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. 2023 Nov;98(11):1780-1790.
doi: 10.1002/ajh.27070. Epub 2023 Sep 4.

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants

Alex Bataller  1 , Sanam Loghavi  2 , Yoheved Gerstein  3 , Alexandre Bazinet  1 , Koji Sasaki  1 , Kelly S Chien  1 , Danielle Hammond  1 , Guillermo Montalban-Bravo  1 , Gautam Borthakur  1 , Nicholas Short  1 , Ghayas C Issa  1 , Tapan M Kadia  1 , Naval Daver  1 , Guilin Tang  2 , Andres Quesada  2 , Keyur P Patel  2 , Farhad Ravandi  1 , Warren Fiskus  1 , Cristopher P Mill  1 , Hagop M Kantarjian  1 , Kapil Bhalla  1 , Guillermo Garcia-Manero  1 , Betul Oran  4 , Courtney D DiNardo  1
Affiliations

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants

Alex Bataller et al. Am J Hematol. 2023 Nov.

Abstract

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Koji Sasaki declares research funding from Novartis, consultancy from Novartis, honoraria from Otsuka Pharmaceuticals, and membership on an entity’s Board of Directors or advisory committees from Novartis, Pfizer, Daiichi-Sankyo. Gautam Borthakur declares research funding from Astex, Ryvu Therapeutics, PTC Therapeutics, membership on an entity’s Board of Directors or advisory committees from Pacyclex, Novartis, Cytomx, Bio Ascend, and consultancy from Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen. Nicholas Short declares consultancy from Takeda Oncology, AstraZeneca, Amgen, Novartis, Pfizer, research funding from Takeda Oncology, Astellas, Stemline Therapeutics, and honoraria from Amgen. Ghayas C. Issa declares consultancy from Novartis, Kura Oncology, Nuprobe, and research funding from Celgene, Kura Oncology, Syndax, Merck, Cullinan, and Novartis. Tapan M. Kadia declares consultancy from Abbvie, Agios, BMS, Genentech, Jazz Pharmaceuticals, Novartis, Servier, PinotBio, research funding from Abbvie, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage, GenFleet, Astellas, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion, Glycomimetics, Regeneron, and honoraria from Astex. The remaining authors declared no competing interests. Naval Daver declares research funding from Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium, advisory role from Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, Shattuck, data monitoring committee member from Kartos, Jazz Pharmaceuticals, consultancy and membership on an entity’s Board of Directors or advisory committees from Agios, Celgene, SOBI, STAR Therapeutics, and research funding from Karyopham Therapeutics, Newave Pharmaceutical. Farhad Ravandi declares research funding from Amgen, Astex/Taiho, BMS/Celgene, Syos, Abbvie, Prelude, Xencor, Astellas, Biomea Fusion, Inc., honoraria from Amgen, BMS/Celgene, Syos, Abbvie, Astellas, membership on an entity’s Board of Directors or advisory committees from Astex/Taiho, consultancy from BMS/Celgene, Syos, Novartis, Abbvie, AstraZeneca, Astellas. Hagop M. Kantarjian declares research funding from Abbvie, Amgen, Ascentage, BMS, Daiichi Sankyo, Immunogen, Jazz Pharmaceuticals, Novartis, and honoraria from Abbvie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Precision Biosciences, Shenzhen Target Rx, Takeda. Guillermo Garcia-Manero declares research funding from Astex Pharmaceuticals, Novartis, Abbvie, BMS, Genentech, Aprea Therapeutics, Curis, Gilead Sciences, consultancy from Astex Pharmaceuticals, Acceleron Pharma, BMS, and honoraria from Astex Pharmaceuticals, Acceleron Pharma, Abbvie, Novartis, Gilead Sciences, Curis, Genentech, BMS. Courtney D. DiNardo declares membership on an entity’s Board of Directors or advisory committees from GenMab, GlaxoSmithKline, Kura, Notable Labs, honoraria from Kura, Astellas, Bluebird Bio, Bristol Myers Squibb, Foghorn, ImmuneOnc, Novartis, Takeda, Gilead, Jazz Pharmaceuticals, current holder of stock options in a privately-held company from Notable Labs, consultancy from Abbvie, Servier, and research funding from Servier, Bristol Myers Squibb, Foghorn, ImmuneOnc, LOXO, Astex, Cleave, Forma.

Figures

FIGURE 1
FIGURE 1
(A) Lollipop plot of the DDX41 variants identified. Splicing mutations are not represented. (B) Relationship between germline (dark green) and somatic (red) DDX41 variants.
FIGURE 2
FIGURE 2
Mutational profile of all patients in the study, together with the type of DDX41 mutation, cytogenetic abnormalities, diagnosis and sample time. Patients with biallelic TP53 alterations (2 or more mutations, VAF >40% or TP53 mutation plus chromosome 17/17p deletion) are represented with a gold dot.
FIGURE 3
FIGURE 3
(A) OS of patients with treatment-naïve AML. (B) OS of patients with treatment-naïve MDS. (C) OS of patients with treatment-naïve AML treated with low intensity treatment (LIT) stratified by venetoclax use. (C) OS of patients with treatment-naïve MDS treated with LIT stratified by venetoclax use. (E) CI of death and relapse in patients with treatment-naïve AML treated with LIT stratified by venetoclax use. (F) CI of death and relapse in patients with treatment-naïve MDS treated with LIT.
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