Present Line-Up of Drug Choices
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?
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.
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.
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.
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.
20 comments on "Bendamustine for Previously Treated Patients"
Thanks Chaya for all you do. This is really timely for me as I am “relapsed” after 30 months post FCR. Now looking at a trial combining BR with PCI-32765 (which I found your write up on CAL-101 valuable). Hoping to get into the trial in May will let you know how it goes. Thanks again John
John:
Good luck with the BR + PCI 32765 trial. It is an important one and I for one am very interested in learning more about it. Please keep in touch and let us know how things are going for you. Feel free to contact me via personal email, if that works better for you. In either case, I am delighted we now have our own “eyes and ears” in this important trial.
I guess I’m one of the fortunate ones. I was the first patient at my center to undergo Bendamustine, I had 10 cycles ever 21 days and faired very well, I think the last 4 treatments she added Rituxin to the mix, since then I have had 2 Rituxin maintenance treatments once every 8 weeks for 2 more years. Have felt great this is the longest I’ve every been in remission 6 months now. I’d like to point out I’ve had 2 lung cancer surgeries and lymphoma at the same time, over 7 years since diagnosed. I also get IVGG every 4-6 weeks. Nancy
Chaya: In 2003 (6 years after diagnosis) I received FCR, which resulted in a severe adverse reaction after the first treatment. However, it did put me into remission. Last year, I was scheduled for 6 cycles of Bendamustine but after only 4 cycles I was in remission. No adverse reactions. In fact, I really didn’t feel that I was in chemo. It”s a wonderful drug as far as I am concerned.
Thanks for your efforts on behalf of all those with CLL.
Roy
Unfortunately I am in the ‘resistant to chemo’ crowd and R + B did nothing for me at all and stopped after 3 rounds. I found the nadir point between cycles very painful and needed pain relief. Glad the combo has worked for some folks though.
A bit disturbed about the Campath news as 6 rounds did clear my marrow for a few months, and kept lymph node escalation under control for a while.
Off to allo transplant with sibling donor in a couple of weeks.
Jaq
Chaya- Great article, thanks! I’ve had 2 rounds of R+B and my WBC dropped from 163k to 4.8k! I feel great and 6 months later my WBC has crept up to 22k. As background for others, I’ve previously had 64 Rituxan treatments as maintenance therapy. Last time with Rituxan alone, my WBC only went down to 33k, so adding Bendamustine made a huge difference with no side effects. I continued to run, bike to work, lift weights, etc.
Best regards,
Malcolm
Diagnosed 11/97.
Thank you,Chaya,for a great aticle,
Be well,
Monique
Chaya, Thanks for reviewing this article on bendumustine. I’m a success case with bendamustine monotherepy. I’m still in remission after 26 months following 6 rounds of bendamustine (100 mg/m^3 for 2 and 70 mg/m^3 for last 4). Not sure if I would be classed ‘Resistant’ or ‘Relapsed’ in that I had 18 months of Chlorambucil treatment previously—it dropped my WBC from 500k to 150k where it leveled off. I had absolutely no side effects from bendamustine treatment (<Grade 1 per your scale). At my last Dr. check my white count had inched up to (I think) 12k but I still feel great and have lots of energy. The Dr. says further treatment may be in order down the road.
Incidentally, I'm a chemist, like you, and was keen on bendamustine because of the bifunctionality you mentioned—even if it is not 'real' it is very intriguing to those of us who love organic molecules.
Thanks for all your efforts.
Al Sullivan
I have to agree with Roy. I have now finished 4 of 6 rounds of BR and do not feel like I’m having chemo. I’ll let you know the end results after the 6th round.
All the best to all,
Dave
I was diagnosised in 2002 with CLL/SLL started treatment 2 mo. ago with WBC 128,000 and enlarged lymphnodes and enlarged spleen. Had severe reaction to the rituxan with 1st treatment only getting a quarter of prescribed. Received full treatment of Treanda. One week later my WBC dropped to 4.6. Received 2nd treatment of Rituxan in the ICU on slow drip to hopefully desensitize me to the drug..which didn’t work had reactions for several days, high doses of steroids and benedryl helped calm things down, but then I had severe bone pain for several days which they treated with morphine. 2 days later had my Treanda treatment. Next week I go back for my 3rd. treatment with Treanda only as the doctor feels it is too risky to do Rituxan again. My WBC is now 3.9. My concern is doing too many treatments, are 6 treatments always necessary?
I had 6 cycles of BR Oct 2009- Mar 2010. Now after one year my blood counts are doing well. Though platelets hover at 100 it sure beats the under 50 at treatment startup. I had a hard time with the first and second BR cycles; mainly fatigue, headaches and GI reactions more or less controllable with generic Zofran but I also had some days of chills and spiking fevers. My dosage at age 70 was 70mg/m2 and 375mg/m2 Rituxan. Basically I am glad that I had this option since I previously had 2 regimens of FR which effective at the time was no longer an option.
Chaya,
This article brought back many memories but I made it with 6 cycles.
Thanks for a very important update.
Blessings,
Rita
Just an FYI .. my sister-in-law’s mom (age 88) is on her third cycle of BR for NHL at the Kellogg Cancer Center at Northwestern University. (Not sure exactly which lymphoma as my sister-in-law hasn’t gotten into the details of the diagnosis). I was amazed that she would receive the treatment at that age. She’s a trouper. Three years ago they told her family that it was time for hospice. Not her .. she continues to travel the country visiting children, grandchildren, attending concerts and museums.
Lynn
Chaya,
Another Great Article, thanks! Another possible option for down the road.
Wife is currently in Clinical Trial with PCO. ½ way through and things so far look good. I’m concerned for the patient that studies don’t make available the details behind patients. IgVH status, trisomy 12, and the list of specific makers vs these different chemo combo’s. As the patient, how do we peruse a specific combo that performs better for groups of IgVH unmutated trisomy +12 CD38 positive vs 11q del mutated CD20 etc. Let’s ask for, no lets demand that if clinical trials are going to evaluate drug combo’s (say FCR vs FR), lets ask them for as well, to identify specifically which/what patient makers are in the groups (good or bad).
And while I’m here, I’m specifically looking for which drug will work best for marker CD49d and an IGH/BCL3 fusion t(14;19) – a protein translocation from chromosome 14 to 19 (q32;q13.3), a complex three-way translocation involving chromosomes 2q, 3q, and 16p. We hear this is rare – but where would I go to find help identifying options?
thank you again
Chaya,
I cannot adequately express my gratitude for the contribution you continue to make to this community, which I involuntarily joined in 2004. I hit the “Donate” button, before I left this post.
My oncologist, an assistant Prof at Hopkins, has discussed B+R with me as a possible next treatment, as I may be showing signs of relapse from a 3 yr CR, achieved after FCR+Lumiliximab (w/ Dr Byrd, OSU). (That followed two years on Rituxan monotherapy.) Prior to the FCR treatment, tests showed that I am unmutated with 11q del. I’ll be going back to see John Byrd in 10 days for his opinion, with a growing node under my chin.
Like many others who have or will relapse from FCR, my struggle is trying to think one or two steps ahead in this chess game-trying to maintain optionality. I am an active, otherwise healthy 54 year old. Do I try to push this disease out further by trying B+R (41% CR odds in this study) or FCR again? Where does that leave my options when I relapse again to get in a sufficiently deep remission to handle SC transplant? Or do I try to get a solid remission now at 54 in order to do SCT when younger and more likely to get a remission? If studies like this had provided information on mutational status or chromosomal abnormalities, how much easier these tortured decisions could be.
As people share their experiences, it’s always helpful,albeit anecdotal,to know their mutational status and relevant chromosomal profile.
Many thanks, Chaya, from another BIG fan
Pat:
Thanks for the kind words and support.
In addition to B+R, you should also consider lenalidomide (Revlimid) or perhaps one of the CAL-101 clinical trials. It may be worth discussing these options with John Byrd when you visit him next.
Dear Chaya,
Thanks for a great article. My father, who is 70, was put on the B+R regimen since his platelet count went down to 75000. He took his first round about three weeks ago. In these three weeks, his platelet count initially increased from 75000 to 125000 before falling down to 60000. Can you please advise what must be causing this? and more importantly, what should be done to stop this? I have read your article “When Platelet Counts Start Dropping” but am not sure what must be the reason for the platelet dropping because my father seems to doing fine and has no side effects thus far. Also, all other blood counts are with normal limits. Please advise.
vallabhsri:
Bendamustine is quite myelosuppressive and for a period of time may reduce the ability of the bone marrow to produce cells of the myeloid lineage – among them, platelets. Reduced counts of platelets (and/or neutrophils, red blood cells etc) are quite common in patients undergoing therapy with any of the myelosuppressive drugs – which is just about all the straight chemotherapy drugs, to varying degrees.
There is not much to do, this is still early part of the therapy regimen. At 60K your father is in no immediate danger of bleeding uncontrollably. While the lower limit of platelet count is generally given as 100K, there is no danger and physicians do not get excited until the number gets as low as 20K-50K. Platelet transfusions are generally used only when the counts get below 20K or thereabouts.
Thanks a lot, Chaya. Really appreciate your prompt response.
What about bendamustine for previously non-treated patients? We’re looking at a two day treatment times four times, each two-day treatment one month apart, with rituxin added. Plus a drug (can’t recall the name just now) starting five days before the first treatment and going for ten days to reduce uric acid level. Many thanks, Chaya.