In spite of the efficacy of the treatment regimen of fludarabine, cyclophosphamide, and rituximab (FCR) in chronic lymphocytic leukemia (CLL), most CLL patients are likely to relapse. Guidance is needed for managing these patients at the time of FCR failure.
To define optimal salvage therapy – and to identify patients who would not benefit from re-treatment with FCR – Constantine S. Tam, MD, MBBS, of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues conducted a retrospective study of 300 CLL patients enrolled in a phase II study of FCR. They found that the duration of first remission (CR1) was a key determinant of survival following disease progression and first salvage.
Patients with a short CR1 (<3 years) had a truncated survival, irrespective of salvage therapy received, while patients with a long CR1 (≥3 years) – and who had salvage treatment with either repeat FCR or lenalidomide-based therapy – had a median survival exceeding five years.
The researchers also found that patients with CR1 <3 years had a median post-salvage survival of 13 months, compared with 63 months for patients with CR1 ≥3 years (p<0.001). After analyzing salvage therapy data spanning 13 years, they confirmed the prognostic significance of CR1 was not due to an effect of the era in which a patient was treated.
What is the take-home message from this study? According to Dr. Tam, “Patients with <3-year remission after FCR are refractory to standard treatments and should be prioritized for novel therapies and/or transplantation.” In addition, “Retreatment with FCR after three years is acceptable,” he told ASH Clinical News.
In further analyses of salvage therapy, the group found that patients receiving either FCR-based or lenalidomide-based salvage had superior survival to those who received other regimens, with a median survival of 82 months versus 29 months (p<0.001), respectively.
Finally, the authors noted that those patients with specific cytogenetic changes, such as 17p deletion or 11q deletion experienced inferior post-progression survival, compared with other cytogenetic subgroups.
Given the results of this study, expanding the ultra-high risk category of CLL patients to include those with early FCR failure, as well as patients with TP53 aberrations, may be a practical and effective way to identify those who may benefit most from novel, high-cost therapies (such as ibrutinib and idelalisib).
“These promising new therapies should be targeted specifically to groups where they can make the greatest contribution, such as those not suitable for FCR retreatment,” Dr. Tam and colleagues wrote. In terms of how the results of the current study can aid in the development of those therapies, Dr. Tam pointed out that “It would concentrate novel agent development to those patients who truly have no alternative treatment options.”
One study limitation was that patients were not managed uniformly on specified protocols post-FCR failure, and patient characteristics may have influenced choice of salvage therapy. Dr. Tam explained that, even now, there are still no specific protocols for FCR failures. These patients are “lumped into relapsed CLL in general, although our studies suggest that we can further dissect out those [patients] truly in need of novel therapies from the big category of relapsed CLL” by focusing on 17p deletion, P53 mutations, and FCR response at <3 years.
- Tam CS, O’Brien S, Plunkett W, et al. Life after FCR: Outcomes of patients with chronic lymphocytic leukemia who progress after frontline treatment with fludarabine, cyclophosphamide and rituximab. Blood. 2014 October 3. [Epub ahead of print]