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Post-ibrutinib management in MCL unclear, speaker says
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.” 
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”
Interventions can treat, prevent iron deficiency in blood donors
ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.
The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.
But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.
Meanwhile, patients in control groups became more iron-deficient over the study period.
The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.
Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).
Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.
“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”
Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.
“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.
This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.
Study design
This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.
In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.
Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.
Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.
The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.
Study completion
Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.
In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.
And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.
Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.
“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”
Results
Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.
Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).
The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).
The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).
The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).
And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.
Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.
Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.
“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.
In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.
“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”
“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”
ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.
The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.
But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.
Meanwhile, patients in control groups became more iron-deficient over the study period.
The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.
Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).
Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.
“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”
Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.
“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.
This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.
Study design
This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.
In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.
Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.
Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.
The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.
Study completion
Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.
In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.
And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.
Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.
“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”
Results
Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.
Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).
The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).
The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).
The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).
And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.
Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.
Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.
“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.
In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.
“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”
“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”
ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.
The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.
But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.
Meanwhile, patients in control groups became more iron-deficient over the study period.
The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.
Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).
Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.
“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”
Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.
“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.
This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.
Study design
This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.
In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.
Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.
Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.
The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.
Study completion
Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.
In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.
And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.
Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.
“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”
Results
Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.
Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).
The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).
The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).
The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).
And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.
Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.
Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.
“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.
In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.
“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”
“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”
Protocol could improve massive blood transfusion
An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.
The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.
One patient received an inadequate amount of blood products and ultimately died.
But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.
David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.
The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.
Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.
This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.
The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.
The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.
Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.
The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.
The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.
Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.
An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.
The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.
One patient received an inadequate amount of blood products and ultimately died.
But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.
David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.
The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.
Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.
This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.
The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.
The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.
Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.
The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.
The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.
Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.
An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.
The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.
One patient received an inadequate amount of blood products and ultimately died.
But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.
David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.
The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.
Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.
This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.
The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.
The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.
Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.
The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.
The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.
Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.
Drug gets orphan designation for BPDCN
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
Assay can detect and classify DOACs
Photo by Juan D. Alfonso
ANAHEIM, CA—A new assay can detect and classify direct oral anticoagulants (DOACs) quickly and effectively, according to researchers.
In tests, the assay detected DOACs with greater than 90% sensitivity and specificity.
The assay classified the direct thrombin inhibitor (DTI) dabigatran correctly 100% of the time and classified factor Xa inhibitors (anti-Xa), which included rivaroxaban and apixaban, correctly 92% of the time.
The researchers believe this assay has the potential to be an effective tool for treating patients on DOACs who experience trauma or stroke, as well as those who require emergency/urgent surgery. And the ability to identify the type of anticoagulant a patient is taking can guide the reversal strategy.
Fowzia Zaman, PhD, of Haemonetics Corporation in Rosemont, Illinois, described the assay at the 2015 AABB Annual Meeting (abstract S60-030K). Haemonetics is the company developing the assay, and this research was supported by the company.
About the assay
“The current coagulation assays are not very sensitive to DOACs, especially in the therapeutic range,” Dr Zaman said. “Right now, there is no assay available that can classify the DOACs. This new assay can both detect and classify, and it will classify the DOACs either as a DTI or an anti-Xa.”
The assay is performed using Haemonetics’ TEG 6s system, a fully automated system for evaluating anticoagulation in a patient. It is based on viscoelasticity measurements using resonance frequency and disposable microfluidic cartridges. Each cartridge has 4 channels, and 2 of the channels are used for detection and classification.
Detection is performed using a factor Xa-based reagent, and classification utilizes an Ecarin-based reagent. All of the reagents are contained within the channel, so there is no reagent preparation required.
Each cartridge is loaded into the unit, and citrated whole blood is added, either with a transfer pipette or a syringe, to start the assay.
Reaction time (R-time) is used for detection and classification. R is defined as the time from the start of the sample run to the point of clot formation. It corresponds to an amplitude of 2 mm on the TEG tracing. It represents the initial enzymatic phase of clotting, and it is recorded in minutes.
Study population
The researchers tested the assay in 26 healthy subjects, 25 patients on DTI (all dabigatran), and 40 on anti-Xa therapy (24 on rivaroxaban, 16 on apixaban).
For healthy subjects, the mean age was 41±13, and 46% of subjects are male. Forty-six percent are Caucasian, 39% are African American, and 15% are Asian/“other”. The partial thromboplastin time (PTT) for these subjects was within the normal range, at 27.2±1.8 seconds.
In the DOAC population, the mean age was 68±12 for the anti-Xa group and 69±10 for the DTI group. Fifty percent and 72%, respectively, are male. And 50% and 64%, respectively, are Caucasian.
Most of the patients receiving DOACs were taking them for atrial fibrillation—88% in the anti-Xa group and 84% in the DTI group. Other underlying conditions were coronary artery disease—28% and 32%, respectively—and hypertension—60% and 64%, respectively.
Some patients were taking aspirin in addition to DOACs—30% in the anti-Xa group and 24% in the DTI group. And some were taking P2Y12 inhibitors—20% in the anti-Xa group and 24% in the DTI group.
The PTT was 30.4±4.6 seconds for the anti-Xa group and 36.6±7 seconds for the DTI group. Creatinine levels were 1.07±0.6 mg/dL and 1.05±0.2 mg/dL, respectively.
Assay results
The researchers analyzed citrated whole blood from the healthy volunteers to establish the baseline reference range. The cutoff for detection was 1.95 minutes, and the cutoff for classification was 1.9 minutes.
“What this means is that a person who does not have DOAC in their system should have an R-time of less than or equal to 1.95 minutes,” Dr Zaman explained.
The researchers also developed an algorithm for the detection and classification of DOACs. According to this algorithm, healthy subjects would have a short R-time in the detection channel and the classification channel.
Patients on anti-Xa would have a long R-time in the detection channel but a short R-time in the classification channel. And patients on a DTI would have a long R-time in both the detection channel and the classification channel.
The researchers found that, in the detection channel, on average, R-time was increased 66% for dabigatran, 125% for rivaroxaban, and 100% for apixaban, compared to the reference range. But the degree of elongation was dependent on the individual patient and the time from last DOAC dosage.
Using a cutoff of 2 minutes, the detection channel demonstrated 94% sensitivity and 96% specificity for all the DOACs combined.
“What this means is that, when a patient had a DOAC in their system, the assay was able to pick it up 94% of the time,” Dr Zaman explained.
In addition, the assay detected dabigatran correctly 100% of the time and anti-Xa therapy correctly 92% of the time.
“This TEG 6s DOAC assay is highly sensitive and specific for detecting and classifying DOACs,” Dr Zaman said in closing. “[T]he cutoffs for both the channels are close to 2 minutes, which means clinically relevant results are available within 5 minutes.”
“There is no reagent prep necessary, and it utilizes whole blood, so [there is] no spinning down to plasma. Therefore, it has the potential to be a point-of-care assay.”
Photo by Juan D. Alfonso
ANAHEIM, CA—A new assay can detect and classify direct oral anticoagulants (DOACs) quickly and effectively, according to researchers.
In tests, the assay detected DOACs with greater than 90% sensitivity and specificity.
The assay classified the direct thrombin inhibitor (DTI) dabigatran correctly 100% of the time and classified factor Xa inhibitors (anti-Xa), which included rivaroxaban and apixaban, correctly 92% of the time.
The researchers believe this assay has the potential to be an effective tool for treating patients on DOACs who experience trauma or stroke, as well as those who require emergency/urgent surgery. And the ability to identify the type of anticoagulant a patient is taking can guide the reversal strategy.
Fowzia Zaman, PhD, of Haemonetics Corporation in Rosemont, Illinois, described the assay at the 2015 AABB Annual Meeting (abstract S60-030K). Haemonetics is the company developing the assay, and this research was supported by the company.
About the assay
“The current coagulation assays are not very sensitive to DOACs, especially in the therapeutic range,” Dr Zaman said. “Right now, there is no assay available that can classify the DOACs. This new assay can both detect and classify, and it will classify the DOACs either as a DTI or an anti-Xa.”
The assay is performed using Haemonetics’ TEG 6s system, a fully automated system for evaluating anticoagulation in a patient. It is based on viscoelasticity measurements using resonance frequency and disposable microfluidic cartridges. Each cartridge has 4 channels, and 2 of the channels are used for detection and classification.
Detection is performed using a factor Xa-based reagent, and classification utilizes an Ecarin-based reagent. All of the reagents are contained within the channel, so there is no reagent preparation required.
Each cartridge is loaded into the unit, and citrated whole blood is added, either with a transfer pipette or a syringe, to start the assay.
Reaction time (R-time) is used for detection and classification. R is defined as the time from the start of the sample run to the point of clot formation. It corresponds to an amplitude of 2 mm on the TEG tracing. It represents the initial enzymatic phase of clotting, and it is recorded in minutes.
Study population
The researchers tested the assay in 26 healthy subjects, 25 patients on DTI (all dabigatran), and 40 on anti-Xa therapy (24 on rivaroxaban, 16 on apixaban).
For healthy subjects, the mean age was 41±13, and 46% of subjects are male. Forty-six percent are Caucasian, 39% are African American, and 15% are Asian/“other”. The partial thromboplastin time (PTT) for these subjects was within the normal range, at 27.2±1.8 seconds.
In the DOAC population, the mean age was 68±12 for the anti-Xa group and 69±10 for the DTI group. Fifty percent and 72%, respectively, are male. And 50% and 64%, respectively, are Caucasian.
Most of the patients receiving DOACs were taking them for atrial fibrillation—88% in the anti-Xa group and 84% in the DTI group. Other underlying conditions were coronary artery disease—28% and 32%, respectively—and hypertension—60% and 64%, respectively.
Some patients were taking aspirin in addition to DOACs—30% in the anti-Xa group and 24% in the DTI group. And some were taking P2Y12 inhibitors—20% in the anti-Xa group and 24% in the DTI group.
The PTT was 30.4±4.6 seconds for the anti-Xa group and 36.6±7 seconds for the DTI group. Creatinine levels were 1.07±0.6 mg/dL and 1.05±0.2 mg/dL, respectively.
Assay results
The researchers analyzed citrated whole blood from the healthy volunteers to establish the baseline reference range. The cutoff for detection was 1.95 minutes, and the cutoff for classification was 1.9 minutes.
“What this means is that a person who does not have DOAC in their system should have an R-time of less than or equal to 1.95 minutes,” Dr Zaman explained.
The researchers also developed an algorithm for the detection and classification of DOACs. According to this algorithm, healthy subjects would have a short R-time in the detection channel and the classification channel.
Patients on anti-Xa would have a long R-time in the detection channel but a short R-time in the classification channel. And patients on a DTI would have a long R-time in both the detection channel and the classification channel.
The researchers found that, in the detection channel, on average, R-time was increased 66% for dabigatran, 125% for rivaroxaban, and 100% for apixaban, compared to the reference range. But the degree of elongation was dependent on the individual patient and the time from last DOAC dosage.
Using a cutoff of 2 minutes, the detection channel demonstrated 94% sensitivity and 96% specificity for all the DOACs combined.
“What this means is that, when a patient had a DOAC in their system, the assay was able to pick it up 94% of the time,” Dr Zaman explained.
In addition, the assay detected dabigatran correctly 100% of the time and anti-Xa therapy correctly 92% of the time.
“This TEG 6s DOAC assay is highly sensitive and specific for detecting and classifying DOACs,” Dr Zaman said in closing. “[T]he cutoffs for both the channels are close to 2 minutes, which means clinically relevant results are available within 5 minutes.”
“There is no reagent prep necessary, and it utilizes whole blood, so [there is] no spinning down to plasma. Therefore, it has the potential to be a point-of-care assay.”
Photo by Juan D. Alfonso
ANAHEIM, CA—A new assay can detect and classify direct oral anticoagulants (DOACs) quickly and effectively, according to researchers.
In tests, the assay detected DOACs with greater than 90% sensitivity and specificity.
The assay classified the direct thrombin inhibitor (DTI) dabigatran correctly 100% of the time and classified factor Xa inhibitors (anti-Xa), which included rivaroxaban and apixaban, correctly 92% of the time.
The researchers believe this assay has the potential to be an effective tool for treating patients on DOACs who experience trauma or stroke, as well as those who require emergency/urgent surgery. And the ability to identify the type of anticoagulant a patient is taking can guide the reversal strategy.
Fowzia Zaman, PhD, of Haemonetics Corporation in Rosemont, Illinois, described the assay at the 2015 AABB Annual Meeting (abstract S60-030K). Haemonetics is the company developing the assay, and this research was supported by the company.
About the assay
“The current coagulation assays are not very sensitive to DOACs, especially in the therapeutic range,” Dr Zaman said. “Right now, there is no assay available that can classify the DOACs. This new assay can both detect and classify, and it will classify the DOACs either as a DTI or an anti-Xa.”
The assay is performed using Haemonetics’ TEG 6s system, a fully automated system for evaluating anticoagulation in a patient. It is based on viscoelasticity measurements using resonance frequency and disposable microfluidic cartridges. Each cartridge has 4 channels, and 2 of the channels are used for detection and classification.
Detection is performed using a factor Xa-based reagent, and classification utilizes an Ecarin-based reagent. All of the reagents are contained within the channel, so there is no reagent preparation required.
Each cartridge is loaded into the unit, and citrated whole blood is added, either with a transfer pipette or a syringe, to start the assay.
Reaction time (R-time) is used for detection and classification. R is defined as the time from the start of the sample run to the point of clot formation. It corresponds to an amplitude of 2 mm on the TEG tracing. It represents the initial enzymatic phase of clotting, and it is recorded in minutes.
Study population
The researchers tested the assay in 26 healthy subjects, 25 patients on DTI (all dabigatran), and 40 on anti-Xa therapy (24 on rivaroxaban, 16 on apixaban).
For healthy subjects, the mean age was 41±13, and 46% of subjects are male. Forty-six percent are Caucasian, 39% are African American, and 15% are Asian/“other”. The partial thromboplastin time (PTT) for these subjects was within the normal range, at 27.2±1.8 seconds.
In the DOAC population, the mean age was 68±12 for the anti-Xa group and 69±10 for the DTI group. Fifty percent and 72%, respectively, are male. And 50% and 64%, respectively, are Caucasian.
Most of the patients receiving DOACs were taking them for atrial fibrillation—88% in the anti-Xa group and 84% in the DTI group. Other underlying conditions were coronary artery disease—28% and 32%, respectively—and hypertension—60% and 64%, respectively.
Some patients were taking aspirin in addition to DOACs—30% in the anti-Xa group and 24% in the DTI group. And some were taking P2Y12 inhibitors—20% in the anti-Xa group and 24% in the DTI group.
The PTT was 30.4±4.6 seconds for the anti-Xa group and 36.6±7 seconds for the DTI group. Creatinine levels were 1.07±0.6 mg/dL and 1.05±0.2 mg/dL, respectively.
Assay results
The researchers analyzed citrated whole blood from the healthy volunteers to establish the baseline reference range. The cutoff for detection was 1.95 minutes, and the cutoff for classification was 1.9 minutes.
“What this means is that a person who does not have DOAC in their system should have an R-time of less than or equal to 1.95 minutes,” Dr Zaman explained.
The researchers also developed an algorithm for the detection and classification of DOACs. According to this algorithm, healthy subjects would have a short R-time in the detection channel and the classification channel.
Patients on anti-Xa would have a long R-time in the detection channel but a short R-time in the classification channel. And patients on a DTI would have a long R-time in both the detection channel and the classification channel.
The researchers found that, in the detection channel, on average, R-time was increased 66% for dabigatran, 125% for rivaroxaban, and 100% for apixaban, compared to the reference range. But the degree of elongation was dependent on the individual patient and the time from last DOAC dosage.
Using a cutoff of 2 minutes, the detection channel demonstrated 94% sensitivity and 96% specificity for all the DOACs combined.
“What this means is that, when a patient had a DOAC in their system, the assay was able to pick it up 94% of the time,” Dr Zaman explained.
In addition, the assay detected dabigatran correctly 100% of the time and anti-Xa therapy correctly 92% of the time.
“This TEG 6s DOAC assay is highly sensitive and specific for detecting and classifying DOACs,” Dr Zaman said in closing. “[T]he cutoffs for both the channels are close to 2 minutes, which means clinically relevant results are available within 5 minutes.”
“There is no reagent prep necessary, and it utilizes whole blood, so [there is] no spinning down to plasma. Therefore, it has the potential to be a point-of-care assay.”
MM-related ESRD on the decline
Photo by Anna Frodesiak
New research suggests the risk of end-stage renal disease (ESRD) caused by multiple myeloma (MM) is declining, and survival is lengthening for patients who do develop ESRD due to MM.
Researchers said these findings are encouraging, but efforts are still needed to develop effective MM treatments with fewer side effects.
They noted that MM treatment has changed substantially in the last decade.
But it hasn’t been clear whether the burden of ESRD due to MM has changed or whether survival has improved for patients with ESRD due to MM.
To gain some insight, Robert Foley, MD, of the University of Minnesota in Minneapolis, and his colleagues examined data from the US Renal Data System database spanning the period from 2001 to 2010.
They reported their findings in the Journal of the American Society of Nephrology.
The team found that, of the 1,069,343 patients with ESRD who were on renal replacement therapy (RRT), 12,703 had developed ESRD due to MM.
However, the incidence of ESRD from MM decreased from 2001 to 2010. Compared to 2001-2002 (1.00), the standardized incidence ratios of ESRD due to MM were 0.96 for 2003-2004 (P<0.05), 0.99 for 2005-2006 (P>0.05), 0.89 for 2007-2008 (P<0.001), and 0.82 for 2009-2010 (P<0.001).
The demography-adjusted incidence ratio for ESRD due to MM decreased (P<0.05) between 2001-2002 and 2009-2010 in the overall population and in most of the subgroups examined.
The exceptions were patients younger than 40, Hispanic patients, and those belonging to the “other” race category. (The race categories were “white,” “black,” and “other,” while the ethnicity categories were “Hispanic” and “non-Hispanic.”)
The data also showed improvements in survival over time among patients with ESRD due to MM.
Compared to 2001-2002, the adjusted hazard ratios (AHRs) for death were 1.02 for 2003-2004 (P=0.5), 0.93 for 2005-2006 (P=0.02), 0.86 for 2007-2008 (P<0.001), and 0.74 for 2009-2010 (P<0.001). (This analysis was adjusted for age, sex, race, ethnicity, ischemic heart disease, diabetes, mode of RRT, estimated glomerular filtration rate, body mass index, serum albumin, and hemoglobin.)
AHRs for death were highest in the first year after RRT initiation (AHR=2.6; P<0.001) and decreased in year 3 (AHR=1.59; P<0.001).
The AHR for death in patients with ESRD due to MM compared to those with ESRD due to all other causes was 2.05 (P<0.001).
“Myeloma is the commonest malignancy leading to kidney failure,” Dr Foley said. “It’s encouraging that we found that kidney failure due to multiple myeloma declined considerably over the last decade.”
Photo by Anna Frodesiak
New research suggests the risk of end-stage renal disease (ESRD) caused by multiple myeloma (MM) is declining, and survival is lengthening for patients who do develop ESRD due to MM.
Researchers said these findings are encouraging, but efforts are still needed to develop effective MM treatments with fewer side effects.
They noted that MM treatment has changed substantially in the last decade.
But it hasn’t been clear whether the burden of ESRD due to MM has changed or whether survival has improved for patients with ESRD due to MM.
To gain some insight, Robert Foley, MD, of the University of Minnesota in Minneapolis, and his colleagues examined data from the US Renal Data System database spanning the period from 2001 to 2010.
They reported their findings in the Journal of the American Society of Nephrology.
The team found that, of the 1,069,343 patients with ESRD who were on renal replacement therapy (RRT), 12,703 had developed ESRD due to MM.
However, the incidence of ESRD from MM decreased from 2001 to 2010. Compared to 2001-2002 (1.00), the standardized incidence ratios of ESRD due to MM were 0.96 for 2003-2004 (P<0.05), 0.99 for 2005-2006 (P>0.05), 0.89 for 2007-2008 (P<0.001), and 0.82 for 2009-2010 (P<0.001).
The demography-adjusted incidence ratio for ESRD due to MM decreased (P<0.05) between 2001-2002 and 2009-2010 in the overall population and in most of the subgroups examined.
The exceptions were patients younger than 40, Hispanic patients, and those belonging to the “other” race category. (The race categories were “white,” “black,” and “other,” while the ethnicity categories were “Hispanic” and “non-Hispanic.”)
The data also showed improvements in survival over time among patients with ESRD due to MM.
Compared to 2001-2002, the adjusted hazard ratios (AHRs) for death were 1.02 for 2003-2004 (P=0.5), 0.93 for 2005-2006 (P=0.02), 0.86 for 2007-2008 (P<0.001), and 0.74 for 2009-2010 (P<0.001). (This analysis was adjusted for age, sex, race, ethnicity, ischemic heart disease, diabetes, mode of RRT, estimated glomerular filtration rate, body mass index, serum albumin, and hemoglobin.)
AHRs for death were highest in the first year after RRT initiation (AHR=2.6; P<0.001) and decreased in year 3 (AHR=1.59; P<0.001).
The AHR for death in patients with ESRD due to MM compared to those with ESRD due to all other causes was 2.05 (P<0.001).
“Myeloma is the commonest malignancy leading to kidney failure,” Dr Foley said. “It’s encouraging that we found that kidney failure due to multiple myeloma declined considerably over the last decade.”
Photo by Anna Frodesiak
New research suggests the risk of end-stage renal disease (ESRD) caused by multiple myeloma (MM) is declining, and survival is lengthening for patients who do develop ESRD due to MM.
Researchers said these findings are encouraging, but efforts are still needed to develop effective MM treatments with fewer side effects.
They noted that MM treatment has changed substantially in the last decade.
But it hasn’t been clear whether the burden of ESRD due to MM has changed or whether survival has improved for patients with ESRD due to MM.
To gain some insight, Robert Foley, MD, of the University of Minnesota in Minneapolis, and his colleagues examined data from the US Renal Data System database spanning the period from 2001 to 2010.
They reported their findings in the Journal of the American Society of Nephrology.
The team found that, of the 1,069,343 patients with ESRD who were on renal replacement therapy (RRT), 12,703 had developed ESRD due to MM.
However, the incidence of ESRD from MM decreased from 2001 to 2010. Compared to 2001-2002 (1.00), the standardized incidence ratios of ESRD due to MM were 0.96 for 2003-2004 (P<0.05), 0.99 for 2005-2006 (P>0.05), 0.89 for 2007-2008 (P<0.001), and 0.82 for 2009-2010 (P<0.001).
The demography-adjusted incidence ratio for ESRD due to MM decreased (P<0.05) between 2001-2002 and 2009-2010 in the overall population and in most of the subgroups examined.
The exceptions were patients younger than 40, Hispanic patients, and those belonging to the “other” race category. (The race categories were “white,” “black,” and “other,” while the ethnicity categories were “Hispanic” and “non-Hispanic.”)
The data also showed improvements in survival over time among patients with ESRD due to MM.
Compared to 2001-2002, the adjusted hazard ratios (AHRs) for death were 1.02 for 2003-2004 (P=0.5), 0.93 for 2005-2006 (P=0.02), 0.86 for 2007-2008 (P<0.001), and 0.74 for 2009-2010 (P<0.001). (This analysis was adjusted for age, sex, race, ethnicity, ischemic heart disease, diabetes, mode of RRT, estimated glomerular filtration rate, body mass index, serum albumin, and hemoglobin.)
AHRs for death were highest in the first year after RRT initiation (AHR=2.6; P<0.001) and decreased in year 3 (AHR=1.59; P<0.001).
The AHR for death in patients with ESRD due to MM compared to those with ESRD due to all other causes was 2.05 (P<0.001).
“Myeloma is the commonest malignancy leading to kidney failure,” Dr Foley said. “It’s encouraging that we found that kidney failure due to multiple myeloma declined considerably over the last decade.”
Reprogramming the immune system
showing Hodgkin lymphoma
NEW YORK—Using a 3-pronged approach to reprogram the immune system—inhibition of critical pathways, activation of others, and depletion of malignant cells—may be the best strategy to optimize immune function in B-cell lymphomas, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“[A]ll told, there are multiple immunological barriers to an effective immune response,” Dr Ansell said at Lymphoma & Myeloma 2015.
“So the questions are how can you use an immune checkpoint approach to try and modulate this and improve the outcome.”
Dr Ansell discussed checkpoint inhibitors, immune signal activators, and the potential of combining the approaches in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in a way that enhances rather than antagonizes their effects.
Blocking CTLA-4
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) functions as an immune checkpoint that downregulates the immune system. A receptor found on the surface of inhibitor T cells, it acts as an off switch when it binds to CD80 or CD86 on the surface of antigen-presenting cells.
Ipilimumab, an antibody that targets CTLA-4, has been approved by the US Food and Drug Administration for the treatment of melanoma and is in clinical trials for lung, bladder, and prostate cancer.
Investigators wanted to see whether it also works in lymphoma, so they conducted a phase 1 study in relapsed/refractory B-cell NHL.
Eighteen patients received 3 mg/kg of ipilimumab. Two patients responded, 1 with a complete response (CR) that lasted more than 31 months, and 1 with a partial response (PR) that lasted 19 months. In 5 of 16 patients (31%), T-cell proliferation to recall antigens increased more than 2-fold.
As Dr Ansell explained, “Immune response doesn’t always correlate directly with the clinical responses. So I think we really have a lot to learn about what is really a biomarker of efficacy.”
Ipilimumab was also evaluated to treat relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in 29 patients with relapsed hematologic disease. Two patients with HL achieved a CR and 1 patient with mantle cell lymphoma achieved a PR.
The investigators observed that ipilimumab did not induce or exacerbate clinical graft-versus-host disease.
Blocking PD-1
Programmed cell death protein 1 (PD-1) is a surface receptor expressed on T cells and pro-B cells. PD-1 binds 2 ligands, PD-L1 and PD-L2.
PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response through PD-1 on immune effector cells. In addition, PD-L1 expressed on malignant cells or in the tumor microenvironment suppresses tumor-infiltrating lymphocyte activity.
Pidilizumab, a humanized monoclonal antibody that binds to PD-1, weakens the apoptotic processes in lymphocytes and augments the antitumor activities of NK cells.
Investigators conducted a phase 2 trial of pidilizumab in patients with diffuse large B-cell lymphoma (DLBCL) after autologous HSCT to modulate the immune system after a transplant.
The team treated 66 patients with the antibody. At 16 months, progression-free survival (PFS) was 72%. For the 24 high-risk patients who were PET-positive after salvage chemotherapy, the 16-month PFS was 70%.
“And I think that what was most interesting,” Dr Ansell said, when focusing on the 35 patients with measurable disease after transplant, pidilizumab produced a 51% response rate “even in patients that actually had active disease.”
When pidilizumab was combined with rituximab in another trial in patients with relapsed follicular lymphoma (FL), 19 of 29 evaluable patients (66%) achieved an objective response: 15 (52%) CRs and 4 (14%) PRs.
“You might say, ‘Who cares? That’s not that great,’” Dr Ansell said. “But I think what was pretty impressive is that 52% CR rate. And most of you who treat patients with rituximab would know that that’s quite surprising, suggesting that there may be additional benefit for the use of PD-1 blockade in this subset of patients.”
Nivolumab, another monoclonal antibody that blocks the PD-1 pathway, is being investigated in a number of lymphoid malignancies, including HL, DLBCL, and T-cell lymphomas.
In a phase 1 study of nivolumab in 81 patients with relapsed or refractory lymphoid malignancies, the best preliminary overall response has been in FL and DLBCL patients, with an objective response rate of 40% and 36%, respectively, including 1 PR and 3 PRs in each subtype.
“I think what is important,” Dr Ansell said, “is that the side effects, as expected, were mainly immune-mediated, not as dramatic as have been seen with other agents, and very similar to what has been seen in solid tumor studies.”
Dr Ansell pointed out that the response rates with nivolumab varied widely by histology, suggesting that “we have a lot to learn about why patients benefit and who exactly benefits.”
There were no responses in patients with multiple myeloma or primary mediastinal B-cell lymphoma, although many patients achieved stable disease.
“Hodgkin lymphoma was completely different,” Dr Ansell said, “and there were responses in virtually every patient.”
Of 23 patients treated with nivolumab, 20 responded—4 achieved a CR and 16 a PR—including patients who had failed autologous HSCT and brentuximab vedotin treatment. Eleven patients, including 2 with CRs, have an ongoing response, some approaching 2 years. So the responses have been durable, Dr Ansell noted.
Yet another PD-1 antibody, pembrolizumab, has prompted reduction in tumor burden in HL in all but 2 of 29 evaluable patients, including 6 CRs and 13 PRs. The median duration of response has not yet been reached, and the side effect profile was similar to what has been seen with nivolumab and in solid tumors.
Activating immune stimulatory signals
Another approach to boosting the immune system is to activate immune stimulatory signals, eg, CD27 and CD40, and get a benefit that way. Varlilumab (CDX-1127) is an unconjugated monoclonal antibody that binds CD27 and activates CD27-expressing T cells.
In a phase 1 trial of varlilumab in 24 lymphoma patients, investigators found no significant depletion in absolute lymphocyte counts, T cells, or B cells. “Not quite the same success story,” Dr Ansell said, with a response—a CR—in only 1 patient.
Investigators did observe, however, evidence of increased soluble CD27, a reduction of circulating Tregs, and the induction of pro-inflammatory cytokines.
And in a phase 1 study of the anti-CD40 monoclonal antibody dacetuzumab in recurrent NHL, “the response rate was disappointingly low,” Dr Ansell said.
Investigators observed 6 objective responses, including 1 CR and 5 PRs, and a decrease in tumor size in approximately one-third of the 50 patients treated.
The investigators of the subsequent phase 2 trial did not want to take the agent forward for further study, Dr Ansell noted, “but there are antibodies now being developed in this space that will hopefully be more effective and create a greater benefit.”
Optimizing immune function
Dr Ansell suggested there are 3 main approaches to treating patients. One is going directly after the malignant cells and depleting them. A second is to inhibit critical pathways that the malignant cell is dependent upon, “starving them, if you like.” The third way is to activate the immune system and thereby create a greater benefit for patients.
“[P]robably our best strategy is to use all 3 in a reprogram approach,” he said. “Because unless you target each one of these areas, the likelihood is that the other sides of the 3-legged stool will take over.”
“This is an encouraging and exciting time for immune checkpoints therapy and an encouraging and exciting time for immune therapies in general. I think this is really the new frontier in lymphomas.”
showing Hodgkin lymphoma
NEW YORK—Using a 3-pronged approach to reprogram the immune system—inhibition of critical pathways, activation of others, and depletion of malignant cells—may be the best strategy to optimize immune function in B-cell lymphomas, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“[A]ll told, there are multiple immunological barriers to an effective immune response,” Dr Ansell said at Lymphoma & Myeloma 2015.
“So the questions are how can you use an immune checkpoint approach to try and modulate this and improve the outcome.”
Dr Ansell discussed checkpoint inhibitors, immune signal activators, and the potential of combining the approaches in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in a way that enhances rather than antagonizes their effects.
Blocking CTLA-4
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) functions as an immune checkpoint that downregulates the immune system. A receptor found on the surface of inhibitor T cells, it acts as an off switch when it binds to CD80 or CD86 on the surface of antigen-presenting cells.
Ipilimumab, an antibody that targets CTLA-4, has been approved by the US Food and Drug Administration for the treatment of melanoma and is in clinical trials for lung, bladder, and prostate cancer.
Investigators wanted to see whether it also works in lymphoma, so they conducted a phase 1 study in relapsed/refractory B-cell NHL.
Eighteen patients received 3 mg/kg of ipilimumab. Two patients responded, 1 with a complete response (CR) that lasted more than 31 months, and 1 with a partial response (PR) that lasted 19 months. In 5 of 16 patients (31%), T-cell proliferation to recall antigens increased more than 2-fold.
As Dr Ansell explained, “Immune response doesn’t always correlate directly with the clinical responses. So I think we really have a lot to learn about what is really a biomarker of efficacy.”
Ipilimumab was also evaluated to treat relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in 29 patients with relapsed hematologic disease. Two patients with HL achieved a CR and 1 patient with mantle cell lymphoma achieved a PR.
The investigators observed that ipilimumab did not induce or exacerbate clinical graft-versus-host disease.
Blocking PD-1
Programmed cell death protein 1 (PD-1) is a surface receptor expressed on T cells and pro-B cells. PD-1 binds 2 ligands, PD-L1 and PD-L2.
PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response through PD-1 on immune effector cells. In addition, PD-L1 expressed on malignant cells or in the tumor microenvironment suppresses tumor-infiltrating lymphocyte activity.
Pidilizumab, a humanized monoclonal antibody that binds to PD-1, weakens the apoptotic processes in lymphocytes and augments the antitumor activities of NK cells.
Investigators conducted a phase 2 trial of pidilizumab in patients with diffuse large B-cell lymphoma (DLBCL) after autologous HSCT to modulate the immune system after a transplant.
The team treated 66 patients with the antibody. At 16 months, progression-free survival (PFS) was 72%. For the 24 high-risk patients who were PET-positive after salvage chemotherapy, the 16-month PFS was 70%.
“And I think that what was most interesting,” Dr Ansell said, when focusing on the 35 patients with measurable disease after transplant, pidilizumab produced a 51% response rate “even in patients that actually had active disease.”
When pidilizumab was combined with rituximab in another trial in patients with relapsed follicular lymphoma (FL), 19 of 29 evaluable patients (66%) achieved an objective response: 15 (52%) CRs and 4 (14%) PRs.
“You might say, ‘Who cares? That’s not that great,’” Dr Ansell said. “But I think what was pretty impressive is that 52% CR rate. And most of you who treat patients with rituximab would know that that’s quite surprising, suggesting that there may be additional benefit for the use of PD-1 blockade in this subset of patients.”
Nivolumab, another monoclonal antibody that blocks the PD-1 pathway, is being investigated in a number of lymphoid malignancies, including HL, DLBCL, and T-cell lymphomas.
In a phase 1 study of nivolumab in 81 patients with relapsed or refractory lymphoid malignancies, the best preliminary overall response has been in FL and DLBCL patients, with an objective response rate of 40% and 36%, respectively, including 1 PR and 3 PRs in each subtype.
“I think what is important,” Dr Ansell said, “is that the side effects, as expected, were mainly immune-mediated, not as dramatic as have been seen with other agents, and very similar to what has been seen in solid tumor studies.”
Dr Ansell pointed out that the response rates with nivolumab varied widely by histology, suggesting that “we have a lot to learn about why patients benefit and who exactly benefits.”
There were no responses in patients with multiple myeloma or primary mediastinal B-cell lymphoma, although many patients achieved stable disease.
“Hodgkin lymphoma was completely different,” Dr Ansell said, “and there were responses in virtually every patient.”
Of 23 patients treated with nivolumab, 20 responded—4 achieved a CR and 16 a PR—including patients who had failed autologous HSCT and brentuximab vedotin treatment. Eleven patients, including 2 with CRs, have an ongoing response, some approaching 2 years. So the responses have been durable, Dr Ansell noted.
Yet another PD-1 antibody, pembrolizumab, has prompted reduction in tumor burden in HL in all but 2 of 29 evaluable patients, including 6 CRs and 13 PRs. The median duration of response has not yet been reached, and the side effect profile was similar to what has been seen with nivolumab and in solid tumors.
Activating immune stimulatory signals
Another approach to boosting the immune system is to activate immune stimulatory signals, eg, CD27 and CD40, and get a benefit that way. Varlilumab (CDX-1127) is an unconjugated monoclonal antibody that binds CD27 and activates CD27-expressing T cells.
In a phase 1 trial of varlilumab in 24 lymphoma patients, investigators found no significant depletion in absolute lymphocyte counts, T cells, or B cells. “Not quite the same success story,” Dr Ansell said, with a response—a CR—in only 1 patient.
Investigators did observe, however, evidence of increased soluble CD27, a reduction of circulating Tregs, and the induction of pro-inflammatory cytokines.
And in a phase 1 study of the anti-CD40 monoclonal antibody dacetuzumab in recurrent NHL, “the response rate was disappointingly low,” Dr Ansell said.
Investigators observed 6 objective responses, including 1 CR and 5 PRs, and a decrease in tumor size in approximately one-third of the 50 patients treated.
The investigators of the subsequent phase 2 trial did not want to take the agent forward for further study, Dr Ansell noted, “but there are antibodies now being developed in this space that will hopefully be more effective and create a greater benefit.”
Optimizing immune function
Dr Ansell suggested there are 3 main approaches to treating patients. One is going directly after the malignant cells and depleting them. A second is to inhibit critical pathways that the malignant cell is dependent upon, “starving them, if you like.” The third way is to activate the immune system and thereby create a greater benefit for patients.
“[P]robably our best strategy is to use all 3 in a reprogram approach,” he said. “Because unless you target each one of these areas, the likelihood is that the other sides of the 3-legged stool will take over.”
“This is an encouraging and exciting time for immune checkpoints therapy and an encouraging and exciting time for immune therapies in general. I think this is really the new frontier in lymphomas.”
showing Hodgkin lymphoma
NEW YORK—Using a 3-pronged approach to reprogram the immune system—inhibition of critical pathways, activation of others, and depletion of malignant cells—may be the best strategy to optimize immune function in B-cell lymphomas, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“[A]ll told, there are multiple immunological barriers to an effective immune response,” Dr Ansell said at Lymphoma & Myeloma 2015.
“So the questions are how can you use an immune checkpoint approach to try and modulate this and improve the outcome.”
Dr Ansell discussed checkpoint inhibitors, immune signal activators, and the potential of combining the approaches in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in a way that enhances rather than antagonizes their effects.
Blocking CTLA-4
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) functions as an immune checkpoint that downregulates the immune system. A receptor found on the surface of inhibitor T cells, it acts as an off switch when it binds to CD80 or CD86 on the surface of antigen-presenting cells.
Ipilimumab, an antibody that targets CTLA-4, has been approved by the US Food and Drug Administration for the treatment of melanoma and is in clinical trials for lung, bladder, and prostate cancer.
Investigators wanted to see whether it also works in lymphoma, so they conducted a phase 1 study in relapsed/refractory B-cell NHL.
Eighteen patients received 3 mg/kg of ipilimumab. Two patients responded, 1 with a complete response (CR) that lasted more than 31 months, and 1 with a partial response (PR) that lasted 19 months. In 5 of 16 patients (31%), T-cell proliferation to recall antigens increased more than 2-fold.
As Dr Ansell explained, “Immune response doesn’t always correlate directly with the clinical responses. So I think we really have a lot to learn about what is really a biomarker of efficacy.”
Ipilimumab was also evaluated to treat relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in 29 patients with relapsed hematologic disease. Two patients with HL achieved a CR and 1 patient with mantle cell lymphoma achieved a PR.
The investigators observed that ipilimumab did not induce or exacerbate clinical graft-versus-host disease.
Blocking PD-1
Programmed cell death protein 1 (PD-1) is a surface receptor expressed on T cells and pro-B cells. PD-1 binds 2 ligands, PD-L1 and PD-L2.
PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response through PD-1 on immune effector cells. In addition, PD-L1 expressed on malignant cells or in the tumor microenvironment suppresses tumor-infiltrating lymphocyte activity.
Pidilizumab, a humanized monoclonal antibody that binds to PD-1, weakens the apoptotic processes in lymphocytes and augments the antitumor activities of NK cells.
Investigators conducted a phase 2 trial of pidilizumab in patients with diffuse large B-cell lymphoma (DLBCL) after autologous HSCT to modulate the immune system after a transplant.
The team treated 66 patients with the antibody. At 16 months, progression-free survival (PFS) was 72%. For the 24 high-risk patients who were PET-positive after salvage chemotherapy, the 16-month PFS was 70%.
“And I think that what was most interesting,” Dr Ansell said, when focusing on the 35 patients with measurable disease after transplant, pidilizumab produced a 51% response rate “even in patients that actually had active disease.”
When pidilizumab was combined with rituximab in another trial in patients with relapsed follicular lymphoma (FL), 19 of 29 evaluable patients (66%) achieved an objective response: 15 (52%) CRs and 4 (14%) PRs.
“You might say, ‘Who cares? That’s not that great,’” Dr Ansell said. “But I think what was pretty impressive is that 52% CR rate. And most of you who treat patients with rituximab would know that that’s quite surprising, suggesting that there may be additional benefit for the use of PD-1 blockade in this subset of patients.”
Nivolumab, another monoclonal antibody that blocks the PD-1 pathway, is being investigated in a number of lymphoid malignancies, including HL, DLBCL, and T-cell lymphomas.
In a phase 1 study of nivolumab in 81 patients with relapsed or refractory lymphoid malignancies, the best preliminary overall response has been in FL and DLBCL patients, with an objective response rate of 40% and 36%, respectively, including 1 PR and 3 PRs in each subtype.
“I think what is important,” Dr Ansell said, “is that the side effects, as expected, were mainly immune-mediated, not as dramatic as have been seen with other agents, and very similar to what has been seen in solid tumor studies.”
Dr Ansell pointed out that the response rates with nivolumab varied widely by histology, suggesting that “we have a lot to learn about why patients benefit and who exactly benefits.”
There were no responses in patients with multiple myeloma or primary mediastinal B-cell lymphoma, although many patients achieved stable disease.
“Hodgkin lymphoma was completely different,” Dr Ansell said, “and there were responses in virtually every patient.”
Of 23 patients treated with nivolumab, 20 responded—4 achieved a CR and 16 a PR—including patients who had failed autologous HSCT and brentuximab vedotin treatment. Eleven patients, including 2 with CRs, have an ongoing response, some approaching 2 years. So the responses have been durable, Dr Ansell noted.
Yet another PD-1 antibody, pembrolizumab, has prompted reduction in tumor burden in HL in all but 2 of 29 evaluable patients, including 6 CRs and 13 PRs. The median duration of response has not yet been reached, and the side effect profile was similar to what has been seen with nivolumab and in solid tumors.
Activating immune stimulatory signals
Another approach to boosting the immune system is to activate immune stimulatory signals, eg, CD27 and CD40, and get a benefit that way. Varlilumab (CDX-1127) is an unconjugated monoclonal antibody that binds CD27 and activates CD27-expressing T cells.
In a phase 1 trial of varlilumab in 24 lymphoma patients, investigators found no significant depletion in absolute lymphocyte counts, T cells, or B cells. “Not quite the same success story,” Dr Ansell said, with a response—a CR—in only 1 patient.
Investigators did observe, however, evidence of increased soluble CD27, a reduction of circulating Tregs, and the induction of pro-inflammatory cytokines.
And in a phase 1 study of the anti-CD40 monoclonal antibody dacetuzumab in recurrent NHL, “the response rate was disappointingly low,” Dr Ansell said.
Investigators observed 6 objective responses, including 1 CR and 5 PRs, and a decrease in tumor size in approximately one-third of the 50 patients treated.
The investigators of the subsequent phase 2 trial did not want to take the agent forward for further study, Dr Ansell noted, “but there are antibodies now being developed in this space that will hopefully be more effective and create a greater benefit.”
Optimizing immune function
Dr Ansell suggested there are 3 main approaches to treating patients. One is going directly after the malignant cells and depleting them. A second is to inhibit critical pathways that the malignant cell is dependent upon, “starving them, if you like.” The third way is to activate the immune system and thereby create a greater benefit for patients.
“[P]robably our best strategy is to use all 3 in a reprogram approach,” he said. “Because unless you target each one of these areas, the likelihood is that the other sides of the 3-legged stool will take over.”
“This is an encouraging and exciting time for immune checkpoints therapy and an encouraging and exciting time for immune therapies in general. I think this is really the new frontier in lymphomas.”
Blood donors’ genetic background affects hemolysis
ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence
red blood cell (RBC) storage and stress hemolysis.
Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.
Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.
Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).
“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”
With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.
They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.
Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.
The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).
Ethnicity and intensity
Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.
RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.
“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”
RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.
“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.
“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”
Group comparisons
Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.
RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.
RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.
RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).
RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)
Gender and age
As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).
“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.
He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.
“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”
Genetic modifiers
The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.
“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.
He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.
ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence
red blood cell (RBC) storage and stress hemolysis.
Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.
Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.
Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).
“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”
With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.
They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.
Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.
The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).
Ethnicity and intensity
Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.
RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.
“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”
RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.
“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.
“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”
Group comparisons
Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.
RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.
RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.
RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).
RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)
Gender and age
As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).
“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.
He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.
“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”
Genetic modifiers
The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.
“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.
He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.
ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence
red blood cell (RBC) storage and stress hemolysis.
Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.
Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.
Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).
“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”
With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.
They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.
Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.
The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).
Ethnicity and intensity
Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.
RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.
“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”
RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.
“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.
“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”
Group comparisons
Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.
RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.
RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.
RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).
RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)
Gender and age
As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).
“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.
He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.
“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”
Genetic modifiers
The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.
“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.
He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.
Canada may shorten deferral for MSM blood donors
Photo by Charles Haymond
ANAHEIM, CA—Lifting the lifetime ban on blood donations from men who have sex with men (MSM) has not altered the safety of the blood supply in Canada, according to a new study.
The study showed no increase in the rate of HIV-positive blood donations since Canada changed its policy regarding MSM blood donors, allowing MSM to donate if they have not had sexual contact with another man in the last 5 years.
Because of this finding, Canada may shorten the deferral period for MSM blood donors to 1 year, according to Sheila F. O’Brien, PhD, of Canadian Blood Services in Ottawa, Ontario, Canada.
Dr O’Brien mentioned this possibility and presented data from the study at the 2015 AABB Annual Meeting (abstract S35-030E*).
Prior to 2013, MSM in Canada were not allowed to donate blood if they had any sexual contact with another male since 1977. Females were barred from donating if, in the last year, they had sexual contact with a man who had sex with another man after 1977.
On July 22, 2013, Canada changed this policy so that MSM can donate blood if they have abstained from sexual contact with another man for the past 5 years. The deferral period for females is still 12 months if they have had sex with a man who has had sex with another man in the last 5 years, but there is no deferral if the man had sex with another man more than 5 years before.
To evaluate the impact of this policy change, Dr O’Brien and her colleagues assessed compliance with the MSM criteria before and after the change, as well as the number of HIV-positive blood donations before and after the change.
The researchers also assessed the number of donors who would have been deferred according to the old MSM criteria but donated blood under the new criteria.
MSM history
The researchers selected random male donors of whole blood each month from October 2012 to February 2013 (pre-change) and from October 2014 to February 2015 (post-change). These donors were invited to complete an anonymous online survey about their MSM history.
The survey was completed by 9669 donors before the policy change and 6881 donors after the change. There were 77 donors with MSM history before the change (20% first-time donors, 80% repeat) and 75 donors with MSM history after the change (22% first-time, 78% repeat).
Compliance with policy
After the change in policy for MSM blood donors, there was no significant change in the proportion of donors who had recent MSM history but donated anyway (non-compliant). Before the change, 0.37% of blood donors had an MSM partner in the last 5 years, compared to 0.43% after the change (P=0.54).
However, there was a significant change in the proportion of blood donors with MSM history further in the past. Before the MSM policy change, 0.42% of donors had an MSM partner but not in the last 5 years, compared to 0.66% of donors after the change (P=0.04).
“So we have an improvement in compliance, but it’s mainly because the donors are no longer deferrable,” Dr O’Brien explained.
“Donating while ineligible because of MSM history is actually quite rare, and the percentage of donors with MSM history in the last 5 years did not change when we changed the criteria. But we did see a modest increase in newly eligible MSM, so those that had more than 5 years since their last male-to-male sex.”
In all, there were 112 donors who were newly eligible due to the policy change and did, in fact, donate blood between July 22, 2013 and July 21, 2015. Five of these donors were females who had sexual contact with MSMs.
There were 70 “reinstated” donors in the first year after the policy change and 42 in the second year.
HIV-positive donations
The researchers monitored HIV rates in all blood donations from January 2010 to March 2015.
The rates of HIV-positive donations were as follows: 0.20 for 2010 (2/989,916), 0.50 for 2011 (5/995,122), 0.51 for 2012 (5/987,527), 0 (0/525,337) from January 1, 2013 to July 21, 2013 (before the policy change), 0.54 from July 22, 2013 to July 21, 2014 (5/929,656), and 0.22 from July 22, 2014 to July 21, 2015 (2/893,513).
“So absolutely no change in HIV rate following implementation of our 5-year deferral,” Dr O’Brien said.
In all, there were 7 HIV-positive donations after the policy change. Four were from male donors, and 3 were from females.
Three of the male donors (2 first-time donors, 1 repeat) denied having MSM risk factors, and 1 first-time male donor was aware he was HIV-positive at the time of donation. This man said he donated to determine if his HIV medication was working.
Two of the females were repeat donors, and 1 was a first-timer. The first-time donor did not acknowledge any MSM risk factors. One of the repeat donors had a sexual relationship with a bisexual male who was HIV-positive. The other repeat donor had multiple sexual partners, 1 of whom was known to be hepatitis C-positive.
Future policy change
Dr O’Brien noted that the LGBTQ community in Canada has advocated abolishing the deferral period for MSM blood donors or changing to a risk-based policy that would allow more individuals with MSM history to donate blood.
She said the combined blood services in Canada—Canadian Blood Services and Héma-Québec—are now considering a 12-month deferral period for individuals with MSM history.
“We’re pretty sure we’re going to go ahead,” she noted.
However, the groups must submit a policy request to Health Canada, which will ultimately make the decision.
*Data in the abstract differ from data presented at the meeting.
Photo by Charles Haymond
ANAHEIM, CA—Lifting the lifetime ban on blood donations from men who have sex with men (MSM) has not altered the safety of the blood supply in Canada, according to a new study.
The study showed no increase in the rate of HIV-positive blood donations since Canada changed its policy regarding MSM blood donors, allowing MSM to donate if they have not had sexual contact with another man in the last 5 years.
Because of this finding, Canada may shorten the deferral period for MSM blood donors to 1 year, according to Sheila F. O’Brien, PhD, of Canadian Blood Services in Ottawa, Ontario, Canada.
Dr O’Brien mentioned this possibility and presented data from the study at the 2015 AABB Annual Meeting (abstract S35-030E*).
Prior to 2013, MSM in Canada were not allowed to donate blood if they had any sexual contact with another male since 1977. Females were barred from donating if, in the last year, they had sexual contact with a man who had sex with another man after 1977.
On July 22, 2013, Canada changed this policy so that MSM can donate blood if they have abstained from sexual contact with another man for the past 5 years. The deferral period for females is still 12 months if they have had sex with a man who has had sex with another man in the last 5 years, but there is no deferral if the man had sex with another man more than 5 years before.
To evaluate the impact of this policy change, Dr O’Brien and her colleagues assessed compliance with the MSM criteria before and after the change, as well as the number of HIV-positive blood donations before and after the change.
The researchers also assessed the number of donors who would have been deferred according to the old MSM criteria but donated blood under the new criteria.
MSM history
The researchers selected random male donors of whole blood each month from October 2012 to February 2013 (pre-change) and from October 2014 to February 2015 (post-change). These donors were invited to complete an anonymous online survey about their MSM history.
The survey was completed by 9669 donors before the policy change and 6881 donors after the change. There were 77 donors with MSM history before the change (20% first-time donors, 80% repeat) and 75 donors with MSM history after the change (22% first-time, 78% repeat).
Compliance with policy
After the change in policy for MSM blood donors, there was no significant change in the proportion of donors who had recent MSM history but donated anyway (non-compliant). Before the change, 0.37% of blood donors had an MSM partner in the last 5 years, compared to 0.43% after the change (P=0.54).
However, there was a significant change in the proportion of blood donors with MSM history further in the past. Before the MSM policy change, 0.42% of donors had an MSM partner but not in the last 5 years, compared to 0.66% of donors after the change (P=0.04).
“So we have an improvement in compliance, but it’s mainly because the donors are no longer deferrable,” Dr O’Brien explained.
“Donating while ineligible because of MSM history is actually quite rare, and the percentage of donors with MSM history in the last 5 years did not change when we changed the criteria. But we did see a modest increase in newly eligible MSM, so those that had more than 5 years since their last male-to-male sex.”
In all, there were 112 donors who were newly eligible due to the policy change and did, in fact, donate blood between July 22, 2013 and July 21, 2015. Five of these donors were females who had sexual contact with MSMs.
There were 70 “reinstated” donors in the first year after the policy change and 42 in the second year.
HIV-positive donations
The researchers monitored HIV rates in all blood donations from January 2010 to March 2015.
The rates of HIV-positive donations were as follows: 0.20 for 2010 (2/989,916), 0.50 for 2011 (5/995,122), 0.51 for 2012 (5/987,527), 0 (0/525,337) from January 1, 2013 to July 21, 2013 (before the policy change), 0.54 from July 22, 2013 to July 21, 2014 (5/929,656), and 0.22 from July 22, 2014 to July 21, 2015 (2/893,513).
“So absolutely no change in HIV rate following implementation of our 5-year deferral,” Dr O’Brien said.
In all, there were 7 HIV-positive donations after the policy change. Four were from male donors, and 3 were from females.
Three of the male donors (2 first-time donors, 1 repeat) denied having MSM risk factors, and 1 first-time male donor was aware he was HIV-positive at the time of donation. This man said he donated to determine if his HIV medication was working.
Two of the females were repeat donors, and 1 was a first-timer. The first-time donor did not acknowledge any MSM risk factors. One of the repeat donors had a sexual relationship with a bisexual male who was HIV-positive. The other repeat donor had multiple sexual partners, 1 of whom was known to be hepatitis C-positive.
Future policy change
Dr O’Brien noted that the LGBTQ community in Canada has advocated abolishing the deferral period for MSM blood donors or changing to a risk-based policy that would allow more individuals with MSM history to donate blood.
She said the combined blood services in Canada—Canadian Blood Services and Héma-Québec—are now considering a 12-month deferral period for individuals with MSM history.
“We’re pretty sure we’re going to go ahead,” she noted.
However, the groups must submit a policy request to Health Canada, which will ultimately make the decision.
*Data in the abstract differ from data presented at the meeting.
Photo by Charles Haymond
ANAHEIM, CA—Lifting the lifetime ban on blood donations from men who have sex with men (MSM) has not altered the safety of the blood supply in Canada, according to a new study.
The study showed no increase in the rate of HIV-positive blood donations since Canada changed its policy regarding MSM blood donors, allowing MSM to donate if they have not had sexual contact with another man in the last 5 years.
Because of this finding, Canada may shorten the deferral period for MSM blood donors to 1 year, according to Sheila F. O’Brien, PhD, of Canadian Blood Services in Ottawa, Ontario, Canada.
Dr O’Brien mentioned this possibility and presented data from the study at the 2015 AABB Annual Meeting (abstract S35-030E*).
Prior to 2013, MSM in Canada were not allowed to donate blood if they had any sexual contact with another male since 1977. Females were barred from donating if, in the last year, they had sexual contact with a man who had sex with another man after 1977.
On July 22, 2013, Canada changed this policy so that MSM can donate blood if they have abstained from sexual contact with another man for the past 5 years. The deferral period for females is still 12 months if they have had sex with a man who has had sex with another man in the last 5 years, but there is no deferral if the man had sex with another man more than 5 years before.
To evaluate the impact of this policy change, Dr O’Brien and her colleagues assessed compliance with the MSM criteria before and after the change, as well as the number of HIV-positive blood donations before and after the change.
The researchers also assessed the number of donors who would have been deferred according to the old MSM criteria but donated blood under the new criteria.
MSM history
The researchers selected random male donors of whole blood each month from October 2012 to February 2013 (pre-change) and from October 2014 to February 2015 (post-change). These donors were invited to complete an anonymous online survey about their MSM history.
The survey was completed by 9669 donors before the policy change and 6881 donors after the change. There were 77 donors with MSM history before the change (20% first-time donors, 80% repeat) and 75 donors with MSM history after the change (22% first-time, 78% repeat).
Compliance with policy
After the change in policy for MSM blood donors, there was no significant change in the proportion of donors who had recent MSM history but donated anyway (non-compliant). Before the change, 0.37% of blood donors had an MSM partner in the last 5 years, compared to 0.43% after the change (P=0.54).
However, there was a significant change in the proportion of blood donors with MSM history further in the past. Before the MSM policy change, 0.42% of donors had an MSM partner but not in the last 5 years, compared to 0.66% of donors after the change (P=0.04).
“So we have an improvement in compliance, but it’s mainly because the donors are no longer deferrable,” Dr O’Brien explained.
“Donating while ineligible because of MSM history is actually quite rare, and the percentage of donors with MSM history in the last 5 years did not change when we changed the criteria. But we did see a modest increase in newly eligible MSM, so those that had more than 5 years since their last male-to-male sex.”
In all, there were 112 donors who were newly eligible due to the policy change and did, in fact, donate blood between July 22, 2013 and July 21, 2015. Five of these donors were females who had sexual contact with MSMs.
There were 70 “reinstated” donors in the first year after the policy change and 42 in the second year.
HIV-positive donations
The researchers monitored HIV rates in all blood donations from January 2010 to March 2015.
The rates of HIV-positive donations were as follows: 0.20 for 2010 (2/989,916), 0.50 for 2011 (5/995,122), 0.51 for 2012 (5/987,527), 0 (0/525,337) from January 1, 2013 to July 21, 2013 (before the policy change), 0.54 from July 22, 2013 to July 21, 2014 (5/929,656), and 0.22 from July 22, 2014 to July 21, 2015 (2/893,513).
“So absolutely no change in HIV rate following implementation of our 5-year deferral,” Dr O’Brien said.
In all, there were 7 HIV-positive donations after the policy change. Four were from male donors, and 3 were from females.
Three of the male donors (2 first-time donors, 1 repeat) denied having MSM risk factors, and 1 first-time male donor was aware he was HIV-positive at the time of donation. This man said he donated to determine if his HIV medication was working.
Two of the females were repeat donors, and 1 was a first-timer. The first-time donor did not acknowledge any MSM risk factors. One of the repeat donors had a sexual relationship with a bisexual male who was HIV-positive. The other repeat donor had multiple sexual partners, 1 of whom was known to be hepatitis C-positive.
Future policy change
Dr O’Brien noted that the LGBTQ community in Canada has advocated abolishing the deferral period for MSM blood donors or changing to a risk-based policy that would allow more individuals with MSM history to donate blood.
She said the combined blood services in Canada—Canadian Blood Services and Héma-Québec—are now considering a 12-month deferral period for individuals with MSM history.
“We’re pretty sure we’re going to go ahead,” she noted.
However, the groups must submit a policy request to Health Canada, which will ultimately make the decision.
*Data in the abstract differ from data presented at the meeting.
Median DOR, PFS not yet reached for ibrutinib in CLL
Photo courtesy of
Janssen Biotech, Inc.
NEW YORK—Long-term follow-up of single-agent ibrutinib at the approved dose of 420 mg daily confirms that the Bruton’s tyrosine kinase inhibitor produces rapid and durable responses in patients with chronic lymphocytic leukemia (CLL), according to an update presented at Lymphoma & Myeloma 2015.
At up to 44 months of follow-up, the median duration of response (DOR) and progression-free survival (PFS) have not yet been reached.
At 30 months, the PFS rate was 96% for treatment-naïve patients and 76% for relapsed or refractory patients. Patients with del 17p had a median PFS of 32.4 months.
“Virtually all the patients do respond to treatment,” said Steven Coutre, MD, of Stanford University School of Medicine in California.
“Only a handful of patients achieve less than CR [complete response] or PR [partial response],” he said during his presentation at the meeting.
Phase 1/2b and extension studies
Ninety-four patients enrolled in the phase 1/2b (PCYC-1102) and extension (PCYC-1103) studies received 420 mg of ibrutinib once daily.
“We initially enrolled patients with relapsed/refractory CLL,” Dr Coutre clarified. “Then, because of the significant efficacy and safety that was observed, we added a second cohort of treatment-naïve patients age 65 and older.”
The treatment-naïve (TN) cohort consisted of 27 CLL patients. The relapsed or refractory (R/R) cohort consisted of 67 patients with CLL or small lymphocytic lymphoma, including patients with high-risk disease, which was defined as disease progression less than 24 months after the start of a chemoimmunotherapy regimen or refractory to the most recent regimen.
The median time on study was 32 months (range, 0–44).
In the TN cohort, the median age was 71, 78% were ECOG performance status 0, and most had advanced disease as indicated by Rai stage.
In the R/R cohort, the median age was 66, 40% were ECOG performance status 0, 57% were ECOG performance status 1, and 52% had bulky nodes greater than 5 cm.
“We had a significant representation of high-risk cytogenetic abnormalities,” Dr Coutre noted.
In the R/R group, 34% of patients had del 17p, and 33% had del 11q. In the TN cohort, 7% of patients had del 17p, and none had del 11q.
“There were also a significant number of cytopenias,” Dr Coutre said, “as one might expect in a heavily pretreated patient population.”
The number of prior therapies was also “quite significant,” he said, with 55% having a median of 4 or more therapies (range, 1–12).
“It really stretches the imagination to figure out what those 12 different regimens were,” he commented.
All R/R patients had prior chemotherapy, 94% a nucleoside analog, 90% an alkylator (including bendamustine), 99% anti-CD20-based therapy, 97% anti-CD20-based chemoimmunotherapy, 24% alemtuzumab, and 6% idelalisib.
The median time on treatment was 30.4 months (range, 1.3–44.2) for TN patients and 21.9 months (range, 0.3–44.6) for R/R patients. The majority of patients in both groups remain on ibrutinib—81% of the TN patients and 60% of R/R patients.
Safety
“Only 1 patient in the treatment-naïve cohort has progressed,” Dr Coutre noted. “That was a patient with deletion 17p [who progressed in about 8 months].”
The primary reasons for discontinuing therapy were progressive disease (1 TN, 11 R/R), adverse events (AEs; 3 TN, 9 R/R), consent withdrawal (1 TN, 2 R/R), investigators’ decision (0 TN, 4 R/R), and other reasons (0 TN, 1 R/R).
“Discontinuations due to AEs occurred predominantly early,” Dr Coutre observed. “So of the 12 patients [who discontinued due to AEs], 7 discontinued in the first year, 3 in the second year, and only 2 beyond year 3.”
Grade 3 or higher AEs occurred in 55 R/R patients (82%) and 17 TN patients (63%). Infection occurred in 48% of R/R patients and 11% of TN patients. Dr Coutre pointed out that most of these AEs were not related to ibrutinib.
Grade 3 or higher ibrutinib-related AEs occurred in 6 TN patients (22%) and 25 R/R patients (37%). One TN patient and 8 R/R patients experienced grade 3 or higher serious ibrutinib-related AEs.
One TN patient and 7 R/R patients required a dose reduction due to an AE. However, the dose reductions occurred predominantly during the first year, Dr Coutre noted.
Regarding time to onset of grade 3 or higher AEs, Dr Coutre said most of the events occurred early and decreased with time. Pneumonia and atrial fibrillation followed this pattern, as did neutropenia and thrombocytopenia. Hypertension was the exception, occurring during all years.
Nonhematologic AEs of grade 3 or higher that occurred in at least 5% of patients were pneumonia, hypertension, diarrhea, hyponatremia, and atrial fibrillation in TN patients, and sepsis, cellulitis, dehydration, and fatigue in R/R patients.
Hematologic AEs of grade 3 or higher in each cohort included neutropenia, thrombocytopenia, and anemia.
“The drug doesn’t seem to be myelosuppressive,” Dr Coutre noted. “We don’t have prolonged cytopenias as patients stay on treatment.”
One TN patient and 7 R/R patients died during the study.
Response and survival
The response rate (as assessed by the investigators) was 85% for TN patients. Twenty-six percent of patients achieved a complete response, 52% a partial response (PR), and 7% a PR with lymphocytosis.
The response rate for R/R patients was 94%. Nine percent achieved a complete response, 82% a PR, and 3% a PR with lymphocytosis.
The median time to the best response was 7.4 months for both cohorts.
The median DOR has not been reached in either cohort, but the 30-month DOR was 95.2% for TN patients and 79.1% for R/R patients.
The 30-month PFS was 95.8% for TN patients and 75.9% for R/R patients.
At 30 months, the PFS rate was 59.6% for patients with del 17p and 82.4% for patients with del 11q. The median PFS for patients with del 17p was 32.4 months, and it was not reached for patients with del 11q. For patients with neither of these abnormalities, the median PFS has not been reached.
“Overall survival was equally impressive,” Dr Coutre said.
The median overall survival has not been reached for any group, and 30-month overall survival is 81.3% for del 17p patients, 88.2% for patients with del 11q, and 90.3% for patients with neither abnormality.
“[I]brutinib induces rapid and durable responses that continue to improve over time . . . ,” Dr Coutre said.
He added that the drug is well-tolerated, “allowing us to continue patients on treatment, which, I think, is particularly important for these types of drugs because we clearly see that patients have significant clinical benefit, despite the fact that they still often have easily detectable disease, particularly in the bone marrow.”
“So one of the challenges is going to be [to determine] how to use these drugs on a long-term basis and [see if we can] use them in a more time-limited fashion.”
Ibrutinib is approved by the US Food and Drug Administration for 4 indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.
Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.
Photo courtesy of
Janssen Biotech, Inc.
NEW YORK—Long-term follow-up of single-agent ibrutinib at the approved dose of 420 mg daily confirms that the Bruton’s tyrosine kinase inhibitor produces rapid and durable responses in patients with chronic lymphocytic leukemia (CLL), according to an update presented at Lymphoma & Myeloma 2015.
At up to 44 months of follow-up, the median duration of response (DOR) and progression-free survival (PFS) have not yet been reached.
At 30 months, the PFS rate was 96% for treatment-naïve patients and 76% for relapsed or refractory patients. Patients with del 17p had a median PFS of 32.4 months.
“Virtually all the patients do respond to treatment,” said Steven Coutre, MD, of Stanford University School of Medicine in California.
“Only a handful of patients achieve less than CR [complete response] or PR [partial response],” he said during his presentation at the meeting.
Phase 1/2b and extension studies
Ninety-four patients enrolled in the phase 1/2b (PCYC-1102) and extension (PCYC-1103) studies received 420 mg of ibrutinib once daily.
“We initially enrolled patients with relapsed/refractory CLL,” Dr Coutre clarified. “Then, because of the significant efficacy and safety that was observed, we added a second cohort of treatment-naïve patients age 65 and older.”
The treatment-naïve (TN) cohort consisted of 27 CLL patients. The relapsed or refractory (R/R) cohort consisted of 67 patients with CLL or small lymphocytic lymphoma, including patients with high-risk disease, which was defined as disease progression less than 24 months after the start of a chemoimmunotherapy regimen or refractory to the most recent regimen.
The median time on study was 32 months (range, 0–44).
In the TN cohort, the median age was 71, 78% were ECOG performance status 0, and most had advanced disease as indicated by Rai stage.
In the R/R cohort, the median age was 66, 40% were ECOG performance status 0, 57% were ECOG performance status 1, and 52% had bulky nodes greater than 5 cm.
“We had a significant representation of high-risk cytogenetic abnormalities,” Dr Coutre noted.
In the R/R group, 34% of patients had del 17p, and 33% had del 11q. In the TN cohort, 7% of patients had del 17p, and none had del 11q.
“There were also a significant number of cytopenias,” Dr Coutre said, “as one might expect in a heavily pretreated patient population.”
The number of prior therapies was also “quite significant,” he said, with 55% having a median of 4 or more therapies (range, 1–12).
“It really stretches the imagination to figure out what those 12 different regimens were,” he commented.
All R/R patients had prior chemotherapy, 94% a nucleoside analog, 90% an alkylator (including bendamustine), 99% anti-CD20-based therapy, 97% anti-CD20-based chemoimmunotherapy, 24% alemtuzumab, and 6% idelalisib.
The median time on treatment was 30.4 months (range, 1.3–44.2) for TN patients and 21.9 months (range, 0.3–44.6) for R/R patients. The majority of patients in both groups remain on ibrutinib—81% of the TN patients and 60% of R/R patients.
Safety
“Only 1 patient in the treatment-naïve cohort has progressed,” Dr Coutre noted. “That was a patient with deletion 17p [who progressed in about 8 months].”
The primary reasons for discontinuing therapy were progressive disease (1 TN, 11 R/R), adverse events (AEs; 3 TN, 9 R/R), consent withdrawal (1 TN, 2 R/R), investigators’ decision (0 TN, 4 R/R), and other reasons (0 TN, 1 R/R).
“Discontinuations due to AEs occurred predominantly early,” Dr Coutre observed. “So of the 12 patients [who discontinued due to AEs], 7 discontinued in the first year, 3 in the second year, and only 2 beyond year 3.”
Grade 3 or higher AEs occurred in 55 R/R patients (82%) and 17 TN patients (63%). Infection occurred in 48% of R/R patients and 11% of TN patients. Dr Coutre pointed out that most of these AEs were not related to ibrutinib.
Grade 3 or higher ibrutinib-related AEs occurred in 6 TN patients (22%) and 25 R/R patients (37%). One TN patient and 8 R/R patients experienced grade 3 or higher serious ibrutinib-related AEs.
One TN patient and 7 R/R patients required a dose reduction due to an AE. However, the dose reductions occurred predominantly during the first year, Dr Coutre noted.
Regarding time to onset of grade 3 or higher AEs, Dr Coutre said most of the events occurred early and decreased with time. Pneumonia and atrial fibrillation followed this pattern, as did neutropenia and thrombocytopenia. Hypertension was the exception, occurring during all years.
Nonhematologic AEs of grade 3 or higher that occurred in at least 5% of patients were pneumonia, hypertension, diarrhea, hyponatremia, and atrial fibrillation in TN patients, and sepsis, cellulitis, dehydration, and fatigue in R/R patients.
Hematologic AEs of grade 3 or higher in each cohort included neutropenia, thrombocytopenia, and anemia.
“The drug doesn’t seem to be myelosuppressive,” Dr Coutre noted. “We don’t have prolonged cytopenias as patients stay on treatment.”
One TN patient and 7 R/R patients died during the study.
Response and survival
The response rate (as assessed by the investigators) was 85% for TN patients. Twenty-six percent of patients achieved a complete response, 52% a partial response (PR), and 7% a PR with lymphocytosis.
The response rate for R/R patients was 94%. Nine percent achieved a complete response, 82% a PR, and 3% a PR with lymphocytosis.
The median time to the best response was 7.4 months for both cohorts.
The median DOR has not been reached in either cohort, but the 30-month DOR was 95.2% for TN patients and 79.1% for R/R patients.
The 30-month PFS was 95.8% for TN patients and 75.9% for R/R patients.
At 30 months, the PFS rate was 59.6% for patients with del 17p and 82.4% for patients with del 11q. The median PFS for patients with del 17p was 32.4 months, and it was not reached for patients with del 11q. For patients with neither of these abnormalities, the median PFS has not been reached.
“Overall survival was equally impressive,” Dr Coutre said.
The median overall survival has not been reached for any group, and 30-month overall survival is 81.3% for del 17p patients, 88.2% for patients with del 11q, and 90.3% for patients with neither abnormality.
“[I]brutinib induces rapid and durable responses that continue to improve over time . . . ,” Dr Coutre said.
He added that the drug is well-tolerated, “allowing us to continue patients on treatment, which, I think, is particularly important for these types of drugs because we clearly see that patients have significant clinical benefit, despite the fact that they still often have easily detectable disease, particularly in the bone marrow.”
“So one of the challenges is going to be [to determine] how to use these drugs on a long-term basis and [see if we can] use them in a more time-limited fashion.”
Ibrutinib is approved by the US Food and Drug Administration for 4 indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.
Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.
Photo courtesy of
Janssen Biotech, Inc.
NEW YORK—Long-term follow-up of single-agent ibrutinib at the approved dose of 420 mg daily confirms that the Bruton’s tyrosine kinase inhibitor produces rapid and durable responses in patients with chronic lymphocytic leukemia (CLL), according to an update presented at Lymphoma & Myeloma 2015.
At up to 44 months of follow-up, the median duration of response (DOR) and progression-free survival (PFS) have not yet been reached.
At 30 months, the PFS rate was 96% for treatment-naïve patients and 76% for relapsed or refractory patients. Patients with del 17p had a median PFS of 32.4 months.
“Virtually all the patients do respond to treatment,” said Steven Coutre, MD, of Stanford University School of Medicine in California.
“Only a handful of patients achieve less than CR [complete response] or PR [partial response],” he said during his presentation at the meeting.
Phase 1/2b and extension studies
Ninety-four patients enrolled in the phase 1/2b (PCYC-1102) and extension (PCYC-1103) studies received 420 mg of ibrutinib once daily.
“We initially enrolled patients with relapsed/refractory CLL,” Dr Coutre clarified. “Then, because of the significant efficacy and safety that was observed, we added a second cohort of treatment-naïve patients age 65 and older.”
The treatment-naïve (TN) cohort consisted of 27 CLL patients. The relapsed or refractory (R/R) cohort consisted of 67 patients with CLL or small lymphocytic lymphoma, including patients with high-risk disease, which was defined as disease progression less than 24 months after the start of a chemoimmunotherapy regimen or refractory to the most recent regimen.
The median time on study was 32 months (range, 0–44).
In the TN cohort, the median age was 71, 78% were ECOG performance status 0, and most had advanced disease as indicated by Rai stage.
In the R/R cohort, the median age was 66, 40% were ECOG performance status 0, 57% were ECOG performance status 1, and 52% had bulky nodes greater than 5 cm.
“We had a significant representation of high-risk cytogenetic abnormalities,” Dr Coutre noted.
In the R/R group, 34% of patients had del 17p, and 33% had del 11q. In the TN cohort, 7% of patients had del 17p, and none had del 11q.
“There were also a significant number of cytopenias,” Dr Coutre said, “as one might expect in a heavily pretreated patient population.”
The number of prior therapies was also “quite significant,” he said, with 55% having a median of 4 or more therapies (range, 1–12).
“It really stretches the imagination to figure out what those 12 different regimens were,” he commented.
All R/R patients had prior chemotherapy, 94% a nucleoside analog, 90% an alkylator (including bendamustine), 99% anti-CD20-based therapy, 97% anti-CD20-based chemoimmunotherapy, 24% alemtuzumab, and 6% idelalisib.
The median time on treatment was 30.4 months (range, 1.3–44.2) for TN patients and 21.9 months (range, 0.3–44.6) for R/R patients. The majority of patients in both groups remain on ibrutinib—81% of the TN patients and 60% of R/R patients.
Safety
“Only 1 patient in the treatment-naïve cohort has progressed,” Dr Coutre noted. “That was a patient with deletion 17p [who progressed in about 8 months].”
The primary reasons for discontinuing therapy were progressive disease (1 TN, 11 R/R), adverse events (AEs; 3 TN, 9 R/R), consent withdrawal (1 TN, 2 R/R), investigators’ decision (0 TN, 4 R/R), and other reasons (0 TN, 1 R/R).
“Discontinuations due to AEs occurred predominantly early,” Dr Coutre observed. “So of the 12 patients [who discontinued due to AEs], 7 discontinued in the first year, 3 in the second year, and only 2 beyond year 3.”
Grade 3 or higher AEs occurred in 55 R/R patients (82%) and 17 TN patients (63%). Infection occurred in 48% of R/R patients and 11% of TN patients. Dr Coutre pointed out that most of these AEs were not related to ibrutinib.
Grade 3 or higher ibrutinib-related AEs occurred in 6 TN patients (22%) and 25 R/R patients (37%). One TN patient and 8 R/R patients experienced grade 3 or higher serious ibrutinib-related AEs.
One TN patient and 7 R/R patients required a dose reduction due to an AE. However, the dose reductions occurred predominantly during the first year, Dr Coutre noted.
Regarding time to onset of grade 3 or higher AEs, Dr Coutre said most of the events occurred early and decreased with time. Pneumonia and atrial fibrillation followed this pattern, as did neutropenia and thrombocytopenia. Hypertension was the exception, occurring during all years.
Nonhematologic AEs of grade 3 or higher that occurred in at least 5% of patients were pneumonia, hypertension, diarrhea, hyponatremia, and atrial fibrillation in TN patients, and sepsis, cellulitis, dehydration, and fatigue in R/R patients.
Hematologic AEs of grade 3 or higher in each cohort included neutropenia, thrombocytopenia, and anemia.
“The drug doesn’t seem to be myelosuppressive,” Dr Coutre noted. “We don’t have prolonged cytopenias as patients stay on treatment.”
One TN patient and 7 R/R patients died during the study.
Response and survival
The response rate (as assessed by the investigators) was 85% for TN patients. Twenty-six percent of patients achieved a complete response, 52% a partial response (PR), and 7% a PR with lymphocytosis.
The response rate for R/R patients was 94%. Nine percent achieved a complete response, 82% a PR, and 3% a PR with lymphocytosis.
The median time to the best response was 7.4 months for both cohorts.
The median DOR has not been reached in either cohort, but the 30-month DOR was 95.2% for TN patients and 79.1% for R/R patients.
The 30-month PFS was 95.8% for TN patients and 75.9% for R/R patients.
At 30 months, the PFS rate was 59.6% for patients with del 17p and 82.4% for patients with del 11q. The median PFS for patients with del 17p was 32.4 months, and it was not reached for patients with del 11q. For patients with neither of these abnormalities, the median PFS has not been reached.
“Overall survival was equally impressive,” Dr Coutre said.
The median overall survival has not been reached for any group, and 30-month overall survival is 81.3% for del 17p patients, 88.2% for patients with del 11q, and 90.3% for patients with neither abnormality.
“[I]brutinib induces rapid and durable responses that continue to improve over time . . . ,” Dr Coutre said.
He added that the drug is well-tolerated, “allowing us to continue patients on treatment, which, I think, is particularly important for these types of drugs because we clearly see that patients have significant clinical benefit, despite the fact that they still often have easily detectable disease, particularly in the bone marrow.”
“So one of the challenges is going to be [to determine] how to use these drugs on a long-term basis and [see if we can] use them in a more time-limited fashion.”
Ibrutinib is approved by the US Food and Drug Administration for 4 indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.
Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.