abt-199 and glasdegib

Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population.. CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs. Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.

Topics: Animals; Antineoplastic Agents; Azacitidine; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Phenylurea Compounds; Prognosis; Sulfonamides

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

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

Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Quinuclidines; Sulfonamides

Acute myeloid leukaemia (AML) is a haematopoietic stem cell disorder, that is characterized by the clonal expansion of myeloid blasts and suppression of normal haematopoiesis. The 3 + 7 regimen is the backbone of standard first-line induction therapy among young/fit patients. However, in elderly and/or unfit patients with newly diagnosed AML, who cannot receive intensive chemotherapy, low-dose cytarabine or hypomethylating agents (azacitidine or decitabine) are the treatment options, which generally cannot induce durable responses. Among young/fit patients, for high-risk disease in first remission, or in cases with relapsed/refractory AML, allogeneic stem cell transplantation should be performed when complete remission is achieved. However, since AML is primarily a disease of the elderly, neither intensive chemotherapy nor allogeneic stem cell transplantation can be generally tolerated in most cases. There is clearly a need for new treatment options in elderly and young/unfit patients who cannot receive intensive chemotherapy. The discovery of novel molecular genetic markers (e.g. FMS-like tyrosine kinase 3, isocitrate dehydrogenase 1 and 2) resulted in the development of new therapeutic options in AML. This review mainly focuses on 4 targeted therapy agents; glasdegib and venetoclax used in combination treatment with low-dose cytarabine or hypomethylating agents among newly diagnosed cases with AML; and ivosidenib and gilteritinib as monotherapy in the treatment of relapsed/refractory AML, which were all approved by the US Food and Drug Administration in 2018.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Disease-Free Survival; Glycine; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Progression-Free Survival; Pyrazines; Pyridines; Remission Induction; Sulfonamides

Conventional chemotherapy with cytarabine and anthracycline (often referred to as "7+3") has been used for many years in the treatment of acute myeloid leukemia (AML). Despite meaningful advances in areas of supportive care and transplantation, little progress has been made in developing new chemotherapy options. In 2018, The Food and Drug Administration (FDA) of the US approved several novel agents for AML treatment as follows: ivosidenib, an inhibitor of isocitrate dehydrogenase-1; venetoclax, a potent inhibitor of bcl2; and glasdegib, an inhibitor of hedgehog signaling pathway. Moreover, clinical trials of alvocidib (flavopiridol), an inhibitor of the CDK9, pevonedistat, an inhibitor of NEDD8, and APR-246, a reactivator of mutant p53, are in progress. These agents will either be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents to improve the outcome of AML therapy, and the results will guide the next stage of precision medicine in the treatment of AML.

Topics: Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cyclopentanes; Drug Approval; Flavonoids; Glycine; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Phenylurea Compounds; Piperidines; Pyridines; Pyrimidines; Sulfonamides; United States; United States Food and Drug Administration

Survival rates for patients with acute myeloid leukemia (AML) older than 75 years are still quite dismal. Recent approvals, therefore, of two agents specifically to treat older patients-glasdegib and venetoclax-have created excitement among the medical community. Clinical data, particularly complete response (CR) rates and CR with incomplete hematologic recovery (CRi), look quite promising and are reviewed here. Yet the question remains whether fit elderly patients should receive combination therapy containing the newer agents, particularly since intensive chemotherapy remains the only treatment that has demonstrated the ability to achieve long-term disease-free survival.

Topics: Aged; Aged, 80 and over; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Leukemia, Myeloid, Acute; Male; Phenylurea Compounds; Sulfonamides; Survival Rate

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cytarabine; Daunorubicin; Glycine; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Proto-Oncogene Proteins c-bcl-2; Pyridines; Sulfonamides; Triazines

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Sulfonamides

Topics: Antineoplastic Agents; Azacitidine; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Europe; Gemtuzumab; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Randomized Controlled Trials as Topic; Sulfonamides