Autologous bone marrow transplantation in high-risk remission B-lineage acute lymphoblastic leukemia using a cocktail of three monoclonal antibodies (BA-1/CD24, BA-2/CD9, and BA-3/CD10) plus complement and 4- hydroperoxycyclophosphamide for ex vivo bone marrow purging

F. M. Uckun, J. H. Kersey, R. Haake, D. Weisdorf, N. K.C. Ramsay

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49 Scopus citations

Abstract

Fourteen patients with high-risk B-lineage acute lymphoblastic leukemia (ALL) in complete remission underwent autologous bone marrow transplantation (BMT) using a combined immunochemopurging protocol. A monoclonal antibody (MoAb) cocktail of BA-1, BA-2, and BA-3 plus rabbit complement (C') plus 4- hydroperoxycyclophosphamide (4-HC) was used to eliminate residual occult leukemia cells from autografts. All patients were conditioned with single- dose total body irradiation (TBI) followed by high-dose Ara-C. All 14 patients engrafted at a median of 24 days (range, 12 to 36 days). Three patients are alive and disease free at 3.5 years, 3.9 years, and 4.1 years post-BMT. The Kaplan-Meier estimate and standard error of the probability of sustained remission was 23% ± 12% at 3.5 years post-BMT with a mean relapse- free interval of 1.4 ± 0.4 years. The disease-free survival (DFS) at 3.5 years was 21% ± 11%, with a mean DFS time of 1.3 ± 0.4 years. A novel and quantitative minimal residual disease (MRD) detection assay, which combines fluorescence-activated multiparameter flow cytometry and cell sorting with leukemic progenitor cell (LPC) colony assays, was used to analyze remission BM samples from B-lineage ALL patients for residual LPC, and to evaluate the efficacy of ex vivo BM purging. Notably, the minimal residual leukemia burden before BMT, as measured by the percentage of B-lineage LPC in the pre-BMT remission BM samples, indicated the outcome of the BMT. The median value for the minimal residual leukemia burden before BMT was 0.0035% (35 LPC/106 mononuclear cells). The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 43% ± 19% for patients whose BM samples contained ≤0.0035% LPC and 0% ± 0% for patients whose BM samples contained greater than 0.0035% B-lineage LPC (P < .05). In contrast to the minimal residual leukemia burden measured by the described MRD assay system, the percentage of blasts or TdT+ cells in the remission BM samples did not correlate with the probability of relapse. The applied purging protocol showed variable success in destroying target B-lineage LPC populations contaminating the autografts. While in some cases purging was highly effective, eliminating up to ≥4 logs of residual B-lineage LPC, in other cases only 0.1 to 0.2 logs of B-lineage LPC were purged. Because of this variation in efficacy, the estimated numbers of B-lineage LPC remaining in autografts, as well as the estimated numbers of reinfused LPC, showed a marked interpatient variation. The investigators conclude that improvements in both pretransplant conditioning and ex vivo BM purging may be needed to significantly increase the percentage of long-term survivors among high-risk B-lineage ALL patients undergoing autologous BMT.

Original languageEnglish (US)
Pages (from-to)1094-1104
Number of pages11
JournalBlood
Volume79
Issue number4
DOIs
StatePublished - 1992

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