Should the treating clinician prescribe anti-CD20 maintenance drugs like rituximab in patients with CLL? The answer is: it depends, says Melbourne leukaemia expert Dr Constantine Tam.
Writing in an editorial published in The Lancet Haematology, Dr Tam from St Vincent’s Hospital and the Peter MacCallum Cancer Centre said several factors had to be considered when deciding on anti-CD20 maintenance.
First, some patients who have a mutated IGHV gene and who are MRD-negative after initial therapy might be functionally cured and have no disease to treat.
Second, both the previously-published PROLONG study and the Mabtenance study showed a reduced benefit in patients who entered maintenance with no detectable MRD in the bone marrow, regardless of mutation status.
“The excellent outlook of these patients combined with the modest risks of maintenance point to observation being the more prudent policy,” he said.
“For the remaining patients, the clinician must weigh up the costs and risks of two years of antibody maintenance, for a gain in time to next treatment of one year or less, and no discernible benefit in overall survival.”
“In the era before the kinase inhibitors, this gain might have been worthwhile, particularly for older or infirm patients with few options for salvage therapy,” he said.
“Whether this benefit is still relevant today depends on the clinician’s access to novel drugs, and whether the safety of these agents hold up with longer-term follow-up.”
Dr Tam was commenting on the ‘Mabtenance’ trial which randomised 263 European patients to two years of maintenance rituximab.
Participants had a complete or partial response to first-line (80%) or second-line (20%) rituximab-containing chemoimmunotherapy.
Rituximab maintenance improved progression-free survival (47.0 vs 35.5 months) as well as time to next treatment and event-free survival, but there was no difference in overall survival.
The cost was an increase in the rate of grade 3-4 neutropenia (21% vs 11%) and all grades of infections (66% vs 50%), but with no increase in infection mortality.
The researchers concluded that rituximab was an affordable option for CLL patients worldwide, but more information was needed to compare it with newer options such as obinutuzumab, lenalidomide and small molecule inhibitors of the B-cell pathway.
According to Dr Tam a “fascinating” aspect of the study was the uniform (3-monthly) testing of minimal residual disease (MRD) with highly sensitive flow cytometry.
“Although use of fludarabine, cyclophosphamide, and rituximab is commonly associated with median progression-free survival of three to seven years, evidence of MRD relapse in the peripheral blood emerged very early at a median of 12·0 months after chemoimmunotherapy, and could be delayed to 31·3 months with rituximab maintenance in the present study.
“An important mechanism of prolonged antibody therapy could be to delay the return of peripheral blood relapse, with less material effect on time to next treatment, which is arguably the more important endpoint for use of medical resources,” he said.
Overall, decisions about maintenance therapy with anti-CD20 drugs like rituximab after a response to initial treatment for chronic lymphocytic leukaemia needs an individual assessment of the likely risks and benefits, he concluded.