Treatment for CML Is Unclear in Later Stages of Disease

An absence of guidelines for third-line treatment of chronic myeloid leukemia (CML) makes it difficult for doctors to make treatment decisions as the disease advances, although next-generation tyrosine kinase inhibitors (TKIs) individually and in combination with other therapies show promise, speakers said at the European Hematology Association 2021 Virtual Congress.

“A substantial proportion of patients experience failure with second-generation TKIs and ponatinib or are not good candidates for these therapies,” said J. Valentin Garcia-Gutiérrez of Hospital Universitario Ramón y Cajal, Madrid, Spain, during the session on unmet needs in CML.

Among therapeutic standouts is asciminib, an allosteric inhibitor that targets ABL myristoyl pocket, Garcia-Gutiérrez said. Asciminib selectively binds to ABL, and promising asciminib trial data for patients resistant or intolerant to TKIs has emerged, and combinations with asciminib, especially for mutated CML, also demonstrate utility.

“The good news is asciminib can be combined with conventional TKIs for resistant patients,” he said. Asciminib has a breakthrough designation for the treatment of patients with Philadelphia chromosome–positive CML in chronic phase (CP), previously treated with 2 or more TKIs.

ASCEMBL

In ASCEMBL, asciminib was compared with bosutinib as third-line treatment for patients with CML-CP. Adults previously treated with ≥ 2 TKIs and failure or intolerance to the most recent TKIs were enrolled. Patients with T3151 or V299L mutations were not enrolled.

“This showed superiority against bosutinib in major molecular response [MMR] and also superiority in complete cytogenetic response [CCyR],” Garcia-Gutiérrez said. Findings showed that 25.5% of patients on asciminib (n = 157) achieved MMR vs 13.2% (n = 76) of patients on bosutinib.

Safety profiles for patients treated with asciminib were generally superior to those for bosutinib, with the exception of thrombocytopenia (28.8% vs 18.4% of patients, respectively) and neutropenia (21.8% vs 21.1%). Notably, adverse events (AEs) leading to discontinuation were 5.8% for asciminib vs 21.1% for bosutinib.

This trial was followed by a compassionate use program study of asciminib in patients with CML who experienced TKI failure. Findings from the real-world study corroborated the earlier data. “Outside of the clinical trial, the possibility of achieving optimal response was very similar, with up to 50% to 60% of patients achieving or maintaining optimal responses,” Garcia-Gutiérrez said.

The most frequent AE was thrombocytopenia, with just 4 patients discontinuing by the 9-month follow-up, and none due to AEs.

Mutated CML

Investigators have evaluated treatment with the third-generation novel TKI olverembatinib (HQP1341) in patients with T3151-mutated CML-CP and CML accelerated phase (CML-AP). Olverembatinib showed significant efficacy with a manageable safety profile, with thrombocytopenia as the most prevalent AE, Garcia-Gutiérrez said.

According to the findings, 97% and 61% of patients with CML-CP and CML-AP achieved complete hematologic response, respectively; and 66% and 39% achieved CCyR. None of these patients were previously responsive to ponatinib, an older TKI, and the incidence of grade 3/4 AEs was minimal.

The TKI vodobatinib has demonstrated activity against a large number of mutations, with limited off-target activity, Garcia-Gutiérrez said. He noted there was a clear difference in efficacy findings between patients previously treated with ponatinib and those who were not. For previously treated patients (n = 16), the most common treatment-emergent AEs were thrombocytopenia, neutropenia, and increased amylase. The most common AE for non-pretreated patients (n = 15) was increased lipase.

In a separate study, the combination of asciminib with nilotinib yielded a “very good efficacy profile, with more than 60% achieving CCyR who did not have this at baseline,” Garcia-Gutiérrez said, noting also patients were heavily pretreated. TKIs combined with asciminib could prove attractive in patients with ABL domain mutations, he said.

“There are some very nice bigger studies in CML resistant patients in which we can see how venetoclax was quite effective. Also, what is important is that venetoclax seemed to be selective with TKIs, especially with ponatinib and dasatinib,” he said.

In a study of dasatinib plus the checkpoint inhibitor nivolumab in patients with previously treated CML, the 12-month MMR rate was 25.8% (95% CI, 11.9%-44.6%), with no incremental toxicity or dose-limiting toxicity, he said.

The ZEROLMC-01 study will look at bosutinib treatment followed by bosutinib plus atezolizumab, and the ACTIW study will evaluate avelumab plus TKIs vs TKIs alone in patients with CML-CP in CCyR without deep molecular response.

“New 3G TKIs with safer profiles could improve current outcomes in patients with CML resistant to other TKIs,” and immune checkpoint inhibitors in CML could improve later line outcomes, Garcia-Gutiérrez concluded.

Guidelines Are Unclear

The development of third-line treatments for CML is essential, as illustrated by statistics. The TKI imatinib has been one of the major success stories for treatment of CML; however, more than 50% of patients with CML-CP treated with this agent will develop resistance or intolerance, said Fabian Lang, MD, of Klinikum der Goethe University in Frankfurt, Germany.

He said 60% to 70% of patients fail to achieve MMR 2 years after initiation of second line treatment, and rates of progression and death are higher for patients who undergo third-line TKI therapy.

Resistance due to mutations is a factor, although patients are not typically screened for mutational risk. “This is one really obvious problem. If you have a patient who’s showing an insufficient response, you always should have a look at his mutational status,” Lang said.

Later-line CML treatment is characterized by adverse events that deeply affect a patient’s quality of life, Lang said. Whereas the disease may be manageable, chronic adverse events may require treatment changes, and patients will experience anxieties, such fear of disease progression and the need for more intense therapies, such as allogeneic stem cell transplantation (SCT) or, simply, not being among the majority of patients who respond well to treatment.

TKIs are associated with rashes, diarrhea, and itching, and patients may be hesitant to even mention these conditions to their physician, speakers said.

Specific TKIs carry strong contraindications in the event of renal impairment (imatinib), respiratory failure (dasatinib), and previous or concomitant arteriovascular disease (nilotinib, second line ponatinib). “You have to change them all the time due to serious side effects,” Lang said. Serious adverse events from TKIs may include risk of arterial occlusive events (ponatinib, nilotinib), pleural effusion (dasatinib), hepatotoxicity and cytopenias (any TKI).

The European Leukemia Net 2020 guidelines for CML beyond second line therapy leave much to be desired, Lang said. They lack definition of acceptable response in third, fourth, or fifth lines of therapy.

National Comprehensive Cancer Network guidelines advise that patients who fail to achieve cytogenetic or molecular responses following second-line and subsequent TKI therapy should be considered for alternative therapies or allogeneic SCT if deemed eligible; however, use of an alternate second generation TKI after treatment failure with 2 prior TKIs, including a second-generation TKI, is not associated with durable responses except in occasional patients with CML-CP, Lang said.

“So, we do not have any kind of clear guidelines. The only thing is in case of failure, mutational analysis should be included every time,” he said.

There is also lack of guidance for choosing third-line treatment. Lang suggested basing these decisions on treatment resistance or intolerance, and noted that allogeneic SCT and clinical trials with novel drugs are an option. “There’s a clear need for treatment optimization and novel strategies,” he said