CD5-positive Diffuse Large B-cell Research Articles

Long-term outcomes with HLX01 (HanliKang®), a rituximab biosimilar, in previously untreated patients with diffuse large B-cell lymphoma: 5-year follow-up results of the phase 3 HLX01-NHL03 study

HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

REFLECT: prospective multicenter non-interventional study evaluating the effectiveness and safety of Sandoz rituximab (SDZ-RTX; Rixathon®) in combination with CHOP for the treatment of patients with previously untreated CD20-positive diffuse large B-cell lymphoma.

REFLECT is the first prospective study of Sandoz biosimilar rituximab (SDZ-RTX) in patients with diffuse large B-cell lymphoma (DLBCL). To evaluate the 2-year effectiveness and safety of SDZ-RTX as first-line treatment for DLBCL. Real-world, multicenter, open-label, single-arm, non-interventional, post-approval study of SDZ-RTX in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with treatment-naïve CD20‑positive DLBCL. Treatment-naïve, CD20-positive adult patients (⩾18 years) with DLBCL eligible for therapy with R-CHOP were treated with SDZ-RTX-CHOP every 2 or 3 weeks for 6-8 cycles. The effectiveness of SDZ-RTX was measured by the complete response (CR) rate at the end of R-CHOP treatment, as assessed by the treating physician. Progression-free survival (PFS) was assessed at 24 months. A total of 169 patients [52.1% female, median (range) age 70 (24-94) years] with DLBCL were included in the full analysis set. At baseline, 19.5% and 24.3% of patients had Ann Arbor disease stage III or IV, respectively, and most patients (80.5%) had Eastern Cooperative Oncology Group Performance Status of 0 or 1. A total of 100 (59.2%) patients completed the 24-month observation period. In total, 110 [65.1%; 95% confidence interval (CI): 57.4-72.3] patients achieved CR as best response and 50 (29.6%; 95% CI: 22.8-37.1) patients achieved partial response. Overall best response rate was 94.7% (95% CI: 90.1-97.5). One-year PFS was 84.9% (95% CI: 78.2-89.6), while 2-year PFS was 78.5% (95% CI: 70.9-84.4); median PFS was not reached within the observational period. A total of 143 (84.6%) patients experienced ⩾1 adverse event, 53 (31.4%) of which were suspected to be related to study drug. This real-world, 2-year study reconfirms that first-line treatment of CD20-positive DLBCL with R-CHOP using SDZ-RTX is effective and well tolerated. N/A.

Primary Diffuse Large B-Cell Lymphoma of the Frontal Sinus.

A 73-year-old male presented with 6 months of right upper eyelid swelling and 3 weeks of progressive binocular diplopia. Examination was notable for right eye vision of 20/70, near-complete motility restriction, proptosis of 4 mm, complete ptosis, periorbital edema, and conjunctival injection (Fig. 1A); slip lamp and dilated examination were otherwise normal. CT demonstrated a large, homogenous, expansile mass extending from the right frontal sinus into the superior extraconal orbit. He was scheduled for surgery and placed on a preoperative prednisone taper. In the intervening month, he experienced rapid progression of disease, with severe periorbital edema and hemorrhagic chemosis (Fig. 1B). He underwent right anterior orbitotomy and frontal sinus exploration, total ethmoidectomy, and maxillary antrostomy. Orbital exploration revealed a firm, grey-tan-colored tumor invading the superior orbit (Fig. 1C). Histopathology revealed CD5 positive diffuse large B-cell lymphoma with MYC gene rearrangement. Staging work-up, including MRI (Fig. 2, top), revealed an interval increase in lesion size, with encasement of the right superior, medial, and lateral rectus muscles, superior oblique muscle, and optic nerve. He was diagnosed with stage IE diffuse large B-cell lymphoma of the frontal sinus and right orbit. He completed 3 cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone and consolidative radiotherapy. Follow-up nasal endoscopy, positron emission tomography, and MRI (Fig. 2, bottom) showed complete metabolic response. Primary frontal sinus lymphoma is a rare entity, typically manifesting with mass effect or cranial nerve palsy. It may mimic benign lesions, such as mucoceles, on imaging. Timely recognition and multidisciplinary management are crucial to reduce associated morbidity.FIG. 1.: From initial presentation (A) to day of surgery (B), the patient experienced rapid progression of disease, with severe periorbital edema and hemorrhagic chemosis. Orbital exploration (C) revealed a firm, grey-tan-colored tumor invading the superior orbit.FIG. 2.: Pre-chemoradiation, magnetic resonance imaging (top) showed a large, expansile mass extending from the right frontal sinus into the superior extraconal space, with encasement of multiple extraocular muscles and the optic nerve. Post-treatment imaging (bottom) demonstrated complete metabolic response.

Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Impact of bone marrow biopsy on response assessment in immunochemotherapy-treated lymphoma patients in GALLIUM and GOYA

AbstractThe utility of posttreatment bone marrow biopsy (BMB) histology to confirm complete response (CR) in lymphoma clinical trials is in question. We retrospectively evaluated the impact of BMB on response assessment in immunochemotherapy-treated patients with previously untreated follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 3 Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With Rituximab Plus Chemotherapy Followed by Obinutuzumab or Rituximab Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM; NCT01332968) and A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA; NCT01287741) trials, respectively. Baseline BMB was performed in all patients, with repeat BMBs in patients with a CR by computed tomography (CT) at end of induction (EOI) and a positive BMB at baseline, to confirm response. Positron emission tomography imaging was also used in some patients to assess EOI response (Lugano 2014 criteria). Among patients with an EOI CR by CT in GALLIUM and GOYA, 2.8% and 4.1%, respectively, had a BMB-altered response. These results suggest that postinduction BMB histology has minimal impact on radiographically (CT)-defined responses in both FL and DLBCL patients. In GALLIUM and GOYA, respectively, 4.7% of FL patients and 7.1% of DLBCL patients had a repeat BMB result that altered response assessment when applying Lugano 2014 criteria, indicating that bone marrow evaluation appears to add little value to response assessment in FL; however, its evaluation may still have merit in DLBCL.

Complete Response Status According to RECIL 2017 Criteria Shows High Concordance with Lugano 2014 Criteria and Is Highly Prognostic for Outcome in Previously Untreated Patients with CD20-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

Complete Response Status According to RECIL 2017 Criteria Shows High Concordance with Lugano 2014 Criteria and Is Highly Prognostic for Outcome in Previously Untreated Patients with CD20-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

Management of post-transplant lymphoproliferative disorders.

Management of post-transplant lymphoproliferative disorders.

286P - First china-manufactured proposed rituximab biosimilar met primary efficacy and safety endpoints in CD20-positive diffuse large B-cell lymphoma (generics)

286P - First china-manufactured proposed rituximab biosimilar met primary efficacy and safety endpoints in CD20-positive diffuse large B-cell lymphoma (generics)

B-chronic lymphocytic leukemia showed triple transformation, to diffuse large B cell, CD20-negative, and T-cell neoplasm during ofatumumab treatment: a case report

BackgroundChronic lymphocytic leukemia (CLL) is a mature lymphoid neoplasm currently categorized as an indolent type of malignant lymphoma. CLL progresses slowly over years, but it eventually transforms to a more aggressive lymphoma such as the diffuse large B-cell (DLBCL) type, also known as Richter’s syndrome.Case presentationWe treated a 69-year-old Japanese male who was histologically diagnosed with Richter’s syndrome after 6 years of CLL. His lymphadenopathy had systemically progressed for years, with lymphocyte counts of less than 10,000 cells/μL and a disease status of Rai classification stage I and Binet classification B. He had high fever and hepatosplenomegaly upon Richter’s transformation. The patient was treated with ofatumumab for refractory CLL, which relieved his febrile lymphadenopathy. He received a total of 11 ofatumumab courses and achieved partial remission. On the day of the 12th course of ofatumumab, his disease relapsed with febrile lymphadenopathy. Computed tomography revealed multiple liver masses and systemic lymphadenopathy, while a liver biopsy confirmed T-cell lymphoma. Concomitantly, CD20-lacking CLL cells were detected in his peripheral blood and bone marrow, and pathological examination of his left cervical lymph node biopsy showed CD20-positive DLBCL. The final diagnosis was three different types of lymphoma pathologies: (1) CD20-positive DLBCL of the lymph nodes, (2) CD20-lacking CLL of the peripheral blood and bone marrow, and (3) peripheral T-cell lymphoma (PTCL) of the liver. He received intravenous and oral dexamethasone therapy as palliative care. He died because of the rapid progression of abdominal masses 2 months after the diagnosis of triple transformation CLL. An autopsy revealed aggressive PTCL with aggressive systemic involvement of the liver, spleen, gall bladder, pericardium, bone marrow, and mediastinal–paraaortic–intraceliac lymph nodes. T-cell receptor study of an autopsy specimen supported the diagnosis of PTCL that spread to the intraceliac organs and lymph nodes. We concluded that his pathogenicity progressed to a mixture of triple lymphoma as a result of double malignant transformations, which included PTCL from CLL, CD20-negative CLL, and CD20-positive DLBCL by Richter’s transformation.ConclusionsOur case provides information on the biology of CLL, to transform from a low-grade chemosensitive status to a malignant chemoresistant status.

Gemcitabine-oxaliplatin plus rituximab (R-GemOx) as first-line treatment in elderly patients with diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial

The combination of rituximab, gemcitabine, and oxaliplatin (R-GemOx) has shown high efficacy with a low toxicity profile in elderly patients with relapsed and refractory diffuse large B-cell lymphoma. We aimed to evaluate the efficacy, safety, and feasibility of the R-GemOx regimen as a first-line treatment in elderly patients with diffuse large B-cell lymphoma. In this single-arm, open-label, phase 2 clinical trial, we enrolled patients with previously untreated, histologically confirmed, CD20-positive diffuse large B-cell lymphoma, aged 70 years or older, or aged 60-69 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or greater. Patients were recruited from Jiangsu Province Hospital (Jiangsu Sheng, China). The R-GemOx regimen was administered intravenously: rituximab 375 mg/m2 on day 0; gemcitabine 1 g/m2 on day 1; and oxaliplatin 100 mg/m2 on day 1. The cycle was repeated every 14 days. Six cycles were planned if the patient achieved at least partial remission after the interim assessment. The primary endpoint was the proportion of patients who achieved an overall response at the end of treatment (defined as complete response plus partial response). Analyses were done by intention to treat. The trial is ongoing but no longer recruiting patients. This study is registered with ClinicalTrials.gov, number NCT01670370. Between Aug 22, 2012, and Dec 31, 2015, 60 patients were enrolled and included in the study. The median age of the patients was 75 years (IQR 70-80) and 27 (45%) patients had a poor performance status with an ECOG score of 2 or greater. 45 (75%) patients achieved an overall response at the end of the treatment, with 28 (47%) achieving a complete response. Common grade 3-4 adverse events were haematological toxicities (thrombocytopenia in five [8%] patients, anaemia in four [7%], and neutropenia in nine [15%]) and gastrointestinal complications (nausea in five [8%] patients, vomiting in three [5%], and diarrhoea in one [2%]). No treatment-related deaths were reported. The R-GemOx regimen shows high efficacy and safety as a front-line treatment in an elderly patient subpopulation and might be a therapeutic option for management of diffuse large B-cell lymphoma in elderly patients. National Natural Science Foundation of China, Jiangsu Province's Medical Elite Programme, Project of National Key Clinical Specialty, National Science & Technology Pillar Program, Jiangsu Provincial Special Program of Medical, and National Science and Technology Major Project.

Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial

Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma. We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m2], cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], and vincristine [1·4 mg/m2, up to 2 mg] all on day 1, and prednisone [40 mg/m2] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m2 (555 MBq/m2) 90Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841. Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy. Fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed. Immunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).

Comparison of Pharmacokinetics and Pharmacodynamics of Two Anti-CD20 Monoclonal Antibodies (Candidate Biosimilar DRL-Rituximab and Innovator Reference Product Rituximab (Mabthera®) in a Randomised, Multi-Centre, Double-Blind, Parallel Group Study of CHOP with Rituximab Chemotherapy in Patients with CD20-Positive Diffuse Large B-Cell Lymphoma

Background: DRL-Rituximab (T) is a proposed biosimilar of rituximab. The similarity of DRL-Rituximab andtheinnovator reference products(USA: Rituxan®; European Union: Mabthera® [R]) has been demonstrated in physicochemical analyses and nonclinical studies. This study was undertaken to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T with R sourced from the European Union.Methods: Multiple-center, randomized, double-blind, two-arm, parallel-group study conducted in patients of both genders, aged 18-60 with a centrally confirmed newly diagnosed CD20 positive diffuse large-B-cell lymphoma (DLBCL) in their first line of treatment. Patients were randomized to receive 6 cycles of 21 days either T or R at an initial dose of 375 mg/m2 along with chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone (CHOP). The primary objective of this study was to compare the PK of T and R. One of the secondary objectives was to establish the similarity of T and R in the pharmacodynamic parameters - as B-cell depletion and repletion in peripheral blood using counts of CD19+ positive cells determined by flow cytometry. The PK similarity criterion was that the 90% confidence intervals (CI) of the geometric mean ratios of AUC0-21days, and Cmax in Cycle 1 were within 80.00% - 125.00%. Cycle 1 PK, PD and summary safety results are reported here. Other PK parameters were evaluated as secondary endpoints.Results: A total of 151 patients were randomized to the study (76 to T, 75 to R). After exclusion of 2 patients with very low exposure (results confirmed to be outliers by a z-score higher than 3 and currently under further investigation), both products met the preset Cycle 1 PK similarity criterion (Table 1), with these 2 patients included the Cmax criterion was met, but for AUC the lower limit of the CI was 78.36% (Table 2). PK parameter values were generally comparable (Table 3). For PD both products appear comparable regarding both B-cell depletion and B-cell repletion, both in terms of proportion of patients as well as median time to depletion/repletion. (Table 4 & Figures 1A and 1B) Safety was also comparable between both products. Grade 3/4 Adverse Events (AEs) showed a similar trend in incidence across the two treatment arms [overall: 121 (80.1%); T: 57 (75.0%); R: 64 (85.3%)]. Neutropenia was the most frequently reported of the grade 3/4 AEs, followed by febrile neutropenia, leukopenia, and anaemia. The most commonly reported TEAEs related to the study drug were neutropenia [overall: 48 (31.8%); T: 29 (38.2%); R: 19 (25.3%)] and leukopenia [overall: 24 (15.9%); T: 16 (21.1%); R: 8 (10.7%)]. A total of 5 deaths are reported in the study amounting to 3.3% fatality rate.Conclusion: DRL-rituximab has equivalent PK profile to Mabthera in Cycle 1 when given in combination with standard CHOP chemotherapy for the treatment of CD20 positive DLBCL. PD and safety results are also similar. While awaiting results of further PK/PD data as well as outcomes from this trial, these results are highly encouraging and provide further impetus to development of DRL-rituximab as a candidate rituximab biosimilar.Acknowledgment: We thank all the Principal Investigators for their participation in conducting this study: Dr. Randeep Singh, Dr. Chiramana Haritha, Dr. Asis Mukhopadhyay, Dr. Anup Majumdar, Dr. Shailesh Bondarde, Dr. Rajnish Vasant Nagarkar, Dr. Vijay Ramanan, Dr. Chetan Dilip Deshmukh, Dr. MVT Krishna Mohan, Dr. SVSS Prasad, Dr. Nalini Kilara, Dr. Poonam Patil, Dr. Shekhar Patil, Dr. Neelesh Reddy, Dr. Suresh Sudalaiandi, Dr. Krishnan Srinivasan, Dr. Sundar Subramanian, Dr. VP Gangadharan, Dr. Auro Viswabandya, Dr. Alok Srivastava, Dr. Sharat Damodar, Dr. Rajesh Grover, Dr. Reena Nair, Dr. Bhausaheb Bagal, Dr. Kasi Viswanathan, Dr. Minish Jain, Dr. Jitendra Singh, Dr. Dipti Samanta, Dr. Sudha Sinha, Dr. Lakshmaiah Kuntegowdanahalli, Dr. Rajendersingh Arora, Dr. Sandip Shah, Dr. Shashikant Janardhan Apte, Dr. Mukul Goyal, and Dr. Prasanth Ganeshan. [Display omitted] [Display omitted] [Display omitted] DisclosuresBatra:Dr. Reddy's Labs: Employment, Equity Ownership. Lazaro:Dr. Reddy's Labs: Employment, Equity Ownership. Kankanwadi:Dr. Reddy's Labs: Employment, Equity Ownership.

CD20-positive primary gastric T-cell lymphoma poorly responding to initial treatment with rituximab plus CHOP, and a literature review

There have been rare reported cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) that co-expressed CD20. A 44-year-old Japanese male was initially misdiagnosed as CD20-positive diffuse large B-cell lymphoma with a background of reactive CD3-positive T-cells in the stomach. After four cycles of R-CHOP [rituximab plus cyclophosphamide (CY), doxorubicin, vincristine, and prednisolone (PSL)], total gastrectomy with regional lymph node dissection was performed due to the poor response to R-CHOP. A final diagnosis of CD20-positive primary gastric PTCL-NOS was made based on the immunohistochemical, flow cytometric, and molecular genetic findings. In the present case, CD20 immunostaining for T-cell lymphoma cells in tumor tissue varied; in a large part, these were strong to weak-positive, and in some parts, absent. We additionally reviewed the literature focusing on CD20-positive PTCL-NOS treated with rituximab. The administration of rituximab has been performed as an initial treatment in 11 cases, including the case reported here. The response was good in cases with high expression of CD20, while it was poor in cases with variable intensity in CD20 staining, which is consistent with our experience in the present case. The efficacy of rituximab may be associated with intensity of CD20 expression in T cells and its homogeneity in the tumor tissue.

Updated Results Confirm Favorable Outcome of Immunocompetent Patients with Primary CNS Lymphoma Treated By C5R Protocol in Combination with Intravenous Rituximab and Intrathecal Liposomal Cytarabine: A Multicentric Prospective Phase 2 Study of the Lymphoma Study Association (LYSA)

Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favorable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years. In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL in the R-C5R protocol. We previously presented the results of the primary objective of the R-C5R protocol, showing an improvement of the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol. We also showed no additional severe toxicities as compare to C5R with the addition of intravenous rituximab and IT liposomal cytarabine. We present here the updated results of the 53 patients included in this multicentric prospective phase 2 study from the lymphoma study association (LYSA) with a median follow-up 28 months (range, 1.08-75.04).Methods: This prospective study was designed for 18 to 60 years old immunocompetent patients with confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2 and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients and then patients were followed every 4 months during the first 2 years and then every 6 months for the next 3 years. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test.Results: The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS)>1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Clinical characteristics according to the MSKCC score was as follows: 16 patients (32%) ≤50 years (class 1); 23 patients (46%) >50 years and KPS≥70 (class 2); 11 patients (22%) >50 years and KPS<70 (class 3). Of the 39 available patients, 38% had 0-1, 38% had 2, 21% had 3 and 3% had 4 adverse IELSG prognostic scores, respectively. Median MMSE score assessed for 42 patients at baseline was 26 (range, 3-30). Forty-five patients (85%) completed the fourth cycles of immune-CT and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 28 months, 20 patients progressed or relapsed (37.7%). The 3-year progression free survival (PFS) rate of whole cohort was 58% (95%CI, 42.5% to 71%). The 3-year PFS rates were 64.2%, 63.5% and 53% for patients with MSKCC class 1, 2 and 3, respectively (P=0.53); the 3-year PFS rates were 86% and 39% for patients with 0-1 and 2-4 adverse IELSG prognostic scores, respectively (P=0.02). The 3-year PFS rates were 66% and 80% for patients who received a reduced whole brain RT with a boost and patients treated with whole brain RT (P=0.25), respectively. At relapse or progression, 18 patients received a salvage treatment that allowed five CR/CRu. Five patients received a high-dose CT with autologous stem cell transplantation at relapse. The 3-year overall survival (OS) rate for whole cohort was 67% (95%CI, 48.3% to 80.1%). The median MMSE score was 29 (range, 23-30) for the 11 patients evaluated between 18 and 24 months after the beginning of treatment.Conclusions: With the addition of intravenous rituximab and IT liposomal cytarabine, R-C5R protocol provided promising outcome results with a 3-year PFS and OS of 58% and 67%, respectively. These results compared favorably with historical controls included in the LNHCP93 who presented a 3-year PFS and OS of 44% and 58%, respectively. IELSG score remained a strong prognostic factor for the patients treated with this schedule and could be helpful to stratify consolidation treatment after response to primary immunochemotherapy in particular patients with 2-4 IELSG score. DisclosuresGhesquieres:Mundipharma: Honoraria. Off Label Use: Liposomal cytarabine formulation had demonstrated better efficacy compared to standard cytarabine for the treatment of lymphomatous meningitis and is off label use in first line therapy of primary CNS lymphoma. Morschhauser:Mundipharma: Honoraria.

Blood Soluble PD-L1 Protein In Aggressive Diffuse Large B-Cell Lymphoma Impacts patient's Overall Survival

PurposeProgrammed death 1 (PD-1) protein is a key immune-checkpoint receptor expressed by activated T cells and it mediates immunosuppression. It has been recently shown that the blockade of PD-1 or its ligand, PD-L1, by monoclonal antibodies may lead to significant antitumor effects. In diffuse large B-cell lymphoma PD-L1 has been reported expressed by tumor cells and PD-1 by tumor-associated T cells. The dosage of soluble programmed death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed during a clinical trial. We evaluated the clinical impact of PD-L1 level measured at the time of diagnosis for newly diagnosed aggressive diffuse large B-cell lymphomas. MethodsTranslating a previous study (NEJMed2004; 350: 1287) in the rituximab era, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang (GOELAMS) 075 study is a multicenter randomized trial in which adults 18 to 60 years old with untreated histologically proved CD20 positive diffuse large B-cell lymphoma were randomly assigned to receive 8 courses of R-CHOP or, high-dose chemotherapy associated to rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379). Patients were required to have an Ann Arbor stage of I or II with bulk greater or equal to 7 cm or, III or IV with 0 to 3 adverse prognostic factors as defined by the age-adjusted International Prognostic Index. The population of interest consisted of 288 of the 340 consecutively enrolled patients with available plasma collected at the time of diagnosis before any treatment. Soluble PD-L1 was measured using an ELISA assay. The median follow-up was 41.4 months. ResultssPD-L1 levels were found significantly increased in the plasma collected at diagnosis for patients compared to healthy -gender and age matched- subjects' levels (P<0.0001). The optimal cut-off point for PD-L1 measured at diagnosis was found to be equal to 1.52 ng/mL. Eighty-nine (30.9%) patients had a PD-L1 level greater than the cut-off point as compared to two (3%) controls. The high-level sPD-L1 group was significantly associated with bone marrow involvement, more than one extranodal localization and, 2-4 performance ECOG status. None of the other patients' characteristics, including the assigned arms of randomization and, the positive vs. negative FDG-PET scan response at the intermediate evaluation, was associated with high PD-L1 level. The PD-L1 immunohistochemical analysis showed that 55 out of the 73 interpretable tissue microarrays presented at least 5% of PD-L1-positive tumor cells. No association was found between sPD-L1 and tumor PD-L1 expressions (p=0.5). The 73 patients were representative of our 288 patients' cohort, with significantly decreased overall survival for patients with a high level of sPD-L1 compared to those with low sPD-L1 levels (64.6 vs. 86.7%, P=0.007). Cell-of-origin analysis using Hans's criteria on the tissue microarrays did not shown any correlation between elevated sPD-L1 and GC or non-GC origin.Patients with elevated PD-L1 experienced a poor prognosis with a three-year overall survival of 76 vs. 89 percent (P<0.001).There was no difference of overall survival rates between the two arms of treatment. Univariate analysis identified age greater than 50 years old, high-intermediate and, high age-adjusted International Prognostic Index score, bone marrow involvement, more than one extranodal localization, Ann Arbor stage after FDG-PET scan of III or IV, abnormal lymphocyte-monocyte score and, high level of sPD-L1 as factors associated with poor survival. High level of sPD-L1, bone marrow involvement and, abnormal lymphocyte-monocyte score were found after multivariate analysis to be the only factors remaining significant after adjustment with a P-value <0.05. Soluble PD-L1 was detectable in the plasma and not in the serum, found elevated in lymphoma patients at diagnosis compared to healthy subjects and its level dropped back to normal value for patients in complete remission. The intention-to-treat analysis showed that elevated PD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). [Display omitted] ConclusionSoluble PD-L1 protein expression in peripheral blood at the time of diagnosis is a potent predicting biomarker in diffuse large B-cell lymphoma and may indicate usefulness of alternative therapeutic strategies using PD1 axis inhibitors. Disclosures:Fest:Roche SA France: Research Funding.

Post‐transplant lymphoproliferative diseases in Asian solid organ transplant recipients: late onset and favorable response to treatment

Nineteen consecutive patients with post-transplant lymphoproliferative disorders (PTLD) in an Asian population were reviewed. The histopathologic diagnoses were monomorphic (CD20-positive diffuse large B-cell lymphoma, n = 14); plasmacytic (n = 1); Burkitt-like (n = 1); natural killer cell lymphoma (n = 1); lymphomatoid papulosis (n = 1); and classical Hodgkin lymphoma (n = 1). Early-onset (<one yr post-transplantation) PTLD constituted only 10% of cases, and all were Epstein-Barr virus (EBV) positive. EBV-negative cases (n = 6) developed at a median of 92 (19-170) months, whereas EBV-positive cases occurred later at 128 (7-230) months. With reduction of immunosuppression followed by local therapy, treatment with the anti-CD20 antibody rituximab with or without combination chemotherapy, complete remission was achieved in 17/19 (90%) of cases. Lactate dehydrogenase level, stage, extranodal involvement, EBV status, and International Prognostic Index had no impact on treatment outcome. EBV-positive PTLD occurred much later in Asian patients. Treatment results of PTLD were favorable.

An Effective Salvage Treatment Using Rituximab, Ifosfamide, Etoposide, Cytarabine, and Dexamethasone (R-IVAD) for Patients with Relapsed or Refractory Aggressive B-Cell Lymphoma

AbstractAbstract 1759 BackgroundThe prognosis of patients with relapsed or refractory aggressive B-cell lymphoma after the conventional first line chemotherapy is still disappointing. Although several rituximab combined salvage regimens were reported, the optimal treatment has not yet been established. We therefore evaluated the efficacy and toxicity of a non-anthracycline based salvage regimen, consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone (R-IVAD) in patients with relapsed or refractory aggressive B-cell lymphoma. Patients and methodsPatients with relapsed or refractory CD20-positive diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL G3) were consecutively enrolled in this treatment. R-IVAD consisted of rituximab (375 mg/m2 on day -2), ifosfamide (1500 mg/m2 on day 1–5), etoposide (150 mg/m2 on day 1–3), cytarabine (100 mg/m2 on day 1–3) and dexamethasone (40 mg/body on day 1–3). Treatment was given every 3 weeks up to a total of 3 courses with support of granulocyte colony stimulating factor. For responders under 65 years old with good performance status (PS), we planed peripheral stem cell collection after the third cycle of R-IVAD and consolidating high-dose chemotherapy (HDC) with cycrophosphamide (60 mg/kg on day -7,-6), etoposide (500 mg/m2 on day -6, -5, -4) and ranimustine (250 mg/m2 on day -3, -2) followed by autologous stem cell transplantation (ASCT). ResultsThirty-two patients (25 DLBCL and 7 FL G3) with a median age of 64 years old (range 38–79) participated in this study and received an average of 2.6 cycles of R-IVAD. There were 21 relapsed and 11 primary refractory patients. The overall response (OR) and the complete response (CR) rate were 72% and 56% respectively. The OR rate of relapsed patients was significantly higher than that of primary refractory patients (86% vs. 45%, p=0.035). With a median 16 months (range 2–99) of follow up, the 2-year overall survival (OS) and the event-free survival (EFS) for all patients were 55% and 36% respectively. Of the 11 eligible patients, 10 successfully proceeded to HDC/ASCT with an average of 5.5 × 106/kg of harvested CD34-positive cells, resulting in the 2-year OS of 90%. No treatment related death was observed during the investigation. Multivariate analysis revealed that the age > 60 years, PS ≥ 2, extranodal sites ≥ 2, and primary refractory disease were independently associated with worse survival. ConclusionR-IVAD regimen, which efficiently mobilizes peripheral stem cells, is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Establishment of a novel CD20 negative mature B-cell line, WILL2, from a CD20 positive diffuse large B-cell lymphoma patient treated with rituximab

Establishment of a novel CD20 negative mature B-cell line, WILL2, from a CD20 positive diffuse large B-cell lymphoma patient treated with rituximab

Diffuse large B-cell lymphoma of the uterine cervix: A rare case managed novelly

Non-Hodgkin's lymphoma (NHL) of the uterine cervix is exceedingly rare. The management of the disease is not standardized. A 44-year-old lady presented with a history of bleeding pervaginum and a foul-smelling discharge of 2 months' duration. A 7 x 7 growth was seen in the cervix. A biopsy revealed it to be a CD20-positive diffuse large B-cell (DLBCL)-type NHL. She was diagnosed as stage IE after staging work-up, and managed with three courses of rituximab, cyclophosphamide, vincristine, adriamycin, and prednisolone followed by external beam radiotherapy (46 Gy in 23 fractions) by 3D conformal technique. She attained a complete response, and has been in remission for 1 year 3 months.

Ocular involvement as first sign of isolated CNS relapse in diffuse large B-cell lymphoma

A 52-year-old man was diagnosed with stage IVB nonHodgkin lymphoma of diffuse large B-cell lymphoma subtype that involved the bone marrow and liver. Analysis of serum samples showed a raised concentration of lactate dehydrogenase, suggesting a high–intermediate risk of non-Hodgkin lymphoma according to the international prognostic index, but no HIV-1. The patient received six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab, and achieved complete remission. 6 months after diagnosis and 2 months after complete remission was achieved, the patient was admitted to hospital because of loss of vision. In the early phase of the examination, a fluorescein angiogram of the right eye (figure A) showed two large hyperfluorescent infiltrates with granularity (arrows) with small regions of retinal pigment epithelial detachments (arrowheads). In the late phase of the study, the left eye (figure B) showed a diffuse retinal pigment epithelial detachment that remained densely hypofluorescent (arrows), suggesting presence of lymphoma. However, bone-marrow biopsy and a CT scan of the neck, chest, and abdomen showed no relapse of lymphoma. 6 days later, the patient became somnolent and agitated, and developed confusion and lethargy. A CT scan (not shown) and an MRI of the brain (figure C) showed multifocal intraparenchymal lesions. Histological and immunohistochemical analysis of a stereotactic biopsy sample of one of the frontal lesions showed presence of B-lymphocyte antigen CD20positive diffuse large B-cell lymphoma, and no presence of Epstein-Barr virus. The patient was given high-dose methotrexate followed by whole-brain radiotherapy. The patient died 1 month after CNS relapse because of disease progression.