Mendler, Jason H.

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Abstract In CN-AML, mutations of specific genes have prognostic significance and are used for treatment guidance. However, these mutations are in general not mutually exclusive and CN-AML patients (pts) frequently harbor mutational combinations with unclear prognostic significance because of the concurrent presence of mutations with favorable (CEBPA, NPM1) and unfavorable (ASXL1, DNMT3A, IDH1, IDH2, FLT3-ITD, MLL-PTD, RUNX1, TET2, WT1) impact on outcome. Here, we report the frequency and clinical significance of isolated mutations and their combinations in 364 CN-AML pts. Younger [<60 years (y); n=163] and older (≥60 y; n=201) pts were intensively treated on frontline CALGB/Alliance protocols and, per protocol, did not undergo allogeneic stem cell transplantation in first complete remission (CR). Median follow-up for pts alive was 8.7 y. Pts were analyzed centrally for mutations in the ASXL1, CEBPA, DNMT3A, IDH1, IDH2, NPM1, RUNX1, TET2, and WT1 genes and the presence of FLT3-ITD, FLT3-TKD and MLL-PTD. We found that 99% of pts had ≥1 and 88% ≥2 of the 12 mutations. Specifically, 11% of pts had 1 gene mutated (n1), 40% had 2 (n2), 31% 3 (n3), and 18% harbored ≥4 mutated genes (n4). The distribution of the different n groups in younger and older pts was similar (Fig 1). The expected frequency of each mutated gene in every numerical (n) group was calculated as follows: [no. of pts with the mutated gene] x [total no. of mutations in the n group] / [total no. of mutations in all pts], and compared with the observed frequency. CEBPA, IDH2, NPM1, and RUNX1 mutations were overrepresented in the n1 and n2 groups (P<.001, P<.001, P=.002, P=.02, respectively) and thus likely represent “early” events in leukemogenesis. In contrast, DNMT3A, FLT3-ITD, and TET2 mutations were more frequent in the n3 and n4 groups (P=.008, P<.001, P=.02, respectively) suggesting that they are likely “late” events. The distribution among age groups and clinical impact of the “early” mutations (i.e., CEBPA, NPM1, IDH2) presenting as isolated mutations or in combination with other mutations were then investigated. Isolated RUNX1 mutations could not be evaluated due to small sample size. Younger pts were more likely to harbor an isolated “early” mutated gene than older pts (21% v 12%, P=.03). Specifically, isolated CEBPA and NPM1 mutations were more frequent in younger pts compared with the older (7% v 2%, P=.007; 7% v 3%, P=.07, respectively). In pts with isolated CEBPA mutations, these were always bi-allelic. Single “early” mutated genes varied in their impact on CR achievement (CEBPA: 100%, NPM1: 94%, IDH2: 67%), and overall survival (OS; 3-y OS: CEBPA: 87%, NPM1: 69%, IDH2: 22%). Acquisition of additional mutations adversely modified the prognostic significance of favorable “early” mutations in the CEBPA (Fig 2A) and NPM1 (Fig 2B) genes, but left unchanged the unfavorable effect of IDH2 mutations (Fig 2C). Two mutational combinations were exceptions to this: younger pts with both NPM1 and DNMT3A mutations (8 pts) had an excellent prognosis with 3-y OS of 100%; and older pts with concurrent NPM1 and IDH2 mutations (9 pts; all IDH2 mutations were in codon R140) had a high 3-y OS rate of 67%. We conclude that CEBPA and NPM1 mutations mainly define pts with favorable prognosis when they present as single markers, whereas mutated IDH2 predominantly associates with adverse outcome. The NPM1+DNMT3A and NPM1+IDH2 mutational patterns may define novel favorable molecular subtypes in younger and older CN-AML pts, respectively, but these results require corroboration in larger pt cohorts. Disclosures: Mrózek: AMERICAN SOCIETY OF HEMATOLOGY: I will review abstracls submitted for presentation at the 55th ASH Annual Meeting in the 611 category Other. Eisfeld:AMERICAN SOCIETY OF HEMATOLOGY: I will review abstracls submitted for presentation at the 55th ASH Annual Meeting in the 608 category Other.

Purpose To evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. Patients and Methods We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155–associated gene and microRNA expression profiles were derived using microarrays. Results Considering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. Conclusion miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.

Abstract High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.