Physician, Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, PA, USA
Received date: May 01, 2015; Accepted date: May 03, 2015; Published date: May 15, 2015
Citation: Pathak P (2015) The Changing Therapeutic Landscape of Chronic Lymphocytic Leukemia. J Blood Lymph 5:e120.doi:10.4172/2165-7831.1000e120
Copyright: © 2015 Pathak P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Chronic lymphocytic leukemia (CLL) is characterized by slowaccumulation of mature but functionally incompetent lymphocyteswhich are monoclonal in origin. The disease course is highly variable--with some patients having long survival times and never requiringtreatment and others who live only for a few years even with treatment.
In the past, the treatment of CLL consisted of chemoimmunotherapy,usually with FCR (fludarabine, cyclophosphamideand rituximab), PCR (pentostatin, cyclophosphamide, rituximab) orBR (bendamustine and rituximab). Not all patients with CLL willrequire treatment. Considering the adverse effects of traditionalchemotherapy, only patients with disabling symptoms or cytopenias proven to be secondary to CLL (not autoimmune related) are usuallytreated. A high white cell count or disfiguring lymphadenopathy are not indications for treatment.
Recent developments in the understanding of the B cell receptor(BCR) and the B-cell receptor pathway signaling have changed thetherapeutic landscape of CLL. Most promising of the small moleculeinhibitors target the bruton tyrosine kinase (BTK), phosphoinositide 3kinase (PI3K) and B cell CLL/lymphoma protein 2 (BCL-2) familyproteins. Out of the novel agents, two of them have already been approved for the treatment of CLL.
Ibrutinib is a first-in-class oral, selective, irreversible inhibitor ofBTK, a member of the Tec kinase family involved in the BCR signalingcascade . The drug was approved by the Food and DrugAdministration (FDA) on February, 2015 for the treatment of patientswith CLL who received at least one prior therapy. The approval wasbased on an open label multi-center study conducted by Byrd et al. .They demonstrated an overall response rate of 58.3% in 48 patientswith CLL who were treated with 420 mg of ibrutinib daily. The patientpopulation was heavily pretreated (median number of previoustherapies was 4) and the responses were independent of high riskfeatures including 17p deletion. Toxic effects were limited, andresponses were often durable with prolonged therapy. This benefit waslater confirmed in a randomized open label multi-center phase III trialof ibrutinib versus ofatumumab in 391 previously treated patients withCLL or small lymhocytic lymphoma (SLL) . The ORR, OS and PFSwere significantly higher in the ibrutinib arm. Treatment withIbrutinib is associated with an initial lymphocytosis which does notsignify disease progression but rather the migration of leukemic B cells from the lymph nodes, bone marrow and spleen into the blood.
Idelalisib is a potent, oral, selective inhibitor of PI3Kdelta andpromotes apoptosis . FDA granted accelerated approval to idelalisibin July 2014 for treatment of relapsed follicular lymphoma or CLL/SLLwho have received at least 2 prior lines of therapy. This was based on a phase II open label; multi-center trial of 125 non-Hodgkin lymphoma patients  25 patients had SLL. Again, the patient population was heavily pretreated. The ORR was 57% with majority of them being PRs and the median duration of response was 12.5 months. Toxicity was higher than with ibrutinib with febrile neutropenia, diarrhea, colitis and pneumonia being the most common serious adverse effects. Transient lymphocytosis due to migration of lymphocytes was also seen with idelalisib.
Another phase III randomized, double blind study of idelalisib with rituximab versus placebo with rituximab in patients with heavily pretreated relapsed/refractory CLL showed significantly improved ORRs (81% versus 13%; p<0.001) and the OS rates at 12 months were 92% versus 80% (p=0.02) . The responses were independent of high risk features and toxicities were slightly higher in the idelalisib group. Considering the results of this study, a combination of idelalisib and rituximab was recently approved for relapsed CLL.
These drugs raise some important points. The efficacy and therelatively low adverse effect profile of these drugs will have an impacton in the upfront setting in the treatment of CLL. In some patientswith indolent disease, these drugs may completely replace traditionalchemotherapy. As the responses are independent of high risk features,current prognostic markers may need to be reexamined. Sincecomplete remissions are less common with these targeted therapies,the implication is that this will be a long term treatment much like theTKIs for CML. The typical scenario is that of an elderly patient in his70’s who needs therapy and will take an oral drug and manage his CLLfor the rest of his life. This also raises issues about compliance as wellas financial aspects of the therapy. We may also start seeing a trend totreat patients in earlier stages of their disease due to their ease ofadministration and low toxicity profile. Lastly, with more novel agentsin development, prioritizing the different lines of therapy warrants a discussion as well.