When full-strength FCR is too much
Someone asked me the other day if there had been any new information regarding FCR “Lite”. I did not think there was any and gave a somewhat snarky answer that chances were slim of this approach getting attention since the lead researcher was no longer at U. of Pittsburgh hospital, rumor had it he now works a big pharmaceutical company.
That should teach me not to respond without doing my due diligence. Almost within days, I came across this abstract presented recently at the European Hematology Association – FCR Lite, with a Czech twist. Interesting results – I think they support the original hypothesis that for a subset of patients (the elderly or those with serious secondary health issues) FCR Lite may well be a good choice.
LOW-DOSE FLUDARABINE AND CYCLOPHOSPHAMIDE COMBINED WITH RITUXIMAB IN THE TREATMENT OF ELDERLY/COMORBID PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: PROJECT Q-LITE OF CZECH CLL STUDY GROUP
M.D., Ph.D. Smolej, Lukas, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic (Presenting author)
Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is currently considered the treatment of choice in physically fit patients (pts) with chronic lymphocytic leukemia (CLL). However, many patients cannot tolerate this aggresive treatment because of advanced age and/or serious comorbid conditions. For these patients, chlorambucil has remained so far the standard of treatment. Low-dose fludarabine-based regimens have recently demonstrated promising results in small studies. Aims: to assess efficacy and safety of low-dose FCR regimen used in elderly/comorbid patients with CLL. Patients and Methods: Between March 2009 and December 2010, we treated 93 pts with active disease (CLL, n=88, SLL, n=5, males, 59%, median age, 70 years [range, 58-83], median Cumulative Illness Rating Score 4 [range, 0-10]) by low-dose FCR at fourteen centers cooperating within Czech CLL Study Group. Dose reduction of chemotherapy was as follows: fludarabine to 50% (12 mg/m2 i.v. or 20 mg/m2 orally on Days 1-3), cyclophosphamide to 60% (150mg/m2 i.v./p.o. D1-3). The dose of rituximab was standard (375mg/m2 in 1st cycle, 500mg/m2 from 2nd cycle). Treatment was repeated every 4 weeks. Antimicrobial prophylaxis with sulfamethoxazol/trimethoprim and aciclovir or equivalents was recommended. Fifty-six per cent of pts were treated in first line, remaining 44% had relapsed/refractory disease. Advanced Rai stages (III/IV) were present in 62% pts; 40% had bulky disease. IgVH genes were unmutated in 74%; according to hierarchical model, del 11q was present in 32% and del 17p in 5%. Results: Based on intention-to-treat principle, the overall response/complete response rate (including clinical CR and CR with incomplete blood count recovery) was 71/39% in first-line treatment and 63/27% in relapse; 18% of pts are still on treatment. Data on PFS/OS are not available yet. Serious (CTC grade III/IV) neutropenia occurred in 54%, thrombocytopenia in 13% and anemia in 11% of pts. Serious infections were diagnosed in 13% of pts. Conclusions: Treatment of elderly/comorbid CLL/SLL patients with low-dose FCR demonstrated promising results. Toxicity was acceptable and manageable. Updated results will be presented. Supported by research project MZO 00179906 from Ministry of Health, Czech Republic.
OK, let’s take a quick look at the design of this trial and the results, as well as compare them as best as we can against the earlier FCR-Lite results from the University of Pittsburgh Medical Center (UPMC). As always, the two trials differ on a number of important criteria and therefore the comparison is hardly apples to apples. More in the realm of apples to bananas. I have tried to capture most of the details in the chart below.
It is important to realize the Czech study used a mix of chemo naive and previously treated patients, roughly half and half, while the earlier UPMC study used all chemo naive patients.
The age group is very important to note as well. The patients treated in the UPMC were veritable spring chickens, a mere 50 years old. In strong contrast, the median age of the Czech group was 70 years. Frankly, I think the Czech study focused on the more appropriate age group. As we have been told many times by now, full strength FCR is contra-indicated in elderly or frail patients with other health issues. By treating 50 year old patients the UPMC study focused on people who would most likely be quite eligible for full strength FCR.
The other big difference between the two studies is the nature of the regimen. UPMC used a boat load of Rituxan. The Czech group got a lot less. The main difference was in the 2 year maintenance phase where the UPMC group continued to get regular Rituxan infusions. There was no such maintenance phase in the Czech group. If you guys have been mulling over the issues we highlighted in our earlier article titled “Cancer Costs“, it is easy to see why the Czech group chose the protocol they did. Fludarabine and cyclophosphamide are relatively cheap (in dollar terms, not in toxicity risk to the patients!), compared to biologic drugs such as Rituxan.
My grandmother had an aphorism she used frequently: the size of the loaf depends on how much dough you have to begin with. The Czech protocol uses a lot less “dough”. You can see the impact, in terms of the overall responses and the percentage of “CR” remissions. How about the adverse effects? If anything, the Czech protocol used less fludarabine (same amount of cyclophosphamide though). So, how come the level of hematological toxicity (neutropenia and thrombocytopenia) were higher? The answer lies in the fact that roughly half the folks were previously treated – with previously acquired bone marrow toxicity to match, no doubt. Then there is the unavoidable impact of age. These guys were significantly older, by a big margin. And no matter how much you exercise and how fit you are, how few wrinkles you have and how good you look, there are some unavoidable consequences of biologic age. One of the consequences is immune health. Older folks in general have poorer immune function than younger people – and that is the long and short of it.
So, where does that leave us? It gives us a messy comparison between the two studies. But it also gives us sort of two book-ends on either side of the spectrum. The UPMC results reflect how FCR lite works when everything is just right – young and fit patients, no restriction on drug costs. The Czech study is a more pragmatic look at a mixed bag of older patients and a regimen that is based on more realistic dollar costs of the drugs involved. Take your pick.
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14 comments on "FCR “Lite” – Czech version"
Chaya,
Thank you so much for keep up this very important website. Your articles are very useful and I espically like the way you bring it all down to earth!
Clint
Chaya –
Well, so THIS is what it feels like to be famous, huh? ;-) Thanks for a lot of hard work to answer one listeners earnest question. Be well.
Hotdog59
Interesting. When I was being treated by Chemo at North Devon, UK, I had had single agent fludarabin, and thought I was vastly improved from the blood count numbers. My locum consultant was Dr Zuzanna Volkova who I presume was Czech and temporarily at North Devon, and she took the trouble, along with the Cancer Nurse Specialist, to show me that although my blood was better, my lymph nodes weren’t, and she suggested FCR which was very new then. Having seen the lymph results I agreed, and as far as I’m concerned FCR was brilliantly successful – I’ve got my life back at least for a while.
The point of this is to say, of course, that when I hear the words “CLL” and “Czech” in the same sentence, I think, “GOOD People”. Although Dr Volkova has returned to her home, I remain grateful to her….
Lawrence
Chaya,
A great follow-up, with super comeback given my Lawrence Hanney above. As usual…good stuff.
Thanks,
William Bates
Very nice comparison in simpler terms! It’s good that they’re getting acceptable results with FCR lite, especially for older folks, or those with co-morbidities.
But I’m still leery of FCR since reading about the small percentage of people who contract tMDS or AML from the traditional FCR dosages. Although 5%, or 1 in 20, aren’t long odds.
You’ve cited many articles and discussed them on CLL Topics. Here is an updated one from June, 2011 from Hamblin’s “Mutations of Mortality” site: http://mutated-unmuated.blogspot.com/2011/06/tmdsaml-in-cll-after-fc.html
I think if I were in a tough group, I might agree to take a chance on FCR, but I’d much rather start with FR. The cyclophosphamide seems to be the culprit. ~Art
Interesting study by the Czchs. Thank you for making the comparison chart, understanding the two groups were not equal for age or some for prior chemo exposure. Still it is a visual, which I appreciate.
Terry had FCR-Lite, four cycles from Jan to April 2011. He showed CR before round three. He had Rituxan each cycle on days 1 and 15. All lymphs shrunk to touch and via CT to followup lung spots. Where before he had large nodes by touch and scans showed enlarged internal nodes plus enlarged liver and spleen by touch and scan. All nodes and organs showed normal after FCR-Lite. His oncologist used a custom dosage. Terry is age 63. His only other health issue is diabetes, well controlled on oral meds. During treatment it was my job to keep his water container filled and bug him to drink. That was directly due to you, Chaya, and your warnings about hydration during treatment. He showed no organ toxicity during or following treatments.
Before FCR in Jan. in September he had IVIG once followed by 5 doses of Rituxan. He got a tumor flare reaction during Rituxan where his nodes became larger than they’d ever been, were visible, aching and tender. That resolved with no intervention. It was like I’ve heard of happening with Revlemid.
Four weeks after completing FCR-Lite he went in for followup and was found to be in marrow failure with #Neuts 0.2. Other counts were depressed. He showed his onc the intensely itching spread of sores on his trunk, upper arms, face and head. If he scratched his trunk showed hives.
Answering questions about anything new in diet, Terry told of recent addition of Goji Berries to his oatmeal. He had already stopped due to the skin problems. Since that appointment and blood and physical checks every 3rd day, his platelets began rising, then #Neuts, which were 1.0 Tuesday. Next check is Friday this week. He was on Levanq. antibiotic, on instructions to stay away from others, monitor his temp and call if over 100.5. He had no fevers and his skin cleared.
His onc did not rule out delayed marrow failure following Terry’s treatment, but he said it did not look like the typical mix of numbers for delayed neutropenia.
We like seeing the numbers go in the right direction! Thanks, again to you, Chaya, we were not shocked to see the slightly delayed marrow failure.
That is Terry’s story of his first treatment. He was dx in 4/2003. He showed mutated cells, high CD 38 and trisomy. He was able to make up missed hours from chemo pretreatment meds and worked from his treatment recliner and from his home office, full time since July. He got a viral and bacterial infection in July that with other signs of advanced disease, triggered his treatments.
Dr. McGee expects a very long-lasting remission. That is our hope too.
Best wishes to our co-fighters!
Fondly, Linda
Thank you Chaya!
You have answered some of my questions but as always, I still have more questions rambling around in my brain. However, I will spare you most of the questions for now.
A bit of background….and one question. At 53 I was dx’d stage IV CLL, Trisonmy 12. After a couple of emergency rounds of “C” to help bring down an extremely high WBC, I started chemo. Round one was FC, round two was FCR, and because the response was so great my doctor recommended that the last four rounds to be FCR-Lite…….to reduce the toxicity…..following up with two years of Rituxan maintenance. Three years later I am happy to report CR with MRD-negative. This leads me to wonder if a combination like what I had would be beneficial to the “younger” set? I must admit that the only problem I seem to have is a very slow to rebound immunity….after three years it is still a bit on the low side.
As always Chaya, great job! Thank you for keeping us in the loop!
Elaine
Thanks for reporting on this study, Chaya. FCR lite is definitely something to consider if I need to be treated again, since I just turned 79. My remission from FCR will be 9 years old this fall and may not last forever!
CathieNicholl
Chaya,
Thanks for great updates.
Be well,
Monique
Chaya:
as always, thanks for the update and comparison. As a patient who was in the FCR-Lite UPMC protocol, I agree with you that these two studies are very different, due to the differences which you highlighted.
At the time I was diagnosed inn early 2006, I was 55 years old (3 months shy of 56) and I was diagnosed with stage 4 cll (the rai staging system). Fortunately, for me, the UPMC Hillman cancer center – where the fcr-lite study was underway – was/is located only 10 minutes from my house.
Again, fortunately, 5 years later I am still in complete remission (cr), although I do receive ivig every 4 to 6 weeks for my immune system (very low igg; and practically no: iga or igm). Thankfully, I continue to be relatively healthy, except for the “normal”: infections (sinus, respiratory); viruses and flu (even though I do receive my annual flu vaccine and I have also received my pneumonia vaccine).
While the “end result” for me was positive, I did have a very rocky road (a roller coaster ride of “ups, downs and all arounds”) while I was on the fcr-lite protocol. (i.e. hospitalizations, neutropenia, infections, digestive problems, liver problems, etc.). I also had severe allergic reactions to rituxan! (as I also do with the ivig!) In fact, after my oncologist conferred with the “Dr, Rai” about my specific information, I was taken off the “maintenance dose”/treatment of rituxan and did fine.
The bottom line – as with any treatment — is that there are possible serious effects – and the term “lite” in the “fcr-lite” protocol does not necessarily mean that the “Lite” treatment is a walk in the park, without risks, side effects, and reactions.
The fcr protocols (regardless of “regular” or “Lite”) were and still are the “gold standard” of treatment for cll, even though there have been some “newer” protocols as you have written about. However, to the best of my knowledge none of the newer treatments (to date) have matched the short or long term success of fcr or fcr-lite. I consider myself to have been extremely fortunate that I was at the right place at the right time to have been able to “participate” with the fcr-lite protocol.
Alan
Chaya,
Thank you for the informative article on comparative studies of FCR lite. I was a recepient of FCR a couple of years ago and now I am in CR with a normal immune system. But in case of a relapse some day, because I am 76, FCR lite is certainly an option I will consider.
I had 5 cycles of FCR in the fall of 201l, following several years of chemos between 2001 and now. I am in remission, but with dysfunctional immune system. I had been allergic to penicillin products for five years. My infectious disease doctor prescribed desensitizing me to my allergy. It has worked, and penicillin is being very effective for me. I feel healthier now than I have in the last five years.
I’m on the alert for chemo strategies for the future, and am pleased to know the information from your article.
A. Frederick: Very interested in who did you de-sensitizing. I’ve been having a difficult time trying to find an allergist willing to test me for penicillin allergy. My PCP was required to write a letter to UCSF saying why I should be tested. We don’t know yet whether they will agree to test me. Did an allergist provide the de-sensitizing? Can you please describe the process .. I’m sure there are many of us who think we cannot take that drug. Thanks !!
Lynn
Interesting issue re penicillin. I have assumed for 30 years that I was allergic until recent testing for all allergies found none. I specifically asked for penicillin testing and got- what I thought was- strange advice. Although I did not (skin)test as allergic, the allergist suggested I avoid it unless ‘necessary’. Makes no sense to me.
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