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1.
Blood ; 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39133931

ABSTRACT

Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, where the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR: 2%) or green (LG: 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC mRNA expression, and the proportion of tumors expressing the dark zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2.

2.
Nat Genet ; 56(8): 1566-1573, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39103649

ABSTRACT

Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.


Subject(s)
Ruminants , Telomere , Telomere/genetics , Animals , Ruminants/genetics , Evolution, Molecular , Genome/genetics , Selection, Genetic , Phylogeny , Diploidy
3.
Nat Med ; 30(6): 1655-1666, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38877116

ABSTRACT

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGESNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGECNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGESNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.


Subject(s)
Circulating Tumor DNA , DNA Copy Number Variations , Machine Learning , Neoplasm, Residual , Tumor Burden , Humans , Circulating Tumor DNA/genetics , Circulating Tumor DNA/blood , Neoplasm, Residual/genetics , Whole Genome Sequencing , Neoplasms/genetics , Neoplasms/blood , Neoplasms/therapy , Neoplasms/pathology , Polymorphism, Single Nucleotide , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Lung Neoplasms/genetics , Lung Neoplasms/blood , Lung Neoplasms/pathology
4.
Leuk Lymphoma ; 65(8): 1044-1054, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38635491

ABSTRACT

In this review we summarize the current evidence describing the management of patients with relapsed/refractory MCL and outline the various novel therapeutics that have been developed over the past two decades. We also describe how overall response rates, complete response rates, duration of responses, and life expectancy have dramatically increased with the introduction of novel therapies, particularly covalent Bruton Tyrosine Kinase inhibitors (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy. The most recent emerging options for patients with progressive disease following BTKi or CAR-T, including non-covalent BTKi, antibody-drug conjugates, Bcl-2 inhibitors, and bispecific antibodies, may further improve response rates and outcomes. Future directions should focus on identifying the best sequencing and/or combinations of the increasingly available treatment options while prioritizing strategies with curative potential.


Subject(s)
Disease Management , Drug Resistance, Neoplasm , Immunotherapy, Adoptive , Lymphoma, Mantle-Cell , Protein Kinase Inhibitors , Humans , Lymphoma, Mantle-Cell/therapy , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Immunotherapy, Adoptive/methods , Protein Kinase Inhibitors/therapeutic use , Neoplasm Recurrence, Local/pathology , Combined Modality Therapy/methods , Molecular Targeted Therapy/methods , Treatment Outcome , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
5.
Br J Haematol ; 205(2): 534-541, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38632873

ABSTRACT

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatment and investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Stomach Neoplasms , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Female , Middle Aged , Aged , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/therapy , Stomach Neoplasms/pathology , Adult , Aged, 80 and over , Rituximab/therapeutic use , Rituximab/administration & dosage , Vincristine/therapeutic use , Vincristine/administration & dosage , Prednisone/therapeutic use , Prednisone/administration & dosage , Cyclophosphamide/therapeutic use , Cyclophosphamide/administration & dosage , Doxorubicin/therapeutic use , Doxorubicin/administration & dosage , Helicobacter Infections/complications , Helicobacter Infections/drug therapy , Helicobacter pylori , Positron-Emission Tomography , Lymphoma, Non-Hodgkin
6.
Haematologica ; 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38654662

ABSTRACT

Not available.

7.
NPJ Breast Cancer ; 10(1): 3, 2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38182588

ABSTRACT

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

8.
Br J Haematol ; 204(1): 160-170, 2024 01.
Article in English | MEDLINE | ID: mdl-37881141

ABSTRACT

Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.


Subject(s)
Lymphoma, Mantle-Cell , Adult , Humans , Aged , Lymphoma, Mantle-Cell/pathology , Rituximab/adverse effects , Bendamustine Hydrochloride/therapeutic use , Biomarkers , Prognosis , Antineoplastic Combined Chemotherapy Protocols/adverse effects
9.
Leuk Lymphoma ; 65(3): 346-352, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38156444

ABSTRACT

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.


Subject(s)
Waldenstrom Macroglobulinemia , Humans , Rituximab/adverse effects , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/etiology , Bendamustine Hydrochloride/adverse effects , Vincristine/adverse effects , Prednisone/adverse effects , Cyclophosphamide/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects
10.
Blood Adv ; 7(24): 7393-7401, 2023 12 26.
Article in English | MEDLINE | ID: mdl-37874912

ABSTRACT

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.


Subject(s)
Lymphoma, Mantle-Cell , Adult , Humans , Lymphoma, Mantle-Cell/therapy , Lymphoma, Mantle-Cell/drug therapy , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Risk Assessment , Progression-Free Survival
11.
J Clin Oncol ; 41(35): 5376-5387, 2023 Dec 10.
Article in English | MEDLINE | ID: mdl-37797284

ABSTRACT

PURPOSE: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, B-Cell , Methotrexate , Adolescent , Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Young Adult , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/prevention & control , Lymphoma, B-Cell/drug therapy , Methotrexate/administration & dosage , Retrospective Studies
12.
J Clin Oncol ; 41(25): 4164-4177, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37319384

ABSTRACT

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. PATIENTS AND METHODS: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. RESULTS: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. CONCLUSION: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse , Humans , Neoplasm Recurrence, Local/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Chronic Disease , Transplantation, Autologous , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
13.
Blood Adv ; 7(16): 4576-4585, 2023 08 22.
Article in English | MEDLINE | ID: mdl-37307169

ABSTRACT

Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton's tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell , Adult , Humans , Lymphoma, Mantle-Cell/pathology , Ki-67 Antigen , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prognosis
14.
Leuk Lymphoma ; 64(6): 1129-1138, 2023 06.
Article in English | MEDLINE | ID: mdl-37086469

ABSTRACT

Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n = 35) and relapsed/refractory (R/R, n = 335) CLL between 2014-2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , British Columbia/epidemiology , Piperidines/therapeutic use , Adenine
15.
medRxiv ; 2023 Mar 08.
Article in English | MEDLINE | ID: mdl-36945587

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease.

16.
Haematologica ; 108(9): 2444-2453, 2023 09 01.
Article in English | MEDLINE | ID: mdl-36815381

ABSTRACT

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.


Subject(s)
Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Humans , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/drug therapy , Prospective Studies , Neoplasm Recurrence, Local , Lymphoma, Non-Hodgkin/pathology , Prognosis , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy
17.
J Clin Oncol ; 41(3): 541-554, 2023 01 20.
Article in English | MEDLINE | ID: mdl-35763708

ABSTRACT

PURPOSE: Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR). METHODS: Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of 1,168 patients from 12 academic centers. RESULTS: Among 3,614 patients with documented 1L treatment, BR was the most used. Among 1,265 patients age < 65 years, 30.5% received cytarabine-based induction and 23.5% received ASCT. There was no significant association between ASCT and real-world time to next treatment (hazard ratio [HR], 0.84; 95% CI, 0.68 to 1.03; P = .10) or overall survival (HR, 0.86; 95% CI, 0.63 to 1.18; P = .4) among ASCT-eligible patients. Among MR-eligible patients, MR after BR versus BR alone was associated with a longer real-world time to next treatment (HR, 1.96; 95% CI, 1.61 to 2.38; P < .001) and overall survival (HR, 1.51; 95% CI, 1.19 to 1.92; P < .001). The efficacy findings were consistent in the validation cohort. CONCLUSION: In this large cohort of patients treated primarily in the US community setting, only one in four young patients received cytarabine or ASCT consolidation, suggesting the need to develop treatments that can be delivered effectively in routine clinical practice. Together with the validation cohort, data support future clinical trials exploring regimens without ASCT consolidation in young patients, whereas MR should be considered for patients after 1L BR and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell , Adult , Humans , Aged , Rituximab , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Treatment Outcome , Cyclophosphamide , Cytarabine , Transplantation, Autologous , Hematopoietic Stem Cell Transplantation/methods
18.
Blood ; 141(20): 2493-2507, 2023 05 18.
Article in English | MEDLINE | ID: mdl-36302166

ABSTRACT

Molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) underlies the variable outcomes achieved with immunochemotherapy. However, outcomes of gene expression profiling (GEP)-defined molecular subgroups in a real-world DLBCL population remain unknown. Here we examined the prevalence and outcomes of molecular subgroups in an unselected population of 1149 patients with de novo DLBCL in British Columbia, Canada. Evaluable biopsies were profiled by fluorescence in situ hybridization (FISH), immunohistochemistry, and digital GEP to assign cell-of-origin and the so-called "double-hit signature" (DHITsig)-a signature originally described as being characteristic for high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). DHITsig was expressed in 21% of 431 germinal center B-cell-like (GCB)-DLBCL and all 55 Burkitt lymphomas examined. Reflecting this latter finding, DHITsig has been renamed the "dark zone signature" (DZsig). DZsigpos-DLBCL, non-DZsigpos GCB-DLBCL and activated B-cell-like (ABC)-DLBCL were associated with a 2 year overall survival of 57%, 89%, and 71%, respectively. 62% of DZsigpos tumors were negative for HGBCL-DH-BCL2 by FISH, but were associated with outcomes similar to HGBCL-DH-BCL2. A small group of HGBCL-DH-BCL2 that lacked DZsig expression had different molecular features compared with DZsig-expressing HGBCL-DH-BCL2 and were associated with favorable outcomes comparable to DLBCL, not otherwise specified. DZsigpos and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI) than GCB-DLBCL, with this metric being associated with outcome. In conclusion, DZsig expression extends beyond HGBCL-DH-BCL2 and captures a poor-prognosis DLBCL subgroup with short DTI, including patients unidentifiable by routine FISH testing, that should be considered for treatment intensification or novel therapies in prospective trials.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Proto-Oncogene Proteins c-myc , Humans , In Situ Hybridization, Fluorescence , Prospective Studies , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, Large B-Cell, Diffuse/genetics , Prognosis
19.
Heliyon ; 8(12): e12140, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36506364

ABSTRACT

Objective: We evaluated survival outcomes for patients with cancer and COVID-19 in this population-based study. Methods: A total of 631 patients who tested positive for severe acute respiratory syndrome coronavirus 2 and were seen at BC Cancer between 03/03/2020 and 01/21/2021 were included, of whom 506 had a diagnosis of cancer and PCR-confirmed positive test for coronavirus disease 2019. Patient clinical characteristics were retrospectively reviewed and the influence of demographic data, cancer diagnosis, comorbidities, and anticancer treatment(s) on survival following severe acute respiratory syndrome coronavirus 2 infection were analyzed. Results: Age ≥65 years (Hazard Ratio [HR] 4.77, 95% Confidence Interval [CI] 2.72-8.35, P < 0.0001), those with Eastern Cooperative Oncology Group Performance Status ≥2 (HR 8.36, 95% CI 2.89-24.16, P < 0.0001), hypertension (HR 3.17, 95% CI 1.77-5.66, P < 0.0001), and metastatic/advanced stage (HR 3.70, 95% CI 1.77-7.73, P < 0.0001) were associated with worse coronavirus disease 2019 specific survival outcomes following severe acute respiratory syndrome coronavirus 2 infection. Patients with lung cancer had the highest 30-day COVID-19 specific mortality (25.0%), followed by genitourinary (18.1%), gastrointestinal (16.0%), and other cancer types (<10.0%). Patients with the highest 30-day coronavirus disease 2019 specific mortality according to treatment type were those on chemotherapy (23.0%), rituximab (22.2%), and immunotherapy (16.7%) while patients on hormonal treatments (2.2%) had better survival outcomes (P = 0.041) compared to those on other anticancer treatments. Conclusion: This study provides further evidence that patients with cancer are at increased risk of mortality from coronavirus disease 2019 and emphasizes the need for vaccination.

20.
Viruses ; 14(11)2022 11 19.
Article in English | MEDLINE | ID: mdl-36423171

ABSTRACT

Infectious Bronchitis (IB) is a respiratory disease caused by a highly variable Gammacoronavirus, which generates a negative impact on poultry health worldwide. GI-11 and GI-16 lineages have been identified in South America based on Infectious Bronchitis virus (IBV) partial S1 sequences. However, full genome sequence information is limited. In this study we report, for the first time, the whole-genome sequence of IBV from Colombia. Seven IBV isolates obtained during 2012 and 2013 from farms with respiratory disease compatible with IB were selected and the complete genome sequence was obtained by NGS. According to S1 sequence phylogenetic analysis, six isolates belong to lineage GI-1 and one to lineage GVI-1. When whole genome was analyzed, five isolates were related to the vaccine strain Ma5 2016 and two showed mosaic genomes. Results from complete S1 sequence analysis provides further support for the hypothesis that GVI-1, considered a geographically confined lineage in Asia, could have originated in Colombia. Complete genome information reported in this research allow a deeper understanding of the phylogenetic evolution of variants and the recombination events between strains that are circulating worldwide, contributing to the knowledge of coronavirus in Latin America and the world.


Subject(s)
Infectious bronchitis virus , Poultry Diseases , Animals , Phylogeny , Colombia/epidemiology , Poultry Diseases/prevention & control , Chickens , Genome, Viral
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