Casey Lee O’connell

Myelodysplastic syndrome (MDS) are clonal myeloid neoplasms that cause cytopenias and can progress to acute myeloid leukemia (AML). Hypomethylating agents (HMA) are the mainstay of treatment for higher risk disease, but they achieve responses in only half of treated patients and complete remission rates are low. Several scientifically based combinatorial regimens have been tested in clinical trials but none has demonstrated a survival benefit over HMA monotherapy. Allogeneic stem cell transplant remains the only curative therapy and is dependent on effective donor lymphocytes for its efficacy. However, access is limited by its toxicity, so alternative approaches are sorely needed. Recent clinical and translational studies have shown that MDS is not only a clonal myeloid disorder, but also associated with immune dysregulation, inflammatory signaling, T-cell repertoire restriction, immune exhaustion, and immune mediated suppression of hematopoiesis. These findings suggest that there is potential for unlocking a novel approach to the treatment of MDS by restoring and/or enhancing the lymphoid immune response. In this review, we discuss the current understanding of the role of normal T lymphocytes in MDS, the causes and manifestations of dysfunctional T lymphocytes as well as the role and dysfunction of natural killer (NK) cells. The role of therapeutic immunosuppression in lower risk MDS is reviewed, as is the impact of HMAs on dysregulated T lymphocytes and NK cells in higher risk disease. We propose that there is tremendous potential for more targeted approaches to engage the lymphoid compartment in addressing the unmet therapeutic need in MDS.

Objectives: These post hoc analyses of 2 phase 3 myelofibrosis trials assessed the kinetics and prognostic value of achieving hemoglobin ≥ 10 g/dL with momelotinib. Methods: Median (range) time to hemoglobin ≥ 10 g/dL was assessed in momelotinib‐randomized patients with baseline hemoglobin < 10 g/dL in the SIMPLIFY‐1 (JAK inhibitor naive) and MOMENTUM (JAK inhibitor experienced) trials. Survival from treatment initiation was evaluated via Kaplan–Meier curves and Cox models. Results: In SIMPLIFY‐1, 54/86 patients (63%) achieved hemoglobin ≥ 10 g/dL by week 24: moderate anemia, 40/58 (69%), 0.6 (0.4–5.1) months; severe anemia, 14/28 (50%), 1.4 (0.5–4.7) months. In MOMENTUM, 45/126 patients (36%) achieved hemoglobin ≥ 10 g/dL by week 24: moderate anemia, 30/64 (47%), 0.5 (0.3–4.6) months; severe anemia, 15/62 (24%), 0.5 (0.5–5.6) months. Achieving hemoglobin ≥ 10 g/dL by week 24 was numerically associated with longer survival: SIMPLIFY‐1 HR, 0.53 (95% CI, 0.27–1.05); MOMENTUM HR, 0.62 (95% CI, 0.33–1.15). In multivariate analysis, only week 24 transfusion independence was associated with survival. Conclusions: Achievement of hemoglobin ≥ 10 g/dL may be a clinically meaningful target in momelotinib‐treated patients with myelofibrosis and anemia. Those without JAK inhibitor experience and/or with moderate anemia were more likely and faster to achieve this threshold, supporting earlier momelotinib initiation to optimize outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT01969838, NCT04173494:

Grade 3 or Higher Toxicities or Toxicities Observed in 10% or More Patients – Excluding Those Defined as Unrelated or Unlikely Related to Protocol Treatment.

A. Gating strategy applied on PBMCs samples evaluated by flow cytometry. CD8+ T cell memory was defined based on the expression of CD45RA and CCR7 (CD197). Cell surface phenotype (PD-1, CD39, and CD69) and intracellular activation (Ki-67) markers were quantified on CD8+ effector T cell (TEFF) based on indicated gates. B, CD8+ naïve and memory T cells in long-and short-survivors quantified before and after the treatment. C, Representative flow cytometry plots showing CD8+ T cells activation in PBMC samples from a short survivor. PD-1+ Ki-67+ expression on CD8+ T cells compared before and after the treatment.

Representativeness of Study Participants

List of Patients Who Experienced Immune-related Adverse Events AEs.

Specific genes sequenced in bone marrow mononuclear cells.

A& B. Frequency (A) and intensity (B) of PD-1+ CD8+ T cells by gender) before (PRE), after second treatment cycle (C2D1 or C2D8; EARLY), and after third or fourth treatment cycle (C4D1, C4D8 or C5D1; LATE). CD8+ T cell expressing CD39 (C) and CD69 (D). F: females, M: males

Median overall survival was longer among patients whose T cells harbored ASXL1 mutations (green) than for those without the mutation (red) or with only myeloid mutations (blue), but ASXL1 mutation status was not associated with survival in a univariate analysis by the logrank test (p=0.11). In a multivariate analysis using a Cox proportional model and adjusted by age at study entry, gender, diagnosis, and the number of prior treatment regimens, ASXL1 was significantly associated with survival (p=0.001 based on likelihood ratio test).

Isolation and DNA extraction of bone marrow cell populations; Targeted DNA sequencing; Peripheral blood mononuclear cell (PBMC) staining and flow cytometry analysis