Final concentration (nmol/L)
bcr-e1 bcr-b2 abl-a2 abl 10-F abl 11-R TaqMan probes
400 400 400 50 50
GCAAGACCGGGCAGATCT ACAGCATTCCGCTGACCAT NEDR-CGAGCGGCTTCACTCAGA AGAGCTGCAGAGCACAGAGACA GCTCTTTTCGAGGGAGCAATG
bcrabl-2a abl 1011-P
Molecular Response to Imatinib in Chronic Phase CML
Table 1. Sequence of primers and probes used in theTaqMan qRT-PCR
Thus, for consistency, only those results obtained with this method- ology are considered for this analysis.
Statistical analysis. Complete cytogenetic remission duration was considered from the time a complete cytogenetic remission was first achieved to the time when any Ph-positive metaphases were first detected again. Survival was calculated from the time the treatment began until death from any cause, or last follow-up. The probability of remission duration was estimated using the Kaplan-Mier product-limit method (19) and compared by means of the log-rank test (20). Associations between categorical variables were assessed via cross- tabulation and Fisher’s exact test or the v2 test (21). Multivariate logistic regression analysis was used to assess the relationship between various predictors of interest and molecular response.
Patients. A complete hematologic remission was achieved in 293 of 305 (96%) patients treated with imatinib for CML in active chronic phase (i.e., abnormal peripheral blood counts and/or splenomegaly). These included 177 of 181 (98%) in early chronic phase (i.e., within 12 months from diagnosis), and 116 of 124 (94%) in chronic phase after IFN-a failure. A major cytogenetic remission was achieved in 310 of 369 (84%) patients who had Ph-positive metaphases by standard cytogenetic analysis at the start of therapy, including 279 (76%) that achieved a complete cytogenetic remission. An additional seven patients had Ph-negative BCR-ABL-positive disease at the start of therapy. Among 286 patients in com- plete cytogenetic remission, 280 had at least one PCR test done for follow-up. These patients constitute the focus of this analysis. The median age of the study group was 50 years (range, 15-84 years). Among them, 117 (42%) patients received imatinib after IFN-a failure and 163 (58%) as first line of therapy. The starting dose of imatinib was 400 mg daily for 144 (51%) patients and 800 mg for 136 (49%) patients. The median BCR-ABL/ABL ratio before treatment with imatinib was started was 39.44% (range, 0.252- 170.53%). The median follow up from the time treatment was started is 31 months (range, 3-52 months). Five patients have died while on therapy with imatinib, with an estimated overall survival of 95% at 48 months. Transformation while on therapy occurred in two patients.
PCR analyses and 44 (54%) have had at least two consecutive undetectable assays. The median time from start of treatment to achievement of a major molecular response was 10 months (range, 2.8-46 months), and 16.7 months (range, 3-48 months) for achievement of a complete molecular response. However, as shown in Fig. 1, these responses may occur late and there is no clear evidence of a plateau for time to molecular response.
We then analyzed the pretreatment clinical characteristics associated with achieving a molecular response. Table 2 shows the clinical characteristics at the start of imatinib therapy for all 280 patients. Characteristics associated with a higher probability of achieving a major molecular response included a lower percentage of peripheral blood blasts, Sokal low-risk group, treatment with high-dose imatinib, and treatment in early chronic phase. Achievement of undetect- able levels of BCR-ABL was associated with Ph-positive metaphases V90% at the start of therapy. In a multivariate analysis, treatment with high-dose imatinib was the only variable independently associated with an increased proba- bility of achieving a major molecular remission (P = 0.02). Multivariate analysis for complete molecular remission identified a lower percentage of Ph-positive metaphases (<90%) as the only variable associated with this response (P = 0.01); treatment with high-dose imatinib was marginally significant (P = 0.08).
Molecular response. A major molecular response was achieved in 174 patients (62%; 46% of all patients treated) and 95 patients (34%; 25% of all patients treated) had at least one analysis showing undetectable BCR-ABL (i.e., complete molecular response). Among these, 81 have had subsequent
Fig. 1. Cumulative probability of achieving a molecular response on imatinib for 280 patients with CML in chronic phase who achieved a complete cytogenetic remission on imatinib. All times are calculated from the start of therapy with imatinib.
Clin Cancer Res 2005;11(9) May 1, 2005
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