ABSTRACT: The survival of patients with chronic lymphocytic leukemia (CLL) has significantly improved in the last 30 years. The introduction of purine analogs in the treatment armamentarium followed by the combination of these compounds with alkylating agents first improved response rates and progression-free survival (PFS) when compared with alkylating agent-based therapy only. However, the great advance arrived with the development of a chemoimmunotherapeutic approach comparing this with chemotherapy alone demonstrating an improvement not only in terms of response rate and PFS but also, for the first time, in the rate of overall survival (OS). The last decade brought significant achievements in the understanding of CLL pathogenesis leading to the development of new agents targeting cell surface, intracellular pathways, and tumor microenvironment. As traditional chemotherapy is associated with acute and long-term toxicity, interest in these non-chemotherapeutic treatments has been constantly growing. The challenge will be to develop a rationale for non-chemotherapeutic approaches using these new agents as monotherapy, or in combination, with the aim of obtaining an individualized strategy based on disease characteristics and even patient basis. Hopefully, an increasing participation of ultra high-risk CLL patients in clinical trials evaluating the efficacy of these new treatments may lead to reasonable success, if not cure, in this unfavorable setting.

KEYWORDS: chronic lymphocytic leukemia, chemoimmunotherapy, monoclonal antibodies, target therapy

CITATION: Montillo et al. a new era is Coming up in the treatment of Chronic Lymphocytic Leukemia. Lymphoma and Chronic Lymphocytic Leukemias 2014:4 9–19 doi:10.4137/LCLL.s13715.

RECEIVED: June 11, 2014. RESUBMITTED: August 8, 2014. ACCEPTED FOR PUBLICATION: august 19, 2014.

ACADEMIC EDITOR: Mitchell Smith, Editor in Chief

TYPE: Review

FUNDING: Authors disclose no funding sources.

COMPETING INTERESTS: Authors disclose no potential conflict of interest.

COPYRIGHT: © the authors, publisher and licensee Libertas academica Limited. this is an open-access article distributed under the terms of the Creative Commons CC-B – C 3.0 License.

CORRESPONDENCE: marco.montillo@ospedaleniguarda.it

This paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. All editorial decisions were made by the independent academic editor. All authors have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants. Provenance: the authors were invited to submit this paper.


There have been tremendous advances in the treatment of chronic lymphocytic leukemia (CLL) over the past two decades, with the treatment goal shifting from symptom palliation to achieve complete remission (CR) and improve survival.

CLL has traditionally been regarded as an incurable dis­ease of the elderly, where the typical patient was expected to die “with CLL” rather than “of CLL.” Chemotherapy was with single-agent alkylators and was purely palliative in intent. The pursuit of maximal disease eradication was not regarded as a worthwhile goal in the majority of patients.

Recent evidence, however, contradicts this traditional view and shows that the majority of patients diagnosed with CLL will die of complications relating to CLL.1

Unlike other types of leukemia, once a diagnosis of CLL is made, treatment may not necessarily be initiated. This current consensus by the international community, initially published in 1988,2 is informed by the observation that single-agent chlorambucil when compared to delayed treatment had no significant impact on overall survival (OS). Findings of a meta-analysis on seven trials conducted in CLL showed that there was no statistically significant difference in survival between those patients who were treated early versus those in whom therapy was deferred until there was a clinical indication for treatment.3

However, these trials were performed by using alkylating agents. Since then, the recommendations were revised but not changed in 19964 and 2008.5

At the present time, treatment should be initiated if the disease is active. Basically, treatment should be started in the presence of cytopenias (anemia and/or thrombocytopenia) because of bone marrow failure, if bulky (>10 cm) or rapidly progressing lymphoadenopathy occurs, or if a rapid increase (doubling within 6 months) in the lymphocyte counts or severe constitutional symptoms (night sweats, fever, weight loss, fatigue) occur.5

Over the last 20 years, there have also been major advances in our understanding of molecular factors associated with increased risk of progression. The clinical utility of these factors is being explored to determine whether we can identify groups of patients who should be treated earlier in their disease course and whether we can tailor therapy for groups of patients with specific molecular markers of disease.