The Perfect Transplant
Year: 2017
Type: article
Abstract: "Did my transplant work? Was it a success? I need to know what to tell my friends and family. What should I say?" We do our best to answer these questions for our patients every day. They search our faces for the hopeful response that says, "Yes, the transplantation was a success." It is easy for us to tell some patients that their transplant "worked;" they promptly and completely engrafted, did not develop graft-versus-host disease (GVHD), and remain in remission from their malignancy. These patients are often back to school or working full-time, or perhaps they are enjoying retirement, without any major limitations. However, for most patients, a binary yes/no answer is inadequate. The answer is complicated, the question even more so—what if the physician's and the patient's definitions of worked are not always the same? For example, it is difficult to tell patients whose lives has been forever altered by chronic GVHD with extensive skin and pulmonary involvement, with steroid myopathy and limited tolerance for physical activity, that their transplant was a complete success even though they are alive and in remission years later. Is this the new normal they expected? In many fields of medicine, and in allogeneic hematopoietic cell transplantation (HCT) especially, it is clear that binary outcomes (alive/dead) do not completely capture the success or failure of the treatment. There are other outcomes, such as the development of severe GVHD, relapse of malignancy, or other post-HCT complications, which may not be acutely fatal but that are clinically meaningful, can shorten life expectancy, and substantially diminish quality of life. To assess these complex outcomes, composite endpoints can be useful. Recognizing the potential utility of a composite endpoint in testing the "success" of novel acute GVHD prophylaxis regimens, the Blood and Marrow Transplant Clinical Trials Network initially proposed GVHD-free, relapse-free survival (GRFS)—meaning no grade III or IV acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death after HCT. Each of these GRFS components is meaningful, and survival without experiencing a GRFS-defining event represented, in a sense, the ideal transplant from the perspective of both the patient and physician. A pilot analysis using Center for International Blood and Marrow Transplant Research data from 628 adult patients determined that the 1-year probability of GRFS was just 23% [1Bolanos-Meade J. Koreth J. Reshef R. A multi-center phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls (1203).http://www.clinicaltrials.gov/ct2/show/NCT02208037Date: 2014Google Scholar]. The Minnesota group expanded upon that analysis and concluded that graft source was a major determinant of GRFS in adult and pediatric HCT. HLA-matched sibling donor marrow resulted in the best GRFS (51%; 95% confidence interval [CI], 46% to 66%) overall, whereas matched sibling donor peripheral blood stem cells were significantly worse (25%; 95% CI, 20% to 30%; P = .01). GRFS after umbilical cord blood and marrow transplantations from matched unrelated donors were similar (31%; 95% CI, 27% to 35% and 32%; 95% CI, 22% to 42%, respectively) [2Holtan S.G. DeFor T.E. Lazaryan A. et al.Composite endpoint of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation.Blood. 2015; 125: 1333-1338Crossref PubMed Scopus (333) Google Scholar]. In a collaboration between Minnesota and Hôpital Saint-Louis, the association of marrow as the graft source with the best GFRS was confirmed [3Mehta R.S. Peffault de Latour R. DeFor T.E. et al.Improved graft-versus-host disease-free, relapse-free survival associated with bone marrow as the stem cell source in adults.Haematologica. 2016; 101: 764-772Crossref PubMed Scopus (19) Google Scholar]. Haploidentical HCT is associated with a GRFS similar to matched sibling or unrelated donor marrow HCT when post-transplantation cyclophosphamide is used as GVHD prophylaxis, although similar to the initial Minnesota report, approximately one-half (45%, 95% CI, 40% to 50%) of all haploidentical marrow recipients experienced a GRFS-defining event at 1 year [4McCurdy S.R. Kasamon Y.L. Kanakry C.G. et al.Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide.Haematologica. 2017; 102: 391-400Crossref PubMed Scopus (121) Google Scholar]. In addition to graft source, baseline patient and hematologic malignancy characteristics also influence GRFS. For example, the European Group for Blood and Marrow Transplantation risk score >2 was recently found to be associated with a nearly doubled risk of experiencing a GRFS event (hazard ratio, 1.9; P < .001) [5Liu Y.C. Chien S.H. Fan N.W. et al.Prognostic factors on the graft-versus-host disease-free and relapse-free survival after adult allogeneic hematopoietic stem cell transplantation.Stem Cells Int. 2017; 2016: 5143071Google Scholar]. These reports show that the major risk factors for poor GRFS—donor source, patient age, and risk of the underlying malignancy—are, largely, not modifiable. They also show that most HCT recipients still experience major complications after the procedure. However, none of previous studies account for the fact that some GRFS-defining endpoints can be improved with treatment. Both relapse and GVHD can be treated and sometimes respond completely. With that in mind, a new multistate GRFS model was proposed by Solomon et al. and published this month's Biology of Blood and Marrow Transplantation. Their proposed composite endpoint, current GVHD-free, relapse-free survival (CGRFS), considers active moderate-to-severe chronic GVHD as a dynamic event that can respond completely to treatment. Therefore, CGRFS reflects the probability of being alive and in remission, with complete resolution of a first or second chronic GVHD episode. In analyzing the outcomes of 422 consecutive patients from 2010 to 2015, 1-year GRFS was 33%, whereas 1-year CGRFS was significantly higher at 45%. The CGRFS model represents a logical and important next step in the evolution of composite endpoints in allogeneic HCT. However, further studies are needed. In the CGRFS model, grade III or IV acute GVHD is eliminated as an endpoint, reasoning that it either leads to death or chronic GVHD if not resolved. Nonetheless, some patients do live with persistent or recurrent acute GVHD, which is every bit the detriment to quality of life that moderate-to-severe chronic GVHD can be, especially for patients with gastrointestinal tract involvement [6Newell L.F. Flowers M.E. Gooley T.A. et al.Characteristics of chronic GVHD after cord blood transplantation.Bone Marrow Transplant. 2013; 48: 1285-1290Crossref PubMed Scopus (26) Google Scholar]. Relapse remains a great challenge, with only 4% to 12% of patients who relapse before 2 years after HCT surviving [7Bejanyan N. Weisdorf D.J. Logan B.R. et al.Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a Center for International Blood and Marrow Transplant Research study.Biol Blood Marrow Transplant. 2015; 21: 454-459Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar]. However, advances in the detection of minimal residual disease, the use of targeted therapies for early relapse, and possibly even novel post-HCT immunotherapies may significantly improve upon these dismal statistics during this decade. The definition of the "perfect" transplant and statistical methods to discern degrees of success after HCT continue to evolve with the development of composite endpoints such as CGRFS. The end goals of these composite scoring systems are to identify modifiable factors to optimize outcomes and to test novel therapies directed at mitigating HCT complications. It will be important to continue to find new ways to smooth the otherwise rocky course that most of our HCT patients still endure as we become better able to describe what success looks like. Financial disclosure: The author has nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.
Author: Shernan G. Holtan
Institution: University of Minnesota
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2613106992