Immunotherapy in AML: Nivolumab Combined with Azacitidine

Adding the immune checkpoint inhibitor nivolumab to azacitidine treatment led to a complete response rate of 18 percent in a phase Ib/II study of patients with relapsed acute myeloid leukemia (AML), suggesting that immunotherapy may have a role in treating AML.

“We hope these immune checkpoint approaches will be an additional tool for improving outcomes in leukemia patients,” lead author Naval Daver, MD, from the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas, said during his presentation of the results.

A total of 51 patients were enrolled in this study (median age = 69 years; range = 45-90 years). All patients had AML and were eligible for inclusion if they had:

  • relapsed after a previous therapy
  • adequate performance status (defined as an Eastern Cooperative Oncology Group score of 2)
  • adequate organ function

Patients had received a median of two prior therapies (range = 1-7 therapies). Most (55%) had secondary AML and almost half (47%) had poor-risk cytogenetics. Common molecular mutations, determined by next-generation sequencing at baseline, were DNMT3A (n=12), TP53 (n=11), TET2 (n=9), ASXL1 (n=7), and RAS (n=7).

In the dose-finding phase of the study, the first six patients enrolled received 75 mg/m2 of azacitidine on days one through seven, as well as 3 mg/kg of nivolumab on days one and 14. Treatment was repeated approximately every four to five weeks indefinitely. After one patient experienced a dose-limiting toxicity (grade 3 pneumonitis), 3 mg/kg of nivolumab was established as the recommended phase II dose. An additional 45 patients were then enrolled, and 35 patients had evaluable results after three courses of therapy.

Six patients (18%) achieved complete remission (CR) or CR with insufficient recovery of counts (CRi) and five patients (15%) had a hematologic improvement (HI; defined as improvement in erythroid, platelet, or neutrophil counts). In addition, nine patients (26%) had >50 percent bone marrow (BM) blast reduction, and three (9%) achieved stable disease in >6 months. Twelve patients (34%) experienced disease progression.

“[This combination] compares favorably to an historic response rate of 12 to 15 percent with azacitidine alone,” Dr. Daver noted. The median overall survival was 9.3 months (range = 1.8-14.3 months), which, Dr. Daver also reported “compares favorably to historical survival with azacitidine-based salvage protocols in similar patients treated at the MD Anderson Cancer Center.”

Among the 11 patients who responded to nivolumab plus azacitidine (CR, CRi, and HI), the median number of treatment cycles was three (range = 1-9 cycles). The investigators deemed the responses “durable,” and no relapses occurred.

The four- and eight-week mortality rates were 0 percent and 6 percent, respectively. Six patients (12%) experienced grade 2 immune-mediated toxicities, while seven patients (14%) experienced grade 3/4 toxicities. These included pneumonitis (n=8), nephritis (n=2), transaminitis (n=2), and skin rash (n=1).

One death was reported due to grade 4 pneumonitis/epiglottitis. For the other 12 reported toxicities, the use of steroids led to resolution, and these patients were able to restart nivolumab.

Dr. Daver and investigators also conducted multicolor flow-cytometry studies and mass-cytometry (CyTOF) studies at baseline and with on-treatment BM aspirate (taken at the end of cycles 1, 2, 4, and 8) and peripheral blood smears to assess patients’ T-cell repertoires and expression of co-stimulatory receptors and ligands on T-cell subsets and leukemic blasts. Analyses revealed that patients who responded to treatment had higher CD3 (p=0.10) and CD8+ T cells (p=0.02) but lower CD4+Foxp3+PD1+ T-regulatory (T-reg) cells (p=0.01) at baseline, compared with non-responders. The ratio of PD1+CD8+ T-effector cells to PD1+CD4+Foxp3+ T-reg cells also was significantly higher in responders than non-responders (208.4 vs. 8.91; p<0.05).

“Full-dose azacitidine and nivolumab are tolerable and produce an encouraging response rate with durable responses in relapsed AML with poor-risk features,” the authors concluded.

Nivolumab is approved by the U.S. Food and Drug Administration for a number of indications in solid tumor oncology, including for the treatment of advanced non-small cell lung cancer, melanoma, and advanced renal carcinoma, and has recently been investigated in hematologic malignancies. The European Commission recently approved nivolumab for patients with relapsed/refractory classical Hodgkin lymphoma after autologous hematopoietic cell transplantation and treatment with brentuximab vedotin.


Daver N, Basu S, Garcia-Manero G, et al. Phase Ib/II study of nivolumab in combination with azacitidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). Abstract #763. Presented at the ASH Annual Meeting and Exhibition, December 6, 2016; San Diego, California.