Safety and efficacy of induction immunochemotherapy with rituximab, methotrexate, ifosfamide, and vincristine (R-MIV) in patients with primary CNS lymphoma including recent COVID-19 pandemic experience.

Clinical data on primary central nervous system (CNS) lymphoma (PCNSL) patients is mostly generated from prospective studies, and many frail real-world patients are not included. Recently,the diagnosis and treatment of PCNSL patients was confounded by the COVID-19 pandemic. In particular, treatment with high-dose cytarabine was linked to increased risk of pneumonia and virus persistence. We report on outcome of the induction regimen R-MIV (rituximab, methotrexate, ifosfamide, and vincristine) involving intensive administration of high-dose methotrexate (3.5 g/m2 ) with ifosfamide, every 2 weeks and rituximab once per week for six doses. The median age and performance status (PS) for 64 patients was 58 years and 2 (PS 3; 22%) respectively. The overall response rate by magnetic resonance imaging/computed tomography (MRI/CT) was 73% (n = 46/63), with an additional 17.5% (n = 11/63) patients without measurable disease at baseline. Grade 3-4 haematological toxicity was low for R-MIV (neutropenia: 25% and thrombocytopenia: 1%). Three patients (4.7%) died from treatment-related toxicity. Co-existence of SARS-CoV-2 infection with cytomegalovirus reactivation and the varicella-zoster virus in two patients was fatal. Fifty patients (78%) were eligible for consolidation. Median progression-free and overall survival were not reached (median follow-up: 44 months). In conclusion, the R-MIV regimen is feasible in routine practice, effective and safe, even during the COVID-19 pandemic.

Early efficacy and safety of obinutuzumab with chemotherapy in previously untreated patients with follicular lymphoma: A real-world retrospective report of the Polish Lymphoma Research Group.

BACKGROUND: The first-line obinutuzumab-based immunochemotherapy improves the outcome of patients with follicular lymphoma (FL) compared with rituximab-based regimens. However, infusion-related reactions occur in almost half of patients during the 1st obinutuzumab administration. OBJECTIVES: The study aimed to evaluate the early effectiveness and safety of obinutuzumab-based induction regimens in a real-world setting. MATERIAL AND METHODS: Outcomes of patients diagnosed with FL and treated with obinutuzumab between January 2020 and September 2021 were analyzed. RESULTS: The study group included 143 treatment-naïve patients with FL. The median age was 52 years (range: 28-89 years); 45.1% of patients had a high-risk disease as assessed using the Follicular Lymphoma International Prognostic Index (FLIPI). Induction chemotherapy included: O-CVP (obinutuzumab, cyclophosphamide, vincristine, prednisolone) in 49.0% of patients, O-CHOP (O-CVP plus doxorubicin) in 28.7% and O-BENDA (obinutuzumab, bendamustine) in 22.4%. Complete response (CR) and partial response (PR) rates were 69.9% and 26.5%, respectively. There was no difference in response rates between different regimens (p = 0.309). Maintenance was started in 115 patients (85.2%). In the 1st cycle, obinutuzumab was administered as a single 1000-milligram infusion in 47.9% of patients, whereas in 52.1%, initial infusions were split over 2 days (100 mg/900 mg). Infusion-related reactions were reported only during the 1st administration of obinutuzumab in 9.1% of patients, with a similar incidence in those receiving the total dose on a single day or split over 2 days (p = 0.458). The most common adverse events were hematological. Five patients died from coronavirus disease 2019 (COVID-19). CONCLUSION: The early responses to induction regimens and adverse events profile were similar for every type of induction treatment. The infusion-related reactions were rare and limited to the 1st dose of obinutuzumab.

Rituximab and Chemotherapy for Newly Diagnosed Follicular Lymphoma: Real-World Report of Polish Lymphoma Research Group.

INTRODUCTION: Follicular lymphoma (FL) is the most common type of indolent B-cell lymphoma with a favorable prognosis in the majority of patients. The induction treatment is still based on rituximab and chemotherapy, though new anti-CD20 antibody and chemo-free regimen have been recently introduced. The aim of the study was to analyze the management, outcomes, and determinants of prognosis of newly diagnosed patients with FL in real-world experience. METHODS: Data of consecutive patients diagnosed with FL in 5 years period (2011-2015) in three oncohematological centers were reviewed. Variables were compared using Mann-Whitney or χ2 test as appropriate, survival outpoints were calculated using Kaplan-Meier method. RESULTS: One hundred eighty-one patients were included in the study. The median patients' age at diagnosis was 56.6 years. Low histological grade (G1-G2) was found in 62.1% of patients and advanced clinical stage in 77.0% of patients. ECOG 0 performance status was observed in 57.1% of patients. The median follow-up was 5.91 years. Initially, 31.5% of the patients were qualified to watch-and-wait (W&W) strategy, and 84.0% of the whole patients' group received systemic treatment during the observation period. As induction treatment, 53.9% and 41.4% of patients received RCVP and RCHOP regimens, respectively; 39.8% received rituximab maintenance (RM) after first-line therapy. During follow-up, transformation to aggressive lymphoma occurred in 7.2% of patients. Median overall survival (OS) was not achieved, and median progression-free survival (PFS) was 8.28 years (95% CI; 7.35, NA), 19.6% of patients relapsed during 24 months from the start of the treatment (POD24). Median PFS for POD24 group was 1.1 years (95% CI; 0.56, 1.45) with a median OS longer than 8 years. ECOG 0, low PRIMA PI, and no POD24 were found as determinants of longer PFS and OS. CONCLUSIONS: Our data from clinical practice showed that rituximab and chemotherapy is still an effective method of FL treatment resulting in survival more than 8 years from diagnosis in most patients. RCVP protocol followed with RM is a reasonable choice for the first-line therapy especially in low/intermediate group of patients. The prognosis was significantly worse in patients with POD24. Therefore, searching for precise initial clinical and biological markers is warranted and development therapies to improve prognosis of POD24 patients.

Peripheral Blood Cells from Patients with Hodgkin's and Diffuse Large B Cell Lymphomas May Be a Better Source of Candidate Diagnostic miRNAs Than Circulating miRNAs.

Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) represent 15% and 20%, respectively, of all lymphoma types. The aim of this study was to identify and compare circulating serum miRNA (c-miRNA) and peripheral whole blood miRNA (wb-miRNA) profiles in patients with these lymphomas. Serum samples (20 HL, 21 DLBCL, and 30 healthy controls) and whole blood samples (21 HL, 17 DLBCL patients, and 30 healthy controls) were collected at the time of diagnosis. Serum and whole blood were also collected from 18 HL/17 DLBCL and eight HL/nine DLBCL patients, respectively, after treatment. Pairwise comparisons identified 125 c-miRNAs (adjusted P value < 0.05) showing significant dysregulation between 30 healthy controls and patients; of these, 47 and 55 differentiated controls from pretherapeutic HL and DLBCL patients, respectively. In addition, 60 and 16 c-miRNAs differentiated controls from posttherapeutic HL and DLBCL, respectively. Pairwise comparisons identified 292 wb-miRNAs (adjusted P value < 0.05) showing significant dysregulation between 30 controls and patients; of these, 103 and 169 differentiated controls from pretherapeutic HL and DLBCL, respectively, and 142 and 151 wb-miRNAs differentiated controls from posttherapeutic HL and DLBCL, respectively. Thus, lymphoma-associated miRNAs may be a better source of noninvasive candidate biomarkers than miRNAs in serum. It is unclear whether miRNA alterations in lymphoma cells are similar to those observed in white blood cells.

EZH2 Expression in Follicular Lymphoma Is Variable and Independent from the Progression of Disease Within 24 Months of First Treatment.

BACKGROUND/AIM: Follicular lymphoma (FL) relapse within 24 months of the first immunochemotherapy (POD24) indicates more precisely poor overall survival and high risk of death. The aim of the study was to assess the potential value of POD24 in FL and describe the enhancer of zeste homolog 2 (EZH2) expression profile, in correlation with clinical/histopathological/immunophenotypical characteristics. MATERIALS AND METHODS: This retrospective single-center study included 75 patients with FL treated under watch and wait (W&W) and immunochemotherapy regimens. All cases were immunohistochemically assessed: assays were performed for EZH2, CD10, BCL6, BCL2, MUM1, MYC and p53. RESULTS: POD24 was independent of clinical/histopathological/immunohistochemical features and separated patients with inferior outcomes. EZH2 high expression was observed in high/low grade and follicular/diffuse FL patterns. BCL2-negative (p=0.042) and MUM1 (p=0.039), MYC (p<0.001), p53 (p<0.001) - positive cases had significantly higher EZH2 expression. CONCLUSION: POD24 is currently the most useful tool for the identification of poor outlook patients. EZH2 is crucial in FL biology, but the value of its protein expression is limited as a prognostic factor.

PD1 distribution pattern, regardless of the cell origin, is an independent microenvironmental prognostic factor for progression-free survival in follicular lymphoma.

Follicular lymphoma (FL) is a well-studied microenvironment-dependent hematological malignancy, but the crosstalk between various involved cell subtypes is still not fully understood. Recent promising results of immunotherapy in recurrent FL warrant the need for an in-depth analysis of the expression and role of immune system-related proteins in the FL microenvironment. Seventy-one patients with FL and available diagnostic paraffin blocks were enrolled in the retrospective analysis. Histopathological diagnoses were revised according to the World Health Organization recommendations. Patients were either observed (watch and wait/W&W group) or immediately treated with chemo(immuno)therapy regimens according to their clinical status. Immunohistochemical assessment of PD1, PDL1, CD4, CD8, CD163, CD68-KP1, CD68-PGM1 was performed. The scoring methods included both semi-quantitative estimation of positive cells and architectural pattern distribution. The differences between PD1 staining distribution and intensity were classified as intra/perifollicular vs. interfollicular/diffuse cells and presented bright vs. dim immunoreactivity, respectively. No statistically significant differences in the density distribution of the immunohistochemical stainings were found between W&W and chemo(immuno)therapy groups. Interfollicular/diffuse pattern of PD1 expression had significantly decreased progression-free survival when analyzing the whole cohort and patients on chemo(immuno)therapy (p = 0.014 and p = 0.07, respectively). The high dependence was not significant in the W&W group. PD1 positivity of cells did not correlate with CD4 or CD8 immunophenotype. Morphologically FL neoplastic cells were entirely PDL1 negative, but granular and membranous staining was detected in the FL microenvironment. In line with previous studies, PD1/PDL1 expression was predominantly localized in the FL microenvironment, indicating that FL cells might not be the direct target for anti-PDL1 therapy. However, we show that the localization of PD1 expression could be a viable progression-free survival biomarker for FL.

Significance of CD10 protein expression in the diagnostics of follicular lymphoma: A comparison of conventional immunohistochemistry with flow cytometry supported by the establishment of BCL2 and BCL6 rearrangements.

INTRODUCTION: Histopathological examination and immunohistochemistry (IHC) with a crucial role of CD10 expression remain a standard diagnostic tool in follicular lymphoma (FL). The results of IHC CD10 detection with different primary antibodies are not fully reproducible, but some reports show that flow cytometry (FCM) can be a reliable method of CD10 identification. METHODS: The aim of the study was to compare results of CD10 expression in FL by IHC and FCM including immunophenotypic features in the context of the BCL2 and BCL6 alterations. RESULTS: Out of 76 histopathologically diagnosed FL, a group of 25 cases had simultaneously FCM. Immunohistochemically 77.6% of cases were CD10-positive with comparable and reproducible results to FCM. Differences between the FCM expression of CD5/CD10/CD11c/CD25/CD43 and BCL2 overexpression (BCL2(+)higher ) correlated with the BCL2 and BCL6 rearrangements (R) status. Lack of CD10 expression corresponded with the absence of BCL2R and higher MUM1 expression by IHC results but had no clinical impact on the long-time outcomes. CONCLUSIONS: Immunohistochemistry staining is a comparable method to FCM assessment in the evaluation of CD10 expression and diagnosis of FL. Fine-needle aspiration biopsy/FCM (FNAB/FCM) could be a useful tool for verifying FL diagnosis and CD10 detection. Despite its heterogeneity, FL has a characteristic immunophenotype. BCL2R and BCL6R FL cases differ mainly in levels of BCL2 and CD10 with CD43 co-expression; BCL2(+)higher by FCM correlates with BCL2R. Moreover, FNAB plays an important role in material provision for supportive karyotyping and BCL2R, BCL6R assessed by FISH.