Highlights from American Society of Hematology (ASH) (December 2009)
20,000 hematologists and other health care professionals flocked to New Orleans for five days. Most spent their time attending academic meetings from 7 o’clock in the morning until 6 to 8 o’clock at night. Of course, it helped a little that the weather was cold and fairly miserable. Below, I will detail a number of the highlights regarding treatment of chronic lymphocytic leukemia (CLL).
Watch and Wait
A number of advances occurred in our understanding of the biology of CLL. Heavy water studies showed the ability to evaluate the doubling time of the early CLL cells in patients. Normally, these patients would be in the “watch and wait” category; the heavy water allowed investigators to identify those more likely to be at risk. There is also an improved understanding of the cellular pathways which switch on CLL cells and make them grow, but so far this has not evolved into information that we can directly apply in the clinic.
As far as the “watch and wait” category goes, there is a group of patients who have truly minimal evidence of CLL with less than 5,000 CLL lymphocytes in the blood. These patients are classified as having monoclonal B-cell lymphocytosis (MBL) as they do not have significant symptoms or enlargement of the lymph nodes and their blood cell production is normal. The likelihood these patients will require therapy for CLL appears to be approximately one percent per year. Thus, we can reassure many patients with very early diagnosis of CLL that it is very likely that they are going to remain well with no need for treatment for many, many years.
During ASH, many interesting studies were presented regarding frontline therapy of CLL. Perhaps the most important one was the comparison of fludarabine and cyclophosphamide (FC) alone or combined with rituximab (FCR). During the 2008 ASH meeting, the German CLL study group reported an improvement in complete response rate and time to relapse of responders. This year, they reported a survival advantage of FCR over other treatment. This was the first time a survival advantage had been reported in a comparative clinical trial. Thus, FCR is the new standard for therapy for patients under the age of 65 who are fit and are able to tolerate the treatment.
Cancer and Leukemia Group B (CALGB) reported the long term follow-up for a number of studies. The first was an analysis of a study in which fludarabine was compared to chlorambucil as frontline treatment. Patients could crossover and receive the other drug as treatment if they failed the initial therapy. Earlier studies had shown that patients given fludarabine had a higher response rate and a longer progression free survival. Dr. Kanti Rai presented the long-term analysis that showed a survival advantage if fludarabine was given first rather than chlorambucil. Long-term follow-up was also presented on study CLB-9712, where fludarabine was combined with rituximab or given alone as induction therapy followed by consolidation treatment. There was an improvement in the group that received fludarabine plus rituximab with regards to late progression free survival but there was no difference in overall survival. The median survival of patients on the study appears to be approximately seven years. The progression free survival appears to be 39 months with either regimen.
A CALGB study used alemtuzumab (Campath) as consolidation treatment after induction therapy with fludarabine/rituximab. Unfortunately, there was a high level of toxicity associated with alemtuzumab and no difference in the progression free survival or overall survival of patients who received alemtuzumab as consolidation treatment. Other studies which utilized alemtuzumab concurrently with chemotherapy showed little advantage of the addition of alemtuzumab for frontline treatment and an increase in toxicity. We continue to try and find the appropriate use of this potent antibody.
Results were also presented for a German Phase II, front-line study using the newly approved drug bendamustine (Treanda) combined with rituximab (the BR regimen). The overall response rate was high with 33% complete remissions and another 58% partial remissions. There were no complete remissions in the group of patients with abnormalities in chromosome 17 but 3 out of 7 with chromosome 17 abnormality obtained a partial response. The BR regimen is now being compared in a frontline comparison with FCR by the German CLL study group.
Another newly approved agent is ofatumumab (Arzerra). Comparisons were reported of two different dose levels of ofatumumab together with FC to make the FCO regimen. This regimen was well tolerated with no clear advantage of one dose over the other. This FCO regimen will now enter into frontline studies in CLL in a number of different countries. Additional information was reported on the ofatumumab studies which led to its FDA approval. A 50% response was seen in the patients which were refractory to fludarabine and alemtuzumab or refractory to fludarabine with bulky lymph nodes. Dr. Anders Osterborg (Karolinska Institute) presented data clearly illustrating that patients with higher concentrations of the drug after administration had a greater probability of obtaining a response and significantly longer progression free survival.
Lenalidomide (Revlimid) continues to show clear activity in previously treated CLL patients and elderly CLL patients requiring frontline treatment. The drug is well established in multiple myeloma and myelodysplastic syndrome and is now being combined with rituximab in CLL. Last year, the CLL group at UCSD reported a favorable outcome and good tolerance with lenalidomide and rituximab as frontline treatment. At this year’s ASH meeting, Dr. Alessandra Ferrajoli (MD Anderson) reported that the revlimid/rituximab (RR) regimen is well-tolerated and associated with a good response rate in patients with relapsed or refractory CLL. Giving rituximab before lenalidomide appears to improve the tolerance of the lenalidomide with minimal episodes of flaring of the lymph glands (tumor flare) or excessively rapid dissolving the cells (tumor lysis). This study has completed accrual and additional data will be shared as the data matures. MD Anderson will combine lenalidomide with ofatumumab to see if there is an improvement in outcome compared to the rituximab experience.
The most interesting new agents are ABT263 and CAL101. ABT263 works to inhibit the BCL-2 family of proteins. This family of proteins enables CLL cells to stay alive for long periods of time. The results of the study showed that seven out of 24 patients obtained a partial response. This response was seen in patients refractory to fludarabine and some with abnormalities in chromosome 17 or 11. The other agent of considerable interest is CAL101 which is a potent inhibitor of the enzyme PI 3-kinase. The response rate in patients with CLL was 24%. Development of the ABT263 and CAL101 is promising because they are effective oral regimens, are well tolerated and can be inserted into other treatment programs.
The rest of the meeting was filled with maturation of studies confirming the steady and significant improvement in outcome for patients at all stages of disease. We clearly understand CLL much better than we did in previous years. We are applying certain biologic characteristics to select treatment programs for the individual patient rather than treating everyone the same. By ASH 2010, we hope even more information will be available to continue to find the right treatment for each patient.