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Alert Number 6

Fludarabine as Front-line Therapy

Date: March 24, 2004.

Fludarabine is an extremely important drug in our fight against CLL. It is used as a single agent and also in a variety of combination chemotherapy regimes, as well as chemo-immunotherapy regimes such as FRC and RPC. Especially in patients with advanced disease, fludarabine can give higher response rates and longer remissions. That potency earned it the status of "gold standard" in CLL. However, it might be time to take a second look at this important drug, define some ground rules for its use.

In recent Topics Alerts as well as full articles on our website, we have discussed present day "Best Practices" suggest patients be given pre-emptive medications to protect them against opportunistic infections that may seize their chance to attack, during the period of immune suppression caused by fludarabine use. But on an even more fundamental note, is there a way of telling ahead of time whether or not a given patient is going to respond well to fludarabine? Do patients have to go through the trial and error approach, or can we make smarter choices ahead of time?

Not all the details are in yet, but some results are coming in that ought to be of interest to all of us. We have discussed the different chromosomal aberrations that are at the root of CLL. One of the worst is mutation, deletion, or poor functioning of the TP53 gene. This important tumor suppressor gene resides on your 17th chromosome, and the exact location is designated as 17p13.1 Below is an abstract from the 2003 American Society of Hematology conference held recently in San Diego. I urge you to wade through the abstract; but at the very least, pay attention to the punch line: Aberrations on TP53 could predict the bad response to fludarabine, and could be used to discard purine analogues such as fludarabine as first line therapy.

I would say that is pretty blunt!

How about 11q22.3 (ATM) deletions? As we discussed in several articles on our website, 11q deletion or mutation means improper functioning of the ATM gene, which may also translate into less than perfect functioning of the TP53 gene. While the line of logic is not as strong for ATM defects as in the case of deletion or mutation of TP53, I would worry that ATM defects may also imply TP53 defects, and may therefore suggest against fludarabine therapy as your best choice.

The article also discusses methylation of the crucial 17p13 region of your DNA. We discussed "epigenetic silencing" of genes in a previous article. The analogy we used before was of a security camera, properly loaded with film, but not doing its job because the lens of the camera is smothered over by a big wad of chewing gum. Epigenetic silencing of TP53 can happen when a whole lot of methyl groups cover up this crucial part of the 17th chromosome, preventing proper functioning of the TP53 gene.

At this point I do not know how we can go about finding out if our TP53 gene in CLL cells is functioning at peak efficiency, whether it is epigenetically silenced. But we sure can find out whether or not it is deleted, and we can also find out if its side-kick 11q (ATM gene) is deleted or not. In case you have missed it, FISH analysis can give you the answers to these questions. Not the whole picture, but a good bit of it. With what we know now, going for fludarabine as front-line therapy without knowing your FISH status is risky business.

On this website, you can read more about FISH, prognostic indicators in CLL, ATM and TP53 gene defects, and modern "Best Practices" in treating CLL.

Be well,

Chaya
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Abstract

Genetic Aberrations of TP53 Predicts Response to Fludarabine as First Line Therapy in Patients with Chronic Lymphocytic Leukemia on Advanced Stage Rai III/IV

Session Type: Poster Session 647-II.

Maria D. Odero, Mikel Valganon, Xabier Agirre, Jose P. Roman, Idoya Lahortiga, Araceli Rubio-Martinez, Daniel Rubio-Felix, Francisco J. Novo, Pilar Giraldo, Maria J. Calasanz Genetics, University of Navarra, Pamplona, Navarra, Spain; Fundacion estudio Hematologia y Hemoterapia (FEHHA), Zaragoza, Spain.

Fludarabine (FLD) in patients with advanced CLL induces higher remission rates and longer progression free survival as first line therapy than chlorambucil or CAP. Genetic aberration that modified the expression of TP53 (deletions and mutations) are independent poor prognostic factors in CLL. Hypermethylation of the promoter regions of some tumor suppressor genes has been associated with transcriptional silencing and tumor progression. We report the genetic analysis of a group of 43 patients with CLL Rai stage III/IV treated with FLD as first line therapy (25mg/m2 IV daily 5 days) every 4 weeks, 4-6 courses until reaching response. The median age at diagnosis was 66.7 years, 26 males and 17 females. We have analyzed biological features with prognostic significance, cytogenetic aberrations, TP53 abnormalities, and the presence of somatic hypermutation of IgVH, in order to assess the frequency and clinical relevance of these features, and the relation with rates of response to FLD on advance stages of CLL. We performed FISH using the probes RPCI-11 241D13 and 415G10 (11q22.3), and LSI D13S25 (13q14), LSI TP53 (17p13.1) and D12Z3 (Vysis). We analyzed the methylation at CpG and CC(A/T)GG sites of the TP53 promoter region. Methylation of CC(A/T)GG sites represent a type of epigenetic marker that could impact transcription by altering DNA-protein complex formation. DNA-methylation was analyzed using restriction enzyme digestion followed by PCR. The association among the presence of TP53 alterations, mutational status of the IgVH genes, cytogenetic aberrations and the response to FLD of our patients, was studied using contingence tables followed by chi square or Fisher exact test. Response of 34 patients was evaluated according to the modified NCI working group criteria for CLL (9 were NV). Seventeen patients (17/34, 50%) achieved CR and 12 (12/34, 35%) PR, with an OR rate of 85% (15% of failures). We detected cytogenetic aberrations in 84% of patients (36/43), 20 (56%) had two or more abnormalities, according to previous studies that correlate the presence of more than one aberration with an advance stage of the disease. Monoallelic loss of D13S25 was the most frequent aberration (63%) followed by del(11)(q22.3) (33%), del(17)(p13.3) (26%) and trisomy 12 (21%). Only 8 cases (35%) had 13q- as the sole abnormality. We detected somatic mutations of IgVH genes (less than 98% homology) in 40% of patients. Ten patients (10/41, 25%) had methylation in the promoter region of TP53, and 3 of these also presented del(17p). Moreover, a high frequency of poor prognosis features as del(17)(p13.1), del(11)(q22.3) and no mutated IgVH genes was detected, if comparing with other series that include patients on early stage of CLL. We only found a significative correlation between the course of the disease and the presence of abnormalities on TP53. Comparing the frequency of patients with del(17p) and/or TP53 methylation versus other variables studied, we observed a significantly different non response rates in the first group (p=0,007). Cytogenetic abnormalities such as del(17)(p13) and del(11)(q22-q23) predict rapid disease progression and inferior survival in CLL. We report the impact of del(17p) and/or TP53 methylation in the resistance to treatment with FLD. Aberrations on TP53 could predict the bad response to FLD and could be used to discard purine analogues as first line therapy in patients with advanced stages of CLL.

Abstract #2476 appears in Blood, Volume 102, issue 11, November 16, 2003.

Keywords: Fludarabine|CLL|TP53.
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