About 20% of otherwise eligible CML patients lack a suitably matched sibling donor. HLA-matched unrelated donors or donors mismatched at one-HLA antigen can be found for about 50% of eligible participants through the National Marrow Donor Program. A retrospective review of 2,444 patients who received myeloablative allogeneic SCT showed OS at 15 years of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and of 87% (95% CI, 83%–90%) for unrelated donor transplant. The cumulative incidences of relapse were 8% (95% CI, 7%–10%) for sibling-matched transplant and 2% (95% CI, 1%– 4%) for unrelated donor transplant.
Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years following BMT. In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable BCR/ABL transcript by PCR analysis. The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.[28,39]
With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. Allogeneic SCT is the preferred choice for patients presenting with accelerated-phase or blast-phase disease, for patients with a T3151 mutation (resistant to currently available tyrosine kinase inhibitors), and for patients with complete intolerance to the pharmacologic options.
In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early allogeneic SCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission. With a 9-year median follow-up, survival still favored the drug treatment arm (P = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[Level of evidence: 2A] Among the many unanswered questions are the following:
- Should younger eligible patients move quickly toward allogeneic SCT after induction failure by imatinib mesylate?
- Does the substantial toxicity and mortality of allogeneic transplantation render its early use obsolete?
Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.
Biologic therapy with or without chemotherapy
Long-term data are available for initial treatment with interferon alpha. A meta-analysis of seven trials that randomly assigned patients to receive interferon or conventional chemotherapy (hydroxyurea or busulfan) demonstrated a 30% reduction in the annual death rate for patients who received interferon (P < .001).[Level of evidence: 1iiA] The annual death rate was reduced by 26% in the trials of interferon versus hydroxyurea (P = .001) and 36% in the trials of interferon versus busulfan (P = .007). Median survival was prolonged by 1 to 2 years; 5-year survival rate was 57% for patients treated with interferon and 42% for patients treated with chemotherapy (P < .001). Further analysis of the two trials, which included a three-way randomization between interferon, hydroxyurea, and busulfan, showed hydroxyurea to be superior to busulfan, decreasing the proportional odds of death by 24% (P = .02). About 20% of the chronic-phase patients treated with interferon alpha have complete cytogenetic remissions with temporary disappearance of Philadelphia chromosome (Ph1)-positive cells in the marrow, and in about 10% of the patients these cytogenetic responses are quite long lasting.[43,44,45] These data have only been published in the context of a review article, rather than a peer-reviewed research manuscript.