Conditioning Regimen of Melphalan, Fludarabine and Total Body Irradiation in Unmanipulated HLA Haploidentical Stem Cell Transplantation Based on Feto-maternal Tolerance

Narimatsu, Hiroto; Morishita, Yoshihisa; Saito, Shigeki; Shimada, Kazuyuki; Ozeki, Kazutaka; Kohno, Akio; Kato, Yukio

doi:10.2169/internalmedicine.43.1063

Cited by 11 publications

(4 citation statements)

References 23 publications

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“…22 Favorable outcomes of haploidentical SCT using T-cell replete grafts from sibling donors mismatched for noninherited maternal antigens have been recently published. [23][24][25][26] These reports have demonstrated the occurrence of sustained chimerism with an acceptably low incidence of GVHD after myeloablative or reduced-intensity conditioning and up to 3-HLA antigen mismatched T-cell replete SCT. In a study of 35 patients with hematologic malignancy from Kyoto, Japan, who received a 2-or 3-antigen mismatched SCT from a microchimeric, non-inherited maternal antigen-mis- This schematic representation of a nonmyeloablative conditioning regimen (cyclophosphamide ± fludarabine, anti-CD2 monoclonal antibody , and thymic irradiation) shows the induction of mixed lymphohematopoietic chimerism followed by delayed DLI to convert the chimerism to full donor, thereby capturing a potent graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD).…”

Section: Haploidentical Stem Cell Transplantation Based On Feto-matermentioning

confidence: 96%

Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor

Spitzer¹

2005

Hematology

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Haploidentical stem cell transplantation is a treatment option for the approximately 70% of patients who do not have an HLA-identical sibling donor. The availability of a haploidentical donor in most families is a potential advantage, both for avoiding the need to find an alternative unrelated donor, and for the potentially more potent graft-versus-tumor effect that can be induced. The early complications of severe graftversus-host disease (GVHD) following T-cell replete stem cell transplantation (SCT), and graft failure and recurrent malignancy (after T-cell depleted SCT) have limited the applications of this approach. Newer strategies employing T-cell depletion of the graft, using either very high-dose peripheral blood stem cells and/ or more intensive conditioning therapy have overcome some of the problems of conventional transplantation. Nonmyeloablative SCT approaches have overcome some of the morbidity and mortality associated with the early complications of SCT and have been associated with favorable engraftment and GVHD profiles. Induction of mixed lymphohematopoietic chimerism as a platform for adoptive cellular immunotherapy (via delayed donor lymphocyte infusions) may have important application in avoiding early GVHD, while ultimately capturing a very potent graft-versus-tumor effect. Current strategies are focusing on improvement of immune reconstitution and prevention of recurrence of the underlying malignancy.Haploidentical related donor stem cell transplantation (SCT) has been evaluated over the past two to three decades as an alternative transplant option for the approximately 70% of patients who do not have an HLA-identical related donor 1-8 ( Table 1). The advantages of haploidentical SCT are that nearly all patients have an immediately available donor and that a stronger graft-versus-tumor effect can be realized with partial HLA disparity. The disadvantages of haploidentical SCT are the immunological consequences of crossing the major histocompatibility barrier, namely graft-versus-host disease (GVHD), graft rejection, and delayed or incomplete immune reconstitution. With very intensive conditioning therapy, graft rejection has been largely overcome. Severe acute or chronic GVHD, however, have been formidable obstacles to the success of T-cell replete transplants following myeloablative conditioning. 1-3 Historical PerspectiveThe early post-transplant complications of myeloablative T-cell replete haploidentical bone marrow transplantation were well described by Powles and colleagues.1 Of 35 patients with advanced acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) who received a one-to three-antigen mismatched bone marrow transplantation (BMT), 12 patients died from an early syndrome characterized by pulmonary edema, seizures, intravascular hemolysis, and acute renal failure. Ten of the 35 patients had engraftment failure, requiring regrafting from the same donor, though 11 patients were alive at the time of reporting. There was no difference in survival between HLA-1 to 2 antigen...

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Section: Haploidentical Stem Cell Transplantation Based On Feto-matermentioning

confidence: 96%

Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor

Spitzer¹

2005

Hematology

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“…This is the largest report to date of FluMelTBI and the first to compare FluMelTBI with a contemporary cohort of FluMel. Flu-MelTBI has been reported as a myeloablative and haplo-cord transplantation regimen [22][23][24][25][26]. It has also been reported as RIC in 14 patients using Flu 200 mg/m 2 , Mel 140 mg/m 2 , and TBI 400 cGy (FluMelTBI-140) [27].…”

Section: Discussionmentioning

confidence: 99%

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity

Chen

Hahn

Wilding

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m 2 , Mel 50 mg/m 2 , and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m 2 , Mel 75 mg/m 2 , and TBI 400 cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m 2 and Mel 140 mg/m 2 . Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis was decreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P = .03). On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.

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“…The risk of GVHD was significantly lower when the donor was NIMA mismatched in the GVHD direction. [46][47][48] A large International Bone Marrow Transplant Registry (IBMTR) analysis showed that after unmanipulated haploidentical HSCT, the incidence of grades II-IV acute GVHD was related to haplotype inheritance; acute GVHD was significantly less frequent after transplants from NIMA-mismatched siblings, but TRM was significantly higher in transplants from a parent. 49 Leukaemia relapse Extensive T-cell depletion might be expected to result in a weak or no GVHD-GVL effect which is conventionally achieved through T cell-mediated alloreactions directed against histocompatibility antigens displayed on recipient leukaemic cells.…”

Section: Engraftment and Gvhdmentioning

confidence: 99%

Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States

Aversa

2008

Bone Marrow Transplant

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Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft. Haploidentical transplant modalities are based mainly on high-intensity conditioning regimen, but reduced intensity regimens have recently been introduced. The graft may be a megadose of extensively T cell-depleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of GVHD-and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling. Improvements will come with successful implementation of strategies to accelerate and strengthen post transplant immune reconstitution as well as transplantation of patients in early stage disease.

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Conditioning Regimen of Melphalan, Fludarabine and Total Body Irradiation in Unmanipulated HLA Haploidentical Stem Cell Transplantation Based on Feto-maternal Tolerance

Cited by 11 publications

References 23 publications

Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor

Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity

Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States

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