Long-Term Results of Allogeneic Hematopoietic Stem Cell Transplantation Using Unrelated or HLA Mismatched Family Donors for Acute and Chronic Lymphoid Malignancy.
Authors: Toze Cynthia L. , Hogge Donna E. , Barnett Michael J. , Nevill Thomas J. , Nantel Stephen H. , Sutherland Heather J. , Shepherd John D. , Song Kevin W. , Forrest Donna L. , Lavoie Julye C. , Connors Joseph M. , Gascoyne Randy D. , Voss Nicholas J. , Smith Clayton A. 
Published: April 2020

Abstract
A substantial proportion of lymphoid malignancy cannot be cured with conventional therapy or autografting, and a matched family donor is available for less than 1/3 of patients (pts) who may benefit from an allograft. Alternate donors (AD) were therefore utilized with curative intent for 87 pts with acute or chronic lymphoid malignancy at the Leukemia/BMT Program of BC between 1983 and 2002. Long-term results for these pts who received stem cells from unrelated donors (UD) (n=73) or mismatched related donors (MMRD) (n=14) were analyzed. UDs were HLA matched in 58 cases for HLA A, B and DR, and mismatched at 1 or 2/6 loci in 15 pts. Related donors were mismatched at 1/6 (n=13) or 2/6 loci (n=1). Diagnoses included ALL in 37 (n=12 Ph+); NHL in 28 ( n=1 Burkitt’s; n=15 aggressive; n=12 indolent); CLL in 3, PLL in 1 and myeloma in 18 pts. Transplant occurred a median (med) of 10 months (range 1.6 mos-14.7 yrs) post diagnosis at a med age of 36 years (range 12–53). The majority (n=57, 66%) were not in CR at the time of transplant; 53 (61%) were male. GVHD prophylaxis included cyclosporine + methotrexate in 72, T-cell depletion in 11, and other in 2 pts. Conditioning was TBI based in the majority (n=80, 92%), and busulfan based in 7 pts (8%). Most (n=83, 95%) received marrow (m) only; 2 received peripheral blood (pb) and 2 pb+m. The med (range) nucleated cell count was 2.6 (0.2–15)x108 CD 34 cells/kg; graft failure was seen in 5 cases (6%). Acute (A) graft-versus-host disease (GVHD) grade 0/1, 2, 3 and 4, (n= %), was seen in 24 (28%); 24 (28%); 19 (22%) and 19 (22%) pts. The majority (n=41/56, 73%) who survived past day 100 developped chronic (C) GVHD. Thirty pts (35%) are currently alive, and 57 (65%) deceased a median of 96 days (range 12 days-4.2 years) post transplant. Death from relapse (n=19) occurred at a med of 1 year (range 17 days-4 years), and from transplant related causes (n=38) at a med of 71 days (range 12 days-17 months). Overall survival (OS) is 32% (95% CI 23–43%) at a med follow-up of 6 years (range 1–15 years); the curve is flat after 50 mos, and 17/30 survivors are out more than 5 years. Cumulative incidence estimates are as follows: acute GVHD (gr 2–4) 72%; (gr 3–4) 44%; chronic GVHD 73%; relapse 27%; non-relapse mortality (NRM) 44%. In univariate analysis AGVHD (3–4) impacted negatively on OS, event-free survival (EFS) and NRM. Relapse risk was higher in pts receiving TCD stem cells. Development of CGHVD was protective against relapse (p=0.03, relative risk = 0.37). In conclusion, one-third of pts with otherwise incurable lymphoid malignancy have achieved long-term disease-free survival using alternate donor stem cell transplant. Strategies to decrease transplant-related mortality are needed. Control of underlying disease remains imperfect, but not unacceptable with 27% long-term risk of disease recurrence. No relapse has occurred after 50 mos, with a plateau seen in the risk curve after 5 years suggesting cure even in pts with ALL or MM. Interestingly, a graft-vs-malignancy effect can still be demonstrated in this population with lymphoid malignancy and alternative donors, with decreased relapse risk seen in pts developing CGVHD.