Key Points• DNMT3A mutations are frequent in younger adults with AML and have no significant impact on survival end points.• Only moderate effects on outcome, depending on molecular subgroup and DNMT3A mutation type, could be observed.In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A mut ) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A mut were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A mut did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P 5 .011).
Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1 mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TL) by RQ-PCR and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TL and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase III AMLSG 09-09 trial. 3733 bone marrow (BM) and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after two treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity consistently revealed as poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TL were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly higher proportion of patients achieving MRD negativity at EOT (56% vs 41%; P=.01). The betterreduction of NPM1mut TL after two treatment cycles in MRD-positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR 29.3% vs 45.7%, P=.009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction of NPM1mut TL across all treatment cycles leading to a significantly lower relapse rate. The AMLSG 09-09 trial was registered at www.clinicaltrials.gov as #NCT00893399.
Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC). Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio >0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014. Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age<60 yrs, n=20 age ≥60 yrs) and 9 pts after salvage outside the protocol or after relapse (n=70 from a matched unrelated and n=24 from a matched related donor). In pts receiving an alloHSCT within the protocol in median 2 chemotherapy cycles were applied before transplant (range 1-4) and the cumulative incidence of relapse and death at 12 months were 9.2% (SE 3.3%) and 19.5% (SE 4.8%). Maintenance therapy was started in 52 pts, 40 pts after alloHSCT and 12 pts after HIDAC. Only 4 adverse events 3°/4° were attributed to midostaurin. First analyses revealed a low cumulative incidence of relapse irrespective of the FLT3-ITD mutant to wildtype ratio (<0.5 versus ≥0.5) in patients proceeding to alloHSCT with 12% and 5% as well as for those after HIDAC consolidation with 28% and 29%, respectively. Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHSCT or HIDAC is feasible and compared to historical data may be most effective in those patients with a high FLT3-ITD mutant to wildtype ratio. Disclosures Schlenk: Novartis: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria.
Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML). The multi-targeted kinase inhibitor midostaurin combined with intensive chemotherapy has shown activity against AML with FLT3 mutations. However, toxicity and potential drug-drug interactions with strong CYP3A4 inhibitors such as posaconazole may necessitate dose reduction. Aims: To evaluate the impact of age and midostaurin dose-adaptation after intensive induction chemotherapy on response and outcome in AML with FLT3-ITD within the AMLSG 16-10 trial (NCT01477606). Methods: The study included adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial. Pts with acute promyelocytic leukemia were not eligible. The presence of FLT3-ITD was analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based DNA fragment-length analysis. Induction therapy consisted of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid was applied from day 8 until 48h before start of the next treatment cycle. A second cycle was allowed in case of partial remission (PR). For consolidation therapy, pts proceeded to allogeneic hematopoietic-cell transplantation (HCT) as first priority; if alloHCT was not feasible, pts received three cycles of age-adapted high-dose cytarabine (HDAC) in combination with midostaurin starting on day 6. In all pts one-year maintenance therapy with midostaurin was intended. The first patient entered the study in June 2012 and in April 2014, after recruitment of n=147 pts, the study was amended including a sample size increase to 284 pts and a dose reduction to 12.5% of the initial dose of midostaurin in case of co-medication with strong CYP3A4 inhibitors (e.g. posaconazole). This report focuses on age and the comparison between the first (n=147) and the second cohort (n=137) of the study in terms midostaurin dose-adaptation. Results: Patient characteristics were as follows: median age 54 yrs (range, 18-70; younger, 68% < 60 yrs; older, 32% ≥ 60 yrs); median white cell count 44.7G/l (range 1.1-1543 G/l); karyotype, n=161 normal, n=16 high-risk according to ELN recommendations; mutated NPM1 n=174 (59%). Data on response to first induction therapy were available in 277 pts; complete remission (CR) including CR with incomplete hematological recovery (CRi) 60%, PR 20%, refractory disease (RD) 15%, and death 5%. A second induction cycle was given in 54 pts. Overall response (CR/CRi) after induction therapy was 76% (76%, younger; 76%, older) and death 6% (4%, younger; 10% older). The dose of midostaurin during first induction therapy was reduced in 53% and 71% of patients in cohort-1 and cohort-2, respectively. Reasons for dose reduction were in 58% and 49% toxicity, and in 9% and 23% co-medication in cohort-1 and cohort-2, respectively. No difference in response to induction therapy was noted between cohorts (p=0.81). Median follow-up was 18 months. Overall 146 pts received an alloHCT, 128 in first CR (n=94 younger, n=34 older; n=92 from a matched unrelated and n=36 from a matched related donor). In pts receiving an alloHCT within the protocol in median two chemotherapy cycles were applied before transplant (range 1-4). The cumulative incidence of relapse (CIR) and death after transplant were 13% (SE 3.2%) and 16% (SE 3.5%) without differences (p=0.97, p=0.41, respectively) between younger and older patients. So far maintenance therapy was started in 86 pts, 61 pts after alloHCT and 25 pts after HDAC. Fifty-five adverse events 3°/4° were reported being attributed to midostaurin; cytopenias after alloHCT were the most frequent (29%). CIR in patients starting maintenance therapy was 20% one year after start of maintenance without difference between alloHCT and HiDAC (p=0.99). In addition, no difference in CIR was identified in patients after consolidation with alloHCT or HDAC according to dose reduction of midostaurin during first induction therapy (p=0.43, p=0.98, respectively). Median overall survival was 25 months (younger, 26 months; older 23 months; p=0.15). Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHCT or HDAC is feasible and effective without an impact of age and dose adaptation on outcome. Disclosures Schlenk: Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Gilead: Other: Travel; Ariad/Incyte: Consultancy; Novartis: Consultancy; Teva: Other: Travel. Lübbert:Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Greil:Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Eisai: Honoraria; Amgen: Honoraria, Research Funding. Greiner:BMS: Research Funding. Paschka:ASTEX Pharmaceuticals: Consultancy; Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria. Heuser:Bayer Pharma AG: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; BerGenBio: Research Funding; Tetralogic: Research Funding.
Background: Activating mutations in receptor tyrosine kinases like FLT3 (FLT3mut) lead to an aberrant signal transduction thereby causing an increased proliferation of hematopoietic cells. Internal tandem duplications (FLT3-ITD) or mutations in the tyrosine kinase domain (FLT3-TKD) occur in about 25% of younger adult patients (pts) with acute myeloid leukemia (AML), with FLT3 -ITD being associated with an unfavourable outcome. FLT3mut present an excellent target for small molecule tyrosine kinase inhibitors (TKI). The multi-targeted kinase inhibitor midostaurin (PKC412) is currently under investigation as a FLT3-inhibitor in combination with intensive chemotherapy. Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome will be of major importance. The plasma inhibitor activity (PIA) assay allows the visualization of the level of dephosphorylation of the target under TKI therapy. Preliminary data suggest a correlation between the grade of dephosphorylation, as a marker for the activity of the TKI, and clinical outcome. Aims: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3-ITD AML pts treated within our AMLSG16-10 trial (NCT: NCT01477606) which combines midostaurin with intensive chemotherapy, and to correlate the results with clinical outcome. Methods: Plasma samples from pts (age 18-70 years) with newly diagnosed FLT3-ITD AML were obtained at different time points for PIA analysis. All pts were enrolled on the ongoing AMLSG 16-10 trial applying intensive therapy in combination with midostaurin (50mg twice a day). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) in combination with midostaurin from day 6 onwards. In all pts one year of maintenance therapy with midostaurin was intended. PIA analyses were performed at defined time points (day 15 of induction, each consolidation cycle, at the end of each treatment cycle, every 3 months during maintenance therapy) as previously described (Levis MJ, et al. Blood 2006; 108:3477-83). Results: So far, PIA analyses were performed in 63 pts (median age, 51.6 years; range, 20-70 years) during (n=63) and after (n=73) first and second induction cycle, during (n=40) and after (n=53) consolidation therapy with HiDAC as well as during maintenance therapy (n=82). During and after induction therapy median levels of phosphorylated FLT3 (p-FLT3) were 46.6% (4.5-100%, <20% in 7.9%) and 39.4% (0.3-100%, <20% in 20.5%), respectively. Co-medication with azoles had no impact on p-FLT3 levels. In pts with a FLT3-ITD mutant to wildtype ratio above our recently defined cut-off value of 0.5, levels of p-FLT3 <20% were associated with a complete remission (CR)-rate of 100%, whereas in those pts with p-FLT3 levels ≥20%, 4 out of 22 pts (18%) had resistant disease. In contrast, response in pts with a mutant to wildtype ratio below 0.5 was independent of the p-FLT3 level. During and at the end of consolidation cycles as well as during maintenance therapy p-FLT3 levels in pts treated with midostaurin were 52% (14.8-100%, <20% in 5%), 63% (7.6-100%, <20% in 7.4%) and 60.2% (11.5-100%, <20% in 3.7%), respectively. In pts concomitantly treated with azoles levels of p-FLT3 were lower without reaching significance. 39 of 63 pts received alloHSCT in first CR; those pts with p-FLT3 levels <20% after induction therapy had an in trend better survival, whereas no impact of phosphorylation levels was evident in pts receiving chemotherapy alone. Conclusion: In our study of FLT3-ITD AML pts treated with midostaurin in combination with intensive chemotherapy we could show that the lowest levels of p-FLT3 were reached during and after induction therapy. In pts with a FLT3-ITD mutant to wildtype ratio >0.5, levels of p-FLT3 <20% during and after induction therapy were associated with a high CR-rate. When receiving alloHSCT these pts had an in trend better survival compared to those with p-FLT3 levels >20%. An update of the data will be presented at the meeting. Disclosures Salwender: Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Horst:Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Ingleheim: Research Funding; Boehringer: Research Funding; MSD: Research Funding; Gilead: Honoraria, Research Funding. Schlenk:Novartis: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Arog: Honoraria, Research Funding.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.