scholarly journals Lifelong TKI therapy: how to manage cardiovascular and other risks

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 113-121
Author(s):  
Michael J. Mauro
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Toxicity ◽  
New World ◽  
State Of The Art ◽  
Myeloproliferative Neoplasm ◽  
Targeted Agents ◽  
Maintenance Chemotherapy ◽  
Functional Cure ◽  
Highly Active ◽  
Treatment Free Remission

Abstract Beginning with imatinib and now spanning 6 oral, highly active, and mostly safe agents, the development of specific targeted therapy for patients with chronic myeloid leukemia (CML) has created a new world featuring chronic maintenance chemotherapy for all treated as such, treatment-free remission, and functional cure after prolonged deep remission in a subset. As a result comes a necessary shift in focus from acute to chronic toxicity, increasing attention to patient comorbidities, and critical thinking around specific adverse events such as metabolic, cardiovascular, and cardiopulmonary effects, which vary from agent to agent. This review aims to pull together the state of the art of managing the “C” in CML—a chronic myeloproliferative neoplasm treated at present over many years with oral BCR-ABL-targeted agents in a population whose overall health can be complex and potentially affected by disease and therapy—and determine how we can better manage a highly treatable and increasingly curable cancer.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

2021 ◽  
Vol 22 (15) ◽  
pp. 7806
Author(s):  
Maria Moschovi ◽  
Charikleia Kelaidi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematopoietic Cell Transplantation ◽  
Adult Life ◽  
Normal Growth ◽  
Molecular Response ◽  
Treatment Paradigm ◽  
Treatment Free Remission

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment-free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and adolescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long-term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation.

scholarly journals Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Mayumi Sugita ◽  
David C. Wilkes ◽  
Rohan Bareja ◽  
Kenneth W. Eng ◽  
Sarah Nataraj ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Myeloproliferative Neoplasm ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Target Engagement ◽  
Cell Level ◽  
Evaluation And Monitoring ◽  
Acute Myeloid

AbstractThe epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.

scholarly journals Treatment-Free Remission—A New Aim in the Treatment of Chronic Myeloid Leukemia

2021 ◽  
Vol 11 (8) ◽  
pp. 697
Author(s):  
Paulina Kwaśnik ◽  
Krzysztof Giannopoulos
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Immune Surveillance ◽  
Gene Transcript ◽  
Clinical Relapse ◽  
Eligibility Criteria ◽  
Treatment Free Remission ◽  
Next Generation Sequencing Ngs ◽  
Specific Symptoms

Tyrosine kinases inhibitors (TKIs) revolutionized chronic myeloid leukemia (CML) treatment for many years, prolonging patients’ life expectancy to be comparable to age-matched healthy individuals. According to the latest the European LeukemiaNet (ELN) recommendations, CML treatment aims to achieve long-term remission without treatment (TFR), which is feasible in more than 40% of patients. Nearly all molecular relapses occur during the first 6 months after TKI withdrawal and do not progress to clinical relapse. The mechanisms that are responsible for CML relapses remain unexplained. It is suggested that maintaining TFR is not directly related to the total disposing of the gene transcript BCR-ABL1, but it might be a result of the restoration of the immune surveillance in CML. The importance of the involvement of immunocompetent cells in the period of TKI withdrawal is also emphasized by the presence of specific symptoms in some patients with “withdrawal syndrome”. The goal of this review is to analyze data from studies regarding TFRs in order to characterize the elements of the immune system of patients that might prevent CML molecular relapse. The role of modern droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) in better identification of low levels of BCR-ABL1 transcripts was also taken into consideration for refining the eligibility criteria to stop TKI therapy.

Development of chronic myeloid leukemia in a patient previously diagnosed with a JAK2-positive myeloproliferative neoplasm

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sander De Bruyne ◽  
Eva Steel ◽  
Marjan Petrick ◽  
Barbara Denys ◽  
Karl Vandepoele ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm

Unique Case of Myeloproliferative Neoplasm with Two Rare Clonal Abnormalities: Rare JAK2 Exon 12 Mutation and Rare e14a3 (b3a3) BCR/ABL Fusion Transcript

2018 ◽  
Vol 141 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Mahesh Swaminathan ◽  
Keyur P. Patel ◽  
Julie Huynh-Lu ◽  
Guilin Tang ◽  
Zhuang Zuo ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Fusion Transcript ◽  
Insertion Mutation ◽  
Unique Case ◽  
Laboratory Features ◽  
Ph Chromosome ◽  
Disease Entities ◽  
Clonal Abnormalities

Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion-insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome.

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