Our understanding of familial predisposition to lymphoma (collectively defined as non-Hodgkin lymphoma NHL, Hodgkin lymphoma HL, and chronic lymphocytic leukemia CLL) outside of rare hereditary ...syndromes has progressed rapidly during the last decade. First-degree relatives of NHL, HL, and CLL patients have an ∼1.7-fold, 3.1-fold, and 8.5-fold elevated risk of developing NHL, HL, and CLL, respectively. These familial risks are elevated for multiple lymphoma subtypes and do not appear to be confounded by nongenetic risk factors, suggesting at least some shared genetic etiology across the lymphoma subtypes. However, a family history of a specific subtype is most strongly associated with risk for that subtype, supporting subtype-specific genetic factors. Although candidate gene studies have had limited success in identifying susceptibility loci, genome-wide association studies (GWAS) have successfully identified 67 single nucleotide polymorphisms from 41 loci, predominately associated with specific subtypes. In general, these GWAS-discovered loci are common (minor allele frequency >5%), have small effect sizes (odds ratios, 0.60-2.0), and are of largely unknown function. The relatively low incidence of lymphoma, modest familial risk, and the lack of a screening test and associated intervention, all argue against active clinical surveillance for lymphoma in affected families at this time.
Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era.
We pooled two cohorts of newly diagnosed ...patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes.
Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis 25.4% v 16.6%) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis.
Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.
The natural history, prognostication and optimal treatment of Richter transformation developed from chronic lymphocytic leukemia (CLL) are not well defined. We report the clinical characteristics and ...outcomes of a large series of biopsy-confirmed Richter transformation (diffuse large B-cell lymphoma or high grade B-cell lymphoma, n=204) cases diagnosed from 1993 to 2018. After a median follow up of 67.0 months, the median overall survival (OS) was 12.0 months. Patients who received no prior treatment for CLL had significantly better OS (median 46.3
7.8 months;
<0.001). Patients with elevated lactate dehydrogenase (median 6.2
39.9 months;
<0.0001) or
disruption (median 8.3
12.8 months;
=0.046) had worse OS than those without. Immunoglobulin heavy chain variable region gene mutation, cell of origin, Myc/Bcl-2 double expression and
double-/triple-hit status were not associated with OS. In multivariable Cox regression, elevated lactate dehydrogenase Hazard ratio (HR) 2.3, 95% Confidence Interval (CI): 1.3-4.1;
=0.01, prior CLL treatment (HR 2.0, 95%CI: 1.2-3.5;
=0.01), and older age (HR 1.03, 95%CI: 1.01-1.05;
=0.01) were associated with worse OS. Twenty-four (12%) patients underwent stem cell transplant (20 autologous and 4 allogeneic), and had a median post-transplant survival of 55.4 months. In conclusion, the overall outcome of Richter transformation is poor. Richter transformation developed in patients with untreated CLL has significantly better survival. Stem cell transplant may benefit select patients.
Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cells in the blood and monoclonal B-cell lymphocytosis (MBL) is a precursor state to CLL. This narrative review provides an overview of the ...genetic studies that identified 43 common variants associated with risk of CLL among individuals of European ancestry. Emerging studies found that ∼50% of these variants are associated with MBL risk. Moreover, the polygenic risk score (PRS) calculated from these CLL variants has been shown to be a robust predictor for both CLL and MBL risk among European ancestry individuals but a weak predictor among African ancestry individuals. By summarizing these genetic studies, we conclude that additional studies are needed in other race/ethnic populations to identify race-specific susceptibility variants, that functional studies are needed to validate the biological mechanisms of the variants, and that the clinical utility of the PRS is limited until preventive strategies for CLL are developed.
In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical ...models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and β2-microglobulin β2m) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (β2m > 3 mg/L), low (β2m ≤ 3 mg/L without bone marrow involvement), and intermediate (β2m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively (P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively (P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.
•In FL, no prognostic index has been built based solely on a large cohort of patients treated with initial immunochemotherapy.•The PRIMA-PI is a simplified index based on β2m and bone marrow involvement for patients treated with immunochemotherapy.
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Some patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively ...followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell–like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio HR = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.
•Concurrent DLBCL and FL has a similar outcome to that of GCB DLBCL; concurrent other indolent lymphoma does not worsen the DLBCL outcome.•Inclusion of patients with concurrent DLBCL and indolent lymphoma should be considered in clinical trials of newly diagnosed DLBCL.
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Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 ...predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC.
Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations.
Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations.
Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.
Background Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to ...determine whether common DNA variation influences antidepressant response. Methods Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification. Results We identified three SNPs associated with response with p values less than 1 × 10−5 near the UBE3C gene (rs6966038, p = 4.65 × 10−7 ), another 100 kb away from BMP7 (rs6127921, p = 3.45 × 10−6 ), and a third that is intronic in the RORA gene (rs809736, p = 8.19 × 10−6 ). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values ≤ .0001 for the response and remission phenotypes. Conclusions Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.
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