Bendamustine is in the news. Again. We have reviewed it several times before, you can find the articles by typing the key word in the search box at the top right hand corner of our websites. Each article has the date of publication right on top, so you can get a sense of the vintage of the information.
This article is for the purpose of reviewing the recently published clinical trial results using B+R in relapsed and / or refractory patients – conducted by some big name CLL researchers in the German CLL Study Group.
Benadamustine + Rituxan
This well conducted clinical trial comes to us from the German CLL group. Makes sense I suppose, after all the newest addition to our arsenal of chemotherapy drugs comes from East Germany. They have had more than 40 years of experience with it. This is hardly a newly invented molecule, more along the lines of a newly packaged molecule with sexy marketing name to match: “Treanda”. You would think a 40 year old drug would be off patent and cheap as dirt, wouldn’t you? Shame on you for being so naive.
Clinical Trial Rationale
Seventy eight relapsed and/or refractory patients were recruited for this multi-center trial. Fortunately for us, the patients are well characterized with all the latest prognostic information. I will try to capture most of the relevant details, but as always, I refer you to the original article if you want to be sure you did not miss anything. The abstract is below. Send me a personal email if you want help locating the full text article.
J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15.
Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group.
Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM.
Department I of Internal Medicine, University of Cologne, Kerpener Str 62, 50937 Köln, Germany; clemens.wendtner@uni-koeln.de.
PURPOSE The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. CONCLUSION Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.
PMID: 2184449
The terms “relapsed” and “refractory” are not quite the same and it is important to know what this group of researchers mean when they use these terms. “Relapsed” is easy to define. The patient had therapy before for his CLL, got some sort of a remission, then the CLL came back and it is now time to treat again. Notice we make no distinction about the nature of his earlier remission(s), how long they lasted etc. Just your garden variety relapsed patient.
“Refractory” has a more dangerous feel to it. A refractory patient is one who did not get a deep enough remission to be classified a “CR” or “PR”. Or, even if he did, the remission did not hold for very long and his disease progressed within 6 months. I think you can see the big difference between merely relapsed patients and those that are refractory.
Now let us look at the term “refractory” a bit more in detail . Let us consider a patient that had low dose single agent Rituxan therapy. Just a little something to take a little of the top, nothing very aggressive at all. It would be unreasonable to expect a deep or lasting remission for this approach and chances are good the patient would relapse within 6 months, needing another round of Rituxan to keep things going.
But how about the prior therapy was not single agent Rituxan, what if it was full strength FCR or FR or some such manly chemoimmunotherapy combo? What if the patient got a bare “PR” remission for his trouble and that remission did not last even six months? Now we are talking about a hard luck case, a patient with some real problems. In other words, it is not enough to say the patient is refractory, it is important to understand what he is refractory to. In this second case, the patient would be classified as a fludarabine refractory patient. Seeing how fludarabine is one of our most powerful drugs and part of the mix in most chemoimmunotherapy regimens, fludarabine refractory patients have very limited choices for salvage therapy.
And that is what makes bendamustine an important and interesting drug. If it gives fludarabine refractory patients a shot at a decent remission that lasts for a while, we are talking major breakthrough.
By now we know addition of Rituxan (or its kissing cousin ofatumumab, Arzerra) makes every chemotherapy drug work much better. It is a question of using Rituxan to latch on to and therefore target every CD20 carrying B-cell in the body. Once the B-cell is thus identified, it is much easier for the chemo drug (fludarabine, bendamustine, chlorambucil, what ever) to deliver the killing blow. Deciding to test bendamustine in combination with Rituxan is therefore not what I would call rocket science.
Patient Characteristics
Understanding the nature of the patient cohort treated and the detailed adverse effect profile are the two most important things before we judge how well a drug worked. After all, if I cherry picked just the right bunch of patients, people with nice prognostic indicators and barely relapsed after a light prior therapy, it is not very hard to get good remissions. And if we did not care about drug related toxicity, it is easy enough to up the dosage and get good response statistics. That would be borderline unethical, but hey, everyone is doing it – right?
So, let us look at the details of this bunch of brave volunteers (who remain unacknowledged and un-thanked by the authors. You surprised? Shame on you for being so naive).
So, this is how the patient profile stacked up. And yes, I agree this was not a cherry picked easy bunch of patients to treat, these were patients with some heavy duty problems. I especially noted the percentage of 17p deleted folks, those with unmutated IgVH and the dreaded fludarabine refractory patients. Finding better therapy options for this hard to treat section of our patient community is definitely worth doing.
Drug Dosages
Patients were scheduled to get six courses of therapy, 4 weeks apart. On days 1 and 2 of each cycle they got 70mg/m2 of bendamustine, along with 500 mg/m2 of Rituxan on day 1. (The Rituxan dose was reduced to 375 mg/m2 for just the first cycle).
78 patients, 6 cycles planned, we are talking of 468 total number of cycles. But in reality only 353 cycles were administered. 44 out of the 78 patients received all 6 planned cycles. For the rest, dose reduction, cutting short the number of cycles etc was carried out mostly as a result of treatment related hematological toxicity (particularly neutropenia). Treatment was discontinued for 34 (44%) of patients as a result of withdrawal of consent, toxicity, progressive disease etc.
Reponses
The paper is chock full of statistics, the patient group sliced and diced into all the subgroups. I have tried to simplify some of the data into the chart below. But you really need to read the original article itself if you want all the fine details.
As you can see, the overall response rate for all 78 patients was 59%, with 9% of them getting the coveted “CR”. Half the patients were still in remission at 15.2 month mark (median remission duration). The median overall survival was 33.9 months, just shy of 3 years.
When you look at the rest of the data, be sure to notice the number of patients that ended up in each sub-category. For example, there were only 5 patients in the Trisomy 12 category, which makes the statistics for this group less than robust.
I highlighted the survival and remission duration for the really hard cases, the ones with 17p deletion, or unmutated or high B2M. While the data is very interesting and useful, please try and not to read too much into minutiae. Small sample sizes makes for poor statistical significance.
The researchers report that there was a strong correlation between the number of cycles a given patient was able to tolerate and the quality of the response. Makes sense to me. And the other equally understandable point is this. Patients with good kidney function were able to tolerate higher doses and more cycles. Patients who went into the program with kidneys operating at less than peak efficiency suffered more toxicity and had to pull their therapy punches. Moral of the story: take care of your kidneys folks. Stop overloading them with all sorts of magic potions and pills, stop heavy drinking, keep yourself well hydrated. Not all that hard to do, given the importance of this often overlooked organ. Obesity, diabetes, and high blood pressure are all tough on the kidneys.
This is what the researchers had to say in comparing their “BR” regimen against the present day gold standard of FCR;
“Compared with recently published trial evaluating the efficacy of FCR and reported ORR (overall response rate) based on investigator assessment of 69.9% with CR rate of 24.3% in relapsed CLL, the response data derived from our trial seem inferior. Interestingly, the authors reported an ORR of 61% with a CR rate of 9% when the analysis was performed on response data assessed by an independent review committee.”
Don’t you find it heart warming, how polite these guys are to each other? In less polite and plain English, it is suggested the original FCR results were just a tad exaggerated and the results of FCR and BR are comparable if there was no gilding of the lily.
Toxicity
The toxicity profile is pretty much what I would have expected, given the substantial oomph of bendamustine. Neither BR nor FCR are for the faint of heart, or those who are elderly, with other medical conditions complicating treatment choices. Below are the Grade 3 and Grade 4 toxicities encountered, broken down by blood toxicities as well as infections. In case you are not familiar with the grading of toxicities, here is a quick cheat sheet. Grade 1 is no big deal, you would be thought a real wimp for complaining. Grade 2 a bit more robust, something your doctors may actually take note of. Grade 3 and 4 are the real kahuna, really something to write home about. Grade 5, forgeddabout it. You have nothing left to worry about, since you would be dead.
Editorial
So, where does all this leave us? If you have been convinced that bendamustine with Rituxan provides a valuable therapy option for refractory patients, you are not far off the mark. It truly helps to have more options, not less, especially in this tough to treat group. Bendamustine based therapy regimens provide much needed extra options.
Are you ready to de-throne FCR and FR as the present day gold standards and crown BR in their place, whether it be for frontline therapy or in a salvage setting? I am not quite there yet. Some of it has to do with just my gut instincts. I will be the first one to admit I have a bit of a bias against bendamustine, based on the company’s prior behavior when trying to get FDA approval.
Here is the short version. In that pivotal trial (conducted by the same German CLL group that did this latest trial), hefty doses of bendamustine single agent were compared against unusually low doses of chlorambucil. As you would expect in this unfair straw-man comparison, bendamustine did better. FDA was impressed (really, this is more than a little bending over backwards on the part of our regulatory watch dog), broad range marketing approval of the drug was given post-haste.
Even leaving aside the fact that they used chlorambucil as the comparison drug, and a low dose regimen of it at that, there is another little nugget of information that got me hot and bothered. The starting dose of bendamustine for these patients was 100 mg/m2. (If you are not familiar with the mg/m2 notation, it is time you read and understood what it means. Body Surface Area or BSA determines the amount of drug tailored for your body size). Compare that to how they handled the dosage for chlorambucil, even the lowly amount was calculated as 70mg/Kg. OK, so they used the patient’s weight, not his body surface area. What is wrong with that? What is amazing is what they buried in the fine print. It was not 70mg/kg of the patient’s actual weight. It was 70 mg/ kg of the patient’s “ideal weight”. In other words, if you are a little overweight (and how many of us at this age are not packing more than a few extra pounds of weight), you were short changed on that account too; the amount of chlorambucil was calculated not by how much you actually weighed, but how much you should weigh in a perfect world. Talk about underhanded tactics!
Same drug companies, same CLL German group, same high pedigree researchers who did the original FDA approval study also did this study. Almost all of them (especially the big marquee names) had paid consultancy agreements with the drug companies involved. (For the record, I received no fee, not one red cent, no perks, not so much as a ballpoint pen with the company logos on it). Fool me once, shame on you. Fool me twice, shame on me. It is going to take a little bit extra effort on the part of bendamustine to get my vote of confidence – not that the companies are going to sit up and take notice.
Where do the experts weigh in on this? A recent article in Oncology Times compared the opinions of Dr. Kanti Rai, Dr. Neil Kay and Dr. Bruce Cheson. It is well written and easy to read. Dr. Kanti Rai is of the opinion that there is not enough data and not enough time-tested data that makes bendamustine (plus Rituxan) a slam dunk new gold standard. And he too thinks the earlier chlorambucil straw-man comparison was, and I quote, “a joke”. Good for him, once in a while it is nice to have an expert call it like it is. Of course, our patron saint Dr. Terry Hamblin has been quite explicit on this subject as well, in his blog entries.
Please join me in thanking the volunteers of this clinical trial. And join me as well in wishing Dr. Hamblin good health and a rapid recovery from his chemotherapy treatments.
16 comments on "B+R in Relapsed Patients"
Chaya, I know this is wishful thinking, but it would be great if the researchers would start posting the effect of B+R on lymph nodes. So far, I’m not seeing it and personal reports are mixed.
Thanks for the great review.
Ann
As a seasoned anthropological researcher, with a husband on the CLL journey, I humbly thank you for your continued and excellent decipherment of the impenetrable maze of research out there. Your explanation is edifying, comforting and stimulating all at once–amazing. Thank you
This article re Bendamustine and R is really helpful. As usual, your writing is so valuable to the CLL community. It is great that you are visiting the Dali Lama. I have been so impressed with the interviews I have seen with him. Be well in your travels.
Chris R
Thank you Chris. But to be honest, I am not “visiting the Dalai Lama”. I am just going to visit his home town. I am not even sure he will be in residence during the days I am there, and in any case I am told it is very difficult to get an audience with him.
Chaya, thank you for another great article which not only tells it like it is but also tells it with stuff others (like me) might not spot. Much appreciated. And don’t undervalue yourself – I now have patient responsibility for all cancers, not just CLL, and I regularly praise CLL Topics, but no one ever jumps up and says, “Did you know that we with cancer xxx have got xxx topics which is also brilliant?”
Thanks Again,
Lawrence
PS – I entirely agree with your views of the DL. I subscribe to him on Facebook and read his stuff whenever I can.
Chaya, thank you for a great update.
Monique
Chaya, I have been reading your articles for about a year now and one of the big benefits for me is the new found ability to talk intelligently with my hematologist. He is a good doctor with an open mind and thus far has responded positively to my questions and suggestions regarding treatment. I can’t tell you how important it is to me to have that kind of control over my situation. Thank you.
Gary
Question: Does anyone have experience with b + r as the very first treatment for someone who has never been treated previously? Is this even a relevant topic?
Many thanks to all.
David
Chaya,
Do all reseachers (clinical trials we hear from) us the same definition for CR and PR? And how does it differ from US and oaverseas?
thanks
Chaya,
I was afraid of Bendamustine but now I have a soft spot in my heart for her.
2002 I started chemo with R/F. My wbc dropped immediately. I had a few infections. I also got Shingles. To be honest, I was not on acyclovir.
I didn’t know about it. I was on w&w for 8 years and all this happened so fast after a colon resection for Colon cancer.
I do not have a fond memory of fludara since then and have refused it. From my research, I feel I am too old. 78 years old. I am on IVIG.
In 2009/10 I was offered B. My problem was the omeprazole in bendamustine, prilosec and cilostazol for peripheral vascular disease.
We substituted zantec for B. My wonderful internist said just don’t take cilostazol the two days of chemo.
I began chemo. My most horrible problem was constipation. Also the usual problems when taking steroids. It was either that or nausea.
It was not a walk in the park but I got through it and have been in remission for 17 months. Cross your fingers.
Many blessings,
Rita
Sorry, a mistake in the above post.
Zantec was substituted for P (prilosec) not B.
Rita
Chaya,
Always good to know of another options in case of relapse. Many thanks for an informative article.
Chaya. Thank you for another great and well-timed article.
It is nice to see when you says: – Are you ready to de-throne FCR and FR as the present day gold standards and crown BR in their place, whether it be for frontline therapy or in a salvage setting? I am not quite there yet. Some of it has to do with just my gut instincts.-
Let me say that we trust your instincts.
It is so great your visit His Holiness Dalai Lama home town. Sometimes I read some articles from dalailama.com that are very interesting and helpful for me.He impress me also so much.
I hope also the quicker recovery of Dr. Hamblin. He is a great person.
I think that the World will be much better with more persons like You ,Dr. Hamblin and Holiness Dalai Lama. Thank you also for the brave volunteers of this clinical trial.
All,
This article is about a year late for me but my experience may be of some help to you. I went through 6 rounds of B + R treatment over a 6 month period last year, completing the last treatment 13 months ago. At my last check-up at the one year point, my red blood cell chemistry was all in the normal range, white blood cell chemistry still on the lower end. I was neutrapenic for about 9 months after treatment.
The treatment regimen consisted of three days at the infusion center getting B + R on the first day, B only on the next two days, followed by a neulasta shot on the fourth day. Then three weeks off before the next round. Only side effects were from the neulasta which produced low grade fever and aches in my long bones for about 24-72 hours afterwards
For Ann, my lymph nodes and spleen have both shrunk to normal. I started treatment with a greatly enlarged spleen and visually obvious lymph nodes on my neck.
FWIW, I’m mid 60’s, fall in the Trisomy-12 “bucket,” and have no other health issues.
Clearly, I’m a a bendamustine fan.
Hi
I am into my 6 mo remission from B+R, I believe I came through it in fair condition. I did get high fevers. hospitalized twice 2nd time 102 temp and had CMV, thrombocytopina, Out side of feeling fatigue, I am doing ok. My cts are doing ok, wbc low to normal. I am 13q 14 w/unmutated and cd 38, I am not quite sure where I am in the remission part of this. my flow report says minute population of B cells w/co expressionof cd5/cd19 on the very low end no signifcant expression of cd23 marrow shows improvement over previous BMB. I am back on W&W. For now it is what it is. It’s the best I’ve felt in more than 2 yrs. When I see the specialst in 3 months. I will have more questions. Oh. I am seeing a dematologist because I have had this horrible rash on my upper torso and the Rx cream I have been given for itching are not helping.
Chaya,
I recently returned from the LRF Conference in Brooklyn where Dr. Bruce Cheson was a principle speaker for the CLL/SLL breakout session. His talk was dominated by the championing of BR.
I did not have time to read your article prior to hearing his talk but being aware of Terry Hamblin’s criticism of the comparison of Bendamustine against Chlorambucil I point blank asked Cheson about the fairness of the trial given the inferior dosing of Chlorambucil. He dismissed it as being “not true” end of discussion. Later in the general auditorium Q&A I put this question to Dr. Cheson: “Given that Bendamustine is considered an alkylating agent could patients expect a higher incidence of MDS or secondary cancers and has there been any data to that effect?” He answered that there had not been enough time to show prolonged effects. I personally find it hard to believe that for all the years it had been used in East Germany that only the “good” results were documented. Germans (East or West) were never noted for lack of careful data gathering.
The Irony of this Conference with its emphasis for the CLL/SLL crowd on the rosy future of Bendamustine/Rituxan, was a guy who sat next to me who had been on a CAL-101 Trial since May after a life threatening reaction from BR. – Caveat Emptor!
Not being a fan of Alkylating agents in general I am in sync with your cautious take on the subject. Nice work and may your trip be renewing.
WWW
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