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Metabolic changes in T cells may limit CAR potential in kids
Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.
This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.
Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.
“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.
“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.
But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.
The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.
Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.
And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.
The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.
“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”
T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.
“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”
The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.
“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”
The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.
The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.
T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.
“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.
“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”
The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.
“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”
Dr Barrett noted that the findings have already altered practice for children at his institution.
They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.
“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.”
Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.
This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.
Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.
“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.
“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.
But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.
The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.
Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.
And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.
The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.
“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”
T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.
“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”
The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.
“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”
The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.
The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.
T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.
“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.
“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”
The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.
“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”
Dr Barrett noted that the findings have already altered practice for children at his institution.
They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.
“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.”
Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.
This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.
Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.
“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.
“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.
But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.
The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.
Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.
And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.
The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.
“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”
T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.
“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”
The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.
“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”
The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.
The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.
T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.
“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.
“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”
The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.
“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”
Dr Barrett noted that the findings have already altered practice for children at his institution.
They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.
“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.”
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.
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.
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.
Study highlights need for induction strategy in elderly, frail MM patients
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
bb2121 induces durable, deepening responses in MM patients
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
Drug allows for treatment-free periods in PV
ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.
Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.
Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.
There were no dose-limiting toxicities (DLTs) in the trial.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*
The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.
Study rationale
Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.
Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.
And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.
So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).
The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.
Study design
The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.
Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.
Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.
If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.
After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.
“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.
Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.
They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.
Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.
Baseline patient characteristics
Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.
They had a median leukocyte count of 11.3 x 109/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 109/L.
They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.
“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”
Efficacy
Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.
“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”
In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.
In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.
In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.
Reasons for discontinuation were patient refusal and investigator decision.
The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.
In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.
“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”
The ORR for both the single-agent and combination parts of the study was 75%.
Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.
“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”
Patients had a median 43% reduction in JAK2 mutation from baseline.
“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”
Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.
Safety
There were no DLTs with either dose of idasanutlin.
“This was a well-tolerated drug,” Dr Mascarenhas said.
Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).
No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.
Investigators also observed no grade 3–4 gastrointestinal (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.
Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.
A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.
Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.
Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.
There were no dose-limiting toxicities (DLTs) in the trial.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*
The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.
Study rationale
Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.
Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.
And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.
So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).
The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.
Study design
The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.
Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.
Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.
If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.
After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.
“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.
Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.
They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.
Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.
Baseline patient characteristics
Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.
They had a median leukocyte count of 11.3 x 109/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 109/L.
They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.
“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”
Efficacy
Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.
“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”
In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.
In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.
In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.
Reasons for discontinuation were patient refusal and investigator decision.
The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.
In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.
“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”
The ORR for both the single-agent and combination parts of the study was 75%.
Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.
“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”
Patients had a median 43% reduction in JAK2 mutation from baseline.
“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”
Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.
Safety
There were no DLTs with either dose of idasanutlin.
“This was a well-tolerated drug,” Dr Mascarenhas said.
Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).
No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.
Investigators also observed no grade 3–4 gastrointestinal (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.
Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.
A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.
Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.
Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.
There were no dose-limiting toxicities (DLTs) in the trial.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*
The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.
Study rationale
Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.
Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.
And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.
So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).
The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.
Study design
The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.
Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.
Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.
If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.
After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.
“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.
Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.
They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.
Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.
Baseline patient characteristics
Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.
They had a median leukocyte count of 11.3 x 109/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 109/L.
They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.
“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”
Efficacy
Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.
“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”
In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.
In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.
In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.
Reasons for discontinuation were patient refusal and investigator decision.
The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.
In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.
“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”
The ORR for both the single-agent and combination parts of the study was 75%.
Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.
“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”
Patients had a median 43% reduction in JAK2 mutation from baseline.
“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”
Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.
Safety
There were no DLTs with either dose of idasanutlin.
“This was a well-tolerated drug,” Dr Mascarenhas said.
Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).
No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.
Investigators also observed no grade 3–4 gastrointestinal (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.
Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.
A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.
*Data in the presentation differ from the abstract.
Risk stratification may be possible with JCAR017
ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.
In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.
If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.
TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.
Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.
Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).
Study design
Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.
Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.
Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.
Patients then had a PET scan and lab tests prior to lymphodepletion.
“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . . that could help us figure out which patients are at higher risk of toxicity, potentially.”
Lymphodepletion consisted of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2 for 3 days).
Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.
Dose levels were 5 x 107 cells as a single or double dose (DL1S) and 1 x 108 cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.
“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”
At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.
Results
Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.
“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.
At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).
At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.
The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.
Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.
“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”
Dr Saddiqi focused the presentation on patient factors.
Patient factors
The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.
Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.
However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.
Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD) ≥ 50 cm2 at baseline had an 8-fold increase in risk of CRS and neurotoxicity.
“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”
Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.
The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.
“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.
And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.
“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.
The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.
The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.
“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.
"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”
The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.
TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.
*Data in the presentation differ from the abstract.
ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.
In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.
If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.
TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.
Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.
Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).
Study design
Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.
Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.
Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.
Patients then had a PET scan and lab tests prior to lymphodepletion.
“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . . that could help us figure out which patients are at higher risk of toxicity, potentially.”
Lymphodepletion consisted of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2 for 3 days).
Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.
Dose levels were 5 x 107 cells as a single or double dose (DL1S) and 1 x 108 cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.
“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”
At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.
Results
Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.
“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.
At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).
At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.
The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.
Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.
“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”
Dr Saddiqi focused the presentation on patient factors.
Patient factors
The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.
Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.
However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.
Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD) ≥ 50 cm2 at baseline had an 8-fold increase in risk of CRS and neurotoxicity.
“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”
Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.
The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.
“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.
And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.
“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.
The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.
The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.
“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.
"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”
The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.
TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.
*Data in the presentation differ from the abstract.
ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.
In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.
If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.
TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.
Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.
Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).
Study design
Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.
Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.
Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.
Patients then had a PET scan and lab tests prior to lymphodepletion.
“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . . that could help us figure out which patients are at higher risk of toxicity, potentially.”
Lymphodepletion consisted of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2 for 3 days).
Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.
Dose levels were 5 x 107 cells as a single or double dose (DL1S) and 1 x 108 cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.
“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”
At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.
Results
Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.
“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.
At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).
At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.
The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.
Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.
“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”
Dr Saddiqi focused the presentation on patient factors.
Patient factors
The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.
Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.
However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.
Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD) ≥ 50 cm2 at baseline had an 8-fold increase in risk of CRS and neurotoxicity.
“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”
Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.
The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.
“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.
And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.
“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.
The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.
The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.
“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.
"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”
The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.
TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.
*Data in the presentation differ from the abstract.
Primary analysis confirms interim findings of CTL019 in DLBCL
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
Is MRD ready for prime time in multiple myeloma?
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.