Congenital Myelodysplastic Syndrome in a Newborn With Germline <i>JAK2</i> Variant Treated With Liposomal Cytarabine–Daunorubicin and Allogeneic Hematopoietic Stem Cell Transplant

To the Editor: Myelodysplastic syndrome (MDS) is a rare clonal hematopoietic disorder in children presenting with cytopenias, ineffective hematopoiesis, and increased risk of progression to acute myeloid leukemia (AML). Here, we present a child with an inherited novel JAK2 variant diagnosed with congenital MDS and describe the disease progression, response to therapy, and durable remission following allogeneic hematopoietic stem cell transplantation (HSCT). Our patient was a full-term female born to a 34-year-old G4P4 mother. There was a maternal history of herpes simplex virus (HSV) infection requiring valacyclovir suppression (no lesions at delivery), COVID-19 infection 3 weeks prior to delivery, and otherwise normal prenatal labs, including no maternal thrombocytopenia and no family history of thrombocytopenia. The infant developed hypoxia, petechiae, and mild respiratory distress at 2 hours of age. A complete blood count showed a white blood cell count of 21.9 × 103/µL, hemoglobin of 12.1 g/dL, and platelets of 18 × 103/µL with 11% blasts. Work-up demonstrated no growth on blood culture and was negative for cytomegalovirus, HSV, toxoplasma, parvovirus B19, rapid plasma reagin, and COVID-19. Parental testing was negative for neonatal alloimmune thrombocytopenia. Echocardiogram, liver, renal and head ultrasounds, and bilateral upper extremity x-rays were normal. A phytohemagglutinin-stimulated peripheral blood karyotype showed 46,XX; however, whole genome single-nucleotide polymorphism microarray identified mosaic copy number gains across multiple chromosomes concerning for neoplasm. Bone marrow (BM) biopsy at 18 days of life revealed atypical/dysplastic megakaryocytes, 6.2% blasts on aspirate smear with aberrant cell differentiation (CD)41, CD42b, and CD61 on multidimensional flow cytometry (MDF), and an abnormal karyotype (Figure 1A–C). Full body magnetic resonance imaging had no evidence of myeloid sarcoma. Comprehensive next-generation sequencing of the BM (Children's Hospital of Philadelphia Comprehensive Hematologic Cancer Panel) identified a heterozygous JAK2 gene variant of uncertain significance (VUS) with no additional variants related to an inherited BM failure (normal chromosome breakage and telomere length testing) or cancer predisposition syndrome. Given her presentation, further germline testing was performed. A pediatric disease panel (Prevention Genetics), including exome-wide copy number variation detection, only identified the same maternally inherited (NM_004972.3)c.3223G>T, p.Val1075Leu heterozygous JAK2 VUS not listed in the ClinVar database. BM evaluation at 47 days of life, in the setting of stable yet persistent cytopenias, again demonstrated dysplastic megakaryocytes with 5% blasts morphologically and 3.9% immunophenotypically aberrant on MDF. She was diagnosed with MDS with excess blasts 1 (MDS-EB-1) per the 2016 World Health Organization classification. Given her very young age, she was initially managed with supportive care and planned for upfront HSCT given reports demonstrating improved outcomes in patients undergoing early HSCT (<140 days from diagnosis) not receiving pre-HSCT chemotherapy [1]. She continued to have severe thrombocytopenia and ineffective erythropoiesis marked by lactate dehydrogenase (LDH) levels greater than 10 times the upper limit of normal (Figure 2). Serial BM evaluations showed ongoing clonal changes in her marrow with stable blasts in the 5%–9% range. An unrelated cord blood transplant was planned at 143 days of life; however, she developed acute COVID-19 and influenza A infections, necessitating a 4-week delay. A repeat marrow then showed 10%–15% blasts with a diagnosis of MDS with excess blasts 2. At 173 days of life, she initiated 5-azacitidine (2.5 mg/kg intravenous daily × 7 days) and venetoclax (1.39 mg/kg × 1, 4 mg/kg × 1, and 6.95 mg/kg oral daily × 26 days) in attempts to decrease disease burden prior to transplant [2]. Unfortunately, BM after 5-azacitidine/venetoclax showed progression with 25% blasts, representing a diagnosis of AML with myelodysplasia-related changes (AML-MRC) and evidence of clonal evolution (Figure 1D). At 215 days of life, she received CPX-351 (liposomal cytarabine and daunorubicin) 41 mg/m2 on days 1, 3, and 5. Following neutrophil recovery, she demonstrated marked improvement in her platelet count with resolution of her elevated LDH (Figure 2). BM after count recovery demonstrated no detectable clonal abnormalities and no atypical blast population on MDF. She proceeded to umbilical cord blood transplant at 284 days of life with myeloablative conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin. She developed veno-occlusive disease of the liver requiring defibrotide and Grade 3 acute skin graft-versus-host disease (GVHD) requiring systemic corticosteroids. Disease re-evaluation at 30 days, 100 days, and 6 months post-transplant demonstrated no disease recurrence and 100% donor chimerism. She weaned off steroids and GVHD prophylaxis and remains in remission 2.5 years post-transplant. Childhood MDS is extremely rare, and congenital presentations are not described in the literature. We sought to highlight this case of congenital/neonatal MDS with progression through 5-azacitidine and venetoclax therapy, response to CPX-351 (liposomal cytarabine and daunorubicin), and durable remission following myeloablative HSCT. This patient had a maternally inherited c.3223G>T, p.Val1075Leu heterozygous JAK2 VUS, which has not been previously described. This variant is located in the kinase domain but is not functionally defined otherwise [3]. The germline variant in this patient is intriguing in that her mother with the same variant is otherwise healthy. Extensive genetic evaluation identified no other variants or predispositions to myeloid malignancy despite a high likelihood of genetic predisposition in children with MDS [4]. In summary, this case report presents a rare diagnosis of congenital MDS, with a previously undescribed germline JAK2 variant. Further investigation into the importance of this JAK2 variant will be critical for understanding its functional and clinical significance. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.