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

Anti-CD20 Monoclonal Antibodies in Association With Alkylating Agents

The results of GCLLSG CLL5 trial suggests that chlorambucil represents the best chemotherapic agent for developing association of chemoimmunotherapy in elderly/unfit patients.[37] Two Phase II trials used a combination of rituximab and chlorambucil (R-CLB) as first-line therapy of elderly/unfit CLL patients.[43–44] In the British CLL208 trial, 100 patients with a median age of 70 years (range: 43–86) received 6 cycles of chlorambucil + rituximab and 6 further cycles of chlorambucil alone in patients continuing to respond. ORR was 82% (complete response (CR) 9%), median PFS 23.9 months and a grade 3–4 neutropenia was recorded in 39% of cases.[43] When these results were compared with results of chlorambucil arm of UK CLL4 trial, ORR was 16% higher for the association of chlorambucil and rituximab.[39,43] In the Italian protocol ML21445, patients received 8 cycles of chlorambucil administered in combination with rituximab.[44] ORR was 81.2% with 16.5% of CR. ORR and CR rates were similar across the age groups (ORR 60–64 years: 84.6%; 65–69 years: 85.2%; 70–74 years: 75.0%; ≥75 years: 81.0%).[44] Grade 3–4 neutropenia occurred in 17% of cases, with no grade 3–4 infections. Finally, patients who achieved a response were randomized to maintenance with rituximab every 2 months for 2 years versus observation alone.[44]

In the CLL2M Phase II trial, 117 patients with previously untreated CLL received rituximab in combination with bendamustine.[45] Twenty six percent of patients were older than 70 years and the ORR was 88% with a CR rate of 23%. Major toxicities were infrequent, grade 3 or 4 neutropenia was documented in 19.7% of patients and severe infections occurred in 7.7%.[45]

Several prospective randomized trials are now evaluating the impact of chemiommunotherapy including an anti-CD20 monoclonal antibody in association with an alkylating agent (Table 1). Ofatumumab is a human monoclonal antibody which targets an epitope in the CD20 molecule encompassing parts of the small and large extracellular loops. The ofatumumab plus chlorambucil versus chlorambucil monotherapy in previously untreated patients with CLL (COMPLEMENT-1) is a Phase III trial that enrolled previously untreated patients who were considered not suitable for fludarabine-based therapies. The trial has completed recruitment and is expected to report data in 2013.[102] RIAltO began the enrollment at the end of 2012. The aim of this trial is to compare ofatumumab and chlorambucil with ofatumumab and bendamustine to find out which is the best combination for people with CLL who are not fit enough for more intensive treatment.[103]

Obinutuzumab (GA101) is a new type II glycoengineered humanized anti-CD20 monoclonal antibody. Recently, Roche announced the positive results of CLL11 study, a Phase III trial designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil compared with rituximab plus chlorambucil or chlorambucil alone. An improvement in PFS was achieved: GA101 plus chlorambucil significantly reduced the risk of disease worsening or death compared with chlorambucil alone.[101] Roche announced that results of CLL11 trial will be early submitted to European and other regulatory authorities as well as the US FDA for potential marketing approval.

MaBLe (ClinicalTrials.gov identifier: NCT01056510) is a randomized, open-label, interventional, Phase IIIb study of rituximab and bendamustine (R-B) versus R-CLB in patients with CLL who are ineligible to receive fludarabine because of age or comorbidities. A total of 126 patients were included in this trial and after six cycles of treatment, 24.1% in the R-B arm had a confirmed CR compared with 10.3% in the R-CLB arm (p = 0.033).[104] On the basis of these preliminary results, the authors conclude that both R-B and R-CLB may represent a useful treatment option for patients with CLL who are ineligible for regimens containing fludarabine. Patient enrollment (n = 358) and randomization were completed in November 2012. The final data analysis of this study is expected in 2014.[104]

In conclusion, several well-conducted studies indicate that an association of chlorambucil or bendamustine and an anti-CD20 monoclonal antibody (i.e., rituximab, ofatumumab and obinutuzumab) is feasible in elderly/unfit CLL patients. Final results of ongoing Phase III studies comparing R-CLB with R-B are awaited.

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