Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial

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Abstract

Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m 2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2–4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)e183-e193
JournalThe Lancet Haematology
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2019

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Hemoglobinopathies
Whole-Body Irradiation
Transplantation
Clinical Trials
Transplants
Graft vs Host Disease
Bone Marrow Transplantation
Cyclophosphamide
Chimerism
Tissue Donors
Sickle Cell Anemia
Bone Marrow
Mycophenolic Acid
Safety
Stem Cell Research
Centers for Medicare and Medicaid Services (U.S.)
Baltimore
Antilymphocyte Serum
Poisons
beta-Thalassemia

ASJC Scopus subject areas

  • Hematology

Cite this

@article{ae46045678db4978b1dc294f9452cc4d,
title = "Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial",
abstract = "Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50{\%} of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m 2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71{\%}) with sickle cell disease and 5 (29{\%}) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6{\%}) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76{\%}) of 17 patients achieved full donor chimerism and three (18{\%}) had mixed donor-host chimerism. Five (29{\%}) of 17 patients developed grade 2–4 acute GVHD, including four (24{\%}) with maximal grade 2 GVHD and one (6{\%}) with grade 3 GVHD. Chronic GVHD developed in three (18{\%}) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6{\%}) of the 16 engrafted patients remained transfusion dependent, and 14 (88{\%}) discontinued immunosuppression. Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.",
author = "{Bolanos Meade}, {F Javier} and Cooke, {Kenneth R} and Christopher Gamper and Ali, {Syed Abbas} and Ambinder, {Richard F} and Borrello, {Ivan M} and Fuchs, {Ephraim J} and Douglas Gladstone and Christian Gocke and Huff, {Carol Ann} and Leo Luznik and Lode Swinnen and Heather Symons and Terezakis, {Stephanie A.} and Nina Wagner-Johnston and Jones, {Richard J} and Brodsky, {Robert A}",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/S2352-3026(19)30031-6",
language = "English (US)",
volume = "6",
pages = "e183--e193",
journal = "The Lancet Haematology",
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}

TY - JOUR

T1 - Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies

T2 - a prospective clinical trial

AU - Bolanos Meade, F Javier

AU - Cooke, Kenneth R

AU - Gamper, Christopher

AU - Ali, Syed Abbas

AU - Ambinder, Richard F

AU - Borrello, Ivan M

AU - Fuchs, Ephraim J

AU - Gladstone, Douglas

AU - Gocke, Christian

AU - Huff, Carol Ann

AU - Luznik, Leo

AU - Swinnen, Lode

AU - Symons, Heather

AU - Terezakis, Stephanie A.

AU - Wagner-Johnston, Nina

AU - Jones, Richard J

AU - Brodsky, Robert A

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m 2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2–4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.

AB - Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m 2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2–4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.

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U2 - 10.1016/S2352-3026(19)30031-6

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JO - The Lancet Haematology

JF - The Lancet Haematology

SN - 2352-3026

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