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Successive relapses from donor and host cells in a patient with DEAD‐box helicase 41 (DDX41)‐associated myelodysplastic syndrome: The lessons to be learned

Germline pathogenic variants (PV) that predispose to hereditary haematological malignancies are being described in a growing number of genes. DEADbox helicase 41 (DDX41)associated familial neoplasm is an inherited autosomal dominant disorder most commonly characterised by an increased risk of myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML).1,2 The following family history illustrates the influence of genetic and microenvironmental factors that mediate sequential host and donor cell leukaemia after allogeneic stem cell transplantation (SCT). The patient (Figure 1, generation II.2), known to have a familial history of acute leukaemia (father and uncle), received an allogeneic peripheral blood SCT from his HLAmatched, 52yearold brother (Figure 1, generation II.3) for an intermediaterisk (level 2) MDS (IRMDS) with a nonspecific translocation t(6;17)(p21;p13). Chimerism monitoring using polymerase chain reaction (PCR) of small tandem repeats and quantitative PCR demonstrated a full donor chimerism for 8 years (Figure 2A) but at this time point, he relapsed into an IRMDS. The chimerism was still full donor, suggesting that relapse had occurred in the donor cells. Molecular genetic analyses (nextgeneration sequencing [NGS], Custom myeloid solution, Sophia Genetics, Switzerland; Table S1) detected a DDX41 K331del PV, associated with a DDX41 R525H PV, a zinc finger CCCHtype, RNA binding motif and serine/arginine rich 2 (ZRSR2) C187Y mutation and two other DDX41 variants with low variant allele frequency (VAF); the DDX41 K331del variant was also identified retrospectively in pretransplant donor cells. A retrospective analysis of the host cells before transplantation found the same DDX41 K331del PV together with the DDX41 R525H PV (Figure 2B). An analysis of the singlenucleotide polymorphism (SNP) in the three samples confirmed that relapse had occurred in the donor cells. The germline nature of the DDX41 K331del PV was confirmed by a host skin biopsy. The patient then received a second allogeneic bone marrow (BM) SCT from his HLA haploidentical 43yearold son, after checking that the latter did not carry the DDX41 K331del mutation. However, he relapsed 2 years later and with chimerism, the NGS analysis confirms that relapse had occurred in the host cells, showing low VAF of the DDX41 K331del and R525H PV already present at diagnosis, together with previously undetected mutations. A fluorescence in situ hybridisation (FISH) analysis demonstrated a 17p and a 7q deletion. Additionally, a loss of Y chromosome (LOY) was observed by K analysis and a retrospective FISH analysis in a sample of BM cells confirmed that the LOY was present in the donor. Defective RNA splicing and subsequent translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly in DDX41mutated cells are considered to be initiating alterations in leukaemogenesis.3 Nevertheless, they may not be sufficient; the sequence of donor and host cell relapses, as reported here, has not been identified before and supports the hypothesis that both genetic and microenvironmental factors mediate the development of MDS. Indeed, in this story, as commonly reported in donor cell leukaemia (DCL), the donor is healthy4; and, as illustrated in Figure 2B, there are higher rates of mutations found in recipient than in donor tissue. The rapid expansion of the haematopoietic system after transplantation, as thought to occur in DCL, is not the only event supporting genetic instability; indeed, in our patient, the second relapse emerged from the host cells, with again additional mutations, supporting that microenvironmental factors may induce or enhance genomic damage. Posttransplant microenvironmental factors, like a conditioning regimen prior to transplantation or immunosuppressive therapy can be involved.4 However, murine studies have demonstrated primary microenvironmental defects that can be primary causes of neoplastic changes.5 Whether this occurs in human disease is not yet established, but current data support the emerging concept of interdependency between MDS and the surrounding BM niche.6,7 The patient did not achieved remission with an association 5azacytidine (Aza; Cellgene Inc., Swiss; 75 mg/m2/day)/venetoclax (Ven; 400 mg/day) days 1– 7, every month for 5 months. Recently, immune dysregulation has been proposed as a key component of MDS pathophysiology8,9 and led us to initiate immunotherapy. On the grounds of the reported improved outcome with granulocytecolony stimulating factorprimed donor leucocyte infusions (DLI) after haploidentical transplantation in MDS,10 the patient subsequently received after Received: 24 May 2022 | Accepted: 15 August 2022