Abruzzo, Lynne V.

Abstract Figure Figure In order to characterize the clinical course of patients (pts) with deletion 17p13.1 (17p-) CLL, we identified 100 consecutive treatment-naïve pts with 17p- from the MD Anderson Cancer Center (MDACC, n=61) and Mayo Clinic (n=39) clinical databases. The diagnosis of 17p- was established by FISH with a median time from initial diagnosis to FISH documenting 17p- of 9 months. Median age was 64 yrs (60 for MDACC pts & 70 for Mayo pts) and Rai stage was 0, 1–2 and 3–4 in 34%, 49% and 17% pts respectively. 17p- was the sole FISH abnormality in 29%. Unmutated IgVH and ZAP-70 positivity were present in 30/62 and 54/84 patients respectively. <<<TIME TO FIRST THERAPY>>> 69 asymptomatic pts were followed until they developed progressive disease requiring therapy as defined by the NCIWG 96 criteria. The 2 year actuarial risk of progression to initiation of therapy was 43% (46% for MDACC pts & 36% for Mayo pts). Only 2 of 10 pts with stable disease >2 years progressed on prolonged follow-up of up to 54 months. Two pts with baseline 17p- in 10% and 13% of nuclei lost their 17p- clone after 23 and 41 months. Independent predictors of shorter time to treatment were Rai stage > 0 (hazard ratio 7.2) and unmutated IgVH (HR 5.3). Pts with 0, 1 or 2 of these factors had a 2 year progression rate of 0%, 48% and >75% respectively (p<0.01). Other prognostic parameters such as ZAP-70 and CD38 did not have independent prognostic utility. <<<RESPONSE TO THERAPY>>> 41 pts from MDACC were assessable for response to first therapy. Overall (OR) and complete response (CR) rates were: rituximab without chemotherapy (n=6), OR 67% CR 17%; purine analogue + rituximab combinations (n=20), OR 75% CR 30%; purine analogue, rituximab + alemtuzumab combinations (n=13), OR 85% CR 54%. The pt who achieved CR after rituximab was negative for minimal residual disease assessed by flow cytometry and consensus primer IgH PCR, and has remained in remission at 29 months. At 2 years, 75% of complete responders remained relapse free. <<<SURVIVAL FROM 17P- DIAGNOSIS>>> Two year survival was 78%. Independent predictors of inferior survival were age 60+ (HR 3.4), B-symptoms (HR 3.7) and 17p- in nuclei 70+% (HR 6.0). Considering age 60+ and 17p- in nuclei 70+% in a prognostic model, 2 year survival was 100%, 82% and 55% for pts with 0, 1 and 2 risk factors respectively. Other prognostic parameters such as ZAP-70, IgVH mutation status and CD38 did not have independent prognostic utility. <<<CONCLUSIONS>>> Pts with de novo 17p- CLL exhibit marked clinical heterogeneity, with some pts experiencing an indolent course with prolonged survival. Survival and time to treatment among patients with 17p- can be predicted using clinical and biological characteristics.

AbstractAlterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Abstract The t(14;19)(q32;q13) involving the IGH@ and BCL3 loci is an infrequent cytogenetic abnormality detected in B-cell malignancies. We describe the clinicopathologic, cytogenetic, and molecular genetic characteristics of 14 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with t(14;19)(q32;q13). All patients (10 men and 4 women) had lymphocytosis; 10 had lymphadenopathy. Blood and bone marrow lymphocytes were predominantly small, but cytologically and immunophenotypically atypical. In all cases, t(14;19) was found in the neoplastic stem line; it was the sole abnormality in 4. Ten cases showed additional cytogenetic abnormalities, including trisomy 12 in 9 and complex karyotypes in 7. Fluorescence in situ hybridization demonstrated IGH@/BCL3 fusion gene in all cases. In all cases, the IGHV genes were unmutated, but only 7 expressed ZAP70. Seven cases preferentially used IGHV4-39. Our results indicate that t(14;19)(q32;q13) identifies a subset of CLL/SLL with distinctive clinicopathologic and genetic features. Furthermore, t(14;19) may represent an early, possibly primary, genetic event.

To determine the clinical fate of patients with de novo deletion 17p13.1 (17p−) chronic lymphocytic leukemia (CLL), we retrospectively studied the outcome of 99 treatment-naive 17p− CLL patients from the M. D. Anderson Cancer Center (n = 64) and the Mayo Clinic (n = 35). Among 67 asymptomatic patients followed for progression, 53% developed CLL requiring treatment over 3 years. Patients who had not progressed by 18 months subsequently had stable disease, with 3 of 19 patients progressing after follow-up of up to 70 months. Risk factors for progressive disease were Rai stage of 1 or higher and unmutated immunoglobulin variable region heavy chain (IgVH). The overall survival rate was 65% at 3 years. Rai stage 1 or higher, unmutated IgVH, and 17p− in 25% or more of nuclei were adverse factors for survival. The 3-year survival rates of patients with 1 or fewer, 2, and 3 of these factors were 95%, 74%, and 22%, respectively (P < .001). Response rates to therapy with rituximab (n = 6); purine analogues and rituximab (n = 25); and purine analogues, rituximab, and alemtuzumab (n = 16) combinations were 50%, 72%, and 81%, respectively. Patients with 17p− CLL exhibit clinical heterogeneity, with some patients experiencing an indolent course. Survival can be predicted using clinical and biologic characteristics.

Abstract The t(2;14)(p16;q32) has been reported previously in only 12 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The clinicopathologic features have been incompletely described. We describe 6 new cases of CLL/SLL with t(2;14)(p16;q32). All had marrow involvement, 4 had absolute lymphocytosis, 4 had lymphadenopathy, and 3 had hepatosplenomegaly. All showed atypical lymphocyte morphologic features with plasmacytoid differentiation and irregular nuclei; 3 had increased prolymphocytes. Flow cytometry demonstrated typical immunophenotypes in 5 and an atypical immunophenotype in 1. All expressed ZAP70; 5 assessed showed unmutated IgVH genes. Karyotyping identified t(2;14)(p16;q32) as the sole abnormality in 1, primary abnormality in 2, and part of a complex karyotype in 3. Fluorescence in situ hybridization analysis revealed BCL11A/IgH rearrangement in all. After chemotherapy, 3 patients died of disease and 3 were alive with disease (median follow-up, 80 months). We conclude that CLL/SLL with t(2;14) (p16;q32) and BCL11A/IgH rearrangement is characterized by atypical morphologic features and unmutated IgVH genes.