Dasatinib is effective in treating chronic myeloid leukemia (CML) patients resistant/intolerant to imatinib. To date, most of the data come from clinical trials on selected patients. Thus, studies based on real life are opportune. Aims. The aim of the study was to evaluate the safety and efficacy of Dasatinib as second line therapy for patients with CML either resistant or refractory to imatinib outside from clinical trials or compassionate use. Patients and Methods. 114 unselected CML patients resistant/intolerant to imatinib received dasatinib as second line therapy outside from clinical trials. All patients had chronic phase (CP-CML). Sokal score was low for 29, intermediate for 44 and high for 41 patients, and they were either resistant (n=88) or intolerant (n=16) or resistant and intolerant (n=10) to imatinib therapy. All patients were evaluated for hematologic, cytogenetic and molecular response, discontinuation/dose reduction of Dasatinib, event-free survival (EFS) and overall survival (OS). Moreover, we analyzed toxicities according to NCI-CTC, focusing on grade III-IV toxicities. Results. At 12 months, cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 94%, 55%, and 35%. Cumulative event-free survival (EFS) and overall survival (OS) were 91 and 93%. Noteworthy, we did not observe any survival difference between patients with low, intermediate or high Sokal score (P=0.4). We did not found any association between the dose of prior imatinib (400, 600 or 800) and the probability of achieving CCyR at 1 year with dasatinib (P=0.7). Furthermore, we did not found any association neither between the duration of the previous treatment with imatinib and the probability of achieving CCyR at 1 year with dasatinib (P=0.9). Nevertheless, we did not observe any difference between patients who received imatinib for more than 3 years with respect to those receiving it for less than 3 years (P=0.9). Finally, we did not observe any association between best response to imatinib and probability of achieving CCyR after 1 year with dasatinib (P=0.8). As a matter of fact, we observed a statistically significant better outcome in term of both DFS (P=0.04) and OS (P=0.04) for the 54 patients who received dasatinib at lower doses continuously without interruption with respect to the 60 patients receiving higher doses but forced to discontinue the treatment due to grade III-IV toxicity. Conclusions. We confirm the safety and efficacy of dasatinib as second line therapy for patients with CML either resistant or refractory to imatinib even outside from clinical trials. This experience challenges the wisdom that dasatinib, a drug characterized by short half life, must achieve nearly continuous target inhibition via high dose therapy for maximal clinical impact. Further studies are warranted, in order to extend the use of low dose continuous dasatinib to real life patients potentially not eligible to receive high dose dasatinib.
LOW DOSE CONTINUOUS THERAPY WITH DASATINIB SIGNIFICANTLY IMPACT ON SURVIVAL OF PATIENTS WITH CHRONIC MYELOID LEUKAEMIA (CML) RESISTANT OR INTOLERANT TO IMATINIB. RESULTS FROM A REAL LIFE-BASED ITALIAN MULTICENTER RETROSPECTIVE STUDY ON 114 UNSELECTED PATIENTS
CAVAZZINI, Francesco;CUNEO, Antonio;
2010
Abstract
Dasatinib is effective in treating chronic myeloid leukemia (CML) patients resistant/intolerant to imatinib. To date, most of the data come from clinical trials on selected patients. Thus, studies based on real life are opportune. Aims. The aim of the study was to evaluate the safety and efficacy of Dasatinib as second line therapy for patients with CML either resistant or refractory to imatinib outside from clinical trials or compassionate use. Patients and Methods. 114 unselected CML patients resistant/intolerant to imatinib received dasatinib as second line therapy outside from clinical trials. All patients had chronic phase (CP-CML). Sokal score was low for 29, intermediate for 44 and high for 41 patients, and they were either resistant (n=88) or intolerant (n=16) or resistant and intolerant (n=10) to imatinib therapy. All patients were evaluated for hematologic, cytogenetic and molecular response, discontinuation/dose reduction of Dasatinib, event-free survival (EFS) and overall survival (OS). Moreover, we analyzed toxicities according to NCI-CTC, focusing on grade III-IV toxicities. Results. At 12 months, cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 94%, 55%, and 35%. Cumulative event-free survival (EFS) and overall survival (OS) were 91 and 93%. Noteworthy, we did not observe any survival difference between patients with low, intermediate or high Sokal score (P=0.4). We did not found any association between the dose of prior imatinib (400, 600 or 800) and the probability of achieving CCyR at 1 year with dasatinib (P=0.7). Furthermore, we did not found any association neither between the duration of the previous treatment with imatinib and the probability of achieving CCyR at 1 year with dasatinib (P=0.9). Nevertheless, we did not observe any difference between patients who received imatinib for more than 3 years with respect to those receiving it for less than 3 years (P=0.9). Finally, we did not observe any association between best response to imatinib and probability of achieving CCyR after 1 year with dasatinib (P=0.8). As a matter of fact, we observed a statistically significant better outcome in term of both DFS (P=0.04) and OS (P=0.04) for the 54 patients who received dasatinib at lower doses continuously without interruption with respect to the 60 patients receiving higher doses but forced to discontinue the treatment due to grade III-IV toxicity. Conclusions. We confirm the safety and efficacy of dasatinib as second line therapy for patients with CML either resistant or refractory to imatinib even outside from clinical trials. This experience challenges the wisdom that dasatinib, a drug characterized by short half life, must achieve nearly continuous target inhibition via high dose therapy for maximal clinical impact. Further studies are warranted, in order to extend the use of low dose continuous dasatinib to real life patients potentially not eligible to receive high dose dasatinib.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
