Thursday, October 23, 2008

FCR: No country for old men

Outcome of treatment for chronic lymphocytic leukemia (CLL) depends more upon the nature of the disease than the type of treatment given. Despite newer treatments producing higher response rates and longer remissions than older ones, no study has ever shown an overall survival benefit from their first-line use compared to treatments that have been available for fifty years.

Some patients survive for decades untreated. Such patients usually have mutated immunoglobulin heavy chain variable region genes (IGHV), low expression of CD38 and ZAP-70 and deletions at chromosome 13q14. Other patients require treatment within a year or two of diagnosis and survive for fewer than eight years. Such patients tend to have unmutated IGHV genes, raised expression of CD38 and ZAP-70 and different chromosomal aberrations including trisomy 12 and deletions at 11q23 or 17p13 [1].

Until now the treatment regimen that has performed best in randomized controlled trials has been the combination of fludarabine and cyclophosphamide (FC) which has been shown to produce a higher response rate and longer remissions than either fludarabine or an alkylating agent used alone [2].

For several years it has been very common for physicians in the United States and some European countries to add the monoclonal antibody rituximab to FC (the combination being designated FCR), even though rituximab has not been licensed for the treatment of CLL. The results of CLL8, a randomized controlled trial comparing FC and FCR, conducted by the German CLL study group will be reported shortly. Media reports suggest that the trial met its primary endpoint which was to demonstrate a 35% increase in progression-free survival for patients in the FCR arm [3].

Despite increased response rates and longer remissions from more intensive treatment, no form of treatment restores the intrinsic immune deficiency caused by CLL and concern has been raised that the lack of overall survival benefit from newer treatments might derive not merely from the availability of effective salvage treatments but also from long term toxicity. A higher rate of transformation to aggressive lymphoma (Richter’s syndrome), more severe and intractable infections and a greater risk of the development of autoimmune complications or myelodysplastic syndrome have been suggested implications of the use of very immunosuppressive combinations of drugs that include fludarabine [4, 5].

In the meantime a very large non-randomized phase II study of treatment with FCR has been taking place at the MD Anderson Cancer Center in Houston and results of this study have now been published [6]. Among 300 patients treated with FCR and followed up for a median of six years, the complete response rate was 72% - far higher than for previous treatments. In CLL a complete response according to the 1996 NCI criteria [7] allows for considerable residual disease and because of this, methods for the detection of minimal residual disease (MRD) have been developed using either flow cytometry or the polymerase chain reaction. Using the most sensitive of their techniques the Houston group found 28% to be negative for MRD. However, the techniques used for the detection of MRD were sub-optimal; others have described and used techniques that are five to ten times more sensitive [1].

Among patients with a partial response or better (all but 15 of the original cohort) the median time to progression was 80 months with a projected 60% progression-free at six years. Again, this is an impressive result but it must be seen in the context of the kinds of patients treated. First, the patients in this study were relatively young; the median age was only 57 and only 14% were aged 70 or older, whereas in the general CLL population, 70 is the median age of presentation. As a group, patients over the age of 70 were significantly less likely to complete the optimum six cycles of therapy (46% vs 79%) and significantly less likely to achieve a complete remission.

Second, most modern prognostic markers were not available for this study. Specifically, ZAP-70 expression, IGHV mutational status and FISH were not available. CD38 expression was tested for, but in only 21% of patients were more than 30% of cells CD38 positive. The comparable figure for my own treated patients is 64%. It is becoming possible to do some of the modern prognostic tests on archived material and we wait with interest the outcome of any future investigation.

Lacking a contemporary comparator, the chief interest in this trial is in the long term safety profile of this regimen. Here there is certainly some encouragement. The actuarial risk of Richter’s syndrome was 2.5% at six years – no more than for historical series. Likewise the actuarial risk of myelodysplastic syndrome was only 2.8% at six years. The well established effect of fludarabine in depleting circulating T cells [5] is certainly responsible for the 10% risk of serious or opportunistic infection during the first year of remission and 4% risk in the second year, but four of the five late deaths from infection were caused by bacteria rather than fungi or viruses.

The most unexpected toxicity was persistent cytopenia after completion of therapy, continuing for at least three months. This occurred in 19% of patients. However, following recovery of blood counts, recurrent late cytopenic episodes occurred in 28% of patients, predominantly in the first year of remission. Salvage of relapsing patients with persistent cytopenias is particularly taxing.

References
1. Dighiero G, Hamblin TJ (2008) Chronic Lymphocytic Leukemia. Lancet 371:1017-1029.
2. Catovsky D, Richards S, Matutes E, et al (2007). Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 trial): a randomised controlled trial. Lancet 370:230-239
3. Roche Media Release 25th January 2008. http://www.roche.com/med-cor-2008-01-25-e.pdf accessed 20th October 2008.
4. Milligan DW, Fernandes S, Dasgupta R et al (2005). Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 105:397-404.
5. Hamblin AD, Hamblin TJ. (2008) The immunodeficiency of chronic lymphocytic leukaemia. British Medical Bulletin 87:49-62.
6. Lam CS, O’Brien S, Wierda W et al. (2008) Long term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112:975-980
7. Cheson BD, Bennett JM, Grever M et al. (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87:4990-4997.

28 comments:

Lael said...

What is the projected outcome for those patients who are unable to use FCR as a first line due to ITP?

Burke said...

Dr. Hamblin,

How long should it take for the T-cells to return to within normal limits following FCR?

Terry Hamblin said...

Usually about 2 years.

Terry Hamblin said...

Lael
I don't think ITP is a contraindication for FCR.

Anonymous said...

Based on your patient stratification, do you have any thoughts on the survival time for someone with very high CD38 (over 60%), trisomy 12 and probably unmutated, dx in 2004 (but probably had cll for two years prior), started treatment June 2008 due to hgb under 10, plt at 80, wbc 120K,and is almost done with FCR + neulasta (and has responded well to treatment so far)?

Terry Hamblin said...

Unmutated CLL has a 40% 6-year progression-free survival with FCR in the under 65s

mag said...

Would you think FCR is the way to go for a 55 year old who has an 11q rearrangement, zap-70 positive, unmutated with bone marrow heavily comprised of CLL cells to the point of steadily increasing anemia (Hg 10 presently) but feeling fine?

Terry Hamblin said...

Yes I would, but with teh provico that something else was needed to keep you in remission - perhaps maintenance with rituximab, or consolidation with Campath or a trial of one of the new agents coming on line like PARP1 inhibitors or Nutlin, or even an allograft

Anonymous said...

What is the prognosis for a 47 year old female patient with unmutated genes, no deletions, but with ZAP negative and CD38 at 15%These prognostic tests seem to be inconclusive.

Terry Hamblin said...

Absolutely impossible to give a prognosis with such mixed markers. 50% live 15 years; some more some less. Remember that the median is not the message. Survival curves tell you about populations, not individuals.

Anonymous said...

Is maintenance therapy with rituximab commonly prescribed? I had HDMP+R but was not offered any maintenance therapy at all.

Now I have bulky nodes. Does this make a difference as to an attempt to do maintenance therapy?

Barry

Terry Hamblin said...

Maintenance therapy is quite commonly prescribed in the US but there is no evidence that it is useful, beyond analagy with lymphoma where it is useful. However, the FCR paper suggests that the newer regimens - FCRM, CFAR, FCR+GMCSF are no improvement on FCR and that maintenance may be the way to go.

Anonymous said...

Could you comment on "post FCR" prophylaxis. The data that I read (including your 9/08 paper) suggests that there is prolonged T cell impairment following FCR, suggesting need for prolonged prophylaxis against CMV, other herpes viruses and PCP is indicated, but when I read the comments on various CLL chat rooms, the patients don't seem to be following any standard pattern...your comments might merit a separate blog post if you think it is worthwhile to disseminate the right information.

Thanks,

DWCLL

Anonymous said...

Where are trials of Nutlins and PARP1 inhibitors being conducted?

Terry Hamblin said...

I agree it does merit a separate blog, but in principle keep the prophylaxis going until the CD4 count hits 200.

Terry Hamblin said...

Nutlin is currently being trialed for liposarcoma, but should soon be tried in CLL. PARP1 is currently being trialed in Birmingham UK.

Burke said...

Dr. Hablin,

You wrote regarding FCR for older patients that:

"As a group, patients over the age of 70 were significantly less likely to complete the optimum six cycles of therapy (46% vs 79%) and significantly less likely to achieve a complete remission."

Suppose an older patient does less than six cycles but still achieves a complete remission, are his odds for a long remission less than or the same as if he were younger?

Terry Hamblin said...

Yes. Then it depends on teh markers, particularly on mutational status.

Anonymous said...

I am looking for information on Campath in elderly CLL patients.Have you written about that, or know of resources? It is being quickly recommended for my 81 year old father.I am cautious.

Terry Hamblin said...

Campath is a poor choice for old people. It is more immunosuppressive than fludarabine and at this age it's use should be confined to those with del 17p on FISH. Even then it is risky.

Burke said...

Dr. Hamblin,

I recently ran across the Abstract for the 2008 Ash conference paper you discuss here(linked below). I don't have access to the full paper.

The first two sentences state:

"The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL."

This left me with a couple of questions:

1. What kind of CR are they referring to? Do they mean the 72%in CR are MRD negative? By Flow, PCR, or what?

2. Are the authors of this paper claiming that they are getting cures with FCR? Seems as they are.

Thank you.

http://abstracts.hematologylibrary.org/cgi/content/abstract/112/11/2090?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=FCR&searchid=1&FIRSTINDEX=0&volume=112&issue=11&resourcetype=HWCIT&eaf

Terry Hamblin said...

They are certainly not claiming cures. The CRs are as defined by the 1996 guidelines. You can still have 30% lymphocytes in the bone marrow and lymph nodes as long as they can't be felt.

Burke said...

I have another question, if you don't mind.

When you look at a stat like the one here which states that the median to relapse for the 72% of CR's is 7 years, what does that mean for those frontline FCR patients who are already well into the 7 years?

Is it like it is with life expectancies? That is, if the average life span for a male in a population is 73, the expectancy for one who is 60 is longer than that because he has already survived longer than those who died before 60?

Can a CR who is still alive 2 or 3 years follwing FCR say the chances are greater that he will be in the group who go longer than 7 years before relapse because he has already gotten through the first difficult 2-3 years?

Thank you.

Terry Hamblin said...

The median time to progression is the time it takes from the start of treatment to the time when 50% of the patients have progressed. In this case it is confined to the cohort who have achieved CR.

If someone has survived the first two years successfully then his median time to progression is longer because he has got past the first two years and a new median time to progression has to be calculated using the cohort of CRs who have not progressed at two years. Similarly you could make this calculation at any time after the remission starts.

Anonymous said...

Hello Dr. Hamblin,

My father is 52 years old and has CLL. He passed 6 cycles of chemotherapy with Fludara 2 years ago. After 24 months, now he have to start new therapy because the number of leukocyte are doubled in last 6 months and has lymph node around 3-4cm in the body. He has no problems with organs.

My question is related to the therapy. The doctor had prescribed FC (maybe because is cheaper), but there are some possibilities to be included in some program which offers FCR.

What is do you think do we have to insist to be included in the program and do FCR instead of FC only (maybe buy Rituximab by ourselves)

Thank you in advance
Greetings from Bulgaria
Ivan
Sorry for my English

Terry Hamblin said...

At your age I wold definitely try and get rituximab as part of the treatment.

Anonymous said...

Dr. Hamblin,
Thank you for your quick answer.
But I mistaked in my previous post. My father is 62 not 52 (10 years older, than I wrote) :(

Ivan

Terry Hamblin said...

62 is not too old.