Trial Information

A RETROSPECTIVE STUDY TO ASSESS THE EFFICACY AND SAFETY OF CHLORAMBUCIL PLUS RITUXIMAB AS FRONT-LINE THERAPY IN ELDERLY AND/OR UNFIT PATIENTS AFFECTED BY B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA

Illness: treatment overview Chronic lymphocytic leukemia (B-CLL) is the most prevalent adult
leukemia among western countries (6.7% Non-Hodgkin Lymphomas- NHL). The incidence rate is
2-6 cases per 100.000 person per year increasing with age and reaching an incidence rate of
about 13/100.000 at 65 years, median age of onset of the disease. There are two clinical
staging systems currently in use for CLL (Rai and Binet staging systems) allowing a rough
division of patients into three prognostic groups: good, intermediate and poor prognosis.
The clinical course ranges from an indolent behaviour (Rai 0, Binet A) with a long term
survival to an aggressive disease with a median survival of 2 years (Rai III and IV, Binet
C). There is non survival benefit associated with an early therapy (Binet stage A and B).
Treatment usually is initiated when patient progress to the advanced stage (Binet stage C)
and/or become symptomatic (fever, night sweats, weight loss). Purine-analogues based
chemo-immunotherapy regimens are now considered the standard of care for fit patient with
B-CLL (Fludarabine-Cyclophosphamyde-Rituximab, FCR regimen). But aging of the host and
biological features of the disease are critical issues in the choice of therapy. The FCR
regimen can result in significant myelosuppression and a high rate of early and late
infections, especially in elderly patients with B-CLL, suggesting that it may be too toxic
and therefore unsuitable for the large subpopulation of elderly and comorbid patients
affected by B-CLL/SLL.

Rationale Chlorambucil, an alkylating agent, was the standard first line treatment for
B-CLL/SLL before the development of the purine analogues and monoclonal antibodies. Later,
phase III trials showed an improved ORR and a prolongation of PFS with fludarabine alone. A
further improvement was obtained with the addition of Cyclophosphamide to Fludarabine.
Eventually, Fludarabine in combination with Cyclophosphamide and the monoclonal anti-CD20
antibody Rituximab became the standard first line therapy for CLL patients 18 to 65 years
old. At the same time, the FCR regimen showed a significant rate of early toxicity
consisting of myelosuppression and infection and also a high rate of late infection. Data
showed by Hallek et al reported a rate of grade 3-4 hematological toxicity and total
infections of 56% and 25%, respectively. They reported 8 treatment-related deaths (2%), five
of these due to infections and 4 deaths occurring before the 3th cycle. Also has been
reported by Tam et al a risk of 10% of late infection for the first year of remission after
FCR treatment. Low-dose FCR was evaluated as an alternative option showing a lower rate of
neutropenia, without reduction of response rate. Nevertheless, it was demonstrated to reduce
the PFS and it has not been evaluated in the elderly or medically unfit population.
Alternative treatments (i.e., low-dose fludarabine, low-dose fludarabine plus
cyclophosphamide, rituximab alone) have been explored in phase II trials in elderly and/or
medically unfit patients with CLL. Since the cohort sizes were small, however, no definitive
recommendations could be made for clinical practice. About three-quarters of CLL patients
are more than 65 years old. Data from the CLL 5 phase III trial of GCLLSG (German CLL study
group) comparing fludarabine vs Chlorambucil in this setting of patients (median age 70
years, range 65-80 years) displayed no differences in OS and PFR between Fludarabine and
Chl, despite a greater percentage of CR and ORR with Fludarabine. This suggests that in
elderly B-CLL patients, Fludarabine alone does not represent a major benefit in respect of
Chl as front-line therapy. However, rates of complete response (CR) with front-line
Chlorambucil single agent are relatively low (up to 7%) as are overall responses
(approximately 65%). Phase II trials are ongoing to investigate the efficacy and safety of
Rituximab in combination with Chl in previously untreated patients affected by B-CLL.