“The management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine [Treanda], and the monoclonal antibodies alemtuzumab [Campath], rituximab [Rituxan], and ofatumumab [Arzerra]), and many more drugs are in advanced clinical development to be approved for the treatment of CLL,” Michael Hallek, MD, of the Center for Integrated Oncology, University of Cologne, Germany, wrote in Blood.
“In addition, the extreme heterogeneity of the clinical course as well as our improved ability for foreseeing the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, and a very aggressive course with high-risk leukemia,” Dr. Hallek commented. “On this background it becomes increasingly challenging to select the right treatment strategy for each condition.”
Dr. Hallek outlined three options using current treatment modalities to achieve long-term control of CLL with optimal quality of life:
1. Combine three, four, or more of the best agents in a simultaneous short-term treatment (up to 6 months) aimed at achieving minimal residual disease complete remissions lasting longer than the remissions achieved so far. For example, such an approach could combine the best currently available chemotherapies with antibodies and with kinase inhibitors or Bcl-2 antagonists, Dr. Hallek suggested. He cautioned, however, that these combinations would need to be compared against the current standard, rituximab plus fludarabine/cyclophosphamide (FCR), and results would not be available for a few years. “Moreover, such a treatment strategy will not be without toxicity and therefore be tolerated only by patients with good physical fitness.”
2. Use sequential monotherapies of new or old agents, giving each agent until maximal response was achieved. “After a long-lasting response, treatment could be repeated with the same agent, whereas alternative agents would be used in case of short remissions,” Dr. Hallek wrote. “This strategy might be applied in elderly or non-fit patients (‘slow go’), where the goal of treatment is symptom control rather than disease control.”
3. Combine the best agents “in a sequence that tailors the treatment according to the initial tumor load and the response to therapy,” Dr. Hallek suggested. “The goal of this strategy would be “to prevent the outgrowth of adverse leukemic subclones and to minimize the use of chemotherapy, thereby reducing the risk for secondary mutations of the CLL clone(s) and for secondary malignancies that are frequent and prognostically unfavorable events in CLL. For this treatment approach, I propose the term ‘sequential TTT (triple T)’ (tailored, targeted, total eradication of MRD),” Dr. Hallek stated. All currently available options would be used in a nonaggressive, nontoxic manner, with an aim of completely eliminating or controlling the malignant clone.
The triple T therapy, according to Dr. Hallek, would be available for fit and unfit patients because of its limited toxicity and could be given in an outpatient setting. Using current treatment options in a tailored and response-adjusted manner could also save money and resources, he noted. The proposed sequenced strategy, which still needs to be validated by clinical research, might consist of debulking, induction, and then maintenance. ■
Hallek M: Blood. September 24, 2013 (early release online).