Citations

Introduction HMAs are the only approved therapy for CMML. In order to improve response rates and survival, the addition of VEN has been utilized in both CMML and after blast transformation (CMML-BT) with conflicting results in small single center studies. To clarify the role of upfront HMA+VEN in CMML and CMML-BT, we performed a large multicenter analysis. Methods We included patients with HMA-naïve CMML and CMML-BT treated with combination HMA and VEN from 4 academic centers. The primary outcome was overall survival (OS) with secondary outcomes including overall response rate (ORR) by 2015 MDS/MPN IWG criteria for CMML and 2022 ELN criteria for CMML-BT. To better appreciate the benefit of adding VEN to HMA treatment, we also performed 1:1 propensity score matched (PSM) analysis of patients treated with HMA alone as upfront therapy for CMML or CMML-BT. Matching was based on age, sex, ECOG performance status, CPSS-Mol, blood counts, peripheral and bone marrow blasts. Results Eighty-nine patients were treated with frontline HMA+VEN, 51 CMML and 38 CMML-BT (5 had received HMA alone for prior CMML). The median age was 71 years, 70% were male, and 83% had ECOG 0-1. Among CMML patients, 55% had MP-CMML subtype, 65% had CMML-2 and 12%, 30%, 58% were CPSS-mol intermediate-1, intermediate-2 and high risk, respectively. In the entire cohort, ASXL1 (63%), TET2 (47%), SRSF2 (39%) and RUNX1 (27%) were the most commonly mutated genes and 55% of patients harbored a RAS mutation ( KRAS [20%], NRAS [18%], CBL [13%], NF1 [11%], PTPN11 [9%]). For HMA combination partner, 46 (52%) were treated with azacitidine, 35 (39%) with decitabine, and 8 (9%) with both during their VEN course. During a median follow-up time of 15.8 months (mos) 52 patients (58%) died: 23 (45%) with CMML and 29 (76%) with CMML-BT. Among CMML patients, the ORR was 90%, including complete remission (CR) in 22%, complete cytogenic remission (CCR) in 4%, optimal marrow response (CMR) in 50%, and partial marrow response (PMR) in 6%. The OS of CMML patients was 25.1 mo (95% CI 15.7 - NR). A PSM population of HMA patients matched to HMA+VEN treated patients showing similar baseline characteristics. ORR was significantly higher with HMA+VEN (95%) as compared those treated with HMA alone (46%), p < 0.001. However, there was no significant OS difference between HMA+VEN vs HMA alone (19.1 mos vs 19.1 mos, p = 0.85, Figure 1). For CMML-BT patients, the ORR of HMA+VEN was 81% including CR in 17%, CR with partial hematologic recover (CRh) in 3%, CR with incomplete hematologic recovery (CRi) in 28%, morphologic leukemia-free state (MLFS) in 22% and partial response (PR) in 11%. The OS of CMML-BT patients was 8 mos (95% CI 4.6 - 26.2). A PSM population of CMML-BT patients treated with HMA alone showed a significantly increased ORR with HMA+VEN (82% vs 40%, p = 0.039). However, there was no difference in OS (7.49 mos vs 9.26 mos, p = 0.83, Figure 2). Among HMA-VEN treated patients, achievement of a CR was associated with an improved OS in the CMML (HR 0.31, 95% CI 0.13 - 0.75) and CMML-BT (HR 0.37, 95% CI 0.19 - 0.74). No predictors of response were identified, including the presence of a RAS mutation. In terms of safety, 7 patients (7.9%) had a grade 3/4 (G3/4) neutropenic infection and 2 patients (2.2%) had a G3/4 hemorrhagic event while being treated with HMA+VEN. A total of 29 patients went on to receive allogeneic transplant (alloSCT): 22 (43%) with CMML and 7 (18%) with CMML-BT. CMML patients who underwent alloSCT after HMA+VEN were younger as compared to non-transplanted patients (64 vs 74 years, p < 0.0001), but had otherwise similar baseline characteristics including stage, CPSS-mol category and prevalence of RAS mutations. Similarly, CMML-BT patients bridged to alloSCT were younger (66 vs 74 years, p < 0.002) and had a better ECOG performance status (p = 0.047). Of patients who received alloSCT, 10 patients (34%) died, 5 with CMML and 5 with CMML-BT. The median OS after alloSCT was 26.7 mo. Conclusions Although the use of VEN with HMA in the upfront treatment of CMML and AML secondary to CMML results in higher response rates compared to HMA alone, this combination does not improve survival based on this multi-center PSM analysis. The current sample size of CMML-BT may limit detection of OS differences between treatment groups. The role of VEN to reduce blasts and serve as a bridge to alloSCT, particularly after HMA failure, requires further investigation in larger studies in both the CMML and CMML-BT populations.

Abstract Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. Patients and Methods: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. Results: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and > 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

Abstract The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.