TKI Leads to Superior Outcomes in ALL With an ABL-Class Fusion, Study Says

Patients with acute lymphoblastic leukemia (ALL) who had an ABL-class fusion had superior outcomes when they received adjuvant therapy with a tyrosine kinase inhibitor (TKI) in first remission, according to a new study.

The findings were reported in the British Journal of Haematology.

Corresponding author Anthony V. Moorman, PhD, of Newcastle University, in the United Kingdom, and colleagues explained that patients with ALL who have BCR-ABL1-like or Philadelphia chromosome-like gene expression profiles tend to have poor outcomes. ABL-class gene fusions are a network of chimeric gene fusions that functionally result in constitutive activation of the ABL pathway. This response mimics BCR-ABL1 fusion.

“A subset of patients with BCR-ABL1-like ALL harbor an ABL-class fusion defined as a fusion between ABL1, ABL2, PDGFRB/A or CSF1R and a variable partner gene,” they said. “Patients harboring ABL-class fusions have high levels of minimal residual disease (MRD) at the end of induction (EOI) and a high risk of relapse.”

Preclinical evidence has suggested that TKIs can be effective against ABL-class fusions, but the research to date is limited. In an effort to bolster the data around the question, Moorman and colleagues identified 191 patients from the UKALL2011 trial who had ALL and at least 1% MRD following induction therapy.

Of those, 126 patients were screened for ABL-class fusions, and 21 were found to harbor an ABL-class fusion. The patients, who had a median age of 9 years, had a median MRD level of 32%, driven largely by 10 patients who harbored EBF1‐PDGFRB.

Some of the patients (13), were identified prospectively, and were given the TKI imatinib (Gleevec) in their first remission. The other 8 patients were identified retrospectively and thus were given standard EOI therapy without a TKI. The latter group was treated as the control group.

The TKI group and the control group had similar demographics, white cell counts, and post-induction MRD. Eight patients in the TKI group had EBF1-PDGFRB, compared to 2 in the control group.

At a median follow up of 3.9 years, none of the patients in the TKI group suffered a leukemia-related event. Conversely, 6 of 8 patients in the control group either relapsed or died from primary refractory disease. That translated into a 4-year relapse/refractory rate of 0% for the TKI group and 62.5% for the control group. Event-free survival and overall survival rates similarly were superior among those receiving TKI.

Three patients in the control group were eventually treated with TKI following relapse, but 2 of the 3 died due to respiratory/multi-organ failure. Two patients in the TKI group died of transplant complications. Overall, 2 of 13 patients in the TKI group died; half of the 8 control-group patients died.

Moorman and colleagues noted that because the patient population considered in this study is so small, it is highly unlikely that a randomized clinical trial will be possible. Instead, they said retrospective studies like this one will likely be among the best evidence for treating these patients.

“We have demonstrated a reduced risk of relapse for ABL-class fusion patients with EOI MRD ≥1% treated with adjuvant TKI without a significant increased risk of severe toxicity,” they said.

Reference

Moorman AV, Schwab C, Winterman E, et al. Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion. Br J Haematol. Published online September 14, 2020.