Bruce D. Cheson, MD; Clemens Wendtner, MD


December 23, 2011

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Bruce D. Cheson, MD: Hello, I am Bruce Cheson, Deputy Chief of Hematology/Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. I would like to welcome you to this edition of Medscape Oncology Insights.

Today we are going to take a look at a number of interesting abstracts about new treatment options -- and some old treatment options -- for patients with chronic lymphocytic leukemia (CLL), presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego in December 2011.

Joining me today is my friend Dr. Clemens Wendtner, who is Professor of Medicine at the University of Cologne, in Cologne, Germany, and Medical Director of the first medical department, Schwabing Hospital in Munchen, Germany.

Clemens Wendtner, MD: Thank you, Bruce.

Ghosts of CLL Past, Present, and Future

Dr. Cheson: This year's ASH meeting, for CLL, was like A Christmas Carol. There were some ghosts of CLL past, some ghosts of CLL present, and perhaps, some hopes of CLL future. What are some of the new ways of looking at standard approaches, what should be the contemporary treatment approaches -- should we be looking at maintenance strategies? -- and what are some new things that are coming down the pike?

Dr. Wendtner: We have seen some interesting data today indicating that chlorambucil still has a role in CLL, especially in elderly patients.[1] CALBG has put the data together, and they showed that at least in the elderly patients, chlorambucil is at least as good as fludarabine and might even have some additional benefits.

Dr. Cheson: That confirms some of the German data.

Dr. Wendtner: That's absolutely right. We built up on chlorambucil in the elderly population -- "elderly" meaning patients with some comorbidities. We tried to add some antibodies to this backbone. But we have also seen some data from Italy. Robin Foa[2]has presented data from a similar combination with chlorambucil and an anti-CD20 antibody (rituximab). So far, these are only phase 2 data. We are tried to put up some evidence within the phase 3 trial, but we still have to wait some years to get the results.

Dr. Cheson: Another drug that keeps coming and going is alemtuzumab, the anti-CD52 antibody. A number of attempts have been made to combine or sequence it with chemotherapy regimens. A study found a lot of opportunistic infections; an older German study from the German CLL Study Group, shut down...

Dr. Wendtner: My trial.

Dr. Cheson: Your trial. It was ended because of excessive toxicity. But people continue to use fluconazole and to combine it with alemtuzumab. There were abstracts discussing those sorts of things as well. And what did we learn from those?

Dr. Wendtner: It is one of the last trials we looked at with respect to alemtuzumab in combination with FC (fludarabine and cyclophosphamide) or with fludarabine alone.[3] The Danish group, the HIVON group, has data from a combination of fludarabine, cyclophosphamide, and alemtuzumab.[4]This was a front-end trial, a randomized, phase 3 trial, compared with just an FC standard -- not up to date on the FC standard.

Dr. Cheson: That's part of the big problem, isn't it?

Dr. Wendtner: Exactly. They used a little dose of alemtuzumab.

Dr. Cheson: How little?

Dr. Wendtner: Once a month, 30 mg. That is not much. We have seen better responses with the FC plus alemtuzumab, but the survival curves didn't separate nicely. We did not see enough minimal residual disease (MRD) data to conclude that this is really changing the rules. So, FCR (fludarabine, cyclophosphamide, and rituximab) remains the standard for the fitter patients. Chlorambucil or bendamustine would be good options for the elderly patients.

Dr. Cheson: Having said that, you are all doing the CLL10 trial, comparing FCR with bendamustine-rituximab (BR). Is that study now completed?

Dr. Wendtner: It is completed. We enrolled the last patient on the first of July. We are very keen to see data next year. It looks good; I would say we are seeing less toxicity.

Dr. Cheson: Don't tell us in which arm.

Dr. Wendtner: Okay, I won't reveal the secret now. Efficacy seems to be quite equal. But we have to really clean up the data and just wait for another 6 months to report definite data on this trial.

Lenalidomide: Drug of Interest, but Toxic

Dr. Cheson: The big study in the United States is FR vs FCR, v. FR followed by lenalidomide. At our institution we just completed a trial of FR followed by lenalidomide, and it was only in about 24-25 patients because the results were actually disappointing. We saw quite a bit of toxicity with the lenalidomide. In fact, I just took the last patient off the study because he had such thrombocytopenia and profound fatigue. He had been a cyclist; he rode in my lymphoma-CLL patient bike ride, just in September. Now on lenalidomide, he could barely get up to go to work. It is a drug of interest and one that we are still trying to figure out what to do with. As you well know, in the Roswell Park study and the MD Anderson study, it had a 35%-45% response rate in relapse-refractory patients. Where is that drug going? What happens when you move it up front? We saw "R-squared," as they call it, the rituximab-lenalidomide abstract.[5] Give us your impression of that abstract.

Dr. Wendtner: This was a trial by the consortium. You can control the toxicity so you get rid of things like tumor-flare syndrome, tumor lysis, things we were really afraid of when we tried to get the drug to patients some years ago for the first time. This has now been controlled, but the efficacy is still suboptimal.

Dr. Cheson: What dose of lenalidomide did they use?

Dr. Wendtner: They started with a 5-mg dose and did step-wise updosing for this trial. Most patients received 10 mg, combined with large amounts of rituximab. In fitter, younger patients, the median progression-free survival is 19 months -- that is a front-line therapy. This is still not the outlook we want to see for this kind of patient with CLL. For the elderly, this treatment might have a niche. Instead of using chlorambucil, maybe if we play around with R-squared, it might be an option.

Dr. Cheson: That is a randomized trial we have to look at -- a Foa regimen vs R-squared, because the cost of these regimens is quite a bit different. Chlorambucil is about $.02, and lenalidomide is about $4000 or whatever it is -- it's thousands of dollars.

Dr. Wendtner: That's a big delta.

Dr. Cheson: The cost may make a big difference. We are looking at some differences of a month or two in progression-free survival, something that may not be worth the expense.

Dr. Wendtner: Right.

Dr. Cheson: We don't know where it's going. The results are so promising in follicular and low-grade lymphoma, which supports the fact that these are really different diseases and you can't lump everything together. I remember being somewhat concerned, having been interested in the relapse data, and seeing what happened when the MD Anderson group brought the single agent up front and there wasn't a single complete remission.

Dr. Wendtner: That's right. Another niche might be the consolidation-maintenance study for this kind of drug.

Maintenance in CLL?

Dr. Cheson: What about maintenance in CLL?

Dr. Wendtner: That is still very experimental. We have seen some data with rituximab in the maintenance setting by the Spanish group; Francesc Bosch presented the data.[6] I was a little disappointed, seeing that you get high-grade 3-4 infection rates using just this antibody in the maintenance setting. This is not acceptable, and the efficacy is also quite limited. So only a very few patients were shifted from a partial response to a complete response or from an MRD-positive complete response to an MRD-negative complete response. Much more has to be explored in this setting, and maybe the anti-CD20 antibody in this kind of maintenance setting is not the right choice.

Dr. Cheson: I thoroughly agree, because here we have a disease characterized by opportunistic and other sources of infection, and now you are subjecting patients to prolonged B-cell depletion of the normal B cells. It is no surprise, because in every randomized study in lymphoma, in which maintenance vs no maintenance was studied, more hospitalizations, infections, and fevers occurred in the maintenance arm.

We have talked about the present and we have talked a little bit about how we can improve on therapy with maintenance. Some would say, "Maintenance is for losers," because if we had good front-line therapy we wouldn't need maintenance. It seems that not only is rituximab not effective for CLL, but it may even be detrimental with respect to infections.

A New Wave of Drugs

Dr. Cheson: What about new drugs and CLL?

Dr. Wendtner: I think the new kids on the block are the PF3 kinase delta inhibitors. Especially a drug called CAL-101 (now GS-1101). This is a protein tyrosine kinase inhibitor, so we are entering the age of tyrosine kinase inhibitors in CLL. The data are still preliminary. We have seen some phase 1/2 data in very refractory patients, where they achieve a 30%-40% response rate.[7] We have to explore these drugs in combination with some chemotherapy agents such as BR -- that's a good backbone. They might also have a role in the maintenance setting.

Dr. Cheson: A very interesting phenomenon is associated with those drugs (tyrosine kinase inhibitors) in CLL, which makes interpretation of response problematic. After giving them, the lymphocyte count, instead of going down, goes way up, and it can stay elevated for a long time. It makes interpreting the response somewhat difficult.

Dr. Wendtner: Right.

Dr. Cheson: However, it seems that when these drugs are combined with bendamustine or rituximab, the effect is abrogated.

Dr. Wendtner: Right.

Dr. Cheson: It's the new wave. Not only are there interesting pathway inhibitors, but there are some new novel monoclonal antibodies that are of some interest, perhaps in CLL as well. GA-101, for example, is a glycosylated anti-CD20 agent. Do we know anything about that drug? Is much work going on with it?

Dr. Wendtner: So far, we only have some phase 1-2 data. It is impressive how you get very quick clearance of CLL just using this antibody by itself. I am keen to see our own data that we are just producing within a phase 3 trial, combining GA-101 plus chlorambucil. This is being compared with chlorambucil plus rituximab (the old C20 antibody).

Dr. Cheson: What is this study population?

Dr. Wendtner: We will include 760 patients in this trial.

Dr. Cheson: Old? Young? All across the board?

Dr. Wendtner: They are elderly patients, based on comorbidity scorings, so these are "non-fit" patients. We will have our first data in the summer of next year.

Steady Progress, No Blockbusters

Dr. Cheson: Was there anything else that really stuck out in CLL at this meeting?

Dr. Wendtner: We have made steady progress, but I would say we haven't seen data for new blockbusters so far.

Dr. Cheson: In that case, I would like to thank my friend, Clemens Wendtner, for being here with Medscape to review the ASH meetings on chronic lymphocytic leukemia.

Thank you for speaking with me today, and I would like to thank our audience for joining us in this edition of Medscape Oncology Insights. This is Bruce Cheson from San Diego at ASH 2011, and we look forward to talking with you again in the future.


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