High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of ...HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.
We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.
We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested.
We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.
A number of novel therapies are under investigation in relapsed or refractory peripheral T-cell lymphoma (PTCL); however, their relative impact on outcome is unknown. We examined the survival of ...patients with PTCL after relapse or progression in the absence of hematopoietic stem-cell transplantation and explored factors influencing survival. The three most common subtypes encountered in North America were evaluated: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL; anaplastic lymphoma kinase ALK positive and ALK negative.
After exclusions, 153 patients were analyzed (PTCL-NOS, n = 79 52%; AITL, n = 38 25%; ALK-positive ALCL, n = 11 7%; ALK-negative ALCL, n = 27 16%; including ALK status unknown, n = 1).
Median time from initial diagnosis to relapse or progression after primary therapy was 6.7 months, and median age at relapse was 66 years (ALK-positive ALCL, 39 years). Median overall survival (OS) and median progression-free survival (PFS) after relapse or progression (second PFS) were 5.5 and 3.1 months, respectively, and were only marginally better in patients who received chemotherapy at relapse (n = 89 58%; 6.5 and 3.7 months, respectively). Patients with good performance status (PS) of 0 or 1 (n = 47) at relapse who received chemotherapy had a more favorable OS (P < .001; median OS, 13.7 months) and PFS (P = .006; median second PFS, 5.0 months), which remained significant in multivariate analysis (OS: hazard ratio HR, 2.09; P = .002; second PFS: HR, 1.66; P = .030).
Most patients with relapsed or refractory PTCL have poor outcomes with short survival. Select patients with good PS have more favorable outcomes with standard chemotherapy.
Despite widespread use of bendamustine and rituximab (BR) as frontline therapy for advanced-stage follicular lymphoma (FL), little is known about the risk of early progression or incidence of ...histological transformation. We performed a retrospective analysis of a population-based cohort of 296 patients with advanced-stage FL treated with frontline BR and maintenance rituximab. As previously demonstrated, outcomes with this regimen are excellent, with 2-year event-free survival estimated at 85% (95% confidence interval 95% CI, 80-89) and 2-year overall survival 92% (95% CI, 88-95). Progression of disease within 24 months (POD24) occurred in 13% of patients and was associated with a significantly inferior outcome with 2-year overall survival of 38% (95% CI, 20-55). The only significant risk factor for POD24 at baseline was elevated lactate dehydrogenase (P < .001). Importantly, the majority of POD24 patients (76%) had transformed disease. Compared with a historical cohort treated with rituximab, cyclophosphamide, vincristine, and prednisone, event-free survival has improved and the risk of POD24 has decreased, but a higher proportion of patients with POD24 harbor transformation. The overall incidence of transformation appears unchanged. The presence of occult or early transformation is the main driver of POD24 in FL patients treated with frontline BR. Identification of biomarkers and improved management strategies for transformation will be crucial to improving outcomes.
•Frontline bendamustine and rituximab in advanced stage FL has marked efficacy in this population-based analysis.•Early progression within 24 months is associated with poor outcome after BR; however, the majority of patients have transformed lymphoma.
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Crovalimab, a novel C5 inhibitor, allows for low‐volume, every‐4‐ week, subcutaneous self‐administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus ...eculizumab in C5 inhibitor‐experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight‐based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT‐Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty‐nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24‐week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab‐treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab‐treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor‐naive patients, these data support crovalimab's favorable benefit–risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.
Phase 3 randomized COMMODORE 1 trial: crovalimab vs eculizumab in complement inhibitor‐experienced patients with PNH.
Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky ...disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative PET-NEG) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.
•Patients with advanced DLBCL who have a negative EOT PET scan have an excellent prognosis without RT.•PET-POS patients with nonprogressing disease given RT at EOT have better-than-expected outcomes, providing rationale for this approach.
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Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called “double-hit ...lymphoma,” has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS–International Prognostic Index CNS-IPI), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non–germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC+ BCL2+ DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.
•Dual expression of MYC and BCL2 is associated with an increased risk of CNS relapse in DLBCL treated with R-CHOP.
Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent ...need to understand the clinical implications of HRD signatures. Whereas
mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.
In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict
status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).
HRDetect predicted
status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89;
= 0.006) with the same optimal threshold, even after adjusting for
mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (
= 0.0003) and 1.3-year extended median OS (
= 0.04).
Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of
mutation status and hope this work will guide the development of clinical trials.
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Summary
Grade 3B follicular lymphoma (G3B FL) is rare, accounting for only 5–10% of FLs. Not only has it been routinely excluded from clinical trials, but data published on diagnosis, outcomes, ...choice of therapies and role of imaging are conflicting. With the advent of increasingly diverse treatment options for low‐grade (G1–3A) FL, and the molecular subcategorisation of high‐grade B‐cell lymphomas, characterisation and treatment of G3B FL is ever more important as extrapolation of data becomes more difficult. New data have emerged exploring unique genetic characteristics, specific features on positron emission tomography imaging, choice of therapy, and outcomes of G3B FL in the current era. The present review will summarise and appraise these new data, and offer recommendations based on current evidence.
The problem of predicting a ship’s form factor and associated scale effects has been subject to many investigations in recent years. In this study, an attempt is made to investigate whether the form ...factor is influenced by a change in the ship’s speed by numerically modelling a geosim series of the KCS hull form by means of a RANS solver. The turbulence dependence of the problem is also studied by altering the closure model among three widely used approaches (the k-ω, k-ω SST, and k-ε models). The results show that at very low speeds (Froude numbers in the range of 0.02–0.06) the numerical model predicts changes in the form factor of a ship between 10% and 20%, depending on the turbulence model and scale factor choices. As the speed is increased further, the form factor exhibits little change, usually in the range of 1% or less. Simulations where the Reynolds number is changed by approximately two orders of magnitude, achieved by altering the value of viscosity, confirmed that the form factor can be considered Froude-dependent only for low speeds, predicting essentially identical values when high speed cases are considered.
•The scale effect on a ship’s form factor is investigated numerically.•Effects of scale factor and speed are considered using linear and viscous scaling.•Turbulence dependence is found to be of greater importance than any other parameter.•Results reveal a Froude number dependence at low speeds.
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