scholarly journals Describing Treatment of Primary Mediastinal Large B Cell Lymphoma Using Rigorously Defined Molecular Classification: A Retrospective Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Carla Casulo ◽  
Myla Strawderman ◽  
Raphael Steiner ◽  
Carolyne Delage ◽  
Tina Faugh ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Molecular Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction Primary mediastinal large B cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma (NHL) with a female predominance; often presenting with a large anterior mediastinal mass. Though PMBCL has clinical and molecular features overlapping with Hodgkin lymphoma, it is a distinct entity defined by the World Health Organization classification. PMBCL is heterogeneously treated, and most patients receive front line therapy with either rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) with radiotherapy (RT), or the more intensive etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with rituximab (EPOCH-R) regimen. Diagnosis of PMBCL is made using clinicopathologic criteria and radiographic imaging, however gene expression profiling (GEP) studies reveal a characteristic genotypic signature distinct from diffuse large B cell lymphoma (DLBCL). Molecular classification of PMBCL using the Lymph3Cx assay from formalin-fixed paraffin-embedded tissue (FFPE) is feasible, reproducible, and highly concordant in a training and validation cohort (Mottok et al. Blood 2018). Using a multicenter cohort of patients, we sought to estimate the rate of mis-match among patients with a clinical diagnosis of PMBCL using Lymph3Cx, and describe treatment selections and outcomes for each group. Methods Patients were identified from a cohort of patients with newly diagnosed NHL from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource, and the Lymphoma Epidemiology of Outcomes cohort. Patients were enrolled between 2002-2019, and included if they had clinically defined PMBCL. FFPE was retrieved from hematopathology archives of participating academic centers. All diagnoses of PMBCL were based on expert hematopathology review at the time of therapy, and all cases underwent classification by GEP using the Lymph3Cx assay. Lymph3Cx was performed in the clinical lab at the Mayo Clinic in Arizona: Contiguous unstained sections were deparaffinized and macrodissected to enrich for tumor content before RNA isolation;100-200 ng of total RNA was used in an nCounter Elements XT, hybridized, and processed the following day using the nCounter FLEX system. Raw counts were processed through the Lymph3Cx algorithm and results reported as probability of PMBCL (≥0.90 as PMBCL, ≤0.10 as DLBCL all other results "Unclear PMBCL/DLBCL") (A. Mottok et al, Blood, 2018). For cases classified as DLBCL, the Lymph2Cx cell-of-origin classifier results was reported (Scott et al, JCO, 2016). Time to event endpoints were described with Kaplan-Meier plots by groups defined by mismatch status and compared with a logrank test. Binary outcomes will be presented with 90% exact confidence intervals. Results Fifty patients were identified. Median age was 35 years (range 19-70). Sixty four percent were women. Median follow up was 47 months. Treatments included R-CHOP (44%), EPOCH-R (44%), and MACOP-B [methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin] (6%), other (4%). Ten patients (20%) had events (defined as progression or death). Three patients in the entire cohort (6%) died. The Kaplan-Meier estimated survival at 47 months (median follow-up) is 92%. The Lymph3Cx assay yielded gene expression data of sufficient quality in 47/50 cases (94%, 90% CI=85.2, 98.3%). Of 47 cases clinically identified as PMBCL, 5 unclear were DLBCL/PMBCL and 1 was Germinal Center B cell subtype of DLBCL. Among these 6 patients, 4 received R-EPOCH (66%), 1 received R-CHOP (16.6%). One patient had missing treatment data. One patient had an event requiring subsequent therapy; all patients remain alive. Conclusions Using 47 patients with PMBCL defined by histology, clinical and radiographic findings, and molecular features, we demonstrate high concordance between clinical phenotype and molecular genotype of PMBCL by Lymph3Cx. Among the 6 patients not classified as PMBCL, most received R-EPOCH. Differences in outcome by mis-match status await longer follow-up and further accrual of subjects to our data base. Our data suggest molecular genotyping may have a role in mediastinal presentations of large cell lymphoma to optimize treatment decision making. Disclosures Maurer: Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Flowers:AbbVie: Consultancy, Research Funding; Kite: Research Funding; Burroughs Wellcome Fund: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; Bayer: Consultancy; National Cancer Institute: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Astellas: Consultancy; Bayer: Consultancy; Kite Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Consultancy; Roche: Other: Travel expenses; Seattle Genetics: Research Funding.

scholarly journals Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 96-96 ◽  
Author(s):  
Dahlia Sano ◽  
Loretta J. Nastoupil ◽  
Nathan H. Fowler ◽  
Luis Fayad ◽  
F. B. Hagemeister ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Ibrutinib for Transformed Lymphoma; A Report of 4 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5115-5115
Author(s):  
Amy Sharma ◽  
Sadia Riaz ◽  
Jonathan E. Kolitz ◽  
Jacqueline C. Barrientos ◽  
Steven L Allen
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large Cell Lymphoma ◽  
Large B Cell

Abstract Introduction Large cell lymphoma transformed from an indolent lymphoproliferative disorder typically carries a worse prognosis than de novo diffuse large B cell lymphoma. When transformation to large cell lymphoma occurs in CLL (Richter's syndrome), traditional anthracycline or platinum based therapy is associated with a median survival of <12 months. Better, more targeted therapies are needed. We describe 4 patients with transformation to large cell lymphoma who responded to ibrutinib. Cases: Patient A, age 68 at transformation, was a 64 year old male at diagnosis with CLL Rai stage 1. He was initially asymptomatic with a performance status of 0. 4 years later he developed dyspnea on exertion after one block and was found to have a left pleural effusion with diffuse lymphadenopathy with increased PET avidity. Biopsy of a supraclavicular node was positive for extracavitary primary effusion lymphoma, HHV8+, CD5-, CD10-. Patient was given R-CHOP x 6 cycles; he relapsed after 18 months and was given ibrutinib 560mg daily with monthly rituximab x 6 and achieved a PR with reversion to CLL. He is currently continuing ibrutinib in this remission for 10+ months. Patient B, age 90 at transformation, was a 68 year old female at diagnosis of CLL, Rai stage 0. She developed stage III CLL 18 years after diagnosis, was treated with BR x 6 cycles. 2 years later she developed Richter's transformation which was CD10+. Although she achieved a PR after 4 months of ibrutinib 560mg with monthly rituximab, her PS was 4 and she was transferred to hospice and expired 4.5 months after initiating ibrutinib/rituximab. Patient C, age 87 at relapse, was a 73 year old male at diagnosis when he originally presented with stage 1 DLBCL transformed from marginal zone lymphoma. He had 3 cycles of R-CHOP and RT to involved area and was disease free for 14 years until he had worsening thrombocytopenia. This was monitored for 3 years until age 87 when CT/PET showed increasing SUV in multiple lymph nodes and the spleen. Biopsy showed diffuse large B cell lymphoma, CD10-. He was started on ibrutinib 560mg with monthly rituximab x 6. He achieved a CR by CT/PET except for persistent splenic disease. He underwent splenectomy and continues in CR on ibrutinib at 9+ months. Patient D is an 83 year old female with large cell transformation from marginal zone lymphoma at diagnosis. She had stage IV disease with large cells involving pleural fluid and bone marrow. She was CD10-. She received R-CHOP x 3 with progressive disease. At that time ibrutinib 560mg alone was initiated. She has a CR based on recent CT/PET findings and is continuing ibrutinib at 18+ months. Conclusion: All of the above patients responded to ibrutinib given with or without rituximab with symptomatic and objective remissions; all of the CD10 negative cases are alive and still responding 9-18 months after initiating therapy. Studies examining the efficacy of ibrutinib in diffuse large B cell lymphoma are underway. This report supports the need for further study of ibrutinib in the transformed setting, particularly in the elderly where patients may not be appropriate for aggressive therapies. Disclosures Off Label Use: Ibrutinib was used to treat transformed large cell lymphoma.. Kolitz:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Barrientos:Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Allen:Millennium: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Equity Ownership; Onconova: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Prefmab: Final Analysis of Patient Preference for Subcutaneous Versus Intravenous Rituximab in Previously Untreated CD20+ Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3972-3972 ◽  
Author(s):  
Mathias Rummel ◽  
Tae Min Kim ◽  
Caterina Plenteda ◽  
Enrico Capochiani ◽  
Maria Mendoza ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Board Of Directors ◽  
Patient Preference ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background Rituximab in combination with chemotherapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). To improve patient convenience and to reduce healthcare resource burden, a subcutaneous (SC) formulation of rituximab has been developed and has been shown to be clinically comparable to intravenous (IV) rituximab. The aim of this study was to evaluate patient preference for rituximab IV or SC administration. Methods Prefmab (NCT01724021) is a randomized, open-label, crossover phase IIIb study. Eligible patients were aged ≥18 to ≤80 years with previously untreated CD20+ DLBCL (IPI 1-4 or 0 with bulky disease) or FL (FLIPI grade 1-3a), at least 1 bidimensionally measureable lesion ≥1.5cm at its largest dimension by computed tomography, and an ECOG performance status ≤3; all provided written informed consent. Patients received 8 cycles of rituximab according to 2 schedules: Arm A received 1 cycle of rituximab IV (375mg/m2) and 3 cycles of rituximab SC (1400mg) then 4 cycles of rituximab IV; Arm B received 4 cycles of rituximab IV (375mg/m2) then 4 cycles of rituximab SC (1400mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (CHOP [cyclophosphamide, doxorubicin, oncovin, prednisone], CVP [cyclophosphamide, vincristine, prednisone], or bendamustine as per standard local practice). A Patient Preference Questionnaire (PPQ) was conducted post-rituximab therapy at cycles 6 and 8. The primary endpoint was overall preference for rituximab IV or SC. The strength of patient preference was also assessed (very strong, fairly strong, or not very strong). Adverse events (AEs), including administration-related reactions, were evaluated according to NCI-CTCAE version 4.0. Results At the primary data cut-off (January 19, 2015), the intent-to-treat population comprised 743 patients (Arm A: n=372; Arm B: n=371). The majority of patients had DLBCL (63%). The median age was 60 years (range 18-80) and baseline characteristics were balanced between arms. One hundred and twenty patients discontinued immunochemotherapy treatment prematurely, primarily due to AEs (n=52), but entered follow-up. A further 108 patients (Arm A: n=48; Arm B: n=60) discontinued the study and did not complete follow-up, primarily due to death (53 patients [DLBCL: n=48; FL: n=5], 19 of whom died due to progressive disease [DLBCL: n=16; FL: n=3]), patient request/withdrawal of consent (n=23), or AEs (n=9). Rates of study discontinuation and treatment discontinuation were balanced between arms. The PPQ was completed by 620 patients at cycle 6 and 591 at cycle 8. At cycle 6, rituximab SC was preferred by 80% (n=495) of patients (Arm A: 79%; Arm B: 81%) and rituximab IV by 10% (n=62; Arm A: 11%; Arm B: 9%), while 10% (n=63) had no preference (Arm A: 10%; Arm B: 10%). At cycle 8, the respective values were 81% (n=477; Arm A: 77%; Arm B: 84%), 11% (n=66; Arm A: 13%; Arm B: 10%), and 8% (n=48; Arm A: 10%; Arm B: 6%). The strength of patient preference for rituximab SC or IV is shown in Figure 1. Of patients who preferred rituximab SC, the main reasons were 'less time in the clinic' (cycle 6: 68%; cycle 8: 69%) and 'feels more comfortable during administration' (cycle 6: 37%; cycle 8: 37%). The mean cumulative rituximab administration time (mean ± standard deviation) was 865 ± 401 min for rituximab IV compared with 37 ± 100 min for rituximab SC. AEs were generally balanced between rituximab IV and SC administration, with the exception of gastrointestinal disorders (IV: 55%; SC: 31%) in patients with FL, notably nausea (IV: 28%; SC: 11%), constipation (IV: 14%; SC: 6%), and vomiting (IV 12%; SC 2%). No new safety signals were detected. Conclusions Most previously untreated patients with CD20+ DLBCL or FL preferred SC compared with IV administration of rituximab, mainly due to reduction in the duration and discomfort of administration. Figure 1. Figure 1. Disclosures Rummel: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plenteda:Roche: Other: Sub-investigator. Mendoza:Roche: Employment. Smith:Roche: Employment. Osborne:Roche: Employment. Grigg:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2177-2177 ◽  
Author(s):  
Alex F. Herrera ◽  
Lu Chen ◽  
Sirin Khajavian ◽  
Matthew Lewis Chase ◽  
Justin Darrah ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a subset of aggressive B-cell non-Hodgkin lymphoma (B-NHL) with distinct biological and clinical features. Although most patients are cured with frontline chemoimmunotherapy with or without radiation therapy (RT), relapsed or refractory (rel/ref) PMBCL is much harder to control. Standard treatment of rel/ref PMBCL is similar to other aggressive B-NHLs, including salvage therapy and autologous (auto) stem cell transplantation (SCT) in chemosensitive patients. Recently, immunotherapy with PD-1 blockade and chimeric antigen receptor modified T-cells has proven to be effective in rel/ref PMBCL. Despite this, allogeneic (allo) SCT retains an important potential role as it has curative potential for patients with advanced aggressive B-NHLs. However, there are scant modern data on alloSCT outcomes in patients with PMBCL, limited to case reports or small series. We therefore performed a multicenter retrospective study to evaluate alloSCT outcomes in patients with rel/ref PMBCL. Methods: We retrospectively studied consecutive patients with rel/ref PMBCL who underwent alloSCT at Fred Hutchinson Cancer Center, Dana-Farber Cancer Institute, Massachusetts General Hospital, or City of Hope between 1/2000 and 5/2014. Baseline and transplant characteristics are reported descriptively. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Incidence of relapse and non-relapse mortality were calculated using competing risks methods. Results: 28 patients with rel/ref PMBCL underwent alloSCT at participating institutions during the study period. Among these patients, median age at SCT was 36 years, 54% were female, median number of prior therapies was 4 (range, 2-7), 57% were refractory to frontline therapy, 86% received prior RT, and 71% had prior autoSCT. At alloSCT, 1 (4%) patient was in complete response (CR), 21 (75%) were in partial response (PR), and 6 (21%) were refractory to pre-alloSCT therapy (18 patients were assessed with PET). Most patients (86%) received reduced intensity conditioning, most commonly fludarabine/melphalan +/- ATG or Zevalin (25%), fludarabine/TBI200 (21%), or fludarabine/busulfan (14%). GVHD prophylaxis most frequently consisted of a calcineurin inhibitor (CNI) with mycophenolate mofetil (12, 43%), CNI with sirolimus +/- methotrexate (8, 29%), or CNI with MTX (4, 14%). 15 (54%) patients had a matched (8/8) related donor, 8 (29%) had a matched unrelated donor, 2 had a mismatched unrelated donor (7/8), and 3 had umbilical cord donors. All patients received peripheral blood stem cell grafts except for the 3 cord recipients. The median follow-up time in survivors was 5.0 (range 0.5-14.0) years. The 2 year PFS and OS in the cohort were 39% and 45%, respectively, while non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 32% and 29%, respectively. The 5-year PFS, OS, NRM, and CIR were 34%, 45%, 32%, and 33%, respectively. The cumulative incidence of grade II-IV and III-IV acute GVHD were 39% and 4% at day 100, while the incidence of chronic GVHD at 1 year was 21% (18% extensive). Among patients in CR/PR at the time of alloSCT, the 2-year PFS and OS were 50% and 58%, respectively, as compared to a 2-year PFS and OS of 0% in patients who were refractory at the time of alloSCT (p=0.046 for PFS, p=0.014 for OS). One patient received post-alloSCT lenalidomide as maintenance therapy and remained in ongoing CR. Of the 9 patients who relapsed after alloSCT, 3 out of 4 patients exhibited a response to immunosuppression taper, while 4 out of 5 patients responded to subsequent systemic therapy. 2 patients underwent a donor lymphocyte infusion (DLI) and both developed subsequent GVHD - 1 patient had a CR documented 64 days after DLI while the other had continued disease progression. In the 9 patients who relapsed after alloSCT, the 2-year OS was 33%. Conclusions: AlloSCT can produce durable remissions in a subset of patients with heavily treated, rel/ref PMBCL. Patients with refractory disease at alloSCT had dismal outcomes. Despite the expanding treatment options available for these patients, alloSCT should be considered in the management of patients with rel/ref PMBCL who are sensitive to salvage therapy. Figure 1A PFS and OS After AlloSCT in Patients with Rel/Ref PMBCL Figure 1B PFS in Patients with Sensitive versus Refractory PMBCL at AlloSCT Disclosures Herrera: Merck, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding. Maloney:Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Shadman:Acerta Pharma: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Genentech: Consultancy.

scholarly journals Integrated Genetic and Topological Analysis Reveals a Hodgkin-like Mechanism of Immune Escape in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1579-1579 ◽  
Author(s):  
Gabriel K Griffin ◽  
Margaretha G.M. Roemer ◽  
Mikel Lipschitz ◽  
Jason Weirather ◽  
Christine J. Pak ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Specific Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive large B cell lymphoma that typically presents with disseminated disease. In contrast to diffuse large B-cell lymphoma, not otherwise specified (DLBCL), TCRLBCL is characterized histologically by rare malignant B-cells within a robust but ineffective inflammatory background composed of numerous T cells and macrophages. TCRLBCL shows a "tolerogenic" immune signature by gene expression profiling, as well as frequent upregulation of PD-L1 (Van Loo et al. PMID: 19797726; Chen et al. PMID: 23674495). Although these features suggest that active immune evasion is central to TCRLBCL pathogenesis, its mechanistic basis is poorly understood. Accordingly, we performed an integrated analysis of tumor genetics and cell-cell interactions within the tumor microenvironment to comprehensively study PD-1:PD-L1 interactions in a multi-institutional cohort of TCRLBCL. Methods: 34 cases of TCRLBCL were identified from the pathology archives of four academic medical centers. Control cohorts containing 21 cases of DLBCL and 106 cases of classic Hodgkin Lymphoma (CHL) were used as comparators. An established fluorescence in situ hybridization (FISH) assay was used to identify copy number changes and structural rearrangements of CD274 (PD-L1) and PDCD1LG2 (PD-L2) on chromosome 9p24.1, which represents the primary genetic mechanism of PD-L1/L2 expression in CHL (Roemer et al. PMID: 27069084). Tumor-specific expression of PD-L1 and PD-L2 protein was assessed by immunohistochemistry (IHC) and scoring by two pathologists using a modified H-score (percentage of positive tumor cells [0-100%] multiplied by the mean staining intensity [0-3+]). The topology of PD-L1/PD-1 expression and cell-cell interactions in the tumor microenvironment was determined by multispectral immunofluorescence (IF) microscopy and spatial image analysis, as previously performed for CHL (Carey et al. PMID: 28893733). Results: By FISH, copy gain or amplification of PD-L1 and PD-L2 was identified in 22/34 (64.7%) cases of TCRLBCL (Figure 1A) and was associated with a 4.9-fold increase in tumor PD-L1 expression relative to cases with disomy or polysomy (mean PD-L1 H-score 72 vs 14.7, p = 0.02). A rearrangement of PD-L2 was identified in one case and associated with diffuse expression of PD-L2. These findings contrasted with those observed in the DLBCL cohort, which showed a low overall frequency of 9p24.1 copy gain/amplification (5/21 cases, 23.8%) and only minimal tumor PD-L1 expression (mean PD-L1 H-score 15.6), and were intermediate to those observed in CHL, which shows near universal copy gain/amplification of 9p24.1 (98/106 cases, 92%) and extensive tumor PD-L1 expression (mean PD-L1 H-score 143.7; Figure 1B). By multispectral IF, TCRLBCL showed prominent infiltration by PD-L1+ tumor-associated macrophages (TAM) (Figure 1C), which were 5.5-fold increased relative to DLBCL and 6.6-fold increased relative to CHL (p < 0.001). TCRLBCL also showed marked infiltration by PD-1+ T cells, which were 12.3-fold increased relative to DLBCL and 3.4-fold increased relative to CHL (p < 0.001). By spatial analysis, PD-L1+ TAMs in TCRLBCL were located in closer proximity to tumor cells than PD-L1- TAMs (p < 0.001, Figure 1D-E) and also showed frequent direct interactions with PD-1+ T cells. These findings contrasted with those in DLBCL, where no local enrichment of PD-L1+ TAMs or PD-1+ T cells was identified, and were similar but more prominent than those observed in CHL. Conclusion: TCRLBCL is characterized by recurrent gains of PD-L1 and PD-L2 on chromosome 9p24.1 in association with tumor-specific expression of PD-1 ligands, as well as prominent infiltration by PD-L1+ TAMs and PD-1+ T cells. PD-L1+ TAMs in TCRLBCL are enriched around individual tumors cells and also show frequent direct interactions with PD-1+ T cells, consistent with the establishment of an immunoevasive-niche. These findings contrast with those observed in DLBCL and are most similar to those identified in CHL. Relative to CHL, however, TCRLBCL shows less frequent gains of 9p24.1 and tumor cell expression of PD-L1, and a greater degree of infiltration by PD-L1+ TAMs and PD-1+ T cells. These findings suggest that the PD-1:PD-L1 pathway is central to immune evasion in TCRLBCL and highlight the need to test the clinical efficacy of PD-1 blockade in this patient population. Disclosures Griffin: Moderna Therapeutics: Consultancy. Freeman:Novartis: Patents & Royalties; AstraZeneca: Patents & Royalties; Dako: Patents & Royalties; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Patents & Royalties; Merck: Patents & Royalties; EMD-Serono: Patents & Royalties; Roche: Patents & Royalties; Xios: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Patents & Royalties; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Origimed: Membership on an entity's Board of Directors or advisory committees. Hodi:Merck: Consultancy. Shipp:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria. Rodig:KITE: Research Funding; Affimed: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Research Funding.

10 Years Follow-up of the GELA LNH98.5 Study, First Randomized Study Comparing R-CHOP to CHOP Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3741-3741 ◽  
Author(s):  
Bertrand Coiffier ◽  
Christian Gisselbrecht ◽  
Andre Bosly ◽  
Raoul Herbrecht ◽  
Reda Bouabdallah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Randomized Study ◽  
B Cell Lymphoma ◽  
Chop Chemotherapy ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 3741 Poster Board III-677 LNH98.5 was the first randomized study with the addition of rituximab to CHOP in patients with diffuse large B-cell lymphoma. 399 patients were randomized, 197 in CHOP arm and 202 in R-CHOP arm. Patients were aged between 60 and 80 years (median 70 years), had disease stage II to IV, and no contra-indication to one of the drugs. 60% had poor risk lymphoma according to IPI. Response to treatment and early survival analyses were previously presented with 2 years and 5 years median follow-up (NEJM 2002;346:235 and JCO 2005;23:4117). With a median follow-up of 10 years, median age of surviving patients is 78 years, oldest patient being 91 years old. Only 4 patients were lost for follow-up, defined as not seen during the last 18 months, at 5, 7, 8, and 8 years. No event was observed in 105 of the 399 patients, 37 (19%) in CHOP arm and 68 (34%) in R-CHOP arm. Relapse was observed in 73 (59%) and 51 (34%) of CR patients, and death without progression in 16 and 33 patients, respectively. Death occurred in 71% and 56% of the patients, most of them from disease progression but 21 and 20 cancers were observed, representing half of the deaths without progression. Most frequent cancers were colon and lung; two MDS were observed in CHOP arm and one AML in R-CHOP arm. One patient with CHOP presented a multiple myeloma 10 years after DLBCL. During the last 3 years, 10 additional patients relapsed, 4 in CHOP arm and 6 in R-CHOP arm, these late relapses representing 4% of CR patients. Median overall survival was 37 months in CHOP arm and 7 y 9 m in R-CHOP arm with 10-y survival of 28% and 43%, respectively (p<0.001). Median survival from progression was 8 months in both arms. This analysis showed that the benefit of combining rituximab with CHOP chemotherapy persists with a median follow-up of 10 years and that over 40% of elderly patients are alive 10 years later confirming these patients could express long-term survival if treated like younger patients. However, late relapses do occur and new strategies should be developed to prolong the response of these patients. Disclosures: Coiffier: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Bosly:Roche: Research Funding, Speakers Bureau. Herbrecht:Roche: Research Funding. Bouabdallah:Roche: Research Funding. Morel:Roche: Research Funding. Van Den Neste:Roche: Research Funding. Bordessoule:Roche: Research Funding. Haioun:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tilly:Roche: Research Funding, Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Prevalence and the Impact of Hypogammaglobulinemia in Newly Diagnosed, Untreated Diffuse Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1604-1604
Author(s):  
Namrata Singh ◽  
Sarah L Mott ◽  
Ashley Noel McCarthy ◽  
Sergei Syrbu ◽  
Thomas M. Habermann ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Treatment Naïve ◽  
Large B Cell

Background: While there is evidence in the literature of increased prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (CLL), there are no studies evaluating the prevalence of hypogammaglobulinemia in newly diagnosed diffuse large B cell lymphoma (DLBCL) or the relationship between hypogammaglobulinemia and presentation or outcomes. The objective of this study was to examine the prevalence of hypogammaglobulinemia in newly diagnosed DLBCL patients and to test the hypothesis that DLBCL patients with baseline hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: We obtained banked frozen sera from 200 newly diagnosed, treatment-naïve, DLBCL patients from the Lymphoma SPORE Molecular Epidemiology Resource (MER), a prospective cohort study conducted at the Mayo Clinic and the University of Iowa. IgG/A/M levels were measured using immunoturbidimetric assay whereas IgE level was measured using electrochemiluminescence immunoassay; deficiency was defined using standard reference ranges. IgE levels were considered deficient if &lt;2 UI/ml. The associations between Ig deficiencies and clinical factors were evaluated with Wilcoxon rank sum and chi-squared (Fisher's exact, where appropriate) tests. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death, and EFS24 was defined as EFS at 24 months after diagnosis (achieve or failure to achieve EFS24). The association of Ig levels with EFS24 was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, and with EFS, overall survival (OS), and lymphoma-specific survival (LSS) was estimated using Kaplan-Meier curves and hazard ratios (HR) and 95% CI from Cox regression. Results: The mean age (SD) of the cohort was 65.6 (13.4) years, 54% were males and 98% of the patients were white. Over a median follow-up of five years, there were 59 (29.5%) deaths. The prevalence of hypogammaglobulinemia, defined as any deficiency, in newly diagnosed, treatment-naïve DLBCL was 22.1% (44/199) in our cohort, and the most common Ig deficiency was for IgG (&lt;700 mg/dL, 13.5%), followed by IgM (&lt;40 mg/dL, 9.0%), IgE (&lt;2 UI/ml, 7.5%) and IgA (&lt;70 mg/dL, 4.0%) (Table1). There were no statistically significant differences between Ig deficient and non-deficient patients in terms of age at diagnosis, gender, stage, cell of origin, or MYC double hit status. However, median LDH levels were higher in Ig deficient patients (228 vs 194, p&lt;0.01). Any immunoglobulin deficiency was associated with inferior EFS (HR 1.94, 95% CI 1.16-3.24) (Figure 1) and OS (HR 2.02, 95% CI 1.17-3.49), and these associations were not attenuated after adjustment for the international prognostic index (IPI). Any Ig deficiency was also associated with failure to achieve EFS24 (OR=2.13, 95% CI 1.00-4.60) after adjusting for IPI. Conclusions: To the best of our knowledge, this is the first study to report the prevalence of hypogammaglobulinemia in treatment naïve DLBCL. We found that any Ig deficiency was not uncommon in our cohort and it was associated with an inferior EFS and OS in DLBCL patients. The prevalence of hypogammaglobulinemia in DLBCL patients seems to be lower than has been described in CLL patients. While the underlying relationship between these two immunologic disorders deserves further study, our findings highlight the interaction between global immune dysfunction and emergence of a clonal B cell process. Disclosures Nowakowski: Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

A Phase III Study Of Enzastaurin In Patients With High-Risk Diffuse Large B Cell Lymphoma Following Response To Primary Treatment: The Prelude Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 371-371 ◽  
Author(s):  
Michael Crump ◽  
Sirpa Leppä ◽  
Luis E Fayad ◽  
Je-Jung Lee ◽  
Alice Di Rocco ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background Despite improvements in outcome following the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP), patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) scores of 3-5 at diagnosis have a poor outcome. Enzastaurin is a potent inhibitor of PKCβ, a component of the B-cell receptor signaling complex, with preclinical activity and clinical activity in a phase II trial in patients with relapsed DLBCL, providing the rationale for this study in the primary therapy setting. Methods PRELUDE was a multi-national, randomized, double-blinded, placebo-controlled study. Patients were required to have a histologic diagnosis of DLBCL, pre-treatment IPI score ≥3, and a complete response (CR) or CRu by International Working Group Criteria, or a negative FDG-PET scan after 6–8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease progression or death. Assuming a 2-year DFS rate in the control group of 70%, the primary analysis had 80% power to detect a HR of 0.67, eg, a 2-year DFS rate of 79% in the enzastaurin group. Secondary endpoints included overall survival (OS) and event-free survival (EFS). Data were analyzed 3 years after the last enrolled patient initiated treatment. Results From May 2006–April 2010, 758 patients were enrolled (enzastaurin, n=504; placebo, n=254). Median age at enrollment was 64 years (range 21-89); at diagnosis, 65% of patients had stage IV disease, 48% had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were well balanced between treatment arms. Fifty-seven percent had a negative PET scan following completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03–80). At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs. placebo was 0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p=0.54). DFS at 24 and 48 months were 79% and 70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs. placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p=0.81). Percent of ITT population patients on therapy at 12, 24, and 36 months was 70.6%, 60.6%, and 20.1% for enzastaurin; 72.3%, 60.6%, and 22.1% for placebo. Biomarker subgroup analysis was performed and will be available at time of presentation. Treatment emergent AEs (all grades) that were possibly study drug-related and significantly different between enzastaurin and placebo included chromaturia (18.5% vs. 0.4%), QTc prolongation (10.8% vs. 3.6%), and diarrhea (10.3% vs. 2.8%). There were no significant differences in number of patients with at least 1 grade 3 or higher AE between treatment arms. No significant differences were observed in the frequency of deaths while on therapy. Conclusion Enzastaurin did not improve DFS, EFS, or OS in patients with high-risk DLBCL and CR following R-CHOP treatment. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Leppä:Eli Lilly: Research Funding. Ogura:Eli Lilly: Research Funding. Rifkin:Millenium, Celgene, ONYX: Membership on an entity’s Board of Directors or advisory committees. Mackensen:Eli Lilly: Consultancy. Offner:Eli Lilly: Membership on an entity’s Board of Directors or advisory committees. Smith:Genentech, Celgene, Spectrum, Seattle Genetics, Gilead, Amgen/Micronet: Consultancy. Tobinai:Eli Lilly: Research Funding. Hahka-Kemppinen:Eli Lilly: Employment. Thornton:Eli Lilly: Employment. Shi:Eli Lilly: Employment. Lin:Eli Lilly: Employment. Kahl:Genentech: Consultancy. Savage:Eli Lilly: Consultancy.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Intrathecal (IT) Chemotherapy for Central Nervous System (CNS) Prophylaxis in Diffuse Large B-Cell Lymphoma (DLBCL): A Single Centre Retrospective Observational Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Luke Attwell ◽  
Benjamin Gray ◽  
Rachel Hall ◽  
Sally Killick ◽  
Helen McCarthy ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Educational Meetings ◽  
Large B Cell

Introduction: CNS relapse of DLBCL is associated with poor prognosis. Estimated incidence varies between 1.9 and 8.4%1. The CNS-International prognostic index (IPI)2 help risk stratify and estimate the 2-year risk of CNS relapse in DLBCL patients treated with R-CHOP chemotherapy. CNS prophylaxis is indicated in patients with a high risk of CNS relapse (a score of ≥4 equated to a 10.2% risk). High-risk DLBCL patients outside the CNS-IPI system include double/triple-hit (MYC/BCL-2/BCL-6 translocations) lymphoma, HIV lymphoma, testicular lymphoma, primary cutaneous lymphoma-leg type, stage IE breast lymphoma3. IT methotrexate or cytarabine administered during the course of systemic chemotherapy has been the most widely employed method of CNS prophylaxis but there is paucity of data validating its efficacy. Aim: The primary aim of the study was to evaluate the CNS relapse rates in DLBCL patients who received CNS prophylaxis. Patients and Methods: This was a single-centre retrospective observational study conducted in a district general hospital. Data was extracted from the regional (Dorset Cancer Network) DLBCL database and laboratory reports for CSF analysis at the time of the first intrathecal chemotherapy. Medical records of patients with DLBCL who received CNS prophylaxis were evaluated for the following patient-related and disease-related demographics: age at diagnosis, gender, stage, systemic treatment, CNS prophylaxis, treatment response, remission duration, systemic relapse rates, CNS relapse rates and survival. CNS-IPI scores were retrospectively calculated and additional indications evaluated for patients who received CNS prophylaxis. Results: Between 2013 and 2018, 178 patients were diagnosed with DLBCL. All patients were treated with RCHOP chemo-immunotherapy. CNS prophylaxis was administered in 47 (26%) patients. Median age was 69 years (range 20-86 years) and 62% were males. All 47 patients (100%) received IT methotrexate as CNS prophylaxis, with 43 (91%) receiving all of the planned 4 doses of IT methotrexate 12.5 mg each. A CNS-IPI score of ³4 was present in 31 (66%) patients, and a score of 2-3 in 9 (19%) patients. Additional risk factors identified included testicular lymphoma in 3 patients, breast lymphoma in 2 patients and oropharyngeal lymphoma in 2 patients. Ten (21%) patients received their treatment at the outset with courses 1-4 of R-CHOP. Of the 47 patients who received CNS prophylaxis, 5 (10%) relapsed; all had isolated CNS lymphoma at relapse. Median time to CNS relapse was 25 months (range 12-36 months) from initial diagnosis of DLBCL. Median survival after CNS relapse was 5 months (range 2-9 months). Of the remaining 141 patients, 2 patients relapsed with isolated CNS lymphoma. Conclusion: Although the overall incidence was low (4%), CNS relapse was observed in 10% of high-risk patients all of whom received CNS prophylaxis with IT methotrexate. The efficacy of CNS prophylaxis with IT chemotherapy remains unproven. There is no randomised study to show that IT prophylaxis alone is effective. Current British guidelines recommend high-dose intravenous methotrexate over IT methotrexate if patient's physiological fitness and renal function are acceptable4. The median age in our cohort was 69 years which makes it challenging to deliver dose-intensive systemic therapy concurrently with intravenous high-dose methotrexate. The role of CNS prophylaxis in high-risk patients including its efficacy and safety in older patients need further evaluation in prospective randomised studies. References Eyre T et al.Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. Hematologica. 2019;105(7):1914-1924.Norbert Schmitz et al.CNS International prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOPJ Clin Oncol 2016; 34:3150-3156.Andrew D Zelenetz et al.National Comprehensive Cancer Network (NCCN) Guidelines: B-Cell Lymphomas.Version 2.2020.Pamela McKay et al.The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Onlinelibrary.wiley.com. 2020. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16866 Disclosures Hall: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Karyopharm:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings.Killick:Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Gilead:Honoraria, Other: Support for attending education meetings.McCarthy:Janssen:Honoraria;Abbvie:Membership on an entity's Board of Directors or advisory committees.Walewska:AbbVie:Other: sponsored for educational meetings, Speakers Bureau;Janssen:Other: sponsored for educational meetings, Speakers Bureau;Gilead:Speakers Bureau;Astra Zeneca:Membership on an entity's Board of Directors or advisory committees.Chacko:Astellas:Honoraria;Daiichi-Sankyo:Honoraria;Novartis:Honoraria, Other: Travel Grants;Gilead:Other: Travel grants;Jazz Pharmaceuticals:Other: Travel grants;Celgene:Other: Travel grants.

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