Unrelated Donor (URD) Hematopoietic Stem Cell Transplantation (HCT) for Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia (ALL) in First Complete Remission (CR1): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis.
Authors: Marks David I. , Pérez Waleska S. , He Vincent , Zhang Mei-Jie , Keating Armand , Tallman Martin , Sierra Jorge , Weisdorf Daniel 
Published: October 2019

Allogeneic HCT has a growing role in the management of adults with ALL in CR1. Recent large prospective donor vs. no donor analyses show HLA-matched sibling allografting to produce superior outcomes to chemotherapy and its use is unquestioned in the highest risk, Ph+ cohort. Investigators have explored the use of allografting with unrelated donors (URD) for patients with Philadelphia negative ALL in CR1 at high risk of relapse. We report outcomes of URD HCT using myeloablative conditioning in 169 patients with ALL in CR1 transplanted between 1995 and 2004, reported to the CIBMTR by 85 centers in 17 different countries. Median (range) age at HCT was 33 (16–59) years and the median white cell count (WCC) at diagnosis was 31 × 109/L. Fifty percent had a WCC >30 × 109/L, 18% had extramedullary disease, 42% achieved CR >8 weeks from diagnosis, 25% had adverse cytogenetics and 19% had T cell disease. Adverse cytogenetics included t(4;11), hypodiploidy or near triploidy or more than 5 abnormalities. Many patients had multiple high risk factors. Twenty-eight of 41 patients with adverse cytogenetics and 28 of 63 patients who took > 8 weeks to achieve CR had a WCC >30 × 109/L. Cyclophosphamide and total body irradiation (TBI) was used as conditioning in 76% of cases; 80% of patients received >13cGy of TBI. 41% were well matched (no known disparity at HLA A,B,C,DR) and 41% partially matched (1 locus known or likely disparity) with their donors; these are analysed together because of similar outcomes. Eighteen percent of patients were more mismatched (≥2 locus disparity). Univariate outcomes, with a median follow-up of 54 (range, 3–133) months were as follows:

Outcomes Probability (95%confidence interval) Acute GVHD @ 100 days, grades II-IV 50 (43–58) Acute GVHD @ 100 days, grades III-IV 25 (19–32) Chronic GVHD @ 5 years 43 (35–51) Transplant-related mortality (TRM) @ 5 years 42 (34–50) Relapse @ 5 years 20 (14–26) Leukemia-free survival @ 5 years 38 (31–46) Overall survival @ 5 years 39 (31–47)

In adjusted multivariate analyses, the risk of TRM was significantly higher with mismatched donors (RR = 1.83, p = 0.037) and T cell depletion (TCD) (RR = 2.67, p = 0.002). The risk of relapse was higher (RR = 2.22, p = 0.045) if the WCC at diagnosis was >100 × 109/L. Acute and chronic GVHD did not significantly affect the incidence of relapse (RR = 0.73, p = 0.39 and RR = 0.47, p=0.09 respectively). Factors associated with mortality included WCC >100 × 109/L (RR = 1.80, p = 0.014), >8 weeks to CR1 (RR = 1.77, p = 0.006), CMV seropositivity of donor or recipient (RR = 1.61, p = 0.04), ≥2 locus HLA mismatch (RR = 2.09, p = 0.003) and T cell depleted graft (RR = 2.50, p = 0.003). The major causes of death were relapse (25%), infection (23%) and GVHD (14%). In summary, nearly 40% of patients with high risk ALL in CR1 survive 5 years after URD-HCT. The risk of relapse is modest and TRM is the major barrier to survival. These data indicate that selection of only closely matched URD and better prevention and management of GVHD and infection will be needed to enhance long term survival.