Adding MYC/BCL2 double expression to NCCN-IPI may not improve prognostic value to an acceptable level.

BACKGROUND: MYC/BCL2 double expression (DE) is associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). This study aimed to determine whether the addition of DE to the National Comprehensive Cancer Network Internal Prognostic Index (NCCN-IPI) could improve the prediction of disease progression in patients with DLBCL treated with R-CHOP. METHODS: This confirmatory prognostic factor study retrospectively recruited patients with newly diagnosed DLBCL between January 1, 2014, and January 31, 2018, at Ramathibodi Hospital (RA) and Thammasat University Hospital (TU). The follow-up period ended on July 1, 2022. Tumors expressing MYC ≥ 40% and BCL2 ≥ 50% were classified as DE. We calculated the hazard ratios (HR) for progression-free survival (PFS) from the date of diagnosis to refractory disease, relapse, or death. Discrimination of the 5-year prediction was based on Cox models using Harrell's concordance index (c-index). RESULTS: A total of 111 patients had DE (39%), NCCN-IPI (8%), and disease progression (46%). The NCCN-IPI adjusted HR of DE was 1.6 (95% confidence interval [CI]: 0.9-2.8; P = 0.117). The baseline NCCN-IPI c-index was 0.63. Adding DE to the NCCN-IPI slightly increased Harrell's concordance index (c-index) to 0.66 (P = 0.119). CONCLUSIONS: Adding DE to the NCCN-IPI may not improve the prognostic value to an acceptable level in resource-limited settings. Multiple independent confirmatory studies from a large cohort of lymphoma registries have provided additional evidence for the clinical utility of DE.

Influence of Geriatric Nutritional Risk Index on Occurrence of Adverse Events and Duration of Treatment in Patients With Lymphoma Receiving R-CHOP Therapy.

BACKGROUND/AIM: No studies have examined the association between the Geriatric Nutritional Risk Index (GNRI) at the initiation of chemotherapy for malignant lymphoma and the occurrence of adverse events. Therefore, we investigated the impact of GNRI at treatment initiation on the occurrence of side effects and time to treatment failure (TTF) in patients with malignant lymphoma undergoing initial rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. PATIENTS AND METHODS: This study included 131 patients who underwent initial R-CHOP therapy between March 2016 and October 2021. Patients were stratified into those with high (GNRI ≥92; n=56) or low (GNRI <92; n=75) GNRI status. RESULTS: Comparing the High GNRI group and Low GNRI group, the incidence of febrile neutropenia (FN) and Grade ≥3 creatinine increase, alkaline phosphatase (ALP) increase, albumin decrease, hemoglobin decrease, neutropenia, and thrombocytopenia were significantly higher in the Low GNRI group. TTF in the High GNRI group was significantly longer than that in the Low GNRI group (p=0.045). Multivariate analysis showed that the factors influencing the duration of treatment were PS (≥2) at the start of treatment, serum albumin level, and GNRI. CONCLUSION: In patients undergoing R-CHOP therapy, GNRI <92 at regimen initiation increased the risks of developing FN and hematologic toxicity. Multivariate analysis revealed that performance status, albumin levels, and GNRI at regimen initiation were the factors influencing treatment duration. Nutritional status at treatment initiation may influence the development of hematologic toxicity and TTF.

Chidamide combined with ibrutinib improved the prognosis of primary bone marrow diffuse large B cell lymphoma.

Primary bone marrow diffuse large B cell lymphoma (DLBCL) is an independent pathologic type with a poor prognosis when treated with standard chemoimmunotherapy. Generally, rituximab-based high-dose chemotherapy regimens such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) can be administered to young patients, followed by autologous stem cell transplantation. For elderly patients, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen is well tolerated, but it is an insufficient induction therapy for this group. Herein, we reported an elderly patient diagnosed with primary bone marrow DLBCL, germinal center B-cell-like subtype. Considering tolerance, the R-CHOP regimen was administered. However, his disease progressed after two treatment cycles. Then, the rituximab, gemcitabine, dexamethasone, cisplatin, lenalidomide regimen was administered, but the patient still experienced disease progression. Subsequently, the histone deacetylase (HDAC) inhibitor chidamide and Bruton's tyrosine kinase (BTK) inhibitor ibrutinib were concurrently administered, and the patient achieved complete remission. We found that the response of primary bone marrow DLBCL to chemotherapy was poorer than that of de novo DLBCL. High-dose chemotherapy regimens such as DA-EPOCH should be administered to young patients in combination with rituximab. For elderly patients, new targeted drugs such as HDAC and BTK inhibitors appear to produce favorable outcomes.

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).

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Brain glucose metabolism in diffuse large B-cell lymphoma patients as assessed with FDG-PET: impact on outcome and chemotherapy effects.

BACKGROUND: There is a lack of data on the effect of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy on brain glucose metabolism of diffuse large B-cell lymphoma (DLBCL) patients, as measured by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, the prognostic value of brain glucose metabolism measurements is currently unknown. PURPOSE: To investigate the use of FDG-PET for measurement of brain glucose metabolism in R-CHOP-treated DLBCL patients, and to assess its prognostic value. MATERIAL AND METHODS: This retrospective study included DLBCL patients who underwent FDG-PET including the brain. FDG-PET metabolic volume products (MVPs) of the entire brain, cerebral cortex, basal ganglia, and cerebellum were measured, before and after R-CHOP therapy. Whole-body total lesion glycolysis (TLG) was also measured. RESULTS: Thirty-eight patients were included, of whom 18 had an appropriate end-of-treatment FDG-PET scan. There were no significant differences (P > 0.199) between pre- and post-treatment brain glucose metabolism metrics. Low basal ganglia MVP was associated with a significantly worse progression-free survival (PFS) and overall survival (OS) (P = 0.020 and P = 0.032), and low cerebellar MVP was associated with a significantly worse OS (P = 0.034). There were non-significant very weak correlations between pretreatment brain glucose metabolism metrics and TLG. In the multivariate Cox regression, only the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) remained an independent predictor of PFS (hazard ratio 3.787, P = 0.007) and OS (hazard ratio 2.903, P = 0.0345). CONCLUSION: Brain glucose metabolism was not affected by R-CHOP therapy. Low pretreatment brain glucose metabolism was associated with a worse outcome, but did not surpass the predictive value of the NCCN-IPI.

Tumor necrosis at FDG-PET is an independent predictor of outcome in diffuse large B-cell lymphoma.

PURPOSE: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. MATERIALS AND METHODS: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS). RESULTS: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively). CONCLUSION: Tumor necrosis at FDG-PET is an NCCN-IPI-independent predictor of outcome in DLBCL.

Prognostic Value of Anemia and C-Reactive Protein Levels in Diffuse Large B-Cell Lymphoma.

PURPOSE: To determine the prognostic value of pretreatment anemia, pretreatment elevated C-reactive protein (CRP) levels, and 6-month posttreatment anemia in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone (R-CHOP). PATIENTS AND METHODS: A total of 104 patients with newly diagnosed DLBCL were retrospectively included. Pretreatment hemoglobin and CRP levels and 6-month posttreatment hemoglobin levels were measured. Cox regression analyses were used to determine the associations of laboratory assessments and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk groups with progression-free survival (PFS) and overall survival (OS). RESULTS: Pretreatment anemia, elevated pretreatment CRP levels, and higher risk NCCN-IPI groups were significantly associated with reduced PFS and OS (P = .001 and P = .003 for pretreatment anemia, P = .035 and P = .029 for elevated CRP, and P < .001 and P < .001 for higher risk NCCN-IPI groups). On multivariate Cox regression analysis, only the NCCN-IPI risk group remained as an independent significant predictor for PFS (P < .001) and OS (P < .001). In the subgroup of patients in complete remission 6 months after chemotherapy (n = 80), 6-month posttreatment anemia was significantly associated with reduced PFS (P = .046) but not OS (P = .062), and higher risk NCCN-IPI groups were significantly associated with both reduced PFS (P = .008) and OS (P = .017). On multivariate Cox regression analysis, only the NCCN-IPI group remained an independent significant predictor for PFS (P = .008) and OS (P = .017). CONCLUSION: Pretreatment anemia, pretreatment CRP levels, and 6-month posttreatment anemia are significantly associated with poor outcome, but were not proven to be of additional prognostic value to the current risk stratification index for DLBCL.

Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project.

BACKGROUND: The role of consolidation radiotherapy was examined for patients with diffuse large B-cell lymphoma who were treated at institutions of the National Comprehensive Cancer Network during the rituximab era. METHODS: Failure-free survival (FFS) and overall survival (OS) were analyzed in terms of patient and treatment characteristics. Potential associations were investigated with univariate and multivariate survival analysis and matched pair analysis. RESULTS: There were 841 patients, and most (710 or 84%) received 6 to 8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 293 (35%) received consolidation radiation therapy (RT). Failure occurred for 181 patients: 126 patients (70%) who did not receive RT and 55 patients (30%) who did. At 5 years, both OS and FFS rates were better for patients who had received RT versus those who did not (OS, 91% vs 83% [P = .01]; FFS, 83% vs 76% [P = .05]). A matched pair analysis (217 pairs matched by age, stage, International Prognostic Index [IPI] score, B symptoms, disease bulk, and response to chemotherapy) showed that the receipt of RT improved OS (hazard ratio [HR], 0.53 [P = .07]) and FFS (HR, 0.77 [P = .34]) for patients with stage III/IV disease, but too few events took place among those with stage I/II disease for meaningful comparisons (HR for OS, 0.94 [P = .89]; HR for FFS, 1.81 [P = .15]). A multivariate analysis suggested that the IPI score and the response to chemotherapy had the greatest influence on outcomes. CONCLUSIONS: There was a trend of higher OS and FFS rates for patients who had received consolidation RT after R-CHOP (especially for patients with stage III/IV disease), but the difference did not reach statistical significance.

Hypocalcemia in Malignancy - Unexpected but Common.

One of the most common metabolic abnormalities found in patients with malignancy is hypercalcemia. Hypocalcemia is a rare occurrence and is often found to be associated with renal failure and patients taking bisphosphonate therapy for bone metastasis in this patient population. Here, we present two different case reports with hypocalcemia. A 66-year-old female with a recent diagnosis of tonsillar diffuse B-cell lymphoma admitted with complaints of generalized weakness after one cycle of R-CHOP, found to have neutropenia, a low calcium level, high PTH, and low 25-hydroxy Vitamin D levels. She was given calcium gluconate and supplemental 25-hydroxy Vitamin D. On day 2, the patient's symptoms and counts improved. The second patient was a 64-year-old male with recurrent metastatic laryngeal carcinoma, along with a second locally advanced primary rectal adenocarcinoma, presented with severe hypocalcemia and a low PTH level. The patient was on adjuvant chemotherapy and exhibited Chvostek's sign, along with perioral numbness, tingling, and twitching sensations, which eventually led to dysphagia. He was treated with calcium gluconate, calcitriol, and calcium carbonate. Signs and symptoms, along with lab values, improved on day 4. These cases suggest that calcium kinetics and 25-hydroxy Vitamin D levels need to be monitored in these patient populations in a routine manner.

Primary cutaneous B-cell lymphomas: part II. Therapy and future directions.

The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma.