In pursuit of a complete remission: exploring novel therapeutic agents in CLL

Achievement of a complete remission is a prerequisite for ultimately improving the long-term survival of patients with most malignant diseases. The feasibility of achieving a complete response in patients with chronic lymphocytic leukemia (CLL) has been markedly improved with recent therapeutic advances. Whereas responses in the past with standard chemotherapy were measured in palliative terms for relatively short intervals, an increase in understanding of patterns of drug resistance coupled with the dedication to innovative clinical trials have substantially improved the quality and quantity of the observed remissions. As a single agent, fludarabine produces complete response in approximately 20% to 40% of previously untreated patients.

Recently, the administration of fludarabine concurrently with rituximab in a trial conducted by Byrd and colleagues produced 47% complete response rate in untreated patients with B-cell CLL (Byrd et al, Blood. 2003;101:6-14). Previously, Flinn reported that 47% of similar patients also achieved a complete response with the combination of fludarabine and cyclophosphamide (Flinn et al, Blood. 2000;96:71-75). In a single institutional study, investigators at M. D. Anderson Cancer Center reported an unprecedented complete response rate of 67% in a preliminary report of treatment for this disease (Keating et al, Blood. 2002;100:205a).

While there has been an increasing complete remission rate in those trials employing combined therapeutic agents, there is uniform concern that both myelosuppression and immunosuppression may become dose-limiting. Therefore, the critical need for identifying new agents with selective toxicity toward the malignant B cells must be recognized. Furthermore, novel agents that circumvent recognized molecular mechanisms of drug resistance (eg, abnormalities inp53) should be pursued. Strategic combinations of agents, preferably working through distinctly different molecular targets, will be needed to achieve the ultimate best results with this disease. Consideration for selective toxicity and tolerability will yield the desired effects for improving long-term remissions. There is hope that these goals can be realistically achieved.

Pepper and colleagues (page 2454) report that a vitamin D₃analog (EB1089) induces apoptosis in leukemic cells obtained from patients with CLL. The observation that this in vitro effect occurred equally in leukemic cells obtained either from previously treated or untreated patients, and in one patient's cells irrespective of ap53 mutation, is encouraging. Indeed, it appears that this agent works through a p53independent mechanism. The reduction in both bcl-2 and mcl-1 protein expression in the apoptotic leukemic cells without an increase in either bax or p21 would be consistent with that observation. The comparative data showing a selective cytotoxic advantage in leukemic B cells compared to normal lymphoid cells may be statistically significant, but its potential relevance in the clinic will need to be further validated. This agent may still be immunosuppressive. A potentially attractive feature of this agent appears to be its unique mechanism of action resulting in phosphorylation of p38 MAP kinase and dephosphorylation of ERK. Park had previously reported similar results with this agent in NCI-H929 myeloma cells (Park et al, Br J Haematol. 2000;109:576-583).

In reviewing the literature, it is apparent that this vitamin D₃ analog has had a positive antitumor effect both in vitro and in vivo with animal models using human tumor cell line xenografts. The preclinical therapeutic index was favorable, and the agent was felt to have less potential for inducing hypercalcemia than other vitamin D derivatives. In the limited phase 1 studies that have been reported, the drug was basically well tolerated. Reversible dose-limiting toxicity manifest as hypercalcemia was observed on the daily dosing schedule at the highest dose administered. Subsequent phase 2 evaluation in patients with lymphoid malignancies has not been extensively reported.

The importance of this report should focus upon the process of searching for novel therapeutic agents that are capable of selectively inducing apoptosis in leukemic cells obtained from patients with CLL. Agents that work through novel molecular targets and induce apoptosis in leukemic cells from patients who have either had prior chemotherapy or exhibit known parameters predicting for poor responsiveness to conventional agents deserve thorough investigation. This specific analog may provide a “lead” for further clinical evaluation or chemical modification to enhance the therapeutic index. Future clinical trials targeting combinations of agents may enable the successful administration of lower doses of the drug that are not associated with hypercalcemia. Alternatively, newer methods for dealing with hypercalcemia may be considered.

New antileukemic agents should be specifically explored in disease-specific phase 1 clinical trials. In remembering the initial phase 1 trials with fludarabine in humans, there was very limited evidence of clinical benefit outside the setting of lymphoid malignancies. We do not have the luxury of dismissing agents prematurely but must continue to search for new agents in our relentless journey toward improving the outlook for patients with this common form of malignant disease.