12 + 4*/5+1*/3
6 + 2*/0/1
>0 and <0.05%
1 + 1*/0/1
Molecular Response to Imatinib in Chronic Phase CML
*Patients lost complete cytogenetic remission only transiently.
Table 3. Significance of achieving molecular response in sustaining a complete cytogenetic remission
No. who lost complete cytogenetic remission to
Median follow-up from molecular
evaluation. Among the 82 patients with subsequent evalua- tions, only 3 (4%) lost their complete cytogenetic remission (one of them later regained a complete cytogenetic remission), compared with 5 of 74 (7%) who had detectable BCR-ABL levels but <0.05%. These differences are not due to a difference in follow up, as there is no difference in follow-up time bet- ween patients who did and did not achieve a major or com- plete molecular response.
To further define the long-term prognostic implications of molecular response and account for the potential lead-time bias, we investigated the complete cytogenetic remission duration according to molecular response at different time points. For this analysis, only patients who had both a molecular analysis and were still on therapy and in complete cytogenetic remission at the specified time points were evaluable. Patients who achieved a major molecular remission by 12 months after the start of therapy have significantly longer cytogenetic remission durations than those without this magnitude of molecular response (Fig. 2C). Molecular response at earlier time points (i.e., 3 and 6 months) shows a similar trend (Fig. 2A and B). Most patients who lost their complete cytogenetic remission still have at least a partial cytogenetic remission. Thus, we repeated the analysis consid- ering only loss to at least 35% Ph-positive metaphases. Because of the few number of events, the results are not statistically significant. In fact, the analysis could not be done for response at 12 months as no patients lost their major cytogenetic response in either group (with or without major molecular response). A trend could be observed in favor of the earlier responders at 3 (P = 0.29) and 6 months (P = 0.11; data not shown).
not statistically significant, the same trend is observed in favor of patients achieving a molecular response at each of these early time points.
Since we identified that achieving a major molecular response after 12 months of therapy is predictive of cyto- genetic remission duration, we investigated the probability of achieving this response at 12 months based on the response achieved at 3 months. Patients who achieve V1-log reduction after 3 months of therapy have a significantly lower prob- ability (55%) of achieving a major molecular response at 24 months, compared with those with greater than 1-log or 2-log reduction (84% and 95%, respectively; P = 0.0002).
Durability of molecular response. We next investigated the durability of molecular responses. Among the 174 patients who achieved a major molecular response, 165 (95%) have had repeated molecular testing (median, five follow-up tests, range, two to eight). The molecular response was sustained in 118 (72%) of them, for a median of 19 months (range, 3-33 months). Subsequent evaluation is available for 81 of the 95 (85%) patients who achieved undetectable levels of BCR-ABL, with a median of two follow-up tests (range, one to six). In 43 patients (53%), BCR-ABL/ABL became detectable again in subsequent testing, whereas 38 (47%) had sustained undetectable BCR-ABL levels over a median of 18 months (range, 3-27 months). Among 47 patients who lost a major molecular response, 13 (28%) did so after having therapy interrupted temporarily or permanently. The most common reasons for treatment interruptions were noncompliance in six, toxicity in five [liver (n = 3), gastrointestinal (n = 1), and weight gain (n = 1)], and hospitalization for other reasons (n = 2).
Other studies used a 3-log reduction rather than an absolute value as a measure of molecular response for patients treated with imatinib (16). We thus repeated the analysis using a 3-log reduction as a measure of major molecular response. For this purpose, published reports have used the median calculated from measuring pretreatment values from a small number of patients as baseline levels. For our analysis we calculated a 3-log reduction in two different ways. First, we used the median of the total population (i.e., 39.44%) as the baseline value. Thus, a 3-log reduction would be considered achieving a ratio of V0.039%. The results are nearly identical to those considering a value <0.05% as a major molecular response. We then used each individual patients’ pretreatment BCR-ABL/ABL value as their own baseline to determine log reduction. Data for this analysis is available for 79 patients. Although the difference is
To determine the significance of an increasing BCR-ABL/ ABL ratio while on therapy, we investigated the clinical signif- icance of a <1-log (n = 23), 1-log (n = 30), or 2-log (n = 8) increase in the BCR-ABL/ABL ratio from the lowest level achieved. Only four (17%), four (13%), and two (25%) patients with each of these magnitudes of increasing transcript levels, respectively, lost their complete cytogenetic remission (P = 0.72). However, 9 of the 10 patients who lost the response had the lowest BCR-ABL/ABL ratio of >0.05, whereas only 1 of 37 patients with nadir levels of V0.05% had lost their response, regardless of their log increase (P = 0.04). If the absolute increase is considered instead of the log increase, an increment of BCR-ABL/ABL of more than 1.0 percentage point from the nadir is associated with an increased risk of cytogenetic relapse (5 of 11, 45%)
Clin Cancer Res 2005;11(9) May 1, 2005
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