FCR as salvage therapy

There is little doubt that when used in chemo naive patients FCR produces impressive number of overall responses and an equally impressive number of “complete responses” (CRs).

The picture is not quite as rosy when it comes to treating patients who have been around the block a few times, had been exposed to prior chemotherapy.  When used as “salvage therapy” (don’t you just hate that phrase?) FCR response statistics are no where as high as in chemo naive patients.  I suppose that is to be expected.  Prior exposure to chemotherapy agents lets the pesky CLL cells learn a couple of new tricks and they are a lot harder to kill the next time around.

Not everyone gets the same response to FCR  used as second or even third line therapy. So, here is the million dollar question.  What type of patient has the best chance of getting a good response to FCR, when this combo is used in relapse setting? After all, the “price” (and I am not talking dollars and cents here) of FCR is not trivial.  Why would you want to go through all that toxicity, if you are not going to get much joy from it?  It would be really nice if we had a good crystal ball that can be consulted to predict the future accurately for each patient.  Since we do not have such a gizmo handy, the next best thing is this recently published article from M. D. Anderson, the original ‘inventors’ of the FCR drug regimen.  What makes this study interesting for patients is that the researchers make an effort to break out relapsed patients into different risk categories and try to give some idea of who is likely to respond well to FCR and who is better served trying something else.  As always, send me a personal email if you want help locating the full text of this article.

Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18.

Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL.

Badoux XC, Keating MJ, Wang X, O’Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG.

Departments of Leukemia,The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.

PMID: 21245487

Trial Design

This paper reports data from 284 patients recruited for almost a decade, from 1999 through 2008.  All patients had received prior treatment (two or more regimens, there was no restriction on that front) for their CLL.  All had active, progressive CLL that required additional therapy according to NCIWG guidelines.  They could not be quite basket cases, they had to be reasonably fit and have reasonable kidney and liver function.

The value of this study is the amount of lab work done to characterize patients.  All patients had bone marrow biopsy and aspiration done prior to start of therapy.  Flow cytometry was done to establish phenotype as well as CD38 levels. Standard CLL  FISH panel was one to detect chromosomal abnormalities.  In patients recruited after 2003, we also have access to IgVH gene mutation status and ZAP70 data.  (If you are new to CLL and our site - and flummoxed by all the different  prognostic indicators and the jargon associated with them - I strongly urge you to spend some quality time with this review of Prognostic Indicators that we did in a recent workshop).

The researchers take trouble to define the term “refractory” to fludarabine or alkylating agents (cyclophosphamide, chlorambucil).  Patient is considered refractory if he failed to get at least a partial response (“PR””) when treated with the drug(s) in question, or the remission he did get was so shabby that it failed in less than six months.  In other words, if you had been treated with some fludarabine containing regimen in the past, got a solid partial response that lasted, say, 2 years or so, the fact that you have now relapsed does NOT make you “fludarabine refractory”.  This distinction between “refractory” and garden variety “relapsed” is an important one to keep in mind as you read on.

The salvage FCR therapy used in this study is pretty much the standard version.  I will not go into the drug dosages or the treatment protocol, since we have discussed it at length in several previous articles.  If you want to get a bucketful of information about FCR regimen, I point you to our second workshop write-up:  “Everything you have ever wanted to know about FCR“.

Responses

Below is a chart that gives the percentage of patients who got a complete response (“CR”) and the percentage of patients who got any kind of a response (“OS”, overall response) broken down into different categories.  The last column is the one we care about most, the median overall survival, in months.  The first row in the table is for all 284 patients in this study as a whole.  74% of the patients got a response of some sort, 30% got the coveted CR, and the median survival was 46.5 months.  Just to remind you, median survival means patients in this group had a 50:50 chance of living at least 46.5 months. Clearly, half the patients lived longer than 46.5 months and half the patients lived less than that.  So, before you pencil in the date of your obituary in your daily planner, be very sure you understand these statistics represent the group as a whole, they do not (repeat, NOT) foretell exactly how long your remission will last or how long you will live.

Believe it or not, I tried to simplify this chart.  The actual table in the article is a lot longer and has even more detail. What can we learn from this detailed study?  Several things.  Some are obvious, some are not quite so obvious.  Here is my cheat sheet, if you are the impatient variety and want to cut to the chase.

  • Age matters.  Younger patients (younger than 60 years old) did a lot better than patients who were older than 70 years.  Overall responses were not all that different, but the percentage of CRs took a huge hit.  In other words, older people got lower quality responses, and this is paralleled by a significant drop in overall survival, from 5 years to less than 2 years.  The message is just getting out:  FCR may be contraindicated for elderly patients.  They have a harder time dealing with the toxicity, their bodies may not recover as well at end of therapy and this is reflected in substantially reduced median overall survival. My guess is that older bone marrows are not quite as resilient as they used to be and they have a harder time recovering from chemotherapy induced damage.  Neutropenia and anemia caused by drug induced bone marrow damage is harder to repair in older individuals and this may in turn cause increased sickness and death.  Something worth remembering.
  • Rai stage matters.  This too would seem to be pretty obvious.  People with very advanced disease (Rai stage IV, infiltrative) have more entrenched disease and it is harder to root out completely. The differences in % CR and % OS and overall survival are all statistically different between patients in early or late stage disease. The article reports significantly poorer results if the patients have bulky disease.  And late stage patients typically have more swollen lymph nodes and more infiltrated bone marrow.  Dr. Kipps and others have shown that CLL cells are harder to kill when they are nicely surrounded by support system of “nurse like cells”, something that is readily available in the bone marrow and lymph nodes but not in peripheral blood.  Waiting until the last bitter moment, when the lymph nodes are truly enormous and the bone marrow is infiltrated to the rafters before initiating FCR salvage therapy may not be such a good idea, if you go by the results of this study.
  • It should not come as a surprise to anyone that chromosomal defects in the crucial 17p region makes a huge difference.  None of the 20 people in this category got a full CR.  The overall response was only 35% and the median survival was a scary 11 months.  I think the message is clear.  If you are a relapsed CLL patient looking for salvage therapy options, and you are unfortunate enough to have 17p defects, you are probably not a good candidate for FCR salvage. You might be better served by more experimental therapy options (Revlimid or Campath based regimens) and possibly a mini-allo stem cell transplant.
  • Surprisingly, folks with 12 trisomy seem to do quite well with FCR salvage.  If you are in this category, count your blessings.
  • 13q deletion folks have the best responses to FCR salvage, as you would expect.  The authors of this paper concur with the conclusions of the REACH study: 11q deleted folks fare reasonably well with FCR salvage.
  • Being truly refractory to fludarabine (please read the definition of refractoriness in the section above) extracts a big and statistically significant penalty. A mere 7% of fludarabine refractory folks got a CR, a big drop from 36% of patients who were not refractory to this important drug.  While there is no data to that effect in this study, I will be willing to bet dollars to donuts that being refractory to pentostatin is not going to be any better.  Pentostatin and fludarabine are both purine analogs, with very similar mechanisms of action.
  • The penalty for being refractory to alkylating agents such as cyclophosphamide and chlorambucil is not quite as bad, but still significant.
  • Now for some good news: prior exposure to Rituxan did not make a difference.  People who were Rituxan naive did just as well as those that had been treated with this monoclonal antibody drug in earlier regimens.  So, all you guys out there with earlier history of Rituxan therapy, looks like you have not burnt any bridges - as per this article.
  • Unfortunately, they started doing IGHV gene mutation status testing only on patients recruited after 2003, so we have information on this modern prognostic indicator for only 86 patients.  The sample size is not large enough to draw statistically robust conclusions.  In any case, not enough time has passed for the mutated group to determine the median overall survival point.  Only time will tell if this group outlives the unmutated group of patients.
  • The authors conclude that patients who had received 3 or fewer prior therapies, were not resistant to fludarabine and did not have high-risk chromosomal abnormalities (17p defects or  complex cytogenetics with multiple FISH defects) demonstrated the best response FCR salvage therapy.

Articles such as this one are both interesting and useful - provided you know how to interpret them.  There is a wealth of information here, guidance that can help physicians offer better therapy choices to relapsed CLL patients.  But if you are going to look at these numbers as cast in concrete projections of exactly how you are going to do after FCR salvage therapy, then you are reading too much into them.  It is nice to know the odds.  But odds do not guarantee that the horse you bet on is going to win the race.

No guarantees, but some strong suggestions in this article:  if you are frail / elderly, if  you have advanced Rai stage disease, you may want to consider a lower impact therapy.  If you have 17p deletion, FCR salvage is probably not your best option.  Fludarabine refractory patients may face poorer odds of getting a solid CR response.  These and many other bits of information I could not do justice to are in this paper.

284 patient-volunteers made this study possible. I just wish the docs at M. D. Anderson thought it important enough to thank them for their service to the patient community.  Please join me in a nice round of applause for our brave volunteers.