Clinical Utility
 

The traditional Rai and Binet clinical CLL staging systems are based on disease burden and have been useful for assigning patients to groups having similar survival times.^1,2 These systems, however, are not effective in predicting survival in early-stage disease when most CLL cases are diagnosed. This has led to development of molecular markers that differentiate those patients who are prone to rapid progression from those who have indolent disease.

In a pivotal study conducted by Döhner et al, titled “Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia,” genomic alterations as determined by FISH were found to be predictive for disease progression and overall survival.³ Multiple studies support the conclusion of Döhner et al. that loss of 17p and of 11q markers predicts reduced survival times as compared to other Döhner groups as determined by FISH aberrations.^4,5,6

Such studies have led to the inclusion of FISH testing in the NCCN practice guidelines as a means to determine CLL prognosis. CLL prognostic categories according to the current NCCN guidelines divide patients into 3 categories – favorable, neutral and unfavorable.⁷

In a 2006 prospective study of 151 patients by Shanafelt et al utilizing Vysis FISH probes, a correlation was established between overall survival and FISH risk category for CLL at diagnosis.⁶ Patients were divided into 2 prognostic groups. They were assigned to the good/intermediate FISH prognosis group if there were no chromosomal aberrations or if only 13q-and/or +12 aberrations were present. If a chromosomal aberration of 17por 11q- was present, the patient was placed in the poor FISH prognosis group. Poor vs. good/intermediate FISH (P=0.004), age at diagnosis (P=0.0006); and Rai stage (P=0.0026) were each significantly associated with overall survival from diagnosis in univariate analysis. When all factors were included in multivariable Cox regression model, each of three factors still remained significant: Poor vs. good/intermediate FISH (P=0.00022), age at diagnosis (P=0.000024); and Rai stage (P=0.00012).⁶

^{The clinical util}ity of the Vysis CLL FISH Probe Kit has been established primarily from its high concordance with the assay employed in the publication by Shanafelt et al.⁶

Also, as noted in the Shanafelt study, all patients with the 17p- abnormality had between 24 to 94% of cells with this abnormality.⁶ Therefore, the effect of 17p- at very low levels could not be determined. In a publication on untreated 17p- CLL patients, Tam et al reported a 3-year overall survival of 92% for patients with < 25% 17p-deleted nuclei, vs. 54% for patients with ≥ 25% 17p-deleted nuclei (P=0.007).⁸

Method Concordance

A study was done comparing the method used in the Vysis CLL FISH Probe Kit and the method used by Shanafelt et al.⁶ This study established the clinical validity of the Vysis CLL FISH Probe Kit by demonstrating concordance to the FISH method used in the Shanafelt study. The clinical validity of the Vysis CLL FISH Probe Kit is documented via peer-reviewed literature. 

The study analyzed 64 specimens whose Döhner classifications were based on previous results using the Shanafelt FISH method. Table 22 shows the distribution of specimens analyzed, by Döhner classification. 

Table 22: Number of Specimens Analyzed, According to Döhner Classification

A Döhner classification was assigned to each result (Table 6), and the Prognostic Category was determined (refer to Table 7). The percent agreement between the Vysis CLL FISH Probe Kit and Shanafelt FISH method for Prognostic Category was 97% (62/64) with a lower bound of the one-sided 95% confidence interval of 90%. Overall agreement was defined as the percentage of specimens that had the same Prognostic Category when tested using the Vysis CLL FISH Probe Kit and the Shanafelt FISH method (refer to Table 23). 

Table 23. Concordance for Prognostic CategoryA

A The values in this table represent the number of specimens

Clinical Trial Information

The clinical trial was a multi-center study testing peripheral blood specimens from relapsed or refractory CLL subjects. The efficacy of VENCLEXTA^® (venetoclax) (a BCL2 inhibitor) was investigated in a single-arm trial of previously treated CLL patients with 17p deletion (Study 1, M13-982 trial). Study 1 was performed with the Vysis CLL FISH Probe Kit on peripheral blood specimens from relapsed/refractory CLL patients. A total of 167 subjects were screened for 17p deletion in the Study 1 main cohort.

Of the 167 subjects screened, 106 were enrolled in Study 1. Demographic and disease characteristics of the study population for Study 1 are provided in Table 24.

Table 24. Demographic and Disease Characteristics in Study 1

^A Race unknown for one patient

In this study, 17p deletion status was determined using the Vysis CLL FISH Probe Kit. Efficacy data from Study 1 are provided in Table 25. The primary efficacy endpoint was overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated Nation Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).⁹

Table 25. Efficacy Results for Patients with Previously Treated CLL With 17p Deletion by IRC (Study 1)

CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = Independent review committee; nPR = nodular partial remission; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial remission.

R/R CLL patients with 17p deletion were evaluated for the efficacy of VENCLEXTA^® (venetoclax) by overall response rate (ORR). 80.2% ORR was observed. Refer to the drug label for more information.

References

1. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-34. 
2. Binet JL, Auguier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1):198-206.
3. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343;1910-6.
4. Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100(4):1410-6.
5. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002; 100(4):1177-84.
6. Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol. 2006; 24(28): 4634-41.
7. NCCN Clinical Practice Guidelines in Oncology™ NON-HODGKIN’S LYMPHOMAS (Version 2.2016). National Comprehensive Cancer Network, Inc. Available at: NCCN.org.
8. Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114:957-64.
9. Hallek, M., et al. (2008). “Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updated the National Cancer Institute-Working Group 1996 guidelines.” Blood 111(12): 5446-5456.