A New Kid on the Block of Therapy for Acute Myeloid Leukemia

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MHE PublicationMHE May 2024
Volume 34
Issue 5

Crenolanib may have advantages over other therapies targeting acute myeloid leukemia with FLT3 gene mutations.

Approximately 63,000 new cases of leukemia will be diagnosed this year in the United States, and approximately one-third of those will be acute myeloid leukemia (AML), according to the American Cancer Society. AML occurs most often in older adults. The average age at which patients are diagnosed is 68, although it is not exclusively an older person’s disease. It also affects younger adults and children.

AML starts in the bone marrow, which makes the myeloid cells that eventually become the cells that make up blood: red blood cells, white blood cells and platelets. With AML, those myeloid cells become malignant, leading to a sharp buildup of immature white blood cells — also known as blasts or leukemia cells — that proliferate rapidly, crowding out the healthy blood cells.

Leukemia cells may have chromosomal abnormalities or gene mutations that drive this unregulated growth. Identifying mutations in the cells can help oncologists make a prognosis and guide treatment choices.

Current treatment

AML is not categorized into stage 1, 2 and so on, as many cancers are. Instead, oncologists consider variables when weighing treatment choices, including characteristics of the AML itself, whether it has spread outside the blood and bone marrow, and the age and fitness of patients. Low-dose chemotherapy or a combination of Venclexta (venetoclax) with other agents are options for patients who cannot tolerate intensive chemotherapy.

In other patients, AML treatment typically starts with intensive chemotherapy in the hospital, known as induction therapy. It usually includes the “seven plus three” regimen: seven days of continuous infusion of cytarabine with an anthracycline agent (usually daunorubicin) on the first three days.

The goal of induction chemotherapy for AML is to reduce the number of blasts and put the cancer into remission, according to National Comprehensive Cancer Network guidelines. Approximately two-thirds of patients with AML who receive induction chemotherapy go into complete remission, which occurs when the bone marrow has fewer than 5% blast cells and blood cell counts return to normal. The second phase of treatment, called consolidation, begins after a successful induction. This phase may include stem cell transplant, which involves replacing the blood-forming, or stem, cells in the bone marrow with cells from a donor or the patient’s own cells; low-intensity chemotherapy; or other treatments, with the goal of preventing the leukemia from recurring.

Eunice Wang, M.D.

Eunice Wang, M.D.

AML with certain mutations is less likely to go into remission with induction therapy or, if it does go into remission, more likely to come back. “Despite the fact that these patients are in for four to six weeks getting chemotherapy and then recovering from chemotherapy, we know that there are certain molecular subtypes of AML that tend not to respond to therapy or tend to relapse really quickly, including patients that have mutations in the FLT3 gene,” says Eunice Wang, M.D., chief of the leukemia service at Roswell Park Comprehensive Cancer Center in Buffalo, New York. Mutations in the FLT3 gene are common in AML, occurring in up to 30% of cases, and tend to be associated with worse outcomes.

A targeted treatment with an FLT3 inhibitor may help prevent relapse in such cases. Rydapt (midostaurin), a first-generation FLT3 inhibitor, was approved by the FDA in 2017 for patients with FLT3 mutations in AML after the drug was shown to improve survival rates when used in combination with chemotherapy.

More potent second-generation FLT3 inhibitors have since been developed. They include Xospata (gilteritinib), which was approved by the FDA in 2018 for the treatment of relapsed or refractory AML with an FLT3 mutation. Vanflyta (quizartinib) was approved in June 2023 for adults with newly diagnosed AML but only for cases with a specific type of
FLT3 mutation called an internal tandem duplication, in conjunction with chemotherapy. Researchers say, though, that additional treatment options for FLT3-mutated AML are needed because the risk of relapse within two years remains high.

Enter crenolanib

A phase 2 trial funded by Arog Pharmaceuticals, a biotech company headquartered in Dallas, was recently conducted to assess the utility of its crenolanib alongside intensive chemotherapy in adults with newly diagnosed FLT3-mutated AML. In early February, Wang, who was the lead author, and a group of researchers reported the results of this trial in the Journal of Clinical Oncology. The trial was designed to assess the safety and efficacy of crenolanib along with intensive chemotherapy in adults with newly diagnosed FLT3-mutated AML. It included 44 patients with FLT3-mutated AML ranging from 19 to 75 years of age. The patients received crenolanib in conjunction with induction chemotherapy, followed by consolidation therapy and, potentially, stem cell transplant. The results showed an overall response rate of 86%, with 90% of patients 60 years and younger responding and80% of older patients. Wang and her colleagues reported favorable survival outcomes, with a median overall survival that had not been reached at a 45-month follow-up. Among adults 60 years and younger, the estimated 3-year survival rate was 71.4% with a low cumulative rate of relapse at 15%. Participants 60 years and younger had a higher survival rate, with more than 50% still alive after four years of
follow-up.

The combination of crenolanib and intensive chemotherapy demonstrated acceptable safety, with adverse events including febrile neutropenia, diarrhea and nausea. Older patients experienced more toxicities and dose reductions and needed to have their dose held up more often than younger patients, the researchers reported. “We think that [these data are] highly promising, and that this regimen should be explored particularly for those younger [adult] patients,” Wang says.

Regarding crenolanib’s potential use in older adults, Wang notes that “those patients are potentially better suited for less intensive backbone therapy, potentially still in combination with this FLT3 inhibitor.” She points out some possible advantages of crenolanib, particularly in older people, as opposed to the other FLT3 inhibitors used in clinical practice. “For example,” Wang says, “crenolanib was not associated with any changes in EKGs [electrocardiograms], and there was no evidence of cardiac issues.” In contrast, she says, many patients have experienced heart-related side effects with Vanflyta that led to the drug being approved with a black box warning for cardiac toxicity.

Wang highlighted other distinguishing characteristics of crenolanib compared with existing FLT3 inhibitors, such as Rydapt. She highlighted the new drug’s short half-life, which means side effects are generally short- lived, allowing patients to resume treatment quickly. Wang says crenolanib is safe to take on a continuous schedule, unlike other FLT3 inhibitors that have dosing limitations.

Head-to-head comparison

Wang says a global phase 3 trial has started. The trial is a head-to-head comparison of crenolanib with Rydapt in medically fit patients ages 18 to 59 with newly diagnosed FLT3-mutated AML. Participants in this study are randomly assigned to receive one drug or the other alongside intensive cytarabine/daunorubicin (seven plus three) chemotherapy. Wang says this will be “the first trial that gives us a good idea of the relative benefit of adding [an] FLT3 inhibitor plus intensive chemotherapy.” That is noteworthy, she explains, because both FLT3 inhibitors currently indicated for this patient population — Rydapt and Vanflyta — were approved by the FDA based on randomized phase 3 trials that demonstrated improved survival with the FLT3 inhibitor plus chemotherapy compared with the outcome of chemotherapy alone.

“We’re also looking into other combinations,” Wang explains. The researchers are considering the possibility of a trial of crenolanib in combination with low-intensity chemotherapy or Venclexta in older patients with AML who may not tolerate intense chemotherapy well. Crenolanib does not appear to cause some of the side effects seen with other FLT3 inhibitors that tend to be problematic for older patients.

Wang says she anticipates that results of further studies may provide additional treatment options and hope for patients with AML with FLT3 mutations.

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