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B. Ball and E.M. Stein et al.
decitabine are nucleoside analogs that irreversibly bind the methylase DNMT1 leading to global hypomethyla- tion, resulting in altered expression and cell death.72,73 Low doses of hypomethylating agents disrupt immune evasion by inducing expression of tumor-associated antigens such as cancer/testis antigens in AML cell lines and antigen presentation molecules such as human leukocyte antigen class I antigens.74-77 Hypomethylating agents also upregu- late expression of endogenous retroviruses that activate viral recognition and interferon response pathways.78,79 In contrast, treatment with hypomethylating agents induced expression of programmed cell death protein 1 (PD1), pro- grammed death-ligand 1 and 2 (PD-L1 and PD-L2) and cytotoxic T-cell ligand antigen 4 (CTLA-4) in patients with MDS, AML and chronic myelomonocytic leukemia and was associated with resistance to treatment with hypomethylating agents.80
In the RELAZA2 trial, patients with advanced MDS or AML who achieved a CR after conventional chemothera- py or allogeneic SCT but had MRD, detected by either quantitative polymerase chain reaction for mutant NPM1 or other leukemia-specific fusion genes or by flow cytom- etry, were treated with azacitidine.81 The study met its pri- mary endpoint with 31 out of 53 (58%) patients being relapse-free at 6 months. Reassessment of MRD status revealed that 19 out of 53 patients achieved MRD negativ- ity and 12 out of 19 MRD-negative patients maintained MRD negativity without hematologic relapse during the median follow-up time of 23 months. Post-hoc analysis demonstrated a difference in relapse-free survival (HR 0.2, P<0.0001), but not overall survival (HR 0.4, P=0.112), between responders and non-responders to azacitidine.81
Immunotherapy targets
Immunotherapy is an approach that uses the potency of the immune system as a therapeutic modality against can- cer.82,83 The rationale for immunotherapy in AML lies in the curative potential of allogeneic SCT as post-remission therapy mediated by a graft-versus-leukemia effect. Similarly, immunotherapy leverages the adaptive immune system, specifically antibodies from B cells and the T-cell receptor on T cells to recognize antigens expressed on the cancer cells. In AML, immunotherapy has the potential to target unique leukemic stem cell surface antigens, thereby selectively eradicating these cells.
Immune checkpoints: PD1, PD-L1, CTLA-4
Immune modulating antibodies against negative regula- tors of T-lymphocyte activation, including anti-CTLA-4 and anti-PD1/PD-L1 have produced unprecedented rates of durable responses in a variety of malignancies.83 In AML, responses to checkpoint inhibitors as monotherapy have been modest. A phase I study of patients treated with the anti-PD1 antibody pidilizumab revealed a response in only one out of eight patients with AML with a reduction in blast percentages from 50% to 5%.84 A phase I/Ib study of 28 patients with relapsed hematologic malignancies after allogeneic transplantation, including 12 patients with AML, evaluated the anti-CTLA-4 antibody ipilimumab, given at doses of 3 mg/kg and 10 mg/kg. Responses were only observed with the ipilimumab 10 mg/kg dose in seven out of 22 (32%) patients and included CR in four patients with extramedullary AML and one
patient with MDS that progressed to AML. Dose-limiting chronic graft-versus-host disease of the liver or gut occurred in four patients but resolved when the treatment was withheld and steroids were administered.85 Active phase II studies evaluating anti-PD1 therapy as post- remission treatment include NCT02532231 with nivolum- ab and NCT02708641 with pembrolizumab.
In order to enhance responses to checkpoint inhibition in AML, combinations with chemotherapy, hypomethy- lating agents, and other checkpoint inhibitors are under investigation. In a phase II study (NCT02464657) patients with newly diagnosed AML received induction chemotherapy with idarubicin and cytarabine followed by nivolumab 3 mg/kg starting on day 24 and continued every 2 weeks for up to 1 year; 34 out of 44 patients (77%) achieved a CR or CRi and 18 out of 43 (53%) had unde- tectable MRD by multiparameter flow cytometry. Responses were durable and the median overall survival was 18.5 months, which compared favorably to that of a contemporary cohort of patients treated with idarubicin and cytarabine induction alone. Among 18 patients who underwent allogeneic SCT, 13 (72%) developed graft-ver- sus-host disease and eight responded to treatment.86 Increased expression of PD1, PD-L1, and CTLA-4 is asso- ciated with resistance to treatment with hypomethylating agents but has the potential to sensitize leukemia cells to checkpoint-blocking monoclonal antibodies.74,80 In a phase II study of azacytidine and nivolumab 3 mg/kg on days 1 and 14 in relapsed/refractory AML, responses occurred in 23 patients (overall response rate, 33%) including 15 patients (22%) with CR or CRi. The median overall sur- vival for all patients enrolled was 6.3 months, while that of the patients who achieved any type of response (CR, CRi, partial response or hematologic improvement) or had stable disease was 16.2 months. When compared to con- trols from historical hypomethylating agent-based clinical trials, patients receiving nivolumab and hypomethylating agents had an increased response rate (33% vs. 20%) and significantly longer median overall survival (6.3 vs. 4.6 months).87 The phase II PEMAZA study is evaluating azac- itidine in combination with pembrolizumab in patients achieving CR after induction chemotherapy but with detectable MRD (NCT03769532).
Dendritic cells
Dendritic cells are the most potent antigen-presenting cells capable of priming new responses or enhancing exist- ing antigen-specific immune responses.88,89 Mature den- dritic cells facilitate cytotoxic T-lymphocyte activation through antigen presentation on major histocompatibility complex class 1 molecules, termed cross-presentation and by upregulating co-stimulatory molecules, such as CD80 and CD86.89,90 Dendritic cell vaccination approaches differ in the source of dendritic precursors, maturation methods, target antigen, antigen loading, and in the administration of the vaccine.89 A phase II study of patients with AML in first CR after induction chemotherapy at high risk for relapse and without a matched sibling donor for allogene- ic hematopoietic SCT revealed that treatment with WT1 mRNA-electroporated dendritic cell vaccine led to a clini- cal response in 13 out of 30 patients (30%) with nine patients achieving molecular remission by WT1 transcript levels.91 The 5-year overall survival rate was 40% among vaccine recipients and compared favorably to a 5-year overall survival rate of 24.7% observed in historical con-
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haematologica | 2019; 104(8)