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KTE-C19 feasible in most young, high-risk ALL patients, study suggests
Photo by Bill Branson
SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).
Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.
The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.
Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).
Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.
At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.
The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).
Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.
The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.
Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.
All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.
Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.
Efficacy
The median follow-up was 18.7 months.
Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.
The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.
The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.
“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.
However, he noted superior response and overall survival rates among patients who received a fludarabine/cyclophosphamide preparative regimen.
“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.
The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.
For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.
Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.
Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)
Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.
The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.
The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.
CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.
Toxicity
“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.
Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.
Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade
3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).
“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”
In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),
dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%). 
Photo by Bill Branson
SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).
Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.
The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.
Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).
Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.
At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.
The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).
Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.
The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.
Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.
All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.
Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.
Efficacy
The median follow-up was 18.7 months.
Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.
The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.
The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.
“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.
However, he noted superior response and overall survival rates among patients who received a fludarabine/cyclophosphamide preparative regimen.
“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.
The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.
For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.
Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.
Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)
Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.
The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.
The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.
CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.
Toxicity
“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.
Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.
Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade
3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).
“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”
In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),
dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).
Photo by Bill Branson
SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).
Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.
The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.
Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).
Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.
At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.
The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).
Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.
The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.
Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.
All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.
Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.
Efficacy
The median follow-up was 18.7 months.
Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.
The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.
The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.
“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.
However, he noted superior response and overall survival rates among patients who received a fludarabine/cyclophosphamide preparative regimen.
“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.
The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.
For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.
Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.
Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)
Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.
The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.
The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.
CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.
Toxicity
“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.
Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.
Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade
3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).
“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”
In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),
dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).
G-CHOP no better than R-CHOP in previously untreated DLBCL
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).
SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.
In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.
There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).
In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.
“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.
“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”
Dr Vitolo presented results from GOYA at ASH as abstract 470.
Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.
In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.
So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.
Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m2 intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.
Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.
Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.
Efficacy
The median follow-up was 29 months.
For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).
There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.
At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.
The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).
In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).
Safety
No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.
Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).
AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.
Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).
Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).
MPNs limit daily activities and ability to work
2016 ASH Annual Meeting
SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.
Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).
Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.
“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.
“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”
Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).
The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.
Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.
Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.
“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”
She noted that many of her PV patients are young, working professionals.
Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).
These results are consistent with those from a previous US LANDMARK survey of MPN patients.
The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.
“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.
In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).
“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”
A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”
*Information presented at the meeting differs from the abstract.
2016 ASH Annual Meeting
SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.
Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).
Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.
“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.
“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”
Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).
The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.
Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.
Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.
“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”
She noted that many of her PV patients are young, working professionals.
Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).
These results are consistent with those from a previous US LANDMARK survey of MPN patients.
The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.
“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.
In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).
“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”
A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”
*Information presented at the meeting differs from the abstract.
2016 ASH Annual Meeting
SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.
Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).
Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.
“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.
“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”
Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).
The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.
Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.
Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.
“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”
She noted that many of her PV patients are young, working professionals.
Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).
These results are consistent with those from a previous US LANDMARK survey of MPN patients.
The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.
“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.
In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).
“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”
A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”
*Information presented at the meeting differs from the abstract.
Half of CML patients can stop TKI therapy, study suggests
© Todd Buchanan 2016
SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.
About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.
Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).
Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.
“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”
Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.
Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.
At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.
Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.
Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”
Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.
The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.
*Information presented at the meeting differs from the abstract.
© Todd Buchanan 2016
SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.
About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.
Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).
Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.
“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”
Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.
Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.
At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.
Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.
Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”
Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.
The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.
*Information presented at the meeting differs from the abstract.
© Todd Buchanan 2016
SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.
About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.
Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).
Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.
“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”
Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.
Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.
At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.
Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.
Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”
Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.
The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.
*Information presented at the meeting differs from the abstract.
Combo shows early promise in newly diagnosed AML
© Todd Buchanan 2016
SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.
In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.
The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).
The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.
Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.
The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.
Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m2 and daunorubicin at 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.
A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.
Results
The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.
Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).
Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.
None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.
A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).
The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.
There was a hint of additional benefit as well, he added.
“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”
MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.
Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.
*Information presented at the meeting differs from the abstract.
© Todd Buchanan 2016
SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.
In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.
The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).
The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.
Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.
The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.
Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m2 and daunorubicin at 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.
A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.
Results
The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.
Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).
Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.
None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.
A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).
The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.
There was a hint of additional benefit as well, he added.
“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”
MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.
Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.
*Information presented at the meeting differs from the abstract.
© Todd Buchanan 2016
SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.
In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.
The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).
The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.
Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.
The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.
Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m2 and daunorubicin at 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.
A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.
Results
The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.
Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).
Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.
None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.
A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).
The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.
There was a hint of additional benefit as well, he added.
“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”
MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.
Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.
*Information presented at the meeting differs from the abstract.
Better ways to drive CAR T-cell therapy
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
Lenalidomide maintenance after transplant improves OS in MM
the ASCO Annual Meeting
© ASCO/Todd Buchanan
CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in
newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.
Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.
Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.
However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.
With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.
Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.
In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.
With a median follow-up of 6.6 years, 491 patients (41%) had died.
After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.
The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.
“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.
The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.
All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.
The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.
Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.
“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.
“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”
Dr McCarthy presented these findings as abstract 8001.
the ASCO Annual Meeting
© ASCO/Todd Buchanan
CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in
newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.
Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.
Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.
However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.
With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.
Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.
In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.
With a median follow-up of 6.6 years, 491 patients (41%) had died.
After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.
The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.
“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.
The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.
All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.
The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.
Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.
“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.
“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”
Dr McCarthy presented these findings as abstract 8001.
the ASCO Annual Meeting
© ASCO/Todd Buchanan
CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in
newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.
Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.
Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.
However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.
With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.
Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.
In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.
With a median follow-up of 6.6 years, 491 patients (41%) had died.
After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.
The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.
“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.
The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.
All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.
The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.
Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.
“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.
“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”
Dr McCarthy presented these findings as abstract 8001.
Most CML patients who stop nilotinib stay in remission
© ASCO/Matt Herp
CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054).
Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).
Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib.
“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia.
ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib.
The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.
The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase.
Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.
Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5.
By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively.
One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study.
“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”
No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase.
Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”
He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”
Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.
© ASCO/Matt Herp
CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054).
Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).
Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib.
“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia.
ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib.
The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.
The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase.
Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.
Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5.
By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively.
One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study.
“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”
No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase.
Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”
He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”
Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.
© ASCO/Matt Herp
CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054).
Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).
Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib.
“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia.
ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib.
The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.
The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase.
Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.
Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5.
By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively.
One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study.
“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”
No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase.
Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”
He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”
Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.
Combo deepens responses and improves PFS in MM
Photo courtesy of the
University of Navarra
ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.
Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.
Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).
In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.
A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.
With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.
The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).
“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.
Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).
Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).
The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.
The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.
“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”
He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.
“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.
The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.
Photo courtesy of the
University of Navarra
ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.
Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.
Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).
In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.
A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.
With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.
The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).
“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.
Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).
Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).
The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.
The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.
“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”
He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.
“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.
The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.
Photo courtesy of the
University of Navarra
ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.
Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.
Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).
In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.
A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.
With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.
The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).
“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.
Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).
Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).
The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.
The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.
“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”
He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.
“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.
The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.
CAR T cells persist for 3 years in young ALL patients
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.
Photo courtesy of Penn Medicine
ORLANDO, FL—CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy, can persist for 3 years or longer in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to the latest results of a pilot study.
This suggests CTL019 can offer long-term disease control without subsequent therapy, such as stem cell transplant, said study author Stephan Grupp, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Grupp presented these results at the 2015 ASH Annual Meeting (abstract 681*).
Previously, Dr Grupp and his colleagues reported that CTL019 led to durable antitumor activity, including sustained complete responses (CRs) in adults and children with ALL (ASH 2012, NEJM 2013, ASH 2013, NEJM 2014, ASH 2014).
At this year’s ASH meeting, he reported on outcomes and longer follow-up of the first 59 patients with relapsed/refractory ALL treated in a pilot trial. The patients had a median age of 11 years.
The median follow-up was 12 months. Fifty-five patients (93%) achieved a CR at 1 month. Six patients went on to receive a transplant, and 1 patient went on to receive donor lymphocyte infusion.
The relapse-free survival was 76% at 6 months and 55% at 12 months. Overall survival was 79% at 12 months.
“There were no relapses past 1 year,” Dr Grupp said, noting that 18 patients beyond 1 year are in remission, and 13 patients have not received further therapy.
“We are able to get patients into remission,” he said, adding that response is similar at high and low disease burden.
“We see massive proliferation of CAR T cells. Prolonged CTL019 persistence is detected by flow cytometry. About 70% of patients maintain CAR T cells.”
Resistance was seen in 7% of patients due to failure of T cells to proliferate. One-third of recurrences occurred in those with CD19-positive relapse and two-thirds with CD19-negative relapse.
Dr Grupp noted that CTL019 has an impact on central nervous system (CNS) disease.
“We are able to control CNS disease,” he said. “We found no CNS relapses in patients who were treated, and 98% of them still have CTL019 in the cerebral spinal fluid.”
B-cell aplasia persists beyond 3.5 years in all responding patients. This is managed by immunoglobulin replacement.
“Patients in remission and with B-cell aplasia at 1 year are still alive at 2 to 3 years,” Dr Grupp said. “We do not know how long this will last and if B cells will recover.”
Severe cytokine release syndrome (CRS), observed in 88% of patients, is the principal toxicity. This is controlled with anti-IL6 therapy. Patients who are less likely to have CRS are those with a lower disease burden.
“IL-6 is a major player but does not predict CRS; it only correlates strongly with it,” Dr Grupp said.
Some toxicity is also associated with macrophage activation syndrome and neurotoxicity.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Most of the researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 1 researcher is employed by the company.
*Data in the abstract differ from the presentation.