Ann Arbor Classification Research Articles

The Interim Efficacy of Epigenetic Priming Regimen with Azacytidine and Chidamide in Patients with Relapsed or Refractory Peripheral T Cell Lymphoma

IntroductionPeripheral T-cell lymphoma (PTCL) is a group of hematological malignancies originating from mature T/NK cells. Most of the subtypes are associated with aggressive clinical features and dismal outcomes. Routine first-line chemotherapy has low efficiency and a high recurrence rate, so there is an urgent need for new drugs. Monotherapy or combination therapy of epigenetic inhibitors have been shown to be effective in several hematologic malignancies. Here, we report the interim efficacy of an epigenetic priming regimen with azacytidine and chidamide prior to salvage chemotherapy for relapsed or refractory (R/R) PTCL.MethodsThe prospective phase II study (ChiCTR2000037232) enrolled pts were pathologically confirmed T/NK cell non-Hodgkin's lymphoma with at least one imaging measurable lesion. Pts needed to have received at least one systemic chemotherapy regimen including hematopoietic stem cell transplantation, radiotherapy, or a single epigenetic drug. Pts received AZA hypodermically at a dose of 100 mg on days 1 to 7, chidamide of 20 mg orally twice per week; the combined chemotherapy regimens included but were not limited to GemOx (gemcitabine, oxaliplatin); CPT (cyclophosphamide, prednisone, thalidomide) , etc. Treatment was performed for up to eight cycles of each 21 days. Pts who achieved partial response (PR) and better remission began maintenance therapy every two months with double epigenetic inhibitors for two years. The trial aimed to explore the efficacy and safety of AZA and chidamide combined chemotherapy in the treatment of R/R PTCL. The primary objective was investigator-assessed best overall response rate (ORR). Secondary objectives included duration of response (DOR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety profiles.ResultsA total of 24 pts have been enrolled, baseline characteristics are shown in Table 1. Pathological subtypes included angioimmunoblastic T-cell lymphoma（AITL, n=15）, PTCL-not otherwise specified (PTCL-NOS, n=4), extranodal NK/T-cell lymphoma (ENKTCL, n=3) and mycosis fungoides(MF, n=2). The median age was 57 (range,38-72) years with male predominance. Ann Arbor Classification ≥ stage III in 20 pts. Twelve pts had B symptoms at the time of diagnosis, five pts had performance status ≥ 3 before treatment. The median number of previous systemic treatment regimens was two. Autologous hematopoietic stem cell transplantation in two pts, radiation in three pts and prior treatments containing chidamide in eight pts. At the time of data cutoff, the median number of treatments for all pts was four cycles (range,1-13). Among 16 pts evaluable for response, the best ORR was 68.8% (11/16) with five pts achieved CR, six achieved PR. In subgroup analysis, eleven AITL pts achieved an objective response. The best ORR was 72.7% (8/11) with four pts attained CR, four attained PR (Table 2). The median follow-up was 12.4 (range, 0.1-18.7) months. For all pts, the median PFS was 6.7 months (95% CI,5.8-7.6), the median OS was 8.4 months (95% CI,0.0-18.3) (Figure 1). And the median DOR was 10.2 months (95% CI,4.9-15.5). For AITL pts, the median PFS was 14.6 months (95% CI,3.6-25.6), and the median OS was not reached (Figure 2). The OS between AITL and other subtypes pts was statistically significant (1-year OS: 76.2% vs 13.9%; p=0.003, Figure 3). Almost all pts had experienced at least one adverse event (AE). The most common grade 3 or 4 AEs were anemia, leukopenia, neutropenia, thrombocytopenia, and infections.ConclusionsEpigenetic priming regimen with azacitidine plus chidamide with salvage chemotherapy is effective and tolerable. The best ORR of all enrolled pts with AITL were 68.8% and 72.7%, respectively. Compare to other subtypes, patients with AITL subtype benefit more obviously from our regimen with durable remission. And further studies will focus on patients with AITL and follicular helper T-cell originated. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

First-Line Treatment and Survival of Stage I(E) Peripheral T-Cell Lymphoma in the Netherlands; A Nationwide Population-Based Cohort Study

Introduction: Peripheral T-cell lymphomas (PTCL) comprise a heterogenous group of mature T-cell neoplasms with generally an unfavorable prognosis. Presentation of PTCL with stage I(E) disease, according to the Ann Arbor classification, is uncommon. Clinical trials in diffuse large B-cell lymphoma (DLBCL) support the use of an abbreviated treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone combined with radiotherapy (combined modality therapy (CMT)) in case of stage I(E) disease. CMT in stage I(E) PTCL has been adapted in daily practice, but clinical trials are lacking. A recent population-based study conducted in Scandinavia indicated that the outcome in patients with limited stage PTCL is as poor as in patients with extensive disease. However, the outcomes of different treatment modalities were not analyzed.Aim: The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL in comparison to advanced stage PTCL.Methods: All newly diagnosed patients ≥ 18 years with stage I(E) PTCL who were diagnosed in 1989-2018 were identified in the Netherlands Cancer Registry (NCR). Survival follow-up was available through February 1, 2021. The PTCL subgroups analyzed included anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma (EATL) and peripheral T-cell lymphoma NOS (PTCL NOS). Patients were categorized according to treatment regimen, i.e. chemotherapy, chemotherapy followed by autologous stem cell transplantation (ASCT), radiotherapy, CMT, and no/other therapy. Calendar period analyses (1989-1999 and 2000-2018) were conducted to assess trends in primary therapy and overall survival (OS) over time. The calendar periods were defined according to the implementation of CMT in patients with limited stage DLBCL from approximately 2000 onward in the Netherlands. The primary endpoint was OS, defined as all-cause-death post-diagnosis.Results: From 1989 to 2018, 854 patients with a median age of 62 years were diagnosed with stage I(E) PTCL, accounting for 19% of all PTCL diagnoses. In stage I(E), the predominant PTCL subtype was PTCL NOS (40%, n=343). Furthermore, 26% (n=222) of patients were diagnosed with ALCL, 3% (n=28) with AITL, 11% (n=93) with EATL and 20% (n=168) with other histological subtypes. In contrast, for patients with advanced stage disease, 42% was diagnosed with PTCL NOS, 23% with ALCL, 24% with AITL, 6% with EATL and 5% with other histological subtypes .To evaluate treatment and survival outcome in patients with stage I(E) PTCL, patients with ALCL, AITL, PTCL NOS and EATL were included for further analyses (n=686). Patients with ALCL, AITL and PTCL NOS were most commonly treated with CMT (n=164; 28%) or chemotherapy only (n=154; 26%). Only 10 patients (1%) received chemotherapy followed by ASCT. The remaining patients were treated with either radiotherapy only (n=116; 20%) or received other/no therapy (n=149; 25%). More patients were treated with CMT in 2000-2018 as compared to 1989-1999 (36% versus 17%, p<0.01). Patients with EATL were most commonly treated with either chemotherapy only or other/no treatment (both n=45; 48%), while 3 patients (4%) received chemotherapy in combination with ASCT (n=2) or CMT (n=1). In EATL, no differences in treatment strategy were observed over time.Overall, 5-year OS for all stage I(E) PTCL was 52%. There was no significant difference in outcome between the two time periods (53% vs. 52%, p=0.92). EATL had a worse prognosis when compared to ALCL, AITL and PTCL NOS (5-year OS 15% vs. 58%, respectively; p<0.01). Five-year OS was significantly higher for patients with ALCL, AITL and PTCL NOS treated with CMT (71%) as compared to patients treated with either chemotherapy alone or with radiotherapy alone (52%, and 53%, respectively; p<0.01). Independent predictors for poor prognosis were higher age, male gender and EATL subtype whereas CMT was associated with a lower risk of mortality when evaluated for in multivariable analysis.Conclusions: For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 58%. This compares favorably to the reported outcomes in advanced stage disease. EATL, even when presenting with limited stage disease, is associated with a very poor prognosis. CMT is associated with superior OS when compared to either chemotherapy or radiotherapy alone. DisclosuresVan Der Poel: Roche, Janssen, Abbvie: Honoraria. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.

Primary Intestinal Lymphoma: Clinicopathological Characteristics of 55 Patients.

IntroductionGastrointestinal (GI) tract is the most common site of extranodal lymphoma accounting for 30–40% of the cases. In Western countries, stomach is the most common site of GI lymphoma, whereas in the Middle East and Mediterranean countries, small intestine is commonly involved. Studies about primary intestinal lymphoma (PIL) are heterogeneous in anatomical distribution, presentation, and histological subtypes. The present study was aimed at studying the anatomical distribution, histological subtypes, and clinical characteristics at tertiary care centers.Materials and methodsThe present study was retrospective, conducted between 2006 and 2020. Patient's data were collected from institutional medical records. PIL was diagnosed by Lewin's criteria. After histological diagnosis, PIL was classified as per the World Health Organization (WHO) criteria and staging was done according to the Ann Arbor classification as modified by Musshoff.ResultsA total of 941 lymphoma cases were diagnosed during the study period between 2006 and 2020 consisting of 238 Hodgkin's lymphoma and 703 non-Hodgkin's lymphoma (NHL) cases. PIL constituted 5.8% of all lymphoma cases (55 out of 941) and 50.9% (55 of 108) of all primary GI lymphoma. Median age at diagnosis was 44 years and comprised predominantly males (85.45%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma were the most common histological subtype (78%) seen. Two patients with primary Hodgkin's lymphoma involving the intestine were seen. T-cell lymphoma was seen in three (5.4%) patients. Ileocecal region was the most common site involved (27%). The common presenting complaints were intestinal obstruction (40%) requiring surgical resection and abdominal pain (32%). Majority of the patients presented in the early stages (I and II).ConclusionOur study demonstrates the pattern of distribution and various histological subtypes of PIL including the rare variants like primary intestinal Hodgkin's lymphoma. Relatively more number of patients presented with intestinal obstruction requiring surgery in comparison with other studies.How to cite this articleMalipatel R, Patil M, Rout P, et al. Primary Intestinal Lymphoma: Clinicopathological Characteristics of 55 Patients. Euroasian J Hepato-Gastroenterol 2021;11(2):71–75.

Ocular adnexal lymphoma: A single-institution retrospective study.

PURPOSE:To characterize demographic, clinical, and histopathologic features of ocular adnexal lymphoma (OAL) at a single institution.METHODS:Retrospective review of all patients with pathologic diagnosis of OAL between 2015 and 2020.RESULTS:There were 133 patients with OAL, with a median age of 65 years (range 23–97) and a slight female predominance (male: female = 1:1.46), (n = 79, 59%). The majority of tumors were non-Hodgkin B-cell lymphomas (n = 131, 99%), most frequently Extranodal Marginal Zone B-Cell Lymphoma (EMZL, n = 93, 70%), followed by follicular lymphoma (n = 21, 16%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7, 5%), diffuse large B-cell lymphoma (n = 5, 4%), and mantle cell lymphoma (n = 5, 4%). The most frequently involved sites included the orbit (n = 85, 64%) and conjunctiva (n = 43, 32%). Information was available on oncologic staging in 78 (59%), treatment in 82 (62%), and follow-up in 75 (56%) patients. By the Ann-Arbor classification system, patients were classified as IE (54/78, 69%), IIE (9/78, 12%), IIIE (6/78, 8%), and IVE (9/78, 12%). The most common treatments included external beam radiotherapy (standard and ultra-low-dose) (48/82, 59%), biologics (22/82, 27%), and surgical excision with cryotherapy (14/82, 17%) (some patients had >1 therapy). Median follow-up time was 24 months (range 0–221 months). Recurrence was observed in 13% (10/75) with a median time to recurrence of 60 months (95% confidence interval 47–73 months). Excision with cryotherapy as a sole treatment modality was associated with earlier recurrence (P = 0.003).CONCLUSION:In this largest single-center study of OAL, we found that most OAL were Ann-Arbor Stage IE EMZL, occurring in older patients with a female predominance. Early recurrence was noted in tumors treated with excision and cryotherapy alone.

Results of Inter-B-NHL Ritux 2010 - Phase II Study of DA-EPOCH-R for Children and Adolescents with Primary Mediastinal Large B-Cell Lymphoma (PMLBL) on Behalf of European Intergroup for Childhood Non Hodgkin's Lymphoma (EICNHL) and Children's Oncology Group (COG)

BackgroundDose Adjusted EPOCH with Rituximab (DA-EPOCH-R) has been shown to deliver excellent survival for adults with PMLBL (Dunleavy K et al. NEJM 2013; 368:1408-16). We evaluated this regimen in a prospective international trial of children and adolescents with this disease.MethodsThe international phase II trial (NCT01516567) sponsored by Gustave Roussy and COG, evaluated the event-free-survival (EFS) following DA-EPOCH-R in patients with PMLBL aged <18 years. A total of 6 courses of DA-EPOCH-R with escalation of doses as in published literature were delivered. A course of cyclophosphamide, vincristine and prednisolone (COP) was allowed 1 week prior to commencement of DA-EPOCH-R for urgent treatment whilst awaiting histological confirmation. The primary endpoint was EFS with events as presence of viable cells in residue after 6th course, progression, relapse, second malignancy or death from any cause. The efficacy of DA-EPOCH-R was assessed by comparing the observed EFS with that of the historical rate modeled by [S(t) = 0.67 + 0.33{exp(-1.5t)}] (t in years), using the one-sample log-rank test. The planned sample size was 40 patients.ResultsBetween April 2012 and April 2016, 47 eligible patients (35 from Europe and 12 from COG) were recruited across 7 countries. Twenty-seven were female and the median age was 15 years. Thirty-two percent of patients had lactate dehydrogenase (LDH)> 2xNormal, 66% had mediastinal mass >10cm and 16% were Stage IV by Ann Arbor classification. Pathological review is ongoing (15/47 cases already reviewed). Due to a protocol error 7 patients received only half dose predniso(lo)ne in DA-EPOCH-R and on the recommendation of the Independent Data Monitoring Committee the additional 7 patients were recruited. The primary analysis was restricted to the 40 patients treated according to the full predniso(lo)ne dosing. Sensitivity analyses were conducted on the whole group of 47 patients. The median follow up was 27 months (range 9.9- 53 months)Forty percent of patients (17/47) received a COP prior to the first course of DA-EPOCH-R. The protocol was well tolerated and 47% (22/47) of patients reached dose level 4 or higher. Febrile neutropenia was seen in 11% (30/281) of courses. One patient experienced left ventricular systolic dysfunction (grade 2) at dose level 6.Eighty-five percent (39/46) of patients achieved complete remission (CR) or CR (unconfirmed). There were 13 events (11 relapse/refractory or progression and 2 second malignancies). Isolated CNS relapse occurred in 2 patients. The observed 2-year EFS among the 40 patients who received full dose prednisolone of 69% (95%CI 52%-82%) did not differ from the historical rate (p=0.71). A similar result was seen in the sensitivity analysis of all 47 patients (EFS 72% (95% CI 57%-84%), p=0.68). The 2-year overall survival rate for all 47 patients was 82% (95%CI 67-91%). An analysis of prognostic factors for the whole group showed that the presence of extrathoracic involvement was associated with associated with inferior outcome in multivariate analysis (HR 5.62[1.49-21.2], p=0.011).ConclusionDA-EPOCH-R did not improve the EFS compared to a historical control in this international study of children and adolescents with PMLBL in contrast to the published adult series. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma. DisclosuresBollard:Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Torque: Membership on an entity's Board of Directors or advisory committees.

Low High-Density Lipoprotein Cholesterol (HDL) Is a Significant Poor Prognostic Factor in Malignant Lymphoma

Objective: HDL is reportedly an independent prognostic factor in some malignant lymphoma (ML). We retrospectively analyzed the correlation between the prognosis of ML, including both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) and dyslipidemia in patient cases from our experience.Methods: Analyzed patients were; ML patients admitted to our hospital between April, 2009 and March, 2015. We excluded the patients who did not receive any treatments or were observed for less than two years after starting treatment. Dyslipidemia was defined as blood serum HDL, low-density lipoprotein cholesterol (LDL), and Triglyceride (TG) levels <40 mg/dL, >140 mg/dL, and >150 mg/dL, respectively. We performed statistically univariate and multivariate analyses.Results: Analyzed patients were: total 221 patients, median age of 68 (20-89), male 130 and female 91, B cell NHL 183, T/NK cell NHL 29, HL 8, and others 1, age under 60 62 and above 60 159, Performance Status (PS) 0-1 172 and 2-4 49, Ann Arbor classification I-II 48 and III-IV 173. 57 patients were deceased and 164 were alive at the analysis. The low HDL group (97 cases) showed a significantly shorter survival than high HDL group (124 cases; p = 0.0001), while there were no correlations between either high TG (38 cases) or high LDL (22 cases) and survival. In multivariate analysis, PS 2 or more, and low HDL were extracted as significant adverse prognostic factors.Discussion: The mechanisms of this correlation between survival of ML and low HDL level are still unclear. It is reported that inflammatory cytokines produced by ML cells may induce dyslipidemia. Because scavenger receptor-B1 with high affinity for HDL is highly expressed on ML cell-surface, it is possible that low HDL is correlated to the ML tumor-volume or fast tumor turnover. Since expression of scavenger receptor-B1 is low on normal lymphocytes, consumption of HDL may occur in ML. In this point there have been several attempts for treatment using HDL, such as an administration of HDL nanoparticle as a drug delivery vehicle in animal lymphoma-models. Thus, we will further investigate this correlation between HDL and ML with more patients and also study the mechanism. DisclosuresNo relevant conflicts of interest to declare.

A Randomized, Double-Blind, Phase III Study Comparing Proposed Biosimilar Rituximab (RTXM83) Versus Reference Rituximab, Both in Combination with CHOP, in the First Line Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Methods: RTXM83 is a proposed biosimilar developed by mAbxience S.A. to the reference medicine product rituximab (MabThera®/ Rituxan®). A prospective, multicenter, double-blind, randomized trial compared the efficacy in terms of non-inferiority, pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of RTXM83 vs rituximab (Mabthera®/Rituxan®), both in combination with CHOP chemotherapy (RTXM83-CHOP vs R-CHOP), as first-line treatment in patients with previously untreated CD20+ Diffuse Large B Cell Lymphoma (DLBCL). Adults aged ≥18 and ≤65 years, with a disease stage of I (only with bulky disease) to IV according to the Cotswolds modification of the Ann Arbor classification, and ECOG performance status ≤2 were included, and randomized (1:1) to receive up to a total of six cycles of either RTXM83-CHOP or R-CHOP. Patients were stratified according to study center and age-adjusted IPI scores (0 versus 1), which are based on: disease stage, ECOG, and lactate dehydrogenase (LDH) levels.The primary endpoint was to assess the response rate (RR) (complete response + partial response) achieved after cycle 6 of treatment by the International Working Group (IWG) criteria. PK, PD, safety and immunogenicity were assessed as secondary study endpoints. For PK, the systemic exposure (AUC and Cmax) were assessed at Cycle 1 and steady-state at Cycle 6 using a population PK (Pop PK) model approach. The serum levels of CD20+/CD19+ cells for PD profile, and of anti-drug antibodies (ADA) for immunogenicity assessment were analysed at different time points: start of treatment (Cycle 1 Day 1, pre-dose), at Cycle 5 Day 1 (pre-dose), at Cycle 6 Day 21 and during the follow-up period: FU 1 (3 months after last dose of treatment) and follow-up 3 if available (9 months after last dose of treatment).Results: A total of 241 patients, 123 in the RTXM83-CHOP arm and 118 R-CHOP arm, from 58 sites in 12 countries were eligible. Demographic and baseline characteristics were well balanced between arms. A difference of 3.9% in the RR in favour of the RTXM83-CHOP arm was achieved in the per protocol population (RR: 84.7% vs 80.8% in RTXM83-CHOP and the R-CHOP arm, respectively). The lower bound of the 95% CI of this difference (-6.20% to 14.03%) was above the non-inferiority margin of -13% that was set for the study.The Pop PK comprised a total of 5341 samples from 251 patients. Geometric least square means ratios (GLSMR) with the 90% CI of RXTM83/rituximab were 99.2% (93.6-105) for AUC and 99.6% (93.9-105) for Cmax,sd at Cycle 1 whereas, at steady-state the GLSMR were 103% (98.5-107) for AUC and 104% (99.5-109) for Cmax,ss. RXTM83 and rituximab exhibited a comparable serum concentration-time profile and the GLSMR were within the predefined margins of 80-125%. PD profile in terms of time of onset, magnitude and duration of response was similar between RTXM83 and rituximab.Safety assessment shows no obvious differential safety profile of RXTM83 and rituximab in terms of nature, frequency and severity of the adverse events (AE); being infections and blood and lymphatic system disorders the most common SAEs reported.A low and similar ADA incidence was observed in both treatment arms, with no relationship with efficacy, safety or PK/PD data was observed.Conclusion: These results demonstrate that RTXM83 has comparable efficacy to rituximab in terms of tumour response, and displays a similar PK profile, PD activity, safety profile and immunogenicity in the first line treatment of patients with newly diagnosed DLBCL, which supports the claim that RTXM83 is highly similar to the reference medicine rituximab (MabThera® / Rituxan®). DisclosuresGonzalez:Lab Eticos: Other: Principal Investigator. Radhakrishnan:Cancer Institute Adyar Chennai India: Employment. Schusterschitz:Libbs: Research Funding. Perez:Mabxience SA: Employment.

Clinical and pathological analysis of ocular adnexal diffuse large B-cell lymphoma

Objective: To summarize the clinical and pathological characteristics of diffuse large B-cell lymphoma of ocular adnexal (OA-DLBCL). Methods: A retrospective case series study. Twenty-three cases of OA-DLBCL were collected in Tianjin Eye Hospital from January 2005 to December 2018. The clinical manifestations and imaging examination results were analyzed. The pathological characteristics and immune subtypes were analyzed with hematoxylin and eosin staining and immunohistochemistry. Eighteen patients completed the follow-up. Overall survival (OS) time was from the date of diagnosis to the date of death or the final follow-up (April 30, 2020). Clinical stages were analyzed by the Ann Arbor classification; Kaplan-Meier plots were used to visualize survival outcomes. The different risk groups were compared using Log-rank test. Results: There were 13 males and 10 females. The median age was 65 years (range, 43 to 82 years). Twenty-two patients had unilateral lymphoma (14 left eyes, 8 right eyes), and one patient had bilateral lymphoma. The OA-DLBCL was in the orbit in 14 patients, in the lacrimal gland in two patients, in both the lacrimal gland and the orbit in three patients, in both the lacrimal sac and the orbit in one patient, in the conjunctiva in one patient, in both the conjunctiva and the orbit in one patient, and in the skin of eyelids in one patient. Imaging examinations showed the tumors were of irregular soft tissue density. MRI showed the tumors were close to the extraocular muscles or ectocinerea. Centroblastic morphology was present in 21 specimens, and 2 specimens had immunoblastic morphology. Six patients were of germinal center B cell-like (GCB) type, and 17 were of non-GCB type. There were 2 patients with double expression of cellular-myelocytomatosis viral oncogene and B-cell lymphoma 2. The follow-up time ranged from 25 to 156 months, and the median follow-up time was 48 months. Five of them had primary OA-DLBCL, and 13 patients had secondary OA-DLBCL. Five patients were at the Ann Arbor clinical stage ⅠE, one was at stage ⅢE, and 12 were at stage ⅣE. During the follow-up, 8 patients survived, and 10 died. The 1-, 3-, and 5-year OS rates were 88.9%, 71.4% and 41.7%, respectively. Log-rank analysis indicated that the Ann Arbor clinical stage and age were related to the OS of OA-DLBCL (χ²=7.448, 8.804; both P<0.01). The gender, tumor size, molecular typing, Ki-67 index, and bone invasion were not related to the OS of OA-DLBCL (all P>0.05). Conclusions: OA-DLBCL mainly occurrs in the elderly population, unilaterally, and in the orbit. Most molecular types are non-GCB subtypes. The Ann Arbor clinical stage and age are associated with prognosis. (Chin J Ophthalmol, 2021, 57: 366-371).

A rare case of nodular lymphocyte predominant Hodgkin lymphoma, which developed 5 years after successful treatment of diffuse large B-cell lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLHLP) – B-cell lymphoma, which has been historically added to the group of Hodgkin's lymphomas, despite the peculiarities of the clinical course, treatment and prognosis, as well as morphological and immunophenotypical differences. In 75% of cases, the disease is detected at early stages (I–II according to Ann Arbor classification), has an indolent course and a favorable prognosis with 10-years an overall survival rate, more than 80%. Despite this, with long-term follow-up and the development of frequent relapses, transformation into diffuse large-cell B-cell lymphoma (DCBCL) or T-lymphocyte/histiocyte-rich DCBCL can occur, isolated cases in children. In the world literature, there are isolated cases of the development of NLHLP after treatment of DCBKL in adults, while among the pediatric population, cases have not been described. This article presents a clinical case of DCBKL in a 10-year-old child who, 5 years after the end of treatment, developed nodular Hodgkin's lymphoma with lymphocytic predominance. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

Gastric Mucosa-associated Lymphoid Tissue Lymphoma: An Important Differential Diagnosis for a Rapidly Growing Gastric Subepithelial Tumor - A Case Report and Literature Review

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade lymphoma with a long median survival time because of its low proliferation rate. A 75-year-old man was referred to the hospital for hematemesis. Upper endoscopy revealed a 30-mm subepithelial tumor (SET). Abdominal CT and EUS revealed a homogeneously hypoechoic lesion arising from the second layer of the stomach, without distant metastasis. Laparoscopic wedge resection was performed. On microscopic examination, the tumor showed diffuse aggregation of small lymphoid cells with abnormal architecture. Neoplastic cells showed positive reactivity for CD20 and prominent lymphoepithelial lesions were observed. The urease breath test was also conducted, with a negative result. Our final diagnosis was &lt;i&gt;Helicobacter pylori&lt;/i&gt;-negative MALT lymphoma (Ann Arbor classification I&lt;sub&gt;E2&lt;/sub&gt;), which is a rapidly growing SET pattern. This case highlights the importance of including gastric MALT lymphoma as a differential diagnosis for rapidly growing gastric SETs.

Radiotherapy for non-gastric intestinal versus gastric MALT lymphoma: a comparison of treatment outcomes.

BackgroundRadiotherapy is often used for treating patients with gastric mucosa-associated lymphoid tissue (MALT) lymphomas who fail to respond to Helicobacter pylori eradication. However, non-gastric intestinal MALT lymphoma is rare, and no standard therapeutic strategies have been established. This study was designed to assess the long-term prognosis of non-gastric intestinal MALT lymphoma treated with radiotherapy and to compare the outcomes with that of post-radiotherapy gastric MALT lymphoma.MethodsThe study included 34 patients with stage I EA gastrointestinal MALT lymphoma according to the Ann Arbor classification who underwent definitive radiotherapy. The primary site was the rectum in 3, the duodenum in 1, and the stomach in 30 patients. The radiotherapy dose was 1.5‒2.0 Gy (median, 1.5 Gy) and the total dose was 30‒40 Gy (median, 30 Gy). The clinical target volume (CTV) was defined as the volume of the entire organ with the lymphoma. Adjacent lymph node areas were not routinely included in the CTV.ResultsComplete response (CR) was achieved in all patients. There were no local recurrences, and two cases of recurrence were observed at other sites. The 5-year overall survival rates for non-gastric and gastric MALT lymphomas were 100% and 94.7%, respectively, and the 5-year disease-free survival rates were 100% and 95.7%, respectively. None of the patients died of the current illness.ConclusionRadiotherapy for non-gastric intestinal MALT lymphoma is expected to result in good local control and long-term survival, similar to that for gastric MALT lymphoma.

Expression features of antigens involved in the formation of immunological synapse in splenic marginal zone lymphoma

Background. Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied.Objective: to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood.Materials and methods. The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis.Results. Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80+, FAS+, PD-1+-cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8+PD-1+ T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

Long-Term Results of the Treatment of Persons with Hodgkin's Lymphoma in a Resource-Constrained Setting: Real-World Data from a Single Center

Background: Hodgkin's lymphoma (HL) is the model of curative care with radiation therapy, combination chemotherapy, staging approaches, peripheral blood stem cell transplantation, and immunotherapy. However, the value of the novel anti cancer drugs has been recently analyzed and questioned in view of the results in the real improvement of overall survival (OS). Material and methods: All consecutive patients seeking medical care after 1986 in our institution as a result of HL and followed for at least 3 months were entered in the study. A diagnosis of HL was based on the histological study of a pathology specimen, mainly a lymph node; the same pathologist analyzed all the specimens and defined the histological subtype. Clinical stage was defined according to the Ann Arbor classification. Bone marrow biopsies were done only in patients with clinical stages III or IV. Computed tomography (CT) scans were done in all cases, prior to starting the treatment. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed since 2002. Between 1986 and 1997, patients were treated with MOPP, and after 1997 with ABVD as frontline therapy. For stages I and II, four cycles of chemotherapy were delivered and a computerized tomography (CT) scan was performed; if lymph node enlargement were present at this point in time, four additional cycles were given, whereas two additional cycles were given if the CT scan was negative. For stages III and IV, the CT scans were performed at the end of six cycles and two or four more cycles. Mediastinal radiotherapy was delivered only to persons with a positive FDG-PET scan at the end of the treatment. Patients showing activity after these treatments were considered as refractory and treated with four courses of ICE (ifosfamide, carboplatin and etoposide). Autologous or allogeneic peripheral blood hematopoietic stem cell transplants (HSCT) were given to refractory patients after achieving a complete remission (CR): High-dose melphalan (200mg/m2) was employed in autologous transplants, whereas cyclophosphamide, fludarabine and busulfan were employed in allogeneic transplants, all of them from HLA-identical siblings. After the completion of the treatment, patients were every two months for one year and every four months later on. No FDG-PET scans were done during the follow up, unless clinically indicated. Results: Among 91 patients with HL identified between 1986 and 2020, 88 were followed three months or more and were included in the analysis. There were 37 females and 51 males. The median age was 29years (range5-73years). There were 62 patients with nodular sclerosing HL (70%), 19 mixed cellularity (HL), 2 lymphocyte depleted HL, and one lymphocyte predominant HL; in 4 cases the histologic variant could not be defined. According to Ann Arbor classification, 5 patients were found in stage I, 48 in stage II, 19 in stage III and 16 in stage IV. Ten patients presented with a mediastinal mass larger than 10 cm. in the chest X-ray film. Three cases presented with relapsed disease. Patients have been followed for a median of 114 months (range4-402). 44 patients are alive, 10 have died and 34 were lost to follow-up. Median OS for all the patients has not been reached, being above 402 months, the OS at 310 months is 88% and at 402 months 77%. Median OS has not been reached and is above 94, 109, 90 and 98 months for stages I, II, III and IV, respectively (p=0.2). The 310-month OS was 83% for patients treated with MOPP and 88% for those treated with ABVD (HR:0.76, 95% CI 0.2-2.8; p=0.6).Sixteen patients (18%) were refractory to the treatment and 9 (10%) relapsed; they were treated with ICE followed by HSCT (autologous 15 patients and allogeneic 10 patients). Patients who underwent auto-HSCT had a median survival of 329.1 months and an OS of 92.3%, whereas those given allo-HSCT had a median survival of 59.3 months and an OS of 45.7% (HR0.2, 95%CI 0.04-1.3, p=0.057). The OS of patients given or not HSCT was 73.5% and 92.9% at 266 and 404 months, respectively (HR4.09, 95%CI 1.0-16.6, p=0.01). The OS was similar. The causes of death were breast carcinoma in 2 cases, liver carcinoma in one and uncontrolled lymphoma activity in the remaining. Conclusion: HL may be less aggressive in Mexican population than in Caucasians. Combined chemotherapy renders acceptable results, irrespective of clinical stage. Disclosures No relevant conflicts of interest to declare.

Non Double-Hit Diffuse Large B Cell Lymphoma Treated with R-CHOP Has Excellent Overall Survival If Interim Scan Shows Partial or Complete Response

R-CHOP chemoimmunotherapy is first line therapy for diffuse large B cell non Hodgkin lymphoma (DLBCL), although R-CHOP may be suboptimal treatment for some subtypes of DLBCL, in particular double-hit (DH) or triple-hit (TH) lymphoma. For assessment of response to chemoimmunotherapy, it has been proposed that PET-CT scan may be superior to CT scan and, in particular, demonstration of metabolic complete response (CR) by PET-CT scan at end of treatment (EOT) may be an important indicator of long term survival. However, the usefulness of follow up scans in asymptomatic patients remains debatable. We wished to assess the role of an interim CT or PET-CT scan (after 3-4 courses of chemoimmunotherapy) in predicting overall survival in patients at our centre with stage II- IV DLCBCL (Lugano Modification of Ann Arbor Classification) who received chemoimmunotherapy with curative intent. We also recorded results of scans at EOT and any further follow up scans. Between 1/7/15 and 1/7/19, 43 consecutive patients receiving R-CHOP had an interim CT or PET-CT scan. 3 of 4 patients with DH lymphoma by FISH testing changed to dose adjusted R-EPOCH after one course of R-CHOP. 39 patients had no evidence of DH, with 37 showing either partial response (PR) (N = 11) or CR (N=26) on interim CT or PET-CT scan. Of these 37 cases, one patient died of neutropenic sepsis, whilst 36 remain alive with 35 in complete remission. 30 of these 37 patients had CT scan and/or PET-CT scan at EOT: 27 were in CR, 2 were in stable PR and 1 patient (in CR on interim PET -CT scan) showed relapse on PET-CT scan. 16 patients in CR at EOT had 55 follow up surveillance scans (median 2, range 1-8) -two further relapses were detected on PET-CT scan, both 4 months after EOT. Two of the relapsed cases are in CR following further chemoimmunotherapy and allogeneic stem cell transplant whilst the other relapsed case is currently responding to further chemoimmunotherapy. 2 patients without evidence of DH showed disease progression on interim scan and were refractory to further chemotherapy, dying within 3 months and 18 months of diagnosis. All 4 patients with DH lymphoma had PR or CR at interim scan but relapsed within 5 to 8 months after diagnosis and proved chemotherapy refractory with death in 3. One patient with DH lymphoma remains in CR following local radiation and maintenance therapy with rituximab, lenalidomide and metformin. In our experience, patients with DLBCL, without DH or TH, who have evidence of response to R-CHOP at interim scan have an excellent prognosis. In this patient cohort, 85 EOT and follow up scans detected 3 relapses, suggesting that the detection rate of follow up scans in asymptomatic patients in this good prognosis group is low and of questionable usefulness. The 3 relapsed patients were readily salvageable by further chemoimmunotherapy with or without allogeneic stem cell transplant. In contrast, patients with DH lymphoma or evidence of disease progression on interim scan have very poor prognosis and urgently require alternative therapy approaches. Disclosures No relevant conflicts of interest to declare.

HL-024: Case Report: Re-Challenging with Pembrolizumab for a Case of Hodgkin Lymphoma with no Transplant with Multiple Relapses

In classical Hodgkin lymphoma (cHl), characterized by the overexpression of PDL1 and PDL2, there is a benefit from novel therapeutic strategy for the relapsed refractory disease, and has been approved by the FDA. A 44-year-old female patient presented in 2007 with diffuse enlarged lymph nodes. Biopsy showed a classical nodular sclerosis HL; stage IV according to the Ann Arbor classification system. She received 6 cycles of chemotherapy ABVD regimen (doxorubicin 25 mg/m2, bleomycin 10 IU/m2, vinblastine 6 mg/m2 IV, dacarbazine 375 mg/m2), leading to complete remission. Upon follow-up, end of 2008, PET-CT showed a relapse. Three cycles of chemotherapy ICE protocol were administered (cisplatin 20 mg/m2 day 1-3, etoposide 75 mg/m2 day 1-3, ifosfamide 1200 mg/m2 day 1-3, mesna 1600 mg/m2 day 1-3). PET-CT showed a complete remission, but the patient refused to have an autologous transplant due to financial difficulties. Early 2017, PET-CT showed a recurrence of disease. Treatment with the anti-CD30 antibody brentuximab vedotin 1.8 mg/kg with bendamustine 100 mg/m2 q3 weeks given for 3 cycles resulted in partial response. We continued the treatment for 3 more cycles with a complete remission. An autologous HSCT was not performed, and she continued the follow up for 1 year. December 2017 a Pet CT scan showed a new relapse, initiation of pembrolizumab 200 mg q3 weeks for 1 year with a partial response on Pet-Ct. November 2018 for financial issues, pembrolizumab was stopped (treatment not approved). A new PET-CT in April 2019 showed a progression of supra and infra diaphragmatic LNs and bone marrow disease. Re-challenging strategy, the patient was re-treated with pembrolizumab 200 mg Q3W, with evidence of disease progression in October 2019, suggesting a pseudo progression. A new PET-CT in January 2020 showed a persistent stable disease. Treatment was continued and new PET-CT in April 2020 showed a stable partial response. In summary, re-treatment with pembrolizumab is still active for non-transplanted recurrent HL with multiple previous relapses treated with pembrolizumab.

Effectiveness and Safety of Subcutaneous Rituximab for Patients With Gastric MALT Lymphoma: A Case–Control Comparison With Intravenous Rituximab

IntroductionRituximab is a standard treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML). We sought to compare the effectiveness and safety of subcutaneous and intravenous rituximab in a retrospective case–control study. Patients and MethodsAll consecutive patients with GML treated with subcutaneous rituximab between January 2017 and December 2018 were included and compared to 3 matched control patients (based on Ann Arbor classification, presence of t(11;18) translocation, history of treatment, and type of current treatment) treated with intravenous rituximab between January 2000 and December 2018. Patients with t(11;18) translocation were treated with rituximab in combination with chlorambucil; the other patients were treated with rituximab alone. Effectiveness was assessed at week 52, and safety was assessed through weeks 0 to 52 and compared by the chi-square test. ResultsTwenty-five patients were included in the subcutaneous rituximab group and 75 in the intravenous group. There was no difference between the groups in complete remission (78% vs. 76%, P = .99) or overall response rates (91% vs. 89%, P = .99) at week 52. Safety profiles were similar in both groups, with a significant decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group. ConclusionIn a small case–control study, we did not find any difference in the effectiveness or safety profiles between subcutaneously and intravenously delivered rituximab for the treatment of patients with GML. We found a decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group.

Burkitt lymphoma of the breast associated with hiv infection – a case report and literature review

Introduction: Breast lymphoma is a rare variety of this class of tumor in extra-nodal sites, accounting for less than 0.5% of malignant breast neoplasms and less than 3% of extra-nodal lymphomas. The most prevalent type of breast lymphoma is non-Hodgkin lymphoma (NHL) of large B cells. Burkitt lymphoma (BL) occurs in less than 6% of cases and is considered an even rarer subtype of the disease. According to the World Health Organization (WHO), BL can be classified into three clinical forms: endemic (associated with the Epstein-Baar virus), sporadic, and immunodeficiency-related. The clinical presentation of breast lymphoma is similar to that of carcinoma, and imaging tests cannot differentiate them. Objective: This case report aims at providing better knowledge about BL of the breast and conducting a literature review. Case report: A 52-year-old woman with a history of left breast carcinoma (2009) was surgically treated with quadrantectomy, sentinel lymph node biopsy in the left axilla, and adjuvant radiotherapy and hormone therapy. In 2019, she was diagnosed with Human Immunodeficiency Virus (HIV) infection and started antiretroviral therapy (ART). Four months later, she noted nodules in her left breast and underwent imaging and histopathological investigation of the lesions. Immunohistochemical results revealed NHL, with characteristics suggestive of BL of the breast. Positron emission tomography-computed tomography (PET-CT) for disease staging indicated lymphoma in stage IV-A (Ann Arbor Classification, 1988). The patient was admitted by the hematology team of the Hospital de Câncer de Barretos to start chemotherapy. Discussion: BL of the breast affects mainly young women, and its association with the pregnancy/lactation period is not unusual, which suggests a hormonal influence on its development. Secondary breast disease is more common, and differentiating primary and secondary lymphoma can be difficult. When associated with immunodeficiency, it is more frequent in patients infected by HIV, and less in individuals with other immunodeficiency causes. The breast lesion can be characterized by a painless nodule and possible systemic symptoms (sweating, fever, or weight loss). The main management of these cases consists of polychemotherapy, and the benefit of radiotherapy is unclear. Surgical treatments, such as mastectomy, are not indicated and are associated with worse survival. Conclusion: BL of the breast associated with immunodeficiency, concomitant with HIV infection, is an uncommon neoplasm that can progress to a poor prognosis. The appropriate and prompt diagnosis allows starting the best form of treatment and avoids unnecessary surgical procedures.

Extranodal Ocular Adnexal Marginal Zone Lymphoma in a Ten-Year-Old Child

A 10-year-old girl was brought to the clinic with the complaint of a salmon-colored conjunctival lesion for 1 month. With the aid of histopathological evaluation and other tests, extranodal ocular adnexal marginal zone lymphoma was diagnosed. The patient was graded as T1bN0M0 according to AJCC and Stage 1 according to Ann Arbor classification. She was treated with external radiotherapy at 1.8 Gy/day for 17 days for a total dose of 36 Gy. She is in remission for 26 months and still being followed up.

A comparative study of interventions in spinal extranodal Non-Hodgkin's lymphoma: A single-center case series from North India

Introduction: Non-Hodgkin's lymphoma (NHL) is highly sensitive to chemotherapy and responds to adjuvant chemotherapy within days. Review of literature reveals very limited studies with low statistical significance that compare the surgical and nonsurgical outcomes of spinal NHL. This study aims to compare the surgical and nonsurgical outcomes of spinal extranodal lymphoma causing metastatic spinal cord compression (MSCC). Materials and Methods: We retrospectively analyzed the treatment records of 14 cases out of 32 cases with biopsy-proven diagnosis of NHL involving the spinal column from January 2014 to January 2020. Five (35%) cases were managed nonsurgically with chemotherapy and 9 (64%) patients were managed surgically with adjuvant chemotherapy. Variables taken for evaluation were Karnofsky Performance Status (KPS), Frankel Grade, Spinal Instability Neoplastic Score, Ann Arbor Staging System, and International Prognostic Index (IPI) score. Results: The mean age was 51.9 ± 9.6 years and the median follow-up was 32.5 months. The most study population belonged to Grade III and IV Ann Arbor classification. At final follow-up, 100% of patients in the nonsurgical group and 66% in the surgery group were able to carry out normal activities (KPS >70). All three reported deaths occurred in the intervention group (KPS ≤40) and all deaths occurred within the 6 months of surgery. Conclusion: Primary chemoradiotherapy is mainly indicated in patients of nonemergent mild-to-moderate (Frankel grade >C) neurological deficit patients. Combination therapy (chemotherapy + surgery) is indicated in patients with emergent severe neurological deficit (Frankel Grade A, B, and C), spinal instability, and patients not responding to systemic or adjuvant chemotherapy.

A comparison of clinical staging using the Lugano versus Ann Arbor classifications in Japanese patients with Hodgkin lymphoma.

The Lugano classification is a novel staging system for lymphomas established in 2014. In this staging system, 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was formally incorporated into standard staging for FDG-avid lymphomas, including Hodgkin lymphoma (HL). We retrospectively analyzed patients with HL who were newly diagnosed and treated at our institution to evaluate the utility of the Lugano classification compared to the Ann Arbor classification in Japanese patients with this type of lymphoma. Patients newly diagnosed with HL between 2005 and 2011 were identified through our departmental database. Data from neck-chest-abdomen-pelvis CT scans, BM examinations, and FDG-PET/CT that were routinely performed for staging at our clinical practice were retrieved and analyzed. Fifty-four patients with a median age of 35.5 years (range: 15-78 years) were investigated in this retrospective study. The Lugano stage matched the Ann Arbor stage in 46 patients (85%). Six patients (11%) were upstaged while two (4%) were downstaged per the Lugano classification. Four patients (7%) were converted from early stage to advanced stage, but none was converted in the reverse. Among 11 patients (20%) with PET-positive bone/bone marrow lesions, only one (2%) exhibited biopsy-proven bone marrow involvement of HL cells. Our data revealed a high concordance rate between the Lugano and Ann Arbor staging system in Japanese patients with HL. Because of its low diagnostic value, routine bone marrow examination might be unnecessary for staging when FDG-PET/CT is used as a substitute.