Response patterns and impact of MRD in patients with IDH1/2-mutated AML treated with venetoclax and hypomethylating agents.
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SUBMITTER: Hammond D
PROVIDER: S-EPMC10514257 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Response patterns and impact of MRD in patients with IDH1/2-mutated AML treated with venetoclax and hypomethylating agents.
Hammond Danielle D Loghavi Sanam S Wang Sa A SA Konopleva Marina Y MY Kadia Tapan M TM Daver Naval G NG Ohanian Maro M Issa Ghayas C GC Alvarado Yesid Y Short Nicholas J NJ Sasaki Koji K Pemmaraju Naveen N Montalban-Bravo Guillermo G Lachowiez Curtis A CA Maiti Abhishek A Garcia-Manero Guillermo G Jabbour Elias J EJ Borthakur Gautam G Ravandi Farhad F Takahashi Koichi K Pierce Sherry R SR Kantarjian Hagop M HM DiNardo Courtney D CD
Blood cancer journal 20230921 1
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Project description:Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN-based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease-negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.
| S-EPMC8095152 | biostudies-literature
Project description:IntroductionAlthough the combination of venetoclax (VEN) and hypomethylating agents (HMAs) results in impressive efficacy in acute myeloid leukemia (AML), there is still a subset of patients who are refractory. We investigated the outcomes of AML patients with monocytic differentiation who were treated with frontline VEN/HMA.MethodsA total of 155 patients with newly diagnosed AML treated with frontline VEN/HMA were enrolled in the study. Monocyte-like AML was identified by flow cytometry with typical expression of monocytic markers, and M5 was identified according to French, American, and British category. We compared the outcomes of patients with different characteristics.ResultsThe rate of complete remission (CR) and CR with incomplete recovery of blood counts (CRi), progression-free survival (PFS), and overall survival (OS) in monocyte-like AML were inferior to those in nonmonocyte-like AML (CR/CRi rates, 26.7% vs. 80.0%, p < 0.001; median PFS, 2.1 vs. 8.8 months, p < 0.001; median OS, 9.2 vs. 19 months, p = 0.013). CR/CRi rate in M5 was lower than that in non-M5 (60.7% vs. 75.5%, p = 0.049). Multivariate analyses showed that monocyte-like AML was associated with lower odds of CR/CRi and higher risk of progression.ConclusionOur study suggested that newly diagnosed AML with a monocytic immunophenotype had a poor prognosis with VEN/HMA treatment.
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Project description:AbstractAlthough intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).
| S-EPMC11416634 | biostudies-literature
Project description:In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P < 0.01), and flow-cytometry negativity (83% versus 38%, P < 0.01) than doublets. At the end of the first cycle, the median time to ANC > 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P < 0.01). LIC combined with FLT3 inhibitor and venetoclax (triplet) may be an effective frontline regimen for older/unfit FLT3 mutated AML that should be further validated prospectively.
| S-EPMC9061716 | biostudies-literature
Project description:Induction of reactive oxygen species (ROS), an important process for the cytotoxicity of various acute myeloid leukemia (AML) therapies including hypomethylating agents (HMAs), concurrently activates the NF-E2-related factor 2 (Nrf2) antioxidant response pathway which in turn results in induction of antioxidant enzymes that neutralize ROS. In this study, we demonstrated that Nrf2 inhibition is an additional mechanism responsible for the marked antileukemic activity in AML seen with the combination of HMAs and venetoclax (ABT-199). HMA and venetoclax combined treatment augmented mitochondrial ROS induction and apoptosis compared with treatment HMA alone. Treatment of AML cell lines as well as primary AML cells with venetoclax disrupted HMA decitabine-increased nuclear translocation of Nrf2 and induction of downstream antioxidant enzymes including heme oxygenase-1 and NADP-quinone oxidoreductase-1. Venetoclax treatment also leads to dissociation of B-cell lymphoma 2 from the Nrf2/Keap-1 complex and targets Nrf2 to ubiquitination and proteasomal degradation. Thus, our results here demonstrated an undiscovered mechanism underlying synergistic effect of decitabine and venetoclax in AML cells, elucidating for impressive results in antileukemic activity against AML in preclinical and early clinical studies by combined treatment of these drugs.
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Project description:The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.
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| S-EPMC9481998 | biostudies-literature
Project description:AbstractHypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3-internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted.
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