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Fludarabine Offers Option for First-Line Treatment of Chronic Lymphocytic Lymphoma: Presented at ICML

By Chris Berrie

LUGANO, SWITZERLAND -- June 10, 2005 -- Fludarabine alone provides a good treatment option for elderly patients with chronic lymphocytic leukaemia (CLL), and it can be combined with cyclophosphamide as a new building block for CLL front-line therapy in younger patients.

The findings, from an analysis of 2 fludarabine-based trials, were reported on behalf of the German CLL Study Group (GCLLSG) here on June 9^th at the 9^th International Conference on Malignant Lymphoma (ICML).

Michael Hallek, MD, trial coordinator and chairman, GCLLSG, director, department of internal medicine 1, University of Cologne, Cologne, Germany, presented the findings.

While there have been dynamic developments in the treatment of CLL, Dr. Hallek indicated that there are only 3 treatment strategies currently being followed with the ultimate aim of induction of molecular remission in patients with CLL. These include combinations of purine analogues with other cytostatic agents or with monoclonal antibodies, and high-dose therapy followed by allogenic or autologous stem cell transplantation.

He discussed 1 study -- CLL4 -- which compared fludarabine versus fludarabine plus cyclophosphamide (FC) in untreated patients who were 65 years or younger and were diagnosed with advanced-stage CLL (Binet stage C or A/B with symptoms).

The treatment regimen for the monotherapy arm was 6 cycles of fludarabine 25 mg/m² on days 1 to 5 every 28 days. The combination arm followed the same cycling, but with a 3-day combination of fludarabine 30 mg/m² on days 1 to 3 and cyclophosphamide 250 mg/m² on days 1 to 3.

Both arms contained 175 evaluable patients, were well balanced according to disease status, and received a median of 6.0 courses of treatment.

Dr Hallek stressed that the complete response (CR) rate for the monotherapy arm appeared lower than in previous trials due to their use of CR confirmation by bone marrow biopsy or imaging. Therefore, he said, this study used stricter CR criteria than those set by the National Cancer Institute.

Results show significant differences (P <.01) between treatment arms for the fludarabine and FC arms, respectively in CR (4.9% vs 16.5%) and overall response (82.9% vs 94.5%), and for decrease in the rate of nonresponders (17.1% vs 5.5%).

"This was accompanied by a doubling of the [mean] progression-free survival from 20 months for fludarabine to 46 to 47 months for FC," Dr Hallek said.

He indicated that the overall survival in both arms gave significantly poorer prognosis for the 2 groups of nonresponders, as compared with those who responded to the treatments (F, P =.005; FC, P <.001). Overall survival was not significant different in the 2 treatment arms (P =.74).

For treatment toxicities at CTC grades 3/4, the FC arm contained more myelotoxicity, but no more infections, with significant increases in the FC arm versus fludarabine for all toxicities (72.6% vs 54.0%, P =.001), myelotoxicity (64.2% vs 39.3%, P <.001) and leukocytopaenia (55.5% vs 26.0%, P <.001).

There was significantly more NCI grades 3/4 thrombocytopaenia in the FC arm (34.9% vs 23.3%, P =.02). However, FC showed a trend towards protection against autoimmune haemolytic anaemia (AIHA) across all grades (2.8% vs 7.7%, P =.06), although for the more severe AIHA grading >/= 3, this significance was lost (2.2% vs 3.8%, P =.37).

Dr Hallek also discussed a comparison between the F arms of the CLL4 trial and another study by the German CLL Study Group -- CLL5 -- with subjects who had similar disease stage. The 66 subjects in CLL5 were older than 65 years and received the same F regimen. Median age in CLL4 subjects was 59.0 years and 70.6 years in the CLL5 trial.

There were no significant differences in the CLL4 and CLL5 studies in rate of OR (84.1% vs 84.2%), progression-free survival (21.0 vs 18.7 months), adverse effects (59.2% vs 64.4%), myelotoxicity (CTC grades 3/4; 15.8% vs 16.5%) and infections (9.8% vs 7.1%).

Dr. Hallek noted that the older patients achieved a higher rate of CR (CLL4, 8.6%; CLL5, 12.3%), which was also accompanied by increased dose reduction (CLL4, 6.6%; CLL5, 19.0%).

The second generation trials of the GCLLSG (CLL7-9) are now risk/stage adapted and comorbidity/fitness adapted in order to provide the most promising, generally FC-plus-rituximab-based, endpoint for the full range of patients with CLL.


[Study title: First-Line Therapy of CLL, Update 2005. Abstract 038]

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