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.