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Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine (FLU)-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced-dose cyclophosphamide (CY) to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at 1 month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pretransplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, are transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality of life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced-dose CY for in vivo T-cell depletion can correct life-threatening aplasia in FA patients.

SUBMITTER: Thakar MS

PROVIDER: S-EPMC3622043 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia.

Thakar M S MS Bonfim C C Sandmaier B M BM O'Donnell P P Ribeiro L L Gooley T T Deeg H J HJ Flowers M E ME Pasquini R R Storb R R Woolfrey A E AE Kiem H P HP

Pediatric hematology and oncology 20120727 6

Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, ...[more]

PMID: 22839094

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Project description:Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

Dataset Information

Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia.

Publications

Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia.

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