Treatment of Elderly Patients With Chronic Lymphocytic Leukemia

An Unmet Clinical Need

Stefano Molica; Maura Brugiatelli; Fortunato Morabito; Felicetto Ferrara; Emilio Iannitto; Nicola Di Renzo; Silvana Capalbo; Pellegrino Musto; Francesco Di Raimondo

Disclosures

Expert Rev Hematol. 2013;6(4):441-449. 

In This Article

Non-chemotherapy-based Therapies

Different studies specifically devised for elderly/unfit patients have used biological agents (i.e., anti-CD20 monoclonal antibodies, immunomodulators, Bruton's tyrosine kinase inhibitors) alone without chemotherapy.

Safety and efficacy of GM-CSF in combination with rituximab in elderly CLL patients has been investigated. The rationale of this association relies on the capacity of GM-CSF to increase surface expression of CD20 on CLL cells and also to enhance antibody-dependent cellular cytotoxicity against CLL cells. Among 93 enrolled patients (32 untreated), all with an age >70 years, ORR was 72%. This combination was well tolerated with the most common toxicity consisting of mild GM-CSF injection site erythema.[51]

Badoux et al. reported results of a Phase II study investigating the activity of lenalidomide as initial therapy in CLL elderly patients.[52] Sixty patients with an age >65 years received an initial daily dose of 5 mg of lenalidomide then titrated up to 25 mg/day as tolerated until disease progression. The ORR with lenalidomide therapy was 65%, including 10% of CR, while estimated 2-year PFS was 60%. Major infections or neutropenic fever occurred in 13% of patients.[52] In a Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory CLL, investigators at the MD Anderson Cancer Center (TX, USA) demonstrated an ORR of 66%. Continued therapy led to durable and some complete remissions.[53]

A Phase III study of lenalidomide versus chlorambucil as first-line therapy for elderly patients (i.e., older than 65 years) with B-cell CLL (ORIGIN trial), is currently recruiting.[105] The primary end point is PFS and the trial is due to end in 2013.

More recently, inhibitors of the BCR signalling pathway, agents directed at re-activating the death pathways, have demonstrated promising activity in CLL.[54–56] Byrd et al. presented data on a Phase Ib/II study of ibrutinib, a Bruton's tyrosine kinase inhibitor, which included only symptomatic, previously untreated CLL patients older than 65 years (74% older than 70 years).[54] This study evaluated two doses of single-agent ibrutinib 420 and 840 mg, respectively, administered daily for 28-day cycles until disease progression. With a median follow-up time of 10.7 months, 73% (19 of 26 patients) in the 420-mg cohort achieved a response by International Workshop on CLL criteria, with 65% partial PRs and 8% CRs. A total of 84% of patients remain on study. Reasons for discontinuation were adverse events in three patients and 'investigator decision' for one patient. None of the patients died, and there was no disease progression, although in one patient, disease transformed to a more aggressive lymphoma, Richter's transformation. Interestingly, the estimated 12-month median PFS for the 420-mg cohort of patients was 93% and responses were good even in patients with genetic high-risk factors such as 17p deletion.[54]

Ibrutinib has shown an interesting pattern of response, in which very rapid nodal shrinkage occurs at the same time as the lymphocyte count rises, suggesting redistribution of CLL cells from the lymph nodes and bone marrow to the peripheral blood.[54] Because of this singular pattern of response at different sites of disease, ibrutinib seems to be a good candidate for combination therapies with other agents. In combination with bendamustine/rituximab or ofatumumab, ibrutinib had high ORRs, rapid onset of response, low rate of progressive disease and good tolerability in heavily pretreated patients with relapsed or refractory CLL.[55–56]

GS-1101, formerly known as CAL-101, is a potent PI3K-delta inhibitor that targets a signaling pathway implicated in malignant B-cell proliferation. The drug has been explored as a monotherapy and in combination with other agents. In a Phase I study of CAL-101 in 37 patients with relapsed or refractory CLL, CAL-101 reduced lymphadenopathy in all of the patients, and 91% achieved a lymph node response (≥50% reduction in target nodal lesions). The ORR was 33% (all PRs) and the median duration of response had not been reached. Interestingly, 75% of patients with CLL-related thrombocytopenia had either an improvement to >100,000/µl or a >50% increase from baseline.[57] A randomized Phase II study is currently investigating CAL-101 activity in patients ≥65 years old with previously untreated CLL who receive CAL-101 in combination with rituximab versus placebo plus rituximab (ClinicalTrials.gov identifier: NCT01203930).[106]

ABT-199 is a small-molecule inhibitor of bcl-2, a protein that is responsible for deregulation of apoptosis in cancer cells. Activity has been observed in patients, including reduction in leukemia counts, reduction in lymph node size and improvement in bone marrow.[58] Like ibrutinib, ABT-199 has also shown activity in patients with the 17p deletion.

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