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Expanding Treatment Options for AML: A Focus on the IDH Inhibitors

26 Sep 2019 1:55 PM | Deleted user

Authors: Nicholas Pauley, PharmD Candidate 2020 and
Mallory Crain, PharmD

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults.1 The average age at diagnosis is 69 years with a 5-year survival rate of 28.3%.2 A key determinant for increased survival is the patient’s ability to undergo intense induction chemotherapeutic regimens. However, intensive therapies are not always an option since some patients are unable to tolerate these treatments due to age and comorbidities. Fortunately, targeted therapies have expanded treatment options for these patients.

Targeting specific genetic mutations in AML has become a large area of research in recent years.  Specifically, isocitrate dehydrogenase (IDH) 1 or 2 mutations are present in approximately 20% (IDH1: 7-14%, IDH2: 8-19%) of newly diagnosed patients with AML.3 Until recently, there were no specific therapies for patients with these mutations.  Two IDH inhibitors, enasidenib and ivosidenib, were FDA approved in August 2017 and July 2018, respectively. Both agents increase myeloid differentiation through inhibition of the IDH enzymes.4,5

Enasidenib is currently FDA approved at a dose of 100 mg by mouth once daily for the treatment of relapsed/refractory AML in patients with an IDH2 mutation.4 Although enasidenib is only FDA approved for relapsed/refractory patients, the NCCN guidelines also recommend enasidenib as an option for older patients who are unfit for intensive therapy.6 No significant drug interactions requiring dose adjustments have been identified.4

A phase 1, dose escalation and expansion study evaluated AML patients with an IDH2 mutation who were treated with enasidenib.  A total of 109 patients in the study had relapsed/refractory AML.  The median age was 67 years, and most patients received at least two prior therapies.  The overall response rate (ORR) was 38.5% with a complete remission (CR) of 20.2%.  The median overall survival (OS) was 9.3 months.  Of note, the median time to first response was 1.9 months.7 This study also evaluated 29 newly diagnosed patients who were deemed unfit for standard regimens. The ORR was 30.8% with a CR of 18%.  The estimated median OS was 11.3 months.8

Ivosidenib is FDA approved at a dose of 500 mg for patients with an IDH1 mutation who have relapsed/refractory AML or are > 75 years with newly diagnosed AML (or those who cannot tolerate intensive induction chemotherapy). Dose adjustments for ivosidenib are recommended if it is given with strong CYP3A4 inhibitors since ivosidenib is a major CYP3A4 substrate. Induction of CYP3A4 has also been reported.5

A phase 1, dose escalation and expansion study evaluated AML patients with an IDH1 mutation who were treated with ivosidenib.  A total of 179 patients had relapsed/refractory AML with a median age of 68 years. The ORR was 41.6% with a CR of 21.6%.  The median OS in the primary efficacy group was 8.8 months.  Similar to enasidenib, the median time to response was 1.9 months.  This study also included 34 patients with untreated AML (median age: 76.5 years).  The ORR was 58.8% with a CR of 26.5%. Survival data was not published for these patients.9

In regard to safety, both agents have a similar adverse effect profile.  The most common adverse events observed in clinical trials were diarrhea, nausea, leukocytosis, febrile neutropenia, and anemia.  In addition, 38% of patients treated with enasidenib had indirect hyperbilirubinemia, and 24.6% of patients who received ivosidenib had a prolonged QTc interval.  Both agents caused differentiation syndrome in approximately 5% of patients, which is a serious complication that can become life-threatening. Therefore, it is imperative that clinicians are able to identify and treat differentiation syndrome when it occurs.7,10,13

Differentiation syndrome results from rapid proliferation and differentiation of myeloid cells leading to cytokine imbalance and inflammation throughout the body.  It can present as a fever, cough, dyspnea, hypoxia, pleural effusions, pulmonary infiltrates, or organ dysfunction of unknown cause.  The median onset was 29 days (range 5 to 59) for ivosidenib and 48 days (range 10 to 340) for enasidenib in the phase 1 trials.7,9 Patients who experience differentiation syndrome should be initiated on dexamethasone 10 mg IV every 12 hours for a minimum of 3 days or until symptoms resolve.  If patients also develop leukocytosis, initiation of hydroxyurea may be considered.  Ivosidenib and enasidenib should only be discontinued if severe symptoms persist for more than 48 hours after the start of dexamethasone.4,5

Within recent years, several new agents, including targeted therapy, have emerged as treatment options for AML.  In a disease state with previously limited options, having additional lines of therapy potentially allows for increased survival compared to historical treatment options. While intensive induction therapy is still the standard of care for those who can tolerate it, it is not an option for every patient. IDH inhibitors provide another treatment option for relapsed/refractory AML patients as well as those who cannot tolerate intensive induction therapy. In addition, an oral medication taken at home may be more convenient or desirable for some patients. When comparing these agents to traditional chemotherapy, one important factor to consider is the longer expected time to response.  The median time to response with IDH inhibitors is 1.9 months compared to an expected response within 30 days with traditional chemotherapy. Although long-term efficacy data is not yet available, the IDH inhibitor phase 1 trials show similar results compared to other standard treatment options given in the relapsed/refractory and newly diagnosed settings.6-9,11 Overall, both of these agents have proven efficacy in AML patients with an IDH mutation, and it is likely that use of IDH inhibitors for the treatment of AML will only continue to grow.

References

  1. Sant M, Allemani C, Teareanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of HAEMECARE project. Blood. 2010;116(19):3724-34.
  2. SEER Cancer Stat Facts: Acute Myeloid Leukemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/amyl.html. Accessed August 20, 2019.
  3. Medeiros BC, Fathi AT, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;(31):272-281. 
  4. IDHIFA [package insert]. Summit, NJ: Celgene Corporation; (2017).
  5. TIBSOVO [package insert]. Cambridge, MA: Agios Pharmaceuticals; 2018.
  6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Published May 5, 2019. Accessed June 26, 2019.
  7. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
  8. Pollyea DA, Tallman MS, deBotton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019.
  9. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study. Blood. 2018;(132):561.
  10. Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777-2782.
  11. 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(25):2386-2398.
  12. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916-24.
  13. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015; 373: 1136–1152.
  14. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53-61.


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