Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT

Fitzhugh, Courtney D.; Hsieh, Matthew M.; Taylor, Tiffani; Coles, Wynona; Roskom, Katherine; Wilson, Delon; Wright, Elizabeth C.; Jeffries, Neal; Gamper, Christopher; Powell, Jonathan D.; Luznik, Leo; Tisdale, John F.

doi:10.1182/bloodadvances.2016002972

Cited by 93 publications

(85 citation statements)

References 62 publications

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“…After our positive results in match related donor HSCT [1], we initially attempted to apply the same alemtuzumab-based regimen with the addition of PTCy in 2 patients undergoing haploidentical HSCT. Both experienced graft failure, consistent with the experience reported using the same approach at the National Institutes of Health [14].…”

Section: Discussionsupporting

confidence: 81%

“…Although several patients may recover spontaneously, others need more aggressive treatment strategies to avoid extensive RBC transfusions and related iron overload [6]. Rapid tapering of immunosuppressive agents, erythropoietin (recombinant human erythropoietin [rHuEPO]), rituximab, bortezomib, plasma exchange (PEX), immunoadsorption, donor lymphocyte infusion, mesenchymal stem cells, antithymocyte globulin, and high-dose steroids have been used for treatment of PRCA; however, results reported in the literature with these therapeutic options are largely variable or even disappointing in many cases [3,[6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Saraf

Patel

et al. 2018

Biology of Blood and Marrow Transplantation

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We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Saraf

Patel

et al. 2018

Biology of Blood and Marrow Transplantation

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“…Rates of acute and chronic GVHD were 29% and 18%, with resolution of GVHD in all patients at most recent follow‐up, and 88% of patients off immunosuppression. In another study, 23 patients with severe disease ( n = 21 with SCD, n = 2 with β‐thalassaemia) were treated with non‐myeloablative conditioning including 400 cGy TBI, alemtuzumab, escalating doses of PTCy, and sirolimus for GVHD prevention (Fitzhugh et al , ). By eliminating fludarabine (Flu), this regimen could be extended to patients with severe organ damage, including renal failure.…”

Section: Haploidentical Transplantation Results In Sickle Cell Diseasementioning

confidence: 99%

“…One patient from HGB‐206 (Group A) developed myelodysplastic syndrome (MDS) within three years of therapy (Mapara et al , ), felt to be related to BU and not related to LentiGlobin gene therapy as the patient’s CD34 + blasts showed negligible amounts of vector integration versus the CD34 − marrow cells (0·02 vs. 0·21 copies per diploid genome) (Mapara et al , ). MDS has also been reported in the haploidentical setting, however, likely as a result of TBI and/or PTCy (Fitzhugh et al , ). Though advantages of non‐myeloablative versus myeloablative regimens are clear, it is also true that stability of mixed chimaerism in the long term is uncertain under current haploidentical protocols.…”

Section: Haploidentical Transplantation Versus Gene Therapymentioning

confidence: 99%

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

2020

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Summary Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft‐versus‐host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

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“…Fitzhugh and colleagues [26] sought to further improve eligibility for haplo-HCT by enrolling adults with multiple comorbidities to an early phase study of alemtuzumab and total body irradiation-based conditioning followed by infusion of granulocyte colony-stimulating factor-primed peripheral blood allografts (Table 1). Twenty-one included patients had sickle cell disease and two had transfusion-dependent beta-thalassemia.…”

Section: Modifications To the Ptcy-based Approach With Peripheral Blomentioning

confidence: 99%

Haploidentical bone marrow transplant with posttransplant cyclophosphamide for sickle cell disease

Patel

Akinsete

Fuente

et al. 2020

Hematology/Oncology and Stem Cell Therapy

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Please cite this article as: D.A. Patel, A.M. Akinsete, J. de la Fuente, A.A. Kassim, Haploidentical bone marrow transplant with posttransplant cyclophosphamide for sickle cell disease: An update, Hematology/Oncology and Stem Cell Therapy (2020), doi: https://doi. AbstractHematopoietic cell transplant (HCT) can cure both children and adults with sickle cell disease. Outcomes have historically been poor for the vast majority of patients who lack a matched sibling donor. However, the development of haploidentical HCT (haplo-HCT) with high doses of posttransplant cyclophosphamide (PTCy) has allowed for curative long-term potential with favorable transplantrelated outcomes, though this has not obviated the potential for graft rejection from human leukocyte antigen mismatch and repeated 2 red blood cell transfusions. Accordingly, multiple strategies have been developed to improve outcomes, the majority of which are based on the Johns Hopkins platform from 2012. Presently, we aim to discuss results from pertinent studies and compare outcomes with the two most recent approaches involving either thiotepa plus 200-cGy total body irradiation or 400-cGy total body irradiation.Direct comparisons are required to determine the optimized curative potential. Transplant-eligible patients must be referred to tertiary medical centers for consideration of haplo-HCT.

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Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT

Abstract: Key Points Patients with SCD and severe organ damage can tolerate nonmyeloablative conditioning with no transplant-related mortality. Posttransplant cyclophosphamide prevents severe GVHD, increases engraftment, and improves the success rate for haploidentical HSCT.

Cited by 93 publications

References 62 publications

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Haploidentical bone marrow transplant with posttransplant cyclophosphamide for sickle cell disease

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