Safety and efficacy of consolidation therapy with ipilimumab plus nivolumab after autologous stem cell transplantation

Published:December 30, 2020DOI:https://doi.org/10.1016/j.jtct.2020.12.026

      Highlights

      • Ipilimumab in combination with nivolumab can be safely used as a consolidation strategy after autologous stem cell transplantation for high-risk hematologic malignancies.
      • Combined checkpoint inhibition has the potential to skew the recovering immune milieu post-ASCT towards an effector, rather than a regulatory phenotype.
      • Combined checkpoint inhibition may be a strategy to improve outcomes following ASCT, particularly in patients with diffuse large B-cell lymphomas.

      Abstract

      Background: Autologous hematopoietic stem cell transplantation (ASCT) is a standard-of-care treatment for many hematological malignancies. Progression of disease after ASCT is the primary cause of treatment failure. Objective: In this Phase Ib trial, we studied the safety and clinical effect of combined checkpoint inhibition with ipilimumab and nivolumab as a consolidation strategy after ASCT for patients with high-risk diffuse large B-cell Lymphoma (DLBCL), mature T-cell lymphoma (TCL) and multiple myeloma (MM). Study Design: Starting 14-28 days after ASCT, patients received ipilimumab (1 mg/kg, intravenous, on day 1 of weeks 1, 4, 7, 10, 16, 22) and nivolumab (3 mg/kg, intravenous, on day 1 of weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26). Results: Patients received a median of five doses of ipilimumab and eight doses of nivolumab. Thirty-five patients were included in the intent-to-treat population. Ninety-four percent of patients experienced immune-related adverse events (irAEs) of any grade. Ninety-seven percent of irAEs resolved spontaneously or by holding study drugs and instituting high-dose corticosteroid therapy. Progression-free and overall survival at 18 months post-ASCT for each disease cohort were, respectively: primary refractory DLBCL, 85.7% and 100%; relapsed DLBCL, 28.6% and 57.1%; frontline TCL: Not Evaluable and 80%; relapsed TCL, 25% and 75%; high-risk transplant-naïve MM, 57.1% and 87% and MM relapsed within 3 years of first ASCT, 40% and 100%. Conclusion: We conclude that combined checkpoint inhibition appears tolerable as a consolidation strategy after ASCT and in addition to the potential clinical efficacy observed in some subsets of disease, T cell receptor repertoire, Tregulatory phenotype and gut microbiota profiles provide a biologic rationale warranting further study of this approach.
      Key Points: Combined immune checkpoint inhibitor therapy is safe as a consolidation strategy following ASCT for high-risk hematologic malignancies and may have clinical efficacy that warrants further evaluation
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      References

        • Philip T
        • Guglielmi C
        • Hagenbeek A
        • et al.
        Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.
        N Engl J Med. 1995; 333: 1540-1545
        • Gisselbrecht C
        • Glass B
        • Mounier N
        • et al.
        Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era.
        J Clin Oncol. 2010; 28: 4184-4190
        • Nishimura KK
        • Barlogie B
        • van Rhee F
        • et al.
        Long-term outcomes after autologous stem cell transplantation for multiple myeloma.
        Blood Adv. 2020; 4: 422-431
        • d'Amore F
        • Relander T
        • Lauritzsen GF
        • et al.
        Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01.
        J Clin Oncol. 2012; 30: 3093-3099
        • Kumar SK
        • Lee JH
        • Lahuerta JJ
        • et al.
        Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.
        Leukemia. 2012; 26: 149-157
        • Lee H
        • Duggan P
        • Chaudhry A
        • et al.
        Early Relapse for Multiple Myeloma Patients Undergoing Single Autologous Stem Cell Therapy: A Single-center Experience.
        Clin Lymphoma Myeloma Leuk. 2018; 18: e69-e75
        • Gay F
        • Engelhardt M
        • Terpos E
        • et al.
        From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives.
        Haematologica. 2018; 103: 197-211
        • Crump M
        • Neelapu SS
        • Farooq U
        • et al.
        Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.
        Blood. 2017; 130: 1800-1808
        • Rezvani AR
        • Kanate AS
        • Efron B
        • et al.
        Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning.
        Bone marrow transplantation. 2015; 50: 1286-1292
        • Donato ML
        • Siegel DS
        • Vesole DH
        • et al.
        The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2014; 20: 1211-1216
        • Armand P
        • Nagler A
        • Weller EA
        • et al.
        Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.
        J Clin Oncol. 2013; 31: 4199-4206
        • Ansell SM
        • Lesokhin AM
        • Borrello I
        • et al.
        PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England journal of medicine. 2015; 372: 311-319
        • Armand P
        • Lesokhin A
        • Borrello I
        • et al.
        A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies.
        Leukemia. 2020;
        • Ansell SM
        • Hurvitz SA
        • Koenig PA
        • et al.
        Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
        Clinical cancer research: an official journal of the American Association for Cancer Research. 2009; 15: 6446-6453
        • Weber J.
        Immune checkpoint proteins: a new therapeutic paradigm for cancer–preclinical background: CTLA-4 and PD-1 blockade.
        Seminars in oncology. 2010; 37: 430-439
        • O'Day SJ
        • Hamid O
        • Urba WJ.
        Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies.
        Cancer. 2007; 110: 2614-2627
        • Larkin J
        • Chiarion-Sileni V
        • Gonzalez R
        • et al.
        Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
        N Engl J Med. 2015; 373: 23-34
        • Fong L
        • Small EJ.
        Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
        Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008; 26: 5275-5283
        • Postow MA
        • Chesney J
        • Pavlick AC
        • et al.
        Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
        N Engl J Med. 2015; 372: 2006-2017
        • Ansell SM
        • Minnema MC
        • Johnson P
        • et al.
        Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study.
        J Clin Oncol. 2019; 37: 481-489
        • Frigault MJ
        • Armand P
        • Redd RA
        • et al.
        PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation.
        Blood Adv. 2020; 4: 122-126
        • Batorov EV
        • Tikhonova MA
        • Pronkina NV
        • et al.
        Increased circulating CD4(+)FOXP3(+) T cells associate with early relapse following autologous hematopoietic stem cell transplantation in multiple myeloma patients.
        Oncotarget. 2018; 9: 27305-27317
        • Muthu Raja KR
        • Kubiczkova L
        • Rihova L
        • et al.
        Functionally suppressive CD8 T regulatory cells are increased in patients with multiple myeloma: a cause for immune impairment.
        PLoS One. 2012; 7: e49446
        • Muthu Raja KR
        • Rihova L
        • Zahradova L
        • Klincova M
        • Penka M
        • Hajek R.
        Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma.
        PLoS One. 2012; 7: e47077
        • Sledzinska A
        • Menger L
        • Bergerhoff K
        • Peggs KS
        • Quezada SA.
        Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy.
        Molecular oncology. 2015; 9: 1936-1965
        • Cheson BD
        • Fisher RI
        • Barrington SF
        • et al.
        Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.
        J Clin Oncol. 2014; 32: 3059-3068
        • Kumar S
        • Paiva B
        • Anderson KC
        • et al.
        International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.
        Lancet Oncol. 2016; 17: e328-e346
        • Robins HS
        • Campregher PV
        • Srivastava SK
        • et al.
        Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells.
        Blood. 2009; 114: 4099-4107
        • Baetz T
        • Chen BE
        • Couban S
        • et al.
        Effect of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant in aggressive CD20+ lymphoma: a cohort comparison from the NCIC Clinical Trials Group Study LY.12.
        Leuk Lymphoma. 2017; 58: 64-69
        • Wilhelm M
        • Smetak M
        • Reimer P
        • et al.
        First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation.
        Blood Cancer J. 2016; 6: e452
        • Peled JU
        • Devlin SM
        • Staffas A
        • et al.
        Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.
        J Clin Oncol. 2017; 35: 1650-1659
        • Peled JU
        • Gomes ALC
        • Devlin SM
        • et al.
        Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.
        N Engl J Med. 2020; 382: 822-834
        • Stein-Thoeringer CK
        • Nichols KB
        • Lazrak A
        • et al.
        Lactose drives Enterococcus expansion to promote graft-versus-host disease.
        Science. 2019; 366: 1143-1149
        • Routy B
        • Le Chatelier E
        • Derosa L
        • et al.
        Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
        Science. 2018; 359: 91-97
        • Gopalakrishnan V
        • Spencer CN
        • Nezi L
        • et al.
        Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
        Science. 2018; 359: 97-103
        • Matson V
        • Fessler J
        • Bao R
        • et al.
        The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.
        Science. 2018; 359: 104-108