Thursday, December 01, 2011

CLL8 the same bad news is bad news.

977 Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG) Anna Fink, Raymonde Busch, Natali Pflug, Sebastian Boettcher, Dirk Winkler, Andreas Buehler, Matthias Ritgen, Kirsten Fischer, Barbara Eichhorst, Clemens-Martin Wendtner, Myriam Mendila, Michael K. Wenger, Hartmut Doehner, Michael Kneba, Stephan Stilgenbauer and Michael Hallek.


For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ³ 24 months. 15 % of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis.


In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10-4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors.


This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-ß2m. A combination of MRD levels of less than 10e2 or of MRD levels of less than 10e4 to less than 10e2 plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970-10.347; p=0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799-11.844, p=0.0001)


The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation.

A predictable picture is emerging. The same old prognostic factors - IGVH mutations and TP53 abnormalities determine the pace of the disease. It confirms my opinion that all CLL patients ought to get them done.


Robert said...

Dr. Hamblin I greatly appreciate the time you have taken to share your reflections on CLL research. I am hoping you might comment on some results that I have found confusing.

I had a Multiplex Litigation-dependent Probe Amplification (MLPA) done on my blood. The report concludes that “evidence of a chromosome 11q23 deletion was detected” in a peripheral blood sample. I also had IvGH done at a different lab. The results reported “Mutation Rate: 3.04%” based on “sequence analysis the clonal IgVH gene belongs to the VH1-69 family.”

I have read up on the 11q deletion and feel I have a reasonable understanding of its possible unfavorable implications for CLL patients. I have also read up on IgVH mutation status and its association with more indolent CLL. I am hoping you can offer an interpretation my IvGH mutation status report because it is unexpected given the 11q-23 deletion.

I read in several places including your blog that 11q deletion is almost always associated with umutated IgVH. In your June 2010 blog while discussing IvGH as a prognostic indicator you wrote, “This isn't a foolproof test. Being unmutated does not guarantee early treatment and being mutated doesn't guarantee late treatment or no treatment. I have written before that there are some borderline cases with 97% homology who tend to include some cases that are effectively unmutated and of course, those who use the V3-21 gene behave as if they were unmutated even when they are mutated.”

Because my mutation rate is 3.04% as reported by my IvGH test and the 11q-23 deletion found in my blood is usually associated with unmutated VH status, could I be one of the borderline cases you wrote about? Could it be that I might actually be unmutated despite the mutated determination of the lab report? If not, what sort of prognosis is associated with 11q coexisting with mutated VH status? I ask this because, to borrow from a remark you have made on your blog, just like I watch the weather forecasts, I want to know something about the possible future so I can plan for it. I will also add that my CD38 was 20% two years ago at diagnosis.

Terry Hamblin said...

Your results are all a bit borderline. Judging by this I would expect that you don't fall in the worst pot, but in an intermediate one. You need to be watched a bit more carefully than most.

Rachel Smith Maher said...

Dr. Hamblin,
As always, your insight is invaluable to us CLL patients. Does the conclusion statement of this artical change your opinion that FCR is the best first line treatment for a patient that is young and relatively healthy?
Thank you so very much.

Terry Hamblin said...

No change in my nuanced aopinion.