Chronic lymphocytic leukemia (CLL) is a slow-growing malignancy of B lymphocytes (B cells) that tends to affect older people and men more than women. More than 17,000 new cases of CLL are reported every year. Patients with CLL do not need treatment with chemotherapy until they become symptomatic or display evidence of rapid progression of the disease. In multiple studies and a meta-analysis, early initiation of chemotherapy has failed to show benefit in managing CLL; indeed, it may increase mortality.1,2
The combination chemotherapy fludarabine, cyclophosphamide, and rituximab (FCR) is often the initial choice for treatment. Other chemotherapy drugs used are chlorambucil, bendamustine, pentostatin or cladribine, rituximab, ofatumumab, and alemtuzumab. Although chlorambucil is a forgotten drug in the U.S., it is still used first line in elderly, fragile populations in Europe, which make up the bulk of true CLL cases.3
Various combination regimens used in CLL treatment have shown improved response rates in several randomized trials but have failed to show any survival advantage until recently. The treatment of patients with CLL has undergone a dramatic transformation and has changed the management paradigm since the FDA approved new, targeted agents. This article includes a brief discussion of these new agents and the pipeline for new agents.
Newly Approved Treatments
Obinutuzumab is a CD20-directed cytolytic antibody, which on binding to CD20, mediates B-cell lysis. Mediation may be (1) through engagement of immune effector cells; (2) by directly activating intracellular deathsignaling pathways; and/or (3) by activation of the complement. The FDA approved obinutuzumab in November 2013 for previously untreated CLL in combination with chlorambucil based on a pivotal phase 3 trial in 356 previously untreated patients with CLL (mean age, 73 years). Those who received obinutuzumab in combination with chlorambucil had significantly better median progression-free survival (PFS) than did those treated with chlorambucil alone (23 months vs 11.1 months; P < .0001). These results effectively end the use of chlorambucil as monotherapy.4
Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Accelerated approval of ibrutinib was based on of a clinical study of participants with CLL who had received 4 previous therapies. At 26 months, estimated PFS was 75%, and the rate of overall survival (OS) was 83%.5 In January 2014, the RESONATE trial was stopped early because of a positive interim analysis showing statistically significant improvement in PFS as well as in OS with oral ibrutinib compared with IV ofatumumab. The RESONATE trial was a phase 3, multicenter study involving 391 patients with relapsed or refractory CLL who had received at least 1 previous therapy.6 At 6 months, 88% of patients treated with ibrutinib were progression free compared with 65% with ofatumumab. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% for patients in the ofatumumab group. By traditional response criteria, the overall response rate (ORR) with ibrutinib was 43% compared with 4% for ofatumumab. Ibrutinib is now approved for chemotherapy-naïve CLL patients with a 17p13.1 deletion, a genetic abnormality that generally portends a poor prognosis.
On July 23, 2014, the FDA approved an oral PI3-kinase delta (PI3K d) inhibitor called idelalisib in combination with rituximab used as a treatment for patients with high-risk CLL. In supporting data from a phase 3 study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% vs placebo and rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression free compared with 50% of patients treated with the placebo. Approval was based on a placebo-controlled study of 220 patients in which patients treated with idelalisib plus rituximab showed significantly longer PFS (10.7 months) than did those who received placebo plus rituximab (5.5 months).7
Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have used this medication in treatment of patients with relapsed and refractory CLL. Response rates of 47% to 38% with complete response rates of 9% and elimination of minimal residual disease (MRD) have also been reported.8
CLL Pipeline
Clinical trials continue to explore new agents, with the most promising being the PI3K δ and γ inhibitor duvelisib (IPI-145) and the BCL-2 inhibitor ABT-199. In
a phase 1 study exploring duvelisib in patients with relapsed or refractory CLL, the ORR was 47%.9 Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion or p53 mutation.
ABT-199 demonstrated efficacy in a phase 1b study when administered to patients with relapsed/refractory CLL in combination with rituximab.10 In 18 evaluable patients, 39% achieved complete remission (CR) or CR with incomplete blood count recovery and 39% achieved partial remissions (78% ORR). Altogether, 22% were deemed MRD-negative. In evaluable patients with 17p deletions, 81% achieved a response to ABT-199. In patients with fludarabine-refractory CLL, 78% achieved a response.
Although it is advantageous to have so many newer effective, targeted drugs for relapsed/refractory advanced CLL, in early-stage CLL when a watch and wait approach might be best, it may become a challenge for the patient as well as for the treating physician. All these drugs are expensive and carry risks. Although PFS is promising, physicians have to make a judgment call in balancing cost and toxicity.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.