Successful lenalidomide treatment in high risk myelodysplastic syndrome with germline <i>DDX41</i> mutation
Authors: Iman Abou Dalle, Hagop Kantarjian, Sarah A. Bannon, Rashmi Kanagal‐Shamanna, Mark Routbort, Keyur P. Patel, Shimin Hu, Kapil Bhalla, Guillermo Garcia‐Manero, Courtney D. DiNardo
Journal: American Journal of Hematology (2019)

The DDX41 gene is a member of the DEAD/H-box RNA helicase family; recurrently mutated in ~1% of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), as well as multiple myeloma and various lymphomas.1, 2 Its exact role in leukemogenesis is not well understood. DDX41 mutations have been involved in the cell mRNA splicing, innate immunity and ribosome biogenesis.2 It can lead to defective RNA splicing and subsequent inactivation of tumor suppressor genes. It can also inactivate the STING pathway and interferon response against foreign DNA, and lastly dysregulate ribosomal assembly and protein translation leading to leukemogeneis.2 DDX41 knockdown resulted in increased proliferation and differentiation block in pre-clinical models.1 Importantly, DDX41 mutations are recently identified as a germline predisposition gene. Individuals with germline DDX41 mutations have an increased lifetime risk of both myeloid and lymphoid malignancies, with a long latency period and higher risk disease.1, 3 While it is inherited in an autosomal dominant fashion, the penetrance of DDX41 mutations is estimated to be modest (~25% lifetime risk).1, 2 Common recurrent DDX41 mutations in the Caucasian population include the p.M1I or the N-terminal frameshift duplication (p.D140Gfs). At the time of hematologic malignancy, a somatic DDX41 mutation of the second allele (most often the p.R525H mutation) can be acquired in ~50% of the cases, often at low variant allele frequency (VAF), and can be considered as a "double hit" event in the initiation of leukemogenesis.1 Other acquired somatic mutations in other genes are relatively uncommon.2 The median age of onset of MDS/AML for germline DDX41 mutation carriers is 62 years; near the average age incidence in de-novo MDS or AML.3 Most individuals with DDX41 mutations who develop MDS/AML present with leukopenia with a hypocellular marrow, erythroid hyperplasia and frequent normal diploid cytogenetics. Note, DDX41 is located on chromosome 5q35, and notably is deleted in only 25% of MDS cases with del(5q) that is usually responsive to lenalidomide therapy.1, 4 Interestingly, in several retrospective analyses, patients with DDX41 mutations without isolated del(5q) have reportedly demonstrated better responses to lenalidomide, mostly in low risk MDS disease.1, 5 Here, we report a case of high risk MDS (MDS with excess blasts-2 (MDS-EB-2) with a germline DDX41 mutation, who responded to single agent lenalidomide as initial therapy. Our patient is a 62-year-old man who presented to our leukemia clinic for evaluation of persistent pancytopenia with concern for MDS. He had been evaluated over four months for slowly progressive cytopenias including mild neutropenia, anemia, and thrombocytopenia. A bone marrow evaluation five months prior to presentation demonstrated 11% blasts without significant dysplasia, with normal cytogenetics and a negative limited next-generation sequencing (NGS) panel. At presentation to our institution, his bone marrow evaluation showed a hypocellular (30%) marrow with mild erythroid hyperplasia, without significant dysplasia, and with 10-15% blasts on manual differential, and 16% aberrant clonal blasts by flow cytometry (IMAGE 1). Blasts expressed an altered immunophenotype including CD34, CD117, CD13, CD33, CD123, CD38 and HLA-DR. Conventional karyotype was diploid male: 46,XY in 20 metaphases, and the MDS FISH panel was negative. The NGS-based molecular panel detected a DDX41 p.D140fs mutation, DDX41 p.R525H at low VAF (<5%), and an ETV6 p.Y104C variant of unknown significance. He was seen in the hereditary hematologic malignancy clinic, where single-site genetic testing on skin fibroblasts confirmed the germline nature of the DDX41 p.D140fs mutation. According to the WHO criteria, he was diagnosed with MDS-EB-2. The patient declined initial therapy. He returned four months later to reconsider initiation of therapy. A repeat marrow evaluation confirmed 15% clonal blasts in a now increasingly cellular (60%) marrow. The patient was unwilling to proceed with standard of care therapy with hypomethylating agents, followed by allogeneic stem cell transplantation, and reports suggested lenalidomide sensitivity. So, he was initiated on therapy with lenalidomide 10 mg daily, on days 1 to 21, per 28-days cycle. In a six-month timespan since initiating lenalidomide, his counts have steadily and consistently improved. A repeated bone marrow evaluation after four months of therapy showed a hypercellular marrow (90%) with hyperplastic megakaryopoiesis, erythroid predominance, rare multilineage dysplasia, mild eosinophilia, mild plasmacytosis with 3% blasts, diploid cytogenetics, and the DDX41 p.R525H mutation no longer detected (IMAGE 1). Flow cytometry was negative for increased aberrant blasts. Patient was continued on lenalidomide single agent treatment with no major adverse events. Polprasert and colleagues first described DDX41 inherited mutations to be involved in leukemia predisposition syndromes, with unique responsiveness to lenalidomide.1 Identical twin brothers with a germline DDX41 variant (c.T1187C; p.I396T) developed refractory anemia with multilineage dysplasia, and were successfully treated with lenalidomide for transfusion dependent anemia. This unexpected response in the absence of del(5q) prompted additional investigation. In a cohort of 19 patients with or without del(5q), somatic DDX41 mutations were evaluated to assess response to lenalidomide.1 Patients with low expression or DDX41 mutations had a higher response rate (78% vs 20%, P = .02) compared to others.1 Moreover, among seven patients with heterozygous DDX41 mutations or deletions, 57% of patients responded to lenalidomide alone.5 In a larger single institution retrospective cohort evaluation, next-generation targeted deep sequencing of 139 patients with MDS, or other myeloid malignancies, was analyzed to predict lenalidomide responsiveness.6 The combination of DDX41 mutations and normal cytogenetics was associated with increased responsiveness to lenalidomide, with a prediction accuracy of 82%.6 In this letter, we substantiate these preclinical and retrospective reports of lenalidomide sensitivity, with the clinical experience of a patient with high risk MDS-EB-2. This is associated with a germline DDX41 mutation with clinical response to single agent lenalidomide. This report validates the importance of genomic testing, both to suggest the presence of an inherited susceptibility mutation, also to propose an individualized, tailored treatment option. The authors declare no potential conflict of interest.