High Doses of Antimetabolites Followed By High-Dose Sequential Chemoimmunotherapy and Autologous Stem Cell Transplant in Patients with Systemic B-Cell Lymphoma and Secondary Central Nervous System Involvement: Final Results of a Multicenter Phase II Trial

Abstract INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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P.108 Diffuse large B-cell Lymphoma secondary to iatrogenic immunosuppression with unusual MRI findings and literature review

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2016.209 ◽

2016 ◽

Vol 43 (S2) ◽

pp. S45-S45 ◽

Cited By ~ 1

Author(s):

AH Naeem ◽

MD Staudt ◽

B Wang ◽

D Lee ◽

A Parrent

Keyword(s):

Literature Review ◽

B Cell ◽

Cell Lymphoma ◽

Immunosuppressive Agents ◽

Primary Cns Lymphoma ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Mri Findings ◽

Axial Mass ◽

Large B Cell

Background: Immunosuppressive therapy is a risk factor for lymphoproliferative disorders. We present a case of primary CNS B-cell lymphoma in the setting of iatrogenic immunosuppression from azathioprine usage. A literature review is provided. Methods: Case report Results: 64-year-old male presents with several weeks of cognitive decline, impaired speech, and headache with a history of ulcerative colitis (on azathioprine and 5-ASA) with no radiological evidence of systemic malignancy. MR showed left frontal extra-axial mass (4.0 x 2.4 x 4.0 cm) with heterogeneous enhancement of a solid component with local dural thickening. The enhancing mass had solid and cystic components. Radiological differential included dural metastasis, atypical meningioma or unusual intra-axial mass including GBM with some dural involvement. He underwent surgical resection, which showed a primary CNS lymphoma, diffuse large B-cell, CD 20 + and EBV +. Post-operatively his cognition improved. Azathioprine was stopped and 5-ASA was increased. He proceeded with MPVC (methotrexate, procarbazine, vincristine, and cytarabine) chemotherapy. Conclusions: Our case shows isolated extra-nodal CNS manifestation of lymphoma in the context of immunosuppressive medications with strikingly atypical MR findings leading to a pre-operative diagnostic dilemma. Treatment is challenging and needs to be individually tailored due to a need for stopping immunosuppressive agents in conjunction with CNS lymphoma treatment.

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Treatment of Diffuse Large B-Cell Lymphoma with Rituximab, Intensive Induction and High-Dose Consolidation: The Final Analysis of the Czech Lymphoma Study Group (CLSG) R-MegaCHOP-ESHAP-BEAM (R-MEB) Trial.

Blood ◽

10.1182/blood.v110.11.21.21 ◽

2007 ◽

Vol 110 (11) ◽

pp. 21-21

Author(s):

Marek Trneny ◽

Robert Pytlik ◽

David Belada ◽

Katerina Kubackova ◽

Ingrid Vasova ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Performance Status ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

High Dose ◽

Cell Transplant ◽

Bulky Disease ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background. Combined immunochemotherapy with CHOP and rituximab have improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). and related diseases. However, the cure rate of patients with IPI 3–5 or aaIPI 3 is still only about 50% with this regimen. Given the feasibility of previous CLSG regimens based on high-dose CHOP-ESHAP induction and BEAM consolidation, we have conducted a phase II trial combining this approach with rituximab immunotherapy. Patients and methods. Patients aged 18–65 years with DLBCL and age-adjusted IPI (aaIPI) 2–3 were treated with three cycles of high-dose CHOP (MegaCHOP - cyclophosphamide, 3 g/m2, vincristine 2 mg, adriamycin, 75 mg/m2, and prednisone, 300 mg/m2) with G-CSF every 3 weeks, followed by three cycles of ESHAP (etoposide, 240 mg/m2, cisplatin, 100 mg/m2, methylprednisolone, 2000 mg and Ara-C 2000 mg/m2) every 3 weeks. Four to six doses of rituximab 375 mg/m2 were administered on day 1 of each cycle of induction therapy. High-dose therapy (BEAM) followed by autologous stem cell transplant (ASCT) was used as consolidation. Radiotherapy was given to residual masses or sites of bulky disease. Primary endpoint was progression-free survival (PFS), while secondary endpoints were overall survival (OS) and feasibility of the treatment. Results. From April 2002 to October 2006, 105 consecutive patients from 10 centers were recruited. 58% were men and 42% women with median age 46 years (19–63 years). 74% of patients had stage IV disease, 92% had elevated LDH, 53% had performance status >1, 55% had B symptoms and 19% had bone marrow involvement. aaIPI was 2 in 62% of patients and 3 in 38% of patients. 68% of patients received the whole treatment according to the protocol, including ASCT and radiotherapy. Stem cells mobilization according to the protocol was performed in 90% of patients and was successful in 86% of mobilized patients (77% of all patients). 73% of patients ultimately received ASCT (including 3 patients transplanted after ammended treatment) and 51% of patients received planned radiotherapy. Complete remission (CR) was achieved in 83% of all patients and partial remission (PR) in 2%. Early toxic death rate was 6% and 9% patients had primary refractory disease. Of patients who achieved CR or PR, only 6 subsequently relapsed (7%) and two suffered late toxic death (2%). With a median follow-up of 32 months for living patients, the estimated 2-year PFS is 77% and 2-year OS is 81%. Age less than median (46 years) was strongest predictor of favorable outcome (p = 0,00006 for PFS and p = 0,00013 for OS), while there was no effect of stage, LDH, performance status or aaIPI (2-year PFS 79% for aaIPI 2 and 77% for aaIPI 3, 2-year OS 81% for aaIPI 2 and 80% for aaIPI 3). Delivery of ASCT or radiotherapy did not significantly affected PFS in patients who did not suffered early progression or early toxic death, but radiotherapy modestly improved OS of these patients (p = 0,03). Conclusion. R-MEB has proved to be an effective treatment strategy for younger patients with high-risk aggressive B-cell lymphoma. Currently, CLSG is testing whether utilization of early PET scan may decrease toxicity and improve treatment tolerance while maintaining the efficacy of this regimen.

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No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v112.11.3615.3615 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3615-3615

Author(s):

Gonzalo Gutiérrez-García ◽

Luis Colomo ◽

Neus Villamor ◽

Leonor Arenillas ◽

Antonio Martínez ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Primary Cns Lymphoma ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood2004;103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies. Complete response CR (%) 5-years OS (%) CT R-CT CT R-CT *p<0.002 R-CT vs. CT All cases (n=230) 59 79* 46 70* Primary nodal (n=148) 54 78* 34 71* Primary extranodal (n=82) 68 78 70 69 Figure Figure

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Rituximab compared to observation after high-dose consolidative first-line chemotherapy (HDC) with autologous stem cell transplantation in poor-risk diffuse large B-cell lymphoma: Updated results of the LNH98-B3 GELA study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8012 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8012-8012 ◽

Cited By ~ 1

Author(s):

C. Haioun ◽

N. Mounier ◽

J. F. Emile ◽

S. Bologna ◽

B. Coiffier ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Rituximab Maintenance ◽

Poor Risk ◽

Large B Cell Lymphoma ◽

Large B Cell

8012 Background: Rituximab has been evaluated as a single agent and also in combination with chemotherapy in aggressive and indolent lymphomas with evidence of efficacy. More recently, rituximab maintenance therapy has been successfully used to keep responding patients in remission. We have shown that consolidative HDC improves outcome of poor risk responder-patients (pts) with aggressive lymphoma. Methods: The aim of the present study was to evaluate the potential benefit, as randomly compared to observation, rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1-d3) as compared to the standard ACVBP induction regimen (R1). Four cycles were delivered every 15 days. In responding pts, HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 × 4d, etoposide 250 mg/m2 × 4d and carmustine 300 mg/m2) was started between d80 and d90. Results: From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. 237 pts were assigned to ACE and 239 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively). Death rate during induction phase was 4% in both arms. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two severe VZV infections. With a median follow-up of 4 years after R2, a trend toward a better 4y-EFS was observed in the rituximab group (80% vs 71%, p=0.098). In addition, a two-sided log-rank test stratified by aa-IPI, induction treatment and response after HDC was performed and confirmed the results of the unstratified analysis. Conclusions: We conclude that early and brief rituximab maintenance is feasible after HDC and may prolong remission status. [Table: see text]

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A phase III trial evaluating glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7575 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7575-TPS7575

Author(s):

Mark Hertzberg ◽

Matthew Ku ◽

Olivier Catalani ◽

Betsy Althaus ◽

Stephen Simko ◽

...

Keyword(s):

B Cell ◽

Bispecific Antibody ◽

Clinical Laboratory ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response Rates ◽

Phase Iii ◽

High Dose ◽

Cell Transplant ◽

Laboratory Test Results

TPS7575 Background: Prognosis is poor for patients with R/R DLBCL, particularly those who are ineligible for autologous stem cell transplant (ASCT) or who relapse after second-line therapy (Gisselbrecht C, et al. Br J Haematol 2018). While chimeric antigen receptor therapies have shown favorable response rates in R/R DLBCL, convenient off-the-shelf options are needed, especially for patients with rapidly progressing disease (Sermer D, et al. Blood Adv 2020). Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with two regions that bind to CD20 (B cells) and one region that binds to CD3 (T cells). In an ongoing Phase I study in patients with R/R non-Hodgkin lymphoma, glofitamab monotherapy has induced high response rates with a manageable safety profile (NCT03075696; Hutchings M, et al. ASH 2020). Rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) is widely used for patients with R/R DLBCL who are not eligible for ASCT (Mounier N, et al. Haematologica 2013). Methods: GO41944 (NCT04408638) is a Phase III, open-label, randomized trial designed to evaluate the safety and efficacy of glofitamab plus gemcitabine and oxaliplatin (glofit-GemOx) vs R-GemOx in patients with R/R DLBCL. Eligible patients must be aged ≥ 18 years, have histologically confirmed DLBCL (excluding transformed indolent disease, and high-grade B-cell lymphoma (BCL) with MYC and BCL2 and/or BCL6 rearrangements), and have received ≥ 1 prior systemic therapies; patients who have failed only one prior line of therapy must not be eligible for high-dose chemotherapy followed by ASCT. Prior treatment with GemOx, R-GemOx or a CD20xCD3 bispecific antibody is not permitted. Patients are randomized 2:1 to receive up to eight 21-day cycles of either glofit-GemOx (intravenous [IV], followed by up to four cycles of glofitamab monotherapy) or R-GemOx (IV). A single dose of obinutuzumab is administered seven days prior to the first glofitamab administration. Randomization is stratified by number of prior lines of therapy and outcome of last systemic therapy (relapsed vs refractory). The primary objective is overall survival from time of randomization. Secondary efficacy objectives include progression-free survival, complete and overall response rates, duration of response, and time to deterioration in physical functioning and fatigue, and in lymphoma symptoms. Safety objectives comprise rate of adverse events, change from baseline in targeted vital signs and clinical laboratory test results, and tolerability. Pharmacokinetic, immunogenicity and biomarker endpoints will also be explored. The study started on February 17, 2021; an estimated enrollment of 270 patients by the study completion date of March 2022 is anticipated. Clinical trial information: NCT04408638.

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Enhanced Delivery of Rituximab In Combination with Methotrexate-Based Blood-Brain Barrier Disruption for Patients with Newly Diagnosed Primary CNS Lymphoma.

Blood ◽

10.1182/blood.v116.21.2792.2792 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2792-2792 ◽

Cited By ~ 1

Author(s):

Nancy D. Doolittle ◽

Dale F. Kraemer ◽

Cynthia Lacy ◽

Rose Marie Tyson ◽

Edward A. Neuwelt

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Single Agent ◽

Primary Cns Lymphoma ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Newly Diagnosed ◽

Blood Brain Barrier Disruption ◽

Brain Barrier Disruption ◽

Grade 3

Abstract Abstract 2792 Introduction: Primary CNS lymphoma (PCNSL) is a rare, aggressive, primarily large B-cell lymphoma confined to the CNS and/or eyes at presentation. High-dose (HD) methotrexate (MTX) - based chemotherapy is standard of care in PCNSL and when combined with enhanced delivery results in extended survival without cognitive loss. The addition of rituximab to HD MTX regimens for B-cell PCNSL is widely used primarily by analogy to the positive results attained in systemic B-cell lymphomas. However, recent pre-clinical and clinical use of single agent rituximab provides stronger rationale. Efficacy has been shown using single agent rituximab in nude rats with intracerebrally implanted MC116 human B-cell lymphoma cells, and in patients with recurrent PCNSL by using 111In-ibritumomab to assess delivery and 90Y-ibritumomab to assess efficacy. Next, safety and efficacy of enhanced delivery of rituximab with MTX-based blood-brain barrier disruption (BBBD) was shown in patients with recurrent PCNSL. Based on these results, we treated patients with newly diagnosed PCNSL with rituximab in combination with MTX-based BBBD. Methods: IRB permission was obtained to retrospectively evaluate patients with newly diagnosed B-cell PCNSL, treated with rituximab in combination with MTX-based (intra-arterial [i.a.]) BBBD chemotherapy as first-line treatment. Treatment consisted of MTX (2500mg/day, i.a.) and carboplatin (200mg/m2/day, i.a.) with BBBD, for 2 consecutive days every 4 weeks for up to one year. Rituximab (375mg/m2, i.v.) was given every 4 weeks, 12 hours prior to the MTX with BBBD treatment. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicities were evaluated. Results: Twelve patients (7 female, 5 male) were treated between April 2003 and October 2008. The median age was 65 years (min 49, max 75); 10 patients were older than 60 years. The median Karnofsky Performance Score (KPS) prior to treatment was 55 (min 20, max 80). All patients had brain parenchyma involvement at presentation. Additionally, CSF cytology was positive in 2 patients and one patient had ocular involvement. One patient with pre-existing cardiac disease died 2 weeks after initiation of MTX without BBBD due to myocardial infarction and was not evaluable for response. The overall response rate was 83% (7 CR, 1 CRU, 2 PR, 1 SD). The median PFS was 3.47 years (95% CI: 0.42, not yet attained) and the 2-year PFS in this cohort is 73%. The median OS was 4.42 years (95% CI: 0.28, not yet attained). Eight patients who attained CR or CRU were alive at data-cut-off; 6 of the 8 patients remain in CR 2 years or more after diagnosis. The most frequent toxicities were hematologic. Eight (67%) patients developed grade 3 or 4 hematologic toxicity and 7 (58%) developed grade 3 infection. Conclusions: We previously reported a 2-year PFS of 50% with 25% survival at 8.5 years in 149 newly diagnosed PCNSL patients treated with MTX-based BBBD without rituximab. The addition of rituximab shows manageable toxicity and provides sustained duration of CR in newly diagnosed PCNSL, with 10 of 12 patients over 60 years old and a median KPS of 55. These pilot data suggest the 2-year PFS may be increased to 70% or more with the addition of rituximab to MTX-based BBBD chemotherapy. A multi-center phase II prospective study is underway. Disclosures: No relevant conflicts of interest to declare.

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Ibrutinib Monotherapy in Relapse or Refractory Primary CNS Lymphoma (PCNSL) and Primary Vitreo-Retinal Lymphoma (PVRL). Result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network

Blood ◽

10.1182/blood.v128.22.784.784 ◽

2016 ◽

Vol 128 (22) ◽

pp. 784-784 ◽

Cited By ~ 27

Author(s):

Sylvain Choquet ◽

Caroline Houillier ◽

Fontanet Bijou ◽

Roch Houot ◽

Eileen Boyle ◽

...

Keyword(s):

B Cell ◽

Disease Progression ◽

Phase Ii ◽

Interim Analysis ◽

Research Funding ◽

Primary Cns Lymphoma ◽

B Cell Lymphoma ◽

Final Analysis ◽

Cns Lymphoma ◽

High Dose

Abstract RATIONAL Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, carrying a pejorative prognosis. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL. METHODS In this prospective, multicenter, open-label phase II, we enrolled immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. Therapeutic responses were assessed according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. This study is a two-stage Simon's design. Patients were evaluable for response if they received > 90 % of the expected dose during the first month of treatment. An interim analysis for futility was planned when 18 patients were evaluable for response. P0 and P1 hypotheses were < 10 % and > 30 % respectively. A total of 35 evaluable patients are required for the final analysis. Exploratory ancillary studies are planned and consist in dosage of ibrutinib in the cerebrospinal fluid after one cycle of treatment, and correlation of therapeutic response with mutational status of the disease. This study is registered with ClinicalTrials.gov, number NCT02542514. RESULTS BetweenSeptember 25, 2015 and June 30, 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. The interim analysis was done on the first 18 patients evaluable for response (median age: 70 y, range 49-80). At initial diagnosis, diagnoses were PCNSL (n = 12) and PVRL (n = 6). Patients were included in the study for a relapse (n = 13) or a progressive disease (n = 5). At time of inclusion in the study, disease status was PCNSL (n = 11) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 7). ECOG performance status was 0, 1 and 2 in 4, 10 and 4 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received 1, 2 or 3 prior treatments in 12, 5 and 1 cases respectively. Three patients had a concomitant meningeal involvement. Five patients received concomitant corticosteroids during the first month of treatment. At the time of analysis (median follow-up = 6.6 months), nine patients discontinued ibrutinib after a median duration of 3 months (range, 0.9 -6.4) because of a disease progressive(n = 8) or a concurrent illness (n=1). Median number of treatment cycles was 5 (range, 1-9). One patient experienced a pulmonary aspergillosis with a favorable outcome. No hemorrhagic complication was reported. Five patients died due to disease progression (n = 4), and concurrent illness (n = 1). After two months of treatment, a DC was achieved in 15/18 patients (83 %, IC 95 %, [59-96%]) (complete and unconfirmed complete response: n =3; partial response: n = 7; stable disease: n =5). CONCLUSION In this interim analysis, Ibrutinib monotherapy demonstrated a high DC rate of 83%, including 56% objective responses in patients with relapse/refractory PCNSL or PVRL. Regarding safety, Ibrutinib might be a risk factor for aspergillosis in this population of PCNSL patients, otherwise not exposed to fungal infection. A security warning was sent to all the investigators for a close monitoring of infections. The second cohort of patients has been recruited. Thirty-three patients are currently on study treatment. The final analysis of the iLOC study is awaited to confirm these encouraging results and better define the positioning of ibrutinib in the therapeutic strategy of PCNSL and PVR patients. Disclosures Choquet: Janssen: Consultancy; Celgene: Consultancy. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soussain:Celgene: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding.

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High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates

Blood ◽

10.1182/blood-2015-01-620518 ◽

2015 ◽

Vol 126 (1) ◽

pp. 76-79 ◽

Cited By ~ 83

Author(s):

Irina Bonzheim ◽

Sabrina Giese ◽

Christoph Deuter ◽

Daniela Süsskind ◽

Manfred Zierhut ◽

...

Keyword(s):

B Cell ◽

Mutation Analysis ◽

High Frequency ◽

Detection Rate ◽

Cell Lymphoma ◽

Diagnostic Yield ◽

Primary Cns Lymphoma ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Key Points

Key Points MYD88 mutation analysis significantly improves the detection rate of vitreoretinal B-cell lymphoma. The high frequency of MYD88 mutations in primary VRL provides further evidence that VRL and primary CNS lymphoma represent the same entity.

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Rituximab, Gemcitabine and Oxaliplatin (R-GEMOX): A Promising Regimen for Refractory/Relapsed B-Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.2483.2483 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2483-2483 ◽

Cited By ~ 4

Author(s):

Taoufik El Gnaoui ◽

Jehan Dupuis ◽

Bertrand Joly ◽

Karim Belhadj ◽

Alain Rahmouni ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Median Number ◽

High Dose ◽

Induction Phase ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background : High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in aggressive lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. Effective and well tolerated salvage therapies with minimal toxicities are thus needed. Methods : We designed the R-GEMOX regimen, with rituximab 375mg/m2 d1, gemcitabine 1000 mg/m2 d2 and oxaliplatin 100 mg/m2 d2 (recycling on d15). Between January 2002 and April 2004, 31 patients with refractory/relapsing B-cell lymphoma not eligible for HDT were enrolled in an open unicenter pilot study whose primary objective was to determine the overall response rate (ORR) after 4 cycles (induction phase) of R-GEMOX. Patients were planned to receive 8 cycles if a good response (at least PR) was observed after 4 cycles. Median age was 63 years (range: 43–77) and histological subtypes were : diffuse large B-cell lymphoma (n=22), follicular (n=6) and mantle cell (n=3). Prior treatment included anthracyclin in 30 patients (98%), rituximab in 16 (52%) and HDT in 8 (26%). International prognostic index at enrollment was ≥ 2 in 13 patients (42%). The median number of prior treatments was 2 (range : 1 to 5) and 9 patients had received at least 3 prior regimens. Results : 226 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 6, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n=5) or preexisting renal insufficiency (n=1). The median number of cycles per patient was 8 (range: 2–8).Three patients progressed during the induction phase. After 4 cycles, observed responses were : 6 CR, 8 CRu, 12 PR and 2 failures resulting in an ORR of 84 %. At the end of treatment, among the 26 responder-patients at 4 cycles, 23 patients achieved CR/CRu and one patient progressed. As of August 2004, 22 patients are alive, 17 in continuous complete remission and 5 with evolutive disease. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 49% and 23% of the cycles. Six patients developed a grade 4 infection during one cycle. There was no renal toxicity. Conclusion : The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in an ongoing multicentric phase II study on diffuse large B-cell lymphoma patients at first relapse. (=69.03% taille max abstract)

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Dexamethasone (D), High Dose Ara-C (HA) and Carboplatin (DHAC) with or without Rituximab (R) Is an Effective Salvage Regimen for Patients with Relapsed/Refractory B-Cell Lymphoma in Preparation for Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.4730.4730 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4730-4730

Author(s):

Raymond Cruz ◽

Myron S. Czuczman ◽

Francisco Hernandez ◽

Ajay Kanra ◽

Swaminathan Padmanabhan

Keyword(s):

Stem Cell ◽

B Cell ◽

Median Survival ◽

Overall Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Cell Transplant ◽

Overall Response

Abstract Introduction: Relapsed/refractory B-cell lymphomas are a constant treatment challenge. High- dose chemotherapy and stem cell transplant (HDC-SCT) continues to be the backbone of treatment for such patients. Adequate cytoreduction with salvage chemotherapy is necessary prior to HDC-SCT and its achievement has been demonstrated to correlate with post-transplant outcomes. Various non-cross resistant salvage regimens have been developed to treat patients with relapsed/refractory B-cell lymphoma. In this report we present our institution’s experience with DHAC±R in patients requiring salvage therapy prior to HDC-SCT. Methods: The DHAC regimen consists of Dexamethasone at 15mg/m2/dose po every 6 hours × 10 doses, High-dose Ara-C at 3gr/m2 (1.5gr/m2 if >50 yrs old) iv over 3 hrs every 12 hrs for 4 doses and Carboplatin at 200mg/m2 iv every 24 hrs for 2 doses. When utilized, patients received rituximab at the standard dose of 375mg/m2, 48 hrs prior to each cycle of DHAC. Growth factor support and anti-microbial prophylaxis was implemented 24 hours after completion of chemotherapy. The regimen was repeated every 21 days for 2-3 cycles prior to HDC-SCT. We treated 37 patients with relapsed/refractory lymphomas, the median age of the entire cohort was 47 years (range 18 – 78); 25 were male and 19 females. While most of the patients treated had diffuse large B-cell lymphoma (DLBCL), various histological subtypes were included (DLBCL (n=16); follicular lymphoma (n=10); marginal zone lymphoma with blastoid features (n=1); small lymphocytic lymphoma (n=1) and Hodgkin’s lymphoma (n=8). The majority of the patients presented with advance stage at the time of DHAC therapy-Stage III (n=43%), Stage IV (n=39%). Seventeen patients were treated with R+DHAC, and 20 were treated with DHAC, either as second line or third line therapy. 19 out of the 37 patients proceeded to Stem cell transplant (SCT). Results: The overall response rate (ORR, CR+PR) for all patients was 61%(CR (n=16); and PR (n=7). The remaining 14 patients had either stable disease (n=10) or progressed (n=4). Complete responders (43%) had a longer mean survival of 107 (range 78 – 136) months compared to 66 months (range 49 – 83) for partial responders (19 percent) and non-responders who had a mean survival of 30.8 months (range 9–54), [P = 0.008]. Patients who proceeded to SCT had an overall response rate of 79% [CR (n=11) and PR (n=4)] compared to only 44% in those who did not [CR (n=5) and PR (n=3)]. The median survival in patients transplanted was longer than non-transplanted patients (92 vs 68 months). Response rates and median survival was similar between patients receiving R-DHAC or DHAC. As expected grade 3&4 hematologic toxicities were seen and effectively managed with appropriate supportive care. Conclusions: DHAC with or without rituximab appears to be an effective salvage treatment for patients with relapsed or refractory advanced-stage B-lymphoma undergoing HDC-SCT. An overall response of 61% which increases to 79% when followed by autologous SCT were demonstrated. Median survival was longer in patients experiencing CRs compared to partial or non-responders suggesting that the quality and quantity of the cytoreduction after salvage chemotherapy is an important predictor factor of post-SCT survival. Data looking at prognostic factors predicting response to DHAC±R treatment are being analyzed and will be reported at the ASH annual meeting.

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