Disease overview
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1‐2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of ...leukemia in adults.
Diagnosis
CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL1 fusion oncogene, which in turn translates into a BCR‐ABL oncoprotein.
Frontline therapy
Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first‐line treatment of newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses, but they had no impact on survival prolongation, likely because of the existence of highly effective salvage therapies for patients who have a cytogenetic relapse with frontline TKI.
Salvage Therapy
For CML post failure on frontline therapy, second‐line options include second and third generation TKIs. Although potent and selective, these exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patientsʼ comorbidities, disease stage, and BCR‐ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Even among older patients who have a cytogenetic relapse post failure on all TKIs, they can maintain long‐term survival if they continue on a daily most effective/less toxic TKI, with or without the addition of non‐TKI anti‐CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).
Disease overview
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1‐2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of ...leukemia in adults.
Diagnosis
CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL1 fusion oncogene, which in turn translates into a BCR‐ABL1 oncoprotein.
Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first‐line treatment of patients with newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long‐term survival, because of the availability of effective salvage therapies.
Salvage therapy: For patients who fail frontline therapy, second‐line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR‐ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.
Disease Overview
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of ...leukemia in adults.
Diagnosis
CML is characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.
Frontline Therapy
Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib are approved by the United States Food and Drug Administration for first‐line treatment of newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy.
Salvage Therapy
For CML post failure on frontline therapy, second‐line options include second and third generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP and failure (due to resistance) of at least two TKIs, and for all patients in advanced phase disease. Older patients who have a cytogenetic relapse post failure on all TKIs can maintain long‐term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non‐TKI anti‐CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan and others).
Conventional cytotoxic chemotherapy used to treat acute lymphoblastic leukemia (ALL) results in high cure rates in pediatric patients but is suboptimal in the treatment of adult patients. The 5-year ...overall survival is approximately 90% in children and 30% to 40% in adults and elderly patients. Adults with ALL tend to have higher risk factors at diagnosis, more comorbidities, and increasing age that often requires dose reductions. Major advancements have been made in redefining the pathologic classification of ALL, identifying new cytogenetic-molecular abnormalities, and developing novel targeted agents in order to improve survival. The addition of new monoclonal antibodies and tyrosine kinase inhibitors to conventional chemotherapy in the frontline setting has resulted in increased rates of complete remission and overall survival. These new developments are changing the treatment of adult ALL from a "one therapy fits all" approach to individualized treatment based on patient's cytogenetic and molecular profile.
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with a bimodal distribution. The progresses made in understanding its biology led to the development of targeted therapies. In this ...review, we summarize the current and future approaches in management of adult ALL. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20, and CD22), bispecific antibodies, and chimeric antigen receptor (CAR)-T therapy are breakthrough treatments. They resulted in FDA approvals of blinatumomab in 2014, inotuzumab ozagamicin in 2017, and tisagenlecleucel in 2017 for relapsed/refractory ALL. Currently, long-term survival is achieved in more than 50% of patients with precursor B-ALL (50-70% in patients with Philadelphia chromosome (Ph)-positive ALL), 50-60% T-ALL, and 80% mature B-ALL. Ongoing efforts exist to optimize therapeutic options in both the relapsed/refractory as well as the frontline settings. In the era of precision medicine, the future lies in using less cytotoxic and more targeted agents.
The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point ...mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.
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