FDA Approves Venetoclax in Combination for AML in Adults
Management of acute myeloid leukemia (AML) in elderly adults can be complicated by patients having concurrent comorbidities that may preclude the use of intensive induction chemotherapy.1 Venetoclax is a small-molecule selective inhibitor of the BCL-2 protein granted accelerated approval by the United States Food and Drug Administration (FDA) for treatment of newly-diagnosed AML in patients 75 years of age or older, or in those with comorbidities that preclude the use of intensive induction chemotherapy.1,2
The efficacy of this agent was studied in two phase Ib/II clinical trials in newly-diagnosed patients with AML. The M14-358 study investigated venetoclax in combination with either azacitidine or decitabine. Treatment with venetoclax and azacitidine led to a complete remission (CR) rate of 37% and a CR with partial hematologic recovery (CRh) rate of 24% with a median time in remission of 5.5 months. Use of venetoclax plus decitabine resulted in a CR of 54% and CRh of 7.7% in patients treated with this combination, with a median time in remission of 4.7 months.1,3 A subpopulation study in this trial included 80 patients 75 years of age or older ineligible for intensive induction chemotherapy. In this subpopulation, the median time to first CR with venetoclax in combination with azacitidine was 1.0 month vs 1.9 months for those who received the venetoclax in combination with decitabine. Five of 67 patients treated with venetoclax in combination with azacytidine went on to receive stem cell transplants.1
The M14-387 trial assessed venetoclax in combination with low-dose cytarabine (LDAC). Both the CR and CRh rates in this treatment cohort were 21%, with a median time in remission of 6 months.1,3 This study also included a patient subgroup 75 years of age or older, and time to first CR or CRh in this subpopulation was 1.0 month.1
The most frequent adverse events (AEs) observed with venetoclax in combination with any of the chemotherapies used in the trials were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, pyrexia, and hypotension.3 It must be noted that the accelerated approval of venetoclax is contingent on the results of a confirmatory trial.1
- Broderick MJM. FDA approves frontline venetoclax in AML. (November 21, 2018). Available at: https://www.onclive.com/web-exclusives/fda-approves-frontline-venetoclax-in-aml.
- American Association for Cancer Research. Venetoclax safe, shows promise in patients with acute myelogenous leukemia (August 12, 2016). Available at: https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=925.
- United States Food and Drug Administration. FDA Approves Venetoclax in Combination for AML in adults. (November 23, 2018). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm.
FDA Approves Glasdegib for AML in Adults Age 75 or Older Who Have Comorbidities
Management of acute myeloid leukemia (AML) in elderly adults can be complicated by patients having concurrent comorbidities that may preclude the use of intensive chemotherapy. Glasdegib is the first and only hedgehog pathway inhibitor approved by the United States Food and Drug Administration (FDA) for treatment of newly-diagnosed AML in in patients 75 years of age or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
The efficacy of this agent was studied in the BRIGHT 1003 clinical trial, where adults with newly-diagnosed AML were treated either with glasdegib combined with low-dose cytarabine or low-dose cytarabine monotherapy. The primary endpoint was overall survival (OS) from the date of randomization to patient death from any cause. Results demonstrated significant improvement in the combination therapy arm in that patients treated with glasdegib had an OS of 8.3 months vs 4.3 months for those in the cytarabine-only cohort over a median follow-up period of 20 months.
The most common side effects seen with glasdegib therapy in clinical trials included anemia, fatigues, hemorrhage, febrile neutropenia, muscle pain, nausea, edema thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The FDA granted this drug application Priority Review and Orphan Drug designation. Glasdegib must be dispensed with a patient Medication Guide describing important information about the agent’s uses and risks. Patients must also be advised not to donate blood or blood products during therapy with glasdegib. Clinicians must also monitor patients taking this agent for electrocardiographic QT prolongation.
- ASCO Post. FDA approves glasdegib for patients with newlyl diagnosed AML who cannot undergo intensive chemotherapy. (November 21, 2018). Available at: http://www.ascopost.com/News/59497.
FDA Approves Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia (AML) with a FLT3 Mutation
Approximately 25% to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 gene, and these mutations are associated with a particularly aggressive form of AML with a higher relapse risk. The United States Food and Drug Administration (FDA) recently approved gilteritinib, an inhibitor of FLT3, for treatment of adult patients with FLT3 mutation-positive relapsed or refractory AML diagnosed using an FDA-approved test for detection of the mutation.1,2
This drug approval was based upon data from the ADMIRAL clinical trial which studied 138 adult patients with relapsed or refractory AML that had a FLT3 ITD, D835, or I836 mutation detected using the FLT3 mutation assay. Gilteritinib was orally administered at a dose at 120 mg daily, and median follow-up was 4.6 months. Results demonstrated that the rate of complete remission (CR) or CR with partial hematologic recovery was 21% in patients treated with this agent. Among patients in the study who were dependent upon red blood cell (RBC) transfusion and/or platelet transfusion at baseline, 31.1% became transfusion-independent. And 53.1% of the remaining patients who were transfusion-independent at baseline remained independent of transfusion during any 56-day post-baseline time period. Gilteritinib is the first drug to be approved as monotherapy for patients with FL3 mutation-positive AML who have relapsed or were unresponsive to initial therapy.1,2
While the final analysis of the ADMIRAL trial is still in process, the available data showed fewer and milder side effects with gilteritinib in comparison to standard chemotherapy.1 The most common adverse events seen with gilteritinib therapy included myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness, and vomiting.2 The drug application for the agent was granted Fast Track and Priority Review, as well as Orphan Drug designation. In addition, the FDA expanded the indication for the companion diagnostic test to include use with gilteritinib.1
- Broderick JM. FDA approves gilteritinib for FLT3+ AML. (November 28, 2018). Available at: https://www.onclive.com/web-exclusives/fda-approves-gilteritinib-for-flt3-aml.
- United States Food and Drug Administration. FDA Approves Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia (AML) with a FL&3 Mutation. (November 28, 2018). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627045.htm.
FDA Approves Ivosidenib, a First-in-Class Isocitrate Dehydrogenase-1 (IDH1) Inhibitor, for Use in Patients with Relapsed or Refractory AML
On July 20, 2018, the United States Food and Drug Administration approved ivosidenib (TIBSOVO®) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a mutation of the isocitrate dehydrogenase-1 (IDH1) gene as detected by an FDA-approved test. The FDA also approved the RealTime IDH1 Assay, a companion diagnostic that can be used to detect this mutation.
The approval of ivosidenib was based on data from an open-label, single-arm, multi-center dose escalation and expansion trial which included 174 adult patients with relapsed or refractory AML with an IDH 1 mutation. Ivosidenib was associated with a complete remission (CR) in some patients and a reduced need for red cell and platelet transfusions. In this study, investigators measured the percentage of patients with a CR and with a CR with partial hematologic recovery (CRh). At a median follow-up of 8.3 months, 32.8% of patients experienced a CR or CRh that lasted a median of 8.2 months. Of the 110 patients who were dependent on red blood cell (RBC) or platelet transfusions at baseline, 41 (37%) became independent of these transfusions during the 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusion at baseline, 38 (59.4%) remained transfusion independent during the same period. In addition, 21 of the 174 patients went on to stem cell transplant following treatment.
The most common adverse reactions, occurring in ≥20% of cases, included fatigue, leukocytosis, joint pain, diarrhea, dyspnea, swelling in the arms or legs, nausea, mucositis, QT prolongation, rash, fever, cough, and constipation.
Ivosidenib includes a boxed warning that a serious adverse reaction (occurring in ≥5% of cases) known as differentiation syndrome may occur and can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, or peripheral edema. At first suspicion of symptoms of differentiation syndrome, patients should be treated with corticosteroids and monitored closely until symptoms are resolved. The FDA recommends using electrocardiograms during treatment with ivosidenib because of the possible risks associated with QT prolongation, a potentially life-threatening condition. It also recommends monitoring patients for nervous system problems because Guillain-Barré syndrome has also occurred in patients treated with ivosidenib.
Women who are breastfeeding should not take ivosidenib as it may cause harm to a newborn baby.
- United States Food and Drug Administration. FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation. (July 20, 2018). Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm614115.htm.
- ClinicalTrials.gov. A phase I, multicenter, open-label, dose-escalation and expansion, safety, pharmacokinetic, pharmacodynamic, and clinical activity study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. Identifier: NCT02074839. February 23, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02074839. Accessed July 24, 2018.
- DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386-2398. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1716984. Accessed July 24, 2018.
- Pollyea DA, Dinardo CD, de Botton S, et al. Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): results of a phase 1 study. J Clin Oncol. 2018;36(suppl; abstr #7000). Presented at 2018 the American Society of Clinical Oncology (ASCO) Annual Meeting, June 1-5, 2018; Chicago, IL. Available at: https://meetinglibrary.asco.org/record/161682/abstract. Accessed July 24, 2018.
- Birendra KC, DiNardo CD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk. 2016;16:460-465. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983480/. Accessed July 24, 2018.
FDA Approves Gemtuzumab Ozogamicin for CD33-positive AML
On September 1, 2017, the United States. Food and Drug Administration granted new approval to gemtuzumab ozogamicin (Mylotarg) for the first-line treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adult patients. The drug was also approved for treatment of relapsed or refractory CD33-positive AML in both adults and pediatric patients ≥2 years of age. This agent may be used in combination with daunorubicin and cytarabine for adult patients, or as a monotherapy for certain adult and pediatric patients.
This approval of gemtuzumab ozogamicin in combination with chemotherapy for adults was based on the ALFA-0701 trial, a multicenter, randomized, phase 3 study of 271 patients between 50 and 70 years of age with newly-diagnosed, previously untreated, de novo AML. Patients were randomized 1:1 to receive standard daunorubicin and cytarabine induction therapy with or without gemtuzumab ozogamicin on days 1, 4, and 7. The primary endpoint was event-free survival. Results demonstrated an estimated median EFS of 17.3 months for patients receiving gemtuzumab ozogamicin vs. 9.5 months for those receiving chemotherapy.
Gemtuzumab ozogamicin was evaluated in 2 clinical trials for use as monotherapy. AML-19 was a multicenter, randomized, open-label phase 3 study where 237 patients were randomized 1:1 to gemtuzumab ozogamicin monotherapy vx best supportive care (BSC). Patients had newly-diagnosed AML, and were either older than 75 years of age or were between 61 to 75 years of age with a WHO performance status greater than 2 (or who were unwilling to receive intensive chemotherapy). Patients with no evidence of disease progression or significant toxicities after initial induction received continuation therapy for up to 8 courses of treatment, including gemtuzumab ozogamicin every 4 weeks. BSC included standard supportive care measures along with hydroxyurea or other anti-metabolites for palliative purposes. Results demonstrated an estimated median overall survival (OS) of 4.9 months for patients who received gemtuzumab ozogamicin vs. 3.6 months for those in the BSC-only group.
The MyloFrance-1 study, a phase 2, single-arm, open-label trial, assessed 57 patients with CD33-positive AML who had an initial disease relapse. Patients received a single course of gemtuzumab ozogamicin along with cytarabine consolidation therapy. Results showed that 26% of patients achieved complete response (CR) following the single administered course of gemtuzumab ozogamicin. Median relapse-free survival was 11.6 months, measured from first-noted CR to the date of either relapse or death.
In 2000 this drug received approval in older AML patients in the first relapse setting but the agent was voluntarily withdrawn after trials failed to confirm benefit and safety concerns arose surrounding a high number of early patient deaths. This new approval includes a lower recommended dose and treatment schedule along with a different indicated patient population than when originally approved. with use.
The FDA has included a boxed warning for hepatotoxicity, including severe or fatal hepatic veno-occlusive disease, which has been reported in 5% of patients treated with either gemtuzumab ozogamicin alone or with chemotherapy.
United States Food and Drug Administration. FDA Approves Gentuzumab Ozogamicin for CD33-positive AML. (September 1, 2017). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574518.htm.Back to top of page
FDA Approves CPX-351 (Vyxeos™) for Adult Patients with Newly-Diagnosed Therapy-Related AML or AML with Myelodysplasia-Related Changes, Based on an Improvement in Overall Survival in a Phase III Study
Chemotherapy has long been a standard for treatment of acute myeloid leukemia (AML). CPX-351 (brand name Vyxeos™) is a new agent that combines the standard chemotherapies daunorubicin and cytarabine into a fixed-combination agent. This new drug has now been approved to treat adults with two types of AML, newly-diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). Patients with either of these types of AML have a very poor prognosis and very low life expectancies. This chemotherapy combination is the first agent approved specifically for patients with these high-risk forms of AML, and may lengthen survival more than would be likely if patients received daunorubicin and cytarabine separately.1,2
The safety and efficacy of this daunorubicin/cytarabine combination was studied in a cohort of 309 patients with either newly diagnosed t-AML or AML-MRC. Patients were randomized to receive the combination chemotherapy or therapy with daunorubicin and cytarabine administered separately. Patients who received the combination drug had a median overall survival (OS) of 9.56 months vs 5.95 months for those who received the two chemotherapies separately.1,2
This combination agent has been associated with hypersensitivity reactions, along with decreased cardiac function, and serious or fatal bleeding.1 Other common side effects recorded include febrile neutropenia, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.2
- Journal of Clinical Pathways. FDA approval alert: first treatment for two types of AML. (August 3, 2017). Available at: http://www.journalofclinicalpathways.com/news/fda-approval-alert-first-treatment-two-types-aml.
- thepharmaletter. FDA approves first treatment for certain types of poor-prognosis AML. (August 4, 2017). Available at: https://www.thepharmaletter.com/article/fda-approves-first-treatment-for-certain-types-of-poor-prognosis-aml.
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FDA Approves Enasidenib for Treatment of Relapsed or Refractory AML
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) are found in approximately 12% of patients who have acute myeloid leukemia (AML). Enasidenib (AG-221/CC-90007) is a first-in-class, oral selective agent that inhibits mutant IDH2 enzymes. The FDA concurrently approved a companion diagnostic, the RealTime IDH2 Assay, used to detect the IDH2 mutation.
Stein, et al., performed a phase 1/2 study that assessed the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. This included clinical effectiveness and safety in the largest patient subgroup, namely patients with relapsed or refractory AML. Following the dose escalation phase, enasidenib at a dose of 100 mg was chosen for the expansion phase due to its PK/PD profiles and efficacy. Among these patients with relapsed/refractory AML disease, the overall response rate (ORR) was 40.3%, and the patients had a median response duration of 5.8 months. Responses were found to be associated with both cellular differentiation and maturation, and they were typically without evidence of cellular aplasia. The median overall survival (OS) for the relapsed/refractory AML subgroup was 9.3 months; 34 patients (19.3%) attained complete remission (CR), with an OS of 19.7 months.
The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. IDH-inhibitor associated differentiation syndrome occurred in 7% who received enasidenib. As differentiation syndrome may be fatal without prompt management, the prescribing information includes a boxed warning and instructions on the risk and need for early intervention.
Overall results demonstrated that continuous daily enasidenib was generally well-tolerated and induced hematologic responses in patients who had failed prior therapy for AML. Inducing differentiation of myeloblasts, not cytotoxicity, appeared to be the driver of clinical efficacy of enasidenib. A multicenter, phase 3 trial of enasidenib vs conventional therapy in older patients with late-stage AML with IDH2 mutation is currently ongoing (IDHENTIFY trial).
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
FDA Approves Midostaurin for Treatment of Adult Patients with Newly-Diagnosed AML (FTL3+ Disease) in Combination with Standard Cytarabine and Daunorubicin Induction and Cytarabine Consolidation
Acute myeloid leukemia (AML) remains a challenging disease to treat for many reasons, including intrinsic biologic factors impacting therapy. Mutations in the fms-related tyrosine kinase 3 gene (FLT3) have been identified in 30% of adults with newly-diagnosed AML, and about 75% of these patients have a FLT3 internal tandem duplication mutation (ITD subtype), which is associated with a poor prognosis owing to a high disease relapse rate.
Midostaurin is a multitargeted kinase inhibitor that was originally assessed to be administered safely at a dose of 50 mg twice daily for 14 days to patients with newly-diagnosed AML, in an early phase 1 study. This agent would be administered beginning on the eighth day after the start of treatment during standard courses of induction and consolidation chemotherapy used for patients with early-stage disease. Stone, et al., conducted a phase 3 trial to determine if midostaurin added to chemotherapy would impact overall survival (OS) in this patient population. A total of 779 patients were randomized to either midostaurin (360 patients) or placebo (357 patients) on the basis of their subtype of FLT3 mutation (ITD-high or ITD-low). Results demonstrated that among the 359 patients who survived (median follow-up of 59 months), median OS was 74.7 months for those who received midostaurin vs 25.6 months for those who received placebo. The 4-year survival rate was 51.4% in the midostaurin group and 44.3% for patients who received placebo. Median event-free survival was 8.2 months in the midostaurin group and 3.0 months for those who received placebo. The benefit of midostaurin was consistent across all FLT3 subtypes, including in patients who underwent allogeneic transplantation. The rate of severe adverse events (AEs) was similar in the two groups, with the most common serious AE being febrile neutropenia in both treatment groups. The researchers concluded that the addition of midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with FT3+ AML.1
It must be noted that the approval for clinical use of midostaurin for AML requires the use of a companion diagnostic test, the LeukoStrat® CDx FLT3 Mutation Assay, also now approved for detecting FLT3 mutations.2
- Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FTL3 mutation. N Eng J Med. 2017;377(5):454-464.
- National Cancer Institute. (June 1, 2017). Midostaurin approved by FDA for acute myeloid leukemia. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-midostaurin-aml.
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