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Nivolumab safe, feasible with standard induction therapy for acute myeloid leukemia
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SAN DIEGO — Adding nivolumab to induction therapy with idarubicin and cytarabine appeared to be a viable and safe treatment option for younger patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome, according to phase 2, open-label study results presented at ASH Annual Meeting and Exposition.
“Despite the improvement of outcomes among younger patients with AML, disease relapse remains the most common cause of treatment failure and death,” Rita Assi, MD, fellow in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during her presentation. “Strategies to improve remission duration are, therefore, needed.
“There is a significant amount of data suggesting that the PD-1/PD-L1 pathway is exploited by myeloblasts for immune evasion, and that blocking this pathway enhances cytotoxic T-cell activity and improves antileukemia response to conventional chemotherapy,” Assi added.
Further, because patients with AML have increased bone marrow expression of PD-1-positive CD8-positive T cells, researchers hypothesized that the addition of nivolumab (Opdivo, Bristol-Myers Squibb) to chemotherapy may improve outcomes.
The analysis included 44 patients aged 18 to 65 years (median age, 54 years; range, 26-66) with recently diagnosed AML (20% blasts or greater by WHO criteria; n = 42) or high-risk myelodysplastic syndrome (10% blasts or greater; n = 2). Of the 42 AML cases, 32 were de novo, seven were secondary, and three were treatment related. Twenty-two patients (50%) had adverse genetic risk according to European Leukemia Net classification, with eight harboring TP53 mutations.
Eligible participants had an ECOG performance status of grade 2 or less and adequate organ function.
Patients underwent one to two induction cycles of cytarabine (1.5 g/m2 over 24 hours on days 1-4) and idarubicin (12 mg/m2 on days 1-3); they initiated 3 mg/kg nivolumab on day 24 (± 2) every 2 weeks for up to a year.
Patients who attained complete response or complete response with incomplete count recovery (CRi) received up to five consolidation cycles of reduced-dose idarubicin and cytarabine. Those who were eligible underwent allogeneic hematopoietic stem cell transplant at any point during or after consolidation.
EFS served as the study’s primary endpoint. Secondary endpoints included OS, RFS and complete remission rate.
Median follow-up was 17.25 months (range, 0.5-30.4).
All patients were evaluable for response.
Overall, 34 (78%) achieved complete response (n = 28) or CRi (n = 6), 18 (54%) of whom had undetectable minimal residual disease by flow cytometry at the time of response. Nine of the remaining 16 responding patients became minimal residual disease negative during additional follow-up at 1 to 3 months of nivolumab therapy, Assi said.
The median number of cycles prior to response was one (range, 1-2) and the median number of total cycles received was two (range, 1-6).
There was a 5% early mortality rate at 4 and 8 weeks.
edian OS was 18.54 months (range, 0.5-30.4) and median RFS for the 34 patients who achieved complete response/CRi was 18.5 months (range, 1.7-25.6). Median EFS was not reached (range, 0.5-13.7). Six patients in complete response died.
In an exploratory analysis, research compared these data with a concurrent patient group treated with idarubicin and cytarabine alone. Results showed a trend of improved OS at a short follow-up interval (median, 18.54 vs. 13.2 months; P = .02); however, differences in EFS and RFS did not reach statistical significance.
Nineteen patients proceeded to allogeneic HSCT at response. Three patients were matched-related to the donor source, 12 were matched unrelated and four were haploidentical.
Grade 3 to grade 4 GVHD occurred in five of these patients, four of whom responded to treatment.
At median follow-up of 12.6 months after HSCT, 12 of these patients remained in complete response, four died in complete response and three relapsed.
Most adverse events observed on the trial were related to myelosuppression, Assi said.
Seven grade 3 to grade 4 immune-related toxicities occurred in six patients (rash, n = 2; colitis n = 2; transaminitis, n = 1; pancreatitis, n = 1), but all responded to treatment with steroids.
Researchers then used multicolor flow cytometry to quantify leukemic progenitor cells and T cells from some patients. Results showed clearance of progenitors and reconstitution of T cells among those who attained complete response.
Researchers also conducted studies of bone marrow cells attained at diagnosis to evaluate predictors of response among 19 responders and five nonresponders. Although total T-cell population appeared higher at diagnosis among responders, this did not reach statistical significance. There also were no significant differences among virus T-cell subsets.
However, when researchers looked at checkpoint markers, they found that the percentage of TIM3-positive (P = .01) and PD-1/TIM3-double positive (P = .04) cells were significantly higher in nonresponders.
“This has previously been described in solid tumors as a phenomenon of immune exhaustion, and this is defined as an acquired state of dysfunction of effector T cells in response to cancer,” Assis said. – by Jennifer Byrne
Reference:
Assi R, et al. Abstract 905. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Assi reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.