Molecular Profiling of elderly patients receiving frontline fludarabine-based chemo-immunotherapy in the ALLG CLL5 study

Xavier Badoux, Stephen Mulligan, Sara Gabrielli, Ying Zhu, Mathias Bressel, Giles Best, Melanie Hayes, Juliana Di Iulio, Bryone Kuss

    Research output: Contribution to journalMeeting Abstractpeer-review


    Abstract Details: Chemoimmunotherapy with fludarabine,
    cyclophosphamide and rituximab (FCR) is currently
    the most effective frontline therapy for younger patients
    with chronic lymphocytic leukemia (CLL). The
    Australasian Leukemia and Lymphoma Group (ALLG)
    CLL5 Study demonstrated that FCR is also safe, tolerable
    and effective first therapy for elderly patients (Mulligan
    et al., iwCLL 2015). We attempted to determine whether
    mutations in CLL-associated genes could predict
    responses and progression free survival in these elderly
    CLL patients. Methods: 120 patients were enrolled in the
    ALLG CLL5 study from November 2008 to July 2012.
    Study protocol received IRB approval and all patients
    approved to study participation and sample collection.
    Patients received up to 6 cycles of oral fludarabine-based therapy (FR5, FCR3 or FCR5). Study procedures and
    patient consent were in accordance with the declaration
    of Helsinki. Fluorescent in-situ hybridization: FISH was
    performed using the Vysis CLL panel (Abbott Molecular)
    with the following probes and cut-off values: D13S319-
    del(13q14.3), 4%; CEP12 (12p11.1-q11), 4%; ATMdel(
    11q22.3), 5% and TP53-del(17p13.1), 7%. DNA purification:
    DNA was purified from all samples. We
    designed a DNA sequencing custom amplicon panel
    using Illumina design studio to identify recurrent mutations
    associated with CLL (prognostic panel). Genes
    included TP53, ATM, NOTCH1, SF3B1, MYD88, XPO1 and
    BIRC3. Other genes were included as part of an exploratory
    panel but not included in this analysis. Samples
    were sequenced utilizing Illumina MiSeq sequencer
    according to manufacturer’s instructions. Genomic variants
    were reported if present in 20 reads with an error
    probability 1:1000 (Q30). Gene mutations were confirmed
    by Sanger sequencing. Data was analyzed using
    Illumina proprietary software, annotated using web
    ANNOVAR software and compared to COSMIC and
    other genomic mutation databases. Results: Clinical
    trial outcome measures (responses, PFS and OS) were
    analyzable for 116 patients. FISH data was available for
    92 patients (79%) and DNA sequencing data available for
    79 patients (68%). The overall response rate (ORR) was
    96% and the bone marrow confirmed complete
    response (CR) rate was 39% (Table 1). There was no
    statistically significant difference in CR, OS or PFS when
    comparing patients according to FISH hierarchy. When
    comparing patients with mutations of genes in the
    prognostic panel, patients with XPO1 mutations had a
    significantly shorter PFS by univariable analysis
    (p¼0.007). There was a trend to shorter PFS for patients
    with TP53 mutations but this did not reach statistical
    significance (p¼0.131, Figure 1b). There was no other
    statistical association between genes tested and PFS although this was limited by the small number of
    samples for each mutation. Conclusions: We had limited
    power to identify statistical associations to response, OS
    or PFS due to our small sample size and short follow-up.
    Nevertheless molecular tools may provide further stratification
    to identify patients with variable benefit from
    Original languageEnglish
    Article numberAbstract 144
    Pages (from-to)120-121
    Number of pages3
    JournalLeukemia and Lymphoma
    Issue numberS1
    Publication statusPublished - 19 Jan 2016
    EventXVI International Workshop on Chronic Lymphocytic Leukemia 2015 - Sydney, Australia
    Duration: 6 Sep 20159 Sep 2015


    • chemoimmunotherapy
    • FCR


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