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Checkpoint Inhibition Consolidation Therapy Promising in High-Risk Hematologic Malignancies

JHOP - March 2019 Vol 9, No 1 - ASH
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Charles Bankhead

Patients with relapsed, refractory, or high-risk hematologic malignancies obtained durable benefits with the combined checkpoint inhibition with nivolumab and ipilimumab as consolidation therapy after stem-cell transplant, according to results of a small prospective study presented at ASH 2018.

Using this combination therapy, the proportion of patients in complete remission increased from 14% to 57% across treatment groups at study entry—to between 71% and 100% at 12 months. Furthermore, progression-free survival (PFS) exceeded historical norms for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), cytogenetically high-risk multiple myeloma, and posttransplant relapsed multiple myeloma.

Ideal Immunologic Window

“The combination of ipilimumab and nivolumab following transplant is safe, and there were no unexpected toxicities. Immune-related adverse events were controlled with systemic steroids. All immune-related adverse events resolved, except for one which ended up being fatal, pneumonitis complicated by viral pneumonia,” said Alan P. Zausner Skarbnik, MD, Director, Lymphoproliferative Disorders Program; Director, Experimental Therapeutics-Malignant Hematology; and Associate Director, Stem Cell Transplantation and Cellular Therapy Program, Novant Health, Charlotte, NC.

“This combination seems to be promising, and we will expand the refractory DLBCL cohort to phase 2. We believe that both myeloma cohorts should be expanded to phase 2, given these results,” Dr Skarbnik added.

Autologous stem-cell transplant (ASCT) remains the standard of care for many patients with several types of high-risk or poor-prognosis hematologic malignancies. However, disease progression frequently occurs within 18 months of ASCT and is associated with poor outcomes. To date, post-ASCT consolidation strategies have provided little or no clinical benefit. The posttransplant immunologic milieu affords a potentially “ideal window” for checkpoint inhibitor consolidation therapy.

Enhanced Antitumor Reconstitution

“The disease burden is at a minimum, and residual disease would likely be more immunogenic due to transplant conditioning–induced apoptosis and inflammation,” said Dr Skarbnik. “Antitumor immune reconstitution would seemingly be enhanced by combined checkpoint inhibition, skewing reconstituting natural killer cells and effector T-cells toward an antitumor immune phenotype and away from tolerance,” he added.

Dr Skarbnik reported updated findings from a phase 1 clinical trial evaluating the combination of nivolu­mab and ipilimumab as posttransplant consolidation therapy for patients with high-risk hematologic malignancies. The primary end points were PFS and overall survival (OS) at 18 months, as well as the rate of complete remission. Eligible patients had early relapsed, primary refractory DLBCL, or peripheral T-cell lymphoma (PTCL); cytogenetically high-risk multiple myeloma; or multiple myeloma that had relapsed within 3 years of the initial transplant. All patients received high-dose conditioning therapy, followed by ASCT.

Consolidation with nivolumab and ipilimumab started 14 to 28 days after ASCT, or when the absolute neutrophil count exceeded 800 mm3 and the platelet count exceeded 20,000 mm3. Patients received a maximum of 6 doses of ipilimumab and 12 doses of nivolumab.

The study accrued 31 patients, including 14 with DLBCL, 5 with PTCL, 7 with high-risk multiple myeloma, and 5 with posttransplant relapsed multiple myeloma. Of 7 patients with refractory DLBCL, 4 patients were in complete remission at study entry, as were 3 of 7 patients with relapsed DLBCL, all of the patients with PTCL, 1 of 7 patients with high-risk multiple myeloma, and 2 of 5 patients with posttransplant relapsed multiple myeloma.

The entire cohort had a median follow-up of 17 months, and 3 subgroups had a median follow-up exceeding 18 months (the primary refractory DLBCL arm, and the 2 multiple myeloma groups). At 3 months post-ASCT, the complete remission rates were 71% in the patients with refractory DLBCL, 57% in the high-risk multiple myeloma group, and 80% in the post-ASCT relapsed multiple myeloma group. The rates increased to 83%, 71%, and 80%, respectively, at 6 months; at 12 months, the rates were 83%, 71%, and 100%, respectively.

The PFS was 85.7% in patients with primary DLBCL at 18 months, and the OS was 100% at 18 months. The median values had yet to be reached. According to Dr Skarbnik, the historical median PFS is <12 months, and the median OS is 14.4 months in this patient population. In this study, at 18 months, the high-risk multiple myeloma group had a PFS of 57.1% and an OS of 85.7%. The median PFS was 22 months; the historical PFS benchmark for similar patients is 14 months.

Furthermore, in patients with relapsed multiple myeloma after first ASCT, the PFS was 100% at 6 and 12 months, declining to 50% at 18 months. The historical benchmark in this patient population is a median PFS of 10.3 months. The OS was 100% at 6, 12, and 18 months.

All but 2 patients had immune-­related adverse events, which were grade 3 or 4 in 17 patients. The most common grade 3 or 4 immune-related events were neutropenia (42%), diarrhea or colitis (13%), rash (10%), and asymptomatic elevation of amylase or lipase (10%). Two-thirds (20 of 31) of the patients required systemic steroids to manage their immune-related adverse events, Dr Skarbnik said.

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Last modified: April 27, 2020