Successful Haploidentical Hematopoietic Cell Transplantation in Patient with Hypodiploid ALL and Biallelic Germline Mutations in ERCC6L2
Authors: Abu Shanap Mayada 
Published: December 2024

Background:
Inherited bone marrow failure syndromes (IBMFS) are a group of disorders leading to inadequate blood cell production due to mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle. Mutations in the ERCC6L2 gene have been associated with bone marrow failure, developmental delay, and microcephaly. We report the clinical and hematopoietic manifestations of a patient with a homozygous mutation in ERCC6L2 presenting with hypodiploid acute lymphoblastic leukemia (ALL).
Method:
A 16-year-old male presented in April 2022 with fatigue, fever, petechiae, along with hepatosplenomegaly. The patient had polydactyly and microcephaly. Blood tests revealed thrombocytopenia and leukopenia (WBC: 2000). Bone marrow aspirate and flow cytometry confirmed pre-B cell ALL. Cytogenetics showed a hypodiploid clone (35,XY), and next-generation sequencing (NGS) revealed a pathogenic variant (c.524&gt;A(P.Arg 175 His)) in the TP53 gene. He received induction chemotherapy per St. Jude Total XV protocol with vincristine, daunorubicin, prednisolone, and PEG-asparaginase. Induction chemotherapy was complicated by a severe perianal infection requiring debridement and colostomy. Though he was maintained on interim low-dose chemotherapy; he was intolerant and experienced prolonged myelosuppression. Bone marrow evaluation at day 15 showed 5% blasts, and at the end of induction, remission with negative minimal residual disease (MRD) was achieved. TP53 by Sanger sequencing was negative, consistent with a somatic mutation pattern. Chromosomal breakage study was negative, and IBMF panel by NGS detected a homozygous VUS variant c.470T&gt;C (p.Leu157Pro) in the ERCC6L2 gene. Capizzi methotrexate at 200 mg/m2 caused severe oral mucositis, upper GI bleeding, and prolonged pancytopenia. Due to excessive toxicity indicative of a DNA repair defect, the patient was maintained on reduced doses of 6-mercaptopurine, methotrexate, alternating with low-dose cyclophosphamide and cytarabine, and vincristine/dexamethasone. In January 2023, early relapse with MRD of 0.01% was noted. Salvage therapy with reduced FLAG chemotherapy (fludarabine 15 mg/m2 for 4 days and cytarabine 500 mg/m2 for 4 days) achieved remission with negative MRD. The patient underwent haploidentical transplantation in April 2023 with reduced-intensity conditioning: fludarabine (30 mg/m2/day for 5 days from day -8 to -4), antithymocyte globulin (2.5 mg/kg/day for 2 days at day -3 and -2), cyclophosphamide (14.5 mg/kg/day at day -3 and -2), and total body irradiation (200 cGy on day -1). Post-transplant cyclophosphamide (25 mg/kg/day on days +3 and +4) with high-dose mesna, tacrolimus, and mycophenolate mofetil was used for GVHD prophylaxis. The donor, his mother, was a 5/10 HLA match, and he received peripheral blood stem cells: TNCs/kg: 11x10^8, CD34+/kg: 8.7x10^6, CD3+/kg: 35x10^7.
Results:
The early post-transplant course was complicated by grade II mucositis and febrile neutropenia. The patient achieved sustained engraftment of neutrophils and platelets at 13 and 17 days, respectively. He experienced CMV reactivation and mild BK cystitis but no acute GVHD. Complete haplo-donor chimerism was confirmed at +30 days. At 15 months post-transplant, the patient remains alive with negative MRD, full donor chimerism, off immunosuppression, no chronic GVHD, and a good quality of life.
Conclusion:
To our knowledge, this is the first report of a child with hypodiploid ALL and ERCC6L2 mutations cured by haploidentical transplant using reduced-intensity conditioning. This case suggests that haploidentical transplantation can be a safe and effective therapeutic strategy for patients with ERCC6L2 mutations.