Clinical Characteristics of Myeloproliferative Neoplasms in Patients with DDX41MT Germline Predisposition Syndrome

Background:

While myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF), are usually sporadic, adult-onset neoplasms, an increasing number of germline risk alleles have been described (e.g. EGLN1, ETV6, SH2B3, and ATM) in these disorders. DDX41^MT Germline Predisposition Syndrome (GPS) is the most common myeloid GPS in adults and while there is extensive data on MDS/AML, little is known regarding MPN occurring in this context. We carried out this study to define the prevalence and characteristics of DDX41^MT-GPS associated MPN.

Methods:

After IRB approval, we retrospectively assessed the Mayo Clinic cohort of 174 patients with DDX41^MT-GPS, which included both pathogenic and clinically relevant germline variants of undetermined significance (VUS), based on our previous analysis (Badar et al Haematologica 2023). Standard statistical measures were applied.

Results:

We identified 12 (6.9%) patients with MPN (ET-5, PV-2, PMF-4, MPN-NOS-1). The median age at MPN diagnosis was 61.2 years (range, 8.-70.4); 58.3% (n=7) were male, and 83.3% (n=10) were Caucasian. A family history of hematologic malignancy was present in 16.7% (n=2, AML and T-LGL), while 50% (n=6) had a family history of visceral malignancies and 41.7% (n=5) had no family history of malignancies.

Among ET patients (n=5) with DDX41^MT-GPS, JAK2V617F was the MPN driver in 4 (80%) while type 1-CALR (L367fs*46) was a driver in 1 (20%). This included a 9-year-old child diagnosed with JAK2V617F^MT ET. The DDX41 variant was classified as pathogenic in 40% (n=2; E113Kfs*14, D140Gfs*2) and VUS in 60% (n=3; V544L, V591I, P38L). Bone marrow (BM) aspirates in the ET patients were hypercellular in 40% (n=2), normocellular in 40% (n=2) and hypocellular in 20% (n=1), and none had increased blasts, or reticulin fibrosis (RF). In addition to JAK2V617F, somatic mutations seen included SF3B1 (K666T, VAF 16%) in 1 patient and IDH2 (R140Q, VAF 6%) and DNMT3A (R882H, VAF 7%) in 1 patient, respectively. With a median follow-up from diagnosis of 3.9yrs (range 2.9-8.9), there were no thrombotic events and no disease progressions was documented.

There were 2 patients with JAK2V167F^MT PV in whom the DDX41^MT were clinically significant VUS (c.138+5G>T and M155I). Both patients had hypercellular BM, with no increase in blasts, no RF, normal karyotypes and no additional somatic mutations. With a median follow up of 7.5yrs (range, 2.1-12.9), 1 patient developed a deep vein thrombosis (DVT) and there were no fibrotic or leukemic transformations.

There were 4 patients with PMF; 3 (75%) with JAK2V617F and 1(25%) with a type 1-CALR driver mutation (L367fs*46). DIPPS-plus scores ranged from 1 to 4 (median 2.5). The DDX41 variants were pathogenic in 50% (n=2, E256K and P78Qfs*3) and VUS in 50% (n=2, P510S and M155I). The median grade of RF at PMF diagnosis was grade 2 (range, 2-3). BM were hypercellular in 75% (n=3) and hypocellular in 25% (n=1), and 1 patient had 3% peripheral blasts (and no BM blasts). Somatic co-mutations included TET2 in 1 patient with a JAK2V617F, and CBL, EZH2 and SRSF2 in 1 patient with a CALR driver-mutation, respectively. PMF patients were treated with ruxolitinib (n=3), stem cell transplant (n=1), and pIFNα (n=1). With a median follow up of 3.9yrs (range,1.1-21.9), all patients were alive, and none had leukemia transformation.

There was 1 patient with a JAK2V617F MPN-NOS with trisomy 9, where the DDX41^MT-GPS was a VUS (I215L). There were no somatic co-mutations and at last follow up (3.1 years), there was no evidence for progression.

Conclusions:

While associations between late onset MDS/AML and DDX41^MT-GPS has been well established, we systematically describe the MPN landscape seen in this context. MPN was diagnosed in 7% of our cohort, with JAK2V617F being the most common driver mutation. Most importantly, unlike in AML/MDS, where somatic DDX41 mutations are frequently associated with neoplastic transformation (30-50%; R525H being most common), none of our MPN patients had a somatic DDX41 mutation. Our work underscores the importance of germline mutation testing in patients with MPN.