Background: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) is a 96-hour continuously infused regimen, aiming to improve first-line treatment of aggressive B-cell lymphoma. Prolonged exposure to chemotherapeutic drugs and dose intensification target to reduce tumor resistance, however toxicity remains a barrier for the broad use of this regimen. Aims: To reveal the experience of our Centre on the treatment of aggressive B-cell lymphoma with DA-EPOCH-R Methods: We retrospectively collected data from 54 consecutive patients treated with DA-EPOCH-R in our Department. Results: Thirty one women and 23 men with median age of 37 years (range 18-76) were diagnosed between 2013 and 2021, with a High Grade B-cell Lymphoma, HGBCL (24 cases) and Primary Mediastinal B cell Lymphoma, PMBCL (30 cases). The Ann Arbor stage was I (16 cases), II (14 cases), III (5 cases) and IV (19 cases). The majority (85%) of patients had good (0-1) ECOG performance status. All but 2 patients were HIV positive. All patients were planed to be treated with 6 cycles of DA-EPOCH-R. Ten patients changed treatment plan due to disease progression (5 patients) and toxicity (5 patients). Among patients with HGBCL, 19 achieved a complete response (CR), 3 manifested resistant disease (RD) and for 3 patients response assessment was not possible due to disease related early death. Among patients with PMBCL, 24 showed CR, 1 patient partial response and 4 patients a RD. With a median follow up of 23 months (range 1- 86), the median progression free survival (PFS) and overall survival (OS) of all patients were not reached. Comparing survival between HGBCL and PMBCL, the latter had significantly better PFS and OS. Among the 42 patients who completed 6 cycles of treatment, only 3 reached the level 5 of dose escalation, 12 the level 4, 13 the level 3, 7 the level 2 and 4 remained at the level 1. Seven cases underwent 1 step of dose increase, 14 patients 2 steps 13 patients 3 levels and 3 patients 4 levels. The administration of high dose methotrexate in 11 patients, hampered the dose escalation. In 7 subjects, level deescalation was required (1 level for 6 patients and 2 levels for 1patient). Toxicity was manifested in 51 out of 54 patients. Haematological toxicity with neutropenia was the most common side effect: grade 4 in 88%, grade 3 in 7%, grade 1 in 5%. Severe thrombocytopenia was manifested in 7 cases. All patients received erythropoietin to treat anaemia. Thirty five subjects (65%) suffered from febrile neutropenia. Fever was related to bacterial infection in 14 cases (37%) and viral infection in 7 cases (20%). Neuropathy was observed in 11% of patients, stomatitis in 24%, gastrointestinal side effects in 13% and grade 3 or greater hepatic toxicity in 11%. Eight patients died, all due to disease relapse or progression. No death was attributed to treatment toxicity. Summary/Conclusion: DA-EPOCH-R is an effective treatment for aggressive B-cell lymphoma limited by tolerability. Its administration should be confined to subgroups where the efficacy of this regimen is clearly superior.

Introduction: Mantle Cell Lymphoma (MCL) is an indolent B-cell non Hodgkin Lymphoma (NHL) with a worse outcome compared to other low grade NHL. The prognosis of the disease is dictated by various biologic and clinical factors. Although MCL is chemosensitive in newly diagnosed patients, soon it relapses. A significant improvement of its outcome has been achieved by the administration of Rituximab (R) based regimens and the intensification of first line treatment by high dose Cytarabine and autologous stem cell transplantation. Methods: To reveal the experience of our Centre on the diagnosis, treatment and outcome of this difficult to treat lymphoma, we collected data from 51 consecutive patients, diagnosed at our department between 1999 and 2020. Results: Thirty nine (39) men and 12 women with median age 68 years (range 33-88) were diagnosed with MCL. All but one had typical histology. One patient manifested the blastoid variant. Ki67 was available for 39 biopsy: In 57% specimens Ki67 was >30% and in 43% Ki67 was ≤30%. In 84% of cases the performance status at diagnosis was good (PS 0-1) and only 16% showed PS 2-4. The majority of patients (90%) had advanced stage disease (III-IV). High MIPI score was observed in 59%, intermediate in 18% and low in 22%. Elevated lactate dehydrogenase was observed in 58% of cases. Nineteen patients received R - Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone (R-CHOP), 11 an intensified regimen, 14 patients R -Bendamustin, 5 patients R - Chlorambucil and 2 subjects had no treatment. Response to treatment showed as follow: Complete Response (CR) 52%, Partial Response (PR) 36%, Stable disease (SD) 2% and Progressive Disease (PD) 10%. Among patients who received an intensified treatment, 9 underwent an autologous transplantation. Twenty two patients with responsive disease beneficed of R maintenance. Over a median follow up of 62.8 months (range 0.3 - 262), the median overall survival (OS) was 165 months (range 0.3 - 262). Twenty three out of 44 (52%) patients with responsive disease, relapsed. The median progression free survival (PFS) was 59 months (range 6 - 140). Sixteen out of 23 (69%) patients achieved a 2nd response. The treatments administered were: R-CHOP (6 patients), R-Bendamustin (6 patients), platinum based regimens (3 patients), Ibrutinib (5 patients), corticosteroids (2 patients), R - Chlorambucil (1 patient). The median PFS and OS after the 1st relapse were 26.4 months (range 6.9 - 165) and 27 months (range 0.2 - 233) respectively. Response to 1st line treatment (p 0.0001), lower MIPI score (p 0.001) and intensified regimen (p 0.0004) were correlated with a better survival. Conclusions: Increasing the percentage of 1st complete response by intensifying the 1st line treatment could improve the survival of patients with MCL. Keywords: Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Background: High-grade B-cell NHL's are 200-fold more common in seropositive as compared to seronegative patients. They have a higher incidence of extranodal involvement, advanced stage and chemoresistance. To add to the complexity, social stigma and financial constraints decrease the compliance to therapy. R-EPOCH is designed to provide a balance between efficacy and safety. We report on our cohort of patients who were treated with this protocol. Aims: The primary objective was the 3-year overall survival (OS), secondary objectives were response rates, the incidence of grade3/4 toxicities, dose intensity and correlation of OS with CD4 count, IPI, duration of HIV, Cyclophosphamide dose intensity (CDI). Methods: We analysed seropositive de-novo high-grade B-cell NHL patients who were treated at Tata Memorial Centre from 2011 till 2015. Patients aged ≥18 years who had received at least 1 cycle were included in the analysis. Demographic features, HIV related details, histological diagnosis, disease characteristics, treatment details, response, toxicity and status, at last, follow up were recorded. Descriptive statistics were summarised, survival outcomes were analysed with Kaplan Meier method and impact of CD 4 count, CDI, IPI and duration of HIV on survival was assessed using log-rank test. Results: A total of 40 patients(31males) with a median age of 40 years (24–65 years) were treated. B symptoms were present in 19(48%). The cohort comprised of DLBCL-19 (48%), BL-16(40%), High-grade B-Cell Lymphoma-Unclassifiable-4 (10%) and PBL 1 (2.5%). 16 (40%) patients had co-morbidities, including co-existent Hepatitis C in 5 and Hepatitis B in 2. HIV infection was detected at the time of lymphoma diagnosis in 18 (45%). The median CD4+ T cell count was 202 cells/mm3, 6 patients (15%) had count of <100/mm3. All patients received HAART while on chemotherapy. Performance status (ECOG) ≤2 was seen in 36(90%) patients. 38 (95%) had stage III/IV disease and bulky disease (defined as size ≥7 cm) was seen in 29(72%) patients. Extranodal involvement was seen in 36(90%) patients. Haemoglobin level ≤11 g/dL in 10(25%) patients (range- 8.2–15.6 g/dL), serum albumin <4 g/dL in 23(58%) patients, serum LDH ≥ upper normal limit −38 (95%) patients. At least 4 cycles of chemotherapy were administered to 35 (93%) patients, with 28 (70%) receiving 6 cycles. CNS prophylaxis was administered with intrathecal methotrexate (median number-6) to 36(90%) patients. High dose methotrexate was given to 5 patients. Rituximab was not administered to 5 patients (3 due to CD4 count <100, 2 due to CD20 negativity). Responses were assessed using 18FDG PET-CT scan with complete response-32(80%), partial response-1(3%), disease progression-4(10%) and not evaluable- 4 (7%). Grade 3/4 toxicities were seen in 33(83%) patients, with febrile neutropenia-26(65%), mucositis-10(25%) and peripheral neuropathy in5(13%) patients. Out of the 210 cycles administered, there were 41(20%) episodes of hospitalization (duration ranged from 2–51 days). There were 11(28%) deaths (progression-7, toxicity-2, Not known-2) and 7(18%) patients had progression (4- on treatment progression, 3- relapses). With a median follow-up of 47 months, estimated 4-year OS is 72% (Figure 1) and 4-year disease-free survival is 82%. There was no difference in survival based on IPI, CD 4+ T cell count, CDI or duration of HIV.Summary/Conclusion: R-EPOCH is a highly effective regimen in seropositive high-grade B-cell lymphoma even in the presence of adverse features.

Background:R‐da‐EPOCH provided excellent results in PMLBCL in a phase 2 NCI trial and appeared to obviate the need for consolidative radiotherapy (RT). However, there is no direct randomized comparison of R‐da‐EPOCH vs R‐CHOP. A recent retrospective comparison revealed a modest, non‐significant benefit in disease control but much less use of RT with R‐da‐EPOCH. However, the selection of each regimen was at the treating physician's discretion, so that bias was inevitably introduced.Aims:To compare the efficacy of R‐da‐EPOCH for disease control and omission of RT in PMLBCL compared to R‐CHOP.Methods:In 10 participating Centers in Greece, R‐da‐EPOCH was adopted at a certain timepoint for all patients with PMLBCL, while R‐CHOP (21‐day >> 14‐day schedule) had previously been the standard of care. Consolidative RT was used at the discretion of the treating physician. R‐CHOP controls (<65 years old) were selected from our database among consecutive patients treated at the same Centers, starting from the most recent patient and selecting, if possible, an equal number of R‐CHOP patients to those treated with R‐da‐EPOCH, going backwards. Thus, selection bias was minimized.Results:R‐da‐EPOCH was given in 52 consecutive patients (median follow‐up 17 months). Appropriate consecutive R‐CHOP‐treated controls were 43 (median follow‐up 34 months), because R‐da‐EPOCH‐treated patients were more than R‐CHOP‐treated ones in 3 participating Centers. The two groups (R‐da‐EPOCH and R‐CHOP) were absolutely: Age (median 30.5 vs 32), gender (female 69% vs 72%), B‐symptoms (31% vs 36%), performance status ≥2 (35% vs 23%; p = 0.21), stage III/IV (17% vs 12%), any extranodal involvement (27% vs 43%, p = 0.11), any serositis (49% vs 46%), bulky disease (71% vs 75%), LDH levels >twice normal (>2x; 41% vs 39%), anemia (48% vs 42%), leukocytosis ≥10x109/L (31% vs 27%), ESR ≥30 mm/h (78% vs 79%), albumin <4 g/dL (49% vs 45%), age‐adjusted IPI (aaIPI) ≥2 (39% vs 38%) (all p‐values >0.40, unless otherwise stated). Among R‐CHOP‐treated patients 10/43 had treatment failure compared to 5/52 for R‐da‐EPOCH. One R‐da‐EPOCH patient developed early‐onset acute leukemia with t(9;11) and was counted as event in event‐free survival (EFS) analysis. The 2‐year freedom from progression (FFP) was 89% vs 77% (p = 0.22), while the 2‐year EFS was 86% vs 77% (p = 0.35). With 5 deaths recorded (4 in R‐CHOP vs 1 in R‐da‐EPOCH; all disease related), the 3‐year overall survival (OS) was 96% vs 90% (p = 0.27). Among R‐CHOP‐treated patients, 5 did not receive RT due to chemorefractory disease; 29/38 potentially eligible patients (76%) received RT. Among 46 R‐da‐EPOCH‐treated patients who had completed final resonse assessment, 5 did not receive RT due to chemorefractory disease; only 6/41 potentially eligible patients (15%) received RT (p < 0.001). In multivariate analysis of FFP and EFS adjusting for any extranodal involvement and LDH >2x, only LDH >2x was an independent prognostic factor, while the R‐da‐EPOCH vs R‐CHOP difference remained non‐significant.Summary/Conclusion:We report here the least biased non‐randomized comparison between R‐da‐EPOCH and R‐CHOP conducted so far with well‐matched subgroups of consecutively treated patients. Incorporation of more R‐da‐EPOCH treated patients and appropriate controls is ongoing. Although the 2‐year FFP and EFS appeared to be less impressive than originally reported by the NCI group, R‐da‐EPOCH minimized the use of RT in a real‐life setting and provided numerically, but not statistically superior disease control than R‐CHOP for the time being.