scholarly journals Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 121-127 ◽  
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rapid Development ◽  
Chronic Phase ◽  
The United States ◽  
Medical Needs ◽  
Treatment Naïve

Abstract The 21st century ushered in the dawn of a new era of targeted therapeutics and a dramatic shift in the management of chronic-phase chronic myeloid leukemia (CP-CML) patients. Groundbreaking scientific and translational studies have led to the rapid development and approval of several effective BCR-ABL tyrosine kinase inhibitors (TKIs). In the United States, there are currently 3 approved BCR-ABL TKIs for newly diagnosed CP-CML patients. It is anticipated that clinical outcomes will continue to improve as more TKIs that address unmet medical needs are approved. However, to achieve this goal, it is critical to carefully monitor and optimally manage patients. To this end, the latest seminal clinical trial results of approved and investigational BCR-ABL TKIs and some of the salient unique features of each of these agents are summarized herein.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

scholarly journals Contemporary practice patterns of tyrosine kinase inhibitor use among older patients with chronic myeloid leukemia in the United States

2021 ◽  
Vol 12 ◽  
pp. 204062072110434
Author(s):  
Rory M. Shallis ◽  
Rong Wang ◽  
Jan P. Bewersdorf ◽  
Amer M. Zeidan ◽  
Amy J. Davidoff ◽  
...  
Keyword(s):  
United States ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Disease Risk ◽  
Chronic Phase ◽  
The United States ◽  
Specific Patient

Introduction: The choice of BCR-ABL1 tyrosine kinase inhibitors (TKI) for the first line of therapy (LOT) for chronic-phase chronic myeloid leukemia (CML) is tailored to disease risk and patient characteristics like comorbidities, which become more prevalent with age. However, contemporary evaluations of frontline TKI choice and the factors associated with TKI switching in this specific patient population are lacking. Methods: We sought to describe TKI use in older patients (age: 66–99 years) with CML in the United States. Using the Surveillance, Epidemiology, and End Results–Medicare-linked database, we identified 810 older (median age: 75 years, interquartile range: 70–80 years) patients diagnosed during 2007–2015. Results: Imatinib was the most common frontline TKI (63.1%) throughout the study period, but its utilization as such decreased from 76% in 2010 to 47% in 2015. Most patients (65.3%) used only one TKI, but 12.5% of the 281 patients who switched from frontline TKI received ⩾4 LOT. Among the 167 patients switching from frontline imatinib, 18.6% eventually returned to imatinib with nearly all as the third LOT, supporting its favorable safety profile and indicating that the initial switch from imatinib might have been premature. Older patients within our cohort, white patients and those with greater comorbidity were less likely to switch from frontline TKI. Diagnosis year, geographic region, and surrogates for socioeconomic status and healthcare access had no impact on TKI switching. Conclusion: As expected, our findings highlight the frequent use of imatinib as the treatment option for older CML patients despite the availability of second-generation TKIs.

scholarly journals Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4839-4842 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Neeli Reddy ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Disease Stage ◽  
Kinase Domain Mutation

Abstract Mutations in codon 317 after treatment with imatinib and dasatinib have been reported. We reviewed patients with chronic myeloid leukemia and mutations after tyrosine kinase inhibitor (TKI) therapy. F317L was detected in 20, including 12/99 (12%) with mutation after imatinib failure, and 8/16 (50%) after dasatinib (P = .001). Median follow-up from mutation detection was 25 months. At the time of F317L, 8 patients were in chronic phase (CP), 6 in accelerated phase, and 6 in blast phase. There was no difference in characteristics between patients with or without F317L mutations, or with no mutations. A complete cytogenetic response was acheived in 3 of 6 patients treated with nilotinib, 2 of 2 with imatinib, and 0 of 3 with dasatinib. Survival of patients with F317L was similar to those with other mutations (P = .45). Patients in CP had better outcome, with a 2-year survival of 75%. F317L mutation is resistant to dasatinib but sensitive to other TKIs. The prognosis is dependent mostly on the disease stage.

scholarly journals Complications of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia - Chronic Phase

2019 ◽  
Vol 70 (8) ◽  
pp. 3017-3020
Author(s):  
Despina Calamar Popovici ◽  
Ioana Ionita ◽  
Mirela Nedelcu ◽  
Claudiu Ionita ◽  
Hortensia Ionita ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Anthropometric Parameters ◽  
Tyrosine Kinase Inhibitor Therapy ◽  
Initiation Of Therapy

Chronic myeloid leukaemia is a malignant tumor of pluripotent haemopoetic stem cell, characterized by increase granulocytes with left shift and the presence of the Ph chromosome.Treatment of chronic phase is made with tyrosine kinase inhibitors administered orally and can have secondary effects: haematological and non-haematological. The purpose of this paper is to assess complications of tyrosine kinase inhibitor therapy in chronic phase of chronic myeloid leukemia and establishing correlations with the type of inhibitor used. The study was performed on a total of 140 patients diagnosed with chronic phase CML in the Hematology Department of the City Clinical Emergency Hospital Timisoara between January 2006 - January 2016. The lot proposed has been studied in terms of anthropometric parameters and also the haematological and biochemical. It showed complications after initiation of therapy with tyrosine kinase inhibitors and also the correlations statistically significant between complications and type of inhibitor used. The study reveals that regardless the type of inhibitor used both haematological complications arise and non haematological. The most common are: neutropenia, thrombocytopenia, anemia, fluid retention, muscle and joint pain. Less common are nausea, diarrhea, abdominal pain, increased liver enzymes. Despite complications of occurring, these modern therapies significantly improve both survival and quality of life of patients.

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2843-2853 ◽  
Author(s):  
Mhairi Copland ◽  
Francesca Pellicano ◽  
Linda Richmond ◽  
Elaine K. Allan ◽  
Ashley Hamilton ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematopoietic Stem

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML.

Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 176-183 ◽  
Author(s):  
Vivian G. Oehler
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Chronic Phase ◽  
Early Response ◽  
Molecular Responses ◽  
Patients At Risk

Abstract Excellent therapeutic options exist for the treatment of chronic-phase chronic myeloid leukemia (CML) patients. Therefore, managing CML patients has become a more common practice for many physicians. Most chronic-phase CML patients achieve durable cytogenetic and molecular responses on first-line tyrosine kinase inhibitor therapy. However, careful monitoring and assessment of adherence are essential for successful outcomes and to identify patients at risk for failing therapy. The European LeukemiaNet and National Comprehensive Cancer Network provide guidance and strategies for monitoring and managing patients treated with TKIs. These recommendations continue to evolve as approved treatment options expand to include second- and third-generation tyrosine kinase inhibitors. How measurements of response are defined and data supporting recent recommended changes to monitoring are reviewed here. These changes include increasing recognition of the importance of early response. The relevance of achieving deep molecular responses will also be addressed.

Patient-Reported Functional Outcomes in Patients with Chronic Myeloid Leukemia after Stopping Tyrosine Kinase Inhibitors

2021 ◽  
Author(s):  
Kelly L Schoenbeck ◽  
Ehab Atallah ◽  
Li Lin ◽  
Kevin P Weinfurt ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Functional Outcomes ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Patient Reported Outcome Measures ◽  
Patient Reported Outcome ◽  
Patient Reported

Abstract Treatment-free remission (TFR) is a goal for patients with chronic myeloid leukemia (CML). Functional outcomes after discontinuing Tyrosine Kinase Inhibitor (TKI) treatment have not been described. PROMIS patient-reported outcome measures (PROMs) of social, physical, cognitive, and sexual function were assessed over 36 months in 172 adult patients with chronic phase CML from 14 sites at baseline (on TKI) and after discontinuation. Linear mixed-effects models described the average trajectories for each PROM after discontinuation and in those who restarted TKI. Of 112 patients in TFR at 12 months, 103 (92.0%) had a ≥ 3-point improvement in social function, 80 (71.4%) in social isolation, 11 (9.8%) in satisfaction with sex life, 4 (3.6%) in physical function, and no patients had a ≥ 3-point improvement in cognitive function or interest in sexual activity. Patients’ scores worsened after restarting TKI. This novel information on functional outcomes in TFR can help guide patient and clinician decision-making.

scholarly journals Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors.

2013 ◽  
Vol 60 (4) ◽  
Author(s):  
Katarzyna Danisz ◽  
Janusz Blasiak
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Chronic Phase

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

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