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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


August 1, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf

On August 1, 2017, the U.S. Food and Drug Administration granted regular approval to enasidenib (IDHIFA®, Celgene Corp.) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.

This is the first FDA approval for relapsed or refractory AML specifically with an IDH2 mutation. The FDA concurrently approved a companion diagnostic, the RealTime IDH2 Assay, used to detect the IDH2 mutation.

The enasidenib approval was based on Study AG221-C-001 (NCT01915498), an open-label, single-arm, multicenter, clinical trial of enasidenib that included 199 adults with relapsed or refractory AML who had an IDH2 mutation as detected by the above assay. Patients were treated with enasidenib 100 mg orally daily. Complete response (CR) and complete response with partial hematologic recovery (CRh) rates, CR/CRh duration, and conversion from transfusion dependence to transfusion independence were the basis of approval.

After a median follow-up time of 6.6 months, 23% of patients experienced CR or CRh lasting a median of 8.2 months, with 19% of patients having a CR lasting a median 8.2 months, and 4% with a CRh lasting a median 9.6 months. The median time-to-first response was 1.9 months (range, 0.5 to 7.5 months) and the median time-to-best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 157 patients who required transfusions at the initiation of the trial, 34% no longer required transfusions during at least one 56-day time period on enasidenib. Of the 42 patients who did not require transfusions at the start of the trial, 76% maintained transfusion independence.

The most common adverse reactions occurring in greater than 20% of patients were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. Differentiation syndrome occurred in 14% of patients. 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.

The recommended dose of enasidenib is 100 mg orally once daily until disease progression or unacceptable toxicity.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf.

FDA previously granted Orphan Drug and Fast Track designations to enasidenib for the treatment of AML, as well as priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

Pharmacist’s Applications to Practice

Enasidenib for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-2 (IDH2) Mutation

Author: Erin Barthelmess, PharmD Candidate
West Virginia University School of Pharmacy
Morgantown, WV

What is the potential role for enasidenib in the treatment of acute myeloid leukemia (AML)?

  • Enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), was granted regular approval by the U.S. Food and Drug Administration (FDA) on August 1, 2017, for use in adult patients with relapsed or refractory AML and an IDH2 mutation on the basis of results from study AG221-C-001. Currently, it is the first and only medication that carries an indication for this population.1,2
    • AG221-C-001 was an open-label single-arm clinical trial (N = 199) evaluating enasidenib in patients with relapsed or refractory AML. The majority (78%) of patients expressed the R140 variant; 22% expressed R172.3
      • 23% of patients enrolled achieved a complete remission (CR) or complete remission with partial hematological recovery (CRh); 19% of patients achieved CR, and 4% of patients achieved CRh.1
      • Median duration of response in patients achieving CR or CRh was 8.2 months.1
      • Median follow-up was relatively short at 6.6 months.1
    • Enasidenib also decreased the need for red blood cell (RBC) and platelet transfusions.1
      • 34% of patients dependent on RBC/platelet transfusions prior to initiation of enasidenib became independent of transfusions during the 56-day postbaseline period.1
      • 76% of patients not already dependent on transfusions at the beginning of enasidenib therapy remained transfusion independent.1
  • Treatment options for relapsed or refractory AML in patients prior to enasidenib’s approval included enrollment in clinical trials (strongly preferred category 2A by National Comprehensive Cancer Network Guidelines), best supportive care, or chemotherapy followed by an allogeneic stem cell transplant if patient was fit for intensive therapy; however, there are no options that specifically target an IDH2 mutation, which occurs in 2%–12% of patients with AML.4-7

What role can the pharmacist play in the management of patients on enasidenib?

  • Enasidenib has a unique adverse-effect profile requiring patient and provider education. The high incidence of gastrointestinal or hepatic toxicity and electrolyte disturbances will necessitate additional monitoring.1
    • Grade 3 hyperbilirubinemia and hypokalemia occurred in 15% of patients on enasidenib.1
    • 37% of patients experienced an elevated total bilirubin of at least twice the upper limit of normal.1
  • In a safety analysis of more than 200 patients, 43% required dose interruptions for adverse events, and 17% of these permanently discontinued therapy.1
  • Based on its mechanism, enasidenib induces myeloproliferation and myeloid cell differentiation, causing the potential for leukocytosis and tumor lysis syndrome.1
    • Enasidenib holds a black-box warning for differentiation syndrome. Reported in 14% of patients, this serious adverse event can present with fever, dyspnea, pleural effusions, peripheral edema, and multi-organ failure.1
      • If differentiation syndrome is suspected, initiate therapy immediately with dexamethasone 10 mg intravenously every 12 hours until symptoms resolve, or for a minimum of 3 days.1,8
      • Steroid therapy may worsen leukocytosis. Consider initiation of hydroxyurea if the white blood cell count exceeds 30,000.8
      • Differentiation syndrome has been observed from 10 days to 5 months after the initiation of enasidenib.1
    • Monitor regularly for leukocytosis and tumor lysis syndrome during the first 3 months of therapy.1
    • Refer to the prescribing information for specific criteria by which enasidenib should be withheld in the event of differentiation syndrome, leukocytosis, and hyperbilirubinemia.1
  • Patient assistance programs are available through Celgene Patient Support for eligible patients with commercial insurance and government-sponsored insurance, as well as for patients with no healthcare insurance.9

Clinical Pearls

  • Because of embryo-fetal toxicity, both males and females should use effective methods of contraception throughout enasidenib therapy and for 1 month after completion of therapy.1
  • Mutational testing must be performed with the companion diagnostic FDA-approved RealTime IDH2 Assay before starting enasidenib therapy.1
  • Patients who possess RAS and other mitogen-activated protein kinase (MAPK) pathway mutations may have decreased response rates to IGH2 inhibition by enasidenib.10
  • A phase-3 study (IDHENTIFY) comparing enasidenib with conventional care methods in relapsed and refractory AML is currently enrolling patients with an estimated primary completion date of April 1, 2019.11
    • This study includes only patients who are age 60 or above.
  • No current studies are examining enasidenib in combination with chemotherapy.
  • Detection of the IDH mutation via the companion diagnostic test may be performed on a bone marrow sample or peripheral blood.1
  • A minimum of 6 months of therapy may be needed before a clinical response is seen; however, the median time to first response was seen in 1.9 months.1

References

  1. IDHIFA [package insert]: Celgene Corp., Summit, NJ. August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf#page=16. Accessed September 5, 2017.
  2. Enasidenib. U.S. Food and Drug Administration: Approved Drugs. August 1, 2017. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm569421.htm. Accessed September 10, 2017.
  3. Clinicaltrials.gov. Phase 1/2 Study of AG-221 in Subjects with Advanced Hematologic Malignancies with an IDH2 Mutation. Updated July 21, 2017. https://clinicaltrials.gov/ct2/show/NCT01915498. NLM identifier: NCT01915498.
  4. Acute Myeloid Leukemia. NCCN Clinical Practice in Oncology (NCCN Guidelines). Updated June 6, 2017. Accessed September 10, 2017. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.
  5. Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutations: frequency and clinicopathologic features. Am J Clin Path. 2011;135:35-45.
  6. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3643-3643.
  7. DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90:732-736.
  8. Enasidenib. Center for Drug Evaluation and Research. Multi-Discipline Review. Application Number: 209606Orig1s000.
  9. Celgene Patient Support. IDHIFA (enasidenib). Available at: www.idhifa.com/wp-content/uploads/2017/07/48341_ceagmm_Patient_Financial_V3_fi3.compressed.pdf
  10. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130:732-741.
  11. Clinicaltrials.gov. An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects with Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation (IDHENTIFY). Updated May 2017. https://clinicaltrials.gov/ct2/show/NCT02577406?term=enasidenib&recrs=a&rank=2. NLM identifier: NCT02577406.
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