Efficacy and safety of tyrosine kinase inhibitors (dasatinib, nilotinib) in the treatment of chronic phase chronic myeloid leukemia

Current treatment options for chronic myeloid leukemia (CML) with imatinib allowed achieving long-term progression-free and overall survival and improved patient quality of life. In cases of imatinib resistance therapy with second-generation tyrosine kinases inhibitors – dasatinib and nilotinib – is also possible. The article represents a literature review evaluating efficacy and toxicity of both drugs and highlighting some of the practical issues of CML treatment after first-line therapy failure.</p

Change of concentration of biochemical markers of dysfunction of endothelium at intake of inhibitors of tyrosinekinase of I and II generations at patients with a chronic myeloid leukemia as risk factor of development of cardiovascular complications

CML), the accepting inhibitors tyrosine of kinases (TKI) I and the II generations (TKI1 and TKI2 respectively), and development of arterial hypertension.Material and methods. Examination of 137 patients with CML in the chronic phase (CP) is conducted, the median of age — 47 years. 24 of them were with for the first time the verified diagnosis of CML and earlier did not accept TKI, they have made group of control. Other patients accepted TKI: 39 patients — imatinib 400 mg/day, 36 — dasatinib 100 mg/day, 38 — nilotinib 800 mg/day) more than 6 months. In biochemical analysis of blood indicators of lipidic range were defined. Level detection of ET-1 and VEGF was made by means of enzyme immunoassay. To all patients measurement of the heart rate (HR) and the arterial blood pressure (ABP) on both hands at an interval of 2 minutes from previous was once taken.Results. In group of patients from CML accepting nilotinib authentically significant increase in levels of systolic and diastolic ABP (р&lt;0,001) in comparison with group of control, with group of the patients accepting imatinib and dasatinib is noted. The most serious changes of lipidic range are noted at the patients accepting nilotinib. In all groups statistically significant increase in level of C-reactive protein, fibrinogen, homocysteine, endothelin-1 and VEGF in comparison with group of control is revealed. The most expressed changes are found in group of the patients accepting nilotinib, values of parameters of C-reactive protein, fibrinogen, homocysteine, endothelin-1 and VEGF are changed authentically (р&lt;0,001) and statistically significantly differ in comparison with group for the first time of the revealed patients with CML and groups of reception of imatinib and dazatinib.Conclusion. As a result of the conducted research endothelium variation of a function at patients from CML accepting TKI1 and TKI2 is revealed. The above-stated indicators can be used as additional diagnostic criteria for assessment of risk of development of arterial hypertension in patients with CML at reception of TKI

Quality of life, symptom profile and clinical efficacy of second-line treatment with dasatinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia: results of 2-year follow-up

The article is focused on the results of the multicenter observational study “Quality of life and symptom profile in patients with chronic myeloid leukemia in chronic phase in long-term follow-up of second-line treatment” (2012–2015). Thirty imatinib-resistant or-intolerant patients with chronic myeloid leukemia in chronic phase were observed in the real-world clinical setting during 24 months after start of second-line treatment with dasatinib. Mean age – 48 years old (SD = 13.1); males / females – 14 / 16; one third of patients were with comorbidity, Charlson Index – 0–5 scores. All the patients received dasatinib in the dosage of 100 mg daily. Study time points – 12, 18 and 24 months after second-line treatment start. Treatment outcomes were analyzed in terms of clinical efficacy and safety as well as in terms of patient-reported outcomes, including quality of life and symptom profile assessment. For quality of life and symptom assessment the SF-36 and CSP-CML questionnaires were used, respectively. Statisticallly significant changes in quality of life and symptom severity were analyzed by generalized estimated equation (GEE). Complete hematological response was observed in 96.3 % patients, complete cytogenetic response – in 66.6 % patients, complete or major molecular response – in 60 % patients. The acceptable tolerability of dasatinib treatment was shown during long-term follow-up: hematological and non-hematological serious adverse events were rare and didn’t lead to treatment discontinuation. Significant improvement of physical functioning, role physical functioning, role emotional functioning, vitality and mental health as compared to base-line parameters was observed (p &lt; 0.05). The severity of a number pronounced symptoms decreased and the proportion of patients with severe symptoms reduced (p = 0.01) after 24 months of second-line treatment start. Quality of life treatment response in terms of stabilization or improvement was registered in 83 % of patients. The data of this real-world study in CML patients are in line with the results of clinical studies in terms of dasatinib treatment efficacy and safety. In addition, they demonstrate the value of patient-reported outcomes to evaluate benefits and risks of long-term dasatinib treatment from patient perspective

CLINICAL AND LABORATORY FEATURES OF ESSENTIAL THROMBOCYTOSIS AND PRIMARY MYELOFIBROSIS DEPENDING ON JAK2 AND CALR1 MUTATION STATUS

Introduction. JAK2V617F mutation is detected in approximately 50 % of patients with essential thrombocytosis (ET) and primary myelofibrosis (PMF). In 2013 most of the JAK2 negative patients showed mutations in the CALR gene. Diagnostic value of JAK2 and CALR mutations is high, but their prognostic significance is not sufficiently clear. Data on impact of JAK2 and CALR mutational status on thrombotic complications in ET and myelofibrosis patients are contradictory.The aim of the study was to identify clinical and laboratory features in patients with ET and PMF in accordance with the mutational status of JAK2V617F and CALR gene.Materials and methods. Patients treated in Almazov National Medical Research Center (St. Petersburg), Chuvash Republican Clinical Hospital (Cheboksary), Irkutsk Regional Clinical Hospital (Irkutsk),  Kirov Research Institute of Hematology and Blood Transfusion (Kirov) was included in the retrospective study. CALR mutation (1 and 2 types), MPL W515L/K and JAK2V617F mutation were detected in peripheral blood cells.Results. We identified that 21 % (n = 16) of ET patients had thrombotic complications, and they occurred more often among JAK2V617F positive patients (p &lt;0.05). The median of hemoglobin level in PMF was the lowest in the group of triple negative patients. The level of leukocytes in PMF was higher in the group of triple negative patients than in the group with mutated CALR (p = 0.014).Conclusion. JAK2V617F mutation in ET patients was associated with a high risk of thrombosis. Patients with CALR mutations may have a favorable prognosis regarding to thrombotic complications. Some laboratory features of CALR mutations in ET and PMF patients have been revealed

CML-047 Post Hoc Analysis of Responses to Ponatinib in Patients With Chronic-Phase Chronic Myeloid Leukemia (CP-CML) by Baseline BCR::ABL1 Level and Baseline Mutation Status in the OPTIC Trial

International audienceObjectives: OPTIC (NCT02467270) is a Phase 2 trial evaluating the safety and efficacy of ponatinib in patients with CP-CML resistant to ≥2 TKIs or have a T315I mutation. We present a post hoc analysis of patient responses by baseline BCR::ABL1 level and mutation status. Methods: Patients with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg once daily. Doses were reduced to 15 mg after achievement of ≤1% BCR::ABL1IS in the 45-mg and 30-mg cohorts. The primary endpoint is ≤1% BCR::ABL1IS at 12 months. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline BCR::ABL1 level in the intent-to-treat (ITT) population. Results: 283 patients were randomized (45-mg/30-mg/15-mg cohorts: n=94/95/94). At baseline, 84.1% of patients had &gt;10% BCR::ABL1IS; 23.8% had T315I mutation. Subanalysis showed that patients with T315I mutations in the 45-mg cohort had the highest ≤1% BCR::ABL1IS response rates (60%) by 3 years versus other cohorts. Across cohorts, 97 patients without T315I mutations achieved ≤1% BCR::ABL1IS. Median duration of response (mDoR) for patients with a T315I mutation at baseline was 27 months in the 45-mg cohort (n=15) and 12 months in the 30-mg cohort (n=5). For patients without T315I mutations, the mDoR was not reached. Across cohorts, 79% of patients who achieved ≤1% BCR::ABL1IS maintained this response during the study. The most common nonhematologic treatment-emergent adverse events (TEAEs) and hematological TEAEs in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), lipase increase (17%), thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of patients experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE. Conclusions: The OPTIC post hoc analysis showed clinical benefit across dosing regimens regardless of T315I mutation status at baseline; the 45-mg cohort showed the highest response rates regardless of baseline BCR::ABL1IS levels. Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction upon achieving BCR::ABL1IS ≤1%. This abstract is an encore from the American Society of Hematology 2021 Annual Meeting

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial

International audienceIn PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270