The signs of negative selection in IGHV framework regions are associated with worse overall survival of chronic lymphocytic leukemia patients.

The mutational status of the variable region of the immunoglobulin heavy chain (IGHV) genes remains the most significant prognostic factor in chronic lymphocytic leukemia (CLL) patients. However, the groups of mutated (M) and unmutated (UM) patients are also heterogeneous, and additional markers are used for a more accurate prognosis. The aim of our work was to determine the prognostic value of the signs of antigen selection determined by BASELINe statistics in M IGHV sequences of CLL patients. Clinical data, IGHV gene configuration, TP53, NOTCH1, SF3B1 mutations were analyzed in 127 CLL patients with M IGHV sequences. The median OS of patients with negative selection in the framework regions (FWRs) of IGHV genes was 120 months compared to 202 month in other CLL patients (P = 0.016). In multivariate Cox regression analysis Binet stage C vs A + B (P < 0.0001), SF3B1 mutations (P < 0.0001), negative selection in the FWRs (HR P = 0.007), and age ≥65 years (P = 0.034) were powerful adverse prognostic factors for OS in CLL patients with M IGHV genes. These preliminary data suggest that the signs of antigen-driven selection may be used as a prognostic factor in CLL patients with M IGHV genes in combination with other markers.

Clinical relevance of TP53 polymorphic genetic variations in chronic lymphocytic leukemia.

OBJECTIVES: To analyze the distribution of single nucleotide polymorphisms (SNPs) in the TP53 gene in chronic lymphocytic leukemia (CLL) patients and to evaluate their associations with clinical behavior of the disease. METHODS: SNPs in exons and parts of adjacent introns of the TP53 gene were analyzed in 235 CLL patients observed during 2005-2012 years. Data on individuals of European descent from the 1000 Genomes Project data set were used as a reference. RESULTS: In the recessive model of inheritance, we found borderline associations between CLL risk and C/C genotype of rs1642785 (p=0.048); G/G genotype of rs2909430 (in men only; p=0.036) and Pro72Pro genotype of rs1042522 (in men only; p=0.045). Risk of CLL was increased also in carriers of rare haplotypes (p=0.0049). Besides, genotypes Pro72Pro of rs1042522, C/C of rs1642785, and G/G of rs2909430 were associated with an increased incidence of TP53 mutations. Median of overall survival in rs1800372 carriers was comparable to that of patients with TP53 mutations. Other evaluated SNPs were not associated with survival. CONCLUSION: Our data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease.

Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial.

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51-0.88; p = .0032). Grade ≥3 adverse events (≤60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00824265).

Health-related quality of life and patient-reported outcomes of ofatumumab plus fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in the COMPLEMENT 2 trial of patients with relapsed CLL.

Chronic lymphocytic leukemia (CLL) is an incurable disease. Quality of life during treatment and periods of subsequent remission is therefore vital. Health-related quality of life (HRQoL) was compared in relapsed CLL during and after treatment with ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 and QLQ-CLL16 were used to assess HRQoL in this open-label, phase 3 study. Improvements in prespecified domains of patient-reported outcomes (Global Health Status [GHS]/HRQoL and B symptom scores) were recorded in both treatment arms after three cycles and were sustained after 18 months of follow-up. The two treatment arms were not significantly different at the nominal 0.05 level for GHS/HRQoL (p = .7278) or B symptoms (p = .5968). Small improvements in quality of life were maintained after therapy. The addition of ofatumumab was without any adverse impact on HRQoL (NCT00824265).

Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia.

We report results of a randomized, phase III study of ofatumumab versus physicians' choice treatment in patients with bulky fludarabine-refractory chronic lymphocytic leukemia and explore extended versus standard-length ofatumumab treatment. Patients (79 ofatumumab, 43 physicians' choice) completed a median 6 (ofatumumab) or 3 (physicians' choice) months' therapy. Ofatumumab-treated patients with stable disease or better were randomized (2:1) to 6 months' extended ofatumumab treatment or observation. Although the study did not meet the primary endpoint of progression-free survival (PFS) by independent review committee (ofatumumab: 5.4 months, physicians' choice: 3.6 months; p = 0.27), median PFS by investigators was significantly longer for ofatumumab versus physicians' choice (7.0 versus 4.5 months; p = 0.003) as was time to next therapy (median 11.5 versus 6.5 months; p = 0.0004). PFS and time to next therapy were significantly longer with ofatumumab extended treatment than observation (p = 0.026 and p = 0.002, respectively; n = 37). The adverse-event profile of long-term ofatumumab administration showed no unexpected findings (Clinicaltrials.gov identifier: NCT01313689).

CD38 gene polymorphism and risk of chronic lymphocytic leukemia.

rs6449182 CD38 gene polymorphism was determined by polymerase chain reaction with restriction of products in 328 chronic lymphocytic leukemia (CLL) patients and 271 age- and sex-matched controls. An association between GG genotype and CLL risk was found in the whole group of patients (OR=2.12; p=0.009) and in patients with unmutated immunoglobulin heavy chain variable genes (OR=2.17; p=0.011) comparing to the controls. In the subgroup of 174 controls with evaluated lipids the genotype distributions in CLL patients and dyslipidemic controls were similar. An association between GG genotype and CLL risk was significant compared to controls without lipids' abnormalities (OR=3.92; p=0.006).

Chronic lymphocytic leukemia patients exposed to ionizing radiation due to the Chernobyl NPP accident--with focus on immunoglobulin heavy chain gene analysis.

Clinical data and immunoglobulin variable heavy chain (IgVH) gene configuration were analyzed in 47 CLL patients, exposed to ionizing radiation (IR) due to Chernobyl NPP accident, and 141 non-exposed patients. Clean-up workers of the second quarter of 1986 (n=19) were picked out as separate group with the highest number of unmutated cases (94.4%), increased usage of IgVH1-69 (33.3%) and IgVH3-21 (16.7%) genes, high frequency of secondary solid tumors (6 cases) and Richter transformation (4 cases). These preliminary data suggest that CLL in the most suffered contingent due to Chernobyl NPP accident might have some specific features.