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Combo shows promise for elderly/unfit ALL patients
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures. 
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
Obesity has negative impact on HSC compartment
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”
CX-01 receives orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
DLBCL survivors at greater risk of autoimmune, infectious diseases
ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.
For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.
“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.
“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”
Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.
Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).
Study design
Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.
“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”
Investigators used the same criteria for the comparator cohorts.
The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.
Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.
They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.
“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.
Survivor characteristics
The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).
“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”
The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.
About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.
DLBCL vs breast cancer
“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.
Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.
“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”
“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”
DLBCL vs prostate cancer
“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.
Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.
“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.
DLBCL vs head and neck cancer
“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.
Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.
DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.
On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.
DLBCL vs melanoma
“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.
“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”
The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.
Risks persist over time
The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.
They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.
“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.
“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”
The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.
“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.
“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”
The findings, she said, have a lot of implications.
“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”
The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.
*Data in the abstract differ from the presentation.
ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.
For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.
“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.
“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”
Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.
Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).
Study design
Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.
“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”
Investigators used the same criteria for the comparator cohorts.
The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.
Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.
They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.
“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.
Survivor characteristics
The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).
“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”
The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.
About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.
DLBCL vs breast cancer
“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.
Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.
“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”
“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”
DLBCL vs prostate cancer
“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.
Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.
“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.
DLBCL vs head and neck cancer
“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.
Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.
DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.
On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.
DLBCL vs melanoma
“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.
“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”
The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.
Risks persist over time
The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.
They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.
“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.
“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”
The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.
“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.
“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”
The findings, she said, have a lot of implications.
“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”
The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.
*Data in the abstract differ from the presentation.
ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.
For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.
“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.
“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”
Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.
Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).
Study design
Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.
“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”
Investigators used the same criteria for the comparator cohorts.
The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.
Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.
They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.
“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.
Survivor characteristics
The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).
“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”
The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.
About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.
DLBCL vs breast cancer
“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.
Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.
“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”
“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”
DLBCL vs prostate cancer
“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.
Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.
“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.
DLBCL vs head and neck cancer
“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.
Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.
DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.
On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.
DLBCL vs melanoma
“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.
“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”
The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.
Risks persist over time
The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.
They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.
“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.
“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”
The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.
“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.
“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”
The findings, she said, have a lot of implications.
“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”
The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.
*Data in the abstract differ from the presentation.
Brentuximab vedotin sBLA receives priority review
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).
With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).
The FDA expects to make a decision on the sBLA by May 1, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.
The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.
Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.
ECHELON-1
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
About brentuximab vedotin
Brentuximab vedotin is already FDA-approved to treat adults with:
- Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
- Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
- Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
- Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).
With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).
The FDA expects to make a decision on the sBLA by May 1, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.
The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.
Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.
ECHELON-1
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
About brentuximab vedotin
Brentuximab vedotin is already FDA-approved to treat adults with:
- Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
- Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
- Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
- Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).
With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).
The FDA expects to make a decision on the sBLA by May 1, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.
The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.
Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.
ECHELON-1
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
About brentuximab vedotin
Brentuximab vedotin is already FDA-approved to treat adults with:
- Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
- Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
- Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
- Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
FDA lifts hold on trial of SEL24 in AML
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
Ixazomib/lenalidomide maintenance promising after ASCT in MM
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.
Repurposed drug could improve HSCT
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.”
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.”
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.”
Carfilzomib poses higher risk of CVAEs, review suggests
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Update reveals ongoing responses in ZUMA-1
ATLANTA—The chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; KTE-C19) is showing consistent, ongoing responses more than a year after infusion.
An updated analysis of the phase 1/2 ZUMA-1 trial showed that 42% of patients who received axi-cel maintained an objective response at a median follow-up of 15.4 months.
Forty percent of patients have maintained a complete response (CR).
This compares with a 44% objective response rate and a 39% CR rate in the primary analysis of phase 2 ZUMA-1 data, when the median follow-up was 8.7 months.
Sattva S. Neelapu, MD, of MD Anderson Cancer Center in Houston, Texas, reported the long-term results from ZUMA-1 at the 2017 ASH Annual Meeting (abstract 578). The findings were published simultaneously in NEJM.
The primary phase 2 analysis was previously presented at the AACR Annual Meeting 2017.
At ASH 2017, Dr Neelapu disclosed that he has received research funding and served as a consultant for Kite Pharma, the developer of axi-cel. Kite Pharma and the Leukemia & Lymphoma Society Therapy Acceleration Program supported ZUMA-1.
Study schema and patient characteristics
Phase 1 of ZUMA-1 enrolled 7 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL).
In phase 2, 101 patients were grouped into 2 cohorts—77 with refractory DLBCL and 24 with refractory PMBCL/TFL.
A total of 108 patients were treated in phases 1 and 2 and were included in the long-term pooled analysis.
Patients received a conditioning regimen of cyclophosphamide and fludarabine and, 2 days later, a fixed dose of axi-cel at 2 x 106 CAR T cells/kg.
“Importantly, the product could be manufactured for 99% of enrolled patients,” Dr Neelapu said. “Moreover, 91% of the enrolled patients were dosed with axi-cel, and there were no patients lost to follow-up.”
Patients in the pooled analysis were a median age of 58 (range, 23–76), and 27 (25%) were 65 or older.
Seventy-three patients (68%) were male, 62 (57%) had an ECOG status of 1, 90 (83%) had stage III or IV disease, and 48 (44%) had an IPI score of 3 to 4.
Seventy-six patients (70%) had received 3 or more prior therapies.
Eighty patients (74%) were refractory to their second or later line of therapy, and 70 (65%) had progressive disease as their best response to their last prior therapy. Twenty-five patients (23%) had relapsed after autologous stem cell transplant.
Response
The data cutoff for the long-term analysis was August 11, 2017.
In addition to the ongoing responses mentioned above, the best objective response was 82% in both the phase 2 primary analysis and the long-term analysis for phases 1 and 2.
CR as the best objective response increased from 54% in the primary analysis to 58% at the longer follow-up.
“We did observe deepening of the responses over time,” Dr Neelapu said. “At the time of the first tumor assessment, 60 patients had either partial remission or stable disease. But 23 of those 60 eventually achieved a complete remission up to 15 months post-infusion without any additional therapy.”
The median time to conversion from partial response to CR was 64 days (range, 49–242).
“The durability of these responses was observed consistently across key covariates,” Dr Neelapu added, “including the refractory subgroups, the disease stage groups, IPI risk groups. The CD19 status at baseline did not matter, nor did the cell of origin, or the CD4/CD8 ratio of the product.”
Furthermore, the investigators observed no differences in patients who received tocilizumab or corticosteroids.
The median duration of response for all patients was 11.1 months. For those who achieved CR, the median duration of response has not yet been reached.
Three of the 7 patients (43%) in the phase 1 part of the trial had an ongoing CR at 24 months.
At the median follow-up of 15.4 months, 42% of patients were progression-free, and 56% were alive.
The median overall survival has not been reached. Investigators estimated the 18-month overall survival to be 52%.
Safety
Adverse events (AEs) of grade 3 or higher occurred in 97% of patients, and serious AEs of grade 3 or higher occurred in 46% of patients in the updated analysis.
No new axi-cel-related AEs of cytokine release syndrome, neurologic events, or grade 5 AEs have arisen since the primary analysis.
There were four grade 5 events, 2 of which were related to axi-cel.
“All these four grade 5 events were previously reported—three in the phase 2 and one in the phase 1 trial,” Dr Neelapu said.
Most patients experienced hypogammaglobulinemia and B-cell aplasia. Eight percent of patients had IVIG support during the study.
Infections, such as pneumonia, influenza, and viral infection, were the most common new-onset treatment-emergent serious AEs occurring after 6 months in 10 patients. All were manageable and resolved prior to the data cut-off.
Persistence and resistance
“We observed long-term persistence of the CAR T cells,” Dr Neelapu said.
CAR T cells persisted in 71% of patients still responding at 1 year. And durable responses were observed in patients with and without detectable CAR T cells.
A central review committee analyzed biopsies of 21 evaluable patients at progression to try to determine the mechanism of resistance.
Fourteen of 21 (67%) biopsies were CD19-positive. Of these, 9 were PD-L1-positive, 4 were PD-L1-negative, and 1 was not evaluable.
Seven patients (33%) were CD19-negative compared to baseline. Of these, 4 were PD-L1-positive, 2 were PD-L1-negative, and 1 was not evaluable.
“This PD-L1 expression was observed in both CD19-positive relapses and CD19-negative relapses,” Dr Neelapu emphasized.
Of the 21 patients, 62% were PD-L1-positive.
Investigators hypothesize that 2 potential mechanisms could contribute to relapse: loss of CD19 and expression of PD-L1.
Axi-cel (Yescarta™) was approved by the US Food and Drug Administration in October for the treatment of adults with relapsed or refractory large B-cell lymphoma.
ATLANTA—The chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; KTE-C19) is showing consistent, ongoing responses more than a year after infusion.
An updated analysis of the phase 1/2 ZUMA-1 trial showed that 42% of patients who received axi-cel maintained an objective response at a median follow-up of 15.4 months.
Forty percent of patients have maintained a complete response (CR).
This compares with a 44% objective response rate and a 39% CR rate in the primary analysis of phase 2 ZUMA-1 data, when the median follow-up was 8.7 months.
Sattva S. Neelapu, MD, of MD Anderson Cancer Center in Houston, Texas, reported the long-term results from ZUMA-1 at the 2017 ASH Annual Meeting (abstract 578). The findings were published simultaneously in NEJM.
The primary phase 2 analysis was previously presented at the AACR Annual Meeting 2017.
At ASH 2017, Dr Neelapu disclosed that he has received research funding and served as a consultant for Kite Pharma, the developer of axi-cel. Kite Pharma and the Leukemia & Lymphoma Society Therapy Acceleration Program supported ZUMA-1.
Study schema and patient characteristics
Phase 1 of ZUMA-1 enrolled 7 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL).
In phase 2, 101 patients were grouped into 2 cohorts—77 with refractory DLBCL and 24 with refractory PMBCL/TFL.
A total of 108 patients were treated in phases 1 and 2 and were included in the long-term pooled analysis.
Patients received a conditioning regimen of cyclophosphamide and fludarabine and, 2 days later, a fixed dose of axi-cel at 2 x 106 CAR T cells/kg.
“Importantly, the product could be manufactured for 99% of enrolled patients,” Dr Neelapu said. “Moreover, 91% of the enrolled patients were dosed with axi-cel, and there were no patients lost to follow-up.”
Patients in the pooled analysis were a median age of 58 (range, 23–76), and 27 (25%) were 65 or older.
Seventy-three patients (68%) were male, 62 (57%) had an ECOG status of 1, 90 (83%) had stage III or IV disease, and 48 (44%) had an IPI score of 3 to 4.
Seventy-six patients (70%) had received 3 or more prior therapies.
Eighty patients (74%) were refractory to their second or later line of therapy, and 70 (65%) had progressive disease as their best response to their last prior therapy. Twenty-five patients (23%) had relapsed after autologous stem cell transplant.
Response
The data cutoff for the long-term analysis was August 11, 2017.
In addition to the ongoing responses mentioned above, the best objective response was 82% in both the phase 2 primary analysis and the long-term analysis for phases 1 and 2.
CR as the best objective response increased from 54% in the primary analysis to 58% at the longer follow-up.
“We did observe deepening of the responses over time,” Dr Neelapu said. “At the time of the first tumor assessment, 60 patients had either partial remission or stable disease. But 23 of those 60 eventually achieved a complete remission up to 15 months post-infusion without any additional therapy.”
The median time to conversion from partial response to CR was 64 days (range, 49–242).
“The durability of these responses was observed consistently across key covariates,” Dr Neelapu added, “including the refractory subgroups, the disease stage groups, IPI risk groups. The CD19 status at baseline did not matter, nor did the cell of origin, or the CD4/CD8 ratio of the product.”
Furthermore, the investigators observed no differences in patients who received tocilizumab or corticosteroids.
The median duration of response for all patients was 11.1 months. For those who achieved CR, the median duration of response has not yet been reached.
Three of the 7 patients (43%) in the phase 1 part of the trial had an ongoing CR at 24 months.
At the median follow-up of 15.4 months, 42% of patients were progression-free, and 56% were alive.
The median overall survival has not been reached. Investigators estimated the 18-month overall survival to be 52%.
Safety
Adverse events (AEs) of grade 3 or higher occurred in 97% of patients, and serious AEs of grade 3 or higher occurred in 46% of patients in the updated analysis.
No new axi-cel-related AEs of cytokine release syndrome, neurologic events, or grade 5 AEs have arisen since the primary analysis.
There were four grade 5 events, 2 of which were related to axi-cel.
“All these four grade 5 events were previously reported—three in the phase 2 and one in the phase 1 trial,” Dr Neelapu said.
Most patients experienced hypogammaglobulinemia and B-cell aplasia. Eight percent of patients had IVIG support during the study.
Infections, such as pneumonia, influenza, and viral infection, were the most common new-onset treatment-emergent serious AEs occurring after 6 months in 10 patients. All were manageable and resolved prior to the data cut-off.
Persistence and resistance
“We observed long-term persistence of the CAR T cells,” Dr Neelapu said.
CAR T cells persisted in 71% of patients still responding at 1 year. And durable responses were observed in patients with and without detectable CAR T cells.
A central review committee analyzed biopsies of 21 evaluable patients at progression to try to determine the mechanism of resistance.
Fourteen of 21 (67%) biopsies were CD19-positive. Of these, 9 were PD-L1-positive, 4 were PD-L1-negative, and 1 was not evaluable.
Seven patients (33%) were CD19-negative compared to baseline. Of these, 4 were PD-L1-positive, 2 were PD-L1-negative, and 1 was not evaluable.
“This PD-L1 expression was observed in both CD19-positive relapses and CD19-negative relapses,” Dr Neelapu emphasized.
Of the 21 patients, 62% were PD-L1-positive.
Investigators hypothesize that 2 potential mechanisms could contribute to relapse: loss of CD19 and expression of PD-L1.
Axi-cel (Yescarta™) was approved by the US Food and Drug Administration in October for the treatment of adults with relapsed or refractory large B-cell lymphoma.
ATLANTA—The chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; KTE-C19) is showing consistent, ongoing responses more than a year after infusion.
An updated analysis of the phase 1/2 ZUMA-1 trial showed that 42% of patients who received axi-cel maintained an objective response at a median follow-up of 15.4 months.
Forty percent of patients have maintained a complete response (CR).
This compares with a 44% objective response rate and a 39% CR rate in the primary analysis of phase 2 ZUMA-1 data, when the median follow-up was 8.7 months.
Sattva S. Neelapu, MD, of MD Anderson Cancer Center in Houston, Texas, reported the long-term results from ZUMA-1 at the 2017 ASH Annual Meeting (abstract 578). The findings were published simultaneously in NEJM.
The primary phase 2 analysis was previously presented at the AACR Annual Meeting 2017.
At ASH 2017, Dr Neelapu disclosed that he has received research funding and served as a consultant for Kite Pharma, the developer of axi-cel. Kite Pharma and the Leukemia & Lymphoma Society Therapy Acceleration Program supported ZUMA-1.
Study schema and patient characteristics
Phase 1 of ZUMA-1 enrolled 7 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL).
In phase 2, 101 patients were grouped into 2 cohorts—77 with refractory DLBCL and 24 with refractory PMBCL/TFL.
A total of 108 patients were treated in phases 1 and 2 and were included in the long-term pooled analysis.
Patients received a conditioning regimen of cyclophosphamide and fludarabine and, 2 days later, a fixed dose of axi-cel at 2 x 106 CAR T cells/kg.
“Importantly, the product could be manufactured for 99% of enrolled patients,” Dr Neelapu said. “Moreover, 91% of the enrolled patients were dosed with axi-cel, and there were no patients lost to follow-up.”
Patients in the pooled analysis were a median age of 58 (range, 23–76), and 27 (25%) were 65 or older.
Seventy-three patients (68%) were male, 62 (57%) had an ECOG status of 1, 90 (83%) had stage III or IV disease, and 48 (44%) had an IPI score of 3 to 4.
Seventy-six patients (70%) had received 3 or more prior therapies.
Eighty patients (74%) were refractory to their second or later line of therapy, and 70 (65%) had progressive disease as their best response to their last prior therapy. Twenty-five patients (23%) had relapsed after autologous stem cell transplant.
Response
The data cutoff for the long-term analysis was August 11, 2017.
In addition to the ongoing responses mentioned above, the best objective response was 82% in both the phase 2 primary analysis and the long-term analysis for phases 1 and 2.
CR as the best objective response increased from 54% in the primary analysis to 58% at the longer follow-up.
“We did observe deepening of the responses over time,” Dr Neelapu said. “At the time of the first tumor assessment, 60 patients had either partial remission or stable disease. But 23 of those 60 eventually achieved a complete remission up to 15 months post-infusion without any additional therapy.”
The median time to conversion from partial response to CR was 64 days (range, 49–242).
“The durability of these responses was observed consistently across key covariates,” Dr Neelapu added, “including the refractory subgroups, the disease stage groups, IPI risk groups. The CD19 status at baseline did not matter, nor did the cell of origin, or the CD4/CD8 ratio of the product.”
Furthermore, the investigators observed no differences in patients who received tocilizumab or corticosteroids.
The median duration of response for all patients was 11.1 months. For those who achieved CR, the median duration of response has not yet been reached.
Three of the 7 patients (43%) in the phase 1 part of the trial had an ongoing CR at 24 months.
At the median follow-up of 15.4 months, 42% of patients were progression-free, and 56% were alive.
The median overall survival has not been reached. Investigators estimated the 18-month overall survival to be 52%.
Safety
Adverse events (AEs) of grade 3 or higher occurred in 97% of patients, and serious AEs of grade 3 or higher occurred in 46% of patients in the updated analysis.
No new axi-cel-related AEs of cytokine release syndrome, neurologic events, or grade 5 AEs have arisen since the primary analysis.
There were four grade 5 events, 2 of which were related to axi-cel.
“All these four grade 5 events were previously reported—three in the phase 2 and one in the phase 1 trial,” Dr Neelapu said.
Most patients experienced hypogammaglobulinemia and B-cell aplasia. Eight percent of patients had IVIG support during the study.
Infections, such as pneumonia, influenza, and viral infection, were the most common new-onset treatment-emergent serious AEs occurring after 6 months in 10 patients. All were manageable and resolved prior to the data cut-off.
Persistence and resistance
“We observed long-term persistence of the CAR T cells,” Dr Neelapu said.
CAR T cells persisted in 71% of patients still responding at 1 year. And durable responses were observed in patients with and without detectable CAR T cells.
A central review committee analyzed biopsies of 21 evaluable patients at progression to try to determine the mechanism of resistance.
Fourteen of 21 (67%) biopsies were CD19-positive. Of these, 9 were PD-L1-positive, 4 were PD-L1-negative, and 1 was not evaluable.
Seven patients (33%) were CD19-negative compared to baseline. Of these, 4 were PD-L1-positive, 2 were PD-L1-negative, and 1 was not evaluable.
“This PD-L1 expression was observed in both CD19-positive relapses and CD19-negative relapses,” Dr Neelapu emphasized.
Of the 21 patients, 62% were PD-L1-positive.
Investigators hypothesize that 2 potential mechanisms could contribute to relapse: loss of CD19 and expression of PD-L1.
Axi-cel (Yescarta™) was approved by the US Food and Drug Administration in October for the treatment of adults with relapsed or refractory large B-cell lymphoma.