NeoTYPE™ CLL Prognostic Profile
Chronic Lymphocytic Leukemia

Comprehensive multivariate profiling for optimal risk stratification

 

NeoTYPE Hematology ProfilesChronic lymphocytic leukemia (CLL) presents a management dilemma with progressive disease occurring in approximately half of patients and steady, indolent disease in the other half. Accuracy in predicting the disease course requires the use of multiple prognostic measures.

The NeoTYPE CLL Prognostic Profile combines into one test the most significant prognostic information available from molecular analysis, flow cytometry, and FISH, including the newest markers, NOTCH1 and SF3B1 mutations. With a single sample submission and our comprehensive report, the ordering physician receives a prognostic profile including:

  • NOTCH1 mutation status
  • SF3B1 mutation status
  • IgVH mutation status
  • ZAP-70 expression level
  • Evaluation for key chromosome abnormalities in CLL

This Profile may be ordered after the diagnosis of CLL. Each test can also be ordered separately.

 

NOTCH1 and SF3B1 – a novel, independent prognostic indicators for CLL

The NeoTYPE CLL Prognostic Profile makes clinical testing for mutations of the NOTCH1 and SF3B1 genes available for the first time. These genes are the most frequently mutated genes in CLL that predict poor prognosis.1

NOTCH1 is a proto-oncogene mutated in approximately 10% of newly-diagnosed CLL cases.2 Recently Rossi et al.2 confirmed the prognostic value of NOTCH1 mutations in a study of 539 previously untreated patients by finding significantly shortened overall survival and higher risk of Richter’s transformation in patients with mutations.2 In >90% of cases, mutations were mutually exclusive of TP53 disruption. TP53 and NOTCH1 mutations had equally detrimental effects on survival. Therefore, NOTCH1 mutation status may serve as an independent indicator of high risk for those 40-50% of high-risk cases that do not have TP53 abnormalities.2

NOTCH1 mutations were associated with unmutated IgVH, also a poor prognostic marker, and Trisomy 12, an intermediate marker.2,3 In a study of 104 patients with CLL positive for Trisomy 12,3 NOTCH1 mutations again predicted significantly shorter survival, similar to +12 with TP53 disruption or 11q22-23 deletion in effect. TP53 or 11q abnormalities rarely occurred with NOTCH1 mutations, however. Mutation distribution was also not related to ZAP-70 expression.

Splicing Factor 3, subunit 1 (SF3B1) is a key component of the spliceosome RNA processing complex, and it is thought to manage mRNA splicing from a subset of genes involved in cell-cycle control, angiogenesis, and apoptosis.4 Mutations have been reported in myelodysplastic syndromes, myeloproliferative neoplasms, and chronic lymphocytic leukemia.4,5

SF3B1 mutations are detected in 10-15% of CLL patients and are noted to be independent predictors of poor prognosis. Quesada et al. found in a study of 279 CLL patients that mutations were associated with significantly shorter time to disease progression and lower 10-year overall survival rates.6 Mutation status was independent of clinical stage and expression of ZAP-70 or CD38.6,7 In a group of 91 patients studied by Wang et al., mutations predicted earlier need for treatment independently from other markers including IgVH, del(17p), and ATM mutations in chromosome 11q.4,8

 

Test overview

Blood or bone marrow samples are tested concurrently by molecular analysis, flow cytometry, and FISH. Results are reported together in a comprehensive summary report in approximately 10 days when all testing is complete.

Mutation Analysis: Highly reliable Sanger sequencing is used to analyze exons 14-17 of the SF3B1 gene, the region harboring mutations in over 90% of the positive cases,5,6 to analyze the most frequent mutated exons 26, 27, and 34 or NOTCH1, and to determine mutation level in the IgVH gene. IgVH is reported as mutated and the mutated VH family is identified if deviation from a germline reference sequence exceeds 3%.

ZAP-70: Multiparameter flow cytometry is used to quantify ZAP-70 expression.

FISH: FISH is performed on interphase nuclei using the comprehensive CLL probe panel described below.

Print Test Description & Specimen Requirements.
Contact us for more information about the NeoTYPE CLL Prognostic Profile.

 

Ordering information

Specimen requirements: Peripheral blood is strongly preferred over other specimen types as most prognostic studies were completed on blood samples. Tech-only options are not available with this Profile. 

  • Peripheral blood: 2 EDTA tubes, 5 mL each
  • Bone marrow: Minimum 1 mL in EDTA, 1-3 mL preferred
  • Fresh lymph node: 0.5 - 1 cm3 in RPMI

TAT: A comprehensive report is issued at 10 days.

TEST OPTIONS: Each test in the Profile may be ordered separately. Also, clients ordering FISH and/or flow cytometry as tech-only tests, or performing them in their own laboratories, may wish to order the CLL Molecular Prognostic Profile, which includes concurrent IgVH, NOTCH1, and SF3B1 Mutation Analysis. Turnaround time is 10 days and specimen requirements are the same as above.

For more information, please contact Customer Care at (866) 776-5907 or from our contact page.

 

References

  1. Rodrigeuz-Vicente AE, Diaz MG, Hernandez-Rivas, JM. Chronic lymphocytic leukemia: a clinical and molecular heterogeneous disease. Cancer Genet. 2013;206(3):49-62.
  2. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119(2):521-529.
  3. Del Giudice I, Rossi D, Chiaretti S, et al. NOTCH1 mutations in +12 CLL confer an unfavorable prognosis. Haematologica. 2012;97(3):437-441.
  4. Wang L, Lawrence MS, Youzhong W, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497-2506.
  5. Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011:118(24):6239-6246.
  6. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2012;44(1):47-52.
  7. Quesada V, Ramsay AJ, Lopez-Ortin C. Chronic lymphocytic leukemia with SF3B1 mutation. N Engl J Med. 2012; 366:2530.
  8. Mori J, Takahashi U, Tanimoto T. SF3B1 in chronic lymphocytic leukemia [author reply]. N Engl J Med. 2012;366(11):1057-1058.

The NeoTYPE CLL Prognostic Profile is one of a suite of Hematology Profiles available at NeoGenomics. Along with our Solid Tumor Profiles, they are part of our growing services in precision medicine. These Profiles enable physicians to easily match their patient’s tumor type to unique test combinations customized for medical impact. More Profiles are in development. Information about current Profiles is available here.