gilteritinib and enasidenib

Among elderly patients with acute myeloid leukemia (AML), especially those who are unfit for intensive chemotherapy, a policy of reduced-intensity chemotherapy or conservative observation has been chosen, resulting in unmet medical needs. Clinical trials using anticancer drugs including antimetabolites or drugs targeted to cell cycle-related molecules failed to show superiority over conventional treatments. Recently, drugs targeted to Bcl-2, SMO, FLT3, and IDH1/2 have been shown to prolong overall survival alone or in combination with reduced-intensity chemotherapy. These treatments are likely to reshape the therapeutic landscape of AML, which will be personalized for individual patients based on leukemia genetics.

Topics: Aged; Aged, 80 and over; Aminopyridines; Aniline Compounds; Antineoplastic Agents; Arsenic Trioxide; Azacitidine; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; fms-Like Tyrosine Kinase 3; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Phenylurea Compounds; Precision Medicine; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Smoothened Receptor; Staurosporine; Sulfonamides; Survival Rate; Tretinoin; Triazines

The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively; CPX-351 (liposomal cytarabine and daunorubicin) for therapy-related AML and AML with myelodysplasia-related changes; gemtuzumab ozogamicin (anti-CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33-positive AML; enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively. Novel therapies have also emerged for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. These include venetoclax (BCL-2 inhibitor) in combination with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine (LDAC), and glasdegib (sonic hedgehog pathway inhibitor) in combination with LDAC. This flurry of new drug approvals has markedly altered the treatment landscape in AML and provided new opportunities, as well as new challenges for treating clinicians. This review will focus on how these drugs might shape clinical practice and the hurdles likely to be faced by new therapies seeking entry into this dynamic and rapidly changing therapeutic landscape.

Topics: Aminopyridines; Aniline Compounds; Cytarabine; Daunorubicin; fms-Like Tyrosine Kinase 3; Gemtuzumab; Glycine; Humans; Leukemia, Myeloid, Acute; Pyrazines; Pyridines; Staurosporine; Triazines; United States; United States Food and Drug Administration

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.

Topics: Aminopyridines; Aniline Compounds; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Azacitidine; Cytogenetic Analysis; Decitabine; Enzyme Inhibitors; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Immunologic Factors; In Situ Hybridization, Fluorescence; Lenalidomide; Leukemia, Myeloid, Acute; Molecular Diagnostic Techniques; Neoplasm, Residual; Nivolumab; para-Aminobenzoates; Protein Kinase Inhibitors; Pyrazines; Pyrrolidines; Recombinant Fusion Proteins; Remission Induction; Transplantation, Homologous; Triazines; Triazoles

The development and approval of novel substances have resulted in substantial improvements in the treatment of acute myeloid leukemia (AML). In the current era of novel treatment options, genetic and molecular testing at the time of diagnosis and relapse becomes increasingly relevant. Midostaurin in combination with intensive chemotherapy is the standard of care as upfront therapy in younger AML patients with mutated fms-related tyrosine kinase 3 (FLT3). Gilteritinib, a second- generation FLT3 inhibitor, represents a key drug for relapsed/refractory (R/R) FLT3-mutated AML patients. Targeted therapy has also been developed for patients with mutated isocitrate dehydrogenase 1 (IDH1) and IDH2. The US Food and Drug Administration (FDA) approved ivosidenib as a monotherapy for newly diagnosed older adult IDH1-mutated patients and enasidenib for R/R IDH2-mutated AML patients. CPX-351, a liposomal formulation of daunorubicin and cytarabine, has become an important upfront treatment strategy for fit patients with therapy-related AML or AML with myelodysplasia-related changes that are generally challenging to treat. The antibody drug conjugate gemtuzumab ozogamicin was approved in combination with intensive therapy for patients with newly diagnosed (FDA/European Medicines Agency [EMA]) as well as R/R CD33+ AML. The combination of venetoclax, an oral selective B-cell leukemia/lymphoma-2 inhibitor, with hypomethylating agents or low-dose AraC (LDAC) has changed the treatment landscape and prognosis for older adult patients very favorably. The addition of glasdegib, a small-molecule hedgehog inhibitor, to LDAC is another example of novel options in older patients. Further substances have shown promising results in early clinical trials.

Topics: Aged; Aminopyridines; Aniline Compounds; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Approval; Drug Discovery; Glycine; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local; Pyrazines; Pyridines; Triazines

The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.

Topics: Adult; Aged; Aminopyridines; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Female; fms-Like Tyrosine Kinase 3; Glycine; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Male; Molecular Targeted Therapy; Mutation; Prognosis; Pyrazines; Pyridines; Sialic Acid Binding Ig-like Lectin 3; Staurosporine; Sulfonamides; Triazines

Topics: Aminoglycosides; Aminopyridines; Aniline Compounds; Antibodies, Monoclonal, Humanized; Drug Approval; fms-Like Tyrosine Kinase 3; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Mutation; Pyrazines; Staurosporine; Triazines