DAURISMO for Acute Myeloid Leukemia

On November 2018, the FDA approved Pfizer’s glasdegib (Daurismo) for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 75 years and older with comorbidities that prevent the use of intensive induction-dose chemotherapy. Glasdegib is a once-daily oral medication that is taken in combination with cytarabine, another type of chemotherapy.¹

In a statement on the approval, Pfizer noted that glasdegib is the only FDA-approved Hedgehog pathway inhibitor for AML. In adults, abnormal activation of the Hedgehog pathway is thought to contribute to the development of cancer stem cells; disrupting it can inhibit the survival of these cells.

AML is a rapidly progressing bone marrow cancer and the most common type of acute leukemia in adults. Compared with other blood cancers, AML has poor survival rates. Typical treatment for patients includes intensive chemotherapy, which is not an option for many elderly adults or those with prior existing medical conditions. However, without treatment, AML can quickly progress and spread to the blood and other parts of the body, such as the lymph nodes, liver, spleen, brain, and spinal cord.¹

Mechanism of Action

Glasdegib binds to and inhibits the transmembrane protein, which is involved in Hedgehog signal transduction. In combination with low-dose cytarabine, glasdegib was shown to inhibit increases in tumor size in a murine xenotransplant model of human AML. Along with low-dose cytarabine, glasdegib also contributed to the reduction of CD45+/CD33+ blasts in the bone marrow compared with either agent alone.²

Dosage and Administration

Glasdegib is an oral tablet administered with or without food. The recommended dose is 100 mg by mouth once daily on days 1 to 28 in combination with subcutaneous cytarabine 20 mg injected twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control.²

Glasdegib tablets should not be split or crushed and should be taken at the same time each day. In the event that a dose is missed or not taken at the normal time, administer the dose as soon as possible as long as it is at least 12 hours before the next scheduled dose. If the dose is vomited, do not administer a replacement dose; instead, wait until the next scheduled dose. Return to the normal schedule the next day. Do not take more than 1 dose of glasdegib in a 12-hour period.²

Prior to starting glasdegib, assess complete blood counts, electrolytes, and renal and hepatic function and monitor at least once weekly for the first month. Also obtain serum creatinine kinase levels prior to initiating glasdegib and as needed thereafter and continue to monitor renal function and electrolytes each month for the duration of treatment. An electrocardiogram (ECG) should be ordered before starting therapy, approximately 1 week after the first dose, and once monthly for the next 2 months to check for QT prolongation. If found to be abnormal, repeat the ECG. Monitor more frequently, depending on the patient.²

Pharmacokinetics and Pharmacodynamics

Oral administration of glasdegib between 5 and 600 mg (0.05-6 times the recommended dose) resulted in a proportional increase in glasdegib peak concentrations (Cmax) and area under the curve (AUC) over the dosing interval. After 8 days of dosing, steady-state plasma levels were reached.²

Following administration of a 100-mg once-daily dose of glasdegib, the median time to peak concentrations at steady state ranged from 1.3 to 8 hours. High-fat and high-calorie meals reduced AUC time to infinity by 16% and C_max by 31%.²

Glasdegib is 91% bound to human plasma proteins in vitro. In patients with hematologic malignancies, the geometric mean apparent volume of distribution was 188 L (20%). Glasdegib is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) pathway, with minor effects by cytochrome P450 2C8 and UDP-glucuronosyltransferase 1A9. The mean half-life is 17.4 hours, and there is an apparent clearance of 6.45 L/h following 100-mg once-daily dosing. Forty-nine percent of the 100-mg dose was found to be eliminated in the urine and 42% in the feces.²

Clinical Studies

The efficacy and safety of glasdegib was evaluated in the pivotal, randomized, international phase 2 BRIGHT 1003 clinical trial, which included 115 patients with newly diagnosed AML. Patients were randomly assigned 2:1 to receive either glasdegib plus low-dose cytarabine or low-dose cytarabine alone. For those who received glasdegib plus low-dose cytarabine, the median overall survival (OS) was 8.3 months compared with 4.3 months for patients treated with low-dose cytarabine alone. The difference in OS represented a 54% reduction in risk of death in patients treated with glasdegib plus low-dose cytarabine.³

Warnings and Precautions

The US labeling for glasdegib includes a boxed warning for embryo-fetal toxicity. It can cause embryo-fetal death or severe birth defects and is not recommended for use during pregnancy. Female patients of reproductive potential should be tested for pregnancy before the start of treatment with glasdegib and are advised to use effective contraceptives during treatment and for at least 30 days after the last dose.² Women also should not breast-feed while taking glasdegib and for at least 30 days after the last dose. Male patients with female partners should also be advised of the potential risk of exposure through semen and to use proper contraception, including condoms, even after vasectomy, during treatment, and at least 30 days after the last dose. Blood donations should also be avoided during and 30 days after treatment in the event that blood products are given to a female of reproductive potential.²

Glasdegib may also contribute to the development of QTc prolongation and ventricular arrhythmias such as ventricular fibrillation and ventricular tachycardia. ECG and electrolytes should be monitored, and concomitantly use with other drugs known to cause QTc prolongation is not recommended. CYP3A4 inhibitors may also increase the risk of developing QTc prolongation. If the QTc increases to greater than 500 ms, interrupt glasdegib. The drug should be permanently discontinued in patients who develop QTc prolongation with signs and symptoms of life-threatening arrhythmia.²

Adverse Events

The following adverse events were reported in more than 10% of patients taking glasdegib plus cytarabine in clinical trials: anemia, hemorrhage, febrile neutro- penia, thrombocytopenia, fatigue, edema, mucositis, pyrexia, chest pain, musculoskeletal pain, muscle spasm, nausea, constipation, diarrhea, abdominal pain, vomiting, dyspnea, cough, decrease in appetite, dysgeusia, dizziness, headache, rash, pneumonia, hyponatremia, decreased platelet count, decreased white blood cell count, weight loss, atrial arrhythmia, and renal insufficiency.

Additionally, the following clinically-significant adverse reactions were found to occur in less than 10% of patients: dental disorders such as loose tooth or toothache, alopecia, and QTc prolongation.²

Jacqueline Hanna, PharmD, MSPBA, CSP

References

• U.S. FDA approves Daurismo (glasdegib) for adult patients with newly-diagnosed acute myeloid leukemia (AML) for whom intensive chemotherapy is not an option [press release]. New York, NY: P zer; November 21, 2018. p zer.com/news/press-release/press-release- detail/u_s_fda_approves_daurismo_glasdegib_for_adult_patients_with_newly_diagnosed_acute_myeloid_leukemia_aml_for_whom_intensive_chemotherapy_is_not_an_option. Accessed April 26, 2019.
• Daurismo [prescribing information]. New York, NY: P zer Labs; 2018.
• Eaton P. FDA approves Daurismo for the treatment of newly-diagnosed AML in patients who are 75 years or older who have comorbidities [news release]. EPG Health Media; November 22, 2018. epgonline.org/global/news/fda-approves-daurismo-for-the-treatment-of-newly-diagnosed- aml-in-patients-who-are-75-years-or-older-or-who-have-comorbidities---pfizer-.html. Accessed April 26, 2019.