For patients with acquired severe aplastic anemia without a matched sibling donor and not responding to immunosuppressive treatment, bone marrow transplantation from a suitable alternative donor is often attempted. We examined risks of graft failure, graft-versus-host disease and overall survival after 318 alternative donor transplants between 1988 and 1998. Sixty-six patients received allografts from 1-antigen and 20 from >1-antigen mismatched related donors; 181 from matched and 51 from mismatched unrelated donors. Most patients were young, had had multiple red blood cell transfusions and poor performance score at transplantation. We did not observe differences in risks of graft failure and overall mortality by donor type. The probabilities of graft failure at 100 days after 1-antigen mismatched related donor, >1-antigen mismatched related donor, matched unrelated donor and mismatched unrelated donor transplants were 21, 25, 15 and 18%, respectively. Corresponding probabilities of overall survival at 5 years were 49, 30, 39 and 36%, respectively. Although alternative donor transplantation results in long-term survival, mortality rates are high. Poor performance score and older age adversely affect outcomes after transplantation. Therefore, early referral for transplantation should be encouraged for patients who fail immunosuppressive therapy and have a suitable alternative donor.
Summary:Allogeneic bone marrow transplantation is an effective treatment for acute lymphoblastic leukemia (ALL). 1 This efficacy is, in part, mediated by graft-versus-leukemia T and B lineage ALL cells express different levels of HLA-class II antigens, which may serve as targets for effects (GVL). 2,3 GVL is greatest in patients with acute or chronic graft-versus-host disease (GVHD). T cells are graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). The object of this study was to determine important in GVHD; 4 removing T cells from donor bone marrow greatly reduces the incidence and severity of whether GVL effects after HLA-identical sibling bone marrow transplantation differed in T and B lineage GVHD but increases the relapse risk. Different leukemias respond differently to GVL. The rea-ALL. We studied 1132 patients with ALL of T lineage (n = 416) or of B lineage (cALLa + ) (n = 716) transson for this is uncertain. Molecules on the surface of leukemia cells may determine susceptibility to GVL. 6 In experiplanted in first (n = 605) or second (n = 527) remission with bone marrow from an HLA-identical sibling mental models, major histocompatibility complex (MHC) class I expression is needed for a CD8 + T lymphocyte donor, between 1982 and 1992, and reported to the IBMTR by 165 teams. Cox proportional hazards response whereas MHC class II is required for both initiating the immune response and serving as a target for cytoregression models were used to determine the relative risk (RR) of relapse in patients with acute (grades IItoxic CD4 + T lymphocytes. [7][8][9][10][11] Experimental data suggest that alloreactive CD4 + lymphocytes are able to kill leuke-IV) or chronic GVHD vs patients without GVHD. Acute and chronic GVHD were considered as time-dependent mia cells. 12,13 In ALL, class II antigen expression (HLA-DR) differs significantly among leukemia phenotypes; it is covariates. Patients transplanted in first and second remission were analyzed separately. GVHD decreased highest in B lineage ALL and less or absent in T lineage ALL. [14][15][16][17][18] It is thus plausible that the antileukemia effect relapse risks to a similar extent in T and B lineage ALL. For first remission transplants, relative risks of relapse of GVHD might occur preferentially in the HLA class IIbearing B lineage leukemias. The object of this study was for patients with vs those without GVHD was 0.34 for T lineage ALL and 0.44 for B lineage ALL. Correspondto address this question by comparing the effects of GVHD on relapse rates in B lineage and T lineage ALL. ing relative risks in second remission transplants were 0.54 and 0.61. This study confirms earlier findings of an antileukemia effect of GVHD in ALL. This effect was similar in T lineage and B lineage ALL, despite probMaterials and methods able differences in HLA-class II antigen expression. Keywords: ALL; bone marrow transplantation; graftPatients versus-leukemia; T lineage; B lineage Between 1982Between and 1992Between , 1955
Approaches to determine whether one transplant-related therapy is better than another include: (1) using experimental data, such as those from randomized controlled trials (RCTs); (2) using observational data, such as those from observational databases (ODBs) and (3) using conclusions from the structured quantification of expert opinion based on a consideration of evidence from RCTs, ODBs and other sources. Large RCTs are widely and appropriately regarded as the gold standard of clinical investigation. However, data from large RCTs are rarely available for transplant-related therapy questions. We discuss some of the limitations of RCTs in the transplant setting often including small size and short follow-up. These limitations are only partly solved by meta-analyses of RCTs. Data from high-quality ODBs are not only often useful in this setting but also have limitations. Biases may be difficult or impossible to identify and/or adjust for. However, ODBs have large numbers of diverse subjects receiving diverse therapies and analyses that often give answers more useful to clinicians than RCTs. Side-by-side comparisons suggest analyses from high-quality ODBs often give similar conclusions to meta-analyses of highquality RCTs. Meta-analyses combining data from RCTs and ODBs are sometimes appropriate. Quantitation of expert opinion, when of high quality, is also useful: experts rarely disagree under precisely defined circumstances and their consensus conclusions are often concordant with results of high-quality RCTs and ODBs. We suggest increased use of ODBs and expert opinion as reliable and effective ways to determine relative efficacies of new therapies in transplant settings.
Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FLT3+ acute myeloid leukemia (AML) that has poor prognosis due to high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126), (HR 0.86, p=0.54) and URD (n=91) (HR 0.81, p=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, p=0.02), but not vs. URD (HR 1.72, p=0.07). All three cohorts had statistically not significant 3-year LFS: 39% (95% CI 30–47) after UCB, 43% (95% CI 30–54) after sibling, and 50% (95% CI 40–60) after URD. Chronic GVHD rates were significantly lower after UCB compared with either sibling (HR 0.59, p=0.03) or URD (HR 0.49, p=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2. UCB is a suitable option for adults with FLT3+AML in the absence of an HLA-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common thus allowing HCT in CR1 when outcomes are best.
demonstrated a partial response at the time of transplant. The conditioning was tolerated well with no treatment related mortality (TRM) within 100 days and no grade 4 toxicities. All pts developed grade 1-3 mucositis, while 13 reported diarrhea (7 pts grade 3) and 21 developed liver toxicity (transaminitis and/or bilirubin elevation); 2 pts with grade 3. Four pts had grade 3 lung toxicities and 1 pt grade 3 colitis. All pts engrafted: ANC .500 achieved on day 8-17 (median 10); platelets .25,000 on day 11-58 (median 18); platelets .50,000 on day 14-119 (median 23). Overall 1-yr survival is 95% (1 pt died 306 days post transplant); 3 year survival is 72%. All deaths were related to a disease recurrence: two pts with Ewing sarcoma, 2 with rhabdomyosarcoma, and one each with neuroblastoma, Wilms and medullodlastoma. These data suggest that the B-M-T preparative regimen followed by an ASCT was tolerated well without unexpected or severe toxicities; pts had prompt engraftment and 0% TRM. The survival data are encouraging compared to historical data. This novel conditioning regimen with a favorable toxicity profile can be used in the future as a platform for gene therapy, immunebased cellular therapies or to intensify local control with prompt administration of intensity modulated radiation therapy (IMRT) such as helical-tomotherapy.
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