Dawning of the Age of FCR

LantanaFlower[1]I must confess I was not an early fan of the FCR regimen. I thought it claimed the mantle of “gold standard” far too soon, based on single arm Phase-II clinical trials at a single institution (M. D. Anderson).

But since those early days this powerful chemoimmunotherapy combination of fludarabine (F), cyclophosphamide (C) and Rituxan (R) has been examined at multiple expert centers with hundreds of patients participating in clinical trials in this country and in Europe. While there is small amount of variability in the results obtained from different centers and different patient cohorts (to be expected), there is now clear indication that FCR gets substantially better results than single agent chlorambucil, single agent fludarabine or fludarabine combined with cyclophosphamide. The age of FCR has arrived. The FDA has approved this combination as frontline therapy for CLL. Honor is due: with availability of more robust statistics and multi-center results, I am delighted to change my mind and accept this combination as a valuable and proven therapy option for CLL patients.

Can We Make FCR Work Better?

This is an obvious question and the race is on among expert centers to find the next best thing, an improved version of FCR. Three criteria are important when judging whether or not new combinations are indeed better than FCR:

  1. Does the new combo yield better response statistics in terms of higher percentage of overall responses, higher percentage of “CR” responses, higher percentage of patients without minimal residual disease even when examined by our most sensitive methods?
  2. Do the remissions last longer?
  3. Are the higher response rates and longer remissions obtained without increased level of toxicity?

From patients’ perspective, the second and third item are most important. When rubber meets the road, what we care about is whether the hard won remission lasts a good long time, and whether we can enjoy the remission without a lot of adverse effects that would otherwise spoil our quality of life.

“More Is Better” – But Only Some Times.

Cancer research has long depended upon the concept of attacking the cancer cells from multiple directions. Hitting the malignant cells with multiple drugs targeting different points of vulnerability makes some sense, since it leaves fewer escape routes for the cancer cells. Obviously this approach can go to crazy extremes, more and more drugs added to the alphabet soup. “Non-overlapping toxicity” (meaning that one drug may make you take up residence on the toilet seat while the second one makes you break out in hives and the third tanks your red blood cell count – as an example of non-overlapping toxicity) is a favorite concept with researchers. But I have yet to find patients who feel as comfortable with this view of life.

FCR +L (lumiliximab)

Back in the spring of 2007 I discussed in detail a new monoclonal antibody called lumiliximab that targeted CD23. . Since all CLL cells express CD23 marker, there was reason to hope that addition of “Lumi”  to existing combinations would further increase efficacy. An early Phase I clinical trial of Lumi as single agent in relapsed CLL patients showed efficacy without undue toxicity. Building on that encouraging news, a larger Phase I / II clinical trial was initiated where Lumi was added to standard FCR protocol. This time too the patients chosen for the study were relapsed / refractory patients. The latest results from this interesting trial have recently been published in Blood. The abstract is below, as well as this link to the full length article.

Blood. 2009 Oct 20. [Epub ahead of print]

Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.

Byrd JC, Kipps TJ, Flinn IW, Castro J, Lin TS, Wierda W, Heerema N, Woodworth J, Hughes S, Tangri S, Harris S, Wynne D, Molina A, Leigh B, O’Brien S.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States;

Preclinical data demonstrate enhanced antitumor effect when lumiliximab, an anti-CD23 monoclonal antibody, is combined with fludarabine or rituximab. Clinical data from a phase 1 trial with lumiliximab demonstrated an acceptable toxicity profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). We therefore pursued a phase 1/2 dose escalation study of lumiliximab added to fludarabine, cyclophosphamide, and rituximab (FCR) in previously treated CLL patients. Thirty-one patients received either 375 mg/m(2) (n = 3) or 500 mg/m(2) (n = 28) of lumiliximab in combination with FCR for 6 cycles. The toxicity profile was similar to that previously reported for FCR in treatment of relapsed CLL. The overall response rate was 65% with 52% of patients achieving a complete response (CR), which compares favorably with the CR rate previously reported for the FCR regimen alone in relapsed CLL. The estimated median progression-free survival for all responders was 28.7 months. The addition of lumiliximab to FCR therapy is feasible, achieves a high CR rate, and does not appear to enhance toxicity in previously treated patients with CLL. A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial were registered at clinicaltrials.gov as NCT00103558.

PMID: 19843887

This was a single arm clinical trial.  Comparison is made to historical statistics for FCR therapy in similar patient cohorts. Three of the 31 patients in the trial got 375mg/m2 of Lumi, in addition to FCR, for 6 cycles. Lumi dose was escalated to 500 mg/m2 for the bulk of the patient cohort (28 patients).

So, did the addition of Lumi make a difference? Is FCRL a better combo than FCR alone? Well, it depends on how you want to spin the results. True, there were higher percentage of overall responses and higher percentage of “CRs”. The adverse effect profile was not significantly different either. But on the important question of response duration, there was no improvement. Bummer! Patients relapsed in just about the same time frame as those who had been treated with just FCR. The rumor mill has it that further development of Lumiliximab in CLL has taken a huge step backward in terms of these ho-hum results. As with all monoclonal antibodies, Lumi is not likely to be a cheap drug and it is hard to make a case for its addition when the remission duration was not any better than just FCR

FCR + Other Chemotherapy Agents

The same issue of Blood where the FCR+L study was published had a very interesting editorial that compared a series of different chemoimmunotherapy combinations against FCR. There is no abstract of this editorial (since it is not very long) but you can read it in full by clicking on the link. I recommend it strongly.

The chart below is from this editorial. Rather than limiting itself to the FCR + L trial reported in the same issue of Blood, the editorial goes further and compares the data for other efforts made in the last few years to “goose” up FCR.  Of note, CFAR (which is a combination of FCR + alemtuzumab – also known as “Campath”) and FCR + Mitoxantrone results are also included.

Improving on FCR

As you can see, the two FCR trials had pretty similar results – within normal variations to be expected in two trials that were not strict back-to-back comparisons.

We had a lot to say about the FCR + Mitoxantrone study both at M. D. Anderson as well as European centers.

Unlike FCR + L where the adverse effect profile did not change significantly from FCR because of adding lumiliximab, addition of mitroxantrone or Campath have substantial effect on adverse effects including cardiac toxicity and hematological toxicity, respectively.  Unfortunately, FCR + Campath (“CFAR”) did not give longer remissions than FCR alone. We are still waiting on the remission duration statistics for FCR+ Mitoxantrone.  I confess I am not holding my breath on that one, I doubt we will see much longer remission durations with FCR + Mitoxantrone either.

Science moves in slow increments. Negative information is just as valuable, because it allows us to rule out certain things and not waste time bashing our heads against a brick wall that will not budge. I do not want you to lose sight of the fact that but for the brave patient volunteers who participated in these clinical trials, we would not have known that these combinations do not work a whole lot better than FCR.  All in all, these results have been disappointing and researchers have to get back to the drawing board to find other ways of improving upon FCR.