CLL (2007)

CHICAGO—Mature data from a single-institution trial of patients with chronic lymphocytic leukemia (CLL) show that 70% of those who achieved a response with a fludarabine-cyclophosphamide-rituximab (FCR) regimen as front-line therapy remained progression-free at five years. The data reported here at the ASCO Annual Meeting in an oral presentation by Constantine S. Tam, MD, a clinical fellow in the Leukemia Department at the University of Texas M. D. Anderson Cancer Center, showed that approximately 95% of the 300 patients responded to the regimen. The complete response rate was 72%, more than double what historical data show for fludarabine-cyclophosphamide alone, and the early-death rate was less than 1% (two patients). “FCR is the most effective CLL frontline regimen reported to date,” Dr. Tam said. In an interview after his presentation, Dr. Tam explained that the FCR regimen is increasingly being used in community practice in the United States as induction therapy because of the good complete-remission rates. The new data now show that time to progression is very favorable as well. Also Addresses Concerns about Opportunistic Infections The study also addresses concerns about opportunistic infection rates after FCR therapy, Dr. Tam said. The rates were very low—10% in the first year, 4% in the second, and 1% thereafter. “The long-term toxicity of FCR is very manageable,” he said. A second study from M. D. Anderson, also reported at the ASCO meeting in an oral presentation, on the same cohort of patients showed that for those who failed to respond or relapsed after initial FCR treatments, salvage therapy was unsatisfactory. First author Michael J. Keating, MD, Professor of Medicine in the Department of Hematology, said the salvage study suggested that patients who fail to obtain a complete or nodular complete response to FCR or first-salvage therapy should be considered for allogeneic stem cell transplant. Frontline FCR Early results of the front-line FCR trial, with 244 CLL patients, were previously reported by Dr. Keating and colleagues in the Journal of Clinical Oncology (2005;23:4079–4088). The new data covered survivors in the full cohort of 300 patients over 62 months. Patients were over age 16 (median of 57) with previously untreated CLL requiring therapy. The planned six cycles of therapy were completed in 74 percent of patients. Dr. Tam reported a complete response rate of 72% with the FCR regimen, a partial response rate of 11% in patients with residual disease in the bone marrow (nodular partial response), and a partial response rate of 12%. He said fludarabine alone would be expected to produce a 15% complete response rate, and fludarabine-cyclophosphamide, about 30%. Median times to progression with FCR were 80 months for patients having a complete response (216 patients), 80 months for those with a nodular complete response (32 patients) and 27 months for partial responders (36 patients). The projected progression-free survival rate at five years was 77% for complete responders, 65% for nodular partial responders, and 28% for partial responders.Figure: First author Michael J. Keating, MD, said the salvage study suggests that patients who fail to obtain a complete or nodular complete response to FCR or first-salvage therapy should be considered for allogeneic stem cell transplantation.The projected five-year survival rates were 90%, 81%, and 37%, respectively. When the analysis was restricted to the 190 patients who had a follow-up of at least five years, the actual five-year time to progression and five-year survival rates were 70% and 88%, respectively, in patients achieving a complete response. “When compared with a historical cohort of patients receiving fludarabine or fludarabine-cyclophosphamide-mitoxantrone, FCR was independently associated with superior time to progression,” Dr. Tam reported. Salvage after FCR Among the 300 patients in these two trials, 15 patients failed to respond to therapy, six died in remission, six developed Richter's transformation, 14 had another malignancy, and 77 relapsed. Dr. Keating reported that 67 patients received first salvage therapy after FCR with a variety of regimens. Median age was 59, 70% were male, and 56% had Rai Stage III-IV disease. The median time to disease failure after initial FCR treatment was 31 months. The initial responses to FCR were complete in 36 patients, nodular partial in 10, and partial in 14; seven patients had no response. Following the first salvage treatment, 17% of patients had a complete response, 8% had a nodular partial response, and 14% had a partial response. An initial complete response or nodular partial response significantly predicted response to the first salvage treatment, as did the patient's Rai stage and level of beta-microglobulin, but the initial time to treatment failure did not. Dr. Keating concluded that refractory/relapsed patients after FCR as initial therapy for CLL have a poor prognosis, and that most of these patients have adverse prognostic factors. Discussant The Discussant for both studies, Kanti R. Rai, MD, Professor in the Department of Medicine at Albert Einstein College of Medicine, began by complimenting Dr. Keating, whom he called his mentor. He credited Dr. Keating with “proving, trial after trial, that therapeutic progress can also be made with nonrandomized, single-arm, single-institution-based clinical trials, by accruing large numbers of patients and excellent follow-up.” “That goes in the face of our otherwise evidence-based medicine,” Dr. Rai said. Moving to the studies at hand, Dr. Rai hailed the trial of front-line FCR as “a huge success.” He noted, however, that there is no plateau on the relapse curve and that patients continue to relapse after first-line FCR even though they relapse very late. Dr. Rai said he was left with several pertinent questions after Dr. Tam's presentation: “Many of the patients with complete response had persistent cytopenias—what is the best way to categorize those patients?” he asked. Dr. Rai said he also was unsure of the best way to categorize patients who meet all of the criteria of a complete response but whose marrows show evidence of persistent lymphoid nodules (nodular partial response—nPR). “Where exactly among the response criteria does nPR belong?” he asked. Because approximately 10% of the patients in Dr. Tam's study were classified as having nPR, Dr. Rai said it might be time to ask the pathologists to help with some conclusion about the nature of a response with infiltrates in the nodule. And he questioned the use of 500 mg/m2 of rituximab in those achieving a nodular complete response, which he considered too high a dose. “It seems to me arbitrarily chosen, and, in my opinion, might be unnecessary,” Dr. Rai said. He said there is convincing evidence of synergy between rituximab and various chemotherapeutic agents, “and really, 375 mg/m2 rituximab seems to be quite adequate.” “Nearly a quarter of the 300 patients either relapsed by a median of 31 months, or failed to respond, after FCR,” Dr. Rai said. “The battle against CLL is far from over.”