Use of Bendamustine in Chronic Lymphocytic Leukaemia Patients with Co-morbidities
Table 1: Selected Ongoing Trials of First-line Treatments for Chronic Lymphocytic Leukaemia Trial Name
Sponsor(s) MaBLe CLL11 Roche
Number of Treatment 1 Treatment 2 Treatment 3 Duration Patients
600
GCLLSG/Roche/ 786 Genentech
COMPLEMENT-1 GSK RIAltO
447 GSK and Napp 670 B + R CLB
+ GA101* CLB + O CLB + O
CLB + R CLB + R CLB B + O – CLB
– –
6 cycles of B + R; up to 12 cycles of CLB + R 6 cycles
12 cycles
6–12 cycles of CLB + O; 3–6 cycles of B + O
Primary
Outcome CR
PFS
PFS PFS
Reference 25 26
29 30
B = bendamustine; C = cyclophosphamide; CLB = chlorambucil; CLL = chronic lymphocytic leukaemia; COMPLEMENT-1 trial = Ofatumumab + chlorambucil vs chlorambucil monotherapy in previously untreated patients with chronic lymphocytic leukemia; CR = complete response; GCLLSG = German CLL Study Group; MaBLe = A study of MabThera (rituximab) added to bendamustine or chlorambucil in patients with chronic lymphocytic leukemia; O = ofatumumab; PFS = progression-free survival; R = rituximab; RIAltO = A randomised investigation of alternative ofatumumab-based regimens for less fit patients with CLL. *GA101 is a humanised glyco-engineered anti-CD20 monoclonal antibody.26
response assessments – which may result in higher response estimates than the more sensitive immunophenotyping response assessments.21
BR
induced durable responses, with 75.8 % of patients still in remission after 18 months, and relatively high MRD rates (58 % in blood and 28 % in bone marrow).21
In addition, it was well tolerated. The majority of the experience with BR to date has occurred in real-world clinical practice in Germany.
Use of Bendamustine Regimens in a German Registry Despite the lack of randomised trial data, BR is the most frequently used regimen in Germany, according to a registry of lymphatic neoplasias. Preliminary results from that registry show that over 30 % of CLL patients receive BR as first-line treatment and nearly 50 % of CLL patients who require second-line therapy also receive it. For first-line treatment, approximately 47 % of CLL patients received a bendamustine-based regimen, 41 % received a fludarabine-based regimen and 12 % received another regimen (mostly chlorambucil). As may be expected, the patients receiving bendamustine-based regimens were older and had slightly worse Charlson scores than those receiving fludarabine-based regimens (72 years versus 67 years and 0.8 versus 0.5, respectively). In turn, patients receiving bendamustine-based regimens were younger than patients receiving chlorambucil (74.5 years and Charlson score of 1.2) (Wolfgang Knauf, personal communication).
Chlorambucil in Combination with Rituximab Two non-comparative studies have investigated the combination of chlorambucil and rituximab. In one study of 100 previously untreated patients of median age 70 years who required therapy,22
According to the study design, patients who responded to treatment would then be randomised to receive rituximab maintenance or observation only. The first 54 evaluable patients were included in an interim analysis. The median age of these patients was 70.5 years and 25.9 % had Binet stage A, 57.4 % Binet stage B and 16.7 % Binet stage C disease. At the end of the induction phase, the ORR with chlorambucil and rituximab was 81.4 %, with 16.7 % of patients achieving CR. A further 3.7 % of patients had incomplete CR, while the nPR and PR rates were 1.9 % and 59.3 %, respectively. Eight of nine patients with CR who were evaluated were MRD-positive. In total, 85.1 % of patients completed the planned course of treatment and the most common adverse events were neutropenia (31.5 %) and thrombocytopenia (14.8 %). The incidence of grade 3/4 neutropenia was 16.7 %; there were no grade 3/4 infections.
Fludarabine–Cyclophosphamide–Rituximab-lite FCR-lite is a regimen comprising a reduced dose of fludarabine plus cyclophosphamide plus an increased dose of rituximab, in an attempt to achieve the efficacy of the standard of care (SOC) FCR regimen but with improved tolerability (notably reduced haematological toxicity). Striking efficacy was reported in a recent single-arm study with FCR-lite followed by rituximab maintenance therapy in 50 untreated CLL patients, with a 100 % ORR and 77 % CR rate.24
into this trial was 58 years and the majority of patients were Rai stage I and II.24
each patient
who received chlorambucil plus rituximab was matched with two patients treated with chlorambucil from the previously conducted UK Leukaemia Research Fund CLL4 trial13
as historical controls. Patients
were matched according to Binet stage (B or C), variable heavy chain gene mutation status (mutated or unmutated), chromosome 11q fluorescence in situ hybridisation (deleted or not) and age.22
The ORR
was 82 % and the CR rate was 9 % with chlorambucil plus rituximab. Chlorambucil plus rituximab was also associated with 15 % nPR and 58 % PR rates and a median PFS of 23.5 months. The ORR was 16 % higher with chlorambucil plus rituximab than with chlorambucil monotherapy in the matched historical control patients. Although 92 % of patients experienced at least one adverse event with chlorambucil plus rituximab, the majority of events were grade 1/2. Grade 3/4 neutropenia occurred in 39 % of patients and serious adverse events occurred in 37 % of patients.22
In the other study, chlorambucil plus rituximab was evaluated in 97 elderly patients with previously untreated CLL who required therapy.23
EUROPEAN ONCOLOGY & HAEMATOLOGY
The Study of MabThera (rituximab) added to bendamustine or chlorambucil in patients with chronic lymphocytic leukemia (MaBLe) is comparing BR with chlorambucil plus rituximab.25
This trial is being
conducted in patients who are ineligible for treatment with fludarabine and includes both treatment-naive and second-line patients; the results are expected in 2014. The GCLLSG CLL11 study26
As well as determining the efficacy and safety of this new agent, this well conducted randomised controlled trial will show how chlorambucil plus rituximab compares with chlorambucil alone.
55
Furthermore, remissions were durable in
all but one patient with CR – patients remained in remission at a median follow-up of 2.4 years.24
However, the median age of patients recruited
In addition, FCR-lite has yet to be evaluated in a randomised clinical trial in elderly CLL patients ineligible for FCR.24
Ongoing Trials in First-line Treatments There are a number of ongoing trials that are likely to influence the way unfit (no go) and/or elderly patients with CLL will be treated in future (some of which are summarised in Table 1).
compares chlorambucil monotherapy with chlorambucil plus rituximab; a third group is being treated with chlorambucil plus GA101, a novel humanised glyco-engineered anti-CD20 monoclonal antibody.27
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