Allografting in chronic myeloid leukemia with cultured marrow: Update of the vancouver study

Abstract

When chronic myeloid leukemia (CML) marrow is set up in long‐term culture (LTC), Philadelphia chromosome (Ph)‐positive (Ph+) cells typically decline and Ph‐negative (Ph−) hematopoietic cells often become detectable. In 1987, we initiated a study to evaluate the feasibility of using 10‐day cultured marrow autografts to allow intensive treatment of CML. Patients were selected on the basis of a previous assessment of the frequencies of normal and leukemic LTC‐initiating cells (LTC‐IC) remaining in their marrow after 10 days of LTC. Of the 87 patients evaluated, 36 (41%) were considered eligible, and 22 (15 in first chronic phase [CP], Group 1; and 7 with more advanced disease, Group 2) were autografted with 10‐day cultured marrow after intensive therapy. Satisfactory hematological recovery occurred in 16 patients, and of these, only Ph− cells were detected in 13 (nine in Group 1), with 76–94% Ph− cells in the other three (two in Group 1). Ph+ cells reappeared between 4 and 36 months post‐autograft in all but one of the 13 patients in whom complete (morphological and cytogenetic) remission had been achieved; the remaining patient died in remission. Nine of these twelve patients were then treated with α‐interferon (IFN‐α) 1–3 × 106 units/m2, 3–7 days/week; four returned to complete remission, three developed increasing numbers of Ph+ cells, and two are still too early to evaluate. Fifteen patients (12 in Group 1) remain alive and well, nine in hematological remission (eight in Group 1), 9 to 64 months (median 28) post‐autograft. Another patient (Group 1) remains alive 30 months post‐autograft but has developed blast phase disease. Four patients (all in Group 1) continue in complete remission after treatment with IFN‐α. These results establish the feasibility of using cultured marrow autografts for the treatment of CML.

Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study

“…This interpretation must be viewed as speculative, however, since we did not perform limiting dilution assays for precise LTCIC quantitation. In addition, others have noted that long-term culture has an intrinsic ability to purge CML marrow, 50,51 although prolonged culture is usually required to achieve this effect. 52 With regard to this concern, however, it is important to note that untreated and antisense-treated cells from the same patient were simultaneously subjected to the same LTCIC procedure ( Figure 1B).…”

A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts

“…[19][20][21][22][23] The feasibility of this approach was established some years ago by early clinical studies that used short-term culture alone to purge CML autografts. This treatment was also associated with delayed hematologic recovery in some patients, 24,25 but these studies also predated the availability of recombinant growth factors now known to support substantial progenitor cell expansion in vitro. 26,27 There are reports that imatinib does not affect quiescent CML stem cells.…”

Cellular determinants affecting the rate of cytokine in cultures of human hematopoietic cells

“…Most clinical experience to date with cultured transplants has involved the use of in vitro conditions that do not support a net expansion of LTC-IC (Barnett et al, 1995;Brenner et al, 1993;Brugger et al, 1995;Chang et al, 1990). Nevertheless, a significant and selective reduction of co-existing leukemic LTC-IC (Barnett et al, 1995) and useful levels of gene transduction to transplantable human stem cells (Brenner et al, 1993) have been achieved without compromising the ability of the cultured grafts to provide satisfactory hematologic recovery in patients given myeloablative treatment regimens.…”

“…Recently several groups (Koller, Bender et al, 1993;Moore and Hoskins, 1994;Zandstra et al, 1994) have reported significant expansions of a very primitive type of hematopoietic human cell, referred to as a longterm culture-initiating cell (LTC-IC) because of its ability to initiate longterm (>5 weeks) hematopoiesis in cultures containing suitable fibroblast feeder layers (Sutherland et al, 1990). Most clinical experience to date with cultured transplants has involved the use of in vitro conditions that do not support a net expansion of LTC-IC (Barnett et al, 1995;Brenner et al, 1993;Brugger et al, 1995;Chang et al, 1990). Nevertheless, a significant and selective reduction of co-existing leukemic LTC-IC (Barnett et al, 1995) and useful levels of gene transduction to transplantable human stem cells (Brenner et al, 1993) have been achieved without compromising the ability of the cultured grafts to provide satisfactory hematologic recovery in patients given myeloablative treatment regimens.…”