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Ivosidenib (Tibsovo®) for the treatment of relapsed and refractory acute myeloid leukemia

Wednesday, March 20, 2019  
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Ivosidenib (Tibsovo®) for the treatment of relapsed and refractory acute myeloid leukemia in patients with an isocitrate dehydrogenase 1 (IDH1) mutation

Ari Marie Leland, Pharm.D Candidate 2019, Jefferson College of Pharmacy

Oludamilola Olugbile, Pharm.D, Magee Rehabilitation Hospital

 

Overview of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common acute leukemia that affects over 20,000 adults each year in the United States (US). The incidence of AML increases with age typically affecting those over 65 years old with rare diagnosis in children. The 2019 estimates for AML in the US are 21,450 new cases and 10,920 deaths.1 Risk factors for developing this disease include male sex, smoking (increased risk after age 60), history of chemotherapy or radiation treatment, history of treatment for child acute lymphoid leukemia (ALL), radiation exposure from atomic bomb, benzene exposure, and past medical history of myelodysplastic syndrome.2

In AML, the myeloid lineage is affected (Figure 1). The bone marrow makes abnormal myeloblasts (immature white blood cells), which are unable to differentiate, causing the immature cells to “crowd out” and suppress the production of normal cells such as red blood cells, or platelets.3 AML is diagnosed when patients present with more than 20% blasts in bone marrow or peripheral blood samples.4 The cancer starts in the bone marrow and quickly moves into the blood and can spread to various organs affecting the lymph nodes, liver, spleen, brain, spinal cord, and testicles. The clinical presentation includes signs and symptoms associated with the loss of normal cells, such as anemia and low platelet counts in addition to, anorexia, fatigue, malaise, and less commonly lymphadenopathy and organomegaly.3

 

Although the majority of AML cases are due to malignancy in otherwise healthy individuals, it can occur in patients with hematological disorders, a history of treatment with alkylating agents or radiation, and genetic mutations or translocations.5 Gene mutations are particularly useful in terms of diagnosis of AML, prognosis (favorable, poor, or intermediate), monitoring parameters, and selecting the appropriate pharmacotherapy. The following mutations are useful to stratify the 40-50% of AML patients with an intermediate prognosis: Fmf-like tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), CCAAT enhancer binding protein (CEBPA), and v-KIT hardy-zuckerman 4 feline sa12rcoma viral oncogene homolog (KIT).3 As advanced practices for gene sequencing have emerged, the number of genes found to be mutated in AML have increased. There are 11 other genes that directly or indirectly affect transcription through epigenetic regulation, but for many of these mutations, their significance is unclear.5 One mutation that is important for targeted therapy is isocitrate dehydrogenase 1 (IDH1), which is a part of a family of enzymes that catalyzes isocitrate to alpha keto-glutarate in the Krebs Cycle for glucose metabolism. Mutations of this enzyme result in the loss of normal enzymatic function and abnormal production of 2-hydroxyglutarate (2-HG), which promotes tumorigenesis through altered DNA and histone methylation. There are several hypotheses for how IDH mutations promote tumorigenesis. One discusses 2-HG functioning as an oncometabolite to promote cellular transformation.6,7,8 Another focuses on the loss of a wild-type allele or gain of a dominant-negative mutant allele that alters normal functioning of the mitochondria, allowing cancer cells to use glycolysis.6,7,8 IDH1 mutation can occur in approximately 6-10% of patients with AML and must be confirmed in the blood or bone marrow before therapy is initiated.9,10 The most common mutations are R132H and R132C substitutions.11,12 The IDH1 mutation can emerge during treatment and at relapse, so patients without the mutation at diagnosis should be retested at relapse, which involves an in vitro polymerase chain reaction (PCR) assay.11,12,13

The chemotherapy regimen for AML is selected based on patient specific-factors such as age, comorbidities, organ function, and risk of leukemia returning after therapy. Treatment is divided into two phases: induction with cytarabine and an anthracycline (daunorubicin or idarubicin), followed by consolidation or post-remission with cytarabine with or without an anthracycline or mitoxantrone.13,14 Induction therapy is often referred to as the “7 +3” regimen because it consists of intravenous cytarabine continuously for 7 days, followed by short infusions of the anthracycline on the first 3 days.14 Consolidation or post-remission therapy consists of high-dose cytarabine given over 5 days and repeated approximately every 4 weeks for a total of 3 to 4 cycles.12 Treatment options for AML have advanced over the years allowing positive patient outcomes in younger populations; however, prognosis for the elderly population is still poor. Despite current therapies, 70% of patients 65 and older will die from AML within 1 year of diagnosis.3

 

Ivosidenib (Tibsovo®)

Ivosidenib is antineoplastic agent that was approved by the FDA on July 20, 2018, for the treatment of relapsed or refractory AML in adults with susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an approved test.9,10

Mechanism of Action

Ivosidenib is small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) enzyme.7Ivosidenib restores differentiation by binding to mutant IDH1 enzyme and consequently decreasing 2-HG levels and normalizing DNA and histone methylation.15 This in turn allows the myeloblasts to differentiate into mature blood cells. 11,12

 

 Important Clinical Trial 11,12

The pivotal trial for ivosidenib was a phase I, open-label, single-arm, multicenter trial conducted by DiNardo and colleagues. 174 adult patients with relapsed or refractory AML with an IDH1 mutation were assigned to receive a 500 mg daily dose of ivosidenib until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Table 1 shows the efficacy results of patients treated with ivosidenib where 33% of patients (57/174) achieved complete remission (CR) or complete remission with partial hematologic recovery (CRh). CR was defined as: < 5 % blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/uL and absolute neutrophil count (ANC) > 500/uL). CRh was defined as: < 5 % blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 50,000/uL and absolute neutrophil count (ANC) > 500/uL). Duration of response (DOR) was measured from time of first response of CR or CRh to relapse or death. The most common adverse reactions associated with treatment are QTc prolongation, differentiation syndrome, non-infectious leukocytosis, and dyspnea. Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome, rash, stomatitis, and increased creatinine. There was one serious adverse effect of progressive multifocal leukoencephalopathy (PML).

 

Conclusion

Ivosidenib (Tibsovo®) is the first antineoplastic agent indicated specifically for patients with relapsed or refractory AML with an IDH1 mutation. Although there are no renal or hepatic dosing adjustments, pharmacists should be aware of dose reductions or reasons for discontinuation in the setting of serious adverse effects. The trial executed by DiNardo and colleagues is still ongoing, but the data compiled thus far reports ivosidenib as an efficacious and safe option for patients with difficult-to-treat AML.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34. doi: 10.3322/caac.21551. Epub 2019 Jan 8.
  2.  American Cancer Society. Risk Factors for AML. https://www.cancer.org/cancer/acute-myeloid-leukemia/causes-risks-prevention/risk-factors.html August 21st, 2018. Accessed December 5, 2018.
  3. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441. Published 2016 Jul 1. doi:10.1038/bcj.2016.50
  4. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed December 10, 2018.
  5. Yohe S. Molecular Genetic Markers in Acute Myeloid Leukemia. J Clin Med. 2015;4(3):460-78. Published 2015 Mar 12. doi:10.3390/jcm4030460.
  6. Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J (August 2004). "Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity". The Journal of Biological Chemistry. 279 (32): 33946–57. doi:10.1074/jbc.M404298200. PMID 15173171.
  7. Liu X, Ling ZQ (October 2015). "Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors". Histology and Histopathology. 30 (10): 1155–60. doi:10.14670/HH-11-643. PMID 26147657.
  8. Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).
  9. 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.[PubMed 29860938]
  10. Ivosidenib. Lexi-Drugs. Hudson, OH: Lexicomp, 2018. http://online.lexi.com/. Updated December 10, 2018. Accessed December 5, 2018.
  11. Tibsovo® (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals, Inc; July 2018.
  12. Prescribing information/Medication Guide. TIBSOVO®. https://www.Tibsovo® pro.com. Accessed December 4th, 2018.
  13. National Cancer Institute. Adult acute myeloid Leukemia Treatment- Health Professional Version. https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq.February 7, 2018. Accessed December 5, 2018.
  14. American Cancer Society. Typical Treatment of Acute Myeloid Leukemia (Except APL). https://www.cancer.org/cancer/acute-myeloid-leukemia/treating/typical-treatment-of-aml.html. August 21st, 2018. Accessed December 5, 2018.
  15. About Tibsovo. Mechanism of Action. https://www.tibsovopro.com/about-tibsovo/#mechanism-of-action Updated 2018. Accessed December 4th, 2018.
  16. Access and Support. Access and reimbursement. https://www.tibsovopro.com/access-and-support/#access-and-reimbursement. Updated 2018. Accessed December 27thth, 2018.

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