Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors

Bone Marrow Transplantation, Oct 2013

Reduced-intensity conditioning (RIC) permits allogeneic hematopoietic progenitor cell transplantation in patients who would not be considered candidates for transplantation using a myeloablative preparative regimen because of age, comorbidities or prior therapy. In the setting of myeloablative transplantation, use of antithymocyte globulin (ATG) can reduce the risk of GVHD without negatively affecting transplant outcomes; however, limited data exist on the impact of ATG in the setting of RIC, particularly when there is HLA-mismatch. We performed a retrospective analysis of 85 patients who received unrelated donor transplants at our institution for hematologic malignancies following conditioning with fludarabine and melphalan (FluMel), with or without rabbit ATG (6 mg/kg). ATG was targeted to patients receiving HLA-mismatched grafts. With a median follow-up of 36 months, those receiving ATG and a mismatched graft had similar rates of acute and chronic GVHD, relapse, and similar OS compared with those receiving HLA-matched grafts without ATG. In a multivariate analysis, HLA-mismatched donor was not associated with a decrement in OS. We conclude that this intermediate dose of ATG is effective in preventing severe GVHD in the setting of HLA-mismatch, without undue compromise of the graft versus tumor effects on which RIC transplants depend.

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Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors

Abstract Reduced-intensity conditioning (RIC) permits allogeneic hematopoietic progenitor cell transplantation in patients who would not be considered candidates for transplantation using a myeloablative preparative regimen because of age, comorbidities or prior therapy. In the setting of myeloablative transplantation, use of antithymocyte globulin (ATG) can reduce the risk of GVHD without negatively affecting transplant outcomes; however, limited data exist on the impact of ATG in the setting of RIC, particularly when there is HLA-mismatch. We performed a retrospective analysis of 85 patients who received unrelated donor transplants at our institution for hematologic malignancies following conditioning with fludarabine and melphalan (FluMel), with or without rabbit ATG (6 mg/kg). ATG was targeted to patients receiving HLA-mismatched grafts. With a median follow-up of 36 months, those receiving ATG and a mismatched graft had similar rates of acute and chronic GVHD, relapse, and similar OS compared with those receiving HLA-matched grafts without ATG. In a multivariate analysis, HLA-mismatched donor was not associated with a decrement in OS. We conclude that this intermediate dose of ATG is effective in preventing severe GVHD in the setting of HLA-mismatch, without undue compromise of the graft versus tumor effects on which RIC transplants depend. Introduction Allogeneic hematopoietic cell transplantation is potentially a curative therapy for many patients with otherwise intractable hematologic malignancies. The incidence of most hematologic malignancies increases with age, which excludes a substantial fraction of patients from consideration for transplantation using a myeloablative conditioning regimen. Over the past decade, numerous studies have demonstrated the feasibility and efficacy of transplantation following reduced-intensity conditioning (RIC) for older patients and those with significant comorbidities.1, 2, 3, 4, 5 In principle, use of a RIC reduces immediate toxicities of the transplant maneuver, but the patient remains subject to morbidity and mortality associated with GVHD.6 The ultimate efficacy of the transplant therefore depends on successful achievement of a balance between graft versus tumor effects necessary for eradication of the malignancy and complications associated with GVHD and immune incompetence.7 The best outcomes with allogeneic transplantation are achieved through transplantation of hematopietic progenitor cells from an HLA-matched related or unrelated donor; however, even in this setting grades II-IV acute GVHD (aGVHD) occur in 30–50% of patients.6, 8 Further, for any degree of HLA disparity, OS generally decreases as a consequence of nonrelapse mortality from GVHD and complications arising from its management.9, 10 The use of antithymocyte globulin (ATG) as in vivo T-cell depletion for the prevention of GVHD has been studied in the unrelated donor (URD) transplant setting, primarily following myeloablative conditioning. Given concurrently with myeloablative conditioning, ATG may reduce the risk of severe acute and chronic GVHD, but often at the cost of higher rates of opportunistic infection and/or relapse.11, 12, 13, 14 In contrast, for patients receiving a RIC followed by a T-cell replete graft, a recent analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) suggested that inclusion of pre-transplant ATG resulted in inferior survival.15 These results must be interpreted cautiously given the heterogeneity of conditioning regimens, preparations of ATG and other differences inherent in analysis of registry data. In an effort to study this question further, we have performed a single institution retrospective analysis of a consecutive series of patients with hematologic malignancies who received URD transplants following a uniform RIC regimen of fludarabine and melphalan (FluMel). We specifically compared outcomes of patients who received pre-transplant ATG in the setting of HLA-mismatch with those of patients who received an HLA-matched URD graft without ATG. Patients and methods Patient characteristics This is an IRB approved retrospective analysis of consecutive patients with hematologic malignancies who underwent allo-SCT from URDs following conditioning with FluMel with or without ATG at Emory University Hospital between May 2004 and December 2011. Baseline data on the transplant maneuver and post-transplant outcomes were extracted from the institutional transplant database and the individual medical record of each patient. Between May 2004 and December 2011, 95 patients received FluMel conditioning before URD transplantation for hematologic malignancies. Ten patients were eliminated from this analysis for the following reasons: three patients were enrolled on a clinical trial of alternative GVHD prophylaxis and seven received HLA-mismatched transplants without the use of pre-transplant ATG. Patient characteristics of the re (...truncated)


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A A Langston, J M Prichard, S Muppidi, A Nooka, M J Lechowicz, S Lonial, R Sinha, M Graiser, J L Kaufman, H J Khoury, C R Flowers, E K Waller. Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors, Bone Marrow Transplantation, 2013, pp. 185-189, Issue: 49, DOI: 10.1038/bmt.2013.168