Summary
There are limited reports that baseline peripheral absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute lymphocyte count (ALC) and serum β2‐microglobulin level ...independently predict survival in patients with diffuse large B‐cell lymphoma (DLBCL). To confirm these findings, we analysed these parameters together with components of the International Prognostic Index (IPI) in patients with newly‐diagnosed DLBCL. We evaluated baseline clinical features for their ability to predict survival in 817 newly diagnosed, previously untreated patients with DLBCL who received frontline treatments between October 2001 and December 2011. The median age at diagnosis was 58 years. Multivariate analysis identified elevated baseline ANC (P = 0·036), AMC (P = 0·028) and serum β2‐microglobulin level (P < 0·001), poor performance status (P < 0·001) and high number of extranodal disease sites (P = 0·0497) as independent unfavourable predictors of OS; serum β2‐microglobulin level was the strongest predictor of survival outcomes among all the parameters. High baseline serum β2‐microglobulin, ANC and AMC levels are independent prognostic factors for short overall survival in patients with newly diagnosed DLBCL. Our new model, based on the above five parameters, better stratifies patients into various risk categories than the IPI for newly diagnosed DLBCL.
Abstract Background Cancer patients are at increased risk of venous thromboembolism; however, the incidence and risk factors for venous thromboembolism in lymphoma patients are not well defined. ...Methods Medical records of 422 newly referred lymphoma patients at our institution were reviewed over 2-year follow-up for all venous thromboembolism events and potential risk factors. Multivariate logistic regression model was used to identify risk factors predictive of venous thromboembolism. Results Among 422 patients, 72 (17.1 %) had 80 new episodes of venous thromboembolism: 59 had deep vein thrombosis, 17 had pulmonary embolism, and 4 had combined deep vein thrombosis and pulmonary embolism. Only 18 of 422 patients (4.3%) were on thromboprophylaxis at baseline. Interestingly, 64% (51/80) of the episodes occurred by the third cycle of chemotherapy. By multivariate logistic regression, female sex (odds ratio OR 3.51, P = .001), high hemoglobin (OR 1.26, P = .020), high serum creatinine (OR 3.23, P = .009), and doxorubicin- or methotrexate-based chemotherapy (OR 3.47, P = 0.003) were important risk factors for new venous thromboembolism. Conclusions Lymphoma patients are at high risk for venous thromboembolism in the initial cycles of chemotherapy; the risk was higher for women, patients with elevated hemoglobin or creatinine, or those receiving doxorubicin or methotrexate. Future studies might focus on validation of these risk factors to identify the high-risk cohort and the potential role of thromboprophylaxis, particularly during initial cycles of chemotherapy.
Observation until the development of symptoms, or ‘watch and wait’, has long been a proposed management technique for patients with indolent lymphomas. However, investigators have found that there ...may be differences in outcomes for various patient groups according to histopathology, clinical features of the disease, biologic factors as yet to be fully recognized, and type of initial therapy offered. Recently, investigators from the UK National Cancer Research Institute reported that progression-free results were significantly improved when asymptomatic patients with indolent follicular lymphomas received initial therapy with single-agent rituximab rather than when they underwent observation alone. These results were further improved when they received maintenance rituximab. Time to chemotherapy was also longer when these patients received initial therapy with rituximab, thereby delaying the need for such treatment. However, overall survival rates for patients who received rituximab as initial therapy were similar to those for patients who underwent initial ‘watch and wait’. Future studies should concentrate on risks of such management, including cost effectiveness of such treatments and development of resistance to subsequent therapies.
Observation until the development of symptoms, or 'watch and wait', has long been a proposed management technique for patients with indolent lymphomas. However, investigators have found that there ...may be differences in outcomes for various patient groups according to histopathology, clinical features of the disease, biologic factors as yet to be fully recognized, and type of initial therapy offered. Recently, investigators from the UK National Cancer Research Institute reported that progression-free results were significantly improved when asymptomatic patients with indolent follicular lymphomas received initial therapy with single-agent rituximab rather than when they underwent observation alone. These results were further improved when they received maintenance rituximab. Time to chemotherapy was also longer when these patients received initial therapy with rituximab, thereby delaying the need for such treatment. However, overall survival rates for patients who received rituximab as initial therapy were similar to those for patients who underwent initial 'watch and wait'. Future studies should concentrate on risks of such management, including cost effectiveness of such treatments and development of resistance to subsequent therapies.
Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured ...with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients who had disease relapse, were included in the analysis. At a median follow-up time of 32.2 months, the median progression-free and overall survival durations were not reached. Our findings suggest that a high density of PD-L1
macrophages is associated with favorable features, such as early disease stage and the absence of B-symptoms, and indicate that a high percentage of PD-L1
macrophages and high densities of CD30
PD-L1
cells and CD30
cells might be associated with a lower risk of relapse within 12 months of therapy initiation. Further studies are needed to develop a biomarker signature predictive of treatment response with therapeutic consequences for patients with newly diagnosed PMBCL.
This phase-I/phase-II study evaluated panobinostat in combination with ifosfamide, carboplatin, etoposide (P-ICE) in relapsed/refractory classical Hodgkin lymphoma. During phase I, panobinostat was ...given daily on Monday/Wednesday/Friday starting one week prior to Cycle 1 (C1) of ICE and during two weeks of C1-2 of ICE (Schedule A). No DLT was observed at 30 mg. However, frequent (84%) grade-4 thrombocytopenia during second week prompted us to omit the second week of panobinostat 30 mg (Schedule B) for phase II, where this regimen was compared to ICE.
In the randomized phase-II study, CR was seen in 9/11 (82%) and 8/12 (67%) for P-ICE and ICE, respectively (p = .64). Grade-4 neutropenia (55% vs. 8%) and thrombocytopenia (100% vs. 33%) were more common in P-ICE. In summary, combination therapy using panobinostat produced high CR rate at the cost of greater bone marrow toxicity. Investigation of panobinostat with less myelosuppressive agents is of interest.
Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse ...tumor and immune cell populations of FL and identified major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T cells. This provides a classification framework of the FL microenvironment in association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHCII expression.
We have characterized the FL-infiltrating T cells, identified cytotoxic CD4 T cells as an important component that is associated with tumor cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T cells that differed from FLs with normal versus low MHC expression. See related commentary by Melnick, p. 374. This article is highlighted in the In This Issue feature, p. 369.
This study investigated the use of a nonablative conditioning regimen to decrease toxicity and achieve engraftment of an allogeneic blood stem cell transplant, allowing a graft-versus-malignancy ...effect to occur. All patients had follicular or small cell lymphocytic lymphoma after relapse from a prior response to conventional chemotherapy. Patients received a preparative regimen of fludarabine (25 mg/m2 given daily for 5 days or 30 mg/m2daily for 3 days) and intravenous cyclophosphamide (1 g/m2given daily for 2 days or 750 mg/m2 daily for 3 days). Nine patients received rituximab in addition to the chemotherapy. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Twenty patients were studied; their median age was 51 years. Twelve were in complete remission (CR) at transplantation. All patients achieved engraftment of donor cells. The median number of days with severe neutropenia was 6. Only 2 patients required more than one platelet transfusion. The cumulative incidence of acute grade II to IV GVHD was 20%. Only one patient developed acute GVHD of greater than grade II. All patients achieved CR. None have had a relapse of disease, with a median follow-up period of 21 months. The actuarial probability of being alive and in remission at 2 years was 84% (95% confidence interval, 57%-94%). Nonablative chemotherapy with fludarabine/cyclophosphamide followed by allogeneic stem cell transplantation is a promising therapy for indolent lymphoma with minimal toxicity and myelosuppression. Further studies are warranted to compare nonablative allogeneic hematopoietic transplantation with alternative treatment strategies.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted ...next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUT
high
) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUT
high
with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUT
high
was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUT
high
in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.
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