Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment

Abstract

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Figure 1

Consort flow diagram of enrollment, allocation, follow-up and analysis of patients. In group B, all 261 patients started with best available drug treatment. During the course of disease, 131 patients received an allogeneic HSCT with an unrelated donor in first CP. Their survival time was censored at the day of transplant. Ph, Philadelphia.

Figure 2

Kaplan–Meier estimates of overall survival of the 427 patients stratified according to genetic randomization. Of 427 patients, 166 were randomized to early allogeneic HSCT (group A) and 261 patients to best available drug treatment (group B). Analysis was performed by intention to treat. In group B, the survival time of patients receiving an allogeneic HSCT with an unrelated donor was censored at the day of transplant. The overall survival differences between the two curves were not significant (Wilcoxon–Gehan test). At 1, 5 and 10 years, horizontal crossbars indicate the upper and lower limits of the 95% CIs for the estimated survival probabilities (s.p.).

Figure 3

(a) Kaplan–Meier estimates of overall survival since diagnosis of the 427 patients eligible for allogeneic HSCT with a related donor. At diagnosis, all 166 patients randomized to group A were stratified according to the adapted EBMT risk score at diagnosis and all 261 patients randomized to group B were stratified according to disease risk (Euro score) at diagnosis. Analysis was performed by intention to treat. In group B, the survival time of patients receiving an allogeneic HSCT with an unrelated donor was censored at the day of transplant. With EBMT score 0 or 1 in group A, survival probabilities were significantly higher compared with the survival probabilities of Euro high- (log-rank test: median P<0.001) and Euro non-high-risk patients (log-rank test: median P=0.047) in group B. At 1 and 5 years, horizontal crossbars indicate the upper and lower limits of the 95% CIs for the estimated survival probabilities. The abbreviation ‘s.p.' stands for 'survival probability'. (b) Simon–Makuch estimates of overall survival of 48 patients with blast crisis. Patients were stratified according to the reception of allogeneic HSCT as salvage therapy. All patients started in the non-transplant group. If transplanted, patients changed to the HSCT group at the time of transplant (finally, 23 were transplanted). Survival differences were not significant (Mantel–Byar test). At 1 year, horizontal crossbars indicate the upper and lower limits of the 95% CIs for the estimated survival probabilities.