Blood, 1 April 2003, Vol. 101, No. 7, pp. 2449-2449
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 in
p53) 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 D3
analog (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 a
p53 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.
Michael R. Grever
The Ohio State
University
