Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine

Abstract

Purpose: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA.

Patients and methods: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival.

Results: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months.

Conclusions: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.

Figure 1.

Swimmer Plot of Patient Outcomes on Guadecitabine and Atezolizumab.

Figure 2.

Mutations in myeloid and T lymphocyte compartments in MDS patients considered short-survivors and long-survivors treated with guadecitabine and atezolizumab

Figure 3.. T cell activation in MDS patients considered short-survivors and long-survivors treated with guadecitabine and atezolizumab.

Comparative evaluation of T cell profiles in short- and long-survivors (>15 months) was performed using flow cytometry analysis on PBMCs from 21 patient samples at three different time points; Before treatment (PRE), after second treatment cycle (C2D1 or C2D8; EARLY), and after the third or fourth treatment cycle (C4D1, C4D8 or C5D1; LATE). Gating strategy of flow cytometry analysis is shown in Supplementary figure 1. A. CD8⁺ effector T cell (T_EFF) subset in long- and short-survivors. B. Expression of cell surface activation markers PD-1, CD39, and CD69 on T_EFF CD8⁺ T cells. Wilcoxon paired t test. Short-survivors, PD-1 p= 0.0002 (PRE vs EARLY) C. Proliferation of T_EFF CD8⁺ T cells measured as intracellular secretion of Ki-67 alone or in combination with expression of PD-1 following the treatment in long-and short-survivors. Wilcoxon paired t test. Short-survivors; Ki-67 p= 0.004 (PRE vs EARLY), Ki-67 and PD-1 p=0.004 (PRE vs EARLY) D. Change in median fluorescence intensity (MFI) of PD-1 expression on overall CD8⁺ T cell population before and after the treatment. Wilcoxon paired t-test. Short-survivors p=0.005 (PRE vs EARLY).