Present Line-Up of Drug Choices

FDA approvals You might be surprised to hear how few drugs have been approved over the last few decades for the treatment of CLL. Let us see. There was chlorambucil. Then fludarabine (and pentostatin) came along. Campath (alemtuzumab) and Arzerra (ofatumumab) are newly approved drugs, along with Treanda (bendamustine). That is it. That is the whole list of drugs approved by the FDA for use as single agents in a variety of situations. Even Rituxan (rituximab) has not yet made the list. Its only approval is in combination with other chemotherapy drugs such as fludarabine and cyclophosphamide (FCR, FR etc).

Campath faces an uncertain future. If the rumor mill is on the right track, it may soon fade away as a CLL drug. It seems the owners of this monoclonal antibody are eyeing the MS (multiple sclerosis) market, where Campath stands to make a whole lot more money. It is rumored that they don’t want a lot of cheap CLL-targeted Campath sloshing around in the market, potentially diluting its demand for much higher priced use in MS patients. Sounds a bit cynical, does it not? Let us hope the rumor proves to be just that, one more false alarm. But keep your eyes peeled on this one. The story is yet to be told on future role of Campath for CLL patients.

Bendamustine for previously treated CLL patients

This paper published in the British Journal of Hematology describes a relatively large scale and multi-center (Italian) trial of bendamustine, with or without the addition of Rituxan, in a group of previously treated patients. The abstract is below. If you wish to read the full text of the article, send me a personal email and I will try to help you find it.

Br J Haematol. 2011 Mar 4. doi: 10.1111/j.1365-2141.2011.08597.x.

Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study.

Iannitto E, Morabito F, Mancuso S, Gentile M, Montanini A, Augello A, Bongarzoni V, D’Arco A, Di Renzo N, Fazzi R, Franco G, Marasca R, Mulè A, Musso M, Musto P, Pennese E, Piccin A, Rota-Scalabrini D, Visani G, Rigacci L.

Abstract

To retrospectively assess the efficacy of bendamustine alone and with rituximab (R-B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39-85). Forty-three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1-8). Twenty-two patients received bendamustine alone and 87 patients received R-B (median B dosage: 100 mg/m(2) per day, range 90-130 mg/m(2) per day). The overall response rate was 69•6% (complete response 28•6%; partial response 41%), and was significantly higher in patients treated with R-B (P = 0•014) and in those responsive to the previous treatment (P = 0•04). After a median follow-up of 7•9 months (range 1-148), the median progression-free survival was 16 months and the median duration of response was 13 months. Median overall survival (OS) was 16•8 months for the whole cohort; patients not responding to the treatment had a significantly worse outcome than those who attained a response (P = 0•0001). In multivariate analysis, only resistant disease status at start of bendamustine treatment (HR 3•2, 95% CI 1•4-7•3, P = 0•006) had an independent prognostic value for OS. Toxicity was manageable and mostly haematological. In conclusion, in our experience R-B was an effective and well-tolerated treatment for relapsed/refractory CLL patients, producing a remarkable high CR rate and mild toxicity.

© 2011 Blackwell Publishing Ltd.

PMID: 21371003

Study rationale and design

Bendamustine (Treanda) is not a new drug. It has been around for a long time, in fact it was invented in East Germany around the time of the second world war. But it is only recently that researchers have started studying the mechanism of how it acts, how to use it, how to combine it with other drugs. There is still a lot we don’t know. Does it indeed work as a single molecule with both purine analog features (i.e., similar to fludarabine and pentostatin) as well as an alkylating agent features built into it (i.e., similar to chlorambucil, cyclophosphamide)? The structure of the bendamustine molecule has bits that look like both sets of drugs. While the jury is still out on this concept, there has been increasing pre-clinical data suggesting combination with Rituxan will make things work a lot better. Now that is not a huge leap of faith, if you ask me. Everything works better when Rituxan is added to it, just about. All the same, it is nice to see an actual clinical trial comparing B+R versus just B. We can use a few more head-to-head comparison trials such as this. For example, I am waiting to see credible clinical trial data comparing FCR with FR.

109 patients with “resistant” or “relapsed” CLL were recruited. The difference between “resistant” and “relapsed” is an important one and I would like to give you a quick handle on it. If you responded to your previous therapy, had a nice long remission from it but now your CLL has gradually grown back to the point where it needs to be treated again, you are a “relapsed” patient. But if on the other hand your brand of CLL basically shrugged away your previous therapy, there was hardly any remission worth writing home about, you are a “resistant” patient. As you can see, it is better to be “relapsed” rather than “resistant”. There are fine-tuned differences between the two terms, but I think you get the idea if you hang on to this obvious difference. Here is the rest of the picture of the patient cohort.

  • Median age: 66 years. Pretty standard for a CLL crowd.
  • 43% of the patients were in the “relapsed” category, but 57% were in the tougher “resistant category. It is interesting to see how these two groups fared in the clinical trial. None of the guys were chemo-virgins. All the patients had prior exposure to either purine analogs and / or alkylating agents. All patients had active disease requiring start of therapy.
  • 22 patients (20%) got single agent bendamustine. 87 patients (80%) got Rituxan + bendamustine. Looks like the researchers had a fairly robust hope that addition of Rituxan will make things better; they put 4 times as many patients in the R+B group.
  • Bendamustine was given at a dose of 70-130 mg/m2 on days 1 and 2 of a 28 day cycle.
  • The cohort that was in the R+B arm got Rituxan on day-1 of each cycle at the now expected dose of 375 mg/m2. Someday I will share with you the interesting story of how researchers came up with the precise 375 mg/m2 number.
  • It is a real pity that this important trial does not report on the prognostic status of the patients prior to therapy. We have no idea how many of these folks were IgVH gene mutated, what kind of FISH abnormality they had. For example, I would have really like to know how B or R+B works on 17p deleted cases.

Response to therapy

Now we come to the main course. How did the patients fare on these two arms?

B+R responses

As you can see, the percentage of “CR” were much higher in the merely “relapsed” patients, whereas the “resistant” patients were tougher nuts to crack. More of the later group got only partial responses or “PR”.

As you would have expected, addition of Rituxan made a difference. The percentage of “CR” responses were significantly higher in the B+R group compared to the single agent bendamustine group.

Did “CR” mean patients had longer remissions, did they live any longer? After all, it is not worth a damn whether the researchers call it a “CR” or “PR” if it did not make any difference on either remission duration (which in turn translates into better quality of life most of the time) or overall life. As you can see below, it made a big difference, whether or not patients got a CR.

B+R remission duration

Every one of the patients lucky enough to get “CR” response were still in remission, almost three years out. The partial response guys were not doing so well. By the time the second anniversary rolled around, almost all of them had relapsed and their CLL was once more progressing.

Did it matter if the patients were merely “relapsed” or “refractory”? You bet it made a difference. More than 60% of the patients who were in the “relapsed” category prior to start of the clinical trial were still alive at the four year mark. Only 30% or so of the “resistant” group were alive even at the 2 year mark.

B+R overall survival

Once again, we see the difference between folks who relapsed from prior therapy after a nice long remission, and the truly hard to treat “salvage” cases. We talked about similar issues in an earlier article titled “Life after FCR”. So far, none of the salvage therapy options seem to work very well in these patients whose CLL has become stubborn and able to thumb its nose at all that we throw at it. Bendamustine (with or without Rituxan) does not seem to be able to break the impasse either. Once again, the best use of salvage therapy in “resistant” patients is to get them queued up for a mini-allo stem cell transplant, if there are no other medical conditions that exclude the possibility of a transplant.

Toxicity

Bendamustine therapy is not for sissies. It packs a substantial wallop when it comes to adverse effects, with or without Rituxan to goose it along. You can see it in the number of patients who were able to finish the planned 6 cycles of therapy. Only 39% of the patients went the whole distance, finished all 6 cycles. A whopping 55% finished only 4 or fewer cycles. The major cause of therapy interruption was lack of sufficient response (disease progression while on therapy or no more than “stable disease”), or too much toxicity.

More than half the patients (57 of them) had grade 3-5 adverse effects. Just in case you are new to this jargon, adverse effects are graded 1-5. Grade 1 is easy stuff, hardly worth mentioning. Grade-2 is a bit more “real” than that, but still nothing worth getting all excited about. Grade 3-4 is serious stuff. How about Grade-5? That is the grade for the patients that actually went and died. Don’t you love the euphemism? See, it is much less scary if they say “patient had Grade-5 adverse effect”, rather than plain English version “patient died”. Here is how the toxicity effects broke down.

B+R toxicity profile

Last words

The authors point out that with the recent crowning of chemoimmunotherapy (FCR, FR etc) as the frontline therapy choices and standard of care, we are seeing a lot more patients  that need therapy after relapsing from such regiments. It is generally not considered a good idea to re-try the same therapy a second time around, if the patient got little joy from it the first time, with remissions that did not last beyond 1-2 years. Even if the patient had relapsed from good old chlorambucil, aggressive combinations such as FCR are not considered appropriate in elderly patients (~ 70 years) or those with other medical conditions that make them ineligible for such heavy duty chemoimmunotherapy combinations. So, the point of doing this trial is to see if B (with or without R) gives us a different option in such cases.

The authors acknowledge a major limitation of their study, namely lack of FISH or IgVH gene mutation status information in their patient cohort. Nor do they have detailed information (beyond age and B-symtoms) on performance status, co-morbid medical conditions etc.

Looking at the glass half-full, they point out that when patients did respond, they did so reasonably rapidly. 41% of the patients got their best response after completing only 4 cycles. (Hint: does that mean in future patients should not grit their teeth and finish all 6 cycles? Are they better off folding their hand after “only” 4 cycles? When is more chemo just too much chemo? We discussed this “Goldilocks dilemma” in an earlier article.)

All in all, if the point of doing this trial is to see if addition of Rituxan helps bendamustine, the answer is YES. Not a huge surprise, but nevertheless good to know. There are a lot more interesting little details presented in the full text of this article. If bendamustine is in your near future, you may be well advised to read it in detail. Heck, make sure your oncologist gets a copy of it as well, before start of therapy, so that you are both on the same page. Send me a personal email if you want help locating the full text version of the article.

Last but not least in my opinion, the authors thanked everyone associated with this study, except the patients who volunteered to participate in it. In future, I will make a point of adding this feature to every clinical trial I review. It may give you some sense of how “patient appreciative” these guys were. The researchers of this study flunked the test on this count.

magic molecule