Treatment with interferon-alpha (IFN-alpha) adequately controls the leukemic cell mass in the majority of newly diagnosed patients with chronic myeloid leukemia (CML). However, the degree of response ranges from no 'hematologic' response to complete suppression of the leukemic clone. The mechanism(s) by which IFN-alpha elicits these responses is unknown, but in vitro studies have indicated that IFN-alpha might function by (1) selective toxicity against the leukemic clone, (2) enhancement of 'immune' regulation, and (3) modulation of bone marrow microenvironmental regulation of hematopoiesis. Using in vitro clonogenic assays we were unable to demonstrate that IFN-alpha selectively inhibited the proliferation of CML progenitor cells. We also found no difference in the expression of LFA-3 on normal or CML CD34+ cells. However, by panning and co-culturing hematopoietic cells on monolayers of bone marrow stromal cells, grown with and without IFN-alpha, we found that IFN-alpha enhanced the adhesion of CML progenitors to stromal cells, whereas adhesion by normal progenitor cells was essentially unaffected. This enhanced adhesion by CML progenitor cells was associated with a reduction in neuraminic acid levels in the extracellular matrix overlying stromal cells. Therefore, it is possible that one of the mechanisms by which IFN-alpha exerts its regulatory effect on the leukemic clone is through enhancement of hematopoietic cell-microenvironmental cell interactions.

We treated 14 patients with Ph-chromosome-positive chronic myeloid leukaemia still in chronic phase by autografting with blood-derived haemopoietic stem cells. Eleven patients were autografted electively after cytoreductive treatment with busulphan (16 mg/kg) and melphalan (60 mg/m2) and three were autografted after marrow cells from HLA-identical sibling donors had failed to engraft. In 13 patients haemopoiesis recovered; one failed to engraft and died 114 d after autografting. Two other patients became pancytopenic and received further stem cell transfusions at 3 and 40 months respectively after first autografting. One patient entered lymphoid transformation and died 14 months after autografting. Twelve patients survive at a median of 41 months (range 24-53) after autografting. Nine of the survivors have required further chemotherapy after autografting and four of the nine were electively autografted on a second occasion. Three patients surviving after autografting for 28, 43 and 53 months respectively have not required further chemotherapy. In two of these patients haemopoiesis is now predominantly Ph-negative. We conclude that autografting in chronic phase might prolong survival in some cases by reducing the size of the leukaemic stem cell population. The fact that initially successful grafts failed in two patients suggests that blood-derived stem cells may have a finite potential for self-replication.

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Primitive blast colony-forming cells (BI-CFC) from chronic myeloid leukemia (CML) patients are defective in their attachment to bone marrow-derived stromal cells compared with normal BI-CFC. We investigated the effect of recombinant interferon-alpha 2a (IFN-alpha) on this interaction between hematopoietic progenitor cells and bone marrow-derived stromal cells by culturing normal stromal cells with IFN- alpha (50 to 5,000 U/mL). At 50 U/mL we found that: (1) the capacity of stromal cells to bind two types of CML primitive progenitor cells (BI- CFC and long-term culture-initiating cells) was increased; and (2) the amount of sulfated glycosaminoglycans (GAGs) in the stromal layer was increased. However, sulfated GAGs were not directly involved in binding CML BI-CFC, unlike binding by normal BI-CFC, which is sulfated GAG- dependent. Neuraminidase-treated control stromal cells bound an increased number of CML BI-CFC, reproducing the effect of IFN-alpha, whereas the binding to IFN-alpha-treated stromal cells was unaffected by neuraminidase treatment. Thus, the enhanced attachment by primitive CML progenitor cells to INF-alpha-treated stromal cells might be due to changes in the neuraminic acid composition in the stromal cell layer. Our in vitro evidence may provide insights into the mechanism of action of IFN-alpha in vivo. Prolonged administration may alter the marrow microenvironment in some patients such that it can restrain the aberrant proliferation of Philadelphia chromosome (Ph)-positive stem cells while permitting Ph-negative stem cells to function normally.