Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients

Therapeutic approach for chronic myeloid leukemia (CML) patients has undergone a revolutionary change with the introduction of tyrosine kinase inhibitors, which improved overall survival and quality of life. Optimal therapy adherence has become of paramount importance to maximize the benefits in the long-term outcome. Several evidences have been reported that personal factors, such as social support, psychological and subjective perceptions about the drug used and the future, could influence adherence. We here report the results of a questionnaire specifically designed to evaluate factors influencing adherence and perceptions about the future, distributed to patients during regional Italian meetings. Overall, 1133 patients compiled the questionnaire: median age was 57 years. High rate of adherence was reported, but 42% of interviewed patients admitted that they had occasionally postponed a dose and 58% had discontinued therapy mainly for forgetfulness. The majority of patients discussed with personal physician about the importance of adherence and received sufficient information about illness and treatment, but would like to have discussed more about discomfort, anxiety and fear of the future. Summarizing personal drug compliance and estimating how many days a month, on average, the patients did not take the drug, the majority answered that it was less than 3 days (55%) and only a minority (4%) admitted that it was more than 7 days. Interviewed about discontinuation, 49% of patients answered that wouldn't interrupt because of fear of losing all the results achieved so far. This study suggests a higher level of satisfaction with more information received but the need of improving communication about possible future treatment free remission

Prognostic Value of BCR-ABL1 Transcript Type in Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib

Background. The fusion protein encoded by the BCR-ABL1 fusion gene may differ in size, but the great majority of chronic myeloid leukemia (CML) patients have a e13a2 (b2a2) or a e14a2 (b3a2) junction. In CML patients treated frontline with imatinib, the e14a2 transcript has been recently associated to faster and deeper molecular responses; in some studies a better outcome has been also reported. Very limited information on the prognostic impact of the BCR-ABL1 transcript type in CML patients treated frontline with second generation tyrosine kinase inhibitors (TKIs) is still available: a study from MDACC reported lower molecular response rates and a trend for inferior event-free survival in e13a2 patients. Aim. To evaluate if the BCR-ABL1 transcript type (e14a2 vs e13a2) affect the response and the clinical outcome in newly diagnosed adult CML patients treated frontline with nilotinib (NIL). Methods. An analysis of 345 CML patients in early chronic phase (ECP) enrolled within 3 multicentric prospective studies of the GIMEMA CML Working Party (ClinicalTrials.gov NCT00481052, NCT00769327, NCT01535391) was performed. The initial treatment was NIL 300 mg BID or NIL 400 mg BID. Definitions: major molecular response (MMR), BCR-ABL1IS ratio 10,000 ABL1 copies; progression, transformation to advanced phases; death, at any time and for any reason. Cumulative incidences of response were estimated under consideration of competing risks (progression, death) and compared by Gray test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank test. Results. Seven patients expressing rare transcripts (e1a2 or e19a2) and 10 patients with unknown transcript type were excluded: 328 out of 345 patients were evaluable, 124 (38%) with e13a2 transcript, 174 (53%) with e14a2 transcript and 30 (9%) expressing both transcripts. The baseline characteristics of patients with e13a2 or e14a2 transcripts were comparable: no significant differences in age, gender, Sokal or EUTOS long-term survival score distribution, presence of clonal chromosomal abnormalities in Ph+ cells, NIL dose were observed; the only difference was a higher platelet count in patients with e14a2 transcript (median 374 vs 313 x 103/µl, p=0.006). The median follow-up was 60 months in both groups (range 24-82 months). The response rates and the survival probabilities were uniformly lower in patients with e13a2 transcript (N=124) compared to patients with e14a2 transcript (N=174), but the differences were not significant: MMR by 12 months, 66% vs 72%, p=0.244; MR4.0 by 36 months, 56% vs 66%, p=0.067; estimated cumulative incidence of MMR, 82% vs 88%, p=0.135; estimated cumulative incidence of MR4.0, 60% vs 69%, p=0.101; estimated PFS, 88% vs 93%, p=0.547; estimated OS, 89% vs 94%, p=0.436 (Figure 1). The responses and the survival probabilities of patients co-expressing the e13a2 and the e14a2 transcripts (N=30) were similar to or even better than the ones of e14a2 patients. Grouping together the patients with e14a2 transcript alone and the patients with co-expression of both transcripts (N=174+30=204), and comparing them to patients with e13a2 transcript alone (N=124), the response differences became significant (cumulative incidence of MMR and MR4.0, p=0.050 and p=0.036, respectively), but no outcome differences emerged (PFS and OS, p=0.340 and p=0.276, respectively). Conclusions. Despite a trend for lower response rates and inferior outcome in patients with e13a2 transcript, the observed differences were small and mostly not significant. Further studies in larger patient cohorts are required to clarify whether nilotinib and other second generation TKIs are able to overcome the adverse prognostic impact of transcript type, potentially affecting the speed and the depth of molecular response, the probability of achieving a treatment-free remission and the patient outcome

Nilotinib 300 mg twice daily: An academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients

The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier:01535391)

Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use

Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use