Comparing Sequential Monotherapy With Combo Therapy in CLL

New York—During his presentation regarding treatments for chronic lymphocytic leukemia (CLL) at the 2019 Lymphoma & Myeloma congress, John Allan, MD, Assistant Professor of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, discussed important considerations for comparing the efficacy of sequential monotherapy with that of combination therapy.

“If curable, what percentage rate will make us happy? Is there even a cure rate in CLL? I believe moving the bar for cure significantly will be tough with current approaches based on fact that even undetectable high-risk patients with unmutated disease do not appear cured,” he told attendees.

Current evidence shows that PFS is not improved with novel agents compared with chemoimmunotherapy among patients with mutated disease.

Citing data from studies, such as RESONATE-2 IBR, iLLUMINATE, and CLL14, Dr Allan also shared his concern about the apparent progression of IGHV in uMRD patients after treatment with fludarabine, cyclophosphamide, and rituximab.

Although ongoing and past studies of CLL include varying patient populations (eg, those with and without del17p; young vs old), there are specific end points that should be considered for future studies in this setting.

“When comparing sequential monotherapy with combination therapy, there are issues in having PFS as the primary end point,” Dr Allan said.

This is because of differing treatment durations, a lack of consideration for time to approach failure of a class of drugs in fixed-duration retreatment strategies and time to progression after second sequential treatment; and no tracking the effect of toxicities and deaths before second-line therapy is initiated.

“Second progression-free survival or overall survival rates from relapse are intrinsically biased, as they assess only those who have had a relapse (ie, the highest risk patients) and underestimate the effects of toxicity or aggressive disease that leads to death before second-line therapy,” Dr Allan told attendees.

There are considerations regarding whether or not specific patient populations are better suited for receipt of different therapeutic approaches (eg, younger vs older, high-risk vs low-risk), and what associated costs (including financial and toxicity-related expenses) exist.

Do certain patients respond better with fixed-duration or continual therapy regimens? Other important factors to consider are toxicity and cost.

Through consideration of such factors and review of study data targeting these end points, the question of whether novel agent combinations are the final answer can potentially be resolved, suggested Dr Allan.—Hina Porcelli