Date: August 12, 2005
by Chaya Venkat
We are pleased to report that Dr. Stefan Faderl, the principal investigator at M. D. Anderson Cancer Center for the FCR+M and Neulasta clinical trial, has responded to our letter and the review of the clinical trial we published yesterday (see Mitoxantrone plus FCR to get the whole story). His detailed and thoughtful response is published in the box below, together with an exchange of emails on the subject of cardiac toxicity. We thank Dr. Faderl for his time and attention. There is a great deal of common ground between patients looking for better therapy options and researchers who spend their lives looking for better answers. The process works a whole lot better when patient groups participate actively in their own healthcare decisions.
We have also reproduced Dr. Terry Hamblin's very relevant post on the ACOR discussion group, in response to a reader's questions.
We are more than willing to concede that the addition of mitoxantrone to the FCR combo has scientific merit, and is worth exploring.
However, in this era when many more options are becoming available for untreated CLL patients, we question the recruitment of chemo-naïve patients across the board. Patients with good prognosis, as determined by modern prognostic assessment (Prognosis at Diagnosis), clearly have many other therapy options that might give them better bang for their buck. We hope the European version of the FCR+M trial will take this point into consideration as they define their recruitment criteria.
Translating strategies used in more acute leukemias wholesale to the much more indolent CLL needs to be thought through carefully. Dr. Terry Hamblin addresses this issue in his post a lot better than we can. Besides his research credentials and medical expertise, Dr. Hamblin has the rare ability to communicate clearly with a layperson audience. We urge you to read his comments as well as his earlier article written exclusively for CLL Topics: Are We there Yet?
We want to highlight our concerns on one aspect of this trial that was not addressed sufficiently in Dr. Faderl’s original response.
We have the following requests for the FRC+M clinical team at MD Anderson:
You can read our comparison of the M. D. Anderson protocol discussed here with information we have on a multi-center British trial launched in 2004: FMC plus R, Brit. Version.
Date: August 12, 2005
You probably know that Chaya has an article about this new trial on her website. It is worth reading it.
The idea that mitoxantrone (or mitozantrone depending on which country you live in) should be added comes form a Spanish trial that showed a complete response rate to FCM that was as good as Houston was getting with FCR. Since adding rituximab to any regimen seems to add another 10% responses to what you get without it, it seemed a good idea to try FCM-R. This combination has been tried in follicular lymphoma without too much toxicity.
Mitozantrone has been around a long time, probably 20 years. It is used in the treatment of AML and recently got a license for the treatment of MS where it is used as an immunosuppressive. It is one of those antibiotics produced by bacteria in the soil and it is similar to adriamycin, which is the H in CHOP. The differences between mitozantrone and adriamycin is that the former tends to produce less hair loss, and persists rather longer in the blood. The major side effects of nausea and vomiting and bone marrow suppression are not much different. All hematologists are very familiar with its use. Like all of these drugs it causes damage to the heart. The effect is seen when a threshold cumulative dose is reached. This usually works out at about 9-10 doses depending on the dose given, whether cyclophospahmide is also being used, whether previous adriamycin has been given and the state of the heart beforehand. The types of damage are cardiomyopathy - where all of the oomph goes out of the heart muscle, causing heart failure, and this is usually irreversible, and arrhythmias which can be fatal.
However, when it is used judiciously it can prove a very useful drug.
In the UK we are preparing for a new trial which will compare FCR with FCM-R in previously untreated patients.
The philosophy behind this strategy is based on the fact that we are not curing patients with CLL except with an allograft, which is hazardous, unavailable to many and may lead to a life of chronic illness. In the field of acute leukemia it is clear that no-one is cured unless they get a good complete remission. In CLL, until recently very few patients got a complete remission, even by the standards of the NCI guidelines which allowed a relatively large volume of residual disease compared to what is allowed in AML. So, a more complete remission was aimed at and measured by assessing minimal residual disease, either by PCR or four color flow. Even FCR fails to produce PCR negative disease in a substantial proportion, so according to this reasoning more treatment is needed.
What is lacking from this strategy is the fact that in order to live a normal lifespan many patients with CLL do not need their CLL to be cured, just controlled.
According to the successful strategy in AML what determines whether or not a patients is cured is getting the best possible remission the first time the leukemia is treated. Therefore, the aim of treatment is to get the highest possible remission rate and the longest possible first remission. Applying that strategy to CLL it makes sense to have an end point of trials as response rate and progression free survival.
But is it valid to adopt the AML strategy in treating CLL? Clearly there are some patients for whom this is valid. There are some patients who do progress rapidly. When these are treated in a conventional way the path is one of a series of remissions, each shorter and less complete than the last with increasing toxicity and desperation. The patient tends to die after a few years of infection or autoimmunity because the immune system is exhausted or of uncontrollable drug-resistant disease. However, some patients need some sort of treatment because they are becoming symptomatic, but even quite simple treatment keeps them well and they survive to live for a natural life span. When these patients are treated with stronger drugs their disease tends to respond more rapidly and more completely than the other sort.
The recent advances in prognostic markers allows us to distinguish these types of disease fairly well. In my opinion it is dangerous to mix them up in clinical trials. If the treatments were without side effects it would not matter, but there is always a price to pay with these new, more effective drugs. You might end up inflicting side effects on patients who never needed the drugs in the first place. Another problem is less obvious. With an unknown leavening of good risk patients, a treatment that's really designed for poor risk patients might appear better than it really is.
The UK trial is designed to exclude good risk patients from the study. We are still trying to decide what we should study for this group.
M. D. Anderson's Response
From: Stefan Faderl , MD
Subject: FCR+M clinical trial (2005-0106)
Dear Dr. Venkat:
Thank you for your interest in the FCM-R (fludarabine, cyclophosphamide, mitoxantrone, rituximab) combination program for patients with CLL.
The idea for this program and the design thereof has been based on three observations: 1) the fact that chemo-immunotherapy combinations achieve higher clinical response rates than has been the experience with chemotherapy alone (or with monoclonal antibodies alone); 2) the fact that some of the patients with clinical responses also achieve molecular responses (i.e. become negative by PCR testing for immunoglobulin rearrangements or else) indicating eradication of minimal residual disease; and 3) previously published experience with the FCM and FCM-R combination in patients with CLL and other lymphoproliferative disorders. You are certainly correct that the topics of molecular responses and residual disease require a lot more discussion and exploration in the future, but I would still like to think that the most recent achievements of better quality responses with chemo-immunotherapy combinations represent a step in the right direction, from whereon we can hopefully experience an improvement in progression-free and and possibly overall survival for some patients. Does a PCR-negative test mean the same for all patients, or, in other terms, do PCR-positive patients always relapse and PCR-negative patients never? Of course not. Let's take acute promyelocytic leukemia (APL) as an example where PCR-testing of patients in remission probably has the highest proven predictive value of any leukemia for relapse (if PCR continuously positive) or ongoing remission (for continously negative PCR-testing), respectively, Even there the association is not perfect and PCR-negative patients do relapse as well (and vice versa). Why should that be any different in CLL or any other leukemia where many disease- and host-related factors come into play most of which remain still poorly understood. However, there is a trend in CLL that a better quality response may be associated with at least better progression-free survival and I think this is a lead that should not be discarded.
If it had been for our own published experience with fludarabine and mitoxantrone (the reference by Dr. Tsimberidou that you mention) alone, adding mitoxantrone to FCR would indeed not have looked very appealing. However, FM was not really the trigger. In addition to the reasons that may speak in favor of chemo-immunotherapy, what was more interesting in this respect has been the experience published from other groups using FCM in patients with relapsed/refractory CLL, and FCM-R (versus FCM alone) in patients with refractory follicular and mantle cell lymphomas. As for the first example, Bosch et al. (Br J Haematol 2002; 119: 976) treated 60 patients with CLL (37 patients receiving mitoxantrone at 6mg/m2 per course, another 23 at 8mg/m2 per course for up to 6 courses maximum). As mentioned these patients were previously treated and in 58% resistant to at least prior alkylator use. Of those patients, 30 (50%) achieved complete response (CR) including 10 patients who turned negative for minimal residual disease (MRD). Furthermore, MRD-negative patients showed better survival than other response groups within the follow up of the study. Similar to other studies, myelosuppression was the major toxicity. No patients were reported who have developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). No patients were recorded with cardiac toxicities at the doses of mitoxantrone as indicated. The second study used the FCM plus R combination versus FCM by itself (Forstpointner et al., Blood 2004; 104: 3064). Although this study did not include CLL patients (all patients either had follicular lymphoma or mantle cell lymphoma) it is nevertheless very instructive for our CLL study. The dose of mitxoantrone in this study was 8mg/m2 per course. The FCM-R combination was significantly more effective in terms of response rate, progression-free survival, and overall survival than the combination without R. Relevant side effects were also not different between the treatment arms (most signifcant was again myelosuppression. No cardiotoxicity occurred at these doses). You mentioned the study by the group of Dr. Catovsky (Hendry et al., Leuk Lymphoma 2004; 45: 945). Their patient group was more heavily pretreated than was the case in some of the other studies. This study also administered mitoxantrone at a lower dose of 5mg/m2 per course. The response rates are still respectable though and the authors themselves conclude that "the FCM regimen is safe to use in relapsed or refractory CLL and low grade NHL with high response rates and long remissions even in heavily pre-treated patients. ... The addition of Rituximab has improved results in FC and we have now started using FCM plus Rituximab (FCMR) as salvage therapy." Care should also be exercised to ascribe transformations to Richter's syndrome and/or development of AML exclusively to the studied combination. Although a watchful eye is necessary in this respect, the 2 patients who developed AML in this report received prior therapy as outlined by the investigators: "Two patients developed AML and this is likely to reflect multiple prior therapies in these patients rather than an effect of FCM itself." In summary and as will hopefully be understandable from these 2 paragraphs the idea of FCM-R is rooted in the literature, represents a combination that is actively being pursued (not only here at MDACC), and will hopefully bring positive results for our CLL patients as well.
To be more specific about the FCM-R trial at MDACC. Please bear in mind that this treatment is not designed for asymptomatic patients, but patients who show the signs and symptoms of the disease that are commonly considered sufficient to start treatment (NCI Working Group Criteria). It should also be emphasized that once patients show progression of the CLL to the point that therapy is becoming necessary, the prognosis of these patients is not quite as favorable as it is for asymptomatic patients and expected survival times are consequently shorter as well. Of course, FCM-R or similar chemo-immunotherapy combations are not for everyone and should not be. Based on experience with FCR and other combinations we are attempting to identify patient groups that may reap the most benefit from this approach. In the case of FCM-R, these patients are restricted to < 70 years of age with lower levels of beta-2-microglobulins whereas other patients may benefit from other programs. Obviously, side effects occur. Most significant is myelosuppression. Immunosuppression is not only a consequence of therapy (which is true for fludarabine single agent just as much as for combinations of whatever kind), but a consequence of the disease itself. This is of particular relevance in advanced-stage patients where there is a high incidence of infections even in the absence of treatment (or one could say because of the absence of effectivetherapy; also see Perkins JG, et al., Cancer 2002; 94: 2033). In appreciation of the fact that myelosuppression is frequent in this and similar combinations all patients are concurrently treated with pegfilgrastim (neulasta). To use hematopoietic growth factor support is a pattern that is becoming more common place with combination treatments in CLL and will hopefully help to reduce the number of patients experiencing significant myelosuppression. The cumulative dose of mitoxantrone in this study is 36 mg/m2 over a total of 6 courses (i.e. 6 mg/m2 per course). Although the FDA letter, which is linked in your article refers to use of mitoxantrone in patients with mulitple sclerosis (and not CLL), the cumulative dose of mitoxantrone is well below even the 100 mg/m2 that you quote. Nobody should underestimate the potential for any type of side effects and careful and conscientious follow up of patients are obviously mandatory and that is being done in our study as well.
We all strive to keep the right balance between benefit and risk of what we propose to our patients. How this balance is best achieved needs to be discussed very individually with each and every patient who considers to participate in a clinical trial. It is unfortunately also true for quite a few patients that the major toxicity is the disease itself and not the treatment. The more we learn about CLL and the way we approach it therapeutically, we will become more and more adept to apply therapies in a risk-adpated fashion. As you said yourself, if we knew everything already, there would be no need for studies of any kind.
To Dr. Stefan Faderl, MD
Subject: FCR+M clinical trial (2005-0106)
Dear Dr. Faderl,
Thank you for your detailed response. I will study it carefully and get back to you with any comments or questions.
From: Stefan Faderl , MD
Dear Dr. Venkat:
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Topic: Clinical Trials