This is a trial designed to see whether adding the anti-CD20 antibody, rituximab, to the previous gold-standard regimen of fludarabine and cyclophosphamide really makes a difference to patients. Previous phase II studies had shown impressive response rates of 95% with 72% achieving a CR (NB according to the 1996 Guidelines which only require normalization of the blood count, disappearance of palpable lymph nodes and spleen and less than 30% lymphocytes in the bone marrow). These response rates and the apparently longer remissions compared with historical controls had made FCR the treatment of choice in the USA (though it was not approved by the FDA). In Europe, regulatory authorities were not convinced because they could see so many potential biases in the phase II studies and in particular, where the taxpayer was picking up the tab (as in the UK) they were not prepared to pay for the expensive drug, rituximab, on such scanty evidence.
This is how the trial was designed. It was planned to treat patients who had never previously received treatment in whom treatment was indicated according to the 1996 NCI treatment guidelines. There was no age limit on the patients enrolled - in fact they were aged 31-81. There performance status should be ECOG 0 or 1. They should have a low co-morbidity score and have a creatinine clearance of at least 1.17 mL/s. Those with autoimmune disease or a clinically active second disease were excluded. It was necessary for the protocol to be approved by the Institutional Review Board and Ethics Committee of every center taking part in the trial.
The randomization was independent of the investigators. After informed consent was obtained from the patients, investigators faxed the required registration sheets to the central study office in Cologne. At first patients were randomly assigned in a one-to-one ratio in a block size of four, to receive fludarabine and cyclophosphamide (chemotherapy) or fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy). After the fist ammendment in July 27, 2004 they were stratified by centre, and then by country and Binet stage since the first amendment, using a randomisation list that was computer generated at the Institute for Medical Statistics and Epidemiology, Technical University of Munich, Germany. Confirmation of patient randomisation and allocation to treatment group was sent through the Central Study Office in Cologne, Germany, to the investigators. Patients were enrolled by the investigators, and assignment to treatment was done centrally at the Institute for Medical Statistics and Epidemiology, Technical University of Munich.
Treatment consisted of six 28-day courses of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each treatment course, with or without rituximab at a dose of 375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses. These are exactly the same regimens as were developed at MDACC. Prophylaxis with antiviral drugs or granulocyte-colony stimulating factor were not recommended in this study. Prophylaxis of pneumonia caused by Pneumocystis jirovecii was recommended for severe leucocytopenia that lasted for more than 7 days.
An interim response assessment was done after three courses of treatment. Patients who achieved at least a partial response or complete remission continued treatment as planned in the protocol. Patients with stable or progressive disease discontinued study treatment and received a different treatment at the discretion of their treating physician. Patients with stable disease or progressive disease after three cycles were assessed as non-responders and included in the analysis of progression-free survival and overall survival.
Did the randomization work in producing very similar patients in each arm?
Click on the picture to enlarge. As you can see the chemotherapy group and the immunochemotherapy groups were well matched in terms of age, sex, Binet stage, performance status, renal function, beta-2 microglobulin, serum thymidine kinase, IGHV mutations, chromosomal abnormalities, ZAP-70 and CD38 expression. There were slightly more patients with B symptoms in the chemotherapy group. Overall, these were two very well matched groups.
Finally, I should say something on the funding of this trial. This trial was planned and initiated in 2003 as an investigator-initiated trial by the German Chronic Lymphocytic Leukaemia Study Group. Since 2004, F Hoffmann-La Roche assumed the sponsorship for this trial, because it intended to use the trial for the approval of rituximab at regulatory agencies. The sponsor was subsequently involved in the first and second amendments of the study protocol. The sponsor of the study was responsible for data gathering, and shared responsibility for medical review of the data with Michael Hallek. Hallek was responsible for data analysis, data interpretation, writing of the report, had full access to all the data in the study, and had the final responsibility for the decision to submit for publication.
It is important to recognize that although Roche paid for this trial, the design was that of Michael Hallek's group. The subsequent ammendments extended the trial to countries outside Germany and guaranteed independent assesment of the results. Roche also paid for an indpendent data monitoring committee which comprised Peter Hillmen (chairman, Leeds Teaching Hospital NHS Trust, Leeds), Guillaume Dighiero (Institut Pasteur, Paris), Francesc Bosch (Hospital Clínic, Barcelona), Maura Brugiatelli (Azienda Ospedaliera Papardo, Messina, Italy) and Iris Pigeot (Bremen Institute for Prevention Research and Social Medicine Bremen). I can tell you something about what they did because I was the chairman of the data monitoring committee (mainly the same personell except me for Peter Hillmen) for the REACH trial (for second line treatment comparing FC v FCR) that was carried on in parallel to CLL8. The sort of things that we monitored were compliance with the trial, assessment of serious adverse events, and whether any unsuspected side effects were apparent. For example we noted that prolonged neutropenia and late neutropenia were a problem in some patients, and we investigated whether this might be due to a latent MDS caused by the regimen (it wasn't).