Komrokji, Rami S.

Abstract Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusions: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.

Abstract Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneity of these diseases has limited our understanding of these domains. The National Heart, Lung, and Blood Institute-sponsored MDS Natural History Study is a prospective cohort enrolling patients undergoing workup for suspected MDS in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/myeloproliferative neoplasm (MPN), idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk.” HRQoL data are collected at enrollment, including the MDS-specific Quality of Life in Myelodysplasia Scale (QUALMS). Vulnerability is assessed with the Vulnerable Elders Survey. Baseline HRQoL scores from 449 patients with MDS, MDS/MPN, AML <30%, ICUS or At-Risk were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (eg, mean Patent-Reported Outcomes Management Information Systems [PROMIS] Fatigue of 56.0 vs 49.5; P < .001) and those with worse prognosis (eg, mean Euroqol-5 Dimension-5 Level [EQ-5D-5L] of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; P = .005). Among vulnerable MDS participants, most had difficulty with prolonged physical activity (88%), such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL, regardless of eventual diagnosis, but with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL. This study is registered at www.clinicaltrials.gov as NCT02775383.

Abstract Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

Abstract To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.

Abstract TGFβ plays a pivotal role in the pathobiology of myelofibrosis (MF) by not only promoting bone marrow fibrosis (BMF) but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs). Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to MKs decreased pSMAD2 without affecting total SMAD2/3 and led to increased numbers of MKs. Treatment of MF MNCs with AVID200 also led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. A phase 1b trial of AVID200 (NCT03895112) was performed and completed in INT-2/high risk MF patients resistant/intolerant to ruxolitinib (rux); baseline platelet count of ≥ 25 x 10 9/L, and grade 2/3 BMF. Subjects received AVID200 intravenously on Day 1 of a 21 day cycle. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200. We previously presented the results of the dose escalation study (Mascarenhas ASH 2020) demonstrating that AVID200 was well tolerated without dose limiting toxicities at 3 tested dose levels (Lots A and B) in dose cohorts of 180 mg (A), 550 mg (A)/70 mg (B), and 180 mg (B). Here we report updated safety and efficacy results of the phase 1b dose expansion stage at the two highest doses tested (70 mg (B) and 180 mg (B). Twenty-two subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 in the dose escalation phase and 12 in the dose expansion phase [Table1]. Median time after rux discontinuation was 7.4 months (0.5-59.9). The most common mutations observed at baseline in this cohort included JAK2V617F (71%), TET2 (29%) ASXL1 (24%) and CALR (19%). (Fig 1) No DLTs were observed and Grade 3/4 AEs were observed in 16 (76.2%) subjects. Grade 3/4 non-hematologic AEs were observed in 8 (38.1%) subjects and included one subject in each case (epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope). Grade 3/4 hematologic AEs were anemia (6; 28.3%) and thrombocytopenia (2; 14.3%) [Table 2]. No fatal events were observed. The median number of cycles received was 5 (range 2 - 13) and 7 (33%) patients received more than 6 cycles. For dose levels 2-3 at cycle 7, a CI was attained in one subject at dose level 2 [anemia, spleen and TSS], 5 subjects had SD, 3 subjects had PD and two subjects with 10% and 15% blasts at screening developed MPN-BP while on study based on central review. Reasons for discontinuation by local PI included PD (n=8), lack of response (n=5), study completed (n=2), other (n=2), patient decision (n=1). Median % change in palpable spleen length was +10% (range -70% to +150%) and TSS change was -50% (-100% to +185.7%) The median platelet count at baseline was 114 x 10 9/L (range: 28-695) and 215 x 10 9/L (range: 66-263) after cycle 6 in 7 evaluable subjects (Fig 2A). Notably, 17 subjects had an increase in platelets from baseline during treatment and two subjects normalized their platelet counts. Maximum changes in platelets from baseline across all cycles was +63.8% [range -15.7%, +505.5%] (Fig 2B). Paired bone marrow biopsy pathology samples for 12 subjects were available for central review and showed no significant changes in BMF score or MK histo topography at end of treatment compared to baseline. All patients had elevated plasma levels of TGF β1, but not TGFβ2/β3 levels as detected by ELISA, which were dramatically reduced 21 days after the last dose of AVID200. AVID200 a TGFβ1/3 protein trap is well tolerated and clinical responses at cycle 7 of therapy in this advanced MF patient population were limited as judged by IWG/MRT response criteria. However, AVID200 therapy resulted in significant reduction in serum TGFβ levels and improvements in platelet counts indicating that TGF β1 plays a pivotal role in MF leading to thrombocytopenia which can be reversed with AVID200 therapy. We conclude that AVID200 may best be employed in combination therapy approaches in thrombocytopenic MF patients. Figure 1 Figure 1. Disclosures Mascarenhas: Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Forbius: Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding. Palmer: PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte: Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding. Kuykendall: Celgene/BMS: Honoraria; Pharmaessentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Incyte: Consultancy; Abbvie: Honoraria; Blueprint: Honoraria. Mesa: Genentech: Research Funding; Promedior: Research Funding; Samus: Research Funding; Gilead: Research Funding; CTI: Research Funding; Abbvie: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Pharma: Consultancy; CTI: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; AOP: Consultancy; La Jolla Pharma: Consultancy; Incyte Corporation: Consultancy, Research Funding. Rampal: Stemline: Consultancy, Research Funding; Memorial Sloan Kettering: Current Employment; BMS/Celgene: Consultancy; Abbvie: Consultancy; CTI: Consultancy; Novartis: Consultancy; Disc Medicine: Consultancy; Blueprint: Consultancy; Pharmaessentia: Consultancy; Incyte: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Kartos: Consultancy; Sierra Oncology: Consultancy. Gerds: PharmaEssentia Corporation: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Novartis: Consultancy. Yacoub: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Talpaz: Imago: Consultancy; Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support ; Celgene: Consultancy. Komrokji: Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau. Kremyanskaya: Astellas: Research Funding; Astex: Research Funding; Chimerix: Research Funding; Bristol Myers Squibb: Research Funding; Constellation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding. OffLabel Disclosure: AVID200 is a TGFb trap and is in clinical testing for fibrotic diseases. It does not have an approved indication at this time.