The outcomes of 293 patients with leukemia undergoing HLA-identical sibling (n ؍ 158) or related HLA-mismatched (n ؍ 135) hematopoietic cell transplantation (HCT) performed during the same time period were compared. Patients received BUCY2 in HLA-identical sibling HCT or BUCY2 ؉ ATG in mismatched HCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the matched and mismatched cohorts were 32% (CI, 25%-39%) versus 40% (CI, 32%-48%, P ؍ .13), respectively, with the relative risk (RR) ؍ 0.64 (95% CI, 0.43-0.94), P ؍ .02. The incidence of chronic GVHD did not differ significantly between the cohorts (P ؍ .97). Two-year incidences of treatment-related mortality and relapse for matched versus mismatched were 14% (range, 9%-20%) versus 22% (range, 15%-29%) with P ؍ .10 and 13% (range, 8%-19%) versus 18% (range, 10%-27%) with P ؍ .40, respectively. Two-year adjusted leukemia-free survival (LFS) and overall survival were 71% (range, 63%-78%) versus 64% (range, 54%-73%) with P ؍ .27 and 72% (range, 64%-79%) versus 71% (range, 62%-77%) with P ؍ .72, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia had increased risk of relapse, treatment failure, and overall mortality. In summary, HCT performed with related HLA-mismatched donors is a feasible approach with acceptable outcomes. (Blood. 2006;107:3065-3073)
and 5 The Jackson Laboratory, Bar Harbor, Maine, USA The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34 þ CD38À fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34 þ CD38 þ CD19 þ , CD34 þ CD38ÀCD19 þ and CD34 þ CD38ÀCD19À bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/ SCID/IL2rc null mice. We found that both CD34 þ CD38 þ CD19 þ and CD34 þ CD38ÀCD19 þ cells initiate B-ALL in primary recipients, whereas the recipients of CD34 þ CD38ÀCD10À CD19À cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34 þ CD38 þ CD19 þ cells and those transplanted with CD34 þ CD38ÀCD19 þ cells. In each of the three cases studied, transplantation of CD34 þ CD38 þ CD19 þ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34 þ CD38 þ CD19 þ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2rc null recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.
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