Bone Marrow Transplantation | 2021
T-cell replete haploidentical transplantation with reduced post-transplant cyclophosphamide in six children with infantile osteopetrosis
Abstract
Infantile osteopetrosis (OP) is a rare genetic disorder of osteoclast development and/or function. Hematopoietic cell transplantation (HCT) is the only curative approach for most children with OP. HCT in children with infantile OP is complicated by a high incidence of graft failure and increased transplant-related toxicity particularly when using alternative donors [1, 2]. In recent years, haploidentical Tcell replete HCT with high-dose post-transplant cyclophosphamide (Haplo-PTCy) has become a valid alternative transplant strategy for patients without HLA-matched donor with malignant and nonmalignant diseases [3, 4]. It is believed that infantile OP requires myeloablative conditioning to overcome graft failure but the use of HaploPTCy is associated with additional toxicity such as hemorrhagic cystitis and high-grade mucositis in patients who already suffer from failure to thrive and narrow airways, plus the increased risks of veno-occlusive disease (VOD) and pneumonitis [1, 2, 5]. We hypothesized that the Haplo-PTCy strategy with fludarabine-based myeloablative conditioning followed by reduced dose of post-transplant cyclophosphamide would achieve long-term engrafted survival for osteopetrosis with lower rate of regimen-related toxicities. Six children with infantile OP presented to our institution without HLA-matched donors, between July 2016 and October 2019. The diagnosis of OP was based on molecular studies, skeletal radiologic changes, and extra-medullary hematopoiesis. Patients’ characteristics are summarized in Table 1. Median age at HCT was 10.6 months (range, 5–39 months). All patients underwent HCT within 2 months of their diagnosis except Patient 4 who received a second transplant after graft failure 1 year after her first cord transplant. After obtaining informed parental consent, all patients received uniform reduced toxicity myeloablative conditioning. The regimen consisted of fludarabine, thiotepa, and busulfan as outlined in Fig. 1. At our institution busulfan pharmacokinetics studies are not available, so busulfan dosing was based on weight of the patient and it was given for 3 days instead of 4 days. Patients received primed bone marrow from their fathers except Patient 6 who received peripheral blood cells HCT from her mother. In this patient anti-thymocyte globulin (Neovii ATG) 2.5 mg/ kg/day for 3 days was added to the conditioning. GvHD prophylaxis for all patients consisted of 25 mg/kg cyclophosphamide (PTCy), days +3 and +5, in addition to cyclosporine A and mycophenolate mofetil. Absolute neutrophil count recovery and platelet–transfusion independence occurred in all patients at a median time of 16 days (range, 13–22 days) and 70.5 days (range, 33–131) respectively. Romiplostim 3–10 μg/kg/dose was administered in three patients with delayed platelet engraftment. All patients except Patient 3 had 100% donor chimerism from day +28 till last follow-up visit. Patient 3 had graft failure by day +90. Acute GvHD Grade I–II was seen in all patients and all responded to a short course of corticosteroids; none of them developed chronic GvHD till last follow-up. Sever mucositis (grade III) and moderate VOD treated with defibrotide developed in two patients (Patients 2 and 5). No patient developed hemorrhagic cystitis or pulmonary hypertension. CMV reactivation developed in five patients but none of them had CMV disease. Late hypercalcemia was observed in Patient 2. At a median follow-up of 22 months (range 4–37 months), five patients were alive of whom four showed complete donor * Amal Al-Seraihy [email protected]