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Elevated factor VIII troughs can lead to a higher proportion of zero bleeds in hemophilia
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
FROM BLOOD
High-dose methotrexate of no CNS benefit for patients with high-risk DLBCL
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.
However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.
The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.
A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.
Equivalent results
The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.
One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.
The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.
“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.
“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.
The authors reported that they had no competing financial interests.
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.
However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.
The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.
A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.
Equivalent results
The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.
One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.
The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.
“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.
“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.
The authors reported that they had no competing financial interests.
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.
However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.
The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.
A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.
Equivalent results
The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.
One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.
The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.
“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.
“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.
The authors reported that they had no competing financial interests.
FROM BLOOD ADVANCES
FDA approves new treatment option for rare anemia
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
Health costs over 25 times higher for hemophilia B patients than controls
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
FROM BLOOD ADVANCES
High variability found in studies assessing hemophilia-related pain
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
FROM THE JOURNAL OF PAIN
Mitochondrial DNA predicts survival in pediatric acute myeloid leukemia
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
FROM MITOCHONDRION
Predicting outcomes in therapy-related AML
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
FROM HEMATOLOGY/ONCOLOGY AND STEM CELL THERAPY
CLL patients: Diagnostic difficulties, treatment confusion with COVID-19
Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.
Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.
The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
Troubling results
Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.
Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.
In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.
With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.
“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.
The authors reported that they had no disclosures.
Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.
Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.
The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
Troubling results
Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.
Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.
In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.
With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.
“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.
The authors reported that they had no disclosures.
Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.
Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.
The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
Troubling results
Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.
Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.
In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.
With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.
“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.
The authors reported that they had no disclosures.
FROM LEUKEMIA RESEARCH REPORTS
Unique oral drug candidate designed to overcome sickle cell disease
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Evidence favors lower-dose R-CHOP for fit, very elderly DLBCL patients
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
FROM CRITICAL REVIEWS IN ONCOLOGY/HEMATOLOGY