Although patients who relapse within 3 years of front-line fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) therapy have poor survival when treated with conventional salvage regimens, these patients may be candidates for novel noncytotoxic therapies, according to an analysis of extended results from the phase II FCR study at the University of Texas MD Anderson Cancer Center in Houston.
To define optimal salvage strategy and identify patients who are not suitable for retreatment with FCR, Constantine S. Tam, MBBS, MD, and colleagues, of the University of Texas MD Anderson Cancer Center in Houston and the Peter MacCallum Cancer Center and the University of Melbourne in Australia, examined the survival and treatment outcome of 300 patients. At a median follow-up of 142 months, 156 patients had developed progressive chronic lymphocytic leukemia, with a median survival of 51 months following disease progression.
“During the study period, there was no protocol-mandated salvage strategy for patients who progressed following FCR, and patients were offered standard or investigational therapy at MD Anderson or treated locally, according to individual clinical status and physician discretion. To consolidate disparate salvage strategies, patients who received similar therapies were grouped together if the treatment outcomes of the individual salvage regimens were found to be similar on survival analysis,” the investigators explained. Salvage therapies were grouped into these six categories: FCR-based (n = 60), rituximab-based (n = 31), alemtuzumab (Campath)-based (n = 15), lenalidomide (Revlimid)-based (n = 8), intensive chemotherapy (n = 12), and other therapies (n = 10).
“The duration of first remission was a key determinant of survival following disease progression and first salvage,” the researchers wrote. “Patients with a short first remission (< 3 years) had short survival irrespective of salvage therapy received; these patients have a high unmet medical need and are good candidates for investigation of novel therapies. In patients with a long first remission (≥ 3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in a subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care.”
The authors pointed out that “significant therapeutic advances have occurred since the patients on this study received their first salvage regimen.” They include the tyrosine kinase inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig), novel anti-CD20 antibodies, bcl2 inhibitors, and chimeric antigen receptor T cells.
“These agents all show promising activity in chronic lymphocytic leukemia but are associated with considerable costs and are not affordable in many health-care systems if applied broadly across large numbers of patients with chronic lymphocytic leukemia. To responsibly and effectively progress the development of these promising new therapies, they should be targeted specifically to groups where they can make the greatest contribution, such as those not suitable for FCR retreatment. Our experience and that of others suggest that an expanded ultra-high risk category including (1) patients with TP53 aberrations and (2) those with early (< 3 years) FCR failure represents an effective and practical way to identify such patients,” the researchers wrote. “Finally, patients with significant marrow failure and thrombocytopenia had very poor treatment outcomes in our series, largely due to poor tolerance of chemotherapy and exclusion from therapeutic trials. The nonmyelosuppressive nature of many of the novel agents provides an opportunity to offer these patients effective salvage.” ■