PHASE IB/II STUDY OF NIVOLUMAB IN COMBINATION WITH 5-AZACYTIDINE (AZA) IN PATIENTS (PTS) WITH RELAPSED ACUTE MYELOID LEUKEMIA (AML)
(Abstract release date: 05/19/16)
EHA Library. Daver N. 06/10/16; 133177; P189
Dr. Naval Daver
Contributions
Contributions
Abstract
Abstract: P189
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
PD1+ T-cells are significantly increased in the bone marrow (BM) of pts with relapsed AML as compared to healthy adult donor BM (Daver et al., AACR 2016). Epigenetic therapy upregulates PD1 and PD-L1 in MDS/AML and upregulation of these genes may be associated with the emergence of resistance and inferior survival (Yang et al., Leukemia 2013).
Aims
This single-center phase Ib/II study was conducted to determine the recommended phase 2 dose (RP2D), efficacy and safety of nivolumab in combination with AZA in pts with relapsed AML.
Methods
Pts are eligible if they have AML and failed prior therapy, have adequate performance status (ECOG ≤ 2), and organ function. The first six pts received AZA 75mg/m2 days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated approximately every 4-5 weeks. One of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was established as the RP2D. 24 additional pts have been treated at the RP2D.
Results
To date, 30 pts (15 de novo, 15 secondary AML) with a median age of 72 years (range, 45 – 76) have been enrolled. They included 9 (30%) pts with diploid, 14 (47%) with adverse, and 7 (23%) with miscellaneous cytogenetics. Median number of prior therapies was 2 (range, 1 - 4), including hypomethylating agent-based (n=17), high dose cytarabine-based (n=15), intermediate dose cytarabine-based (n=7), and targeted therapies (n=5). Median bone marrow blast %, WBC, hemoglobin, and platelet counts were 43% (13 – 90), 2.3 x 109/L (0.5 – 81), 9.3 g/dL (7.4 – 12.7), and 28 x 109/L (8 – 145), respectively. Baseline bone marrow samples from all pts were analyzed for common myeloid mutations by next generation sequencing. The most frequently detected mutations were DNMT3A (n=9), ASXL1 (n=6), CEBPA (n=4), RAS (n=4), TP53 (n=3), and TET2 (n=4). 22 pts are evaluable for response (Fig 1): 4 (18%) achieved complete remission (CR)/ complete remission with insufficient count recovery (CRi), 2 (9%) had hematologic improvement (HI) with blast reduction, 5 (23%) had HI only, and 5 (23%) had ≥50% BM blast reduction only. 6 pts had stable disease (n=2) or progression (n=4). 8 pts are too early for response assessment at this time. Median number of cycles to any response was 2 (1 – 4). The median follow-up is 3.6 months (1.5 – 8.7). Grade 3/4 and Grade 2 immune toxicities were observed in 6 (20%) and 5 (17%) pts, respectively. These included 6 pneumonitis, 2 nephritis, 1 skin rash, and 2 transaminitis. Time to onset of toxicities ranged from 4 days to 3.5 months. All toxicities responded rapidly to steroids and all pts were successfully rechallenged with nivolumab. No pts came off study due to immune toxicities. No association between toxicities and response was identifiable. The median progression free and overall survival for 22 evaluable pts was 3.5 and 5.9 months, respectively. These results compare favorably to a historical cohort of 99 relapsed AML pts treated on other hypomethylating agent combination protocols at our institution between 2005-2015 (Table 1). Identification of baseline and dynamic biomarkers of response and survival by sequential immunohistochemistry, flow-cytometry, and RNA-sequencing is currently ongoing.Table 1: AZA+nivolumab versus historical HMA-combinations at MDACC
Conclusion
Combination of AZA and nivolumab is effective in pts with relapsed AML. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Hypomethylation, Immunotherapy
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
PD1+ T-cells are significantly increased in the bone marrow (BM) of pts with relapsed AML as compared to healthy adult donor BM (Daver et al., AACR 2016). Epigenetic therapy upregulates PD1 and PD-L1 in MDS/AML and upregulation of these genes may be associated with the emergence of resistance and inferior survival (Yang et al., Leukemia 2013).
Aims
This single-center phase Ib/II study was conducted to determine the recommended phase 2 dose (RP2D), efficacy and safety of nivolumab in combination with AZA in pts with relapsed AML.
Methods
Pts are eligible if they have AML and failed prior therapy, have adequate performance status (ECOG ≤ 2), and organ function. The first six pts received AZA 75mg/m2 days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated approximately every 4-5 weeks. One of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was established as the RP2D. 24 additional pts have been treated at the RP2D.
Results
To date, 30 pts (15 de novo, 15 secondary AML) with a median age of 72 years (range, 45 – 76) have been enrolled. They included 9 (30%) pts with diploid, 14 (47%) with adverse, and 7 (23%) with miscellaneous cytogenetics. Median number of prior therapies was 2 (range, 1 - 4), including hypomethylating agent-based (n=17), high dose cytarabine-based (n=15), intermediate dose cytarabine-based (n=7), and targeted therapies (n=5). Median bone marrow blast %, WBC, hemoglobin, and platelet counts were 43% (13 – 90), 2.3 x 109/L (0.5 – 81), 9.3 g/dL (7.4 – 12.7), and 28 x 109/L (8 – 145), respectively. Baseline bone marrow samples from all pts were analyzed for common myeloid mutations by next generation sequencing. The most frequently detected mutations were DNMT3A (n=9), ASXL1 (n=6), CEBPA (n=4), RAS (n=4), TP53 (n=3), and TET2 (n=4). 22 pts are evaluable for response (Fig 1): 4 (18%) achieved complete remission (CR)/ complete remission with insufficient count recovery (CRi), 2 (9%) had hematologic improvement (HI) with blast reduction, 5 (23%) had HI only, and 5 (23%) had ≥50% BM blast reduction only. 6 pts had stable disease (n=2) or progression (n=4). 8 pts are too early for response assessment at this time. Median number of cycles to any response was 2 (1 – 4). The median follow-up is 3.6 months (1.5 – 8.7). Grade 3/4 and Grade 2 immune toxicities were observed in 6 (20%) and 5 (17%) pts, respectively. These included 6 pneumonitis, 2 nephritis, 1 skin rash, and 2 transaminitis. Time to onset of toxicities ranged from 4 days to 3.5 months. All toxicities responded rapidly to steroids and all pts were successfully rechallenged with nivolumab. No pts came off study due to immune toxicities. No association between toxicities and response was identifiable. The median progression free and overall survival for 22 evaluable pts was 3.5 and 5.9 months, respectively. These results compare favorably to a historical cohort of 99 relapsed AML pts treated on other hypomethylating agent combination protocols at our institution between 2005-2015 (Table 1). Identification of baseline and dynamic biomarkers of response and survival by sequential immunohistochemistry, flow-cytometry, and RNA-sequencing is currently ongoing.Table 1: AZA+nivolumab versus historical HMA-combinations at MDACC
| AZA+nivolumab N=22 | Hypomethylator-combination protocolsN=99 | P-value | |
| CR/CRi | 18% | 11% | 0.36 |
| 8-week mortality | 5% | 20% | 0.08 |
| Med PFS | 3.5 m | 2.2 m | <0.001 |
| Med OS | 5.9 m | 4.1 m | 0.25 |
Conclusion
Combination of AZA and nivolumab is effective in pts with relapsed AML. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Hypomethylation, Immunotherapy
Abstract: P189
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
PD1+ T-cells are significantly increased in the bone marrow (BM) of pts with relapsed AML as compared to healthy adult donor BM (Daver et al., AACR 2016). Epigenetic therapy upregulates PD1 and PD-L1 in MDS/AML and upregulation of these genes may be associated with the emergence of resistance and inferior survival (Yang et al., Leukemia 2013).
Aims
This single-center phase Ib/II study was conducted to determine the recommended phase 2 dose (RP2D), efficacy and safety of nivolumab in combination with AZA in pts with relapsed AML.
Methods
Pts are eligible if they have AML and failed prior therapy, have adequate performance status (ECOG ≤ 2), and organ function. The first six pts received AZA 75mg/m2 days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated approximately every 4-5 weeks. One of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was established as the RP2D. 24 additional pts have been treated at the RP2D.
Results
To date, 30 pts (15 de novo, 15 secondary AML) with a median age of 72 years (range, 45 – 76) have been enrolled. They included 9 (30%) pts with diploid, 14 (47%) with adverse, and 7 (23%) with miscellaneous cytogenetics. Median number of prior therapies was 2 (range, 1 - 4), including hypomethylating agent-based (n=17), high dose cytarabine-based (n=15), intermediate dose cytarabine-based (n=7), and targeted therapies (n=5). Median bone marrow blast %, WBC, hemoglobin, and platelet counts were 43% (13 – 90), 2.3 x 109/L (0.5 – 81), 9.3 g/dL (7.4 – 12.7), and 28 x 109/L (8 – 145), respectively. Baseline bone marrow samples from all pts were analyzed for common myeloid mutations by next generation sequencing. The most frequently detected mutations were DNMT3A (n=9), ASXL1 (n=6), CEBPA (n=4), RAS (n=4), TP53 (n=3), and TET2 (n=4). 22 pts are evaluable for response (Fig 1): 4 (18%) achieved complete remission (CR)/ complete remission with insufficient count recovery (CRi), 2 (9%) had hematologic improvement (HI) with blast reduction, 5 (23%) had HI only, and 5 (23%) had ≥50% BM blast reduction only. 6 pts had stable disease (n=2) or progression (n=4). 8 pts are too early for response assessment at this time. Median number of cycles to any response was 2 (1 – 4). The median follow-up is 3.6 months (1.5 – 8.7). Grade 3/4 and Grade 2 immune toxicities were observed in 6 (20%) and 5 (17%) pts, respectively. These included 6 pneumonitis, 2 nephritis, 1 skin rash, and 2 transaminitis. Time to onset of toxicities ranged from 4 days to 3.5 months. All toxicities responded rapidly to steroids and all pts were successfully rechallenged with nivolumab. No pts came off study due to immune toxicities. No association between toxicities and response was identifiable. The median progression free and overall survival for 22 evaluable pts was 3.5 and 5.9 months, respectively. These results compare favorably to a historical cohort of 99 relapsed AML pts treated on other hypomethylating agent combination protocols at our institution between 2005-2015 (Table 1). Identification of baseline and dynamic biomarkers of response and survival by sequential immunohistochemistry, flow-cytometry, and RNA-sequencing is currently ongoing.Table 1: AZA+nivolumab versus historical HMA-combinations at MDACC
Conclusion
Combination of AZA and nivolumab is effective in pts with relapsed AML. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Hypomethylation, Immunotherapy
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
PD1+ T-cells are significantly increased in the bone marrow (BM) of pts with relapsed AML as compared to healthy adult donor BM (Daver et al., AACR 2016). Epigenetic therapy upregulates PD1 and PD-L1 in MDS/AML and upregulation of these genes may be associated with the emergence of resistance and inferior survival (Yang et al., Leukemia 2013).
Aims
This single-center phase Ib/II study was conducted to determine the recommended phase 2 dose (RP2D), efficacy and safety of nivolumab in combination with AZA in pts with relapsed AML.
Methods
Pts are eligible if they have AML and failed prior therapy, have adequate performance status (ECOG ≤ 2), and organ function. The first six pts received AZA 75mg/m2 days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated approximately every 4-5 weeks. One of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was established as the RP2D. 24 additional pts have been treated at the RP2D.
Results
To date, 30 pts (15 de novo, 15 secondary AML) with a median age of 72 years (range, 45 – 76) have been enrolled. They included 9 (30%) pts with diploid, 14 (47%) with adverse, and 7 (23%) with miscellaneous cytogenetics. Median number of prior therapies was 2 (range, 1 - 4), including hypomethylating agent-based (n=17), high dose cytarabine-based (n=15), intermediate dose cytarabine-based (n=7), and targeted therapies (n=5). Median bone marrow blast %, WBC, hemoglobin, and platelet counts were 43% (13 – 90), 2.3 x 109/L (0.5 – 81), 9.3 g/dL (7.4 – 12.7), and 28 x 109/L (8 – 145), respectively. Baseline bone marrow samples from all pts were analyzed for common myeloid mutations by next generation sequencing. The most frequently detected mutations were DNMT3A (n=9), ASXL1 (n=6), CEBPA (n=4), RAS (n=4), TP53 (n=3), and TET2 (n=4). 22 pts are evaluable for response (Fig 1): 4 (18%) achieved complete remission (CR)/ complete remission with insufficient count recovery (CRi), 2 (9%) had hematologic improvement (HI) with blast reduction, 5 (23%) had HI only, and 5 (23%) had ≥50% BM blast reduction only. 6 pts had stable disease (n=2) or progression (n=4). 8 pts are too early for response assessment at this time. Median number of cycles to any response was 2 (1 – 4). The median follow-up is 3.6 months (1.5 – 8.7). Grade 3/4 and Grade 2 immune toxicities were observed in 6 (20%) and 5 (17%) pts, respectively. These included 6 pneumonitis, 2 nephritis, 1 skin rash, and 2 transaminitis. Time to onset of toxicities ranged from 4 days to 3.5 months. All toxicities responded rapidly to steroids and all pts were successfully rechallenged with nivolumab. No pts came off study due to immune toxicities. No association between toxicities and response was identifiable. The median progression free and overall survival for 22 evaluable pts was 3.5 and 5.9 months, respectively. These results compare favorably to a historical cohort of 99 relapsed AML pts treated on other hypomethylating agent combination protocols at our institution between 2005-2015 (Table 1). Identification of baseline and dynamic biomarkers of response and survival by sequential immunohistochemistry, flow-cytometry, and RNA-sequencing is currently ongoing.Table 1: AZA+nivolumab versus historical HMA-combinations at MDACC
| AZA+nivolumab N=22 | Hypomethylator-combination protocolsN=99 | P-value | |
| CR/CRi | 18% | 11% | 0.36 |
| 8-week mortality | 5% | 20% | 0.08 |
| Med PFS | 3.5 m | 2.2 m | <0.001 |
| Med OS | 5.9 m | 4.1 m | 0.25 |
Conclusion
Combination of AZA and nivolumab is effective in pts with relapsed AML. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Hypomethylation, Immunotherapy
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