User login
Addition of ublituximab to ibrutinib improves response in r/r CLL
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study. 
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
Other adverse events of all grades occurring in 10% of patients or more for the combination and monotherapy arms, respectively, were: diarrhea (42% and 40%), fatigue (27% and 33%), insomnia (24% and 10%), nausea (22% and 21%), headache (20% and 28%), arthralgia (19% and 17%), cough (19% and 24%), abdominal pain (15% and 9%), stomatitis (15% and 9%), upper respiratory infection (15% and 12%), dizziness (15% and 22%), contusion (15% and 29%), anemia (14% and 17%), and peripheral edema (10% and 21%).
Neutropenia was higher in the experimental arm, 22% any grade, compared with 12% in the ibrutinib arm, although grade 3 or higher neutropenia was similar in the 2 arms. Other laboratory abnormalities were similar between the arms.
Efficacy
The best ORR in the combination arm was 78%, with 7% achieving CR compared with 45% in the monotherapy arm with no CRs (P<0.001).
Nineteen percent of the combination arm achieved MRD negativity in peripheral blood compared with 2% of the monotherapy arm (P<0.01).
The reduction in lymph node size was similar between the arms.
In contrast, lymphocytosis was very different between the arms.
“As has been reported multiple times with targeted B-cell receptor signaling inhibitors,” Dr Sharman said, “patients treated with ibrutinib experienced rapid increase in their lymphocytes, returning approximately to baseline by 3 months and decreasing thereafter.”
“By contrast,” he continued, “those patients treated with the additional antibody had much more rapid resolution of their lymphocytosis. This was true whether patients were considered rituximab refractory or not.”
The investigators performed an additional analysis of ORR, this time including patients who achieved partial response with lymphocytosis (PR-L). These patients were not included in the primary endpoint because the iwCLL 2008 criteria had not yet been updated to include PR-L.
The best overall response including active PR-L patients was 83% in the experimental arm and 59% in the ibrutinib monotherapy arm (P<0.01).
PFS showed a trend toward improvement in the patients treated with the combination, with a hazard ratio of 0.559, which was not of statistical significance at the time of analysis.
The investigators concluded that the study met its primary endpoint, with a greater response rate and a greater depth of response than ibrutinib alone.
And the addition of ublituximab did not alter the safety profile of ibrutinib monotherapy.
TG Therapeutics, Inc, funded the study.
*Data in the abstract differ from the meeting presentation.
CAR T cells elicit durable, potent responses in kids with EM relapse of ALL
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL.
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL.
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL.
Study confirms increased adiposity in HSCT survivors
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors. 
*Some details in the abstract differ from the presentation.
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors.
*Some details in the abstract differ from the presentation.
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors.
*Some details in the abstract differ from the presentation.
Study advances precision opioid dosing for mucositis
ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.
Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.
“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.
The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.
She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.
Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.
Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.
The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.
Study design
In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.
The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.
“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”
The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).
Demographics
Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.
The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).
More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.
Results—mucositis
Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.
The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).
Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).
For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.
Results—opioid efficacy
The opioid efficacy analysis was based on 63 patients.
Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).
“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”
Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.
The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).
“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.
Results—opioid toxicity
Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.
Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.
“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”
Results—impact of race
Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).
Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.
The total equivalent dose of morphine used also did not differ between the groups.
“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.
Genetic findings
The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.
Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).
On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.
There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).
However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.
“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”
Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.
“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”
“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.”
*Data in the abstract differ slightly from the presentation.
ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.
Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.
“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.
The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.
She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.
Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.
Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.
The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.
Study design
In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.
The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.
“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”
The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).
Demographics
Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.
The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).
More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.
Results—mucositis
Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.
The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).
Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).
For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.
Results—opioid efficacy
The opioid efficacy analysis was based on 63 patients.
Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).
“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”
Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.
The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).
“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.
Results—opioid toxicity
Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.
Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.
“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”
Results—impact of race
Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).
Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.
The total equivalent dose of morphine used also did not differ between the groups.
“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.
Genetic findings
The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.
Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).
On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.
There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).
However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.
“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”
Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.
“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”
“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.”
*Data in the abstract differ slightly from the presentation.
ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.
Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.
“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.
The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.
She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.
Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.
Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.
The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.
Study design
In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.
The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.
“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”
The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).
Demographics
Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.
The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).
More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.
Results—mucositis
Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.
The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).
Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).
For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.
Results—opioid efficacy
The opioid efficacy analysis was based on 63 patients.
Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).
“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”
Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.
The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).
“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.
Results—opioid toxicity
Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.
Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.
“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”
Results—impact of race
Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).
Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.
The total equivalent dose of morphine used also did not differ between the groups.
“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.
Genetic findings
The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.
Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).
On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.
There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).
However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.
“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”
Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.
“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”
“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.”
*Data in the abstract differ slightly from the presentation.
Single dose of ZA pre-transplant prevents bone loss
ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.
The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.
However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.
Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.
“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.
And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.
So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.
Study design
The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.
All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.
Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.
Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks
The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.
The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.
Patient characteristics
Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.
“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”
Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.
Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.
Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.
Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.
“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”
Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.
Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.
At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.
Results
At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).
For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.
Sixty-five patients were available for the day 365 efficacy analysis.
Bone density did not change significantly between day 100 and 365 for the entire group.
“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”
But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).
Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).
When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100 (P=0.001) and day 365 (P<0.0001).
The researchers observed no serious adverse events with ZA.
Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”
ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.
The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.
However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.
Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.
“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.
And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.
So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.
Study design
The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.
All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.
Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.
Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks
The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.
The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.
Patient characteristics
Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.
“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”
Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.
Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.
Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.
Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.
“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”
Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.
Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.
At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.
Results
At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).
For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.
Sixty-five patients were available for the day 365 efficacy analysis.
Bone density did not change significantly between day 100 and 365 for the entire group.
“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”
But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).
Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).
When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100 (P=0.001) and day 365 (P<0.0001).
The researchers observed no serious adverse events with ZA.
Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”
ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.
The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.
However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.
Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.
“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.
And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.
So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.
Study design
The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.
All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.
Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.
Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks
The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.
The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.
Patient characteristics
Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.
“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”
Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.
Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.
Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.
Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.
“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”
Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.
Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.
At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.
Results
At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).
For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.
Sixty-five patients were available for the day 365 efficacy analysis.
Bone density did not change significantly between day 100 and 365 for the entire group.
“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”
But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).
Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).
When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100 (P=0.001) and day 365 (P<0.0001).
The researchers observed no serious adverse events with ZA.
Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”
Inpatient palliative care improves QOL for HSCT patients
ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.
Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).
She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”
So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.
The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).
The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.
Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.
“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”
Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.
Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.
They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).
They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.
The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.
Demographics
Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.
Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).
Results
At baseline, patients in each group had comparable QOL and mood scores.
However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.
In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.
At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and PTSD symptom (P=0.002) scores were significantly improved in the intervention group.
And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.
The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.
“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.
“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”
The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.
ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.
Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).
She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”
So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.
The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).
The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.
Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.
“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”
Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.
Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.
They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).
They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.
The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.
Demographics
Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.
Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).
Results
At baseline, patients in each group had comparable QOL and mood scores.
However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.
In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.
At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and PTSD symptom (P=0.002) scores were significantly improved in the intervention group.
And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.
The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.
“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.
“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”
The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.
ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.
Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).
She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”
So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.
The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).
The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.
Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.
“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”
Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.
Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.
They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).
They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.
The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.
Demographics
Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.
Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).
Results
At baseline, patients in each group had comparable QOL and mood scores.
However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.
In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.
At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and PTSD symptom (P=0.002) scores were significantly improved in the intervention group.
And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.
The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.
“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.
“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”
The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.
All cases of CRS are not created equal
2016 ASH Annual Meeting
SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.
MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.
The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.
What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.
“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).
“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”
Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).
In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.
“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”
Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.
Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.
CRS with CTL019
Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.
“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”
The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.
“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”
Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.
The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.
“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.
Studying CRS
IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.
He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.
With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.
“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.
To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.
The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.
The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.
“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”
The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.
“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.
The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.
“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.
To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.
The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.
On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.
Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.
The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.
Nanostring profiling
The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.
They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.
“There was a clear separation in cytokine production in this model,” Dr Barrett said.
The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.
“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.
In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.
“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”
The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.
They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.
“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”
2016 ASH Annual Meeting
SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.
MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.
The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.
What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.
“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).
“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”
Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).
In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.
“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”
Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.
Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.
CRS with CTL019
Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.
“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”
The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.
“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”
Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.
The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.
“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.
Studying CRS
IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.
He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.
With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.
“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.
To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.
The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.
The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.
“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”
The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.
“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.
The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.
“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.
To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.
The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.
On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.
Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.
The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.
Nanostring profiling
The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.
They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.
“There was a clear separation in cytokine production in this model,” Dr Barrett said.
The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.
“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.
In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.
“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”
The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.
They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.
“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”
2016 ASH Annual Meeting
SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.
MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.
The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.
What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.
“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.
Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).
“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”
Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).
In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.
“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”
Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.
Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.
CRS with CTL019
Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.
“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”
The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.
“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”
Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.
The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.
“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.
Studying CRS
IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.
He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.
With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.
“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.
To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.
The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.
The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.
“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”
The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.
“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.
The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.
“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.
To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.
The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.
On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.
Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.
The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.
Nanostring profiling
The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.
They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.
“There was a clear separation in cytokine production in this model,” Dr Barrett said.
The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.
“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.
In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.
“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”
The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.
They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.
“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”
HU trial to prevent stroke in SCA feasible in Nigeria
© Todd Buchanan 2016
SAN DIEGO—High rates of recruitment (90%), enrollment (92%), and adherence to study drug and follow-up visits have confirmed the feasibility of conducting a trial of hydroxyurea (HU) for stroke prevention in Nigeria (the SPIN trial), researchers say.
The 235 children with sickle cell anemia (SCA)enrolled on the SPIN trial did not miss any of the scheduled monthly visits, and drug adherence was 84% based on the increase in their mean corpuscular volume (MCV) by 10 fL.
These data provide strong evidence, researchers believe, for patient and family acceptability of the trial and potential safety of a moderate dose of HU to prevent stroke in children with SCA in Nigeria.
Nigeria has the largest burden of sickle cell disease (SCD) in the world, Najibah Galadanci, MBBS, of Bayero University/Aminu Kano Teaching Hospital in Nigeria, said at the 2016 ASH Annual Meeting.
Every year, about 150,000 children in Nigeria are born with SCD. This compares with 2400 children in the United States and 300 children in the United Kingdom.
“And it is estimated that 15,000 children with SCA per year in Nigeria will have strokes,” Dr Galadanci added.
She presented data from the SPIN trial (NCT01801423) at ASH as abstract 122.
At present, she explained, primary stroke prevention consists of regular blood transfusions for patients with transcranial Doppler (TCD) measurements higher than 200 cm/second.
However, distinct challenges with this prevention method exist in sub-Saharan Africa, such as inadequate blood supply, cost, unsafe transfusion practice, and the high probability of blood-borne infections.
HU is the only drug approved by the US Food and Drug administration to treat SCD. It increases total hemoglobin level, which is associated with a decreased risk of strokes.
In addition, HU significantly decreases TCD ultrasound velocity in children with SCD and abnormal TCD and is cost-effective and practical in sub-Saharan Africa.
So investigators at Aminu Kano teaching hospital in Nigeria undertook to study the feasibility of using HU to prevent stroke in children with SCD.
The team based their decision on 3 main components: recruitment rate, retention rate, and adherence to study medication.
SPIN trial
Children ages 5 to 12 were eligible if they had a diagnosis of SCA, either HbSS or HbSb0. They had to have 2 independent readings of elevated TCD velocity of 200 to 219 cm/second or 1 reading of 220 cm/second or higher.
Investigators enrolled 25 children on the treatment arm. The children received a moderate dose (20 mg/kg/day) of HU for 3 years.
Investigators also enrolled a comparison group of 210 children with SCA who had a TCD velocity of less than 200 cm/second.
The median follow-up was 2.1 years. The median age was 6.8 years and 8 years in the treatment and comparison groups, respectively.
The treatment group had a total of 603 follow-up visits.
The recruitment rate was 90% (335 of 370 families), the enrollment rate for the treatment arm was 92% (25 of 27 patients), and the adherence rate to monthly visits was 100%. Eighty-four percent of patients (21/25) adhered to the medication regimen, based on their increased MCV.
HU therapy
Investigators observed no laboratory evidence of severe myelosuppression or toxicity.
Of 712 complete blood counts performed on 25 study participants, 2 patients had repeated hemoglobin counts of less than 6 g/dL, and no participant had a repeat platelet count below 80 x 109/L nor a repeat absolute neutrophil count of less than 1.2 x 109/L.
Investigators found no significant difference overall (P=0.37) in the rate of hospitalization between the treatment and comparison groups based on hospitalizations for acute chest syndrome, pain, stroke, transfusion, malaria, and infection.
Investigators also found no significant difference (P=0.67) in rates of severe adverse events between the study and comparison groups.
Twelve deaths occurred during the study period, 2 in the treatment group (2.69/100 patient years) and 10 in the comparison group (1.81/100 patient years).
Deaths in the treatment arm were due to sepsis and progressive renal disease. Deaths in the comparison group were due to severe anemia, infection, and malaria.
“The most interesting finding of our study,” Dr Galadanci indicated, “was the 85% reduction in TCD velocity after starting hydroxyurea therapy.”
Baseline TCD measurements went from 211 cm/second to 165 cm/second at 24 months.
Dr Galadanci said next steps include conducting a phase 3, multicenter, randomized controlled trial (NCT 02560935) comparing low-dose (10 mg/kg/day) and moderate-dose (20 mg/kg/day) HU therapy for preventing primary strokes in children with SCA living in Nigeria (SPRING Trial).
Investigators hypothesize there will be a 66% reduction over 3 years in relative risk of primary strokes in children with SCA and elevated TCD velocity in the moderate-dose group compared to the low-dose group.
© Todd Buchanan 2016
SAN DIEGO—High rates of recruitment (90%), enrollment (92%), and adherence to study drug and follow-up visits have confirmed the feasibility of conducting a trial of hydroxyurea (HU) for stroke prevention in Nigeria (the SPIN trial), researchers say.
The 235 children with sickle cell anemia (SCA)enrolled on the SPIN trial did not miss any of the scheduled monthly visits, and drug adherence was 84% based on the increase in their mean corpuscular volume (MCV) by 10 fL.
These data provide strong evidence, researchers believe, for patient and family acceptability of the trial and potential safety of a moderate dose of HU to prevent stroke in children with SCA in Nigeria.
Nigeria has the largest burden of sickle cell disease (SCD) in the world, Najibah Galadanci, MBBS, of Bayero University/Aminu Kano Teaching Hospital in Nigeria, said at the 2016 ASH Annual Meeting.
Every year, about 150,000 children in Nigeria are born with SCD. This compares with 2400 children in the United States and 300 children in the United Kingdom.
“And it is estimated that 15,000 children with SCA per year in Nigeria will have strokes,” Dr Galadanci added.
She presented data from the SPIN trial (NCT01801423) at ASH as abstract 122.
At present, she explained, primary stroke prevention consists of regular blood transfusions for patients with transcranial Doppler (TCD) measurements higher than 200 cm/second.
However, distinct challenges with this prevention method exist in sub-Saharan Africa, such as inadequate blood supply, cost, unsafe transfusion practice, and the high probability of blood-borne infections.
HU is the only drug approved by the US Food and Drug administration to treat SCD. It increases total hemoglobin level, which is associated with a decreased risk of strokes.
In addition, HU significantly decreases TCD ultrasound velocity in children with SCD and abnormal TCD and is cost-effective and practical in sub-Saharan Africa.
So investigators at Aminu Kano teaching hospital in Nigeria undertook to study the feasibility of using HU to prevent stroke in children with SCD.
The team based their decision on 3 main components: recruitment rate, retention rate, and adherence to study medication.
SPIN trial
Children ages 5 to 12 were eligible if they had a diagnosis of SCA, either HbSS or HbSb0. They had to have 2 independent readings of elevated TCD velocity of 200 to 219 cm/second or 1 reading of 220 cm/second or higher.
Investigators enrolled 25 children on the treatment arm. The children received a moderate dose (20 mg/kg/day) of HU for 3 years.
Investigators also enrolled a comparison group of 210 children with SCA who had a TCD velocity of less than 200 cm/second.
The median follow-up was 2.1 years. The median age was 6.8 years and 8 years in the treatment and comparison groups, respectively.
The treatment group had a total of 603 follow-up visits.
The recruitment rate was 90% (335 of 370 families), the enrollment rate for the treatment arm was 92% (25 of 27 patients), and the adherence rate to monthly visits was 100%. Eighty-four percent of patients (21/25) adhered to the medication regimen, based on their increased MCV.
HU therapy
Investigators observed no laboratory evidence of severe myelosuppression or toxicity.
Of 712 complete blood counts performed on 25 study participants, 2 patients had repeated hemoglobin counts of less than 6 g/dL, and no participant had a repeat platelet count below 80 x 109/L nor a repeat absolute neutrophil count of less than 1.2 x 109/L.
Investigators found no significant difference overall (P=0.37) in the rate of hospitalization between the treatment and comparison groups based on hospitalizations for acute chest syndrome, pain, stroke, transfusion, malaria, and infection.
Investigators also found no significant difference (P=0.67) in rates of severe adverse events between the study and comparison groups.
Twelve deaths occurred during the study period, 2 in the treatment group (2.69/100 patient years) and 10 in the comparison group (1.81/100 patient years).
Deaths in the treatment arm were due to sepsis and progressive renal disease. Deaths in the comparison group were due to severe anemia, infection, and malaria.
“The most interesting finding of our study,” Dr Galadanci indicated, “was the 85% reduction in TCD velocity after starting hydroxyurea therapy.”
Baseline TCD measurements went from 211 cm/second to 165 cm/second at 24 months.
Dr Galadanci said next steps include conducting a phase 3, multicenter, randomized controlled trial (NCT 02560935) comparing low-dose (10 mg/kg/day) and moderate-dose (20 mg/kg/day) HU therapy for preventing primary strokes in children with SCA living in Nigeria (SPRING Trial).
Investigators hypothesize there will be a 66% reduction over 3 years in relative risk of primary strokes in children with SCA and elevated TCD velocity in the moderate-dose group compared to the low-dose group.
© Todd Buchanan 2016
SAN DIEGO—High rates of recruitment (90%), enrollment (92%), and adherence to study drug and follow-up visits have confirmed the feasibility of conducting a trial of hydroxyurea (HU) for stroke prevention in Nigeria (the SPIN trial), researchers say.
The 235 children with sickle cell anemia (SCA)enrolled on the SPIN trial did not miss any of the scheduled monthly visits, and drug adherence was 84% based on the increase in their mean corpuscular volume (MCV) by 10 fL.
These data provide strong evidence, researchers believe, for patient and family acceptability of the trial and potential safety of a moderate dose of HU to prevent stroke in children with SCA in Nigeria.
Nigeria has the largest burden of sickle cell disease (SCD) in the world, Najibah Galadanci, MBBS, of Bayero University/Aminu Kano Teaching Hospital in Nigeria, said at the 2016 ASH Annual Meeting.
Every year, about 150,000 children in Nigeria are born with SCD. This compares with 2400 children in the United States and 300 children in the United Kingdom.
“And it is estimated that 15,000 children with SCA per year in Nigeria will have strokes,” Dr Galadanci added.
She presented data from the SPIN trial (NCT01801423) at ASH as abstract 122.
At present, she explained, primary stroke prevention consists of regular blood transfusions for patients with transcranial Doppler (TCD) measurements higher than 200 cm/second.
However, distinct challenges with this prevention method exist in sub-Saharan Africa, such as inadequate blood supply, cost, unsafe transfusion practice, and the high probability of blood-borne infections.
HU is the only drug approved by the US Food and Drug administration to treat SCD. It increases total hemoglobin level, which is associated with a decreased risk of strokes.
In addition, HU significantly decreases TCD ultrasound velocity in children with SCD and abnormal TCD and is cost-effective and practical in sub-Saharan Africa.
So investigators at Aminu Kano teaching hospital in Nigeria undertook to study the feasibility of using HU to prevent stroke in children with SCD.
The team based their decision on 3 main components: recruitment rate, retention rate, and adherence to study medication.
SPIN trial
Children ages 5 to 12 were eligible if they had a diagnosis of SCA, either HbSS or HbSb0. They had to have 2 independent readings of elevated TCD velocity of 200 to 219 cm/second or 1 reading of 220 cm/second or higher.
Investigators enrolled 25 children on the treatment arm. The children received a moderate dose (20 mg/kg/day) of HU for 3 years.
Investigators also enrolled a comparison group of 210 children with SCA who had a TCD velocity of less than 200 cm/second.
The median follow-up was 2.1 years. The median age was 6.8 years and 8 years in the treatment and comparison groups, respectively.
The treatment group had a total of 603 follow-up visits.
The recruitment rate was 90% (335 of 370 families), the enrollment rate for the treatment arm was 92% (25 of 27 patients), and the adherence rate to monthly visits was 100%. Eighty-four percent of patients (21/25) adhered to the medication regimen, based on their increased MCV.
HU therapy
Investigators observed no laboratory evidence of severe myelosuppression or toxicity.
Of 712 complete blood counts performed on 25 study participants, 2 patients had repeated hemoglobin counts of less than 6 g/dL, and no participant had a repeat platelet count below 80 x 109/L nor a repeat absolute neutrophil count of less than 1.2 x 109/L.
Investigators found no significant difference overall (P=0.37) in the rate of hospitalization between the treatment and comparison groups based on hospitalizations for acute chest syndrome, pain, stroke, transfusion, malaria, and infection.
Investigators also found no significant difference (P=0.67) in rates of severe adverse events between the study and comparison groups.
Twelve deaths occurred during the study period, 2 in the treatment group (2.69/100 patient years) and 10 in the comparison group (1.81/100 patient years).
Deaths in the treatment arm were due to sepsis and progressive renal disease. Deaths in the comparison group were due to severe anemia, infection, and malaria.
“The most interesting finding of our study,” Dr Galadanci indicated, “was the 85% reduction in TCD velocity after starting hydroxyurea therapy.”
Baseline TCD measurements went from 211 cm/second to 165 cm/second at 24 months.
Dr Galadanci said next steps include conducting a phase 3, multicenter, randomized controlled trial (NCT 02560935) comparing low-dose (10 mg/kg/day) and moderate-dose (20 mg/kg/day) HU therapy for preventing primary strokes in children with SCA living in Nigeria (SPRING Trial).
Investigators hypothesize there will be a 66% reduction over 3 years in relative risk of primary strokes in children with SCA and elevated TCD velocity in the moderate-dose group compared to the low-dose group.
Old drug, new tricks possible in MM
SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.
According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.
In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.
Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.
Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.
High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.
Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.
“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.
So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.
In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.
Three patients achieved a partial response (PR) and 3 a minor response (MR).
The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.
Study design
Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:
- Nelfinavir at 2 x 2500 mg orally on days 1–14
- Bortezomib at 1.3 mg/m2 intravenously or subcutaneously on days 1, 4, 8, and 11
- Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.
Trial therapy lasted for a maximum of 6 cycles (18 weeks).
Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”
The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.
Investigators considered a 30% or higher response rate promising.
Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.
Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.
Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.
Patient population
Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.
They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.
The time from last dose of prior therapy to enrollment on the study was a median of 27 days.
“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.
All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.
Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.
“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.
Efficacy
Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).
Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.
Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).
Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.
Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.
In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.
Efficacy by prior therapy
Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.
For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.
For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.
And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.
Adverse events
“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.
“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”
Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).
Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”
The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.
SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.
According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.
In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.
Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.
Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.
High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.
Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.
“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.
So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.
In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.
Three patients achieved a partial response (PR) and 3 a minor response (MR).
The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.
Study design
Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:
- Nelfinavir at 2 x 2500 mg orally on days 1–14
- Bortezomib at 1.3 mg/m2 intravenously or subcutaneously on days 1, 4, 8, and 11
- Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.
Trial therapy lasted for a maximum of 6 cycles (18 weeks).
Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”
The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.
Investigators considered a 30% or higher response rate promising.
Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.
Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.
Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.
Patient population
Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.
They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.
The time from last dose of prior therapy to enrollment on the study was a median of 27 days.
“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.
All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.
Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.
“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.
Efficacy
Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).
Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.
Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).
Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.
Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.
In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.
Efficacy by prior therapy
Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.
For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.
For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.
And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.
Adverse events
“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.
“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”
Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).
Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”
The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.
SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.
According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.
In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.
Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.
Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.
High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.
Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.
“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.
So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.
In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.
Three patients achieved a partial response (PR) and 3 a minor response (MR).
The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.
Study design
Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:
- Nelfinavir at 2 x 2500 mg orally on days 1–14
- Bortezomib at 1.3 mg/m2 intravenously or subcutaneously on days 1, 4, 8, and 11
- Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.
Trial therapy lasted for a maximum of 6 cycles (18 weeks).
Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”
The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.
Investigators considered a 30% or higher response rate promising.
Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.
Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.
Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.
Patient population
Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.
They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.
The time from last dose of prior therapy to enrollment on the study was a median of 27 days.
“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.
All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.
Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.
“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.
Efficacy
Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).
Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.
Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).
Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.
Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.
In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.
Efficacy by prior therapy
Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.
For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.
For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.
And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.
Adverse events
“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.
“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”
Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).
Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”
The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.
MM patients with t(11;14) benefit from venetoclax
SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).
Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.
Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.
“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).
“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”
Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-XL) mRNA. BCL-2 and MCL-1 promote survival of MM cells.
Study design and enrollment
The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.
Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.
Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.
They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.
The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.
Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.
Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.
Patient characteristics
Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.
Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.
“I want to draw your attention to two features here,” Dr Kumar said.
“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”
Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.
“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”
Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.
Patient disposition
At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.
The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.
Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.
The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1).
“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”
Adverse events
The toxicity profile was primarily hematologic and gastrointestinal.
All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.
“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”
Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).
Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).
Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).
Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.
No events of tumor lysis syndrome (TLS) were reported. Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.
Response
The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.
“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”
The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.
“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.
Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.
“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”
Duration of response for patients with t(11;14) was close to 10 months.
Biomarker analysis
The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.
So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).
The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.
Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.
Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.
Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.
The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.
Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.
*Data in the abstract differ from the presentation.
SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).
Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.
Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.
“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).
“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”
Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-XL) mRNA. BCL-2 and MCL-1 promote survival of MM cells.
Study design and enrollment
The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.
Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.
Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.
They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.
The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.
Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.
Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.
Patient characteristics
Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.
Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.
“I want to draw your attention to two features here,” Dr Kumar said.
“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”
Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.
“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”
Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.
Patient disposition
At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.
The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.
Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.
The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1).
“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”
Adverse events
The toxicity profile was primarily hematologic and gastrointestinal.
All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.
“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”
Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).
Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).
Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).
Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.
No events of tumor lysis syndrome (TLS) were reported. Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.
Response
The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.
“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”
The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.
“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.
Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.
“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”
Duration of response for patients with t(11;14) was close to 10 months.
Biomarker analysis
The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.
So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).
The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.
Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.
Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.
Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.
The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.
Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.
*Data in the abstract differ from the presentation.
SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).
Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.
Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.
“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).
“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”
Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-XL) mRNA. BCL-2 and MCL-1 promote survival of MM cells.
Study design and enrollment
The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.
Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.
Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.
They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.
The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.
Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.
Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.
Patient characteristics
Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.
Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.
“I want to draw your attention to two features here,” Dr Kumar said.
“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”
Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.
“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”
Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.
Patient disposition
At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.
The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.
Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.
The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1).
“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”
Adverse events
The toxicity profile was primarily hematologic and gastrointestinal.
All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.
“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”
Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).
Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).
Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).
Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.
No events of tumor lysis syndrome (TLS) were reported. Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.
Response
The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.
“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”
The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.
“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.
Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.
“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”
Duration of response for patients with t(11;14) was close to 10 months.
Biomarker analysis
The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.
So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).
The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.
Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.
Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.
Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.
The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.
Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.
*Data in the abstract differ from the presentation.