Reduced Intensity Conditioning Is Safe and Effective for Transplantation of Patients with Shwachman Diamond Syndrome.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for the bone marrow dysfunction seen in patients with Shwachman-Diamond Syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced intensity conditioning protocol in 7 patients with SDS and bone marrow aplasia or MDS/AML. Patient demographics are summarized in Table 1 below. The preparative regimen consisted of Campath-1H for 4 successive days (day -22 to day -19), Fludarabine 30 mg/m2/day for 5 days (Day - 8 to day -4) followed by Melphalan 140 mg/m2 for 1 day (day -3). Four patients received matched related marrow, 2 received matched unrelated peripheral blood stem cells (PBSC) and 1 received matched unrelated marrow. All but one were 8/8 allele HLA matched. Graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporine(CSA) and Methotrexate in all except one patient who received tacrolimus and mycophenolate mofetil as she was CSA intolerant. All patients established 100% donor-derived hematopoiesis. No major regimen related toxicity was seen except hyperglycemia requiring insulin in one patient and Grade II renal insufficiency in 1 patient which resolved with conservative management. Transplant outcomes are described in Table 2. These data indicate that HSCT with reduced intensity conditioning is feasible in patients with SDS and associated with excellent hematopoietic recovery and modest morbidity. | Patients | #1 | #2 | #3 | #4 | #5 | #6 | #7 | |:------------------- | -------------------------------------------- | ---------------- | ---------- | ---------------- | ---------------- | -------------------------------------------- | --------------------- | | Age(yrs) | 8 | 10 | 12 | 6 | 3 | 29 | 1 | | Gender | Male | Male | Male | Male | Male | Female | Female | | SBDS mutation | 183_184 TA to CT | 183_184 TA to CT | K62X | 183_184 TA to CT | 183_184 TA to CT | IVS2+2 T to C | 183_184 TA to CT | | | | | | | | | | | | | | | | | | | | Clinical status | Transfusion dependence, recurrent infections | Cytopenias | Cytopenias | Dysplasia | Cytopenias | Acute myeloid leukemia | Dysplasia, Cytopenias | | | | | | | | | | | Marrow cytogenetics | del20q12 and del7q31 | i(7)(q10) | del20q12 | del20q12 | del20q12 | Complex karyotype including monosomy 7,del5q | Normal | Table 1. Patient Demographics | Patients | #1 | #2 | #3 | #4 | #5 | #6 | #7 | |:--------------------------- | ---------- | ---- | ---- | ---- | ---- | --------- | ------------- | | Days to myeloid engraftment | 15 | 12 | 15 | 11 | 14 | 14 | 13 | | Platelet Recovery(days) | 27 | 39 | 33 | 18 | 68 | 14 | not engrafted | | Donor Chimerism | 100% | 100% | 100% | 100% | 100% | 99.8% | 100% | | Hospital stay(days) | 29 | 32 | 35 | 28 | 29 | 22 | 46 | | Length of follow-up(days) | 758 | 723 | 679 | 385 | 218 | 65 | 33 | | Acute GVHD | Gd II skin | None | None | None | None | Gd I skin | None | | Lansky scale | 100% | 100% | 100% | 100% | 100% | 90% | 60% | Table 2. Transplant outcomes Patients