Pitting new treatments for chronic lymphocytic leukemia against old ones: how do they fare?

ABSTRACT

Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) patients during the last two decades. In this review we present a personal case study for discussion on contemporary management in CLL. Presently immunochemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) is the standard upfront regimen for physically fit patients requiring treatment. Patients older than 65 years can be treated with modified doses of FCR, bendamustine, or chlorambucil combined with anti-CD20 antibody. This treatment can be repeated at relapse when the duration of response is over 2 years. Patients at high risk (with 17p deletion or early relapse) need alternative treatment with novel agents, e.g. ibrutinib or idelalisib. However, the optimal use of the novel agents in terms of duration, combinations, and long-term adverse effects is unknown. In selected eligible patients at high risk, allogeneic transplantation should be considered. Clinical trials in all stages of treatment are encouraged.

KEYWORDS:

• Chronic lymphocytic leukemia
• prognosis
• immunochemotherapy
• novel agents
• target treatment

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Despite recent therapeutic advances, CLL remains an incurable disease, and treatment should be initiated only for symptomatic or progressive disease.

• Genetic risk stratification by FISH study should be performed prior to starting treatment for the selection of the best treatment.

• FCR is the first drug combination changing the natural history of CLL and accepted as the gold standard for eligible patients. The alternative choice of chemotherapy (fludarabine plus cyclophosphamide, bendamustine, or chlorambucil) and anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) varies according to patient status.

• Optimal therapy for patients with 17p del CLL remains to be determined. The BCR and Bcl2 inhibitors showed efficacy and acceptable toxicity profile and are the preferred upfront treatment. Eligible patients should be considered for allogeneic stem cell transplant in the first remission.

• The role of consolidation or maintenance treatment after immunochemotherapy has not yet been established and should only be undertaken in the context of a clinical trial. There is no place for ASCT in CLL.

• Allogeneic stem cell transplantation as a treatment option should be discussed in young patients with early relapse of CLL.

• Although the response rate and duration with chemoimmunotherapy have improved considerably, a curative therapy in CLL is still lacking. Even patients achieving molecular response eventually will relapse. The attempts to cure CLL switched from increasing intensity of cytotoxic combinations to discovery of the smart molecules targeting the pathogenetic pathways of the disease. How to best incorporate old and new therapies now is not clear. Novel agents have the potential to replace chemotherapy in the future treatment of CLL.

• As seen in Figure 1 there is an important place for clinical trials evaluating novel strategies in each of the CLL patient requiring treatment.

• Novel agents are the most important for the elderly who represent the majority of patients and for patients with comorbidities who do not fit intensive immunochemotherapy.

• The recent advances in the research of CLL biology give hope for finding agents targeting pathophysiology and improving the outcome of all CLL patients.