By Gérard Socié, MD, PhD

2009-03-01

Dr. Socié indicated no relevant conflicts of interest.

Ringden O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood. 2008. [Epub ahead of print]
 
Immune-mediated eradication of leukemias, the so-called graft-versus-leukemia (GVL) effect, is a major beneficial effect observed after allogeneic hematopoietic cell transplantation (HCT). Patients with graft-versus-host disease (GVHD) (especially chronic GVHD) have a lower risk of relapse compared with patients without GVHD. In 1990, Mary Horowitz and coworkers at the International Bone Marrow Transplant Registry (IBMTR) published a seminal paper addressing whether GVL reactions are important in preventing leukemia recurrence after bone marrow transplantation. Of the 2,254 subjects in their registry receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase, they observed fewer relapses in recipients of non-T-cell-depleted allografts with acute, chronic, and both acute and chronic GVHD, as compared with those without GVHD. These data support an anti-leukemic effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse compared with allograft recipients without GVHD, suggesting a GVL effect independent of GVHD. CML patients who received T-cell-depleted transplants with or without GVHD had higher probabilities of relapse than recipients of non-T-cell-depleted allografts without GVHD, suggesting that the anti-leukemic effect independent of GVHD is altered by T-cell depletion. This highly cited study has since been confirmed by many other clinical papers and the curve derived from this analysis used in thousands of lectures on GVL (see Figure).¹

Investigators from the IBMTR have now revisited this clinical concept to ask whether patients benefit from an unrelated donor (URD) transplant because of a stronger GVL effect. The authors analyzed 4,099 patients with AML, ALL, and CML undergoing a myeloablative allogeneic HCT from a URD (8/8 HLA-matched, n=941) or HLA-identical sibling donor (n=3158). In multivariate analysis, URD transplant recipients with AML had a higher risk for transplant-related mortality and relapse than those receiving transplants from HLA-identical sibling donors. This difference was not seen in patients with ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving URD transplant, but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse, but decreased LFS for URD transplants for all three diagnoses. The authors concluded that the risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared to HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

The GVL effect has not been evaluated as frequently in URD transplants as in sibling transplants. Today, approximately one-third of patients in need of HCT have an available HLA-identical sibling to serve as a donor. The growth of donor registries worldwide has improved the overall chance that a patient who lacks a family donor will have a suitable URD. In a previous Diffusion selection (The Hematologist March/April 2008 issue), I discussed two major studies relevant to this subject. One by Lee and coworkers clearly highlighted the fact that there is a 10 percent loss of survival with any mismatch (although of marginal significance for HLA-DQ), but that classical risk factors including patient age, race, disease tage, and CMV status were as predictive of survival as donor HLA matching.² The other by Shaw and coworkers confirmed in a large number of patients that DPB1 functions as a classical transplantation antigen. The increased risk of GVHD associated with HLA-DPB1 mismatching was accompanied by a lower risk of relapse.³

Thus the study by Ringden and coworkers basically confirms the strong anti-leukemic effect of GVHD. However, even if transplant with URD is associated with more GVHD, this does not seem to translate to better leukemic control. The caveat of this study is the fact that authors included only 8/8-matched URD (HLA-A, -B, -C, -DRB1 matched). Thus, they exclude DPB1, which is the allele reported by Shaw and coworkers to be linked to lower relapse and GVL effect.

1. Horowitz MM, Gale RP, Paul M, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555-62.

2. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576-83.

3. Shaw BE, Gooley TA, Malkki M, et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood. 2007;110:4560-6.

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