Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR–ABL inhibitors as first-line therapy

Background: Research has shown that treatment interruptions are associated with worse failure-free survival in chronic myeloid leukemia (CML); however they are commonly used in clinical trials to manage adverse events. Objectives: This study assessed the comparative rates of treatment interruption and regimen change between patients initiating first-line therapy with a first-generation tyrosine kinase inhibitor (1GTKI) imatinib versus second-generation TKI (2GTKI), dasatinib or nilotinib, for the treatment of CML in clinical practice. Methods: This was a retrospective cohort study using the Humana Research Database. Patients with CML who were between the ages of 18 and 89 and newly initiated 1GTKI or 2GTKI therapy between June 1, 2010 and December 31, 2011 were included. Treatment interruption and regimen change were compared using multivariable Cox proportional hazard regression models. Treatment interruption was defined as a gap in any TKI pharmacy claim that was longer than an allowable refill gap plus days’ supply from the previous TKI medication claim. Regimen change was defined as 1) a prescription claim for a different TKI therapy, or 2) increase in dose for the same medication. Results: 368 patients met the inclusion criteria: 1GTKI n=237, 2GTKI n=131. Patients initiating therapy with a 2GTKI had a 48% higher risk of treatment interruption versus patients initiating therapy with a 1GTKI (hazard ratio=1.48, 95% confidence interval 1.08-2.02). The time to treatment interruption was significantly longer in patients initiating therapy with a 1GTKI. Approximately 19% of patients had a regimen change, but there were no differences in rates of regimen changes between the two generations. Conclusions: In this study from a large single health plan population, treatment interruptions were more common among patients initiating therapy with a 2GTKI, yet regimen change rates did not vary by generation of TKI. Future research should assess reasons for treatment interruption and investigate these associations in other populations.

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Treatment patterns and healthcare costs among newly-diagnosed patients with chronic myeloid leukemia receiving dasatinib or nilotinib as first-line therapy in the United States

Journal of Medical Economics ◽

10.1080/13696998.2016.1225578 ◽

2016 ◽

Vol 20 (1) ◽

pp. 63-71 ◽

Cited By ~ 3

Author(s):

Dominick Latremouille-Viau ◽

Annie Guerin ◽

Roy Nitulescu ◽

Patrick S. Gagnon ◽

George J. Joseph ◽

...

Keyword(s):

United States ◽

Chronic Myeloid Leukemia ◽

Healthcare Costs ◽

Myeloid Leukemia ◽

The United States ◽

Treatment Patterns ◽

Newly Diagnosed ◽

First Line ◽

First Line Therapy ◽

Line Therapy

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Outcome After Failure of Second Generation Tyrosine Kinase Inhibitors Treatment As First-line Therapy for Patients With Chronic Myeloid Leukemia

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2013.02.025 ◽

2013 ◽

Vol 13 (4) ◽

pp. 477-484 ◽

Cited By ~ 14

Author(s):

Alireza Eghtedar ◽

Hagop Kantarjian ◽

Elias Jabbour ◽

Susan O'Brien ◽

Elizabeth Burton ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Second Generation ◽

Kinase Inhibitors ◽

First Line ◽

First Line Therapy ◽

Line Therapy

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Nilotinib as the First Line Therapy in Managing Chronic Myelogenous Leukemia

e-CliniC ◽

10.35790/ecl.v9i2.32699 ◽

2021 ◽

Vol 9 (2) ◽

pp. 342

Author(s):

Yuswanto Setyawan

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Myelogenous Leukemia ◽

Newly Diagnosed ◽

First Line ◽

Hematopoietic Stem ◽

First Line Therapy ◽

Line Therapy ◽

Imatinib Resistant

Abstrak: Leukemia mieloid kronis (chronic myeloid leukemia/CML) adalah penyakit klonal dari sel induk hematopoietik, secara sitogenetik ditandai dengan adanya kromosom Philadelphia (t[9,22][q34;q11]), yang merupakan fusi BCR-ABL1 onkogen. Nilotinib, generasi kedua inhibitor kinase tirosin, merupakan turunan aminopirimidin yang menghambat aktivitas kinase tirosin protein BCR-ABL. Dengan aktivitas penghambatan yang 10-60 kali lebih besar daripada imatinib, pada terapi lini pertama standar untuk CML, nilotinib efektif untuk CML fase kronik dan akselerasi yang resisten terhadap imatinib, namun terapi kombinasi nilotinib dengan agen lainnya masih diperlukan untuk pasien dengan CML krisis blas. Nilotinib aktif terhadap beberapa mutan BCR-ABL yang resisten terhadap imatinib, kecuali mutan T315I. Mutasi spesifik E255K/V, Y253H/F, F359C/V, dan L248V umumnya kurang sensitif terhadap nilotinib. Sebagai terapi lini pertama pada pasien CML fase kronik dengan Ph+ yang baru terdiagnosis, nilotinib menunjukkan CCyR dan MMR yang lebih tinggi serta pengembangan menjadi fase akselerasi/krisis blas serta resiko kematian yang lebih rendah, bila dibandingkan dengan imatinib. Simpulan penelitian ini ialah nilotinib lebih unggul dibandingkan dengan imatinib sebagai terapi lini pertama pada pasien CML fase kronik dengan Ph+ yang baru terdiagnosis,Kata kunci: chronic myeloid leukemia (CML), nilotinib, imatinib, terapi lini pertama Abstract: Chronic myeloid leukemia (CML) is a clonal disease of the hematopoietic stem cells, cytogenetically characterized by Philadelphia chromosome (t[9,22][q34;q11]) leading to the fusion of BCR-ABL1 oncogene. Nilotinib, the second-generation tyrosine kinase inhibitor (TKI), is an aminopyrimidine derivative that inhibits the tyrosine kinase activity of the chimeric protein BCR-ABL. Its inhibitory activity is 10-60 times that of imatinib, therefore, as the standard first-line therapy for CML, nilotinib is effective in the case of CML-CP and CML-AP with imatinib resistant or intolerant. Albeit, novel approaches with nilotinib-based combinations are required for patients in CML-BP. Nilotinib is active against several imatinib-resistant BCR-ABL mutants with the exception of T315I. Specific mutations that are less sensitive to nilotinib include E255K/V, Y253H/F, F359C/V, and L248V. As the first-line therapy of patients with newly diagnosed Ph+ CML-CP, nilotinib has higher rates of CCyR and MMR, lower rates of progression to AP or BC, and lower risk of CML related death when compared with imatinib. In conclusion, nilotinib is superior to imatinib as the the first-line therapeutic option in newly diagnosed Ph+ CML-CP patients.Keywords: chronic myeloid leukemia (CML), nilotinib, imatinib, first line therapy

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Clinical Outcome of Chronic Myeloid Leukemia Patients who Switch from First-line Therapy with a Second Generation Tyrosine Kinase Inhibitor to an Alternative TKI

Leukemia Research ◽

10.1016/j.leukres.2021.106674 ◽

2021 ◽

pp. 106674

Author(s):

Chen-En Ma ◽

Sunita Ghosh ◽

Catherine Leyshon ◽

Nikki Blosser ◽

Deonne Dersch-Mills ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Outcome ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Second Generation ◽

Kinase Inhibitor ◽

First Line ◽

First Line Therapy ◽

Line Therapy

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Clonal chromosomal abnormalities in Philadelphia-negative cells in chronic myeloid leukemia patients treated with nilotinib used in first-line therapy

Annals of Hematology ◽

10.1007/s00277-013-1816-z ◽

2013 ◽

Vol 92 (12) ◽

pp. 1625-1632 ◽

Cited By ~ 6

Author(s):

Huafeng Wang ◽

Jie Jin ◽

Yungui Wang ◽

Xin Huang ◽

Jian Huang

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

First Line ◽

First Line Therapy ◽

Line Therapy

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Medical decision analysis for first-line therapy of chronic myeloid leukemia

Leukemia & Lymphoma ◽

10.3109/10428194.2013.858149 ◽

2014 ◽

Vol 55 (8) ◽

pp. 1758-1767 ◽

Cited By ~ 3

Author(s):

Ursula Rochau ◽

Gaby Sroczynski ◽

Dominik Wolf ◽

Stefan Schmidt ◽

Annette Conrads-Frank ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Decision Analysis ◽

Myeloid Leukemia ◽

Medical Decision ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Medical Decision Analysis

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Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia

Hematology Reports ◽

10.4081/hr.2018.7474 ◽

2018 ◽

Vol 10 (3) ◽

Cited By ~ 1

Author(s):

Aya Nakaya ◽

Shinya Fujita ◽

Atsushi Satake ◽

Takahisa Nakanishi ◽

Yoshiko Azuma ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Features ◽

Myeloid Leukemia ◽

De Novo ◽

Late Onset ◽

Molecular Response ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Treatment Agent

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

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Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7007 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7007-7007

Author(s):

Jessica K. Altman ◽

Jamie Koprivnikar ◽

James K. McCloskey ◽

Vamsi Kota ◽

Olga Frankfurt ◽

...

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

Single Agent ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

First Line ◽

Standard Chemotherapy ◽

First Line Therapy ◽

Line Therapy ◽

De Novo Aml

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade > 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

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