Do FCR Response Statistics Translate Into Longer Life?

There is no question that addition of Rituxan to FC (fludarabine + cyclophosphamide) improves the response statistics. Study after study has shown this. There are better overall response rates, more CRs, more pcr negative remissions (really deep remissions where we cannot detect even a trace of CLL with our most sensitive detection methods) with FCR compared to FC. Mouse juice (Rituxan) seems to improve response rates every time it is added to straight chemotherapy.

But, and this is the most important question as far as patients are concerned, do our guys live longer because of addition of R to FC? Who cares about the tag researchers give to your particular remission, CR, PR, nPR – whatever. What matters to you and your family is if this means you will live longer and your quality of life is better. These question had not been answered satisfactorily – up to now.

German Study Group: FC versus FCR, frontline therapy

ASH 2009 abstracts are now available on line, and one of the most interesting abstracts is the one from the German study group. Excellent paper, very credible group, and most encouraging results – I was delighted to read it. The abstract is below. My two cents follow right after, in plain English.

Abstract number 535

First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group

Michael Hallek, MD1, Guenter Fingerle-Rowson, MD, PhD1*, Anna-Maria Fink, MD1*, Raymonde Busch2*, Jiri Mayer, MD3*, Manfred Hensel, MD4*, Georg Hopfinger, MD5*, Georg Hess, MD6*, Ulrich von Gruenhagen, MD7*, Manuela A. Bergmann, MD8, John Catalano, MD9, Pier Luigi Zinzano, MD10*, Federico Caligaris Cappio, MD11*, John F Seymour, MD, PhD12*, Alain Berrebi, MD13*, Ulrich Jaeger, MD14, Bruno Cazin, MD15*, Marek Trneny, MD16, Anne Westermann1*, Clemens-Martin Wendtner, MD1, Barbara F. Eichhorst, MD1, Peter Staib, MD17*, Sebastian Boettcher, MD18*, Matthias Ritgen, MD18*, Myriam Mendila, MD19*, Michael Kneba, MD, PhD18, Hartmut Doehner, MD20*, Stephan Stilgenbauer, MD20 and Kirsten Fischer, MD1*

Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo).

Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively.

A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p<0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p<0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001).

Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p<0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p<0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p<0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p<0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p<0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168).

As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity.

Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and ß2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS.

Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy.

 

Trial Description

This trial did a head-to-head comparison of F+C versus F+C+R in a large cohort of previously untreated patients. 817 patients were recruited for the trial and randomly assigned to either the FC or the FCR arm. Patients in the two arms were well matched for sex, age, FISH and IgVH status. This is an important point. Without well matched and randomized double arm studies such as this one, it would be impossible to do a truly kosher apples-to-apples comparison and the results would be suspect.

All the patients received 6 cycles of therapy (roughly 6 months). Or that was the intent going in. As it actually turned out, on average the FCR crowd got 5.2 cycles of treatment and the FC guys called it a day after 4.8 cycles, on average. As you can imagine, some of the patients just could not handle all six cycles and that dropped the group averages from the optimum six cycles, in both FC and FCR arms. Some of the patients needed dose reductions in order to tolerate the treatments. It is encouraging that the FCR combo was not harder to tolerate than FC, if anything the number of patients who failed to finish all 6 cycles was smaller in the FCR arm.

Looking at the overall group, only 5% of the patients were in the early Binet Stage A; a further 31% were in the intermediate Binet Stage B and a whopping 64% were in the advanced Binet Stage C. There was the usual smattering of tough FISH abnormalities (25% 11q deletions and 8% 17p deletions). In other words, these were by no means “easy” patients cherry picked to improve response statistics. That has been a nagging worry at the back of my mind every time I read the stellar response statistics in earlier single arm FCR studies.  Call me a cynic, but I am enough of a scientist to be convinced by credible results when I see them.

Results

As of June 2009, the patients in this trial had clocked a median observation time of 38 months. This is not very long, but long enough that interesting statistics have begun to emerge. No doubt this precious group of study volunteers will be followed for as long as possible and we will get full length papers based on this study in the years to come. Longer follow-up will further solidify the results. But let me hasten to repeat: the results published in this abstract are statistically significant and valid. They are not due to happenstance or wishful thinking. That is what makes the good news so very encouraging.

As you can see in the table above, FCR did better than FC on all counts. We have come to expect FCR will do better on response statistics, and it did: better overall response, more CRs and longer remission times; and all of these met the test of statistical significance.

I have highlighted the new information. Patients who got randomized into the FCR arm lived longer than those that got only FC. The overall survival rate at 37.7 months (the duration of the trial at the time of writing of this abstract) was 84.1% in the FCR arm versus 79.0 % in the FC. And the difference met rigorous test for statistical significance, meaning you can actually have some faith this result is not a fluke. The difference may not seem like much to you, just a 5%. But these are early days. It will be interesting to see if the difference becomes more and more pronounced over time. My bet is that it will. We will see more starkly the advantage of adding R to FC in terms that matter to us – longer life.

My cheat-sheet table also breaks out the causes of death, since this was interesting as well. As you would expect, CLL progression was less of an issue in FCR than in FR. But did the addition of R cause the FCR arm to have more immune suppression and therefore more infections or more secondary cancers? It seems not. While there was indeed a bit more neutropenia in the FCR arm, there were not more infections. And there were not more deaths due to secondary cancers. Both of these are very good things to see, since they suggest FCR is no more immunosuppressive than plain FC.

Careful reading of the abstract points out a couple more details: the advantage of FCR over FC was most obvious in the earlier stage patients, those that were in Binet Stage A and B. Patients who were further along, in Binet Stage C, did not see as much of a benefit. This has huge implications and I will talk about them in the Editorial section.

Careful sub-set analysis revealed what we have come to expect. Prognostic indicators do make a difference. Patients with good prognostics did better, whether they got FC or FCR. Some of the indicators that influenced overall survival and progression free survival were:

  • Age (younger patients did better, in both arms. No surprise, younger patients are in better shape overall and have fewer co-morbidities. I would expect your actual physical health matters more than your chronological age - another reason to get into shape while you are in W&W! )
  • Sex (women fared better)
  • FCR-treatment (lucky ones got inducted into the FCR arm)
  • 17p-deletion (lucky patients did not have this bad prognostic indicator),
  • Increased serum levels of thymidine kinase (not good)
  • Increase ß2-microglobulin (not good)
  • Unmutated IGVH genes (not good

Editorial

First things first. Please join me in offering our heartfelt thanks and gratitude to the 817 brave volunteers who made this trial possible. They put their necks on the line so that we and future generations of CLL patients can benefit from these important findings.

This trial points out some of the human heartache that is unavoidable in the process of conducting double arm randomized trials such as this. How would you like to be the spouse of one of the patients that got randomized to receive FC, and your guy died soon after? Would he have lived if he had been lucky enough to get into the FCR arm instead? Toss of a coin or toss of a few bits in a computer code that randomized him into the FC arm might have made all the difference between life and death.  Bitter pill to swallow, and that makes their sacrifice all the more poignant.

But it is precisely because the study used such an ‘inhuman’ and unbiased method for putting patients into the two groups that the results are so very credible. Randomized and double arm clinical trials such as this one are truly the gold standard of clinical research. Because of this trial, we now know that any patient in future treated with FC rather than FCR is not being given the best possible therapy. FCR is now the gold standard, no questions about it.  There are always exceptions to the rule.  One exception is older patients who may not be able to tolerate FCR.  For them chloramabucil may be a better choice, as pointed out in Dr. Gribben’s Best Practices article that we reviewed last week.

Patients who were in earlier Binet stages A and B got more bang for buck with FCR, patients who were further along in their disease progression did not see as much of an advantage because of the addition of Rituxan to FC. Does this mean patients will be better off pulling the trigger and opting for initiating FCR therapy, sooner rather than later? Are they risking shooting themselves in the foot by waiting until the last bitter moment before initiating therapy? Remember, conventional wisdom to date is that Watch & Wait is the best thing to do until onset of B-symptoms and falling platelet counts and red blood cell counts require start of therapy. Should these guidelines be modified, suggesting patients are better off starting therapy sooner?

The results of this trial seem to suggest it is better not to wait too long, not to drag out W&W just a bit longer. That is a finding that can have a huge impact on how we treat CLL patients. But I wonder if there is a twist in this particular finding, if there is a bit more to it than just that.

Let us do a thought experiment. Let us invent two identical CLL patients (there are no such identical pairs, but hey this is a thought experiment, right?). Patient A goes through W&W for only 2 years and while he is still in Binet Stage A, decides to opt for FCR therapy. Patient B is a bit more dogged about resisting therapy for as long as he can, he waits it out for 5 years – by which time he is in Binet Stage C – before starting FCR. Patient A gets a good remission, his overall survival is a solid 10 years after completion of FCR. Patient B is not so lucky, he lives for “only” 7 years after completing FCR. Who came out ahead?

The answer is neither patient lived longer than the other. Patient A had 2 years of W&W + 10 years after FCR, a total of 12 years after CLL diagnosis. Patient B had 5 years of W&W + 7 years after FCR, he too had a total of 12 years post CLL diagnosis.

I have obviously jury rigged the numbers in this thought experiment to illustrate my point. It may be that there is real advantage to initiating FCR sooner, but this trial does not confirm that. The other issue to consider is quality of life. Did Patient B do himself a disservice struggling along with increasing CLL load, increasing B-symptoms and poor quality of life in the last couple of years of his dogged W&W? Would he have had better overall quality of life, averaged over his 12 years, if he had gone into therapy sooner? Conversely, did Patient A sail through his FCR therapay and did he get a really clean and hassle free remission that gave him good quality of life for the next 10 years? Or was his immune system so shot by the FCR that he remained neutropenic and prone to infections for a big chunk of his 10 year remission?

These are important questions and I doubt any clinical trial will give us slam dunk answers that are right for all patients. It is never easy to decide to wait or not to wait. Each of us is unique in our own way and each of us has unique therapy needs. The smart thing to do is get yourself top notch medical advice, then sit down with your family and trusted advisors and make your decisions, the ones that are right for you and your family. And remember this: once you have made your decision, know it is the right one – for you. Don’t look back, don’t second guess yourself, don’t torture yourself with what –ifs.  No one is more qualified to make decisions for you than you are.  Don’t let anyone bully you into thinking otherwise.  It is your life, your body, you and your family have most skin in this game.  Just remember that, OK?