The results of this study using sequential F→C→R yield similar findings to two other reported combination regimens used as initial therapy for CLL.13,14
There are obvious limitations in comparing phase II trials, and the apparent differences in the frequency of CR may be a result of several factors including schedule and dosing of agents administered and patient selection. The M. D. Anderson Cancer Center group reported that therapy with concurrent FCR achieved a CR in 70% of patients (95% CI, 63% to 76%).13
Myelosuppression was the major toxicity, with 26% of patients unable to complete six courses of therapy mainly because of persistent cytopenias; in addition, one third of the patients had more than one episode of infection, and an additional 10% had fever of unknown origin. In a Cancer and Leukemia Group B study of two different regimens combining fludarabine and rituximab, there was a higher frequency of CR for concurrent administration compared with sequential therapy (47% v
28%, respectively); however, rituximab dosing in the two groups was not similar.14
The concurrent arm received 11 doses (total dose = 4,125 mg/m2
) compared with four doses (total dose = 1,500 mg/m2
) in the sequential group. Despite more CRs in the concurrent arm, there was no difference in progression-free survival or overall survival between these groups, and in later analyses, these groups were combined.15
We chose a sequential program to take advantage of the activity of these agents without sacrificing dose-intensity with the goal of inducing high-quality sustained responses. We anticipated that this would allow patients to complete the planned therapy with less toxicity than concurrent strategies. Despite grade 3 or 4 neutropenia occurring in 50% of patients during fludarabine treatment and in 67% of patients during high-dose cyclophosphamide, only five patients (14%) experienced grade 3 or 4 infectious complications. There were no early withdrawals because of treatment-related toxicity. With the exception of the four patients who experienced treatment failure and were removed from study, all patients completed the entire sequential program. The median age of patients was 59 years (similar to previously published studies) with all patients having either Rai intermediate-risk (39%) or high-risk (61%) disease. Four patients (11%) achieved a CR after single-agent fludarabine. This is similar to the 6% to 20% CR frequency reported by others when single-agent fludarabine is used as initial therapy.1,6,14,16–20
With the subsequent consolidations, most patients improved the quality of their response, with 39% and 61% achieving a CR after high-dose cyclophosphamide and rituximab, respectively. As shown in , the quality of response correlates significantly with survival. Patients who achieve a CR/nPR have a longer survival compared with patients who only achieve a PR or who experience treatment failure (5-year survival, 92% v
33%, respectively; P
= .0008). Importantly, achieving a high-quality response overcomes the prognostic significance of high-risk disease because patients with Rai high-risk disease who achieve a CR/nPR have an overall survival comparable to intermediate-risk patients achieving a CR/nPR (5-year survival, 89% v
93%, respectively; ).
Compared with our previously reported F→C regimen, the addition of rituximab may convey a survival advantage (F→C: median overall survival, 58 months; F→C→R: median overall survival has not been reached; P
= .10). The finding that rituximab, when added to purine analog–based therapy for CLL, prolongs survival has been reported in at least three prior settings.13,15,21
Although none of these trials are prospective/randomized, the consistency of this finding across different regimens supports the concept that rituximab may prolong survival in CLL.
In addition, we used a highly sensitive PCR to assess MRD in patients who achieved a CR after treatment with this regimen. Nineteen percent of all patients (32% of those tested) were PCR negative after high-dose cyclophosphamide, and this further increased to 33% (52% of those tested) after completion of the entire regimen. Comparable MRD testing has not been routinely reported after chemoimmunotherapy. In patients who achieved a CR by NCI criteria, we find that a PCR-negative state imparts an excellent prognosis, with 90% still in remission at 5 years compared with 0% of the patients who were PCR positive. Patients in CR who are PCR positive have an excellent overall survival but a much shorter response duration. This finding further reinforces the concept that, in CLL, achieving high-quality responses predicts for longer response duration, longer time to next chemotherapy, and likely prolonged survival.1,2,6,18,21
The observation that CR and nPR correlate with prolonged survival has suggested to some that aggressive combination strategies (which yield more CRs than monotherapy) will lead to prolonged survival and should therefore be offered to most patients. However, we do not yet know whether achieving a CR is what permits patients to live longer or whether it is a biologic marker that identifies patients with sensitive disease who would do well in the salvage setting regardless of initial therapy. In line with this concern are the results of prospective randomized trials that indicate that more aggressive treatments yield more CRs but do not improve overall survival.1,18,19
This is important because combination regimens tend to be more toxic than monotherapy and most of the published literature for such regimens treat a group of patients 10 to 15 years younger than the median age for CLL. Furthermore, because these current strategies are not curative, it is necessary to balance the benefits of therapy against the risks, particularly in older individuals.
Patients treated on this regimen achieved high-quality responses that improved after each phase of therapy, including eradication of MRD as measured by flow cytometry and a highly sensitive PCR. The clinical benefit of attaining such high-quality responses and the plateau seen in the PCR-negative response duration curve is encouraging as we improve our therapies for patients with CLL.
Currently, there are two reported approaches to administering fludarabine, cyclophosphamide, and rituximab to previously untreated patients with CLL—the concomitant approach13
reported by M. D. Anderson and our sequential treatment program. Although both regimens produce long-lasting CRs in the majority of treated patients and either regimen can be considered state of the art therapy for selected patients, it is currently not possible to know which (if either) of these regimens is superior in terms of response and toxicity. Only a prospective randomized comparison of these regimens can answer this question.