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. 2024 Dec 10;8(23):6067-6080.
doi: 10.1182/bloodadvances.2024013758.

Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin

Frank G Rücker  1 , Lars Bullinger  2 , Sibylle Cocciardi  1 , Sabrina Skambraks  1 , Tamara J Luck  1   2 , Daniela Weber  1 , Julia Krzykalla  3 , Ema Pozek  3 , Isabelle Schneider  1 , Andrea Corbacioglu  1 , Verena I Gaidzik  1 , Annika Meid  1 , Sophia Aicher  1 , Frank Stegelmann  1 , Anika Schrade  1 , Frauke Theis  1 , Walter Fiedler  4 , Helmut R Salih  5 , Gerald Wulf  6 , Hans Salwender  7 , Thomas Schroeder  8 , Katharina S Götze  9 , Michael W M Kühn  10 , Michael Lübbert  11 , Richard F Schlenk  12   13 , Axel Benner  3 , Felicitas Thol  14 , Michael Heuser  14 , Arnold Ganser  14 , Hartmut Döhner  1 , Konstanze Döhner  1
Affiliations

Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin

Frank G Rücker et al. Blood Adv. .

Abstract

Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)-based MRD assay (limit of detection 10-4 to 10-5), we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .001) and overall survival (OS) (4y-OS; 70% vs 44%; P = .012). This survival advantage was also seen among patients who underwent allogeneic hematopoietic-cell transplantation during first complete remission (4y-CIR, 14% vs 39%; P = .001; 4y-OS, 71% vs 49%; P = .029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (hazard ratio [HR], 0.29; P = .006) and OS (HR, 0.39; P = .018). During follow-up, conversion from MRDneg to MRD positivity (MRDpos) was a strong, independent factor for inferior CIR (HR, 16.64; P < .001) and OS (HR, 4.05; P < .001). NGS-based FLT3-ITD MRD monitoring identifies patients at high risk for relapse and death following treatment with intensive chemotherapy and midostaurin. Using NGS-based technology.

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Conflict of interest statement

Conflict-of-interest disclosure: F.G.R. reports receiving honoraria from and serving as a consultant for Jazz Pharmaceuticals, Novartis, and Bristol Myers Squibb (BMS)/Celgene, and receiving travel support from Jazz Pharmaceuticals. L.B. reports receiving honoraria from AbbVie, Amgen, Astellas, BMS/Celgene, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Roche, and Sanofi, and receiving research support from Bayer and Jazz Pharmaceuticals. V.I.G. reports serving in an advisory role for Jazz Pharmaceuticals, AbbVie, and Boehringer Ingelheim; serving on the speakers' bureau of Pfizer, Janssen, and AbbVie; and receiving travel support from AbbVie. F.S. reports receiving honoraria from and serving as a consultant for AOP Orphan Pharmaceuticals, MorphoSys, BMS/Celgene, Incyte, Novartis, and Pfizer. W.F. reports receiving personal fees and nonfinancial support from AbbVie; receiving grants, personal fees, and nonfinancial support from Amgen and Pfizer; receiving personal fees from Jazz Pharmaceuticals, Celgene, MorphoSys, Incyte, Stemline Therapeutics, Clinigen, Daiichi Sankyo, Otsuka, and Servier outside the submitted work; receiving research support from Apis; filing a patent with Amgen; and receiving support for medical writing for Amgen, Pfizer, and AbbVie. H.S. reports receiving honoraria from AbbVie, Amgen, AstraZeneca, BMS/Celgene, Genzyme, GlaxoSmithKline, Janssen, Oncopeptides, Pfizer, Roche, Sanofi, Stemline Therapeutics, and Takeda, and travel expenses from Amgen, BMS/Celgene, Janssen, and Sanofi. K.S.G. reports serving in an advisory role for BMS, Jazz Pharmaceuticals, Pfizer, and AbbVie. M.W.M.K. reports receiving honoraria from and serving as a consultant for Pfizer, Kura Oncology, Jazz Pharmaceuticals, BMS/Celgene, and AbbVie, and serving on the speakers bureau of Gilead. M.L. reports serving in an advisory role for AbbVie, Astex Pharmaceuticals, Imago BioSciences, Janssen, Otsuka, and Syros, and receiving research support from Janssen and Cheplapharm. R.F.S. reports serving in an advisory role or as a consultant for Daiichi Sankyo, Pfizer, Astellas, and Novartis; receiving research funding from PharmaMar, AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Daiichi Sankyo, and Recordati; and receiving funding for travel, accommodation, and expenses from Daiichi Sankyo. F. Thol reports serving in an advisory role for Novartis, BMS, AbbVie, Menarini, and Rigel. M.H. reports receiving honoraria from Certara, Jazz Pharmaceuticals, Janssen, Novartis, and Sobi; serving as a paid consultant for AbbVie, Amgen, BMS/Celgene, Glycostem, Delbert Lab, Pfizer, Pinotbio, and Servier; and receiving research funding to his institution from AbbVie, Agios, Astellas, BMS/Celgene, Glycostem, Jazz Pharmaceuticals, Karyopharm, Loxo Oncology, and Pinotbio. H.D. reports serving in an advisory role for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, BMS/Celgene, Daiichi Sankyo, GEMoaB, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Servier, Stemline Therapeutics, and Syndax, and receiving research funding from AbbVie, Agios, Amgen, Astellas, BMS/Celgene, Jazz Pharmaceuticals, Kronos Bio, Novartis, and Pfizer. K.D. reports serving in an advisory role for Amgen, BMS/Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Roche, and receiving research funding from Agios, Astex, Astellas, BMS/Celgene, and Novartis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Kinetics of FLT3-ITD VAF during treatment and early FU. (A) For the entire cohort of 157 FLT3-ITDpos, ITD VAF significantly decreased during therapy and during early FU. FLT3-ITD MRDneg was achieved in 78% after Cy2, 94% at EOT, and 85% during FU. (B) Patients separated according to NPM1mut status, demonstrating a significantly higher VAF reduction after Cy2 and higher frequencies of MRDneg for concurrent NPM1mut patients. Dx, diagnosis; wt, wild-type.
Figure 2.
Figure 2.
Prognostic impact of FLT3-ITD MRDneg after Cy2. (A) Marginal Aalen-Johansen plot of CIR and (B) marginal Kaplan-Meier plot of OS for the 142 FLT3-ITDpos patients during CR according to FLT3-ITD MRD status. (C) CIR and (D) OS according to FLT3-ITD MRD status before HCT in CR1. HRs and 95% CIs are given for FLT3-ITD MRDneg status.
Figure 3.
Figure 3.
Individual disease and treatment course after Cy2 according to FLT3-ITD MRD status. (A) Course of events for the 111 patients who were FLT3-ITD MRD negative after Cy2 and (B) for the 31 patients who were FLT3-ITD MRD positive after Cy2. (C) Course of events for the 22 patients who were FLT3-ITD MRD positive during FU.
Figure 4.
Figure 4.
Outcome according to FLT3-ITD MRD cutoffs after Cy2. CIR (A) and OS (B) according to various FLT3-ITD MRD cutoffs after Cy2. Results of pairwise comparisons are provided below the x-axis.
Figure 5.
Figure 5.
Paired FLT3-ITD and NPM1mut MRD status. (A) MRD kinetics of FLT3-ITD and NPM1mut and corresponding frequencies of MRDneg status of respective pts during therapy and early FU. (B) CIR and (C) OS according to FLT3-ITD MRD and NPM1mut MRD status after Cy2 (1 pt with FLT3-ITD MRDpos/NPM1mut MRDneg was excluded). Dx, diagnosis; pts, patients.
See this image and copyright information in PMC

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