Apr 17, 2012 - Van Dyke DL, Shafely TD, Call TG, et al. A comprehensive evaluation ... The University of Texas MD Anderson Cancer Center. Houston, Texas.
Correspondence
The Prognostic Difference of Monoallelic Versus Biallelic Deletion of 13q in Chronic Lymphocytic Leukemia In a recent online paper on del13q14 chronic lymphocytic leukemia (CLL), Garg at al1 state that neither pattern of deletion (mono- versus biallelic) nor the percentage of deleted cells influences risk of progression. Interestingly, in 12 patients who had a repeat fluorescent in situ hybridization (FISH) analysis, an increase in the number of deleted cells was detected. In light of these data, we reviewed our del13q14-CLL patients who were monitored by FISH during their clinical course. Between 2001 and 2009, del13q14 was identified as the sole abnormality in 137 of 352 CLL patients (39%). Baseline FISH analysis was performed at diagnosis or within 12 months (probes: LSID13S319 and LSI-Rb1, LSI-ATM, LSI-p53, CEP12; Vysis, Downers Grove, Ill). D13S319 deletion was monoallelic in 121 cases (88%) and biallelic in 16. The median percentage of abnormal nuclei was 50% (range, 15%-96%) and was higher in patients with a biallelic pattern (73% vs 49%; P < .0001, MannWhitney test). With a median follow-up of 59 months (range, 12-124 months), the 5-year treatment-free survival rate was 54% (Kaplan-Meier). As a continuous variable, the baseline percentage of abnormal nuclei was related to progression (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.04; P ¼ .0002; Cox regression), whereas the pattern of deletion was not significant. Repeat FISH analyses were performed on 100 patients (median interval from baseline to repeat FISH analysis, 36 months; range, 9-97 months). A significant increase in the proportion of del13q14 cells was detected (P < .0001, Wilcoxon matched pairs), and change in the percentage of deleted cells per unit of time (1 month) significantly affected the risk of treatment requirement (HR, 2.03; P ¼ .016; 95% CI, 2.03-3.6; Cox regression). Although del13q14 CLL carries a good prognosis, it is clinically and biologically heterogeneous. Although prognostic impact of baseline FISH profile is controversial, our experience confirms2,3 that the percentage of deleted cells at diagnosis represents an useful prognostic parameter. Additionally, we advise FISH monitoring for a dynamic outcome estimate and to guide clinical surveillance.
Cancer
October 15, 2012
FUNDING SOURCES No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Garg R, Wierda W, Ferraiolj A, et al. The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. Cancer. 2012;118:3531-3537. 2. Van Dyke DL, Shafely TD, Call TG, et al. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2009;148:544-550. 3. Dal Bo M, Rossi FM, Rossi D, et al. 13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2011;50: 633-643. Ester M. Orlandi, MD Paolo Bernasconi, Prof Cristiana Pascutto, PhD Hematology Unit Department of Hematology-Oncology Fondazione IRCCS Policlinico San Matteo Pavia, Italy DOI: 10.1002/cncr.27525, Published online: April 17, 2012 in Wiley Online Library (wileyonlinelibrary.com)
Reply to The Prognostic Difference of Monoallelic Versus Biallelic Deletion of 13q in Chronic Lymphocytic Leukemia Orlandi et al report on 137 patients with chronic lymphocytic leukemia and deletion 13q followed between 2001 and 2009, 16 of whom were biallelic. The median percentage of abnormal nuclei was higher in patients with a biallelic pattern (73% vs 49%). We evaluated our patients in light of this letter. Similarly to other pretreatment factors that we examined, we did not see any difference between the 2 groups. The median number of abnormal nuclei in the biallelic group was 32.5% (range, 7%78.5%) versus 34% (range, 8.5%-89.5%) in the monoallelic group. Orlandi et al also report that the baseline percentage of abnormal nuclei was related to progression. We did report that the median percentage of 13q deletion was higher in both groups for those subsequently requiring
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treatment, but that it did not reach statistical significance. Because the trend was the same in each of the groups, we reexamined this by combining the data from all patients (biallelic and monoallelic). The median number of abnormal nuclei was 44.5% (range, 8.5%-89.5%) in the 46 patients subsequently progressing. In the 130 patients who had not required treatment, the median number of baseline abnormal nuclei was 31.5% (range, 7%-85%; P ¼ .17). As reported in our paper, in the patients (n ¼ 12) in whom fluorescent in situ hybridization (FISH) was performed at the time of treatment, the median percentage of positive cells had increased from 35% to 79%. We examined the data using the cutpoints described in the large series by Van Dyke et al.1 One hundred forty-seven patients had 65.5% abnormal nuclei; 34 patients required treatment. Twelve of 29 patients having >65.5% abnormal nuclei required treatment (P ¼ .041). The median time to treatment in the group with AP/BC), Hasford risk score, response to treatment, and (in patients with CP CML) with the duration until disease progression to AP/BC.4,5 Based on these results, telomere length, at least in the context of intact cell cycle checkpoints, could represent a valuable prognostic and/or predictive biomarker for disease progression, response to TKIs, and potentially for maintenance of response upon cessation of TKI treatment.6 These questions are being addressed prospectively as part of a scientific subproject performed in patients with CP CML who are undergoing nilotinib as front-line treatment (the ENEST1st study).
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In conclusion, increasing evidence points to a strong direct or indirect interaction between BCR-ABL activity and telomere maintenance in CML, which is most likely mediated via effects on TA. Whether this phenomenon could be used clinically as a predictive biomarker, and even for selection of individual TKIs most suitable for individual patients, remains to be demonstrated.
CONFLICT OF INTEREST DISCLOSURES Dr. Manley is an employee of Novartis Pharma AG. The other authors made no disclosure.
REFERENCES 1. Nicolini FE, Turkina A, Shen ZX, et al. Expanding Nilotinib Access in Clinical Trials (ENACT): an open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant philadelphia chromosome-positive chronic myeloid leukaemia in the chronic phase. Cancer. 2012;118:118-126. 2. Bakalova R, Zhelev Z, Spasov L. Nilotinib versus imatinib: molecular mechanism(s) of its better efficacy. Cancer. 2012;118:5180-5181. 3. Drummond MW, Balabanov S, Holyoake TL, Brummendorf TH. Telomere biology in normal and leukemic hematopoietic stem cells. Stem Cells. 2007;25:1853-1861. 4. Keller G, Brassat U, Braig M, Heim D, Wege H, Bru¨mmendorf TH. Telomeres and telomerase in chronic myeloid leukaemia: Impact for pathogenesis, disease progression and targeted therapy. Hematol Oncol. 2009;27:123-129. 5. Bru¨mmendorf TH, Holyoake TL, Rufer N, et al. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood. 2000;95:1883-1890. 6. Mahon F-X, Re´a D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029-1035. Franck E. Nicolini, MD, PhD1 Paul W. Manley, MD, PhD2 Tim H. Bru ¨ mmendorf, MD3 1
He´matologie Clinique 1G, Centre Hospitalier Lyon Sud, Pierre Be´nite, France 2 Novartis Pharma AG, Basel, Switzerland 3 Medizinischen Klinik IV, Ha¨matologie und Onkologie, Universita¨tsklinikum Aachen, Aachen, Germany DOI: 10.1002/cncr.27481, Published online: April 25, 2012 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
October 15, 2012
