glasdegib and Leukemia--Myeloid--Acute

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute

Advancements in the understanding of the pathogenesis of acute myeloid leukemia (AML) have led to the introduction and approval of a number of novel drugs in AML. Glasdegib, an oral hedgehog pathway inhibitor, was approved in 2018 in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients unfit for intensive chemotherapy. In this review, we discuss the preclinical rationale for glasdegib, important clinical trials that led to glasdegib's approval, and future trials of glasdegib in AML and other myeloid diseases. Notably, 2 large randomized, placebo-controlled phase 3 trials (AML BRIGHT 1019) are currently recruiting patients with newly diagnosed AML to evaluate glasdegib in combination with intensive chemotherapy or azacitidine, depending on the patient's ability to tolerate induction chemotherapy. While glasdegib and low-dose cytarabine have been eclipsed by venetoclax and hypomethylating agent combinations for newly diagnosed AML in the United States, we discuss other areas where glasdegib may still have an opportunity to improve outcomes in this devastating disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzimidazoles; Cell Line, Tumor; Clinical Trials as Topic; Cytarabine; Drug Approval; Drug Evaluation, Preclinical; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Mice; Phenylurea Compounds; Signal Transduction; Smoothened Receptor; United States

Acute myeloid leukemia (AML) is an aggressive blood cancer that proves fatal for the majority of affected individuals. Older patients are particularly vulnerable due to more unfavorable disease biology and diminished ability to tolerate intensive induction chemotherapy (ICT). Safer, more efficacious therapies are desperately needed.. We briefly summarize the challenges facing AML treatment and introduce the rapidly expanding therapeutic landscape. Our focus is on the Hedgehog (Hh) pathway and how preclinical evidence has spurred the clinical development of selective inhibitors for oncology indications. Glasdegib is the first Hh pathway inhibitor approved for the treatment of a hematologic malignancy, and we review its pharmacology, safety, efficacy, and potential clinical impact in AML patients.. Advances in the mechanistic understanding of AML have started to translate into improved therapeutic options for patients with contraindications to ICT. Glasdegib improved overall survival in this population when combined with low-dose cytarabine. While an encouraging development for these difficult to treat patients, alternative combination therapy approaches such as venetoclax plus azacitidine have gained greater clinical traction. Further investigation of glasdegib combination strategies and predictive biomarkers, particularly in regard to overcoming chemoresistance and preventing relapse, is needed to better define its clinical utility.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds

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

Despite the approval of 8 new drugs for acute myeloid leukemia (AML) since 2017, the disease remains challenging, given the significant toxicity associated with available treatments and relatively low cure rates, especially in older adults. Although advantageous for patients, self-congratulatory rejoicing about the new agents would be extremely premature. Questions abound about the need for a specific versus less specific FLT3 inhibitor (eg, midostautin) in the upfront setting and whether a single agent (gilteritnib), albeit better than chemotherapy, is sufficient for relapsed disease. Is the new liposomal formulation of daunorubicin/cytarabine better than '3 + 7' only in secondary AML? Should only those newly diagnosed patients with core binding factor AML routinely receive gemtuzumab ozogamicin? The isocitrate dehydrogenase inhibitors were approved based on non-randomized data; thus, one wonders whether single-agent isocitrate dehydrogenase inhibitor therapy is appropriate for relapsed patients. Glasdegib, an orally available hedgehog inhibitor, is approved in conjunction with low-dose cytarabine in unfit patients but is rarely used in favor of a combination of hypomethylating agents or low-dose cytarabine with venetoclax, which are hopeful newly approved combinations for the older and/or unfit previously untreated. Perhaps venetoclax-based combinations should be more widely used, but the data is currently lacking. Thus, a temperate approach, more clinical research, and a critical analysis of the available data remain important in this "optimistic" new era of AML therapeutics.

Topics: Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Pyrazines

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

Glasdegib, in combination with low-dose cytarabine (LDAC), is the first smoothened inhibitor approved for treatment of acute myeloid leukemia. Glasdegib plus LDAC is indicated for patients in whom therapy options are limited, e.g. older patients and those ineligible for intensive chemotherapy due to preexisting comorbidities. This review summarizes the recommendations of a panel of hemato-oncologists regarding the selection of patients best suited for treatment with glasdegib plus LDAC and the management during therapy with this combination. The panel considered the impact of concomitant medications and comorbidities during treatment with glasdegib plus LDAC, and discussed common adverse events (AEs) associated with glasdegib plus LDAC. Management strategies for AEs discussed by the panel included dose modifications, supportive care therapies, and prophylactic treatments. Finally, the panel highlighted the importance of patient communication and education regarding the possible AEs that may occur during treatment.

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

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

Topics: Adult; Animals; Antineoplastic Agents; Benzimidazoles; Hedgehog Proteins; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Phenylurea Compounds; Signal Transduction; Stem Cells

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

Glasdegib (DAURISMO™) is an oral inhibitor of the Hedgehog signalling pathway, the activation of which is associated with a number of malignancies. It has been developed by Pfizer and was approved in November 2018 in the USA for use in combination with low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukaemia (AML) in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. Glasdegib is the first Hedgehog pathway inhibitor to be approved for AML in the USA. It received orphan designation for the treatment of AML in the USA in June 2017 and in the EU in October 2017, and for the treatment of myelodysplastic syndrome (MDS) in the USA in October 2017. It is also undergoing clinical development for use in select haematological and other malignancies, including MDS, in various countries worldwide. This article summarizes the milestones in the development of glasdegib leading to its use in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Drug Approval; Europe; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Signal Transduction; United States

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

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Nausea

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Topics: Adult; Azacitidine; Benzimidazoles; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Risk Assessment; Treatment Outcome

Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC).. Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Drug Interactions; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Male; Pharmacists; Phenylurea Compounds; Physicians

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms, Second Primary; Phenylurea Compounds; Survival Analysis; Treatment Outcome

In a randomized study, glasdegib (a hedgehog inhibitor) plus low-dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) approach was used to evaluate comparative quality-adjusted survival.. Overall survival was partitioned into the following: time with any treatment-emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q-TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility-adjusted time.. At 20 months of follow-up, the survival probabilities for the glasdegib-LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib-LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8-5.2 months) and TOX (+0.8 months; 95% CI, 0.1-1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, -1.9 to 2.3 months). Q-TWiST was 4.0 months (95% CI, 2.1-5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality-adjusted survival with respect to LDAC. Results were robust to the length of follow-up (6-24 months) and remained significant when all adverse events, regardless of grade, were included.. These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively "good" health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Phenylurea Compounds; Survival Analysis

Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS).. Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses.. The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS.. Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD.. NCT01546038.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Benzimidazoles; Cytarabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Hedgehog Proteins; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Phenylurea Compounds; Time Factors; Treatment Outcome; United States

Pharmacologic inhibition of the Hedgehog pathway significantly enhanced the sensitivity of leukemic cells to cytotoxic drugs. Glasdegib (PF-04449913; DAURISMO™) is a potent and selective oral inhibitor of the Hedgehog signaling pathway with clinical activity in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), particularly in combination with chemotherapy. The results of Phase Ib/II studies evaluating safety and efficacy of glasdegib combined with chemotherapy in previously untreated patients with AML or high-risk myelodysplastic syndrome have recently been published. In the BRIGHT AML 1003 study, glasdegib in combination with low-dose cytarabine (LDAC) was well tolerated and demonstrated a significant 54% reduction in mortality compared with LDAC for AML patients. In 2018, the US FDA approved glasdegib in combination with LDAC for the treatment of newly diagnosed patients with AML who are 75 years old or older or who have co-morbidities that preclude use of intensive induction chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Drug Evaluation; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Phenylurea Compounds; Prognosis; Survival Rate

Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Clinical Protocols; Female; Humans; Leukemia, Myeloid, Acute; Male; Phenylurea Compounds; Research Design

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39-0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit-risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Benzimidazoles; Cytarabine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phenylurea Compounds; Prognosis; Survival Rate

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Comorbidity; Cytarabine; Dose-Response Relationship, Drug; Drug Approval; Drug Labeling; Female; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Phenylurea Compounds; Smoothened Receptor; Survival Analysis; Treatment Outcome; United States; United States Food and Drug Administration

Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies.. We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758.. Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily.. Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis.. Pfizer.

Topics: Administration, Oral; Benzimidazoles; Half-Life; Humans; Italy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Maximum Tolerated Dose; Myelodysplastic Syndromes; Phenylurea Compounds; Primary Myelofibrosis; Treatment Outcome; United States

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Compassionate Use Trials; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phenylurea Compounds

We retrospectively collected clinical data on 31 relapsed or refractory acute myeloid leukemia (R/R AML) patients who were treated with outpatient glasdegib and low-dose Cytarabine (LDAraC) at our institution. The median age was 67 years (45-86). The median Eastern Cooperative Oncology Group performance status was 2 (1-3). The patients had previously received a median number of 2 (1-4) treatment lines, 61% (19/31) had been treated with intensive chemotherapy, 29% (9/31) had relapsed after allogeneic stem cell transplantation, and 45% (14/31) had had venetoclax exposure. Adverse cytogenetics were identified in 45% (14/31) of the cases. The CR + CRp rate was 21% (6/29) among evaluable patients. The median overall survival was 3.9 months for all patients. Different median overall survival times were observed in responders, patients achieving stable disease and those diagnosed with progressive disease: not reached vs 3.9 months vs 0.8 months, respectively (p < 0.001). The most common adverse events were pneumonia (29%, 9/31), sepsis (23%, 7/31), and febrile neutropenia (16%, 5/31). Glasdegib + LDAraC is a fairly safe, non-intensive, outpatient regimen inducing complete remission and resulting in prolonged survival in some R/R AML patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Phenylurea Compounds; Retrospective Studies; Treatment Outcome

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

Topics: Benzimidazoles; Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Phenylurea Compounds; Stem Cell Transplantation

The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015).. This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR.. In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41-0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively.. Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR.. ClinicalTrials.gov NCT01546038 (March 7, 2012).

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Blood Transfusion; Cause of Death; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Multicenter Studies as Topic; Phenylurea Compounds; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome

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

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Clinical Trials, Phase II as Topic; Cytarabine; Drug Approval; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

A multitude of regulatory approvals has recently changed the therapeutic landscape of acute myeloid leukemia. Among these was upfront therapy with the Hedgehog inhibitor glasdegib with low-dose cytarabine. Understanding the process of and rationale for approval of this promising combination is timely and valuable for the oncology community.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds