FCR: No country for old men

Outcome of treatment for chronic lymphocytic leukemia (CLL) depends more upon the nature of the disease than the type of treatment given. Despite newer treatments producing higher response rates and longer remissions than older ones, no study has ever shown an overall survival benefit from their first-line use compared to treatments that have been available for fifty years.

Some patients survive for decades untreated. Such patients usually have mutated immunoglobulin heavy chain variable region genes (IGHV), low expression of CD38 and ZAP-70 and deletions at chromosome 13q14. Other patients require treatment within a year or two of diagnosis and survive for fewer than eight years. Such patients tend to have unmutated IGHV genes, raised expression of CD38 and ZAP-70 and different chromosomal aberrations including trisomy 12 and deletions at 11q23 or 17p13 [1].

Until now the treatment regimen that has performed best in randomized controlled trials has been the combination of fludarabine and cyclophosphamide (FC) which has been shown to produce a higher response rate and longer remissions than either fludarabine or an alkylating agent used alone [2].

For several years it has been very common for physicians in the United States and some European countries to add the monoclonal antibody rituximab to FC (the combination being designated FCR), even though rituximab has not been licensed for the treatment of CLL. The results of CLL8, a randomized controlled trial comparing FC and FCR, conducted by the German CLL study group will be reported shortly. Media reports suggest that the trial met its primary endpoint which was to demonstrate a 35% increase in progression-free survival for patients in the FCR arm [3].

Despite increased response rates and longer remissions from more intensive treatment, no form of treatment restores the intrinsic immune deficiency caused by CLL and concern has been raised that the lack of overall survival benefit from newer treatments might derive not merely from the availability of effective salvage treatments but also from long term toxicity. A higher rate of transformation to aggressive lymphoma (Richter’s syndrome), more severe and intractable infections and a greater risk of the development of autoimmune complications or myelodysplastic syndrome have been suggested implications of the use of very immunosuppressive combinations of drugs that include fludarabine [4, 5].

In the meantime a very large non-randomized phase II study of treatment with FCR has been taking place at the MD Anderson Cancer Center in Houston and results of this study have now been published [6]. Among 300 patients treated with FCR and followed up for a median of six years, the complete response rate was 72% - far higher than for previous treatments. In CLL a complete response according to the 1996 NCI criteria [7] allows for considerable residual disease and because of this, methods for the detection of minimal residual disease (MRD) have been developed using either flow cytometry or the polymerase chain reaction. Using the most sensitive of their techniques the Houston group found 28% to be negative for MRD. However, the techniques used for the detection of MRD were sub-optimal; others have described and used techniques that are five to ten times more sensitive [1].

Among patients with a partial response or better (all but 15 of the original cohort) the median time to progression was 80 months with a projected 60% progression-free at six years. Again, this is an impressive result but it must be seen in the context of the kinds of patients treated. First, the patients in this study were relatively young; the median age was only 57 and only 14% were aged 70 or older, whereas in the general CLL population, 70 is the median age of presentation. As a group, patients over the age of 70 were significantly less likely to complete the optimum six cycles of therapy (46% vs 79%) and significantly less likely to achieve a complete remission.

Second, most modern prognostic markers were not available for this study. Specifically, ZAP-70 expression, IGHV mutational status and FISH were not available. CD38 expression was tested for, but in only 21% of patients were more than 30% of cells CD38 positive. The comparable figure for my own treated patients is 64%. It is becoming possible to do some of the modern prognostic tests on archived material and we wait with interest the outcome of any future investigation.

Lacking a contemporary comparator, the chief interest in this trial is in the long term safety profile of this regimen. Here there is certainly some encouragement. The actuarial risk of Richter’s syndrome was 2.5% at six years – no more than for historical series. Likewise the actuarial risk of myelodysplastic syndrome was only 2.8% at six years. The well established effect of fludarabine in depleting circulating T cells [5] is certainly responsible for the 10% risk of serious or opportunistic infection during the first year of remission and 4% risk in the second year, but four of the five late deaths from infection were caused by bacteria rather than fungi or viruses.

The most unexpected toxicity was persistent cytopenia after completion of therapy, continuing for at least three months. This occurred in 19% of patients. However, following recovery of blood counts, recurrent late cytopenic episodes occurred in 28% of patients, predominantly in the first year of remission. Salvage of relapsing patients with persistent cytopenias is particularly taxing.

References
1. Dighiero G, Hamblin TJ (2008) Chronic Lymphocytic Leukemia. Lancet 371:1017-1029.
2. Catovsky D, Richards S, Matutes E, et al (2007). Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 trial): a randomised controlled trial. Lancet 370:230-239
3. Roche Media Release 25th January 2008. http://www.roche.com/med-cor-2008-01-25-e.pdf accessed 20th October 2008.
4. Milligan DW, Fernandes S, Dasgupta R et al (2005). Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 105:397-404.
5. Hamblin AD, Hamblin TJ. (2008) The immunodeficiency of chronic lymphocytic leukaemia. British Medical Bulletin 87:49-62.
6. Lam CS, O’Brien S, Wierda W et al. (2008) Long term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112:975-980
7. Cheson BD, Bennett JM, Grever M et al. (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87:4990-4997.