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Does cannabis cause psychosis? A brief review of the evidence
As more and more states consider legalizing marijuana for recreational use, the widely held belief that cannabis is associated with few serious health consequences has been challenged by many medical and substance use professionals. One potential risk that has been discussed is the possibility that cannabis use increases the risk for psychotic symptoms that may be long lasting and develop into schizophrenia. The data, however, have not been completely consistent and often are methodologically flawed, leading proponents of legalization to downplay this possible risk. This debate has even made its way to prominent science journals such as Nature where scholars have presented opposing views (Nature. 2015 Sep 24;525[7570]:S14and Nature. 2015 Nov 19;527[7578]:305).
These divergent opinions can lead to some confusion and hesitancy on the part of pediatricians who may be asked to offer an opinion about the dangers of cannabis use to individual patients and families during this time of public debate. Thus, this column will attempt to offer a brief overview and synthesis of the evidence that cannabis plays a causal role in the progression of psychotic disorders.
A recent review of the subject examined 10 epidemiological studies that have now been performed on the association between cannabis and psychotic disorders. Overall, a nearly 50% increased risk of psychosis was found among cannabis users, compared to nonusers (Biol Psychiatry. 2015 Aug 12. pii: S0006-3223[15]00647-2). This association rises among heavier cannabis users (Lancet. 2007 Jul 28;370[9584]:319-28). Because all of these longitudinal studies were observational in nature, however, proving causation in the face of association has remained challenging. Many of these studies have attempted to control for baseline psychotic symptoms to address the “reverse causation hypothesis,” which posits that early psychotic symptoms leads to cannabis use rather than the other way around. It is also worth pointing out that the inevitable limitations and potential biases of these studies could potentially lead to both overestimation and underestimation of the actual risk.
Putting all of this together, the authors concluded that “there is a strong body of epidemiologic evidence to support the view that regular or heavy cannabis use increases the risk of developing psychotic disorders that persist beyond the direct effects of exogenous cannabinoids.” In making this conclusion, despite the inherent uncertainties of interpreting observational studies, the authors describe a number of lines of evidence that support the likelihood of a causal connection. These include the following:
• The well-known fact that acute intoxication of cannabis can produce transient psychotic symptoms.
• The replicated finding that there is a dose-dependent response between amount of cannabis use and psychosis.
• An increased risk of psychosis among cannabis users who carry specific risk genes (Biol Psychiatry. 2012 Nov 15;72[10]:811-6).
• Increasing evidence that the more potent marijuana that is available now may be associated with additional risk.
• The finding that the link between cannabis and psychosis is not equal for all age groups, but may be stronger for adolescents.
One line of argument against a causal role of cannabis in the development of psychotic disorders is that the rate of schizophrenia has remained relatively flat over the years that cannabis use has increased. Countering that assertion, however, Large and colleagues pointed out that some studies do show increasing rates of schizophrenia (Nature. 2015 Nov 19;527[7578]:305). Further, it is somewhat precarious to conclude that a possible risk factor is not consequential when it moves in a different direction than a multifactorial disorder such as schizophrenia. Lead toxicity, for example, is an accepted risk factor for attention-deficit/hyperactivity disorder (ADHD), yet exposure has been decreasing while rates of ADHD climb.
Overall, the data appear to be strengthening that cannabis does play a causal role in the development of psychosis and psychotic disorders. This risk is combined with data showing links between cannabis use and decreased IQ, academic underachievement, car accidents, and use of other types of drugs (Addiction. 2015 Jan;110[1]:19-35). These dangers need to be articulated in discussions about the wisdom of legalizing cannabis at the state and federal level.
Dr. Rettew is associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He said he has no relevant financial disclosures. Follow him on Twitter @pedipsych. E-mail him at [email protected].
As more and more states consider legalizing marijuana for recreational use, the widely held belief that cannabis is associated with few serious health consequences has been challenged by many medical and substance use professionals. One potential risk that has been discussed is the possibility that cannabis use increases the risk for psychotic symptoms that may be long lasting and develop into schizophrenia. The data, however, have not been completely consistent and often are methodologically flawed, leading proponents of legalization to downplay this possible risk. This debate has even made its way to prominent science journals such as Nature where scholars have presented opposing views (Nature. 2015 Sep 24;525[7570]:S14and Nature. 2015 Nov 19;527[7578]:305).
These divergent opinions can lead to some confusion and hesitancy on the part of pediatricians who may be asked to offer an opinion about the dangers of cannabis use to individual patients and families during this time of public debate. Thus, this column will attempt to offer a brief overview and synthesis of the evidence that cannabis plays a causal role in the progression of psychotic disorders.
A recent review of the subject examined 10 epidemiological studies that have now been performed on the association between cannabis and psychotic disorders. Overall, a nearly 50% increased risk of psychosis was found among cannabis users, compared to nonusers (Biol Psychiatry. 2015 Aug 12. pii: S0006-3223[15]00647-2). This association rises among heavier cannabis users (Lancet. 2007 Jul 28;370[9584]:319-28). Because all of these longitudinal studies were observational in nature, however, proving causation in the face of association has remained challenging. Many of these studies have attempted to control for baseline psychotic symptoms to address the “reverse causation hypothesis,” which posits that early psychotic symptoms leads to cannabis use rather than the other way around. It is also worth pointing out that the inevitable limitations and potential biases of these studies could potentially lead to both overestimation and underestimation of the actual risk.
Putting all of this together, the authors concluded that “there is a strong body of epidemiologic evidence to support the view that regular or heavy cannabis use increases the risk of developing psychotic disorders that persist beyond the direct effects of exogenous cannabinoids.” In making this conclusion, despite the inherent uncertainties of interpreting observational studies, the authors describe a number of lines of evidence that support the likelihood of a causal connection. These include the following:
• The well-known fact that acute intoxication of cannabis can produce transient psychotic symptoms.
• The replicated finding that there is a dose-dependent response between amount of cannabis use and psychosis.
• An increased risk of psychosis among cannabis users who carry specific risk genes (Biol Psychiatry. 2012 Nov 15;72[10]:811-6).
• Increasing evidence that the more potent marijuana that is available now may be associated with additional risk.
• The finding that the link between cannabis and psychosis is not equal for all age groups, but may be stronger for adolescents.
One line of argument against a causal role of cannabis in the development of psychotic disorders is that the rate of schizophrenia has remained relatively flat over the years that cannabis use has increased. Countering that assertion, however, Large and colleagues pointed out that some studies do show increasing rates of schizophrenia (Nature. 2015 Nov 19;527[7578]:305). Further, it is somewhat precarious to conclude that a possible risk factor is not consequential when it moves in a different direction than a multifactorial disorder such as schizophrenia. Lead toxicity, for example, is an accepted risk factor for attention-deficit/hyperactivity disorder (ADHD), yet exposure has been decreasing while rates of ADHD climb.
Overall, the data appear to be strengthening that cannabis does play a causal role in the development of psychosis and psychotic disorders. This risk is combined with data showing links between cannabis use and decreased IQ, academic underachievement, car accidents, and use of other types of drugs (Addiction. 2015 Jan;110[1]:19-35). These dangers need to be articulated in discussions about the wisdom of legalizing cannabis at the state and federal level.
Dr. Rettew is associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He said he has no relevant financial disclosures. Follow him on Twitter @pedipsych. E-mail him at [email protected].
As more and more states consider legalizing marijuana for recreational use, the widely held belief that cannabis is associated with few serious health consequences has been challenged by many medical and substance use professionals. One potential risk that has been discussed is the possibility that cannabis use increases the risk for psychotic symptoms that may be long lasting and develop into schizophrenia. The data, however, have not been completely consistent and often are methodologically flawed, leading proponents of legalization to downplay this possible risk. This debate has even made its way to prominent science journals such as Nature where scholars have presented opposing views (Nature. 2015 Sep 24;525[7570]:S14and Nature. 2015 Nov 19;527[7578]:305).
These divergent opinions can lead to some confusion and hesitancy on the part of pediatricians who may be asked to offer an opinion about the dangers of cannabis use to individual patients and families during this time of public debate. Thus, this column will attempt to offer a brief overview and synthesis of the evidence that cannabis plays a causal role in the progression of psychotic disorders.
A recent review of the subject examined 10 epidemiological studies that have now been performed on the association between cannabis and psychotic disorders. Overall, a nearly 50% increased risk of psychosis was found among cannabis users, compared to nonusers (Biol Psychiatry. 2015 Aug 12. pii: S0006-3223[15]00647-2). This association rises among heavier cannabis users (Lancet. 2007 Jul 28;370[9584]:319-28). Because all of these longitudinal studies were observational in nature, however, proving causation in the face of association has remained challenging. Many of these studies have attempted to control for baseline psychotic symptoms to address the “reverse causation hypothesis,” which posits that early psychotic symptoms leads to cannabis use rather than the other way around. It is also worth pointing out that the inevitable limitations and potential biases of these studies could potentially lead to both overestimation and underestimation of the actual risk.
Putting all of this together, the authors concluded that “there is a strong body of epidemiologic evidence to support the view that regular or heavy cannabis use increases the risk of developing psychotic disorders that persist beyond the direct effects of exogenous cannabinoids.” In making this conclusion, despite the inherent uncertainties of interpreting observational studies, the authors describe a number of lines of evidence that support the likelihood of a causal connection. These include the following:
• The well-known fact that acute intoxication of cannabis can produce transient psychotic symptoms.
• The replicated finding that there is a dose-dependent response between amount of cannabis use and psychosis.
• An increased risk of psychosis among cannabis users who carry specific risk genes (Biol Psychiatry. 2012 Nov 15;72[10]:811-6).
• Increasing evidence that the more potent marijuana that is available now may be associated with additional risk.
• The finding that the link between cannabis and psychosis is not equal for all age groups, but may be stronger for adolescents.
One line of argument against a causal role of cannabis in the development of psychotic disorders is that the rate of schizophrenia has remained relatively flat over the years that cannabis use has increased. Countering that assertion, however, Large and colleagues pointed out that some studies do show increasing rates of schizophrenia (Nature. 2015 Nov 19;527[7578]:305). Further, it is somewhat precarious to conclude that a possible risk factor is not consequential when it moves in a different direction than a multifactorial disorder such as schizophrenia. Lead toxicity, for example, is an accepted risk factor for attention-deficit/hyperactivity disorder (ADHD), yet exposure has been decreasing while rates of ADHD climb.
Overall, the data appear to be strengthening that cannabis does play a causal role in the development of psychosis and psychotic disorders. This risk is combined with data showing links between cannabis use and decreased IQ, academic underachievement, car accidents, and use of other types of drugs (Addiction. 2015 Jan;110[1]:19-35). These dangers need to be articulated in discussions about the wisdom of legalizing cannabis at the state and federal level.
Dr. Rettew is associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He said he has no relevant financial disclosures. Follow him on Twitter @pedipsych. E-mail him at [email protected].
A Look at Speakers, Educational Tracks Planned for Hospital Medicine 2016
Get ready for hospital medicine’s main event—Hospital Medicine 2016 (HM16). SHM remains at the forefront of healthcare, leading the charge to provide the best care for hospitalized patients. We invite you to join us on the sunny shores of San Diego from March 6-9, to learn about the latest advances in hospital medicine and connect with over 3,000 hospital-based professionals.
On hand this year will be some world-class faculty, who will examine today’s issues and challenge everyone to be a part of the solution. HM16’s renowned speakers are leaders in the field. We proudly welcome:
Karen DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health, U.S. Department of Health and Human Services
Dr. DeSalvo has made a tremendous impact on quality in healthcare through direct patient care, medical education, policy and administrative roles, research, and public service. She has received many honors, including recognition as a “Woman of Excellence in Health Care” by the Louisiana Legislative Women’s Caucus. Join her for her featured address, “Public Health 3.0, the Role of the Hospitalist and Hospital.”
Robert M. Wachter, MD, MHM
Professor and interim chair, department of medicine, University of California San Francisco, author of “The Digital Doctor: Hope, Hype and Harm at the Dawn of Medicine’s Computer Age,” and of the HM-focused blog, “Wachter’s World."
Dr. Wachter, national thought leader in healthcare quality improvement, in his always entertaining style, will address important and interesting work going on in medical leadership, teamwork, artificial intelligence, and physician evaluation. Join him for his closing keynote address: “Hospital Medicine Turns 20: Celebrating the Past While Charting a New Course.”
In addition to these much anticipated keynotes, be sure to check out new tracks for HM16, including:
• Co-Management/Perioperative Medicine: This hospitalist core competency increases in complexity, yet many physicians were not even taught the basics in residency. This new track explores the perioperative and consultative medicine questions that challenge hospitalists on a daily basis.
• Health IT for Hospitalists: Technology has changed the practice of medicine. The new Health IT for Hospitalists track focuses on topics to help frontline clinicians perform better by using technology, while helping those with leadership roles in Health IT obtain tools to make them more effective. HM2016 will mark the beginning of an annual update on the best mobile apps in the healthcare sector.
• Post-Acute Care: This track targets two audiences: 1) mainstream hospitalists, who increasingly are being asked to assume responsibility for the full episode of care, including post-acute care services after discharge; 2) hospitalists in programs who have assumed responsibility for post-acute care services, either in skilled nursing facilities, independent rehabilitation facilities, or long-term acute care hospitals. This track will provide information on how hospitalists can build and operate a successful post-acute care practice.
These are sessions you won’t want to miss! If you haven’t registered, now is the time. SHM members save $325 on HM16 registration, and if you’re new to SHM, you can receive one free year of membership after registering.
Get the scoop on all things HM16, and register now, at www.hospitalmedicine2016.org.
See you in San Diego! TH
Brett Radler is SHM’s communications coordinator.
Get ready for hospital medicine’s main event—Hospital Medicine 2016 (HM16). SHM remains at the forefront of healthcare, leading the charge to provide the best care for hospitalized patients. We invite you to join us on the sunny shores of San Diego from March 6-9, to learn about the latest advances in hospital medicine and connect with over 3,000 hospital-based professionals.
On hand this year will be some world-class faculty, who will examine today’s issues and challenge everyone to be a part of the solution. HM16’s renowned speakers are leaders in the field. We proudly welcome:
Karen DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health, U.S. Department of Health and Human Services
Dr. DeSalvo has made a tremendous impact on quality in healthcare through direct patient care, medical education, policy and administrative roles, research, and public service. She has received many honors, including recognition as a “Woman of Excellence in Health Care” by the Louisiana Legislative Women’s Caucus. Join her for her featured address, “Public Health 3.0, the Role of the Hospitalist and Hospital.”
Robert M. Wachter, MD, MHM
Professor and interim chair, department of medicine, University of California San Francisco, author of “The Digital Doctor: Hope, Hype and Harm at the Dawn of Medicine’s Computer Age,” and of the HM-focused blog, “Wachter’s World."
Dr. Wachter, national thought leader in healthcare quality improvement, in his always entertaining style, will address important and interesting work going on in medical leadership, teamwork, artificial intelligence, and physician evaluation. Join him for his closing keynote address: “Hospital Medicine Turns 20: Celebrating the Past While Charting a New Course.”
In addition to these much anticipated keynotes, be sure to check out new tracks for HM16, including:
• Co-Management/Perioperative Medicine: This hospitalist core competency increases in complexity, yet many physicians were not even taught the basics in residency. This new track explores the perioperative and consultative medicine questions that challenge hospitalists on a daily basis.
• Health IT for Hospitalists: Technology has changed the practice of medicine. The new Health IT for Hospitalists track focuses on topics to help frontline clinicians perform better by using technology, while helping those with leadership roles in Health IT obtain tools to make them more effective. HM2016 will mark the beginning of an annual update on the best mobile apps in the healthcare sector.
• Post-Acute Care: This track targets two audiences: 1) mainstream hospitalists, who increasingly are being asked to assume responsibility for the full episode of care, including post-acute care services after discharge; 2) hospitalists in programs who have assumed responsibility for post-acute care services, either in skilled nursing facilities, independent rehabilitation facilities, or long-term acute care hospitals. This track will provide information on how hospitalists can build and operate a successful post-acute care practice.
These are sessions you won’t want to miss! If you haven’t registered, now is the time. SHM members save $325 on HM16 registration, and if you’re new to SHM, you can receive one free year of membership after registering.
Get the scoop on all things HM16, and register now, at www.hospitalmedicine2016.org.
See you in San Diego! TH
Brett Radler is SHM’s communications coordinator.
Get ready for hospital medicine’s main event—Hospital Medicine 2016 (HM16). SHM remains at the forefront of healthcare, leading the charge to provide the best care for hospitalized patients. We invite you to join us on the sunny shores of San Diego from March 6-9, to learn about the latest advances in hospital medicine and connect with over 3,000 hospital-based professionals.
On hand this year will be some world-class faculty, who will examine today’s issues and challenge everyone to be a part of the solution. HM16’s renowned speakers are leaders in the field. We proudly welcome:
Karen DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health, U.S. Department of Health and Human Services
Dr. DeSalvo has made a tremendous impact on quality in healthcare through direct patient care, medical education, policy and administrative roles, research, and public service. She has received many honors, including recognition as a “Woman of Excellence in Health Care” by the Louisiana Legislative Women’s Caucus. Join her for her featured address, “Public Health 3.0, the Role of the Hospitalist and Hospital.”
Robert M. Wachter, MD, MHM
Professor and interim chair, department of medicine, University of California San Francisco, author of “The Digital Doctor: Hope, Hype and Harm at the Dawn of Medicine’s Computer Age,” and of the HM-focused blog, “Wachter’s World."
Dr. Wachter, national thought leader in healthcare quality improvement, in his always entertaining style, will address important and interesting work going on in medical leadership, teamwork, artificial intelligence, and physician evaluation. Join him for his closing keynote address: “Hospital Medicine Turns 20: Celebrating the Past While Charting a New Course.”
In addition to these much anticipated keynotes, be sure to check out new tracks for HM16, including:
• Co-Management/Perioperative Medicine: This hospitalist core competency increases in complexity, yet many physicians were not even taught the basics in residency. This new track explores the perioperative and consultative medicine questions that challenge hospitalists on a daily basis.
• Health IT for Hospitalists: Technology has changed the practice of medicine. The new Health IT for Hospitalists track focuses on topics to help frontline clinicians perform better by using technology, while helping those with leadership roles in Health IT obtain tools to make them more effective. HM2016 will mark the beginning of an annual update on the best mobile apps in the healthcare sector.
• Post-Acute Care: This track targets two audiences: 1) mainstream hospitalists, who increasingly are being asked to assume responsibility for the full episode of care, including post-acute care services after discharge; 2) hospitalists in programs who have assumed responsibility for post-acute care services, either in skilled nursing facilities, independent rehabilitation facilities, or long-term acute care hospitals. This track will provide information on how hospitalists can build and operate a successful post-acute care practice.
These are sessions you won’t want to miss! If you haven’t registered, now is the time. SHM members save $325 on HM16 registration, and if you’re new to SHM, you can receive one free year of membership after registering.
Get the scoop on all things HM16, and register now, at www.hospitalmedicine2016.org.
See you in San Diego! TH
Brett Radler is SHM’s communications coordinator.
Venetoclax produces deep responses in ultra-high-risk CLL
Photo courtesy of ASH
ORLANDO, FL—The pivotal phase 2 study of venetoclax monotherapy in patients with relapsed/refractory 17p-deleted chronic lymphocytic leukemia (CLL) has achieved unprecedented deep responses, according to investigators.
More than 10% of patients had a complete response (CR), complete response with incomplete blood count recovery (CRi), or near partial response (nPR), as confirmed by an independent review committee (IRC).
And more than 20% of responders became negative for minimal residual disease (MRD).
Venetoclax is an orally bioavailable, selective BCL-2 inhibitor that directly induces apoptosis in CLL cells independent of p53.
The US Food and Drug Administration granted venetoclax breakthrough therapy designation for relapsed/refractory CLL earlier this year.
“Patients with a 17p deletion in CLL have very poor prognosis,” said Stephan Stilgenbauer, MD, of University of Ulm in Germany, “and limited treatment options.”
The median progression-free survival (PFS) with frontline chemoimmunotherapy in this population is less than 12 months.
The first-in-human study of venetoclax, which was recently published in NEJM, showed a 79% overall response rate (ORR) in relapsed/refractory CLL patients.
Dr Stilgenbauer presented the pivotal phase 2 results at the 2015 ASH Annual Meeting as LBA-6.
Study overview
The primary objective of the trial was ORR by independent review committee. The secondary endpoints were CR/PR rates, time to first response, duration of response, PFS, overall survival (OS), and safety.
Investigators also included the exploratory endpoint of MRD as determined by flow cytometry with a sensitivity of less than 10-4.
Patients had to have an ECOG score of 2 or less, an absolute neutrophil count of 1000/μL or greater, a platelet count of 40,000/mm3 or higher, and a hemoglobin count of at least 8 g/dL. They also had to have a creatinine clearance of 50 mL/min or more.
“With regard to performance status, blood counts, and creatinine clearance,” Dr Stilgenbauer said, “inclusion criteria were relatively liberal, allowing patients with comorbidity on the trial.”
Patients were excluded if they had prior allogeneic stem cell transplantation, Richter’s transformation, uncontrolled autoimmune cytopenia, other malignancy, or major organ dysfunction.
Trial design
Patients received an oral dose of venetoclax once daily continuously until disease progression or discontinuation for another reason.
Because tumor lysis syndrome (TLS) was a concern, investigators devised a step-wise weekly ramp-up with risk-based prophylaxis to mitigate TLS.
Patients started on a dose of 20 mg on day 1. If they did not experience any electrolyte abnormalities, they received a 50 mg daily dose for the rest of the first week, escalating to 100 mg, 200 mg, and to the target dose of 400 mg daily on subsequent weeks. Patients continued on 400 mg daily for the remainder of the study.
The investigators assessed response using iwCLL 2008 criteria with monthly physical exams and blood counts, CT scans to confirm clinical response at week 36, and a bone marrow biopsy to confirm CR.
Patient population and disposition
Investigators enrolled 107 patients with a median age of 67 (range, 37–85). Seventy (65%) were male.
Patients had a median of 2 prior therapies (range, 1–10): 54 (50%) had prior bendamustine and 38 (70%) were refractory to it; 78 (73%) had prior fludarabine and 34 (44%) were refractory to it; and 90 (84%) had a prior CD20 monoclonal antibody.
About half (52%) were ECOG grade 1, 53% had 1 or more nodes 5 cm or larger, and 51% had absolute lymphocyte (ALC) levels 25 x 109/L or higher.
Eighty-two percent of patients were in the medium and high TLS risk categories, slightly less than half were Rai stage III or IV, and 81% were IGHV unmutated.
As of the data lock on April 30, 2015, patients remained a median of 12.1 months on study (range, 0.03–21.5). Seventy are still active on venetoclax, and 37 discontinued the treatment.
Eleven patients discontinued due to Richter’s transformation, 11 due to CLL progression, and 9 due to adverse events. Three patients proceeded to stem cell transplant, 2 withdrew consent, and 1 was noncompliant.
Eighteen patients died, 14 due to disease progression.
Response
Eighty-five patients responded, for an ORR of 79.4% by IRC. Eight patients (7.5%) achieved a CR or CRi, 3 (2.8%) had an nPR, and 74 (69.2%) had a PR. Twenty-two patients (20.6%) had no response.
Twenty-five of 48 patients had no evidence of CLL in their bone marrow by immunohistochemistry, and 18 of 45 patients assessed were MRD-negative in the peripheral blood.
Reduction in lymphocytosis “was quite a universal phenomenon across this trial,” Dr Stilgenbauer said. Only 4 patients of 87 with baseline lymphocytosis failed to reduce their lymphocyte count to below 4 x 109/L, the usual threshold for a CR. And the median time to normalization was 22 days (range, 2–122).
Eighty-nine of 96 patients had 50% or more reduction in their nodal size in a median of 2.7 months (range, 0.7–8.4).
The median time to first response was 0.8 months (range, 0.1–8.1), and the median time to CR/CRi was 8.2 months (range, 3.0–16.3).
“And this number still appears to evolve over the duration of the trial,” Dr Stilgenbauer said.
The median duration of response has not yet been reached. But investigators estimated that of the 85 responders, 84.7% would maintain their response at 12 months, 100% of patients in the CR/CRi and nPR groups would maintain their response, and 94.4% of patients who were MRD-negative would maintain their response.
The median PFS and OS have not been reached. The PFS estimate for 12 months was 72.0%, and the OS estimate was 86.7%.
Adverse events
Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%).
The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%).
Dr Stilgenbauer pointed out that 22.4% of patients had neutropenia at baseline. Neutropenia was managed with dose interruption or reduction, G-CSF, and/or antibiotics.
Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher.
“The types of infections were the usual expected ones,” Dr Stilgenbauer said.
Laboratory TLS occurred in 5 patients exclusively during the ramp-up period. Two required a dose interruption of 1 day each. There were no clinical TLS events.
Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
The investigators concluded that venetoclax offers a favorable risk-benefit profile. The risk of TLS can be effectively mitigated with no clinical TLS, and the incidence of neutropenia and infection are similar to frontline chemoimmunotherapy.
“Venetoclax may provide an attractive treatment option for 17p-deleted CLL as monotherapy or as a component of novel combination strategies,” Dr Stilgenbauer said.
AbbVie and Genentech, collaborators in the development of venetoclax, provided financial support for the study design, study conduct, analysis, data interpretation, writing, and review. 
Photo courtesy of ASH
ORLANDO, FL—The pivotal phase 2 study of venetoclax monotherapy in patients with relapsed/refractory 17p-deleted chronic lymphocytic leukemia (CLL) has achieved unprecedented deep responses, according to investigators.
More than 10% of patients had a complete response (CR), complete response with incomplete blood count recovery (CRi), or near partial response (nPR), as confirmed by an independent review committee (IRC).
And more than 20% of responders became negative for minimal residual disease (MRD).
Venetoclax is an orally bioavailable, selective BCL-2 inhibitor that directly induces apoptosis in CLL cells independent of p53.
The US Food and Drug Administration granted venetoclax breakthrough therapy designation for relapsed/refractory CLL earlier this year.
“Patients with a 17p deletion in CLL have very poor prognosis,” said Stephan Stilgenbauer, MD, of University of Ulm in Germany, “and limited treatment options.”
The median progression-free survival (PFS) with frontline chemoimmunotherapy in this population is less than 12 months.
The first-in-human study of venetoclax, which was recently published in NEJM, showed a 79% overall response rate (ORR) in relapsed/refractory CLL patients.
Dr Stilgenbauer presented the pivotal phase 2 results at the 2015 ASH Annual Meeting as LBA-6.
Study overview
The primary objective of the trial was ORR by independent review committee. The secondary endpoints were CR/PR rates, time to first response, duration of response, PFS, overall survival (OS), and safety.
Investigators also included the exploratory endpoint of MRD as determined by flow cytometry with a sensitivity of less than 10-4.
Patients had to have an ECOG score of 2 or less, an absolute neutrophil count of 1000/μL or greater, a platelet count of 40,000/mm3 or higher, and a hemoglobin count of at least 8 g/dL. They also had to have a creatinine clearance of 50 mL/min or more.
“With regard to performance status, blood counts, and creatinine clearance,” Dr Stilgenbauer said, “inclusion criteria were relatively liberal, allowing patients with comorbidity on the trial.”
Patients were excluded if they had prior allogeneic stem cell transplantation, Richter’s transformation, uncontrolled autoimmune cytopenia, other malignancy, or major organ dysfunction.
Trial design
Patients received an oral dose of venetoclax once daily continuously until disease progression or discontinuation for another reason.
Because tumor lysis syndrome (TLS) was a concern, investigators devised a step-wise weekly ramp-up with risk-based prophylaxis to mitigate TLS.
Patients started on a dose of 20 mg on day 1. If they did not experience any electrolyte abnormalities, they received a 50 mg daily dose for the rest of the first week, escalating to 100 mg, 200 mg, and to the target dose of 400 mg daily on subsequent weeks. Patients continued on 400 mg daily for the remainder of the study.
The investigators assessed response using iwCLL 2008 criteria with monthly physical exams and blood counts, CT scans to confirm clinical response at week 36, and a bone marrow biopsy to confirm CR.
Patient population and disposition
Investigators enrolled 107 patients with a median age of 67 (range, 37–85). Seventy (65%) were male.
Patients had a median of 2 prior therapies (range, 1–10): 54 (50%) had prior bendamustine and 38 (70%) were refractory to it; 78 (73%) had prior fludarabine and 34 (44%) were refractory to it; and 90 (84%) had a prior CD20 monoclonal antibody.
About half (52%) were ECOG grade 1, 53% had 1 or more nodes 5 cm or larger, and 51% had absolute lymphocyte (ALC) levels 25 x 109/L or higher.
Eighty-two percent of patients were in the medium and high TLS risk categories, slightly less than half were Rai stage III or IV, and 81% were IGHV unmutated.
As of the data lock on April 30, 2015, patients remained a median of 12.1 months on study (range, 0.03–21.5). Seventy are still active on venetoclax, and 37 discontinued the treatment.
Eleven patients discontinued due to Richter’s transformation, 11 due to CLL progression, and 9 due to adverse events. Three patients proceeded to stem cell transplant, 2 withdrew consent, and 1 was noncompliant.
Eighteen patients died, 14 due to disease progression.
Response
Eighty-five patients responded, for an ORR of 79.4% by IRC. Eight patients (7.5%) achieved a CR or CRi, 3 (2.8%) had an nPR, and 74 (69.2%) had a PR. Twenty-two patients (20.6%) had no response.
Twenty-five of 48 patients had no evidence of CLL in their bone marrow by immunohistochemistry, and 18 of 45 patients assessed were MRD-negative in the peripheral blood.
Reduction in lymphocytosis “was quite a universal phenomenon across this trial,” Dr Stilgenbauer said. Only 4 patients of 87 with baseline lymphocytosis failed to reduce their lymphocyte count to below 4 x 109/L, the usual threshold for a CR. And the median time to normalization was 22 days (range, 2–122).
Eighty-nine of 96 patients had 50% or more reduction in their nodal size in a median of 2.7 months (range, 0.7–8.4).
The median time to first response was 0.8 months (range, 0.1–8.1), and the median time to CR/CRi was 8.2 months (range, 3.0–16.3).
“And this number still appears to evolve over the duration of the trial,” Dr Stilgenbauer said.
The median duration of response has not yet been reached. But investigators estimated that of the 85 responders, 84.7% would maintain their response at 12 months, 100% of patients in the CR/CRi and nPR groups would maintain their response, and 94.4% of patients who were MRD-negative would maintain their response.
The median PFS and OS have not been reached. The PFS estimate for 12 months was 72.0%, and the OS estimate was 86.7%.
Adverse events
Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%).
The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%).
Dr Stilgenbauer pointed out that 22.4% of patients had neutropenia at baseline. Neutropenia was managed with dose interruption or reduction, G-CSF, and/or antibiotics.
Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher.
“The types of infections were the usual expected ones,” Dr Stilgenbauer said.
Laboratory TLS occurred in 5 patients exclusively during the ramp-up period. Two required a dose interruption of 1 day each. There were no clinical TLS events.
Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
The investigators concluded that venetoclax offers a favorable risk-benefit profile. The risk of TLS can be effectively mitigated with no clinical TLS, and the incidence of neutropenia and infection are similar to frontline chemoimmunotherapy.
“Venetoclax may provide an attractive treatment option for 17p-deleted CLL as monotherapy or as a component of novel combination strategies,” Dr Stilgenbauer said.
AbbVie and Genentech, collaborators in the development of venetoclax, provided financial support for the study design, study conduct, analysis, data interpretation, writing, and review.
Photo courtesy of ASH
ORLANDO, FL—The pivotal phase 2 study of venetoclax monotherapy in patients with relapsed/refractory 17p-deleted chronic lymphocytic leukemia (CLL) has achieved unprecedented deep responses, according to investigators.
More than 10% of patients had a complete response (CR), complete response with incomplete blood count recovery (CRi), or near partial response (nPR), as confirmed by an independent review committee (IRC).
And more than 20% of responders became negative for minimal residual disease (MRD).
Venetoclax is an orally bioavailable, selective BCL-2 inhibitor that directly induces apoptosis in CLL cells independent of p53.
The US Food and Drug Administration granted venetoclax breakthrough therapy designation for relapsed/refractory CLL earlier this year.
“Patients with a 17p deletion in CLL have very poor prognosis,” said Stephan Stilgenbauer, MD, of University of Ulm in Germany, “and limited treatment options.”
The median progression-free survival (PFS) with frontline chemoimmunotherapy in this population is less than 12 months.
The first-in-human study of venetoclax, which was recently published in NEJM, showed a 79% overall response rate (ORR) in relapsed/refractory CLL patients.
Dr Stilgenbauer presented the pivotal phase 2 results at the 2015 ASH Annual Meeting as LBA-6.
Study overview
The primary objective of the trial was ORR by independent review committee. The secondary endpoints were CR/PR rates, time to first response, duration of response, PFS, overall survival (OS), and safety.
Investigators also included the exploratory endpoint of MRD as determined by flow cytometry with a sensitivity of less than 10-4.
Patients had to have an ECOG score of 2 or less, an absolute neutrophil count of 1000/μL or greater, a platelet count of 40,000/mm3 or higher, and a hemoglobin count of at least 8 g/dL. They also had to have a creatinine clearance of 50 mL/min or more.
“With regard to performance status, blood counts, and creatinine clearance,” Dr Stilgenbauer said, “inclusion criteria were relatively liberal, allowing patients with comorbidity on the trial.”
Patients were excluded if they had prior allogeneic stem cell transplantation, Richter’s transformation, uncontrolled autoimmune cytopenia, other malignancy, or major organ dysfunction.
Trial design
Patients received an oral dose of venetoclax once daily continuously until disease progression or discontinuation for another reason.
Because tumor lysis syndrome (TLS) was a concern, investigators devised a step-wise weekly ramp-up with risk-based prophylaxis to mitigate TLS.
Patients started on a dose of 20 mg on day 1. If they did not experience any electrolyte abnormalities, they received a 50 mg daily dose for the rest of the first week, escalating to 100 mg, 200 mg, and to the target dose of 400 mg daily on subsequent weeks. Patients continued on 400 mg daily for the remainder of the study.
The investigators assessed response using iwCLL 2008 criteria with monthly physical exams and blood counts, CT scans to confirm clinical response at week 36, and a bone marrow biopsy to confirm CR.
Patient population and disposition
Investigators enrolled 107 patients with a median age of 67 (range, 37–85). Seventy (65%) were male.
Patients had a median of 2 prior therapies (range, 1–10): 54 (50%) had prior bendamustine and 38 (70%) were refractory to it; 78 (73%) had prior fludarabine and 34 (44%) were refractory to it; and 90 (84%) had a prior CD20 monoclonal antibody.
About half (52%) were ECOG grade 1, 53% had 1 or more nodes 5 cm or larger, and 51% had absolute lymphocyte (ALC) levels 25 x 109/L or higher.
Eighty-two percent of patients were in the medium and high TLS risk categories, slightly less than half were Rai stage III or IV, and 81% were IGHV unmutated.
As of the data lock on April 30, 2015, patients remained a median of 12.1 months on study (range, 0.03–21.5). Seventy are still active on venetoclax, and 37 discontinued the treatment.
Eleven patients discontinued due to Richter’s transformation, 11 due to CLL progression, and 9 due to adverse events. Three patients proceeded to stem cell transplant, 2 withdrew consent, and 1 was noncompliant.
Eighteen patients died, 14 due to disease progression.
Response
Eighty-five patients responded, for an ORR of 79.4% by IRC. Eight patients (7.5%) achieved a CR or CRi, 3 (2.8%) had an nPR, and 74 (69.2%) had a PR. Twenty-two patients (20.6%) had no response.
Twenty-five of 48 patients had no evidence of CLL in their bone marrow by immunohistochemistry, and 18 of 45 patients assessed were MRD-negative in the peripheral blood.
Reduction in lymphocytosis “was quite a universal phenomenon across this trial,” Dr Stilgenbauer said. Only 4 patients of 87 with baseline lymphocytosis failed to reduce their lymphocyte count to below 4 x 109/L, the usual threshold for a CR. And the median time to normalization was 22 days (range, 2–122).
Eighty-nine of 96 patients had 50% or more reduction in their nodal size in a median of 2.7 months (range, 0.7–8.4).
The median time to first response was 0.8 months (range, 0.1–8.1), and the median time to CR/CRi was 8.2 months (range, 3.0–16.3).
“And this number still appears to evolve over the duration of the trial,” Dr Stilgenbauer said.
The median duration of response has not yet been reached. But investigators estimated that of the 85 responders, 84.7% would maintain their response at 12 months, 100% of patients in the CR/CRi and nPR groups would maintain their response, and 94.4% of patients who were MRD-negative would maintain their response.
The median PFS and OS have not been reached. The PFS estimate for 12 months was 72.0%, and the OS estimate was 86.7%.
Adverse events
Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%).
The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%).
Dr Stilgenbauer pointed out that 22.4% of patients had neutropenia at baseline. Neutropenia was managed with dose interruption or reduction, G-CSF, and/or antibiotics.
Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher.
“The types of infections were the usual expected ones,” Dr Stilgenbauer said.
Laboratory TLS occurred in 5 patients exclusively during the ramp-up period. Two required a dose interruption of 1 day each. There were no clinical TLS events.
Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
The investigators concluded that venetoclax offers a favorable risk-benefit profile. The risk of TLS can be effectively mitigated with no clinical TLS, and the incidence of neutropenia and infection are similar to frontline chemoimmunotherapy.
“Venetoclax may provide an attractive treatment option for 17p-deleted CLL as monotherapy or as a component of novel combination strategies,” Dr Stilgenbauer said.
AbbVie and Genentech, collaborators in the development of venetoclax, provided financial support for the study design, study conduct, analysis, data interpretation, writing, and review.
CAR T cells persist for 3 years in young ALL patients
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.
Graft source and timing of HSCT affect survival in SCD
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
Preoperative VTE prophylaxis is safe for cancer patients, team says
Preoperative anticoagulant therapy is safe and effective for cancer patients, a single-center study suggests.
Among patients undergoing major cancer operations, the preoperative use of anticoagulants did not increase rates of major bleeding or transfusion.
And the treatment proved effective, decreasing the risk of venous thromboembolism (VTE).
Researchers reported these results in the Journal of the American College of Surgeons.
The team conducted this study after discovering that their institution, Memorial Sloan Kettering Cancer Center in New York, New York, had higher-than-expected rates of deep vein thrombosis (DVT) and pulmonary embolism (PE).
This was according to the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP®) database, a nationally validated, risk-adjusted, outcomes-based program to measure and improve the quality of surgical care in hospitals.
So the researchers set out to identify the reason for their high VTE rate and lower it.
“We weren’t sure if our VTE rate was due to the complexity of our operations, the fact that our patients had cancer, or that we weren’t administering heparin, which could decrease the blood clots,” said study author Vivian Strong, MD.
“There was serious concern that administering preoperative VTE prophylaxis to our patients, who undergo extensive surgical resection, would increase the risk of bleeding,” said Luke V. Selby, MD.
“Knowing, from NSQIP, that we had a higher-than-expected VTE rate, the question was whether it was safe to expose our patients to the additional bleeding risk from VTE prophylaxis.”
To find out, the researchers selected 2058 patients undergoing major operations for cancer to receive preoperative VTE prophylaxis with low-molecular-weight heparin or unfractionated heparin.
The team compared these patients—called the “post-intervention cohort”—with a group of 4960 cancer patients who had already undergone a major surgical procedure a year earlier but, for the most part, did not receive preoperative VTE prophylaxis—the “pre-intervention cohort.” Forty patients in this group did receive VTE prophylaxis.
There was no significant difference in the rate of major bleeding between the pre- and post-intervention cohorts. The major bleeding rates were 0.8% and 0.5%, respectively (P=0.2).
The rate of any documented bleeding was actually higher in the pre-intervention group—4.2% vs 2.5% (P=0.001)—as was the rate of transfusion—17% vs 14% (P=0.0003).
As expected, rates of DVT and PE were significantly lower in the post-intervention group. The rate of DVT was 1.3% in the pre-intervention group and 0.2% in the post-intervention group (P<0.0001). The rates of PE were 1.0% and 0.4%, respectively (P=0.017).
Because of these findings, Memorial Sloan Kettering Cancer Center has adopted a routine anticoagulation approach for patients who meet certain selection criteria.
“This research has been a practice-changing study for our institution,” Dr Strong said. “Our study results demonstrate to other institutions that you can use preoperative VTE prophylaxis safely, so I think that it has very broad-reaching, practice-changing implications.”
Preoperative anticoagulant therapy is safe and effective for cancer patients, a single-center study suggests.
Among patients undergoing major cancer operations, the preoperative use of anticoagulants did not increase rates of major bleeding or transfusion.
And the treatment proved effective, decreasing the risk of venous thromboembolism (VTE).
Researchers reported these results in the Journal of the American College of Surgeons.
The team conducted this study after discovering that their institution, Memorial Sloan Kettering Cancer Center in New York, New York, had higher-than-expected rates of deep vein thrombosis (DVT) and pulmonary embolism (PE).
This was according to the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP®) database, a nationally validated, risk-adjusted, outcomes-based program to measure and improve the quality of surgical care in hospitals.
So the researchers set out to identify the reason for their high VTE rate and lower it.
“We weren’t sure if our VTE rate was due to the complexity of our operations, the fact that our patients had cancer, or that we weren’t administering heparin, which could decrease the blood clots,” said study author Vivian Strong, MD.
“There was serious concern that administering preoperative VTE prophylaxis to our patients, who undergo extensive surgical resection, would increase the risk of bleeding,” said Luke V. Selby, MD.
“Knowing, from NSQIP, that we had a higher-than-expected VTE rate, the question was whether it was safe to expose our patients to the additional bleeding risk from VTE prophylaxis.”
To find out, the researchers selected 2058 patients undergoing major operations for cancer to receive preoperative VTE prophylaxis with low-molecular-weight heparin or unfractionated heparin.
The team compared these patients—called the “post-intervention cohort”—with a group of 4960 cancer patients who had already undergone a major surgical procedure a year earlier but, for the most part, did not receive preoperative VTE prophylaxis—the “pre-intervention cohort.” Forty patients in this group did receive VTE prophylaxis.
There was no significant difference in the rate of major bleeding between the pre- and post-intervention cohorts. The major bleeding rates were 0.8% and 0.5%, respectively (P=0.2).
The rate of any documented bleeding was actually higher in the pre-intervention group—4.2% vs 2.5% (P=0.001)—as was the rate of transfusion—17% vs 14% (P=0.0003).
As expected, rates of DVT and PE were significantly lower in the post-intervention group. The rate of DVT was 1.3% in the pre-intervention group and 0.2% in the post-intervention group (P<0.0001). The rates of PE were 1.0% and 0.4%, respectively (P=0.017).
Because of these findings, Memorial Sloan Kettering Cancer Center has adopted a routine anticoagulation approach for patients who meet certain selection criteria.
“This research has been a practice-changing study for our institution,” Dr Strong said. “Our study results demonstrate to other institutions that you can use preoperative VTE prophylaxis safely, so I think that it has very broad-reaching, practice-changing implications.”
Preoperative anticoagulant therapy is safe and effective for cancer patients, a single-center study suggests.
Among patients undergoing major cancer operations, the preoperative use of anticoagulants did not increase rates of major bleeding or transfusion.
And the treatment proved effective, decreasing the risk of venous thromboembolism (VTE).
Researchers reported these results in the Journal of the American College of Surgeons.
The team conducted this study after discovering that their institution, Memorial Sloan Kettering Cancer Center in New York, New York, had higher-than-expected rates of deep vein thrombosis (DVT) and pulmonary embolism (PE).
This was according to the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP®) database, a nationally validated, risk-adjusted, outcomes-based program to measure and improve the quality of surgical care in hospitals.
So the researchers set out to identify the reason for their high VTE rate and lower it.
“We weren’t sure if our VTE rate was due to the complexity of our operations, the fact that our patients had cancer, or that we weren’t administering heparin, which could decrease the blood clots,” said study author Vivian Strong, MD.
“There was serious concern that administering preoperative VTE prophylaxis to our patients, who undergo extensive surgical resection, would increase the risk of bleeding,” said Luke V. Selby, MD.
“Knowing, from NSQIP, that we had a higher-than-expected VTE rate, the question was whether it was safe to expose our patients to the additional bleeding risk from VTE prophylaxis.”
To find out, the researchers selected 2058 patients undergoing major operations for cancer to receive preoperative VTE prophylaxis with low-molecular-weight heparin or unfractionated heparin.
The team compared these patients—called the “post-intervention cohort”—with a group of 4960 cancer patients who had already undergone a major surgical procedure a year earlier but, for the most part, did not receive preoperative VTE prophylaxis—the “pre-intervention cohort.” Forty patients in this group did receive VTE prophylaxis.
There was no significant difference in the rate of major bleeding between the pre- and post-intervention cohorts. The major bleeding rates were 0.8% and 0.5%, respectively (P=0.2).
The rate of any documented bleeding was actually higher in the pre-intervention group—4.2% vs 2.5% (P=0.001)—as was the rate of transfusion—17% vs 14% (P=0.0003).
As expected, rates of DVT and PE were significantly lower in the post-intervention group. The rate of DVT was 1.3% in the pre-intervention group and 0.2% in the post-intervention group (P<0.0001). The rates of PE were 1.0% and 0.4%, respectively (P=0.017).
Because of these findings, Memorial Sloan Kettering Cancer Center has adopted a routine anticoagulation approach for patients who meet certain selection criteria.
“This research has been a practice-changing study for our institution,” Dr Strong said. “Our study results demonstrate to other institutions that you can use preoperative VTE prophylaxis safely, so I think that it has very broad-reaching, practice-changing implications.”
An Update on the Diagnosis and Treatment of Hidradenitis Suppurativa
Hidradenitis suppurativa (HS) is a chronic, inflammatory, scarring disease that occurs most frequently along the milk lines of the body from axillae to groin, is most common in the second and third decades of life, and is rarely observed before puberty. It disproportionately affects women and is associated with a host of comorbidities and dramatically reduced quality of life. The delay from HS symptom onset to diagnosis is approximately 7 years, with drastic consequences for patient well being. Early diagnosis and treatment are of paramount importance. While several nonpharmacologic, pharmacologic, and surgical treatment modalities exist for HS, only one agent, adalimumab, has been approved by the US Food and Drug Administration for this indication. Lifestyle modifications, dietary changes, patient education, and psychosocial support are important components of HS therapy.
Hidradenitis suppurativa (HS) is a chronic, inflammatory, scarring disease that occurs most frequently along the milk lines of the body from axillae to groin, is most common in the second and third decades of life, and is rarely observed before puberty. It disproportionately affects women and is associated with a host of comorbidities and dramatically reduced quality of life. The delay from HS symptom onset to diagnosis is approximately 7 years, with drastic consequences for patient well being. Early diagnosis and treatment are of paramount importance. While several nonpharmacologic, pharmacologic, and surgical treatment modalities exist for HS, only one agent, adalimumab, has been approved by the US Food and Drug Administration for this indication. Lifestyle modifications, dietary changes, patient education, and psychosocial support are important components of HS therapy.
Hidradenitis suppurativa (HS) is a chronic, inflammatory, scarring disease that occurs most frequently along the milk lines of the body from axillae to groin, is most common in the second and third decades of life, and is rarely observed before puberty. It disproportionately affects women and is associated with a host of comorbidities and dramatically reduced quality of life. The delay from HS symptom onset to diagnosis is approximately 7 years, with drastic consequences for patient well being. Early diagnosis and treatment are of paramount importance. While several nonpharmacologic, pharmacologic, and surgical treatment modalities exist for HS, only one agent, adalimumab, has been approved by the US Food and Drug Administration for this indication. Lifestyle modifications, dietary changes, patient education, and psychosocial support are important components of HS therapy.
Poor stewardship
To those of us who live and practice in the northeast, it comes as no surprise that the mortality rate for middle class whites is climbing. Obituaries in our local papers often include men and women in their forties “dying at home,” with no mention of cancer or chronic disease. Rarely, the family can bring itself to announce that their loved one has died of a drug overdose.
Deaths attributable to prescription opioid overdoses quadrupled in the decade from 1999 to 2010, and the trend shows little sign of abating as the number of prescriptions for opioids has risen tenfold over the last 20 years (“How Doctors Helped Drive the Addiction Crisis,” by Dr. Richard Friedman, New York Times, Nov. 7, 2015). Could physician behavior have contributed to outbreak of this deadly plague of addiction? That is like asking if something the zookeeper did or didn’t do could have been responsible for the escape of the man-eating tiger that is devouring the neighborhood children. Regardless of what other factors might be responsible for the epidemic of fatal prescription opioid overdoses, physicians must admit some culpability.
Until recently, I assumed that the problem of prescription opioids finding their way to addicts was unique to physicians treating adults. However, a study reported at the annual meeting of the American Society of Anesthesiologists reveals pediatricians and other clinicians prescribing for children must share in the blame.
Dr. Myron Yaster at Johns Hopkins University Hospital, Baltimore, has found that in a group of nearly 300 pediatric patients (average age, 11 years and average weight of 44 kg), overall the patients used only 42% of the prescribed amount of opioids. Almost half of the patients had a teenage sibling, a group that Dr. Yaster describes as the “target population of drug abuse.”
What’s going on here? Some of the problem dates back to the 1990s when physicians were urged to shift their focus toward the problem of inadequately treated pain. With the help of nurses armed with pain-rating schemes and smiley/grumpy face charts, the mantra became “no pain shall go unmedicated,” when the better response should have been “no pain shall go unmanaged.” But good pain management takes time. It requires that the physician and staff consider each patient as a unique individual. In many cases, reassurance and education can make a non–opioid medication or even no medication a better choice.
However, according to Dr. Yaster, “leftover medicine is the most important element in drug addiction.” Why did physicians prescribe 10 days of medication when his study revealed that most patients took the medication for only 5? It could just be a bad habit. Or it could be ignorance or inexperience. How many physicians ask at follow-up appointments “How long did you take your medication? Tell me the history of your pain.”
Or could it be that physicians are simply trying to prevent those annoying calls from patients who have run out of their medication? Dr. Yaster’s findings suggest that those calls would be few and far between. More careful thought into how much medication we prescribe also would mean that when a patient called for more medication that there was a problem. Either the patient’s recuperation has hit a worrisome bump in the road or possibly her medication is being diverted.
History tells us that physicians, even pediatricians, have been poor stewards of the powerful medications with which we have been entrusted. First, it was antibiotics and now opioids have joined the list.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.” Email him at [email protected].
To those of us who live and practice in the northeast, it comes as no surprise that the mortality rate for middle class whites is climbing. Obituaries in our local papers often include men and women in their forties “dying at home,” with no mention of cancer or chronic disease. Rarely, the family can bring itself to announce that their loved one has died of a drug overdose.
Deaths attributable to prescription opioid overdoses quadrupled in the decade from 1999 to 2010, and the trend shows little sign of abating as the number of prescriptions for opioids has risen tenfold over the last 20 years (“How Doctors Helped Drive the Addiction Crisis,” by Dr. Richard Friedman, New York Times, Nov. 7, 2015). Could physician behavior have contributed to outbreak of this deadly plague of addiction? That is like asking if something the zookeeper did or didn’t do could have been responsible for the escape of the man-eating tiger that is devouring the neighborhood children. Regardless of what other factors might be responsible for the epidemic of fatal prescription opioid overdoses, physicians must admit some culpability.
Until recently, I assumed that the problem of prescription opioids finding their way to addicts was unique to physicians treating adults. However, a study reported at the annual meeting of the American Society of Anesthesiologists reveals pediatricians and other clinicians prescribing for children must share in the blame.
Dr. Myron Yaster at Johns Hopkins University Hospital, Baltimore, has found that in a group of nearly 300 pediatric patients (average age, 11 years and average weight of 44 kg), overall the patients used only 42% of the prescribed amount of opioids. Almost half of the patients had a teenage sibling, a group that Dr. Yaster describes as the “target population of drug abuse.”
What’s going on here? Some of the problem dates back to the 1990s when physicians were urged to shift their focus toward the problem of inadequately treated pain. With the help of nurses armed with pain-rating schemes and smiley/grumpy face charts, the mantra became “no pain shall go unmedicated,” when the better response should have been “no pain shall go unmanaged.” But good pain management takes time. It requires that the physician and staff consider each patient as a unique individual. In many cases, reassurance and education can make a non–opioid medication or even no medication a better choice.
However, according to Dr. Yaster, “leftover medicine is the most important element in drug addiction.” Why did physicians prescribe 10 days of medication when his study revealed that most patients took the medication for only 5? It could just be a bad habit. Or it could be ignorance or inexperience. How many physicians ask at follow-up appointments “How long did you take your medication? Tell me the history of your pain.”
Or could it be that physicians are simply trying to prevent those annoying calls from patients who have run out of their medication? Dr. Yaster’s findings suggest that those calls would be few and far between. More careful thought into how much medication we prescribe also would mean that when a patient called for more medication that there was a problem. Either the patient’s recuperation has hit a worrisome bump in the road or possibly her medication is being diverted.
History tells us that physicians, even pediatricians, have been poor stewards of the powerful medications with which we have been entrusted. First, it was antibiotics and now opioids have joined the list.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.” Email him at [email protected].
To those of us who live and practice in the northeast, it comes as no surprise that the mortality rate for middle class whites is climbing. Obituaries in our local papers often include men and women in their forties “dying at home,” with no mention of cancer or chronic disease. Rarely, the family can bring itself to announce that their loved one has died of a drug overdose.
Deaths attributable to prescription opioid overdoses quadrupled in the decade from 1999 to 2010, and the trend shows little sign of abating as the number of prescriptions for opioids has risen tenfold over the last 20 years (“How Doctors Helped Drive the Addiction Crisis,” by Dr. Richard Friedman, New York Times, Nov. 7, 2015). Could physician behavior have contributed to outbreak of this deadly plague of addiction? That is like asking if something the zookeeper did or didn’t do could have been responsible for the escape of the man-eating tiger that is devouring the neighborhood children. Regardless of what other factors might be responsible for the epidemic of fatal prescription opioid overdoses, physicians must admit some culpability.
Until recently, I assumed that the problem of prescription opioids finding their way to addicts was unique to physicians treating adults. However, a study reported at the annual meeting of the American Society of Anesthesiologists reveals pediatricians and other clinicians prescribing for children must share in the blame.
Dr. Myron Yaster at Johns Hopkins University Hospital, Baltimore, has found that in a group of nearly 300 pediatric patients (average age, 11 years and average weight of 44 kg), overall the patients used only 42% of the prescribed amount of opioids. Almost half of the patients had a teenage sibling, a group that Dr. Yaster describes as the “target population of drug abuse.”
What’s going on here? Some of the problem dates back to the 1990s when physicians were urged to shift their focus toward the problem of inadequately treated pain. With the help of nurses armed with pain-rating schemes and smiley/grumpy face charts, the mantra became “no pain shall go unmedicated,” when the better response should have been “no pain shall go unmanaged.” But good pain management takes time. It requires that the physician and staff consider each patient as a unique individual. In many cases, reassurance and education can make a non–opioid medication or even no medication a better choice.
However, according to Dr. Yaster, “leftover medicine is the most important element in drug addiction.” Why did physicians prescribe 10 days of medication when his study revealed that most patients took the medication for only 5? It could just be a bad habit. Or it could be ignorance or inexperience. How many physicians ask at follow-up appointments “How long did you take your medication? Tell me the history of your pain.”
Or could it be that physicians are simply trying to prevent those annoying calls from patients who have run out of their medication? Dr. Yaster’s findings suggest that those calls would be few and far between. More careful thought into how much medication we prescribe also would mean that when a patient called for more medication that there was a problem. Either the patient’s recuperation has hit a worrisome bump in the road or possibly her medication is being diverted.
History tells us that physicians, even pediatricians, have been poor stewards of the powerful medications with which we have been entrusted. First, it was antibiotics and now opioids have joined the list.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.” Email him at [email protected].
Antidepressants highly effective against binge-eating disorder
People with binge-eating disorder have the greatest chance of achieving normal eating habits and alleviating symptoms associated with the disorder by taking second-generation antidepressants, topiramate, and lisdexamfetamine and engaging in cognitive-behavioral therapy, an analysis of several studies showed.
The findings should be used to “address other treatments, combinations of treatments, and comparisons between treatments; treatment for postbariatric surgery patients and children; and the course of these illnesses,” according to the report, released as part of the Comparative Effectiveness Review No. 160 by the Agency for Healthcare Research and Quality.
The authors of the report examined a total of 52 randomized controlled trials and 15 observational studies collected through searches of MEDLINE, EMBASE, the Cochrane Library, Academic OneFile, and the Cumulative Index to Nursing and Allied Health Literature databases, with 48 of the included studies specifically concerning binge-eating disorder (BED). English-language studies up through Jan. 19, 2015, were included for analysis, and the investigators specifically looked for studies of individuals who met DSM-IV or DSM-5 criteria for BED and studies of postbariatric surgery patients, including children, experiencing loss-of-control (LOC) eating habits.
Each study was evaluated based on a set of 15 “key questions” to determine the effectiveness and harms of the treatments involved. The key questions used by the investigators sought to determine the evidence of effectiveness and harms of BED treatments; LOC eating among bariatric surgery patients; and the effectiveness of any LOC treatments based on age, sex, race, ethnicity, initial body mass index, duration of illness, and coexisting conditions. In addition, similar questions were used to ascertain the effectiveness of treatments on pediatric patients.
“Broadly, we included pharmacological, psychological, behavioral, and combination interventions,” the report stated. “We considered physical and psychological health outcomes in four major categories: binge behavior (binge eating or LOC eating); binge-eating–related psychopathology (e.g., weight and shape concerns, dietary restraint); physical health functioning (i.e., weight and other indexes of metabolic health, e.g., diabetes); and general psychopathology (e.g., depression, anxiety).”
Antidepressants were found to be more effective than placebos across the studies included in the survey, specifically second-generation antidepressants, and were 1.67 times more likely to help BED patients achieve abstinence than placebos used in these trials; 41% of subjects receiving antidepressants ultimately achieved abstinence, compared with 23% on placebos.
With topiramate, binge eating generally decreased to as little as one episode per week, and a higher portion of subjects (58%) achieved abstinence than those on placebo (28%). In addition, topiramate was found to decrease “obsessive thoughts and compulsions related to binge eating” by nearly 30%, versus 23% in subjects taking placebos.
Studies involving lisdexamfetamine showed abstinence achieved in 40% of subjects, far higher than the 15% on placebos, and a likelihood of achieving abstinence 2.61 times higher than for those in the placebo cohorts. Binge-eating episodes per week also decreased, and were, on average, anywhere from 1.7 to 1.3 fewer than those in subjects taking placebo. Subjects receiving cognitive-behavioral therapy – whether led by a therapist or self-led, though the former was found to have stronger evidence of effectiveness than the latter – had an average of 2.3 fewer binge-eating episodes per week, and subjects involved with therapy were 4.95 times more likely to achieve abstinence than those who were not receiving therapy.
“Findings about BED treatment interventions are likely to be applicable to all adults age 18 and older with the disorder, but chiefly to overweight or obese women,” the report stated. “We cannot comment on the applicability of treatment findings for specific subgroups of adults (even among women) or whether findings extend to BED patients diagnosed based on DSM-5 criteria.”
The authors also noted that the findings are unclear with respect to adolescents with BED or members of ethnic groups, and children with loss-of-control eating or who have undergone bariatric surgery.
“A convention for reporting and analyzing” outcomes is necessary for the findings of this study to take on real-world applications that can be beneficial to clinicians and their patients in the near future, the authors concluded. However, more multisite randomized, controlled trials are needed.
People with binge-eating disorder have the greatest chance of achieving normal eating habits and alleviating symptoms associated with the disorder by taking second-generation antidepressants, topiramate, and lisdexamfetamine and engaging in cognitive-behavioral therapy, an analysis of several studies showed.
The findings should be used to “address other treatments, combinations of treatments, and comparisons between treatments; treatment for postbariatric surgery patients and children; and the course of these illnesses,” according to the report, released as part of the Comparative Effectiveness Review No. 160 by the Agency for Healthcare Research and Quality.
The authors of the report examined a total of 52 randomized controlled trials and 15 observational studies collected through searches of MEDLINE, EMBASE, the Cochrane Library, Academic OneFile, and the Cumulative Index to Nursing and Allied Health Literature databases, with 48 of the included studies specifically concerning binge-eating disorder (BED). English-language studies up through Jan. 19, 2015, were included for analysis, and the investigators specifically looked for studies of individuals who met DSM-IV or DSM-5 criteria for BED and studies of postbariatric surgery patients, including children, experiencing loss-of-control (LOC) eating habits.
Each study was evaluated based on a set of 15 “key questions” to determine the effectiveness and harms of the treatments involved. The key questions used by the investigators sought to determine the evidence of effectiveness and harms of BED treatments; LOC eating among bariatric surgery patients; and the effectiveness of any LOC treatments based on age, sex, race, ethnicity, initial body mass index, duration of illness, and coexisting conditions. In addition, similar questions were used to ascertain the effectiveness of treatments on pediatric patients.
“Broadly, we included pharmacological, psychological, behavioral, and combination interventions,” the report stated. “We considered physical and psychological health outcomes in four major categories: binge behavior (binge eating or LOC eating); binge-eating–related psychopathology (e.g., weight and shape concerns, dietary restraint); physical health functioning (i.e., weight and other indexes of metabolic health, e.g., diabetes); and general psychopathology (e.g., depression, anxiety).”
Antidepressants were found to be more effective than placebos across the studies included in the survey, specifically second-generation antidepressants, and were 1.67 times more likely to help BED patients achieve abstinence than placebos used in these trials; 41% of subjects receiving antidepressants ultimately achieved abstinence, compared with 23% on placebos.
With topiramate, binge eating generally decreased to as little as one episode per week, and a higher portion of subjects (58%) achieved abstinence than those on placebo (28%). In addition, topiramate was found to decrease “obsessive thoughts and compulsions related to binge eating” by nearly 30%, versus 23% in subjects taking placebos.
Studies involving lisdexamfetamine showed abstinence achieved in 40% of subjects, far higher than the 15% on placebos, and a likelihood of achieving abstinence 2.61 times higher than for those in the placebo cohorts. Binge-eating episodes per week also decreased, and were, on average, anywhere from 1.7 to 1.3 fewer than those in subjects taking placebo. Subjects receiving cognitive-behavioral therapy – whether led by a therapist or self-led, though the former was found to have stronger evidence of effectiveness than the latter – had an average of 2.3 fewer binge-eating episodes per week, and subjects involved with therapy were 4.95 times more likely to achieve abstinence than those who were not receiving therapy.
“Findings about BED treatment interventions are likely to be applicable to all adults age 18 and older with the disorder, but chiefly to overweight or obese women,” the report stated. “We cannot comment on the applicability of treatment findings for specific subgroups of adults (even among women) or whether findings extend to BED patients diagnosed based on DSM-5 criteria.”
The authors also noted that the findings are unclear with respect to adolescents with BED or members of ethnic groups, and children with loss-of-control eating or who have undergone bariatric surgery.
“A convention for reporting and analyzing” outcomes is necessary for the findings of this study to take on real-world applications that can be beneficial to clinicians and their patients in the near future, the authors concluded. However, more multisite randomized, controlled trials are needed.
People with binge-eating disorder have the greatest chance of achieving normal eating habits and alleviating symptoms associated with the disorder by taking second-generation antidepressants, topiramate, and lisdexamfetamine and engaging in cognitive-behavioral therapy, an analysis of several studies showed.
The findings should be used to “address other treatments, combinations of treatments, and comparisons between treatments; treatment for postbariatric surgery patients and children; and the course of these illnesses,” according to the report, released as part of the Comparative Effectiveness Review No. 160 by the Agency for Healthcare Research and Quality.
The authors of the report examined a total of 52 randomized controlled trials and 15 observational studies collected through searches of MEDLINE, EMBASE, the Cochrane Library, Academic OneFile, and the Cumulative Index to Nursing and Allied Health Literature databases, with 48 of the included studies specifically concerning binge-eating disorder (BED). English-language studies up through Jan. 19, 2015, were included for analysis, and the investigators specifically looked for studies of individuals who met DSM-IV or DSM-5 criteria for BED and studies of postbariatric surgery patients, including children, experiencing loss-of-control (LOC) eating habits.
Each study was evaluated based on a set of 15 “key questions” to determine the effectiveness and harms of the treatments involved. The key questions used by the investigators sought to determine the evidence of effectiveness and harms of BED treatments; LOC eating among bariatric surgery patients; and the effectiveness of any LOC treatments based on age, sex, race, ethnicity, initial body mass index, duration of illness, and coexisting conditions. In addition, similar questions were used to ascertain the effectiveness of treatments on pediatric patients.
“Broadly, we included pharmacological, psychological, behavioral, and combination interventions,” the report stated. “We considered physical and psychological health outcomes in four major categories: binge behavior (binge eating or LOC eating); binge-eating–related psychopathology (e.g., weight and shape concerns, dietary restraint); physical health functioning (i.e., weight and other indexes of metabolic health, e.g., diabetes); and general psychopathology (e.g., depression, anxiety).”
Antidepressants were found to be more effective than placebos across the studies included in the survey, specifically second-generation antidepressants, and were 1.67 times more likely to help BED patients achieve abstinence than placebos used in these trials; 41% of subjects receiving antidepressants ultimately achieved abstinence, compared with 23% on placebos.
With topiramate, binge eating generally decreased to as little as one episode per week, and a higher portion of subjects (58%) achieved abstinence than those on placebo (28%). In addition, topiramate was found to decrease “obsessive thoughts and compulsions related to binge eating” by nearly 30%, versus 23% in subjects taking placebos.
Studies involving lisdexamfetamine showed abstinence achieved in 40% of subjects, far higher than the 15% on placebos, and a likelihood of achieving abstinence 2.61 times higher than for those in the placebo cohorts. Binge-eating episodes per week also decreased, and were, on average, anywhere from 1.7 to 1.3 fewer than those in subjects taking placebo. Subjects receiving cognitive-behavioral therapy – whether led by a therapist or self-led, though the former was found to have stronger evidence of effectiveness than the latter – had an average of 2.3 fewer binge-eating episodes per week, and subjects involved with therapy were 4.95 times more likely to achieve abstinence than those who were not receiving therapy.
“Findings about BED treatment interventions are likely to be applicable to all adults age 18 and older with the disorder, but chiefly to overweight or obese women,” the report stated. “We cannot comment on the applicability of treatment findings for specific subgroups of adults (even among women) or whether findings extend to BED patients diagnosed based on DSM-5 criteria.”
The authors also noted that the findings are unclear with respect to adolescents with BED or members of ethnic groups, and children with loss-of-control eating or who have undergone bariatric surgery.
“A convention for reporting and analyzing” outcomes is necessary for the findings of this study to take on real-world applications that can be beneficial to clinicians and their patients in the near future, the authors concluded. However, more multisite randomized, controlled trials are needed.
Prior authorization sausage factory turns approvals into denials
“We are just statistics, born to consume resources.” –Horace
You know the winter is coming when rheumatologists spend their weekends writing appeal letters for sildenafil.
I inherited a scleroderma patient from a retired colleague. She has had severe Raynaud’s for which she’d been on sildenafil since 2013. On Nov. 23, 2015, I received a letter stating that the medication would no longer be covered because the patient did not meet criteria (in this case, pulmonary arterial hypertension).
I had to submit a letter of appeal, in which I explained how, despite maximum tolerated doses of nifedipine and pentoxifylline, she continued to have digital ischemia, and how, when she finally started the sildenafil, which they had approved prior, the problem went away. I continued to say:
“In the medical literature on this problem, the PDE-5 inhibitors, of which sildenafil is one, is typically recommended, after vasodilation, on the basis of Level I evidence (that is, evidence from high quality randomized controlled trials). Sildenafil has been shown to promote complete healing of digital ulcers and prevents the formation of new ulcers. Thought leaders in the field uniformly recommend this drug as an important part of therapy particularly in patients who have already had digital ulcers. I am happy to provide you with the literature upon request.
“I urge you to reconsider your decision. If you withhold this drug there is a chance that the patient will end up with ulcers again and this could potentially cost you even more. Not only would it impair the patient’s ability to work, which leads to loss of income for her, it would also cost you more in terms of paying for her health care.”
On Nov. 28, I received a second denial, no different than the first letter: “Your request was reviewed by a Medical Doctor specialized in Internal Medicine/Rheumatology. Upon review of the available information, it was determined that the previous decision should be upheld because the Prior Authorization criteria is not met. This determination was made based upon our review of your health condition in relation to the prior authorization criteria and/or guidelines listed below. You have CREST ... with Raynaud’s phenomenon which is not a covered diagnosis. You do not have Pulmonary Arterial Hypertension. Therefore the requested drug sildenafil citrate is not medically necessary according to plan criteria. The denial is therefore appropriate and consistent with your benefits.
“Sildenafil will be approved based on one of the following criteria:
(1) All of the following:
(A) Pulmonary arterial hypertension is symptomatic; AND
(B) Submission of medical records documenting diagnosis of pulmonary arterial hypertension that is confirmed by right heart catheterization; OR
(2) Patient is currently on any therapy for the diagnosis of pulmonary arterial hypertension.”
On Dec. 4, I fired off the following response:
“I received your decision letter dated 11/28/2015 in which you reiterate that your criteria for approval requires a diagnosis of pulmonary hypertension, as if you had not read my first letter at all. This request is not for pulmonary hypertension, it is to prevent limb-threatening gangrene and ischemia from Raynaud’s phenomenon. Please reconsider your decision. We do not want this young patient to lose any digits.”
It’s quite ironic that on the same weekend that I wrote my first letter, a mentor and friend of mine who is a rheumatologist also wrote a letter of appeal to get a prescription for sildenafil approved for a scleroderma patient with Raynaud’s who failed previous medications. She got sildenafil approved. At her suggestion, I attached a copy of the 2005 study published in Circulation demonstrating the efficacy of sildenafil for Raynaud’s to support my letter after the second denial (Circulation. 2005 Nov 8;112[19]:2980-5). As of this writing, I still have not heard back.
Dr. Chan practices rheumatology in Pawtucket, R.I.
“We are just statistics, born to consume resources.” –Horace
You know the winter is coming when rheumatologists spend their weekends writing appeal letters for sildenafil.
I inherited a scleroderma patient from a retired colleague. She has had severe Raynaud’s for which she’d been on sildenafil since 2013. On Nov. 23, 2015, I received a letter stating that the medication would no longer be covered because the patient did not meet criteria (in this case, pulmonary arterial hypertension).
I had to submit a letter of appeal, in which I explained how, despite maximum tolerated doses of nifedipine and pentoxifylline, she continued to have digital ischemia, and how, when she finally started the sildenafil, which they had approved prior, the problem went away. I continued to say:
“In the medical literature on this problem, the PDE-5 inhibitors, of which sildenafil is one, is typically recommended, after vasodilation, on the basis of Level I evidence (that is, evidence from high quality randomized controlled trials). Sildenafil has been shown to promote complete healing of digital ulcers and prevents the formation of new ulcers. Thought leaders in the field uniformly recommend this drug as an important part of therapy particularly in patients who have already had digital ulcers. I am happy to provide you with the literature upon request.
“I urge you to reconsider your decision. If you withhold this drug there is a chance that the patient will end up with ulcers again and this could potentially cost you even more. Not only would it impair the patient’s ability to work, which leads to loss of income for her, it would also cost you more in terms of paying for her health care.”
On Nov. 28, I received a second denial, no different than the first letter: “Your request was reviewed by a Medical Doctor specialized in Internal Medicine/Rheumatology. Upon review of the available information, it was determined that the previous decision should be upheld because the Prior Authorization criteria is not met. This determination was made based upon our review of your health condition in relation to the prior authorization criteria and/or guidelines listed below. You have CREST ... with Raynaud’s phenomenon which is not a covered diagnosis. You do not have Pulmonary Arterial Hypertension. Therefore the requested drug sildenafil citrate is not medically necessary according to plan criteria. The denial is therefore appropriate and consistent with your benefits.
“Sildenafil will be approved based on one of the following criteria:
(1) All of the following:
(A) Pulmonary arterial hypertension is symptomatic; AND
(B) Submission of medical records documenting diagnosis of pulmonary arterial hypertension that is confirmed by right heart catheterization; OR
(2) Patient is currently on any therapy for the diagnosis of pulmonary arterial hypertension.”
On Dec. 4, I fired off the following response:
“I received your decision letter dated 11/28/2015 in which you reiterate that your criteria for approval requires a diagnosis of pulmonary hypertension, as if you had not read my first letter at all. This request is not for pulmonary hypertension, it is to prevent limb-threatening gangrene and ischemia from Raynaud’s phenomenon. Please reconsider your decision. We do not want this young patient to lose any digits.”
It’s quite ironic that on the same weekend that I wrote my first letter, a mentor and friend of mine who is a rheumatologist also wrote a letter of appeal to get a prescription for sildenafil approved for a scleroderma patient with Raynaud’s who failed previous medications. She got sildenafil approved. At her suggestion, I attached a copy of the 2005 study published in Circulation demonstrating the efficacy of sildenafil for Raynaud’s to support my letter after the second denial (Circulation. 2005 Nov 8;112[19]:2980-5). As of this writing, I still have not heard back.
Dr. Chan practices rheumatology in Pawtucket, R.I.
“We are just statistics, born to consume resources.” –Horace
You know the winter is coming when rheumatologists spend their weekends writing appeal letters for sildenafil.
I inherited a scleroderma patient from a retired colleague. She has had severe Raynaud’s for which she’d been on sildenafil since 2013. On Nov. 23, 2015, I received a letter stating that the medication would no longer be covered because the patient did not meet criteria (in this case, pulmonary arterial hypertension).
I had to submit a letter of appeal, in which I explained how, despite maximum tolerated doses of nifedipine and pentoxifylline, she continued to have digital ischemia, and how, when she finally started the sildenafil, which they had approved prior, the problem went away. I continued to say:
“In the medical literature on this problem, the PDE-5 inhibitors, of which sildenafil is one, is typically recommended, after vasodilation, on the basis of Level I evidence (that is, evidence from high quality randomized controlled trials). Sildenafil has been shown to promote complete healing of digital ulcers and prevents the formation of new ulcers. Thought leaders in the field uniformly recommend this drug as an important part of therapy particularly in patients who have already had digital ulcers. I am happy to provide you with the literature upon request.
“I urge you to reconsider your decision. If you withhold this drug there is a chance that the patient will end up with ulcers again and this could potentially cost you even more. Not only would it impair the patient’s ability to work, which leads to loss of income for her, it would also cost you more in terms of paying for her health care.”
On Nov. 28, I received a second denial, no different than the first letter: “Your request was reviewed by a Medical Doctor specialized in Internal Medicine/Rheumatology. Upon review of the available information, it was determined that the previous decision should be upheld because the Prior Authorization criteria is not met. This determination was made based upon our review of your health condition in relation to the prior authorization criteria and/or guidelines listed below. You have CREST ... with Raynaud’s phenomenon which is not a covered diagnosis. You do not have Pulmonary Arterial Hypertension. Therefore the requested drug sildenafil citrate is not medically necessary according to plan criteria. The denial is therefore appropriate and consistent with your benefits.
“Sildenafil will be approved based on one of the following criteria:
(1) All of the following:
(A) Pulmonary arterial hypertension is symptomatic; AND
(B) Submission of medical records documenting diagnosis of pulmonary arterial hypertension that is confirmed by right heart catheterization; OR
(2) Patient is currently on any therapy for the diagnosis of pulmonary arterial hypertension.”
On Dec. 4, I fired off the following response:
“I received your decision letter dated 11/28/2015 in which you reiterate that your criteria for approval requires a diagnosis of pulmonary hypertension, as if you had not read my first letter at all. This request is not for pulmonary hypertension, it is to prevent limb-threatening gangrene and ischemia from Raynaud’s phenomenon. Please reconsider your decision. We do not want this young patient to lose any digits.”
It’s quite ironic that on the same weekend that I wrote my first letter, a mentor and friend of mine who is a rheumatologist also wrote a letter of appeal to get a prescription for sildenafil approved for a scleroderma patient with Raynaud’s who failed previous medications. She got sildenafil approved. At her suggestion, I attached a copy of the 2005 study published in Circulation demonstrating the efficacy of sildenafil for Raynaud’s to support my letter after the second denial (Circulation. 2005 Nov 8;112[19]:2980-5). As of this writing, I still have not heard back.
Dr. Chan practices rheumatology in Pawtucket, R.I.
