Pharma Strategy Blog

At the American Society of Clinical Oncology (ASCO) meeting earlier this year, we learned that rituximab added to standard fludarabine plus cyclophosphamide improved overall survival in patients with chronic lymphocytic leukemia (CLL), even in elderly patients of 70 years old.

Six months later, one of the highlights of the American Society of Hematology
(ASH) meeting held in a rather cold, wet and windy New Orleans, was updated data presented by
the same German CLL Study Group (GCLLSG) confirming the combination of
fludarabine, cyclophosphamide and rituximab (FCR) as the current front-line
standard of care in chronic lymphocytic leukemia (CLL).

Increased overall survival for CLL patients receiving the combination of fludarabine, cyclophosphamide and rituximab (FCR)

Michael Hallek of the University of Cologne reviewed updated results from the GCLLSG CLL8 study, in which FCR was compared against the combination of fludarabine and cyclophosphamide (FC).   At ASH in 2008, data was presented showing FCR to be superior to FC in terms of response rate and progression free survival (PFS).  This year at ASH, Hallek presented updated data showing that patients in the FCR study arm still had a statistically significant higher overall survival (OS) compared to those receiving FC.

The published abstract shows the OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).  At the conference, Hallek presented data showing an 87.2% OS in the FCR arm versus 82.5% in the FC arm (P=0.012) at three years for those who achieve a complete response.  There is a clear survival benefit from treatment with FCR as compared to FC, particularly in those patients who have Binet A or B stage disease.

GLLSG phase II trial combining bendamustine with rituximab (BR) in first-line therapy of advanced CLL

The data for this combination suggested that it appears to be safe and effective.  Response rates for BR were similar to those obtained with FCR. However, there were significantly less neutropenias with BR than would be expected with FCR.  This has led the GCLLSG to initiate a protocol (CLL10) comparing FCR against BR in front-line CLL.  The results from this study will show whether the new standard of care in front-line CLL should become bendamustine in combination with rituximab in the future.

In the poster sessions, a number of interesting ones jumped out at me that may be worth looking at in the clinic for the future. 

Lenalidomide (Revlimid) has shown early promise in CLL in the CLL5 AGMT study.  This was a phase I/II study that looked at combining fludarabine with rituximab with escalating doses of lenalidomide.  Although only a small number of evaluable patients (n=6) were available, all 6 patients responded and 3 achieved a complete response.  40% of the patients were dose limited due to skin and vascular toxicities so the protocol was amended to include thrombo-prophylaxis and delayed start of prophylaxis against pneumocystis.  It is too early to tell whether this regimen will reach the prime time but the risk-benefit trade-off may turn out to an issue.

An interesting compound that I have been following for a little while is Trubion's TRU-016, which is a small modular immunopharmaceutical protein (SMIP) being tested in relapsed and rferactory CLL.  It targetes CD37, expressed predominantly on B-cells.  In a phase I study, interim results were presented from CLL patients (n=33), demonstrating a manageable safety profile despite grade 3/4 myelosuppression.  The DLT and MTD had not yet been reached.  Reductions in peripheral lymphocytosis were observed, together with some objective responses in the higher dose cohorts.  hopefully, further data will be available on this novel agent at ASCO in the summer.

Overall, with new monoclonal antibodies in development and the recent approval of ofatumumuab in refractory CLL, it is likely there will be interesting new data and further changes to the standard of care over the next two or three years.  Biomarkers are also slowly emerging in CLL research, and while it is early days yet, it is good to see some attention finally being given some importance in this disease both from a predictive and a prognostic standpoint. 

We can expect some compelling new data in the treatment of CLL, hopefully by ASCO in June 2010. 

Watch this space!