Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia.

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion (TCD) using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi anemia (FA). With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple pre-transplant comorbidities died, one from sepsis and one from sepsis with associated chronic GVHD. Four patients without preexisting comorbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that adjusted-dosing post-transplant CY is effective in in vivo TCD to promote full donor engraftment in patients with FA

Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation: Current Perspectives

AbstractAllogeneic HCT after myeloablative conditioning is an effective therapy for patients with hematologic malignancies. In an attempt to extend this therapy to older patients or those with comorbidities, reduced intensity or truly nonmyeloablative regimens have been developed over the past decade. The principle underlying reduced intensity regimens is to provide some tumor kill with lessened regimen-related morbidity and mortality and then rely on graft-versus-tumor (GVT) effects to eradicate remaining malignant cells, whereas nonmyeloablative regimens rely primarily on GVT effects. In this article, 3 representative approaches are described, demonstrating the clinical application for hematopoietic and nonhematopoietic malignancies. Current challenges include controlling GVHD while allowing GVT to occur. In the future, clinical trials using reduced intensity and nonmyeloablative conditioning will be compared with myeloablative conditioning in selected malignancies to extend the application to standard-risk patients

Intracellular Disposition of Fludarabine Triphosphate in Human Natural Killer Cells

Purpose. Fludarabine is a key component of several reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Shortly after reduced-intensity conditioning, the percent of donor natural killer (NK) cells has been associated with progression-free survival. Insufficient suppression of the recipient’s NK cells by fludarabine may lead to lower donor chimerism; however, the effect of fludarabine upon NK cells is poorly understood. Thus, in purified human NK cells we evaluated the uptake and activation of fludarabine to its active metabolite, fludarabine triphosphate (F-ara-ATP), and assessed the degree of interindividual variability in F-ara-ATP accumulation. Methods. Intracellular F-ara-ATP was measured in purified NK cells isolated from healthy volunteers (n = 6) after ex vivo exposure to fludarabine. Gene expression levels of the relevant transporters and enzymes involved in fludarabine uptake and activation were also measured in these cells. Results. F-ara-ATP accumulation (mean ± s.d.) was 6.00 ± 3.67 pmol/1x106 cells/4 hours, comparable to average levels previously observed in CD4+ and CD8+ T-lymphocytes. We observed considerable variability in F-ara-ATP accumulation and mRNA expression of transporters and enzymes relevant to F-ara-ATP accumulation in NK cells from different healthy volunteers. Conclusions. Human NK cells have the ability to form F-ara-ATP intracellularly and large interindividual variability was observed in healthy volunteers. Further studies are needed to evaluate whether F-ara-ATP accumulation in NK cells are associated with apoptosis and clinical outcomes

Early Results of a Phase II Study Adding Peri-Transplant Rituximab to Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients (PTS) with High-Risk Fludarabine-Refractory Chronic Lymphocytic Leukemia (Cll)

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Unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with poor risk, relapsed or refractory multiple myeloma

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