach has been advocated to promote reporting and improve ambulatory safety [10]. Historically, our ambulatory medical group clinics have had a strong culture of safety and, with patient safety coaches present in all of our clinics, we have supported a nonpunitive, team-based approach to SER [11].
In our intervention, we made reporting safety events easy, reporters knew which events to report, events could be reported anonymously, and reporters were rewarded, at least with data feedback, for reporting. The only factor known to have changed was discontinuation of monthly feedback. Which factors are most important could not be determined by our work, but we strongly suspect that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, [email protected].
Financial disclosures: None.
1. Clegg HW, Cardwell T, West AM, Ferrell F. Improved safety event reporting in outpatient, nonacademic practices with an anonymous, nonpunitive approach. J Clin Outcomes Manag 2015;22:66–72.
2. Newland JG, Stach LM, De Lurgio SA, et al. Impact of a prospective-audit-with-feedback antimicrobial stewardship program at a children’s hospital. J Pediatric Infect Dis Soc 2012; 1:179–86.
3. Penfold RB, Zhang F. Use of interrupted time series analysis in evaluating health care quality improvements. Acad Pediatr 2013;13 (6 Suppl):S38–44.
4. Gerber JS, Prasad PA, Fiks AG, et al. Durability of benefits of an outpatient antimicrobial stewardship intervention after discontinuation of audit and feedback. JAMA 2014;312:2569–70.
5. Steen S, Jaeger C, Price L, Griffen D. Increasing patient safety event reporting in an emergency medicine residency. BMJ Qual Improv Rep 2017;6(1).
6. Fox M, Bump G, Butler G, et al. Making residents part of the safety culture: improving error reporting and reducing harms. J Patient Saf 2017. [Epub ahead of print]
7. Dunbar AE 3rd, Cupit M, Vath RJ, et al. An improvement approach to integrate teaching teams in the reporting of safety events. Pediatrics 2017;139:e20153807.
8. Institute of Medicine. To err is human: Building a safer health system. National Academies. www.nationalacademies.org/hmd/~/media/Files/Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20Human%201999%20%20report%20brief.pdf Published November 1999. Accessed August 22, 2018.
9. Miller N, Bhowmik S, Ezinwa M, et al. The relationship between safety culture and voluntary event reporting in a large regional ambulatory care group. J Patient Saf 2017. [Epub ahead of print]
10. Neuspiel DR, Stubbs EH. Patient safety in ambulatory care. Pediatr Clin North Am 2012;59:1341–54.
11. West AM, Cardwell T, Clegg HW. Improving patient safety culture through patient safety coaches in the ambulatory setting. Presented at: Institute for Healthcare Improvement Annual Summit on Improving Patient Care in the Office Practice and the Community; March 2015; Dallas, Texas.
From Novant Health and Novant Health Medical Group, Winston-Salem, NC (Dr. C
Abstract
- Objective: An educational intervention stressing anonymous, voluntary safety event reporting together with monthly regular audit and feedback led to significantly increased reporting of safety events in a nonacademic, community practice setting during a 15-month intervention period. We assessed whether these increased reporting rates would be sustained during the 30-month period after the intervention was discontinued.
- Methods: We reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016, and selected 6 clinics that comprised the intervention collaborative and 18 specialty- and size-matched clinics (1:3 match) that comprised the comparator group. To test the changes in safety event reporting (SER) rates between the intervention and postintervention periods for the intervention collaborative, interrupted time series analysis with a control group was performed.
- Results: The SER rate peaked in the first month following the start of the intervention. Following discontinuation of regular auditing and feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention.
- Conclusion: It is likely that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Keywords: patient safety; safety event reporting; voluntary reporting system; risk management; ambulatory clinic.
We have previously shown that patient safety reporting rates for a 6-practice collaborative group in our non-academic community clinics increased 10-fold after we implemented an improvement initiative consisting of an initial education session followed by provision of monthly audit and written and in-person feedback [1]. The intervention was implemented for 15 months, and after discontinuation of the intervention we have continued to monitor reporting rates. Our objective was to assess whether the increased reporting rates observed in this collaborative during the intervention period would be sustained for 30 months following the intervention.
Methods
This study’s methods have been described in detail previously [1]. For this improvement initiative, we reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016. We identified 6 clinics, the intervention collaborative, in family medicine (n = 3), pediatrics (n = 2), and general surgery (n = 1), and 18 specialty- and size-matched clinics (1:3 match), the comparator group [1]. For the intervention collaborative only, we provided an initial 1-hour educational session on safety events with a listing of all safety event types, along with a 1-page reporting form for voluntary, anonymous submission, with use of the term “safety event” rather than “ error,” to support a nonpunitive culture. After the educational session, we provided monthly audit and written and in-person feedback with peer comparison data by clinic. Monthly audit and feedback continued throughout the intervention and was discontinued postintervention. For event reporting, in our inpatient and outpatient facilities we used VIncident (Verge Solutions, Mt. Pleasant, SC) for the period 2012–2015 and RL6: Risk (RL Solutions, Toronto, ON) for 2016.
The baseline period was 15 months (January 2012–March 2013), the intervention period was 15 months (April 2013–June 2014), and the postintervention period was 30 months (July 2014–December 2016). All 24 clinics were monitored for the 60-month period.
To test the changes in the rate of safety event reporting (SER) between the pre-intervention and postintervention periods and between the intervention and the postintervention periods, interrupted time series (ITS) analysis with a control group was performed using PROC AUTOREG in SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC). Because SER rates are reported monthly, ITS analysis was used to control for autocorrelation, nonstationary variance, seasonality, and trends [2,3].
Results
The SER rate was assessed monthly, so the number of SER rates for each group (intervention and comparator) was 15 during the pre-intervention and intervention periods, respectively, and 30 during the postintervention period. During the pre-intervention period, the intervention collaborative’s baseline median rate of safety events reported was 1.5 per 10,000 patient encounters (Figure). Also, for the intervention collaborative, the pre-intervention baseline mean (standard deviation, SD) SER rate (per 10,000 patient encounters by month) was 1.3 (1.2), the intervention mean SER rate was 12.0 (7.3), and the postintervention rate was 3.2 (1.8). Based on the ITS analysis, there was a significant change in the SER rate between the intervention and postintervention periods for the intervention collaborative (P = 0.01).
The SER rate peaked in the first month following the start of the intervention. After discontinuation of feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention (Figure). The postintervention SER rate was also significantly higher than the pre-intervention rate (P = 0.001).
For the comparator clinics, no significant change in SER rates occurred for the 3 time periods.
Discussion
In this initiative with a 5-year reporting window, we had previously shown that with education and prospective audit and feedback, we could achieve a 10-fold increase in patient SER rates among a multi-practice collaborative while the intervention was maintained [1]. Even though there was a modest but significant increase in the SER rate in the postintervention period for the 6-clinic intervention collaborative compared to baseline, the substantial gains seen during the course of the intervention were not maintained when monthly audit and feedback ceased and monitoring continued for 30 months.
Limitations of this study include possible selection bias resulting from including clinics felt likely to participate rather than identifying clinics in a random fashion. In addition, we did not attempt to determine the specific reasons for the decrease in reporting among these clinics.
The few studies of ambulatory SER do not adequately address the effect of intervention cessation, but researchers who implemented other ambulatory quality improvement efforts have reported that gains often deteriorate or revert to baseline without consistent, ongoing feedback [4]. Likewise, in hospital-based residency programs, a multifaceted approach that includes feedback can increase SER rates, but it is uncertain if the success of this approach can be maintained long-term without continuing feedback of some type [5–7].
There are likely many factors influencing SER in ambulatory clinics, many of which are also applicable in the hospital setting. These include ease of reporting, knowing what events to report, confidentiality of reporting, and the belief that reporting makes a difference in enhancing patient safety [8]. A strong culture of safety in ambulatory clinics may lead to enhanced voluntary SER [9], and a nonpunitive, team-based approach has been advocated to promote reporting and improve ambulatory safety [10]. Historically, our ambulatory medical group clinics have had a strong culture of safety and, with patient safety coaches present in all of our clinics, we have supported a nonpunitive, team-based approach to SER [11].
In our intervention, we made reporting safety events easy, reporters knew which events to report, events could be reported anonymously, and reporters were rewarded, at least with data feedback, for reporting. The only factor known to have changed was discontinuation of monthly feedback. Which factors are most important could not be determined by our work, but we strongly suspect that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, [email protected].
Financial disclosures: None.
From Novant Health and Novant Health Medical Group, Winston-Salem, NC (Dr. C
Abstract
- Objective: An educational intervention stressing anonymous, voluntary safety event reporting together with monthly regular audit and feedback led to significantly increased reporting of safety events in a nonacademic, community practice setting during a 15-month intervention period. We assessed whether these increased reporting rates would be sustained during the 30-month period after the intervention was discontinued.
- Methods: We reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016, and selected 6 clinics that comprised the intervention collaborative and 18 specialty- and size-matched clinics (1:3 match) that comprised the comparator group. To test the changes in safety event reporting (SER) rates between the intervention and postintervention periods for the intervention collaborative, interrupted time series analysis with a control group was performed.
- Results: The SER rate peaked in the first month following the start of the intervention. Following discontinuation of regular auditing and feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention.
- Conclusion: It is likely that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Keywords: patient safety; safety event reporting; voluntary reporting system; risk management; ambulatory clinic.
We have previously shown that patient safety reporting rates for a 6-practice collaborative group in our non-academic community clinics increased 10-fold after we implemented an improvement initiative consisting of an initial education session followed by provision of monthly audit and written and in-person feedback [1]. The intervention was implemented for 15 months, and after discontinuation of the intervention we have continued to monitor reporting rates. Our objective was to assess whether the increased reporting rates observed in this collaborative during the intervention period would be sustained for 30 months following the intervention.
Methods
This study’s methods have been described in detail previously [1]. For this improvement initiative, we reviewed all patient safety events reported in our ambulatory clinics for the period 2012–2016. We identified 6 clinics, the intervention collaborative, in family medicine (n = 3), pediatrics (n = 2), and general surgery (n = 1), and 18 specialty- and size-matched clinics (1:3 match), the comparator group [1]. For the intervention collaborative only, we provided an initial 1-hour educational session on safety events with a listing of all safety event types, along with a 1-page reporting form for voluntary, anonymous submission, with use of the term “safety event” rather than “ error,” to support a nonpunitive culture. After the educational session, we provided monthly audit and written and in-person feedback with peer comparison data by clinic. Monthly audit and feedback continued throughout the intervention and was discontinued postintervention. For event reporting, in our inpatient and outpatient facilities we used VIncident (Verge Solutions, Mt. Pleasant, SC) for the period 2012–2015 and RL6: Risk (RL Solutions, Toronto, ON) for 2016.
The baseline period was 15 months (January 2012–March 2013), the intervention period was 15 months (April 2013–June 2014), and the postintervention period was 30 months (July 2014–December 2016). All 24 clinics were monitored for the 60-month period.
To test the changes in the rate of safety event reporting (SER) between the pre-intervention and postintervention periods and between the intervention and the postintervention periods, interrupted time series (ITS) analysis with a control group was performed using PROC AUTOREG in SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC). Because SER rates are reported monthly, ITS analysis was used to control for autocorrelation, nonstationary variance, seasonality, and trends [2,3].
Results
The SER rate was assessed monthly, so the number of SER rates for each group (intervention and comparator) was 15 during the pre-intervention and intervention periods, respectively, and 30 during the postintervention period. During the pre-intervention period, the intervention collaborative’s baseline median rate of safety events reported was 1.5 per 10,000 patient encounters (Figure). Also, for the intervention collaborative, the pre-intervention baseline mean (standard deviation, SD) SER rate (per 10,000 patient encounters by month) was 1.3 (1.2), the intervention mean SER rate was 12.0 (7.3), and the postintervention rate was 3.2 (1.8). Based on the ITS analysis, there was a significant change in the SER rate between the intervention and postintervention periods for the intervention collaborative (P = 0.01).
The SER rate peaked in the first month following the start of the intervention. After discontinuation of feedback, reporting rates declined abruptly and reverted to baseline by 16 months post intervention (Figure). The postintervention SER rate was also significantly higher than the pre-intervention rate (P = 0.001).
For the comparator clinics, no significant change in SER rates occurred for the 3 time periods.
Discussion
In this initiative with a 5-year reporting window, we had previously shown that with education and prospective audit and feedback, we could achieve a 10-fold increase in patient SER rates among a multi-practice collaborative while the intervention was maintained [1]. Even though there was a modest but significant increase in the SER rate in the postintervention period for the 6-clinic intervention collaborative compared to baseline, the substantial gains seen during the course of the intervention were not maintained when monthly audit and feedback ceased and monitoring continued for 30 months.
Limitations of this study include possible selection bias resulting from including clinics felt likely to participate rather than identifying clinics in a random fashion. In addition, we did not attempt to determine the specific reasons for the decrease in reporting among these clinics.
The few studies of ambulatory SER do not adequately address the effect of intervention cessation, but researchers who implemented other ambulatory quality improvement efforts have reported that gains often deteriorate or revert to baseline without consistent, ongoing feedback [4]. Likewise, in hospital-based residency programs, a multifaceted approach that includes feedback can increase SER rates, but it is uncertain if the success of this approach can be maintained long-term without continuing feedback of some type [5–7].
There are likely many factors influencing SER in ambulatory clinics, many of which are also applicable in the hospital setting. These include ease of reporting, knowing what events to report, confidentiality of reporting, and the belief that reporting makes a difference in enhancing patient safety [8]. A strong culture of safety in ambulatory clinics may lead to enhanced voluntary SER [9], and a nonpunitive, team-based approach has been advocated to promote reporting and improve ambulatory safety [10]. Historically, our ambulatory medical group clinics have had a strong culture of safety and, with patient safety coaches present in all of our clinics, we have supported a nonpunitive, team-based approach to SER [11].
In our intervention, we made reporting safety events easy, reporters knew which events to report, events could be reported anonymously, and reporters were rewarded, at least with data feedback, for reporting. The only factor known to have changed was discontinuation of monthly feedback. Which factors are most important could not be determined by our work, but we strongly suspect that sustaining enhanced reporting rates requires ongoing audit and feedback to maintain a focus on event reporting.
Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, [email protected].
Financial disclosures: None.
1. Clegg HW, Cardwell T, West AM, Ferrell F. Improved safety event reporting in outpatient, nonacademic practices with an anonymous, nonpunitive approach. J Clin Outcomes Manag 2015;22:66–72.
2. Newland JG, Stach LM, De Lurgio SA, et al. Impact of a prospective-audit-with-feedback antimicrobial stewardship program at a children’s hospital. J Pediatric Infect Dis Soc 2012; 1:179–86.
3. Penfold RB, Zhang F. Use of interrupted time series analysis in evaluating health care quality improvements. Acad Pediatr 2013;13 (6 Suppl):S38–44.
4. Gerber JS, Prasad PA, Fiks AG, et al. Durability of benefits of an outpatient antimicrobial stewardship intervention after discontinuation of audit and feedback. JAMA 2014;312:2569–70.
5. Steen S, Jaeger C, Price L, Griffen D. Increasing patient safety event reporting in an emergency medicine residency. BMJ Qual Improv Rep 2017;6(1).
6. Fox M, Bump G, Butler G, et al. Making residents part of the safety culture: improving error reporting and reducing harms. J Patient Saf 2017. [Epub ahead of print]
7. Dunbar AE 3rd, Cupit M, Vath RJ, et al. An improvement approach to integrate teaching teams in the reporting of safety events. Pediatrics 2017;139:e20153807.
8. Institute of Medicine. To err is human: Building a safer health system. National Academies. www.nationalacademies.org/hmd/~/media/Files/Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20Human%201999%20%20report%20brief.pdf Published November 1999. Accessed August 22, 2018.
9. Miller N, Bhowmik S, Ezinwa M, et al. The relationship between safety culture and voluntary event reporting in a large regional ambulatory care group. J Patient Saf 2017. [Epub ahead of print]
10. Neuspiel DR, Stubbs EH. Patient safety in ambulatory care. Pediatr Clin North Am 2012;59:1341–54.
11. West AM, Cardwell T, Clegg HW. Improving patient safety culture through patient safety coaches in the ambulatory setting. Presented at: Institute for Healthcare Improvement Annual Summit on Improving Patient Care in the Office Practice and the Community; March 2015; Dallas, Texas.
1. Clegg HW, Cardwell T, West AM, Ferrell F. Improved safety event reporting in outpatient, nonacademic practices with an anonymous, nonpunitive approach. J Clin Outcomes Manag 2015;22:66–72.
2. Newland JG, Stach LM, De Lurgio SA, et al. Impact of a prospective-audit-with-feedback antimicrobial stewardship program at a children’s hospital. J Pediatric Infect Dis Soc 2012; 1:179–86.
3. Penfold RB, Zhang F. Use of interrupted time series analysis in evaluating health care quality improvements. Acad Pediatr 2013;13 (6 Suppl):S38–44.
4. Gerber JS, Prasad PA, Fiks AG, et al. Durability of benefits of an outpatient antimicrobial stewardship intervention after discontinuation of audit and feedback. JAMA 2014;312:2569–70.
5. Steen S, Jaeger C, Price L, Griffen D. Increasing patient safety event reporting in an emergency medicine residency. BMJ Qual Improv Rep 2017;6(1).
6. Fox M, Bump G, Butler G, et al. Making residents part of the safety culture: improving error reporting and reducing harms. J Patient Saf 2017. [Epub ahead of print]
7. Dunbar AE 3rd, Cupit M, Vath RJ, et al. An improvement approach to integrate teaching teams in the reporting of safety events. Pediatrics 2017;139:e20153807.
8. Institute of Medicine. To err is human: Building a safer health system. National Academies. www.nationalacademies.org/hmd/~/media/Files/Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20Human%201999%20%20report%20brief.pdf Published November 1999. Accessed August 22, 2018.
9. Miller N, Bhowmik S, Ezinwa M, et al. The relationship between safety culture and voluntary event reporting in a large regional ambulatory care group. J Patient Saf 2017. [Epub ahead of print]
10. Neuspiel DR, Stubbs EH. Patient safety in ambulatory care. Pediatr Clin North Am 2012;59:1341–54.
11. West AM, Cardwell T, Clegg HW. Improving patient safety culture through patient safety coaches in the ambulatory setting. Presented at: Institute for Healthcare Improvement Annual Summit on Improving Patient Care in the Office Practice and the Community; March 2015; Dallas, Texas.