CologneBendamustine 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).

BR patient profile, relapsed cohort

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.

BR response stats, relapsed cohortAs 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.

BR toxicity, relapsed cohort

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.

Bendamustine structure

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Dalai LamaGreetings from hot and humid India.  After spending a little time with my Mom, assorted cousins and the like, I am taking a little trip to visit Dharamsala - the seat of His Holiness the Dalai Lama.  Coincidentally enough, I met him in person back in 1959, right after he and his followers fled Chinese incursion into Tibet.   He impressed me a great deal then, a mere 11 year old peeping from behind my Mom during our audience with this brilliant young man.  He has continued to impress me as I grew older, with his serenity, integrity, intelligence and real commitment to peace.  I will try to write at least one (totally off topic!) blog about my visit when I get back.  You can skip it if it is not your cup of Tibetan ‘chai’.

In the meanwhile, I will be out of email contact for the duration of the trip - September 25 through October 5.  I am sure you will manage just fine, no one is really indispensable.  Well, perhaps he is indispensable.