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Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen.

ABSTRACT: BACKGROUND AND PURPOSE:Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow (BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function. MATERIALS AND METHODS:We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n=42) and reduced intensity (RIC, n=56) doses of TBI from 2003-2013, including BM cellularity, histologic features of injury and repair, hematologic and immunologic recovery. RESULTS:Following MA conditioning, a 30% decrease in the marrow cellularity persisted at 1 year post-transplant (p=0.03). RIC HCT marrow cellularity transiently decreased but returned to baseline by 6 months even though the RIC group received mostly umbilical cord blood (UCB) grafts (82%, vs. 17% in the MA cohort, p<0.01). There was no evidence of persistent marrow vascular damage or inflammation. Recipients of more intensive conditioning did not show more persistent cytopenias with the exception of a tendency for minimal thrombocytopenia. Immune recovery was similar between MA and RIC. CONCLUSIONS:These findings suggest that TBI associated with MA conditioning leads to prolonged reductions in marrow cellularity, but does not show additional histological evidence of long-term injury, which is further supported by similar peripheral counts and immunologic recovery.

SUBMITTER: Wilke C

PROVIDER: S-EPMC4764403 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen.

Wilke Christopher C Holtan Shernan G SG Sharkey Leslie L DeFor Todd T Arora Mukta M Premakanthan Priya P Yohe Sophia S Vagge Stefano S Zhou Daohong D Holter Chakrabarty Jennifer L JL Mahe Marc M Corvo Renzo R Dusenbery Kathryn K Storme Guy G Weisdorf Daniel J DJ Verneris Michael R MR Hui Susanta S

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20151130 1

<h4>Background and purpose</h4>Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow (BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function.<h4>Materials and methods</h4>We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n=42) and reduced intensity (RIC, n=56) doses of TBI ...[more]

PMID: 26653357

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Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.

Project description:Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.

Dataset Information

Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen.

Publications

Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen.

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