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In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients’ long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR 4.5 ; BCR-ABL ⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

The treatment of chronic myeloid leukemia (CML) achieved a great leap forward with the development of imatinib, a BCR-ABL kinase inhibitor. Alterations in the chemical structure of the inhibitor have produced agents that are more potent in vitro. In these studies, two new second-generation BCR-ABL kinase inhibitors, nilotinib and dasatinib, are compared with imatinib; these new drugs produce more complete responses and do so faster than imatinib. Both also appear to reduce the rate of progression to accelerated-phase and blast-phase disease. The use of the BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals) improved outcomes for patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML) and established BCR-ABL–targeted therapy as the standard of care for this disease. In the International Randomized Study of Interferon and STI571 (IRIS; ClinicalTrials.gov number, NCT00006343), imatinib was associated with a superior response rate and improved progression-free survival, as compared with the previous standard therapy, interferon alfa plus low-dose cytarabine. 1 – 3 Eight-year follow-up of IRIS revealed that responses to imatinib were durable and had an acceptable adverse-event profile, with an estimated rate of overall survival of 85%. . . .

In this study, adding pegylated interferon alfa-2a to imatinib therapy for chronic myeloid leukemia resulted in a greater reduction in the number of cells bearing BCR-ABL in a higher fraction of patients than did imatinib alone. However, pegylated interferon alfa-2a also has toxic effects. Chronic myeloid leukemia (CML) is characterized by translocation t(9;22)(q34;q11) — which causes the Philadelphia chromosome — on which a BCR-ABL fusion gene codes for a protein with constitutive tyrosine kinase activity. 1 – 3 Imatinib, a rationally designed tyrosine kinase inhibitor, has shown activity against leukemic cells in vitro and in vivo. 4 , 5 On the basis of the results of the large phase 3 International Randomized Study of Interferon and STI571 (IRIS; ClinicalTrials.gov number, NCT00006343), imatinib is recommended as first-line therapy. 6 , 7 However, in some patients, the response to imatinib is not optimal and the risk of blast crisis is increased. 8 The . . .

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib ( n =259) or imatinib ( n =260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n =17; imatinib, n =18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

The treatment of chronic myeloid leukemia (CML) achieved a great leap forward with the development of imatinib, a BCR-ABL kinase inhibitor. Alterations in the chemical structure of the inhibitor have produced agents that are more potent in vitro. In these studies, two new second-generation BCR-ABL kinase inhibitors, nilotinib and dasatinib, are compared with imatinib; these new drugs produce more complete responses and do so faster than imatinib. Both also appear to reduce the rate of progression to accelerated-phase and blast-phase disease. Chronic myeloid leukemia (CML) in the chronic phase, a clonal myeloproliferative disorder, is caused by the constitutively active BCR-ABL tyrosine kinase resulting from the translocation that produces the Philadelphia (Ph) chromosome. 1 , 2 Imatinib (Gleevec, Novartis Pharmaceuticals), an inhibitor of the BCR-ABL kinase, is the standard first-line therapy for patients with chronic-phase CML. 3 – 6 Dasatinib (Sprycel, Bristol-Myers Squibb), a second-generation BCR-ABL kinase inhibitor, has been approved as a second-line treatment for patients with CML if imatinib therapy fails. 4 – 7 Dasatinib therapy induces a complete cytogenetic response in approximately 50% of patients who do not have a response to imatinib or cannot . . .

BackgroundIn the phase 3 BFORE trial (NCT02130557), treatment with bosutinib resulted in a significantly higher major molecular response rate at 12 months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective.MethodsPatients with newly diagnosed CP CML were randomized 1:1 to receive once-daily bosutinib 400 mg or imatinib 400 mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (bosutinib: n = 246; imatinib: n = 241).ResultsMean FACT-Leu combined and subscale scores were similar at baseline in the bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with bosutinib and imatinib at month 12.ConclusionsSimilar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with bosutinib.

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

Purpose We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase. Methods Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models. Results Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months. Conclusions There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1 IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.

Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib’s efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome—overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)—were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3–85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3–51), 18 months (3–72), and 24 months (3–100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.