Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma.

Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard-of-care CAR T-cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B-cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi-cel) at our institution. The median change in absolute lymphocyte count from pre-LD to time of axi-cel infusion was -0.6×109 /L in bendamustine cohort and -0.7×109 /L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%-91.4%)/48.1% (95% CI: 28.7%-68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%-91.4%)/50.0% (95% CI: 34.2%-65.8%) among Flu/Cy cohort. Six-month progression-free survival were 43.8% (95% CI: 24.7%-61.3%) and 55.6% (95% CI: 39.0%-69.3%) in bendamustine and Flu/Cy cohorts, while 6-month overall survival were 81.5% (95% CI: 61.1%-91.8%) and 90.4% (95% CI: 76.4%-96.3%), respectively. Relative to Flu/Cy-treated patients, bendamustine-treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7-2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5-5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy-treated patients experienced grade ≥3 neutropenia compared with bendamustine-treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi-cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi-cel.

A PET in a time of need: toward early PET-adapted therapy in DLBCL in first relapse.

Salvage chemotherapy and autologous stem cell transplant remain a standard of care in the management of diffuse large B cell lymphoma (DLBCL) at first relapse. However, this paradigm is increasingly being challenged by novel immunotherapies, such as chimeric antigen receptor T-cells (CART-cells). Traditional positron emission tomography-based (PET) prognostication takes place after salvage and before autologous stem cell transplant (ASCT), and while useful, for many patients this information comes too late and at the expense of unnecessary toxicity. In this edition of Leukemia & Lymphoma, two groups present their findings on the use of early quantitative PET markers and the correlation with outcomes in patients embarking on second line salvage chemotherapy. These approaches have the potential to better identify patients who are destined for treatment failure and help guide appropriate sequencing of alternative therapies or the development of PET-adapted clinical trials.

Primary gastric non-Hodgkin lymphomas: Recent advances regarding disease pathogenesis and treatment.

Primary gastric lymphomas (PGLs) are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly. Their main histological types are diffuse large B-cell lymphoma (DLBCL) or mucosa-associated lymphoma tissue. PGL has been one of the main fields of clinical research of our group in recent years. Although gastric DLBCLs are frequent, sufficient data to guide optimal care are scarce. Until today, a multidisciplinary approach has been applied, including chemotherapy, surgery, radiotherapy or a combination of these treatments. In this minireview article, we provide an overview of the clinical manifestations, diagnosis and staging of these diseases, along with their molecular pathogenesis and the most important related clinical published series. We then discuss the scientific gaps, perils and pitfalls that exist regarding the aforementioned studies, in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies. Aiming to fill this gap, we retrospectively evaluated the trends in clinical presentation, management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014. The study cohort was divided into two subgroups, comparing the main 2 therapeutic options [cyclophosphamide doxorubicin vincristine prednisone (CHOP) vs rituximab-CHOP (R-CHOP)]. A better outcome with immunochemotherapy (R-CHOP) was observed. In the next 2 mo, we will present the update of our study with the same basic conclusion.

Patterns and Predictors of Failure in Recurrent or Refractory Large B-Cell Lymphomas After Chimeric Antigen Receptor T-Cell Therapy.

PURPOSE: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies. METHODS AND MATERIALS: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression. RESULTS: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02). CONCLUSIONS: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.

Potential of the tumor­derived extracellular vesicles carrying the miR­125b­5p target TNFAIP3 in reducing the sensitivity of diffuse large B cell lymphoma to rituximab.

Diffuse large B­cell lymphoma (DLBCL) is the most common and aggressive form of non­Hodgkin's lymphoma. Extracellular vesicles (EVs) derived from cancer cells are known to modify the tumor microenvironment. The aim of the present study was to investigate the role of miR­125b­3p carried by EVs in DLBCL in vitro and in vivo. TNFAIP3 expression in patient lesions was measured and the upstream miR that regulates TNFAIP3 was predicted using the starBase database. EVs were isolated from DLBCL cells and identified. DLBCL cells were transfected with pcDNA to overexpress TNFAIP3 or inhibit miR­125b­5p expression, incubated with EVs, and treated with rituximab to compare cell growth and TNFAIP3/CD20 expression. DLBCL model mice were administered EVs, conditioned medium, and rituximab to observe changes in tumor size, volume, and weight. TNFAIP3 was downregulated in patients with DLBCL and its levels further decreased in patients with drug­resistant DLBCL. Overexpression of TNFAIP3 in DLBCL cells enhanced the inhibitory effect of rituximab and increased CD20 expression. miR­125b­5p targeted TNFAIP3. Inhibition of miR­125b­5p enhanced the inhibitory effect of rituximab in DLBCL cells. The EV­carried miR­125b­5p reduced the sensitivity of DLBCL cells to rituximab, which was averted by overexpression of TNFAIP3. EVs reduced the sensitivity of DLBCL model mice to rituximab via the miR­125b­5p/TNFAIP3 axis. The study findings indicate that the tumor­derived EVs carrying miR­125b­5p can enter DLBCL cells and target TNFAIP3, thus reducing the sensitivity of DLBCL to rituximab, which may provide a novel therapeutic approach for DLBCL.

Impact of Double- or Triple-Hit Pathology on Rates and Durability of Radiation Therapy Response Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

PURPOSE: Double-hit lymphomas and triple-hit lymphomas (DHL/THL), also known as high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, are associated with chemoresistance and inferior survival. However, whether radiation therapy (RT) efficacy is altered in DHL/THL is less well characterized. Among patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), we compared rates and durability of response between patients with and without DHL/THL. METHODS AND MATERIALS: We retrospectively reviewed consecutive R/R LBCL patients who were irradiated at a single institution from January 2008 to June 2017. Patients in whom c-MYC rearranged status was known were evaluated for response to RT, in-field control, progression-free, and overall survival. RESULTS: Among 245 irradiated patients with LBCL, 41 patients with confirmed c-MYC status were treated for R/R disease (14 DHL/THL, 27 non-DHL/THL) and formed our cohort. Compared with non-DHL/THL, more DHL/THL patients had progressive disease at RT (71% vs 48%), had larger gross tumor volumes (GTV; median 696 mL vs 117 mL), and were treated with palliative intent (71% vs 41%). Despite similar RT doses (median 35 Gy), radiographic complete response rate was lower among DHL/THL patients: 14.3% versus 64.7% (P = .01). With a median 2 years of follow-up, one in-field failure was observed in each group. DHL/THL patients had inferior progression-free survival (7% vs 46%; P = .02) and overall survival (14% vs 68%; P = .03) at 6 months. CONCLUSIONS: R/R LBCL is responsive to RT, although rates of response are lower among DHL/THL patients. Given poor survival after RT, in-field control was hard to evaluate in this cohort. Larger cohorts are required to better elucidate whether differences in response rates are driven by larger disease burden at RT versus tumor biology. These findings are of increasing pertinence in light of use of RT as bridging therapy to cellular immunotherapies.

A case report of primary prostate intravascular large B cell lymphoma presenting as prostatic hyperplasia.

RATIONAL: Intravascular large B-cell lymphoma (IVLBCL) is a rare condition with a poor prognosis. The clinical presentation of primary lymphoma of the prostate is non-specific and it is difficult to distinguish from other prostatic diseases. The primary prostate IVLBCL is very rare, the diagnosis and treatment of which remains unclear. We reported a rare case to explore the diagnosis and treatment for the primary prostate IVLBCL. PATIENTS CONCERNS: This report described a case of a 71-year-old male diagnosed as primary prostate IVLBCL who presented with prostatic hyperplasia. DIAGNOSIS: The patient first visited an outpatient clinic of urinary surgery because of urinary urgency and frequency and was diagnosed as benign prostatic hyperplasia in about January 2010. Four years later, the symptoms worsened quickly within two months. The diagnosis was still prostatic hyperplasia according to the physical examination and imaging. However, histopathology showed IVLBCL of prostate after transurethral resection of the prostate. INTERVENTIONS: With the clear diagnosis of primary prostate stage I IVLBCL, the patient received immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone) for 4 cycles and intensity-modulated radiation therapy (IMRT) including the region of prostate with the dose of 45Gy/25f. OUTCOMES: The response was complete remission after all treatment. The last follow-up time of the patient was June 20th, 2019, and no evidence of disease progression was observed. The progression-free survival of the patient was about 49 months until now. LESSONS: The biopsy of prostate by prostatectomy plays an important role in the diagnosis and removal of the original lesion of primary prostate lymphoma. There is no consensus on therapeutic modalities for the treatment of primary prostate IVLBCL till now. Individual treatments include immunochemotherapy and/or radiotherapy according to the National Comprehensive Cancer Network (NCCN) practice guideline of diffuse large B cell lymphoma (DLBCL) based on the performance status and tumor staging of the patient. Timely and accurate diagnosis as well as the appropriate treatment may improve the clinical outcome.

Diagnosis and Management of Cutaneous B-Cell Lymphomas.

Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.

High Red Cell Distribution Width is an Adverse Predictive and Prognostic Factor in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemoimmunotherapy.

INTRODUCTION: The red blood cell distribution width (RDW) is an easy-to-obtain laboratory value that has emerged as a potential prognostic factor in solid and hematologic malignancies. PATIENTS AND METHODS: We evaluated 121 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with standard chemoimmunotherapy at our institution between 2010 and 2012. We categorized patients with high RDW (> 14.6%) and normal RDW (11.6%-14.6%). We fitted multivariate regression models for complete response (CR) and overall survival (OS). RESULTS: Patients with high RDW were less likely to achieve CR to chemoimmunotherapy than patients with normal RDW (48% vs. 83%; P < .001). The 5-year OS rate for patients with high RDW was lower than in patients with normal RDW (51% vs. 79%; P = .001). In multivariate regression models, high RDW was independently associated with lower odds of achieving CR (odds ratio, 0.32; 95% confidence interval [CI], 0.12-0.83; P = .02) and with higher risk of death from any cause (hazard ratio [HR], 2.04; 95% CI, 1.03-4.02; P = .04) than normal RDW in patients with DLBCL treated with chemoimmunotherapy. High RDW remained an independent adverse factor for OS after adjustment for the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index scores with HR 2.20 (95% CI, 1.12-4.31; P = .02) and HR 2.67 (95% CI 1.28-5.59; P = .009), respectively. CONCLUSION: High RDW appears to be an adverse predictive and prognostic factor in patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

A better prediction of progression-free survival in diffuse large B-cell lymphoma by a prognostic model consisting of baseline TLG and %ΔSUVmax.

In the era of rituximab, the International Prognostic Index (IPI) has been inefficient in initial risk stratification for patients with R-CHOP-treated diffuse large B-cell lymphoma (DLBCL). To estimate the predictive values of PET/CT quantitative parameters and three prognostic models consisting of baseline and interim parameters for three-year progression-free survival (PFS), we conducted an analysis of 85 patients in China with DLBCL underwent baseline and interim PET/CT scans and treated at the Department of Hematology of Peking University Third Hospital from November 2012 to November 2017. The PET/CT parameters, viz. the baseline and interim values of standardized uptake value (SUVmax ), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG), and their rates of change, were analyzed by a receiver operating characteristics curve, Kaplan-Meier analysis, and log-rank test. Besides, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) was also included in the multivariate Cox hazards model. Owing to the strong correlation between TMTV and TLG at baseline and interim (Pearson's correlation coefficient, r = 0.823, P-value = 0.000, and 0.988, P-value = 0.000, respectively), only TLG was included in the multivariate Cox hazards model, where TLG0  > 1036.61 g and %ΔSUVmax  < 86.02% showed predictive value independently (HR = 10.42, 95% CI 2.35-46.30, P = 0.002, and HR = 4.86, 95% CI 1.27-18.54, P = 0.021, respectively). Replacing TLG in the equation, TMTV0 and TMTV1 both showed significantly predictive abilities like TLG (HR = 8.22, 95% CI 1.86-32.24, P = 0.005, and HR = 2.96, 95% CI 1.16-7.54, P = 0.023, respectively). After dichotomy, NCCN-IPI also gave a significant performance (P = 0.035 and P = 0.010, respectively, in TLG and TMTV models). The baseline variables, that is, TMTV0 , TLG0 and dichotomized NCCN-IPI, and the interim variables TMTV1 and %ΔSUVmax , presented independent prognostic value for PFS. In prognostic model 2 (TLG0  + %ΔSUVmax ), the group with TLG0  > 1036.61 g and %ΔSUVmax  < 86.02% recognized 19 (82.6%) of the relapse or progression events, which showed the best screening ability among three models consisting of baseline and interim PET/CT parameters.

Prevalence and clinical significance of hypercalcemia at diagnosis in diffuse large B-cell lymphoma.

The reported prevalence of hypercalcemia at diagnosis in non-Hodgkin-lymphoma ranges between 1.3% and 7.4%. These studies included all patients, regardless of lymphoma subtype. We performed a retrospective case-control study to determine the prevalence of hypercalcemia at time of diagnosis in patients with diffuse large B-cell lymphoma (DLBCL). Among 250 newly diagnosed patients, 46 (18%) had hypercalcemia. When compared with age-sex matched patients and normal calcium levels, those with hypercalcemia had higher levels of LDH, lower levels of albumin and more advanced stage. These differences were translated to shorter progression-free-survival and overall survival, but only in patients with hypercalcemia and low levels of parathyroid hormone (PTH). These findings suggest that in newly diagnosed patients with DLBCL, hypercalcemia is more frequent than previously appreciated. Furthermore, lymphoma-related but not primary hyperparathyroidism-related hypercalcemia is associated with adverse prognostic factors and adverse clinical outcomes in DLBCL. Hence, PTH should be obtained in patients with DLBCL and hypercalcemia at diagnosis.

Prognostic Nomogram for Overall Survival in Patients with Diffuse Large B-Cell Lymphoma.

PURPOSE: This study aimed to develop a prognostic nomogram in diffuse large B-cell lymphoma (DLBCL) and compare it with traditional prognostic systems. MATERIALS AND METHODS: We included 1,070 consecutive and nonselected patients with DLBCL in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, between 2006 and 2012. A nomogram based on the Cox proportional hazards model was developed. RESULTS: The entire group were divided into the primary (n = 748) and validation (n = 322) cohorts. The 5-year overall survival (OS) rate was 64.1% for the entire group. Based on a multivariate analysis of the primary cohort, seven independent prognostic factors including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status score, lactate dehydrogenase, ß2-microglobulin, CD5 expression, and Ki-67 index were identified and entered the nomogram. The calibration curve showed the optimal agreement between nomogram prediction and actual observation. In addition, the concordance index (C-index) of the nomogram for OS prediction was 0.77 (95% confidence interval [CI], 0.73-0.81) in the primary cohort and 0.76 (95% CI, 0.70-0.81) in the validation, superior to that of the international prognostic index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network (NCCN)-IPI (range, 0.69-0.74, p<.0001). Moreover, in patients receiving rituximab plus CHOP (R-CHOP) or R-CHOP-like regimens, compared with IPI (C-index, 0.73; 95% CI, 0.69-0.77), R-IPI (C-index, 0.70; 95% CI, 0.66-0.74), or NCCN-IPI (C-index, 0.71; 95% CI, 0.66-0.75), the DLBCL-specific nomogram showed a better discrimination capability (p < .0001). CONCLUSIONS: The proposed nomogram provided an accurate estimate of survival of patients with DLBCL, especially for those receiving R-CHOP or R-CHOP-like regimens, allowing clinicians to optimized treatment plan based on individualized risk prediction. IMPLICATIONS FOR PRACTICE: A diffuse large B-cell lymphoma (DLBCL)-specific prognostic nomogram was developed based on Chinese patients with DLBCL. As a tertiary hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences is the number 1 ranked cancer center in China, with more than 800,000 outpatients in 2018. Patients included in this study were nonselected and came from 29 different provinces, municipalities, and autonomous regions in China. Thus, the data is believed to be representative to an extent.

Prognostic value of metabolic tumour volume on baseline 18F-FDG PET/CT in addition to NCCN-IPI in patients with diffuse large B-cell lymphoma: further stratification of the group with a high-risk NCCN-IPI.

PURPOSE: The purpose of this study was to determine the prognostic value of metabolic volumetric parameters as a quantitative index on pre-treatment 18F-FDG PET/CT in addition to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 103 consecutive patients with DLBCL and baseline FDG PET/CT were retrospectively evaluated. Quantitative metabolic parameters, including total metabolic tumour volume (TMTV) using a standardized uptake value (SUV) of ≥2.5 as the threshold, were estimated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values for the metabolic parameters. The relationships between study variables and patient survival were tested using Cox regression analysis. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. RESULTS: Median follow-up was 34 months. In patients with a low TMTV (<249 cm3), the 3-year progression free survival (PFS) rate was 83% and the overall survival (OS) rate was 92%, in contrast to 41% and 57%, respectively, in those with a high TMTV (≥249 cm3). In univariate analysis, a high TMTV and NCCN-IPI ≥4 were associated with inferior PFS and OS (P < 0.0001 for all), as was a high total lesion glycolysis (P = 0.004 and P = 0.005, respectively). In multivariate analysis, TMTV and NCCN-IPI were independent predictors of PFS (hazard ratio, HR, 3.11, 95% confidence interval, CI, 1.37-7.07, P = 0.007, and HR 3.42, 95% CI 1.36-8.59, P = 0.009, respectively) and OS (HR 3.41, 95% CI 1.24-9.38, P = 0.017, and HR 5.06, 95% CI 1.46-17.60, P = 0.014, respectively). TMTV was able to separate patients with a high-risk NCCN-IPI of ≥4 (n = 62) into two groups with significantly different outcomes; patients with low TMTV (n = 16) had a 3-year PFS rate of 75% and an OS rate of 88%, while those with a high TMTV had a 3-year PFS rate of 32% and an OS rate of 47% (χ2 = 7.92, P = 0.005, and χ2 = 8.26, P = 0.004, respectively). However, regardless of TMTV, patients with a low-risk NCCN-IPI of <4 (n = 41) had excellent outcomes (3-year PFS and OS rates of 85% and 95%, respectively). CONCLUSION: Pretreatment TMTV was an independent predictor of survival in patients with DLBCL. Importantly, TMTV had an additive prognostic value in patients with a high-risk NCCN-IPI. Thus, the combination of baseline TMTV with NCCN-IPI may improve the prognostication and may be helpful guide the decision for intensive therapy and clinical trials, especially in DLBCL patients with a high-risk NCCN-IPI.

Available prognostic models for risk stratification of diffuse large B cell lymphoma patients: a systematic review.

The International Prognostic Index (IPI) has been used for risk stratification for a long time in diffuse large B cell lymphoma (DLBCL). Based on new clinical and biological prognostic markers, many new prognostic models have been described. This review aims to present the progress in development and validation of these prognostic models. A comprehensive literature review was performed to identify studies that proposed a new prognostic model in DLBCL. A total of 38 studies met the inclusion criteria. The IPI, revised IPI (R-IPI), and National Comprehensive Cancer Network (NCCN)-IPI were the most studied prognostic indexes, externally validated and commonly used to compare to other models. Despite an increasing number of prognostic models have been proposed lately, most of them lack external validation. Further studies, that combine biological and clinical markers with prognostic significance, are needed to determine the optimal prognostic tool for more personalized treatment approach to DLBCL patients.

The rationale for combination therapy in patients with aggressive B-cell non-Hodgkin lymphoma: ten questions.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone immunochemotherapy remains standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). High-dose chemotherapy and stem cell transplantation is offered to most relapsing/refractory patients who respond to salvage therapy. This Q&A review evaluates recommended management strategies for second and subsequent lines of therapy in patients with DLBCL, outlining the relative efficacies of currently available options including novel agents such as ibrutinib and CAR-T cells. The combination of pixantrone and rituximab is currently under investigation as a second-line treatment for patients ineligible for stem cell transplantation, while pixantrone monotherapy is the only therapeutic option approved for multiply relapsed and refractory DLBCL beyond the second line at this time.

Intralymphatic Spread is a Rare Finding Associated With Poor Prognosis in Diffuse Large B-Cell Lymphoma With Extranodal Involvements.

Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements.

[Survival of patients with primary central nervous system diffuse large B-cell lymphoma: impact of gene aberrations and protein overexpression of bcl-2 and C-MYC, and selection of chemotherapy regimens].

Objective: To investigate the impact of clinicopathological features, gene rearrangements and protein expression of bcl-6, bcl-2, C-MYC and chemotherapy regime on the prognosis of patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Methods: Thirty-three cases of PCNS-DLBCL diagnosed from January 2006 to December 2016 at Zhejiang Cancer Hospital were collected. The expression of CD10, bcl-6, bcl-2, MUM1 and MYC were detected by immunohistochemical staining (IHC). The presence of EB virus was detected by in situ hybridization(EBER). Copy number variation (ICN) and translocation status of bcl-6, bcl-2 and C-MYC genes were detected by fluorescence in situ hybridization (FISH). The relationship between the above indexes and the prognosis was analyzed by univariate, bivariate survival analysis and multiple Cox hazard regression analysis. Results: The study included 33 patients of PCNS-DLBCL, without evidence of primary or secondary immunodeficient disease. Male to female ratio was 1.36∶1.00, and the average age was 56 years. Twenty cases had single lesion while 13 had multiple lesions. Deep brain involvement was seen in 12 cases. All patients underwent partial or total tumor resection. Five patients received whole brain post-surgery radiotherapy, nine patients received high-dose methotrexate (HD-MTX) based chemotherapy, and 12 patients received whole-brain radiotherapy combined with HD-MTX based chemotherapy. Severn patients received no further treatment and rituximab was used in 8 patients. According to the Hans model, 27 cases were classified as non-GCB subtypes (81.8%). Bcl-2 was positive in 25 cases (75.8%, 25/33) and highly expressed in 8 (24.2%). MYC was positive in 12 cases (36.4%) and double expression of bcl-2 and MYC was seen in 6 cases. EBER positive rate was 10.0%(3/30), all of which had multiple lesions. Two bcl-6 gene translocations and 3 amplifications were found in 28 patients. Two translocations, 3 ICN or with both bcl-2 gene translocation and ICN were found in 30 patients. Four ICNs of C-MYC gene were found in 28 patients. Elevated protein in cerebrospinal fluid (CSF) was found in 13 patients. LDH increased in 10 cases. Follow-up period was 2-90 months with the average survival time of (23.0±3.7) months and two-year survival rate of 39.0%. Univariate survival analysis showed that overexpression of bcl-2 protein (≥70%) and MYC protein (≥40%), bcl-2 gene abnormality (including copy number increase and translocation), C-MYC gene copy number increased were adverse factors for survival. C-MYC/ bcl-2 gene double hit was seen in 2 cases. Bivariate survival analysis found that of bcl-2/MYC protein double expression and bcl-2 and C-MYC genes double aberration were significantly associated with adverse outcomes. Cox multivariate risk regression analysis found that gender, cerebrospinal fluid protein increasing, and ICN of C-MYC gene were independent poor prognostic factors. DH-MTX based comprehensive chemotherapy was associated with better prognosis. Conclusions: Double hit at genomic level (copy number variations and gene rearrangements) and double protein expression of bcl-2 and C-MYC in PCNS-DLBCL are significantly associated with an adverse outcome. DH-MTX based comprehensive treatment may prolong the patient survival.

[Treatment of indolent cutaneous B­cell lymphoma]. / Therapie indolenter kutaner B­Zell-Lymphome.

Primary cutaneous B­cell lymphomas are rarely encountered and represent 25% of all cutaneous lymphomas. Follicular B­cell lymphoma and marginal zone lymphoma belong to indolent subtypes which as a rule have no systemic dissemination and, thus, a mostly unchanged life expectancy. Therefore, skin-directed treatment options such as excision or radiotherapy are usually sufficient to control the disease. In contrast, cutaneous diffuse large B­cell lymphoma and EBV-associated B­cell lymphomas of the skin belong to more aggressive entities which demand a systemic first-line upfront therapy with R­CHOP. Nevertheless, mortality is still high and comparable to that of systemic/nodal large B­cell lymphomas so that the identification of pathogenetic driver mutations or novel therapeutic targets may pave the way to better target-oriented therapies.

Multimodality Treatment of Gastric Lymphoma.

Gastric lymphoma is rare, accounting for 3% of gastric neoplasms and 10% of lymphomas. Treatment should be stratified based on histologic type, stage, Helicobacter pylori infection, and t(11;18) translocation status. Surgery is no longer a mainstay for treatment and should be reserved for rare situations such as perforation, fistula formation, and severe bleeding. Multimodal treatment, including H pylori eradication, radiation therapy, chemotherapy, and immunotherapy, should be provided as appropriate and can result in excellent outcomes.

State-of-the-art Therapy for Advanced-stage Diffuse Large B-cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) represents the most common lymphoid malignancy in adults, with a median age of 60 to 70 years. Clinical behavior is usually rapidly aggressive, with extranodal involvement in 40% of cases. Chemoimmunotherapy administered every 21 days is still the standard of care in the advanced stage. Optimization of frontline therapy and the amelioration of salvage strategies remain the most important targets in the treatment of patients with DLBCL. Novel drugs directed to specific molecular targets have been introduced as single agents or in addition to standard chemoimmunotherapy for the treatment of DLBCL.