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. 2021 Sep 29;11(9):162.
doi: 10.1038/s41408-021-00557-6.

Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements

Ghayas C Issa #  1 , Jabra Zarka #  2   3 , Koji Sasaki  2 , Wei Qiao  4 , Daewoo Pak  4   5 , Jing Ning  4 , Nicholas J Short  2 , Fadi Haddad  2 , Zhenya Tang  6 , Keyur P Patel  6 , Branko Cuglievan  7 , Naval Daver  2 , Courtney D DiNardo  2 , Elias Jabbour  2 , Tapan Kadia  2 , Gautam Borthakur  2 , Guillermo Garcia-Manero  2 , Marina Konopleva  2 , Michael Andreeff  2 , Hagop M Kantarjian  2 , Farhad Ravandi  8
Affiliations

Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements

Ghayas C Issa et al. Blood Cancer J. .

Abstract

Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.

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Conflict of interest statement

G.C.I. received research funding from Celgene, Kura Oncology, Syndax, and Novartis, and received consultancy fees from Novartis and Kura Oncology. K.S. received research funding from Novartis and consulting or advisory fees from Otsuka, Novartis, Pfizer, and Takeda. N.J.S. has served as a consultant for Takeda Oncology, AstraZeneca, and Jazz Pharmaceuticals, reports receiving research grants from Takeda Oncology and Astellas Pharma Inc. and has received honoraria from Amgen. C.D.D. received research funding from Abbvie, Agios, Calithera, Cleave, BMS/Celgene, Daiichi-Sankyo, Forma, ImmuneOnc, Loxo, and received consultancy or advisory board fees from AbbVie, Agios, Novartis, Aprea, Celgene/BMS, ImmuneOnc, Notable Laboratories, and Takeda. E.J. received research funding from Abbvie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Pfizer, and Takeda and received advisory board fees from Genetech. N.D. has received research funding from Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, and Agios. T.K. has received research funding from Bristol Myers Squibb, Celgene, Sanofi, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet, Cyclacel and received consulting or advisory board fees from Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, and Agios. G.B. has received research funding from Incyte, GlaxoSmithKline, Cyclacel, BiolineRx, MedImmune, Lilly, Oncoceutics, Ryvu Therapeutics, Janssen Scientific Affairs, Bristol Myers Squibb, AbbVie, Novartis, AstraZeneca, Mundipharma Research, PTC Therapeutics, BioTheryX, XBiotech, Arvinas, Astex Pharmaceuticals, TCR2 Therapeutics, Nkarta, Treadwell Therapeutics, Cellestia Biotech, and consulting or advisory board fees from Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, and Takeda. G.G.-M. received research funding from Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, AbbVie, Bristol Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck and consulting or advisory board fees from Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, and AbbVie. M.K. has received research funding from AbbVie, Genentech, Roche, Lilly, Cellectis, Calithera Biosciences, Ablynx, Agios, Ascentage Pharma, AstraZeneca, Sanofi and received honoraria or advisory board fees from AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, KisoJi Biotechnology, Stemline Therapeutics, Forty Seven, and Janssen. M.A. received research funding from Daiichi-Sankyo, and consultancy honoraria from Syndax, Jazz, Celgene, Amgen, AstraZeneca, Dimensions Capital, and equity ownership from Reata, Aptose, Europics, Senti Bio, Chimerix, and Oncolyze. H.M.K. received research funding from Ariad, Astex, Bristol Myers Squibb, Cyclacel, Daiichi-Sankyo, Pfizer, Immunogen, Jazz, Novartis and honoraria from Pfizer, Immunogen, Actinium, and Takeda. F.R. received research funding from Amgen, Bristol Myers Squibb, Sunesis Pharmaceuticals, Pfizer, Xenecor, Macrogenetics, Taiho, Astex, Abbvie and honoraria for consulting or advisory role from Jazz, Amgen, Celgene, Astellas, Syros, Taiho, Novartis, AstraZeneca, Agios, and Bristol Myers Squibb.

Figures

Fig. 1
Fig. 1. Fusion partner genes and mutational profile of adults with newly diagnosed KMT2Ar AML.
A Distribution of fusion partner genes. B Cytogenetics and distribution of 11q23 translocations. C Genes most commonly mutated in KMT2Ar AML compared to an age-matched cohort of AML with a diploid karyotype. D Circos plot depicting patterns of co-occurrence between mutations and various translocations leading to KMT2Ar. E Number of mutations per patient comparing KMT2Ar AML to an age-matched cohort of AML with a diploid karyotype.
Fig. 2
Fig. 2. Dynamic changes of the cytogenetic burden in adults with KMT2Ar AML following treatment.
Numbers depict the estimated % of KMT2Ar measured by fluorescence in situ hybridization (FISH) or conventional cytogenetics when FISH was not performed. Numbers below the X-axis indicate the proportion (%) of patients with KMT2Ar among those with available cytogenetic data. This analysis included unique patients from the newly diagnosed cohort in addition to patients who presented to our institution with relapsed or refractory disease. The long-term remission graph depicts those who achieved and maintained a morphologic remission whereas the relapse graph depicts those with initial morphologic remission following induction treatment and subsequent relapse.
Fig. 3
Fig. 3. Cumulative incidence of relapse and overall survival for patients with KMT2Ar AML by a line of therapy compared with an age-matched cohort of AML with diploid karyotype.
A Cumulative incidence of relapse following first-line therapy. B Overall survival following first-line therapy. C Cumulative incidence of relapse following second-line therapy. D Overall survival following second-line therapy. E Cumulative incidence of relapse following third-line therapy. F Overall survival following third-line therapy. Treatment start date for second-line treatment and beyond was used for the calculation of time-to-event.
Fig. 4
Fig. 4. Risk of relapse and overall survival in newly diagnosed KMT2Ar AML.
A Cumulative incidence of relapse by subtype of KMT2Ar. B Overall survival by subtype of KMT2Ar. C Overall survival of newly diagnosed KMT2Ar AML by therapy-related status. D Landmark analysis comparing overall survival of patients with newly diagnosed KMT2Ar AML who underwent an allogeneic hematopoietic stem cell transplant following the first remission to those who did not undergo transplant.
Fig. 5
Fig. 5. Univariate and multivariate analyses of factors predicting risks of relapse or death in newly diagnosed KMT2Ar AML.
Variables with P ≤ 0.05 were included in the multivariate analysis. RFS relapse-free survival, OS overall survival, HR hazard ratio, WBC white blood cell count, Hgb hemoglobin, BM bone marrow, t-AML therapy-related AML, allo-HSCT allogeneic hematopoietic stem cell transplant.
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