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.

Clinical efficacy and tolerability of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia-a real-world analysis of the Polish Adult Leukemia Study Group.

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma.

The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.

[A rare CD5-positive subgroup of diffuse large B-cell lymphoma - clinical, morphological and immunophenotypic features in Polish patients].

The aim of the study was to assess the incidence of CD5-positive diffuse large B-cell lymphoma (DLBCL) in the Polish population and to describe its morphologic and clinical characteristics. The study included 36 patients with CD5-positive DLBCL, diagnosed and treated in the Maria Sklodowska-Curie Institute and Oncology Centre, Warsaw, Poland and the Medical University of Warsaw, Poland in the years 2002-2013. The control group consisted of 28 patients with CD5-negative DLBCL. CD5-positive DLBCL accounted for 6.26% of all DLBCL cases diagnosed in the Maria Sklodowska-Curie Institute and Oncology Centre in the years 2008-2012. The incidence is comparable to other European countries, lower than noted in Japan and higher than in the US. Patients with CD5-positive DLBCL, in comparison to the CD5-negative group, were characterized by: (1) older age (≥ 60 vs. younger) and worse general status (ECOG ≥ 2 vs. < 2), (2) lower frequency of complete remission (CR), (3) higher expression of unfavorable prognostic factors (BCL2, FOXP1, CD44) and MMP-9, and (4) lower expression of favorable prognostic factors (CD30, cyclin D1, cyclin D3) and TIMP-2.

Autologous stem cell transplantation as consolidation therapy for patients with peripheral T cell lymphoma in first remission: long-term outcome and risk factors analysis.

This report is a retrospective analysis of 65 patients with peripheral T cell lymphoma (PTCL), who underwent high-dose therapy and autologous hematopoietic stem cell transplantation (autoHCT) as a consolidation of first response achieved with either induction or salvage chemotherapy. We intended to determine the prognostic factors that influenced outcome after autoHCT and to define the predictive value of the scoring systems most often applied for transplant outcomes. Nineteen patients in either complete or partial remission underwent autoHCT after induction chemotherapy. Forty-six patients received second-line chemotherapy as a consolidation of partial response after induction chemotherapy (n = 34) or as a salvage therapy after primary induction failure (n = 12), and thereafter proceeded to autoHCT. Finally, the 36 patients were in complete remission, and 29 in partial remission at autoHCT. The median follow-up of survivors was 53 months (range 7-157 months). The 5-year overall survival and progression-free survival for all patients were 61.5% (95% CI 47.0-74.2%) and 59.4% (95% CI 46.1-71.5%), respectively. In multivariate analysis, bone marrow involvement at diagnosis and less than partial remission after induction chemotherapy were factors independently predictive for overall survival and progression-free survival. The prognostic index for PTCL could reliably stratify the prognosis of PTCL in this analysis.

Bendamustine as monotherapy and in combination regimens for the treatment of chronic lymphocytic leukemia and non-hodgkin lymphoma: a retrospective analysis.

BACKGROUND/AIM: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. METHODS: Bendamustine was administered both as monotherapy and in combined protocols to 92 patients, including 76 patients with chronic lymphocytic leukemia (CLL) and 16 patients with indolent lymphomas. Bendamustine plus rituximab was used to treat 65.2% of the patients, and 34.8% of the patients received bendamustine as monotherapy. RESULTS: The overall response rate was 64.2%, including the complete response rate (18.5%) and the partial response rate (45.7%). The median overall survival (OS) was 11.5 months. Among the pretreatment parameters, ß2-microglobulin (RR = 1.413; p = 0.001) and hemoglobin levels (RR = 0.85; p = 0.03) significantly influenced survival. The OS was significantly longer in patients who received ≤2 lines of previous therapy compared to >3 lines (p = 0.043; log-rank test) and those who received ≥4 courses of therapy with bendamustine (p = 0.0007; log-rank test). Toxicity was predominantly hematological, including grade III/IV neutropenia in 33.7%, thrombocytopenia in 13%, and anemia in 13% of patients. CONCLUSION: Bendamustine, both in monotherapy and in combination regimens, is an effective therapy with a favorable toxicity profile in patients with indolent B-cell malignancies.

High efficacy of intensive immunochemotherapy for primary mediastinal B-cell lymphoma with prolonged follow up.

Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85-95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m2 for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18-59) years, and 60% were female. With a median (range) follow up of 9 (1-17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography-computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.

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.

Angiogenesis in CD5-positive Diffuse Large B Cell Lymphoma: A Morphometric Analysis.

BACKGROUND: CD5-positive diffuse large B cell lymphoma (DLBCL) is the least frequent immunohistochemical subgroup of DLBCL. The relatively little available data suggests a worse outcome in this population, resulting from a resistance to chemotherapy. OBJECTIVES: The aim was the comparative assessment of angiogenesis in both CD5-positive and CD5-negative DLBCL, as well as in lymphatic tissues without lymphoproliferative diseases. MATERIAL AND METHODS: The analysis included 36 cases of CD5-positive DLBCL (19 females and 17 males) aged 29-87 years (mean age 69), diagnosed and treated in the Maria Sklodowska-Curie Institute and Oncology Center and Medical University of Warsaw in 2002-2013. The control group comprised 28 cases of CD5-negative DLBCL (14 females and 14 males) aged 24-82 years (mean age 58.5). The secondary control group (13 cases) consisted of normal lymphatic tissue obtained from patients without lymphoproliferative diseases. The level of angiogenesis was assessed on the basis of immunohistochemical CD34, vWF and HIF1α expression measured using morphometric methods. RESULTS: CD5-positive DLBCL, in comparison to CD5-negative DLBCL, was characterized by: (1) higher mean of total blood vessel area, (2) higher mean total ratio of blood vessel area and staining intensity, (3) higher mean of total blood vessel area in regions defined as hot spots, (4) higher mean of total ratio of blood vessel area and staining intensity in hot spots. The measurements in lymph nodes without lymphoproliferative diseases lay between the values obtained in both DLBCL subgroups. CONCLUSIONS: We observed a significant exacerbation of angiogenesis in CD5-positive DLBCL in comparison to the CD5-negative subgroup, possibly explaining its more aggressive clinical course. Our data does not substantiate the hypothesis that angiogenesis is more pronounced in frequent CD5-negative DLBCL subgroup in comparison to benign lymphatic tissue.

Results of a prospective dose intensity and neutropenia prophylaxis evaluation programme (DIEPP) in cancer patients at risk of febrile neutropenia due to myelosuppressive chemotherapy.

OBJECTIVE: To describe the incidence of febrile neutropenia (FN) and use of pegfilgrastim in cancer patients with high overall risk of FN and to investigate the relationship between granulocyte-colony stimulating factor (G-CSF) guideline adherence and chemotherapy delivery in Central and Eastern Europe (CEE) and Austria. METHODS: Dose Intensity Evaluation Program and Prophylaxis (DIEPP) was a multicentre, prospective, and observational study of adult patients with breast cancer, lymphoma, lung cancer, gastric cancer, and ovarian cancer, who received chemotherapy with pegfilgrastim support and who had an overall risk of FN ≥ 20 %. Physicians assessed patient risk factors and reported their reasons for administering pegfilgrastim. RESULTS: Patients were enrolled from 113 centres in CEE and Austria between August 2010 and July 2013, and data were analysed from 1072 patients. The most common tumour types were breast cancer (50 %) and lymphoma (24 %). FN incidence was 5 % overall. FN occurred in 3 % of patients (28/875) who received pegfilgrastim as primary prophylaxis (PP) and 13 % of patients (19/142) who received it as secondary prophylaxis (SP); 79 % of FN events in SP patients occurred in the first cycle before pegfilgrastim was administered. The three most frequently chosen reasons for using pegfilgrastim were planned chemotherapy with high FN risk, female gender, and advanced disease. Overall, 40 % of patients received > 90 % of their planned chemotherapy dose within 3 days of the planned schedule. CONCLUSION: FN incidence was relatively low with pegfilgrastim PP in patients with a physician-assessed overall FN risk of ≥ 20 %. The most important reasons for pegfilgrastim use were consistent with the investigators' risk assessment and international guidelines.

Increased risk of gastrointestinal lymphoma in carriers of the 657del5 NBS1 gene mutation.

The NBS1 gene mutation, 657del5, frequent in the Slavic populations of Central Europe, is found in most patients with Nijmegen breakage syndrome (NBS), a recessive autosomal disorder with a very high incidence of non-Hodgkin lymphoma (NHL). We have previously described 2 heterozygous 657del5 mutation carriers among 42 adult NHL probands from Central Poland. Here we report 6 additional carriers of the 657del5 mutation and 2 carriers of the pathogenic NBS1 R215W mutation, among 186 other NHL patients also from Central Poland. The 657del5 carrier frequency in the pooled group of these 228 patients was significantly higher than in population controls (OR 5.85, 95% CI: 2.29-15.00, p = 0.0001). Interestingly, 4 of these carriers were found among 37 patients with gastrointestinal lymphoma (OR 19.52, 95% CI: 5.82-65.42, p = 0.0002). These findings imply that heterozygous NBS1 germline mutations may contribute significantly to the overall incidence of NHL, especially of the gastrointestinal tract, in Central Europe.