Imatinib (STI571, Gleevac) as Initial Therapy for Patients with Newly Diagnosed Ph + Chronic Myeloid Leukemia (CML): Results of a Randomized Phase III Study vs Interferon-Alpha + Cytarabine (IFN + AraC)

Reviewer: Ryan Smith, MD
Last Modified: December 8, 2002

Presenter: Richard A. Larson
Presenter's Affiliation: International Randomized IFN vs. STI571 Study Group
Type of Session: Plenary


    Imatinib is a specific inhibitor of the BCR-ABL tyrosine kinase, which is the oncogene classically associated with Philadelphia chromosome positive chronic myeloid leukemia (CML). It has been shown to produce high response rates in chronic phase CML in patients after failure of IFN therapy. This study documents the efficacy of imatinib monotherapy vs. IFN + AraC (previously accepted first line therapy) as first line therapy for CML.

Materials and Methods

  • 1106 patients with Phliadelphia chromosome positive CML in chronic phase (i.e.-not blast crisis or accelerated phase) with no prior therapy formed the study group.
  • Patients were randomized to one of two arms: Arm 1: imatinib 400 mg/d (n=553) Arm 2: IFN (5 million units/m2/d) + AraC (20 mg/m2 x 10 days q mon. (n=553)
  • Dose escalation of imatinib to 600-800 mg/d was allowed if no response was obtained
  • Crossover was allowed for lack of response to therapy, loss of response to therapy, or Grade 3/4 non-hematologic toxicity
  • Patients were well-balanced between study arms, except that 12% had other chromosomal abnormalities in the imatinib arm vs. 8% in the IFN + AraC arm
  • Patients were evaluated for hematologic response, cytogenetic response, toxic effects, and progression free survival (primary endpoint)
  • Median follow up was 19 months


  • All results presented as 18 mo data and as intention to treat
  • Crossover occurred in 2% of the imatinib group compared to 58% of the IFN + AraC group. Mainly due to toxicity.
  • Complete hematologic response was 97% (imatinib) vs 69% (IFN + AraC)
  • Major cytogenetic response was 85% (imatinib) vs 22% (IFN + AraC)
  • Complete cytogenetic response was 76% (imatinib) vs 14% (IFN + AraC)
  • 18 month progression free survival was 92.3% (imatinib) vs 73.6% (IFN + AraC)
  • Imatinib was significantly better tolerated (1-2% grade 3/4 non-hematologic toxicity vs 24% fatigue, 5% nausea, 13% depression in the IFN + AraC group)
  • 86% of patients remained on imatinib, 11% remained on IFN + AraC

Author's Conclusions

  • Imatinib is superior in every aspect to IFN + AraC as first line therapy in patients with CML
  • More follow-up time is needed to determine the duration of remission and effect on overall survival

Clinical/Scientific Implications

    These are extremely impressive data for the support of imatinib as first line treatment in CML. Imatinib is superior to IFN + AraC (previously first line therapy) in every aspect, from efficacy to toxicity. Imatinib should now be considered first line therapy in patients with newly diagnosed chronic phase CML. Remaining questions include the optimal dosing and whether it should continue to be used as a single agent. Also, with these impressive results of imatinib, an innocuous therapy, bone marrow transplant's role is questioned. Allogenic bone marrow transplant (BMT) is still the only known cure for CML, and it is best done within one year of diagnosis. However, it is much more toxic and aggressive. BMT carries a 20% mortality rate when using sibling donors and a 35-40% mortality rate in unrelated donors. In addition, the majority of patients are not eligible, because of age, overall health, or lack of an adequate donor. Though imatinib is probably not a cure in the sense that BMT is (as those with cytogenetic complete responses are still PCR positive for the BCR-ABL oncogene), it may result in a "functional cure", meaning patients may never relapse. A randomized trial between imatinib and BMT will likely never be completed, given the vast difference in toxicity between the two treatments. However, even though imatinib's effect on BMT is not known, given the results of this study, patients will likely be treated with imatinib rather than BMT in many cases. It should be noted that, thus far, there is no effect on overall survival. However, this is likely the result of short follow up and the significant amount of crossover between the two arms. In that light, it should also be noted that the results for imatinib compared to IFN + AraC would be even more impressive if crossover was not allowed. Regardless of these remaining questions, imatinib is a very large advancement in the treatment of CML.

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