Intentional Induction of Mixed Chimerism and Achievement of Antitumor Responses after Nonmyeloablative Conditioning Therapy and HLA-Matched Donor Bone Marrow Transplantation for Refractory Hematologic Malignancies

Thomas R. Spitzer, Steven McAfee, Robert Sackstein, Christine Colby, Han Chong Toh, Pratik Mulkani, Susan Saidman, Dina Weymouth, Frederic Preffer, Cathleen Poliquin, Alicia Foley, Benjamin Cox, David Andrews, David H. Sachs, Megan Sykes

Research output: Contribution to journalArticle

210 Citations (Scopus)

Abstract

Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.

Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalBiology of Blood and Marrow Transplantation
Volume6
Issue number3 A
StatePublished - Dec 1 2000
Externally publishedYes

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Chimerism
Behavior Therapy
Hematologic Neoplasms
Bone Marrow Transplantation
Tissue Donors
Leukocytes
Graft vs Host Disease
Cyclophosphamide
Antilymphocyte Serum
Transplants
Drug Therapy
Hematopoiesis
Cell- and Tissue-Based Therapy

Keywords

  • Allogeneic
  • Bone marrow transplantation
  • Hematologic malignancies
  • Mixed chimerism
  • Nonmyeloablative

ASJC Scopus subject areas

  • Transplantation

Cite this

Intentional Induction of Mixed Chimerism and Achievement of Antitumor Responses after Nonmyeloablative Conditioning Therapy and HLA-Matched Donor Bone Marrow Transplantation for Refractory Hematologic Malignancies. / Spitzer, Thomas R.; McAfee, Steven; Sackstein, Robert; Colby, Christine; Toh, Han Chong; Mulkani, Pratik; Saidman, Susan; Weymouth, Dina; Preffer, Frederic; Poliquin, Cathleen; Foley, Alicia; Cox, Benjamin; Andrews, David; Sachs, David H.; Sykes, Megan.

In: Biology of Blood and Marrow Transplantation, Vol. 6, No. 3 A, 01.12.2000, p. 309-320.

Research output: Contribution to journalArticle

Spitzer, TR, McAfee, S, Sackstein, R, Colby, C, Toh, HC, Mulkani, P, Saidman, S, Weymouth, D, Preffer, F, Poliquin, C, Foley, A, Cox, B, Andrews, D, Sachs, DH & Sykes, M 2000, 'Intentional Induction of Mixed Chimerism and Achievement of Antitumor Responses after Nonmyeloablative Conditioning Therapy and HLA-Matched Donor Bone Marrow Transplantation for Refractory Hematologic Malignancies', Biology of Blood and Marrow Transplantation, vol. 6, no. 3 A, pp. 309-320.
Spitzer, Thomas R. ; McAfee, Steven ; Sackstein, Robert ; Colby, Christine ; Toh, Han Chong ; Mulkani, Pratik ; Saidman, Susan ; Weymouth, Dina ; Preffer, Frederic ; Poliquin, Cathleen ; Foley, Alicia ; Cox, Benjamin ; Andrews, David ; Sachs, David H. ; Sykes, Megan. / Intentional Induction of Mixed Chimerism and Achievement of Antitumor Responses after Nonmyeloablative Conditioning Therapy and HLA-Matched Donor Bone Marrow Transplantation for Refractory Hematologic Malignancies. In: Biology of Blood and Marrow Transplantation. 2000 ; Vol. 6, No. 3 A. pp. 309-320.
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abstract = "Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1{\%} donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70{\%}) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56{\%}) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27{\%}) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14{\%}) and grade II or greater GVHD in 6 patients (29{\%}). One patient (5{\%}) died from a complication of BMT, and 1 patient (5{\%}) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.",
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T1 - Intentional Induction of Mixed Chimerism and Achievement of Antitumor Responses after Nonmyeloablative Conditioning Therapy and HLA-Matched Donor Bone Marrow Transplantation for Refractory Hematologic Malignancies

AU - Spitzer, Thomas R.

AU - McAfee, Steven

AU - Sackstein, Robert

AU - Colby, Christine

AU - Toh, Han Chong

AU - Mulkani, Pratik

AU - Saidman, Susan

AU - Weymouth, Dina

AU - Preffer, Frederic

AU - Poliquin, Cathleen

AU - Foley, Alicia

AU - Cox, Benjamin

AU - Andrews, David

AU - Sachs, David H.

AU - Sykes, Megan

PY - 2000/12/1

Y1 - 2000/12/1

N2 - Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.

AB - Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.

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