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Alert Number 118

Balancing Risks and Rewards: FCR+M Clinical Trial

Date: August 10, 2005

Last night I sent out an Alert on the subject of adding mitoxantrone to the FCR combination. Several of you responded right away, saying you were considering this new clinical trial and asking if I had additional information. I now have a bit more information on the subject, and I thought I would share it with you. There will be a full-length article on the subject of this trial in the next few days, keep an eye out for it.

We do not know exactly how the combination of FCR+M (fludarabine, cyclophosphamide, Rituxan + the new addition of mitoxantrone) will play out. That is the whole point of doing clinical trials: if we knew the answers ahead of time there would be no point in doing the clinical trial, right? But that does not mean we sign on the dotted line of the consent form without checking a few things first, asking a few questions about the combination. Heck, you donít walk into a car dealership and buy the first car the salesman shows you, do you? I hope you ask a few questions, check out Consumer Reports, walk around and kick the tires, check out the price tag, etc., even as you admire the shiny new machine.

Here is what I have found so far. The abstract below is from the Royal Marsden, highly regarded expert center and has Dr. Catovsky as the lead author. 24 CLL patients were treated with FC+M. In other words, the new clinical trial at M. D. Anderson adds on Rituxan to this combination - that is the new twist. We also do not know if the drug dosages and scheduling are comparable in the Marsden study and the MDA clinical trial. But this abstract is not a bad place to start, as we judge the potential risks and rewards of the FCR+M combination. At least now we have a handle on the FC + M part of it.

The 24 CLL patients in the Royal Marsden study were of the heavily pre-treated variety, most of them had had fludarabine and some were refractory. 8 out of the 24 patients got a CR (ďComplete ResponseĒ). The remissions lasted a median of 19 months, and the median survival was 42 months. But what blew me away was the high level of neutropenia (57%), infection complications (43%), transformation to the much more dangerous large cell lymphoma (the dreaded Richterís Syndrome) as well as acute myeloid cancer. 6 out of the 24 patients (that is a whopping 25%) morphed from their relatively benign CLL to the much more dangerous RS and AML.

I have said this over and over - managing CLL and making smart therapy choices is all about balancing the risks and rewards. We understand a certain amount of risk comes with just about every cancer therapy out there. The judgment call to make is whether the risk is worth the potential reward. Would the addition of another drug, Rituxan in this case, make the combination of FC+M (the three chemotherapy agents used here in the Marsden trial) any kinder and gentler? One can reasonably hope that the response rate would increase since Rituxan seems to improve the % of CRs obtained in every combo, especially if less heavily pre-treated or even chemo-naÔve patients are recruited for the trial, as seems to be the case. M. D. Anderson has pioneered in this aspect of CLL therapy, going for very high CRs and even pcr negative remissions, in the hope that these stellar response rates translate into long and durable remissions.

On the cost side of the equation, even if you were fludarabine refractory, is a 25% rate of conversion into much more aggressive and short fuse cancers such as Richterís and AML justified as a reasonable risk? Would not Campath be a better choice even for these patients? Several articles have been published recently suggesting that Campath works even in fludarabine refractory patients, and it works in patients with the poor prognosis abnormalities such as 17p deletion. Time will tell how the FCR+M combination will play out. But judging from the results reported in the abstract below for the FC+M combination, the high response statistics may come at the risk of serious immune suppression, neutropenia, infection complications, Richterís transformation and AML. You are well advised to discuss these issues in detail with your doctors, before you start this clinical trial.

The bar has been raised on what is available out there for treating CLL patients, especially chemo-naÔve CLL patients. New clinical trials have to be designed in the context of that information. While we appreciate and honor the brave and generous patients who participate in early stage clinical trials, that participation has to be in the context of a thoughtful choice, after sober consideration of the potential risks and rewards involved.

Be well,


Leuk Lymphoma. 2004 May;45(5):945-50.

Fludarabine, cyclophosphamide and mitoxantrone in relapsed or refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma.

Hendry L, Bowen A, Matutes E, Swansbury J, Catovsky D.

Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK.

A regimen combining fludarabine, cyclophosphamide and mitoxantrone (FCM) was used to treat 29 patients with relapsed or refractory chronic lymphocytic leukemia (CLL, N = 24) and low-grade non-Hodgkin's lymphoma (NHL, N = 5) based on evidence suggesting synergism between the 3 drugs. Patients were treated with mitoxantrone 5mg/m2 i.v. day 1 only, fludarabine 25 mg/m2 i.v. for 3 days or 24 mg/m2 orally for 5 days, cyclophosphamide 250 mg/m2 i.v. for 3 days or 150 mg/m2 orally for 5 days inclusive. Eighteen patients had previously received fludarabine and most were heavily pretreated with 40% having >2 prior treatments. A median number of 4 FCM courses (range of 1-9) were given. The response rate was 78.5%: 32% complete remission, 25% nodular partial remission, 21.5%, partial remission. Median duration of response was 19 months and median survival was 42 months. Sixteen patients (57%) developed neutropenia to < 0.5 x 10(9)/l and 12 (43%) infectious complications. Four patients developed large cell lymphoma (Richter's syndrome) and 2 acute myeloid leukemia. FCM is a useful combination for relapsed or refractory CLL and low grade NHL with high response rates and long duration of response. The role of FCM as first line therapy deserves study as well as its combination with the monoclonal antibody Rituximab.

PMID: 15291353 [PubMed - indexed for MEDLINE]

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