FCR therapy comes of age

FCR combination (fludarabine, cyclophosphamide and Rituxan) clinical trials were just getting talked about back in the summer of 2001 when my husband PC was diagnosed.  Eight years later, this combination (with a few dosage and protocol tweaks along the way) has become the de-facto gold standard therapy for CLL.  One of these days I will review the results of the benchmark clinical trial conducted in Germany.  While there are differences in the response statistics between this trial and the results reported earlier by M. D. Anderson, there is no question FCR is a very potent combination that has added significantly to our therapy options.

Anyone out there hoping FCR therapy will actually CURE their CLL, once and for all?  Here is a quote from the team that spearheaded the development of FCR regimen at M. D. Anderson:

“The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL.”

OK, most patients will eventually relapse. We get it. It is a matter of when, not if.  By now enough time has passed since the first batches of patient volunteers have graduated from FCR clinical trials and we can ask the question: what is life like for patients after their hard-won FCR remission ends?

Life after FCR

I have attached at the end of this review an important abstract from ASH 2008 conference that tries to answer this particular question. This is straight from the horse’s mouth as it were, the authors listed are the very folks that pioneered the FCR combination. I urge you to read the abstract for yourself.  My two cent comments are below – cheap at the price if I say so myself.

One can argue about the exact response statistics of patients going through FCR as front-line therapy (we discussed some of the reasons why response statistics can vary pretty dramatically in an earlier ‘Updates’ article titled “FCR versus PCR”).  But that is not the point of this review. This article focuses on the fate of patients who have already relapsed after their FCR therapy.

This study looks at 97 patients who have completed “salvage treatment” after their FCR remissions relapsed.  (I wonder if oncologists know how much that phrase “salvage  treatment” sticks in the craw of patients and their spouses).

Who had the best shot with Salvage after FCR relapse?

Turns out this is a no-brainer.  While the “median” FCR relapsed patient lived 32 months after completion of salvage therapy, patients who were lucky enough to have good prognostics and therefore responded well to FCR also responded well to salvage therapy after their FCR relapse. Here is how it shakes out:

  • Median survival after salvage for the whole group was 32 months.
  • Patients who got a CR and a remission that lasted at least 18 months after their FCR therapy did better with salvage therapy too, patients with this ‘good’ profile lived on average for 47 months.
  • For the unfortunate patients who did poorly with FCR (only partial response and remission lasting less than 18 months) salvage therapy did not work any miracles either.  The median survival was only 13 months.
  • M. D. Anderson is a big believer in the prognostic value of beta-2-microglobulin (B2M). Median survival after salvage has not yet been reached for folks with good B2M. Patients with B2m higher than 3.0 did not do well on FCR or subsequent salvage therapy (median survival of 17 months after salvage).
  • Also as you would expect, folks with the good IgVH mutated variety of CLL did better with the FCR front-line therapy and also subsequent salvage therapy when the first remission ended.

Moral of the story, if you are lucky enough to have relatively easy going CLL to begin with, if your disease was still relatively early stage when you decided to pull the plug and initiate therapy (good platelet counts, for example), you are more likely to do well on FCR, get a long remission from it, and when you relapse, you are also likely to get good response to salvage therapy and have several year survival horizon to contemplate.  Unfortunately, the small numbers of patients whose FISH abnormalities were documented is small, and conclusions drawn on the basis of small groups of patients are notoriously undependable.

A nagging thought at the back of my mind: there has been some discussion that the chemo-naive patients recruited for the early M. D. Anderson FCR trials were not exactly the worst case scenario patients.  There have been comments about cherry-picking, leading to better response statistics at MDA than documented in similar studies done elsewhere. Does this mean the salvage therapy response statistics we are discussing here are also similarly over optimistic? Heaven forbid.  These statistics are grim enough as they are!

What kind of salvage therapy is best?

If you are like me, you will want to think through a couple of chess moves ahead of time in this deadly serious cancer ‘game’.  Assuming you relapse after front-line FCR therapy, hopefully not any time soon, what are your best options for second string salvage therapy?

The patients in this study got a whole slew of different salvage therapies, depending on the judgment of their local practitioners. Out of the 97 patients followed in this study

  • 30 patients tried a second attempt at FCR. 17% (5 patients) of these got another CR (my guess is that these folks were among the lucky ones who did well on the first go-around of FCR and tried their luck with a second shot at what worked well before). Not an overwhelming vindication of a second bite at the apple, if you ask me.
  • 25 optimistic folks tried single agent Rituxan, and as you would expect, very few of them- only 4% (a single patient) got a CR.  Rituxan does not have the oomph needed to treat CLL patients after they have relapsed from high impact chemoimmunotherapy combinations such as FCR. It is in this context that we are placing our hopes on early approval of Humax-CD20.
  • 16 patients tried a combination of Campath + Rituxan. This double monoclonal therapy did a bit better, 31% (5 patients) got CR. This makes sense, Campath targets a different marker (CD52) than Rituxan, one that is heavily expressed by all CLL cells.
  • Working on the more-is-better approach, 9 patients tried CFAR (Campath + FCR). An impressive 56% of these guys got a CR following this high impact approach.

 While the number of patients who tried CFAR as salvage therapy is small (only 9 patients), I am pretty sure the response statistics will prove to be robust, give or take a few percent points. CFAR gave, by far, the highest CR response rates following FCR relapse. But before we celebrate and sign up for CFAR as a slam-dunk choice after FCR relapse, here is the kicker:

“patients who opted for CFAR as opposed to another go at FCR did not get longer remission or live longer following their chosen salvage therapy (30 month remission, 40 month overall survival)”

Perhaps we will glean some statistically significant differences between CFAR and FCR as salvage therapy when we have larger number of patients to compare, and the higher response stats for CFAR will be reflected in longer remissions and longer life.  For now, the jury is still out on this question.

Any silver lining for the “salvage” folks?

The above statistics are grim reading for patients who have opted for FCR and now coming out of remission.  Based on this credible study, half the patients did not live beyond 3 years after salvage.  “None of the regimens showed a significant survival benefit.” is the down-beat assessment of the authors.  Can you think of any better reason for looking for options other than the dog’s breakfast of chemo/immunotherapy combinations tried by the patients we have discussed thus far?

The abstract does hold forth a glimmer of hope.  27 out of the 97 patients went the route of getting a mini allo stem cell transplant.  Here is a telling quote from the authors:

Patients receiving Stem Cell Transplant had a significantly superior Overall Survival than those who did not undergo SCT”.

Only 14 out of the full cohort of 97 patients survived more than 4 years.  Of these, a large majority (11 out of 14 – a whopping 79%) had chosen the transplant route. In fact, the median survival has not yet been reached in patients who chose to get a stem cell transplant, compared to a mere 30 month overall survival for those that did not.

Editorial

Forgive me for putting this picture in blunt terms. Here is a potential scenario:

You have had FCR.  You had a nice remission.  Like all good things, it has come to an end.  Now you need to do decide what to do next.  You want to live more than 4 years?  Your odds of doing so are 79% if you go for a transplant, and only 21% if you choose some other salvage therapy – statistically speaking.

Aha. There is that sneaky little phrase, statistically speaking.  Any one of us can have outcomes that are not predicted by statistics. They can be much better than predicted or much worse depending on your individual case.  The horse that is given the poorest odds of winning the race can still win, make you rich beyond your dreams. Or the nag can come dead last.  But given the choice of betting on only one of the horses in the race, with your life on the line, do you think you should bet on the horse with the best statistics, the one most likely to win the race?

I will be the first to admit, stem cell transplants are tough love. Luck plays a significant part, starting with finding a suitable source of stem cells (adult sibling, matched unrelated adult donor, matched cord blood – these are your three choices).

Even mini-allo transplants are not all that “kind & gentle”. Older patients with health problems other than the CLL carry additional risks.  The procedure costs an arm & leg, not to mention other bits of you – unless you have good insurance coverage. Not to be glossed over, it requires strong family support – patients will need 24/7 devoted care from a dedicated caregiver for several weeks.  “Harvey’s Journal” highlights some of the issues, including the heartbreak of devastating failure even with the best of efforts and planning.

Should you opt for a stem cell transplant after FCR remission comes to an end?  Perhaps you will get lucky with the far less risky CFAR, or even a repeat FCR combo? Only you can make that decision.

No one in their right mind would consider a transplant if there were better ways of staying alive. The fact that you are even thinking about this option says you have the proverbial cocked gun pointing at your head. The prudent thing to do would be to learn as much about it as you can ahead of time, get your ducks in a row. Our flagship website  www.clltopics.org carries several detailed articles on what to expect. This is your body, your life. I can try to provide a CLL “Owner’s Manual” of sorts, but only you can make decisions that are right for you.

And oh yes, I heard recently from “Richard” of our Catch-22 article fame.  He and his wife are enjoying a second honeymoon.  With his very aggressive CLL profile I doubt he would have had this chance but for the mini-allo MUD transplant he had early in 2008. For every “Harvey” that did not make it, there are “Richard“s out there that did. What you read into these case histories depends on your personality, your specific situation, your resources.

Life after Fludarabine, Cyclophosphamide, & Rituximab (FCR) – the Clinical Outcome of Patients with Chronic Lymphocytic Leukemia Who Receive Salvage Treatment after Frontline FCR

Sunday, December 7, 2008, 6:00 PM-8:00 PM

Constantine S. Tam1, William G. Wierda, M.D., Ph.D2, Susan O’Brien3, Susan Lerner3*, Issa F Khouri4*, Hagop M. Kantarjian3*and Michael J Keating, M.D.3*

1Haematology, St Vincent’s Hospital, Fitzroy, Australia
2Leukemia, UT M. D. Anderson Cancer Center, Houston, TX
3Leukemia, UT MD Anderson Cancer Center, Houston, TX
4Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX

The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL. In order to evaluate how these patients should be subsequently managed, we analyzed our institutional experience with 300 patients treated with frontline FCR (Blood 112:975). After a median follow-up of 6 years, 116 patients (39%) had failed FCR therapy with 13 primary refractory disease and 103 relapses from partial remission (PR), nodular PR (nPR) or CR. Compared with patients in ongoing remission, relapsed / refractory patients had more adverse baseline characteristics including a greater proportion with performance status ≥1 (71% vs 53% p=0.002), elevated β2m (54% vs 36% p=0.002), white cell count ≥150 x 10^9/L (25% vs 12% p=0.003), unmutated IgVH (81% vs 44% p<0.001) and ZAP-70 positivity (78% vs 49% p<0.001). The aim of the current analysis was to determine the duration of survival (OS) following second-line therapy in 97 patients who had completed salvage treatment. The median follow-up was 32 (range 3 – 69) months, and the median OS (mOS) was 32 months. Characteristics associated with favorable OS were: (1) previous best response to FCR of nPR/CR lasting ≥18 months (mOS 47 months, vs 13 months for primary refractory disease, PR or nPR/CR lasting <18 months p=0.002); (2) β2m < 3.0 mg/L (mOS not reached, vs 17 months p=0.0003) and (3) platelets ≥ 100×10^9/L (mOS 47 months, vs 15 months p=0.004). Poor risk cytogenetic abnormalities were common at FCR failure: among 38 assessable patients, 7 (18%) had 17p- and 18 (47%) had 11q- by conventional karyotyping and/or FISH. Although patients with 17p- or 11q- had an inferior survival, this survival disadvantage was confined entirely to those who also had an elevated β2m ≥3.0 mg/L. Surprisingly, patients relapsing after durable FCR remissions (≥5 years) and patients with slowly progressive relapse (time to salvage ≥12 months after FCR failure) had similar OS as their more adverse counterparts (p=0.76 and 0.86 respectively). A prognostic model comprising β2m and platelet count effectively divided patients into low, intermediate and high risk categories with mOS of >45, 32 and 13 months respectively (p<0.0001). Patients received treatment chosen at the discretion of individual treating physicians and the CR rate of second-line therapy were: FCR (n=30), 17%; rituximab (n=25), 4%; alemtuzumab ± rituximab (n=16), 31%; FCR & alemtuzumab (CFAR, n=9), 56%; lymphoma-type chemotherapy (n=5), 0%; other treatment (n=12), 0%. The CR rate for CFAR was significantly higher than that of FCR (p=0.03), although the median remission duration (30 vs 20 months) and OS (44 vs 32 months) were similar (p=0.87 and 0.51 respectively). None of the regimens showed a significant survival benefit. Allogeneic stem cell transplantation (SCT) was performed in 27 (28%) patients at a median of 15 months after first salvage. Patients receiving SCT had a significantly superior OS than those who did not undergo SCT (not reached vs 30 months, p=0.03). Of the 14 patients surviving for more than four years, 11 (79%) had undergone a SCT. Patients who fail FCR therapy had high risk disease features including elevated β2m, unmutated IgVH and ZAP-70 positivity, and most had adverse cytogenetic findings at relapse. Results of salvage therapy in this group were poor with a median survival of less than three years. The majority of long-term survivors had received allogeneic stem cell transplantation.