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MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.

ABSTRACT: Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.

SUBMITTER: Wei Y

PROVIDER: S-EPMC10088064 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.

Wei Yue Y Zheng Hong H Lockyer Pamela Pennington PP Darbaniyan Faezeh F Li Ziyi Z Kanagal-Shamanna Rashmi R Soltysiak Kelly A KA Yang Hui H Ganan-Gomez Irene I Montalban-Bravo Guillermo G Chien Kelly S KS Do Kim-Anh KA Daver Naval N Garcia-Manero Guillermo G

Leukemia & lymphoma 20220905 13

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In <i>TP53</i> wildtype myeloid cell line, combinational ...[more]

PMID: 36059252

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Project description:Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; P<0.0001), or only received red blood cell transfusions (19.8% versus 16.7%; P=0.037). A larger percentage of patients with chronic myelomonocytic leukemia progressed to acute myeloid leukemia (42.6% versus 15.5%, respectively; P<0.0001), with shorter time to progression. Chronic myelomonocytic leukemia patients had a shorter median survival (13.3 versus 23.3 months; P<0.0001) and lower 3-year survival rate (19% versus 36%; P<0.0001). Adjusted estimates, controlling for baseline characteristics and selected treatments, indicate that chronic myelomonocytic leukemia was associated with an increased risk of progression to acute myeloid leukemia or death (HR 2.22; P<0.0001), compared to myelodysplastic syndromes. In conclusion, chronic myelomonocytic leukemia is less frequently treated in older adults and is associated with worse outcomes, even after controlling for the patients' baseline characteristics and selected treatments. Our data suggest the need for continued evaluation of the biological differences between these diseases and clinical trials targeting chronic myelomonocytic leukemia.

Project description:Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

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MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.

Publications

MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.

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