Comment on Eichhorst et al, page 885

In this issue, Eichhorst and colleagues show in a large randomized phase 3 clinical trial that combination therapy using fludarabine and cyclophosphamide is superior to fludarabine alone for younger previously untreated CLL patients. In addition, they found a reduced level of clinical responses when imaging was considered as part of restaging compared with responses defined by recommended NCI standards.

These are heady times for chronic lymphocytic leukemia (CLL) caregivers, with significant progress in both prognosis evaluation and treatment options. The course of this complicated heterogeneous disease may be very difficult to predict for a given patient even with the novel prognostic tools now available.1  In addition, we now have an increasing array of choices for use, including single or combination use of various purine nucleosides, alkylating agents, and monoclonal antibodies.

CLL treatment options by decade. A timeline over the last several decades of the increases in complete remission (CR) in relation to the drug protocols used for treatment of previously untreated B-CLL. CR percentages are shown for previously untreated B-CLL. Illustration by Paulette Dennis.

CLL treatment options by decade. A timeline over the last several decades of the increases in complete remission (CR) in relation to the drug protocols used for treatment of previously untreated B-CLL. CR percentages are shown for previously untreated B-CLL. Illustration by Paulette Dennis.

For many years, treatment options in CLL were relatively limited and not capable of inducing high levels of overall responses or complete responses (CRs), or achieving a negative minimal residual disease state. The figure, however, shows the ability to induce higher and higher levels of complete responses in CLL—from the alkylator era of approximately 5% CR to more modern times where a 10-fold enhancement of CR is achieved. The current “hot” treatment option may be chemoimmunotherapy where phase 2 trials have been reported to result in overall responses near 100% and CR rates from 45% to 70%.2-4 

However, there have been very few randomized clinical trials that validate the effectiveness of combination therapies for CLL. The trial conducted by Eichhorst and colleagues builds on prior in vitro and in vivo work demonstrating nonoverlapping mechanisms of action for fludarabine (F) and alkylators where the former inhibited DNA repair induced by agents such as cyclophosphamide (C) and phase 2 trials showing efficacy for F and C combinations. In the present trial, Eichhorst and colleagues randomized CLL patients who were 65 years or younger to receive either the standard 5 days of F (25 mg/m2) or F (30 mg/m2) for 3 days with C (250 mg/m2)upto6 cycles. Both response rates and treatment-free intervals were better with F plus C (FC) versus F.

This trial has illustrated several important issues. First, it shows higher overall responses for fludarabine monotherapy compared with a recent intergroup trial, likely the result of older patients in that trial5 ; second, the use of large randomized phase 3 trials such as this study underscore that overall response rates and CR levels seen in phase 2 trials are influenced by patient selection and are often higher than those observed in large phase 3 studies. Of most importance, they have reported that with the use of computed tomography scans and ultrasound a significant downstaging of CR rates occurs particularly for the FC. This outcome should give clinicians pause when telling patients that they are in CR and strongly endorses the need for updating the NCI 96 standards used to determine levels of clinical response in CLL. As the efficacy of therapy has improved, how to perform assessment of clinical response in CLL is not a trivial issue and includes not only what imaging tests to perform but also what kind of minimal residual test should be done in the true CR patient. ▪

1
Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL.
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2
Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.
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3
Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712).
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4
Kay NE, Geyer SM, Lin T, et al. Combination chemotherapy with pentostatin, cyclophosphamide and rituximab induces high rate of remissions including complete responses and achievement of minimal residual disease in previously untreated B-chronic lymphocytic leukemia [abstract].
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5
Finn IW, Grever MR, Neuberg D, et al. Fludarabine and cyclophosphamide produces a significantly higher response rate and more durable remissions than fludarabine in patients with previously untreated CLL [abstract].
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2004
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