Acute Myeloid Leukemia Coverage From Every Angle

Ivosidenib

Posted: Wednesday, September 1, 2021

A New Target in AML

In more than a decade, scientific breakthroughs have transformed IDH gene mutations from a virtually unknown phenomenon in acute myeloid leukemia (AML) to a viable target in the approximately 15% to 20% of patients with AML who harbor a mutation.1 They have also led to the U.S. Food and Drug Administration (FDA) approval of two small-molecule inhibitors of mutated isocitrate dehydrogenase (IDH) enzymes: ivosidenib2 and enasidenib,3 which target IDH1 and IDH2, respectively. 

On July 20, 2018, the FDA approved ivosidenib or adults with relapsed or refractory AML with an IDH1 mutation, as detected by an FDA-approved test. The approval was based on the open-label, single-arm, multicenter AG120-C-001 trial (ClinicalTrials.gov identifier NCT02074839), which included 174 adults with relapsed or refractory AML with an IDH1 mutation.4 Findings from the study demonstrated a rate of complete remission or complete remission with partial hematologic recovery of 32.8%, a median time to response of 2 months, and a median response duration of 8.2 months.

According to Daniel A. Pollyea, MD, Associate Professor of Medicine, Clinical Director of Leukemia Services, and Robert H. Allen MD Chair in Hematology Research at the University of Colorado Medicine, the lack of effective treatment options for this patient population was a contributing factor in the FDA’s decision. Its decision was also based on a single-arm study, not a randomized controlled trial, and on the demonstrated ability of ivosidenib to improve blood cell counts and decrease transfusion support. Among the 110 patients dependent on red blood cell and/or platelet transfusions at baseline, 41 patients (37.3%) were independent of red blood cell and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both red blood cell and platelet transfusions at baseline, 38 patients (59.4%) remained transfusion-independent during any 56-day post-baseline period.

“Even when a patient did not obtain an objective response, this quality-of-life metric [decreased transfusion support] was felt to be very promising and worthy of consideration,” Dr. Pollyea told JNCCN 360.

Ivosidenib Mechanism of Action

On average, patients with AML have three to five detectable mutations.5 Although most of these mutations occur in the later stages of disease, the IDH1 mutation is thought to be early, stable, and important for disease biology.

“Targeting a late mutation is less appealing because you are not going to wipe out the entire disease, maybe just a subset of it,” said Dr. Pollyea. “However, because AML cells depend on the IDH1 mutation, targeting it could effectively impact the disease.”

Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate in leukemia cells. High levels of 2-hydroxyglutarate may interfere with enzymes that rely on alpha-ketoglutarate, a contributor to the disease.

According to Dr. Pollyea, identification of the IDH mutations showed that AML has targetable metabolic deficits.

“Most of the AML community had not understood this to be a disease that disrupted metabolism before,” Dr. Pollyea explained. “This was one of the first opportunities to appreciate that problems with metabolism, or mutations in genes that control metabolism, can contribute to this disease.”

Ivosidenib is a small-molecule inhibitor that targets the mutant IDH1 enzyme. It is administered as a once daily oral 500-mg tablet until disease progression or unacceptable toxicity. Ivosidenib can restore balance in cell differentiation and lead to meaningful remissions by significantly lowering levels of 2-hydroxyglutarate and allowing normal cellular function to resume.

Patient Eligibility for Ivosidenib

In 2019, ivosidenib was also approved by the FDA for newly diagnosed AML with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.6

According to Rhonda Hewitt, NP, a nurse practitioner who specializes in hematology at Stanford Cancer Center, in California, because hypomethylating agents in combination with venetoclax work so well in newly diagnosed AML—and are effective in patients with the IDH1 mutation—ivosidenib is usually reserved for patients who experience disease progression on this combination.

Because hypomethylating agents in combination with venetoclax work so well in newly diagnosed AML—and are effective in patients with the IDH1 mutation—ivosidenib is usually reserved for patients who experience disease progression on this combination.

“We tend not to use ivosidenib in the first-line setting at our institution,” said Ms. Hewitt. “We’ll consider it for patients younger than age 65 who are frail with multiple comorbidities, but patients receiving ivosidenib are usually older than age 70.” As Ms. Hewitt explained, ivosidenib works well in older patients because their leukemia tends not to be as proliferative, and they do not require an immediate response.

“Ivosidenib is not given with curative intent,” she added. “It’s life-prolonging and maintains patients’ quality of life because it is not associated with a lot of side effects.

Ivosidenib is life-prolonging and maintains patients’ quality of life because it is not associated with a lot of side effects.

Ivosidenib is typically administered after treatment with venetoclax plus a hypomethylating agent. However, patients receiving ivosidenib may have already developed prolonged cytopenia, treatment-emergent fungal infections, or other toxicities associated with previous therapy.

Key Toxicities

Ivosidenib is generally well tolerated, and premedication is not usually prescribed. Although nausea can be a side effect with ivosidenib, prophylactic antiemetics are typically reserved for patients with a history of nausea, said Ms. Hewitt. Diarrhea is more common and may require antidiarrheal medication.

Like many novel oral agents, ivosidenib is also associated with QTc interval prolongation. Therefore, the FDA label recommends monitoring electrocardiograms at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy.

“It’s important to monitor electrocardiograms and electrolytes and pay attention to the medication list, as patients receiving ivosidenib may have issues with atrial fibrillation or preexisting cardiac conditions,” Ms. Hewitt told JNCCN 360. “When patients take cardiovascular medications, we will work with cardiology colleagues to find another treatment that does not prolong QT. If QTc prolongation occurs, we [will then] dose reduce or withhold, then resume the regular dose or permanently discontinue ivosidenib.”

According to the FDA label, the most common adverse reactions observed in at least 20% of study patients taking ivosidenib were fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, QTc prolongation on electrocardiogram, rash, cough, decreased appetite, myalgia, constipation, and pyrexia.

The FDA label for ivosidenib also recommends assessing blood cell counts and blood chemistries before initiating ivosidenib. This should be done at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy.

Differentiation Syndrome

[Editor’s Note: The FDA’s approval of ivosidenib includes a Black Box warning for differentiation syndrome.]

The most serious complication associated with ivosidenib is differentiation syndrome, which occurs in upward of 10% of patients 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; hypotension; and hepatic, renal, or multiorgan dysfunction. Differentiation syndrome occurs when under the pressure of an IDH inhibitor, immature IDH-mutated leukemia cells mature too quickly.

“Ivosidenib allows cellular differentiation to happen, correcting the problem of arrested development,” Ms. Hewitt explained. “However, when a blockade of white blood cells that were all paused suddenly differentiate at the same time, it can lead to hyperleukocytosis and cause issues in patients’ lungs. Whereas healthy lung tissue appears black on a chest x-ray, the inflammation associated with differentiation syndrome can cause a complete white-out on imaging.”

According to Dr. Pollyea, differentiation syndrome can be difficult to recognize because it can be so diffuse and may manifest in many ways. Nevertheless, he told JNCCN 360, it is important to identify it and manage it properly.

Ms. Hewitt highlighted shortness of breath, cough, fever, dizziness or lightheadedness, swelling of arms and legs, and sudden weight gain as symptoms that require immediate medical attention. If differentiation syndrome is suspected, corticosteroid therapy should be initiated, with hemodynamic monitoring until symptom resolution. Patients may also be treated with hydroxyurea to lower their white blood cell count quickly.

“Even though differentiation syndrome is most likely in the first few weeks of treatment, it can happen any time a patient is on therapy,” Ms. Hewitt added. “It should always be on your differential.”

Clinical Pearl: Patience

Although ivosidenib may induce deep and durable remissions in patients with AML, responses can take at least 3 months.7 For this reason, Ms. Hewitt cautioned patience when waiting for results.

“In many hematologic malignancies, we will know within days of initiating therapy whether the drugs are working,” said Ms. Hewitt. “With ivosidenib, on the other hand, it’s going to take a while.” The pivotal trial demonstrated a median time to response of 2 months (range = 0.9–5.6 months), but it is recommended to keep patients on ivosidenib for 6 months before discontinuing treatment, Ms. Hewitt said.

Although ivosidenib may induce deep and durable remissions in patients with AML, responses can take at least 3 months.

Future Directions

According to Dr. Pollyea, several important clinical trials are underway exploring various combinations of ivosidenib or enasidenib and intensive chemotherapy for relapsed or refractory AML. In addition, ongoing studies are testing combinations of ivosidenib or enasidenib plus a hypomethylating agent backbone for less fit patients. Finally, a phase I study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed IDH1/2-mutated AML.8

“There is also interest,” Dr. Pollyea said, “in combining ivosidenib with FLT3 inhibitors in patients with FLT3 mutation.”

In a small study of patients with IDH1-mutated myeloid malignancies, treatment with ivosidenib plus venetoclax, with or without azacitidine, had an acceptable safety profile and led to high rates of complete responses in patients with newly diagnosed AML.9

DISCLOSURES

Daniel A. Pollyea, MD, has received research funding from AbbVie and Teva, and serves as a consultant for AbbVie, Celgene, Bristol Myers Squibb, Syros, Kiadis, Novartis, Takeda, Foghorn Therapeutics, Aprea, Astellas Pharma, Gilead Sciences, Karyopharm Therapeutics, Syndax Pharmaceuticals, and Jazz Pharmaceuticals.

Rhonda Hewitt, NP, reported no conflicts of interest.

REFERENCES

  1. Kattih B, Shirvani A, Klement P, et al. IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction: a retrospective propensity score analysis. Leukemia 2021;35:1301–1316.
  2. S. Food and Drug Administration. FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia. July 20, 2018. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-relapsed-or-refractory-acute-myeloid-leukemia. Accessed July 12, 2021.
  3. S. Food and Drug Administration. FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia. August 1, 2017. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-targeted-treatment-relapsed-or-refractory-acute-myeloid-leukemia. Accessed July 10, 2021,
  4. Norsworthy KJ, Luo L, Hsu V, et al. FDA approval summary: ivosidenib for relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-1 mutation. Clin Cancer Res 2019;25:3205–3209.
  5. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology Am Soc Hematol Educ Program 2016;2016:348–355.
  6. S. Food and Drug Administration. FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation. May 2, 2019. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation. Accessed July 12, 2021.
  7. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020;135:463–471.
  8. Stein EM, DiNardo CD, Fathi AT, et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 2021;137:1792–1803.
  9. Lachowiez CA, Borthakur G, Loghavi S, et al. A phase Ib/II study of ivosidenib with venetoclax ± azacitidine in IDH1-mutated myeloid malignancies. J Clin Oncol 2021;39(suppl):7012.

 



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