Combination Checkpoint Therapy Gains Ground in AML and MDS

Naval G. Daver, MD
Published: Friday, Dec 29, 2017
Dr. Naval Daver

Naval Daver, MD
Checkpoint-based immunee therapies have revolutionized the therapy of solid tumors by achieving breakthrough improvements in melanoma, lung cancer, renal cancer, bladder cancers, and head and neck tumors, among others. Recent studies have demonstrated encouraging results with immune checkpoint inhibition in hematologic malignancies, including Hodgkin lymphoma, primary central nervous system and testicular lymphoma, nasal natural killer/T-cell lymphoma, primary mediastinal lymphoma, follicular lymphoma, and multiple myeloma (MM). The optimal benefits of immune checkpoint inhibitors in the majority of patients with non-Hodgkin lymphoma and MM (who do not have a 9p24 sensitizing alteration) were obtained not by single-agent therapy but when these agents were combined with standard therapies to further improve response rates and progression-free and overall survival (OS).

As with follicular lymphoma and MM, rational combinations of immune checkpoint inhibitors with other standard antileukemic agents may be needed to improve the response rates, the durability of response, and the OS in patients with AML/MDS.

Immune Response to PD Expression

DNA-methyltransferase inhibitors (DNMTi), such as azacitidine, enhance the immune response to tumors by upregulating tumorcell antigen expression, antigen presentation via histocompatibility complex class 1 molecules, and expression of costimulatory molecules, while concurrently dampening the immune response by upregulating the expression of checkpoint molecules, including PD-1, PD-L1, and PD-L2. Higher expression of PD-1, PD-L1, and PD-L2 was noted in patients with AML/MDS resistant to DNMTi therapy compared with sensitive patients, suggesting PD-1 upregulation may be involved in resistance to DNMTi.6

The combination of azacitidine with nivolumab similarly produced encouraging response rates (80%) as frontline treatment for a small cohort of patients with high-risk MDS.4 In patients with MDS failing DNMTi therapy, single-agent nivolumab did not demonstrate activity, but single-agent ipilimumab (anti–CTLA-4) was able to produce responses in 35% of patients.

References

  1. . Daver N, Basu S, Garcia-Manero G, et al. Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia (AML). Blood. 2016; 128:2900.
  2. Boddu P, Kantarjian H, Allison J, Sharma P, Daver N The emerging role of immune checkpoint based approaches in AML and MDS, Leuk Lymphoma. 2017;1-13. doi: 10.1080/10428194.2017.1344905.
  3. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044-3051. doi: 10.1158/1078-0432.CCR-07-4079.
  4. Garcia-Manero G, Daver N, Montalban-Bravo G, et al. A phase II study evaluating the combination of nivolumab (nivo) or iIpilimumab (Ipi) with azacitidine in Pts with previously treated or uUntreated myelodysplastic syndromes (MDS). Blood. 2016;128:344.
  5. Davids MS, Kim HT, Bachireddy P, et al. Leukemia and Lymphoma Society Blood Cancer Research Partnership. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143-153. doi: 10.1056/NEJMoa1601202.
  6. Yang H, Bueso-Ramos C, DiNardo C. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280-1288. doi:10.1038/leu.2013.355.
  7. Daver N, Basu S, Garcia-Manero G, et al. Phase IB/II study of nivolumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML), Blood. 2016;128:763.

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