Chronic phase chronic myeloid leukemia patients who failed interferon alpha and switched to imatinib: Long-term 9-year follow-up of 134 patients
Authors: Massimo Breccia, Roberto Latagliata, Matteo Molica, Gioia Colafigli, Marco Mancini, Daniela Diverio, Agostino Tafuri, Giuliana Alimena
Journal: American Journal of Hematology (2015)

Several studies have reported the outcome of patients who received imatinib after interferon (IFN) failure but few studies showed the long-term outcome 1-3. Aim of our study was to report the outcome of 134 adult Ph+ chronic phase chronic myeloid leukemia (CML) patients who switched to imatinib after IFN failure in a single institution. All patients were treated outside clinical trials with available commercial drug. Standard response criteria were used for cytogenetic response and analyses were performed on bone marrow every 6 months until the achievement of complete cytogenetic response (CCyR) and then every year. Real quantitative polymerase chain reaction (RQ-PCR) was performed on peripheral blood every 3 months: results were expressed according to International Scale (IS). Cumulative incidences of responses were reported and estimated taking into account competing risks for events. Survival (OS) was calculated from start of therapy to death for any cause (including non-related disease deaths). Progression-free survival (PFS) was calculated from start of therapy until the onset of accelerated (AP) or blastic (BP) phase. Event-free survival (EFS) was calculated from start of therapy until the development of any event, including loss of CCyR or molecular response achieved, unacceptable toxicity, death, or progression. OS, PFS, and EFS were analyzed with Kaplan–Meier method and compared using the log-rank test. Overall, there were 74 males and 60 females with a median age of 47 years (range 18–71). Median follow-up was 108 months. Sokal score identified 66 patients as low risk, 49 as intermediate, and 17 as high risk, whereas Eutos score retrospectively identified 107 patients as low risk and 10 as high risk. Median time of IFN treatment was 27 months at a median dose of 4.5 MU/day. Cumulative incidence of CCyR during IFN treatment was 35.8% obtained in a median time of 20.5 months. None of the patients enrolled in this study achieved a molecular response with IFN. Twenty-seven patients switched from IFN to imatinib for intolerance (grade 3/4 or persistence of grade 2, but only two patients in CCyR), whereas all the others changed for resistance to treatment (less than CCyR in all patients). Median time to switch to imatinib was 38 months. With imatinib, overall, 103 patients (76.8%, all previously without CCyR except two) achieved a CCyR as the best cytogenetic response and 68 (51%) achieved a major molecular response (MMR), after a median time of 52 months. A deep molecular response (identified as MR4 and MR4.5) was achieved as best response in 60 patients (44.7%) after a median follow-up of 76 months. Estimated 9-year OS rate was 74% (Fig.1), the PFS rate was 71% (Fig. 2) and the EFS was 54%. Progression to AP/BP phase was detected in 19 patients (14%). Due to resistance or intolerance to imatinib, 22 patients switched to dasatinib (12 for cytogenetic resistance, 5 for intolerance, 2 for molecular resistance, and 3 for BC) and 17 patients switched to nilotinib (11 for cytogenetic resistance and 6 for molecular resistance): overall, 18 of the 22 patients (64%) achieved or maintained CCyR and 11 patients (35%) achieved MMR. In details, of 12 patients who switched to dasatinib for cytogenetic resistance 9 obtained a CCyR (after a median time of 9 months) and 6 obtained an MMR (2 patients who switched for molecular resistance and 4 patients with previous cytogenetic resistance to imatinib). Of 17 patients who switched to nilotinib: 9/11 who switched for cytogenetic resistance obtained a CCyR and 5 patients obtained a MMR (3 patients who switched from imatinib to nilotinib for molecular resistance and 2 for cytogenetic resistance). Only three patients underwent allogeneic bone marrow transplant: 1 after resistance to nilotinib with development of T315I mutation (alive after 2 years), 1 after resistance to both second generation tyrosine kinase inhibitors (TKIs) (alive in MR4.5), and 1 after developed BC (dead after 11 months from BMT). We then analyzed prognostic factors associated to OS: achieving at 12 months a CCyR was associated with a significant better OS in the long-term (82%) as compared to obtaining less than PCyR (70%) or only complete hematologic response (CHR) (12%, P = 0.01). Baseline factors that correlated with a poor OS were clonal cytogenetic evolution, higher percentage of basophils and blast cells in peripheral blood, high Sokal and Eutos score, whereas age did not correlate with a worse OS. Other authors also reported the outcome of this subset of patients, but in most cases inside large series of patients that also received imatinib as firstline treatment. In the ILTE study 1, 478 patients out of 832 treated with imatinib had previously received IFN, but only safety and long-term side effects were described. The Swedish group 2 indirectly reported an improvement of OS in patient diagnosed since 2001 (more than 80%) as compared to patients treated in the previous years with IFN (20–50%), but they did not separate patients starting imatinib as firstline treatment from those who started the drug after IFN failure. The MD Anderson Cancer Center described a series of 368 patients in late chronic phase (CP) that switched to imatinib after IFN failure 3. They reported a cumulative incidence of CCyR of 67%, an MMR rate of 63%, and a rate of undetectable molecular response of 30%, over a long follow-up of 10 years. The estimated OS rate was 68% and multivariate analysis showed that age > 60 years, haemoglobin < 10 g/dl, bone marrow basophils >5%, or the presence of peripheral blasts and clonal evolution were adverse prognostic factors associated to worse outcome. Also in our experience, we found a similar OS: our results showed that achieving a CCyR at 12 months or an MMR was associated with a significant better OS in the long-term (82%), but not for a PCyR (70%), as indeed reported in the MDACC experience. Analysis of prognostic factors that correlated with a poor OS showed also in our study similar correlations. Imatinib had overcome the unfavorable outcome of patients resistant to IFN, a group of patients whose median survival was usually 3 years 4. The advantage in OS, subsequently observed, was probably related to the introduction into clinical practice of dasatinib and nilotinib that rescued about 50% of patients resistant to previous lines of therapies 5, 6. It remains to be established the advantage of previous exposure to IFN in patients that, if have reached a deep molecular response, may also attempt to discontinue treatment in the long-term. In several trials aimed to investigate on discontinuation 7-9, most of the patients were previously treated with IFN and it seems that the exposure to this agent may offer an advantage in terms of a low rate of relapses. In conclusion, the results of our study support the validity of rescuing with imatinib patients who failed IFN, with an OS similar to that reported in other previous observations. It remains to be determined which role can have IFN either in terms of treatment preceding TKIs or in terms of associated administration. OS after a median follow-up of 9 years. Progression-free survival. Massimo Breccia,* Roberto Latagliata, Matteo Molica, Gioia Colafigli, Marco Mancini, Daniela Diverio, Agostino Tafuri, and Giuliana Alimena Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy