Treating Refractory or Relapsed CLL

Making the right therapy choices at each point in your CLL journey are probably the most important decisions you and your medical team will face.  How long to stay in “Watch & Wait“?  Should you bring out the big guns right away, perhaps start out with the ‘gold standard’  FCR?  Would you be better off with a lower impact regimen such as single agent Rituxan, ofatumumab, even if remissions are likely to be short?  Who is best served by regimens such as FCR-Lite?  Is there a risk in pulling your punches early on, will you wake up to find the window of opportunity has closed while you fiddled with ineffective therapy options?  How about an early stage clinical trial using a sexy new drug, or is that too much like buying a lottery ticket and hoping for the best? None of these are easy questions.  A lot depends on your clinical history, your prognostic indicators, your overall health situation and age, and not to forget, your own personality. And your oncologist’s level of comfort with thinking outside the box.

If making front line therapy decisions is tough, making the right choices when you have been around the block a couple of times and relapsed is even harder.  What are some of the criteria that should go into making smart therapy choices in the case of relapsed or refractory CLL patients?

Right upfront, I would like to highlight the difference between “relapsed” and “refractory” patients.  A relapsed patient is someone who had a reasonable remission to his prior therapy, reasonable being defined by the nature of the therapy chosen.  Relapse 6-12 months after single agent Rituxan is reasonable.  Majority of  patients fall into this bracket and they would be classified as merely “relapsed”. Chances are pretty good that they will respond again to re-treatment by the same drug.  But a one year remission after completion of a higher impact regimen such as FCR is not good news.  Most chemo naive patients respond with longer remissions than that.  There are grounds for expecting such patients will not respond again to re-treatment with FCR (or similar combinations), that they are in fact “refractory” to one or more drugs in the combination.

So, what are the choices available to relapsed and /or refractory CLL patients? Clearly, in such patients the disease is tougher to treat.  It might have learned a trick or two during its prior exposure to therapy, it may be a tougher nut to crack.  However, it is important to remember that during this process the patient has changed too.  He is older.  His immune system has absorbed some body blows as he went through his prior therapies.  He may have experienced cytopenias (anemia, neutropenia, low platelets) during his prior therapies, perhaps an infection of two as a consequence of the resulting immune suppression. Another consequence of poorer immune surveillance, does he now have more issues with skin cancer?  Chemotherapy drugs are not friendly to bone marrow function or the precious stem cells that live there.  Very likely the patient has less “bone marrow reserve” after going through prior rounds of therapy.

When treating relapsed / refractory patients, should we focus on treating the disease, hit it harder than we did before, because it is now a tougher clone to kill?  Or should we pull our punches, treat the patient who is now likely not in as good shape and therefore pay more attention to minimizing toxicity of the next regimen?  These are two very different approaches.  In this first of this set of two articles, I would like to highlight what happens when the focus is on treating relapsed/refractory disease.  The second one will look at the other side of the coin, making therapy choices based on the condition of the patient.

I also need to point out that I am a strong believer in treating the patient, the whole patient, and nothing but the patient.  Does this color how I review these two different approaches?  You betcha. In other words, there is a lot more editorial content in these two articles, not “just the facts ma’am” approach I try to present most of the time.  Remember that caveat as you read and make up your own mind.

CFAR

This “cute’ acronym is pronounced “See Far” and stands for cyclophosphamide, fludarabine, alemtuzumab (also known as Campath) and Rituxan.  In other words, using far  more familiar terminology, it stands for FCR + Campath - administered concurrently. Too bad the cleverness of the acronym is not matched by clinical results, CFAR does not see far reaching remissions for its patients.

As most of you know, I am not a big fan of Campath consolidation after initial induction with combinations such as FR or FCR or even R+HDMP (Rituxan + high dose methyl prednisolone).  “Consolidation” is the term used to drive the number of cancer cells left in the body to even lower levels, after the initial “induction” regimen has taken care of the bulk of the disease.  Several studies have shown that Campath consolidation started too soon after completion of FCR or FR induction may have more toxicity than most patients can tolerate.

CFAR kicks it up a notch, delivering the Campath right along with FCR.  Why bother with waiting, an induction phase followed by a consolidation phase, why not do it all in one massive concurrent administration of all drugs? CFAR is definitely not-for-sissies type of drug combination.  The idea is very simple.  These are heavily pre-treated patients.  Chances are good that their CLL has grown fangs and become a tougher beast to kill.  How do you kill a cancer that has grown fangs?  You increase your fire power too.  (Seems to be based on logic similar to that in the movie “Untouchables“: You wanna get Capone? Here’s how you get him. He pulls a knife, you pull a gun. He sends one of yours to the hospital, you send one of his to the morgue!)

The results of this clinical trial are just published in “Blood”.  Some of the big names at M. D. Anderson that many of you may recognize are on the author list.  The abstract is below.  Do send me a personal email if you need help locating the full text of this paper.

Blood. 2011 Jun 13. [Epub ahead of print]

Cyclophosphamide, fludarabine, rituximab and alemtuzumab (CFAR) as salvage therapy for heavily pre-treated patients with chronic lymphocytic leukemia.

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

Department of Leukemia, U.T. M.D. Anderson Cancer Center, Houston, TX, United States;

Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features such as fludarabine refractoriness, complex karyotype or abnormalities of chromosome 17p experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase II study of cyclophosphamide, fludarabine, alemtuzumab and rituximab (CFAR). All patients were assessed for response and progression according to 1996 CLL-working group criteria. For the intention to treat analysis, the overall response rate (ORR) was 65%, including 29% CR. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher CR in high-risk patients following CFAR compared to a similar population who had received FCR as salvage therapy, there was no significant improvement in PFS and OS appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pre-treated high-risk group of patients there was no benefit in survival outcomes.

PMID: 21670470

CFAR Clinical Trial Design

  • This was a single arm trial, at a single institution.  But what is interesting is that M. D. Anderson compared this group getting CFAR with an exactly matched group of prior patients that they had treated with just FCR.  The hope was that addition of Campath to FCR would improve things.
  • 80 patients with relapsed or refractory CLL participated in this study, between Dec 2002 and October 2006.
  • Patients had adequate liver and kidney function; no uncontrolled infections; HIV or carriers of hepatitis B and C were excluded.
  • Treatment consisted of standard drug dosages of FCR, in addition to 30mg of Campath on days 1,3 and 5 of each 28 day cycle.  Campath was administered intravenously, not a subcutaneous injection. Allopurinol was given for 1 week prior to start of therapy.
  • Standard premeds of Tylenol, Benadryl prior to Rituxan infusion and hydrocortisone prior to Campath infusion.
  • I guess they knew better than to tempt fate, all the patients were on infection prophylaxis: Bactrim twice daily (to prevent bacterial infections, especially bacterial pneumonia) and valacyclovir daily for prevention of Herpes infections.

All this is pretty standard, no punches were pulled on dosages and all protective pre-medications and prophylaxis medications were given.  All patients who entered the trial were in need of therapy, as defined by the NCIWG guidelines.  Below is a chart that describes more detailed profile of the patients.  No question about it, these were indeed a tough crowd to treat.  What you would expect given the fact they all had an average of three sets of therapy under their belt.

FCR is no walk in the park and here we have added the other big drug, Campath to create the new acronym CFAR.  How bad was the hematological toxicity for this four string combo? Funny you should ask.  Here are the scary statistics.

As always, it is important to pay attention to the grade of the toxicity.  Grade 1 is easy stuff.  Grade 2 is a little more note-worthy.  It is grade 3 or grade 4 that are worrisome (just so you know, Grade 5 means the patient died). A substantial percentage of patients experienced Grade 3 or higher hematological toxicity.

How about infections?  Remember, these patients all got the recommended protective medications (Bactrim for bacterial infections, especially bacterial pneumonia; and valacyclovir for prevention of Herpes infections). Once again, the infections are broken down by grades, so we can better judge the seriousness of the infection.  The grim news is that roughly half the patients experienced a serious Grade 3 or Grade 4 infection. Even with Bactrim prophylaxis, the number of patients with pneumonia was surprisingly high.

Well, nobody said this was a therapy combo for sissies, the patients were all heavily pre-treated and they were a tough crowd to treat.  We knew that going in.  As always, the $64,000 question is what did we get for this high price?  Did the patients get longer remissions than just garden variety FCR without Campath?  Did patients who went through the tough love of CFAR live longer?

22 patients died while they were undergoing CFAR therapy or while they were still being followed after conclusion of therapy.  That is 22 out of 80 patients recruited for this study.  Here is the sad break-down.

22 patients died, starting from a cohort of 80 patients. 13 patients were still undergoing CFAR when they died, and another 9 died during the post therapy monitoring program.  The authors also report many more deaths that occurred after the end of the monitoring period.  I just did not have the heart to report those numbers as well.  Send me a personal email if you wish to read the full text of the article, it has all the gory details.

How did the CFAR statistics for remission duration and overall survival compare against garden variety FCR?  The authors matched the patients in this group against an exactly matched group of patients who had undergone FCR therapy at their institution.  They say a picture is worth a thousand words.  Below is the chart for overall survival, for a subset of the CFAR group that was considered high risk - because of their clinical situation and prognostic background.  These were particularly the group that the researchers hoped would benefit from CFAR, as compared to FCR.

The dark line is for CFAR, the light line is for FCR.  As the authors themselves pointed out in their abstract there was no significant improvement in progression free survival (i.e., remission length) and overall survival appeared worse for CFAR. The median survival was 31 months for FCR, but only 14 months for CFAR.  One does not have to look hard to find the reasons for this disappointing result.  CFAR caused a lot more toxicity, a lot more infections.  For a significant number of patients, this was a case of death due to therapy.

Editorial

OK, there was no way you could have missed my personal bias in the analysis above.  I think CFAR is far too toxic for majority of relapsed / refractory patients.  True, there may be a few unfortunate folks here and there that may have no other choice - though I find it hard guessing exactly who they are likely to be.  But for the majority of relapsed / refractory patients, there does not seem to be much to be gained by the addition of Campath therapy, concurrently with FCR therapy - namely, CFAR.

Which brings me to a question that I cannot answer to my satisfaction.  Prior studies have shown that Campath consolidation after completion of FCR therapy resulted in too many deaths if the waiting period between completion of FCR and start of Campath consolidation was not long enough. We are talking of a waiting period of several months between FCR induction and Campath consolidation.  And these studies were done in chemo naive patients to begin with.

If a short wait between FCR and Campath was not good enough, what ever convinced these researchers that no wait at all was safe?  The patients in the CFAR trial were heavily pre-treated.  They had already absorbed quite a lot of toxicity from earlier therapies.  Their bone marrow reserves were already depleted.  And this study put them through full strength FCR along with concurrently administered Campath.  I wish someone will explain the logic of doing this trial.  I expect they were looking at the fact that these patients probably had very tough to kill CLL varieties -  looking at the disease and not the patients - and decided to bring out the biggest guns they had at their disposal.  They were treating the disease and not necessarily giving sufficient weight to the nature of the patients.

I guess we should be relieved the researchers themselves declared the trial a failure: the intent was to see if relapsed / refractory patients got longer remissions or lived longer with CFAR compared to FCR. The sad answer is that they did not, on both counts.

The end of the M. D. Anderson paper lists the usual author contributions, acknowledgements and conflicts of interest.  But no “thank you” to the patient volunteers that suffered and died for this study.  Surely they deserved that?!   Please join me in thanking these brave but unfortunate volunteers - and their families.