Mutations of the BCR-ABL kinase domain represent a frequent cause of Imatinib (IM) resistance in chronic myeloid leukemia (CML) patients (pts). Dasatinib (DS) is highly effective against the majority of BCR-ABL mutants detected in pts failing IM. However, little is known about the incidence of mutations in elderly CML pts resistant to IM and on their impact on response to DS in this setting. Aim and Methods. To evaluate the role of pre-DS BCR-ABL mutations, we analysed 81 pts aged >60 years who received DS for chronic phase (CP) CML resistant to IM. Forty-five pts (55.5%) did not display any BCR-ABL mutation, while 36 (44.5%) had one or more mutations. Twenty-four different mutations were detected in the 36 mutated pts, with 4 cases displaying multiple mutated clones. Most frequent mutations were: M244V (n=7), Y253H (n=4), F317L (n=3), F359V (n=5), M531I (n=3) and H396R (n=3). Overall, these 6 mutations represented 69% of all cases. V299L and T315I mutations insensitive to DS were detected in one case each. Results. The mutated and non-mutated groups were comparable for sex distribution, age at DS start, concomitant diseases, medications and cause of IM resistance. DS daily starting dose was higher in mutated pts (140 mg in 24 pts, 100 mg in 11 pts, < 100 mg in 1 pt) than in non-mutated ones (140 mg in 13 pts, 100 mg in 27 pts, < 100 mg in 5 pts). Consequently, the dose reduction rate, owing to toxicity, was higher in the mutated pts (26/36, 72% vs. 19/45, 42%; P=0.01). Final DS dose was almost identical in the two groups (mean dose: 90 mg in mutated and 100 mg in non-mutated), as was the percentage of pts that suspended therapy and the rate of adverse events (including pleural effusion). When considering best response to DS therapy, non-mutated patients did significantly better than mutated ones. Complete cytogenetic responses (CCyR) and/or major/complete molecular responses (MMolR and CMolR) were obtained in 24 of the 39 evaluable non-mutated patients (61.5%) and in 11 of the 35 evaluable mutated patients (31.5%) (P=0.02). The rate of primary resistance was higher in the mutated group (16/36 vs. 7/45, P=0.009), and even excluding the 5 pts with mutations unresponsive to DS (i.e. 3 with F317V, 1 with V299L and 1 with T315I), mutated pts had a lower CCyR/MolR rate (11/31 vs. 24/39, P=0.05) and more frequently displayed primary resistance (13/31 vs. 7/45, P=0.02). On the contrary, secondary resistance (4/36 vs. 0/45), severe toxicities (4/36 vs. 6/45) and suspensions due to other causes (2/36 vs. 5/45) did not significantly differ in the two cohorts. Summary. Our data suggest that BCR-ABL mutations account for roughly half of IM resistance in elderly CP-CML pts, a proportion similar to that found in the general population. In the elderly setting, however, presence of pre-DS BCR-ABL mutations seems to reduce optimal response to therapy, in terms of lower CCyR and MolR rates
IMPACT OF BCR-ABL MUTATIONS ON RESPONSE TO DASATINIB IN ELDERLY CHRONIC MYELOID LEUKEMIA PATIENTS RESISTANT TO IMATINIB
CAVAZZINI, Francesco;
2010
Abstract
Mutations of the BCR-ABL kinase domain represent a frequent cause of Imatinib (IM) resistance in chronic myeloid leukemia (CML) patients (pts). Dasatinib (DS) is highly effective against the majority of BCR-ABL mutants detected in pts failing IM. However, little is known about the incidence of mutations in elderly CML pts resistant to IM and on their impact on response to DS in this setting. Aim and Methods. To evaluate the role of pre-DS BCR-ABL mutations, we analysed 81 pts aged >60 years who received DS for chronic phase (CP) CML resistant to IM. Forty-five pts (55.5%) did not display any BCR-ABL mutation, while 36 (44.5%) had one or more mutations. Twenty-four different mutations were detected in the 36 mutated pts, with 4 cases displaying multiple mutated clones. Most frequent mutations were: M244V (n=7), Y253H (n=4), F317L (n=3), F359V (n=5), M531I (n=3) and H396R (n=3). Overall, these 6 mutations represented 69% of all cases. V299L and T315I mutations insensitive to DS were detected in one case each. Results. The mutated and non-mutated groups were comparable for sex distribution, age at DS start, concomitant diseases, medications and cause of IM resistance. DS daily starting dose was higher in mutated pts (140 mg in 24 pts, 100 mg in 11 pts, < 100 mg in 1 pt) than in non-mutated ones (140 mg in 13 pts, 100 mg in 27 pts, < 100 mg in 5 pts). Consequently, the dose reduction rate, owing to toxicity, was higher in the mutated pts (26/36, 72% vs. 19/45, 42%; P=0.01). Final DS dose was almost identical in the two groups (mean dose: 90 mg in mutated and 100 mg in non-mutated), as was the percentage of pts that suspended therapy and the rate of adverse events (including pleural effusion). When considering best response to DS therapy, non-mutated patients did significantly better than mutated ones. Complete cytogenetic responses (CCyR) and/or major/complete molecular responses (MMolR and CMolR) were obtained in 24 of the 39 evaluable non-mutated patients (61.5%) and in 11 of the 35 evaluable mutated patients (31.5%) (P=0.02). The rate of primary resistance was higher in the mutated group (16/36 vs. 7/45, P=0.009), and even excluding the 5 pts with mutations unresponsive to DS (i.e. 3 with F317V, 1 with V299L and 1 with T315I), mutated pts had a lower CCyR/MolR rate (11/31 vs. 24/39, P=0.05) and more frequently displayed primary resistance (13/31 vs. 7/45, P=0.02). On the contrary, secondary resistance (4/36 vs. 0/45), severe toxicities (4/36 vs. 6/45) and suspensions due to other causes (2/36 vs. 5/45) did not significantly differ in the two cohorts. Summary. Our data suggest that BCR-ABL mutations account for roughly half of IM resistance in elderly CP-CML pts, a proportion similar to that found in the general population. In the elderly setting, however, presence of pre-DS BCR-ABL mutations seems to reduce optimal response to therapy, in terms of lower CCyR and MolR ratesI documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
