A Role for CFAR?
“CFAR” stands for cyclophosphamide, fludarabine, alemtuzumab and Rituxan – think of it as FCR + Campath. I guess the researchers were looking for a sexier acronym and came up with “see far”. In an earlier article we discussed the role of this aggressive combination in treating relapsed and / or refractory CLL patients. I can’t say I was thrilled with the results of that M. D. Anderson clinical trial. In that case, the “see far” acronym was almost ironic – I would have preferred if the researchers had seen far enough to shut down the clinical trial earlier, when the death count started to add up. Frankly, way too many of those volunteers died during or soon after completion of the CFAR regimen.
But now we have the second chapter of the CFAR story. If the shoe did not fit refractory and relapsed patients, how about chemo naive patients with reasonably aggressive CLL, but otherwise healthy? Mind you, this is not a frivolous question. We still do not have adequate therapy choices for high risk CLL patients, especially those with (FISH test) deletions in the 17p location. Can the oomph of FCR combined with the potential ability of Campath to get past the 17p defects give these folks a better shot at deep and lasting remissions?
The detailed clinical trial results of CFAR as frontline therapy have just been published in “Blood”. The abstract of the article is below, followed by my cheat-sheet version and editorial comments. If you wish to read the full text of the article, send me a personal email and I will help you locate it. It is certainly worth reading if you are considering CFAR regimen in your own case.
Blood. 2011 Jul 12. [Epub ahead of print]
Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab (CFAR) for high-risk chronic lymphocytic leukemia.
Parikh SA, Keating MJ, O’Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, Wierda WG.
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States;
Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) is associated with superior overall survival (OS) for patients (pts) with CLL. Alemtuzumab (A) was added to FCR (CFAR) in a Phase II trial for high-risk untreated pts <70 years with serum β-2 microglobulin (β2M) ≥4 mg/L. Sixty pts were enrolled; median age was 59 yrs (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 pts with 17p deletion, CR was achieved by 8 (57%). Of 57 bone marrow samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable to historic high-risk FCR treated pts. CFAR may be a useful frontline regimen to achieve CR in pts with 17p deletion prior to allogeneic stem cell transplantation.
This was not a small or quickie trial. As many as 60 patients participated in it and the followup data spanned 4 years. The study is also valuable because they report quite a lot of prognostic information about the patients.
What do we know about these 60 patients? I have summarized their profile below. The inclusion criteria were quite specific. The volunteers were:
- Younger than 70 years – the authors concede older patients may not be able to handle the toxicity of chemoimmunotherapy such as FCR, let alone FCR + Campath.
- Previously untreated but at the end of their W&W and ready to start therapy.
- B2M (beta 2 microglobulin) greater than 4.0 MDA favors this particular prognostic indicator and indeed it is an easy blood test that has a lot to recommend it. B2M of 2 or lower is considered normal.
- Relatively fit. These were by no means basket cases. I get the sense they were healthy, other than the CLL.
- Good liver and kidney function.
- No uncontrolled infections.
While these volunteers were relatively healthy, their CLL was generally an aggressive variety. Here are the details of their CLL prognostics:
As you can see, not everyone was in the dreaded “Bucket C”, but enough of them had poor prognostic indicators that it makes the trial a realistic one.
Basically, the CFAR regimen consisted of M. D. Anderson’s standard FCR therapy drug dosages and sequence, with the addition of 30mg of intravenous Campath on days 1, 3 and 5 of each cycle. As with FCR, each course lasted 4 weeks and the intent was to have patients go through 6 such cycles. Dose reduction was allowed if the patient developed pneumonia, sepsis or life threatening infections. Phew.
All patients got a shot of Neulasta (neutrophil growth factor) on day 6 of each cycle, since it is pretty much certain these patients were going to have neutropenia problems. All patients also got allopurinol to protect against tumor lysis syndrome. Since pneumonia is constant worry, double strength Bactrim was a mandatory prophylaxis as well as valacyclovir for prevention of herpes virus infections (shingles, CMV, EBV). Especially when Campath is part of the mix, viral infections and reactivations are some thing to be taken seriously. All in all, these patients were as well protected as possible against opportunistic infections and neutropenia.
Not everyone completed the planned 6 cycles. As a matter of fact, only 24 out of the original 60 patients finished all 6 cycles. The single biggest reason for not completing all 6 cycles was neutropenia and decreased platelet counts (18/60 patients). Infections was the second most common reason, at 8/60 patients.
Just how many infections were there? There were a total of 46 infections reported, of which 27 were considered “major infections”. Four patients had the dangerous Richter’s transformation and two more developed acute myeloid leukemia (AML). Of the 60 volunteers, 11 have died so far: 9 because of disease progression, one due to metastatic lung cancer, one due to CMV pneumonia. All in all, this is not a regimen for sissies. In spite of all precautions taken to protect them, there was significant hematological and infectious toxicity, as well as secondary cancers and Richter’s transformation to worry about.
So, what did our guys get for their efforts? The overall response rate was an impressive 92%, of which 70% had a “CR”. Half of the folks were still in progression free survival (think of it as the length of time the remission lasted and the patient was alive) at 38 months.
Response statistics are not always easy to understand or put in context. Fortunately, the authors took pains to compare the results of this CFAR study with the results obtained in a similar group of patients who had the “gold standard” FCR. Mind you, this is not a double arm study. The researchers compared the results they got in this single arm CFAR study with patients who had undergone FCR therapy in earlier studies, chosen so as to match this group of volunteers.
This is how long the remissions lasted, and even more importantly, how long the patients remained alive. The charts are from the MDA paper, the red lines are my contribution to highlight stuff. As you can see, half the people were still in remission and half had relapsed at the 38 month mark for CFAR. Compared to that, half of the patients who had undergone FCR were still in remission at a tad more than 56 months. That is an 18 month advantage for FCR remissions.
We have not yet reached median survival for either the FCR group of the CFAR group. So, I looked at the 4 year mark for both groups. Roughly 64% of the CFAR group were alive 4 years later. Compared to that, about 77% of the FCR group were alive four years later. Remember, the researchers are comparing well matched groups of patients undergoing CFAR and FCR, so this is a pretty kosher comparison.
Oh-Oh. This is not such encouraging news. Compared to plain vanilla FCR, remissions obtained from CFAR did not last as long and more of the patients had died at the four year mark.
Was there anything encouraging in this study? Yes, if you splice the data to look only at folks who had 17p deletion. Remember, that was one of the main objectives of this study: to see if combining the oomph of FCR with the potential effectiveness of Campath against 17p defects could yield a better therapy option for these high risk patients. This is how that comparison went.
When you splice and dice research results into smaller groups of patients, the results are not as credible, statistically speaking. We are talking about 14 patients in the CFAR group and 18 in the comparison FCR group that had 17p deletions and made it into this comparison. It is interesting to note that while the overall response statistics were not all that different (79% vs 67%, not statistically different), a significantly larger percentage of those responses were the coveted “CR” response in the case of CFAR (57% versus 17% – statistically significant). In other words, CFAR seems to give significantly deeper remissions than FCR and that is good news. The bummer is that these deeper remissions did not last longer. Median duration of remission was about the same between both groups, about a year – give or take a couple of months. As for median overall survival, the CFAR group has not been followed long enough at this stage. All we know is that it is longer than 25 months. But I am willing to bet that given enough time to nail this statistic, we are likely to see that the median survival for CFAR is not going to be better than the impressive 55 months of FCR patients.
So, is there a role for CFAR, as frontline therapy for high risk CLL patients? What do you think?
I must confess I am a little disappointed. In general, high risk frontline CFAR patients did not have longer lasting remissions and most likely will not have longer overall survival either, compared to FCR patients. If you are like me, it does not particularly matter what the label is on the type of remission, whether they call it CR, PR or whatever. What matters is how long the remission held, how long people continued to live, how much toxicity there was to mess up quality of life. Taken as a whole, CFAR does not seem to come out ahead of plain vanilla FCR on any of these counts.
But there is one statistic that is worth paying attention to, one niche play where CFAR may be a better choice than FCR. If you are a relatively fit and young (younger than 70 years old) frontline patient with 17p deletion, and you are pretty sure the long term game plan for you is to get a mini-allo stem cell transplant, CFAR may be a better choice than FCR. Why is that? Because CFAR gave significantly higher percentage of “CR” remissions in this narrow group of patients. Mini-allo transplants work much better when the patient goes into them with as clean a remission as possible. In other words, 17p deleted patients undergoing CFAR are more likely to be better positioned to dovetail their remission into a mini-allo transplant. But they are well advised not to wait too long after the CFAR (or FCR), since their remissions are not going to last long! By the way, the authors seem to have reached the same conclusion. Here is a quote from their abstract: “CFAR may be a useful frontline regimen to achieve CR in pts with 17p deletion prior to allogeneic stem cell transplantation”.
Except for its potential use in this small niche, I fail to see the advantages of CFAR compared to better understood and definitely less toxic FCR therapy, even for this relatively healthy group of patients.
Par for the course, these sixty volunteers did not merit official recognition or thanks for their generosity. Please join me in correcting that oversight and giving them a sincere round of applause.