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).

We and others have noted that among a variety of checkpoint receptors evaluated in patients with acute myeloid leukemia (AML), there were significantly more PD-1—positive T cells (including increased CD8+, T effector cells, and regulatory cells [Tregs]) in bone marrow aspirates from patients with AML as compared with healthy donors.

The same pattern was seen for OX40 on CD8+ T cells and Tregs, but was less prominent than for PD-1.

Preliminary data suggest that PD-1 inhibitors have limited single-agent activity in AML and myelodysplastic syndromes (MDS).

CTLA-4 inhibition may have single-agent activity in AML/MDS, as has been shown in post—stem cell transplant relapsed AML, where single-agent ipilimumab (Yervoy) produced a durable complete response in 5 of 12 patients

 and in post—hypomethylating agent MDS, where ipilimumab produced an overall response in 33% of patients.

 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.

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.

These findings have resulted in clinical trials combining PD-1/PD-L1 inhibitors with azacitidine in AML and MDS. Recent data presented on the combination of azacitidine with nivolumab (Opdivo; anti—PD-1) demonstrated an encouraging response rate, low early mortality, and, most important, durable responses in patients with relapsed/refractory AML, with 80% of the responders alive at 1 year.

  Both responders and nonresponders had an increase in CTLA-4+ CD8+ cells in the bone marrow aspirate on therapy, suggesting that a combination blockade of these 2 major co-inhibitory pathways may improve response rate and durability. Grade 2-4 immune-related adverse events (irAEs) were observed in 23% of treated patients. There was a wide variation in the time to onset of irAEs, with irAEs observed as early as 4 days to 3.5 months from the initiation of the nivolumab therapy. The irAE profile differed from those seen in solid tumors, with the most common being pneumonitis, nephritis, colitis, and dermatitis, as opposed to endocrine insufficiencies, skin rash, and transaminitis described frequently in solid tumor immuno-oncology trials. The irAEs were reversible with early intervention.

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.

. 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.

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.

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.

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.

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.

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.

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.

Articles

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 overall survival in patients with AML/MDS.

Naval G. Daver, MD

Articles

Combination Checkpoint Therapy Gains Ground in AML and MDS