Cml Treated With Imatinib

Imatinib has not been available for a long enough period of time to make firm conclusions with regard to long-term prognosis using the Sokal and Hasford scoring systems. Data are becoming available, however, with regard to the ability of imatinib to induce cytoge-netic and molecular remissions that perhaps can be used as surrogate markers of long-term prognosis.

In the International Randomized Study of Interferon and STI-571 (IRIS) trial, patients with chronic-phase CML were randomized to treatment with either the combination of interferon and cytarabine or imatinib at a dose of 400 mg/day. The IRIS investigators attempted to calculate Sokal and Hasford scores at the time of enrollment into the trial. Unfortunately, 30% of patients lacked the necessary values to calculate the prognostic score. However, for those patients with a high-risk Sokal or Hasford score, the rates of CCR at 18 months were 56% and 66%, respectively, for patients treated with imatinib.20 At the time the study was published, the duration of follow-up was too short to determine with confidence the applicability of either scoring system to survival in patients treated with imatinib. In contrast, a study of 77 patients treated with imatinib 400 mg daily in combination with interferon showed that both the Sokal and Hasford systems were useful in predicting major cytogenetic remission rates.21 In this study, only 23% and 17% patients with high-risk scores by Sokal and Hasford criteria, respectively, achieved a major cytogenetic remission. Thus, firm conclusions about the applicability of these scoring systems to patients treated with imatinib await further analysis. Given the uncertainty surrounding the applicability of the Sokal and Hasford scoring systems, these scoring systems should not be routinely applied to patients treated with imatinib.

The prognostic scoring systems applied to patients with CML may be supplanted by newer, biologically-based, prognostic factors. Derivative chromosome 9 deletions are found in 10-15% of patients with chronic-phase CML at diagnosis.22 23 The presence of these deletions clearly portends a worse prognosis in patients treated with either hydroxyurea or interferon and does so independently of either the Sokal or Hasford scores.24 Patients harboring derivative chromosome 9 deletions have a better prognosis when treated with imatinib, but may not have as favorable a prognosis as those patients treated with imatinib in the absence of deletions.25 In addition, the prognosis of patients with derivative chromosome 9 deletions treated with allogeneic HSCT may be poorer compared to those patients without deletions.26

Additional analysis of the IRIS trial has provided insight into other potential markers of prognosis in patients treated with imatinib for chronic-phase CML. Approximately 25% of patients fail to achieve CCR with imatinib 400 mg daily. These patients have a median progression-free survival of 85% at 24 months of follow-up. In contrast, patients achieving a CCR with imatinib have a 95-100% 24-month progressionfree survival (P = <0.001) depending on the degree of molecular remission.12 20 Therefore, the features of patients that predict for failure to achieve CCR with imatinib are also likely to portend poor survival and these patients might be suitable candidates for allo-geneic HSCT as an initial treatment strategy.

Another strategy to predict outcome in patients treated with imatinib may be to monitor the quantitative reduction in bcr/abl transcript levels. In one study of 106 patients treated with imatinib and monitored by quantitative RT-PCR, the probability of a major cytogenetic response was significantly higher in patients with a bcr-abl/bcr ratio <20% after 2 months of imatinib therapy.27

Some patients have CML that is intrinsically resistant to imatinib at diagnosis. As many as 23% of untreated CML patients fail to achieve major cytogenetic remission after 6 months of imatinib dosed at 400 mg daily.20 These patients generally acquire resistance to imatinib, although imatinib resistant mutations in bcr/abl have been reported before the treatment begins.2829 Acquired mutations that confer resistance are not useful as a prognostic tool at diagnosis. However, once recognized, some acquired mutations are associated with a worse prognosis than others.30 There is no consensus as to how the detection of such mutations should guide therapy and whether or not allogeneic HSCT can impact on an otherwise poor prognosis.

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