Search

Summary: Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries but very rare in Asia. Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 194 patients with CLL were analysed to determine the ethnic difference in genetic abnormalities. Mutated IGHV was detected in 71·2% of Taiwanese CLL and IGHV3‐23 was the most frequently used gene. Stereotyped BCR was present in 18·3% with subset 8 being the most frequent. All cases with subset 8 belonged to IGHV 4‐39 and were exclusively associated with un‐mutated IGHV and poor outcome. Mutation frequencies of SF3B1 (9·7%), NOTCH1 (8·6%), BIRC3 (1·1%), ATM (16·9%) or TP53 (8·1%), and frequencies of cytogenetic abnormalities including trisomy 12 (18·6%), del(17p) (10·4%), del(13q) (43·7%) and IGH translocation (10·1%) were comparable to those reported from Western countries, except del(11q) (6·9%) which was lower in our patients. Patients with un‐mutated IGHV, subset 8, disrupted TP53, trisomy 12, and SF3B1 mutations had a worse outcome compared to patients without these mutations. In conclusion, IGHV3‐23 usage, stereotyped subset 8 and lower frequency of del(11q) show an ethnicity‐dependent association in Taiwanese CLL patients. [ABSTRACT FROM AUTHOR]

Summary: The treatment of low‐tumour burden follicular lymphoma (LTBFL) remains a challenge. Rituximab‐based strategies may be improved by adding chemotherapy. This Lymphoma Study Association multicentre phase II study assessed rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score ≥2. Induction comprised 4 weekly cycles of rituximab 375 mg/m2 intravenously combined with 2 cycles of bendamustine 90 mg/m2 days 1–2 with a 28‐day interval, followed by twelve cycles of 375 mg/m2 rituximab maintenance therapy every 8 weeks. The primary endpoint was complete response (CR)/unconfirmed CR (CRu), at 12 weeks. Median age was 67·4 years and median FLIPI was 3. Ultimately, 18 patients (29%) had high tumour burden according to Groupe d'Etude des Lymphomes Folliculaires criteria. The 12‐week CR/CRu rate was 54·0% and the overall response rate was 93·7%. Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm). Progression‐free survival was 85·4% at 24 months. In LTBFL patients with FLIPI ≥2, two cycles of rituximab and bendamustine result in a CR rate of 54·0%. However, the treatment‐related deaths observed do not allow this regimen to be recommended for LTBFL patients aged over 60 years. EudraCT: 2010‐020757‐14; ClinicalTrials.gov: NCT01313611. [ABSTRACT FROM AUTHOR]

Chronic Lymphocytic Leukaemia (CLL) is a heterogeneous disease with a clinical course dependent on cytogenetic features. However, in 15–20% of cases both chromosome banding and fluorescence in situ hybridisation analyses do not show any kind of abnormality. With the aim to identify dependable molecular prognostic factors in this subgroup, we performed a comprehensive analysis on 171 patients including genomic arrays (comparative genomic hybridisation and single nucleotide polymorphism), immunoglobulin heavy chain variable region genes (IGHV) status, flow cytometry and targeted sequencing. Genomic arrays detected 73 aberrations in 39 patients (23%). Most frequently, patients had 1 aberration (25/171; 15%), while 14 patients (8%) had at least 2 aberrations. IGHV status was unmutated in 53/171 (31%) patients. SF3B1 was the most frequently mutated gene (26/171 patients; 15%), followed by NOTCH1 (15/171; 9%). At univariate analysis, an adverse impact on time to treatment (TTT) was evident for SF3B1 mutations, higher white blood cell count, higher CLL cells percentage by flow cytometry, CD38 positivity, IGHV unmutated status and at least 2 genomic array abnormalities. Of these, SF3B1 mutations, CLL cells percentage, IGHV unmutated status and number of genomic array aberrations maintained their impact in multivariate analysis. In conclusion, by integrating genomic and molecular data, we identified patients at higher risk for treatment need. [ABSTRACT FROM AUTHOR]

Summary: Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL‐NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL‐NOS were retained for study. At a median follow‐up of 46 months, the median overall survival (OS) and progression‐free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3‐year OS of 76% [95% confidence interval 61–88], 43% [35–51], and 11% [4–21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes. [ABSTRACT FROM AUTHOR]

An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia ( CLL) and CLL-like monoclonal B-cell lymphocytosis ( MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL-like ( n = 84) and CLL ( n = 139) clones with stereotyped ( n = 32) versus non-stereotyped ( n = 191) immunoglobulin heavy chain variable region ( IGHV) amino acid sequences. Overall, stereotyped CLL-like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower I GHV 3 gene family usage ( P = 0·03), longer IGHV complementary determining region 3 ( HCDR3) sequences ( P = 0·007) and unmutated IGHV ( P < 0·001) versus non-stereotyped clones. Whilst the overall size of the stereotyped B-cell clones in peripheral blood did not appear to be associated with the CLL-related cytogenetic profile of B-cells ( P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome ( MDS)-associated immunophenotypes on peripheral blood neutrophils and/or monocytes ( P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non-stereotyped CLL and CLL-like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis. [ABSTRACT FROM AUTHOR]

NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia ( CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis ( MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O- CLL1 multicentre trial. The NOTCH1 c.7541_7542del CT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]