abt-199 and midostaurin

Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered "unfit" for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3-4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.

Topics: Antineoplastic Agents; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Drug Approval; Gemtuzumab; Glycine; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Pyridines; Randomized Controlled Trials as Topic; Staurosporine; Sulfonamides; United States; United States Food and Drug Administration

Acute myeloid leukemia (AML) is primarily a disease of older adults. Many older patients with AML are not candidates for intensive chemotherapy regimens aimed at inducing remission before transplantation. The prognosis for this patient population remains poor, with 5-year overall survival (OS) rates of less than 10 %. At present, there is no standard of care, and clinical trials should be considered. Hypomethylating agents often are the mainstay of treatment in this setting; however, improved genetic profiling and risk stratification based on molecular, biological, and clinical characteristics of AML enhance the ability to identify an individual patient's risk and can refine therapeutic options. Over the past 2 years, several novel agents have been approved for AML patients in either the frontline or relapsed settings. Additional agents have also shown promising activity. It is becoming a challenge for physicians to navigate these different options and select the optimal therapy or combination of therapies. The aim of this review is to summarize the available information to assist with treatment decisions for leukemia patients who are not suitable for intensive chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Decitabine; Gemtuzumab; Glycine; Humans; Leukemia, Myeloid, Acute; Male; Molecular Targeted Therapy; Phenylurea Compounds; Precision Medicine; Pyridines; Recurrence; Remission Induction; Staurosporine; Sulfonamides

Topics: Aged; Allografts; Anemia, Refractory, with Excess of Blasts; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Cytarabine; Daunorubicin; Fatal Outcome; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm, Residual; Neoplasms, Radiation-Induced; Oncogene Proteins, Fusion; Peripheral Blood Stem Cell Transplantation; Point Mutation; Protein Kinase Inhibitors; Pyrazines; Remission Induction; Salvage Therapy; Staurosporine; Sulfonamides

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

Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.

Topics: Antineoplastic Agents; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytochrome P-450 CYP3A Inhibitors; Drug Approval; Drug Interactions; Drugs, Investigational; Humans; Leukemia, Myeloid, Acute; Long QT Syndrome; Phenylurea Compounds; Protein Kinase Inhibitors; Staurosporine; Sulfonamides

Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely benefit from treatment. Based on randomized trials CPX 351, midostaurin, gemtuzumab ozogamicin, and venetoclax, the latter three when combined with other drugs, should now be considered standard therapy. Knowledge of the likely results with these therapies is essential in deciding whether to recommend them or participate in a clinical trial, possibly including these drugs. Hence here, in the context of established prognostic algorithms, we review results with the recently- approved drugs compared with their predecessors and describe other potential options. We discuss benefit/risk ratios underlying the decision to offer allogeneic transplant and emphasize the importance of measurable residual disease. When first seeing a newly-diagnosed patient physicians must decide whether to offer conventional treatment or investigational therapy, the latter preferably in the context of a clinical trial. As noted below, such trials have led to changes in what today is considered "conventional" therapy compared to even 1-2 years ago. In older patients decision making has often included inquiring whether specific anti-AML therapy should be offered at all, rather than focusing on a purely palliative approach emphasizing transfusion and antibiotic support, with involvement of a palliative care specialist.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Gemtuzumab; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Risk Assessment; Staurosporine; Sulfonamides; United States

Acute myeloid leukemia (AML) is characterized by a malignant transformation and proliferation of myeloid progenitor cells that cause a replacement of normal hematopoiesis. Diagnostic workup for AML includes cytogenetic analysis and mutational screening covering frequently mutated genes in AML. The genetic analysis is required for risk stratification and treatment decisions. Very recently, three novel drugs have been approved for patients who can be intensively treated: a tyrosine kinase inhibitor (midostaurin) for patients with FLT3 mutations, a liposomal formulation of chemotherapy (CPX) for patients with features of secondary AML, and a CD33 antibody-drug conjugate (gemtuzumab-ozogamicin) for AML with CD33 expression. Allogeneic stem cell transplantation remains an important treatment strategy for patients with intermediate- or high-risk AML and for patients with relapsed AML. For elderly patients who cannot undergo intensive treatment, demethylating agents are the treatment of choice. The aim is to prolong life expectancy with acceptable quality of life. In recent clinical trials, novel drugs have shown promising results in this patient population. Some of these drugs have already been approved in the US. Among these drugs are the Bcl‑2 inhibitor venetoclax, which is already approved in Germany for chronic lymphatic leukemia, as well as IDH1/IDH2 inhibitors (the latter for patients with IDH1/IDH2 mutated AML). Acute promyelocytic leukemia represents a special type of AML that should be treated with a combination of all-trans retinoic acid and arsenic trioxide leading to excellent outcome.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Germany; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Quality of Life; Staurosporine; Sulfonamides

In 2017, 4 drugs received US Food and Drug Administration marketing approval for acute myeloid leukemia (AML) treatment: targeted therapies for mutant

Topics: Aminoglycosides; Aminopyridines; Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cytarabine; Daunorubicin; fms-Like Tyrosine Kinase 3; Gemtuzumab; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Liposomes; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins c-bcl-2; Sialic Acid Binding Ig-like Lectin 3; Staurosporine; Sulfonamides; Treatment Outcome; Triazines

The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

Topics: Actin Cytoskeleton; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Mutation; Proto-Oncogene Proteins c-bcl-2; Pyrones; Quinolines; rac1 GTP-Binding Protein; Staurosporine; Sulfonamides

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

Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; CRISPR-Cas Systems; Female; fms-Like Tyrosine Kinase 3; Gene Knockout Techniques; Genetic Therapy; Humans; Leukemia, Myeloid, Acute; Mice, SCID; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Staurosporine; Sulfonamides

To investigate the efficacy of the combination of the FLT3 inhibitors midostaurin or gilteritinib with the Bcl-2 inhibitor venetoclax in FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) and the underlying molecular mechanism.. Using both FLT3-ITD cell lines and primary patient samples, Annexin V-FITC/propidium iodide staining and flow cytometry analysis were used to quantify cell death induced by midostaurin or gilteritinib, alone or in combination with venetoclax. Western blot analysis was performed to assess changes in protein expression levels of members of the JAK/STAT, MAPK/ERK, and PI3K/AKT pathways, and members of the Bcl-2 family of proteins. The MV4-11-derived xenograft mouse model was used to assess. The combination of midostaurin or gilteritinib with venetoclax potently and synergistically induces apoptosis in FLT3-ITD AML cell lines and primary patient samples. The FLT3 inhibitors induced downregulation of Mcl-1, enhancing venetoclax activity. Phosphorylated-ERK expression is induced by venetoclax but abolished by the combination of venetoclax with midostaurin or gilteritinib. Simultaneous downregulation of Mcl-1 by midostaurin or gilteritinib and inhibition of Bcl-2 by venetoclax results in "free" Bim, leading to synergistic induction of apoptosis.. Inhibition of Bcl-2 via venetoclax synergistically enhances the efficacy of midostaurin and gilteritinib in FLT3-mutated AML.

Topics: Aniline Compounds; Animals; Apoptosis; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; fms-Like Tyrosine Kinase 3; Gene Duplication; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Mice; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Staurosporine; Sulfonamides; Xenograft Model Antitumor Assays