By John C. Byrd, MD
2009-03-01
Dr. Byrd receives support for the cost of clinical trials with agents that are currently
being developed by Genentech and Biogen IDEC.
Lamanna N, Jurcic JG, Noy A, et al. Sequential
therapy with fludarabine, high-dose cyclophosphamide, and rituximab in
previously untreated patients with chronic lymphocytic leukemia
produces high-quality responses: molecular remissions predict for
durable complete responses. J Clin Oncol. 2009;27:491-7.
The initial use of chemotherapy for CLL has evolved over the past 15
years from alkylator-based monotherapy to fludarabine and then to
fludarabine/cyclophosphamide (FC) based upon well-designed randomized
phase III studies demonstrating improved overall response (OR),
complete remission (CR), and progression-free survival (PFS) with
successive treatment regimens. Several phase II studies adding
rituximab to the fludarabine regimens demonstrated further promising
incremental increases in CR rates and durations of PFS as compared to
historical trials. At the 2008 ASH meeting, two large randomized phase
III trials demonstrated that FC plus rituximab (FCR) was better than FC
alone with respect to OR, CR, and PFS. All of the large phase III
combination studies of FC or FCR to date have administered the
therapeutic agents together based upon multiple preclinical studies
suggesting synergy between each agent. While this approach is based
upon pre-clinical work, disadvantages to concurrent therapy include the
inability to deliver dose intensity of each agent and also the
potential of enhanced toxicity, such as secondary acute myeloid
leukemia.
Lamanna, et al., from the Memorial Sloan-Kettering Lymphoma Program,
have now reported promising data with sequential use of standard-dose
fludarabine, high-dose cyclophosphamide, and consolidation rituximab
(F→C→R) for previously untreated CLL where they demonstrate similar
response, CR, and PFS as observed with the FCR-based regimens. This
regimen was well tolerated despite a high proportion of advanced Rai
stage patients, as compared to most other trials reported for CLL. This
group rightfully calls attention to their previous study of sequential
fludarabine followed by cyclophosphamide (F→C) and a randomized phase
II study comparing sequential versus concurrent rituximab with
fludarabine that all demonstrated no obvious disadvantage to sequential
treatment with respect to PFS but improved tolerability for patients.
It is only through a randomized phase III trial that this will be
adequately evaluated, and this study suggests that performing such a
trial should be considered in the future.
The phase II trial reported by Lamanna, et al. brings
forth other important points that are worthy for consideration in the
practice of caring for CLL patients. Specifically, they demonstrated
that patients attaining a CR with absence of minimal residual disease
(MRD) in the bone marrow had an extended PFS and overall survival (OS).
This finding provides impetus to consider a bone marrow biopsy/aspirate
with appropriate diagnostics for detecting MRD in all CLL patients
receiving combination therapy. Given the short PFS and OS of patients
not attaining a CR in this and other previously reported studies, it
emphasizes that additional therapies should be considered as part of
future clinical trials. It is in this context that sequential treatment
to the point of absence of detectable MRD might provide an interesting
study question and potentially limit unnecessary exposure to multiple
agents among early-treatment responders.
Finally, the long-term results of this study support
other phase II studies that have suggested that the addition of
rituximab to CLL therapy may improve OS, as compared to historical
controls. The recently reported randomized phase III trial by the
German CLL study group should address this question in the future.
Lamanna, Weiss, and colleagues are to be commended
for their systematic pursuit of the sequence-treatment concept over the
past decade that has added another relevant question for future
clinical trials in CLL.
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