Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-Cell–Depleted Hematopoietic Allograft

Horwitz, Mitchell E.; Barrett, A. John; Brown, Margaret R.; Carter, Charles S.; Childs, Richard; Gallin, John I.; Gress, Ronald E.; Holland, Steven M.; Linton, Gilda F.; Miller, Judi A.; Leitman, Susan F.; Read, Elizabeth J.; Schermerhorn, James; Malech, Harry L.

doi:10.1056/nejm200103223441203

Cited by 251 publications

(178 citation statements)

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“…A defect in any of 4 proteins of the reduced nicotinamide adenine dinucleotide phosphate oxidase complex can be responsible for this disease, 53 with about two thirds of the patients with CGD having a deficiency in the X-linked gene encoding gp91phox. CGD can be cured with HLA-identical allogeneic BMT, 53 although haploidentical T-depleted BMT is not similarly successful 54 because of toxicity from myeloablation regimens or GVHD. Gene therapy studies in mice with targeted disruptions of either gp47phox or gp91phox have been performed with demonstrable correction of oxidase activity and protection from bacterial infections.…”

Section: Cgdmentioning

confidence: 99%

Successes and risks of gene therapy in primary immunodeficiencies

Chinen

Puck

2004

Journal of Allergy and Clinical Immunology

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Section: Cgdmentioning

confidence: 99%

Successes and risks of gene therapy in primary immunodeficiencies

Chinen

Puck

2004

Journal of Allergy and Clinical Immunology

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“…Even in the setting of refractory fungal infection bone marrow transplantation has been effective (65). Nonmyeloablative transplants in CGD have been more successful in children than adults (66). Although bone marrow transplantation is an attractive option for the definitive cure of CGD, survival without bone marrow transplantation is roughly comparable, but attended by continuing CGD morbidities like like boiwel disease and mildly reduced growth.…”

mentioning

confidence: 99%

Chronic Granulomatous Disease

Holland

2009

Clinic Rev Allerg Immunol

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300

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“…Donor and recipient cells were detected by quantitative analysis of informative microsatellite sequences of DNA as previously described. 11 …”

Section: Engraftment Analysismentioning

confidence: 99%

Safety and outcome after fludarabine–thiotepa–TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies

Besien

Devine

Wickrema

et al. 2003

Bone Marrow Transplant

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Summary:Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haploidentical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were Tcell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and minimethotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimenrelated causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progressionfree survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six longterm survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen. Bone Marrow Transplantation (2003) 32, 9-13. doi:10.1038/ sj.bmt.1704088 Keywords: transplantation; TBI; fludarabine; thiotepa; toxicity Allogeneic transplantation is curative for only a limited proportion of patients with advanced hematologic malignancies. Its impact is limited because of high recurrence rates and because of treatment-related complications in patients with considerable comorbidities. We studied a conditioning regimen containing fludarabine, thiotepa and total body irradiation (TBI). A similar regimen had previously been used in recipients of haplo-identical transplants. 1 Based on its reported favorable toxicity profile and its excellent antileukemic and immunosuppressive properties, we expanded its use to recipients of HLAidentical transplants and matched unrelated donor transplantation. We report safety data of 30 consecutive patients treated with this regimen. Patients and methods Patients and protocol designPatients were eligible if they had hematologic malignancies including acute and chronic leukemia and myeloproliferative disorders, non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma. Patients with acute leukemia in first remission were enrolled only if they had adverse prognostic characteristics at diagnosis.Eligibility criteria included, Karnofsky performance status greater than or equal to 60%, bilirubin less than or equal to 2 mg/dl, creatinine less than 1.5 times normal.The trial was designed as a single-arm phase II equivalence trial using methodology developed by Thall et al. 2 The four elementary patient outcomes, each defined ...

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Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-Cell–Depleted Hematopoietic Allograft

Abstract: Nonmyeloablative conditioning followed by a T-cell-depleted hematopoietic stem-cell allograft is a feasible option for patients with chronic granulomatous disease, recurrent life-threatening infections, and an HLA-identical family donor.

Cited by 251 publications

References 42 publications

Successes and risks of gene therapy in primary immunodeficiencies

Successes and risks of gene therapy in primary immunodeficiencies

Chronic Granulomatous Disease

Safety and outcome after fludarabine–thiotepa–TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies

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