Elevated Pre-Treatment Serum Immunoglobulin Free Light Chains (FLC) Are Associated with Poor Event-Free and Overall Survival in Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 136-136 ◽  
Author(s):  
Matthew J Maurer ◽  
Ivana N Micallef ◽  
Jerry A Katzmann ◽  
Daniel Nikcevich ◽  
Thomas E Witzig
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Light Chains ◽  
Large B Cell Lymphoma ◽  
Pre Treatment ◽  
Large B Cell

Abstract Abstract 136 Background: The serum free light chain (FLC) assay quantitates free kappa and free lambda immunoglobulin light chains. This assay has prognostic value in MGUS, multiple myeloma (MM), solitary plasmacytoma, and AL amyloidoisis, and has been incorporated in response criteria for both MM and AL amyloidosis. A percentage of non-Hodgkin's lymphoma (NHL) patients also present with abnormal FLC concentrations and recent data suggest that AIDS patients with elevated serum FLC are at higher risk of developing NHL. Here we assess the impact of FLC in a cohort of patients with diffuse large B-cell lymphoma (DLBCL) enrolled on a cooperative group clinical trial. Methods: Newly diagnosed DLBCL patients were treated with epratuzumab + R-CHOP (ER-CHOP) on NCCTG clinical trial N0489. Serum FLC was quantitated prior to treatment and after cycles 2 and 6 using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Patients were followed per clinical trial protocol for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively). Results: 107 patients were enrolled on the trial. 80 patients had a pre-treatment serum draw and a central pathology confirmed diagnosis of DLBCL, of which 47 had a post-cycle 2 sample (C2) and a 54 had a post-cycle 6 sample (C6). At a medium follow-up of 25 months (range 7-39), 22 patients (28%) had an event and 17 patients died (21%). Prior to treatment 23 patients (29%) had abnormal kappa concentrations (all elevated), 16 (20%) had abnormal lambda concentrations (11 elevated, 5 decreased), and 9 (11%) had an abnormal kappa/lambda ratio. FLC concentrations were significantly reduced in patients during treatment, with a median reduction in kappa (C2: 46%, C6: 64%) and lambda (C2: 44%, C6: 49%), all p<0.0001. Elevated FLC prior to treatment was highly associated with both OS (logrank p=0.009) and EFS (logrank p=0.006); these associations remained significant after adjusting for IPI (both p = 0.01). Conclusions: A significant percentage of DLBCL patients present with abnormal FLC concentrations. Kappa and lambda are significantly reduced for most patients during treatment. Elevated pre-treatment FLC concentrations are associated with inferior EFS and OS in DLBCL and this association is independent of the IPI. A follow-up study of FLC and prognosis is currently underway in a cohort of 1500 NHL patients from the Mayo Clinic and University of Iowa SPORE. Disclosures: No relevant conflicts of interest to declare.

Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients Treated with Immunochemotherapy Who Are Alive and Progression Free 12 Months After Diagnosis Have a Subsequent Overall Survival Similar to That of the General Population

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1540-1540 ◽  
Author(s):  
Matthew J Maurer ◽  
Herve Ghesquieres ◽  
Thomas E. Witzig ◽  
Carrie A. Thompson ◽  
Ivana N. Micallef ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
General Population ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Age And Sex

Abstract Abstract 1540 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma in the western world. Outcomes have improved with the standard initial therapy of rituximab and anthracyline based chemotherapy (immunochemotherapy). However, 20–40% of patients will either fail to achieve remission or relapse following initial immunochemotherapy. Most relapses occur early, and long-term outcome of relapsed/refractory patients is generally poor despite salvage regimens and stem cell transplant. Traditionally, studies for DLBCL have been evaluated using progression-free and/or overall survival. However, the event rate in DLBCL slows significantly approximately 12–18 months after diagnosis, and late events are often due to competing (non-DLBCL related) risks, especially in older patients. Here we examine outcome of DLBCL patients based on their event status at 12 months. Methods: Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER). Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for events (progression, re-treatment, or death due to any cause) and overall survival (OS). Event-free status at 12 months after diagnosis (EFS12) was assessed as a dichotomous variable. Cause of death was determined by medical record and death certificate review using prospectively determined definitions. Expected survival was based on age and sex matched survival using the Minnesota population death rates. Confirmation cohorts were from a Lyon, France hospital based registry and NCCTG clinical trial N0489. Results: 680 patients with newly diagnosed DLBCL and treated with rituximab + anthracycline based chemotherapy were enrolled in the MER from 2002 to 2009. The median age was 62 years (range 18–92). 53% were male. At a median follow-up of 59 months (range 8–116), 266 patients (39%) had an event and 188 patients (28%) died. 162 patients (24%) had an event in the first 12 months after diagnosis, comprising 60% of all events. Patients with an event in the first 12 months had poor survival with death almost exclusively due to disease (Figures 1a, 2a). In contrast, patients who were event-free at 12 months had comparable survival to the age and sex matched general population (Figure 2b) and were more likely to die of other causes than DLBCL (Figure 1b). Overall survival rates by EFS12 status were validated in patients from a French hospital-based registry (N=265) and the NCCTG N0489 clinical trial (N=87) with additional replication studies underway. Conclusions: DLBCL patients who are event-free at 12 months after diagnosis have an excellent prognosis with an overall survival similar to that of an age- and sex- matched general population and are more likely to die of other causes than DLBCL. This finding has implications for clinical management, new clinical trials, and follow-up testing in this patient population. In contrast, patients with an event within the first 12 months after diagnosis have a poor prognosis with almost all deaths secondary to DLBCL. EFS status at 12 months identifies patients with poor outcomes due to disease. This can be utilized as an endpoint in biologic studies and clinical trials to address early treatment failures. EFS status at 12 months should be incorporated into prognostic models to identify high risk patients in newly diagnosed DLBCL. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety of Liposomal Cytarabine as Intrathecal Prophylaxis in Patients with Diffuse Large B Cell Lymphoma at High Risk of CNS Involvement: A Multicentric Study Including 80 Patients in Spain.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1663-1663
Author(s):  
Adolfo de la Fuente ◽  
Antonio Salar ◽  
Carlos Panizo ◽  
Belen Navarro ◽  
Teresa Olave ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Retrospective Study ◽  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Liposomal Cytarabine ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 1663 Poster Board I-689 Introduction Lymphomatous meningitis (LM) in patients with Diffuse Large B Cell Lymphoma (DLBCL) is usually an early complication and with poor prognosis. Risk factors have been previously identified for this complication. DepoCyte is an extended released liposomal cytarabine formulation (LC) which has demonstrated better efficacy compared to standard cytarabine for the treatment of LM in one randomized clinical trial. Purpose and Methods A retrospective study was carried out in 24 Spanish sites including patients diagnosed of DLBCL and at risk of LM – defined by the presence of at least one of the following: retroperitoneal mass ≥ 10 cm; Waldeyer ring, sinus, vertebral or bone, and testicular involvement; LDH more than twice the upper normal limit; bone marrow involvement > 30% and serology VIH+. All patients had received LC as IT prophylaxis for LM in the period April 2005 – June 2009. Main endpoints were effectiveness (leptomeningeal involvement rate) and safety of the IT prophylaxis. Results Data from 80 patients were analyzed. Baseline characteristics were: Mean age 55 ± 16 years (range: 18-80 years). Males 74%; Ann Arbor stage IV 54%. All patients received alkylating based regimens, being R-CHOP as the most frequent one (88%). LC was administered as intrathecal prophylactic treatment for LM in all patients. 64 patients completed the IT prophylaxis treatment with a mean of 2,8 ± 0,83 administrations and a median follow up of 17 months (range: 3-40 months) (8 patient still on treatment and 8 patients died before finish prophylaxis). Just one patient (1,6%) had leptomeningeal spread: 76 years old man with primary testicular DLBCL, treated with R-CHOP regime, who did not reach complete response and died after 8 months of follow up due to respiratory failure. Twenty four patients out of eighty (30%) showed adverse events, being headache the most frequent side effect (27%), and 14% grade IV. Headache was reversible in all cases. Chemical arachnoiditis prophylaxis was given to 70 patients. Conclusions This retrospective study has shown that in DLBCL patients and high risk of LM, prophylaxis with LC was feasible and well tolerated. With a median follow up of 17 months (range: 3-40 months) the incidence of LM was 1,6 %. Prospective, randomized comparative studies versus conventional prophylaxis regimes are needed. Disclosures Off Label Use: DepoCyte is an extended released liposomal cytarabine formulation (LC) which has demonstrated better efficacy compared to standard cytarabine for the treatment of LM in one randomized clinical trial. Prphylaxis effectiveness..

Tumor Associated Macrophage Expression, CD163, Is Associated with Poorer Outcome in Diffuse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1583-1583
Author(s):  
Olga L. Bohn ◽  
Jocelyn C. Maragulia ◽  
Hilda Crispin ◽  
Camille Gonzalez ◽  
Cornelius Miething ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Volume ◽  
Tumor Associated Macrophages ◽  
Large B Cell Lymphoma ◽  
Cd163 Expression ◽  
Large B Cell

Abstract Abstract 1583 Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma with various subtypes. Recent data of Tumor Associated Macrophages (TAM) in DLBCL have shown association with poor overall survival. We were interested in assessing these markers, in particular, for practical daily clinical use at a high volume cancer center. We therefore performed a retrospective study to evaluate expression of macrophage markers (CD68 and CD163) in DLBCL and determine overall survival (OS) and event free survival (EFS). Design: A total of 128 DLBCL cases were reviewed. Tissue microarrays (TMA) were constructed with cores in triplicate. CD163 and CD68 expression was assessed by immunohistochemistry (IHC) using anti-CD68 (KP-1, Ventana) and anti-CD163 (Vector Laboratories) performed on the automated Ventana XT platform according to manufacturer protocols (Tucson, AZ). The assessment of intratumoral CD163 infiltration was performed at objective magnification 40X by three observers (OB, HC and JTF) and a consensus was obtained. The number of CD163 macrophages was counted in three cores. The mean was calculated and the results were scored as follows: 0 (0 to 25 positive cells); 1 (between 26 to 50 positive cells); 2 (51 to 75 positive cells); 3 (76 to 100 positive cells). CD68 expression was assessed by IHC and the degree of intratumoral infiltration was scored as follows: 0 (less than 5% positive cells); 1 (between 5% to less than 50% of positive cells); 2 (more than 50% positive cells). Of 128 patients, 13 had limited clinical data, 23 were biopsies at relapse, and 92 were evaluable for OS and EFS from initial therapy. EFS was defined as progression of disease, secondary malignancy, or death due to disease or any other reason. OS was calculated from date of death or last follow-up date to date of diagnostic biopsy. EFS was calculated from event date or date of last follow-up to end of treatment date. SPSS software was used to calculate Kaplan Meier survival curves and statistics. Results: There were 51 (55%) males and 41 (45%) females (M:F ratio 1.2). The median age was 60 years (range from 10 to 90). A high number of tumor infiltrating CD163 expression (scores 0 [n=19], 1 [n=6], 2 [n=9] vs 3 [n=58]) was associated with significantly poorer OS (p=0.028) and EFS (p=0.005). A statistically significant difference was observed in patients with tumors that had abundant tumor associated macrophages with CD163 (score 3 >75 positive cells) on IHC. CD68 expression did not correlate with OS and EFS. Conclusion: High CD163 expression is statistically significantly associated with decreased OS and EFS in DLBCL. Because of cleaner staining, scoring on a daily practical basis in a high volume center is useful. Our data supports initial few prior reports of this marker in DLBCL. Disclosures: No relevant conflicts of interest to declare.

MAL Is Expressed in a Subset of Hodgkin Lymphomas and Identifies a Population of Patients with Poor Prognosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3117-3117
Author(s):  
Eric D. Hsi ◽  
Stephen J. Sup ◽  
Carlos Alemany ◽  
Elisa Tso ◽  
Marek Skacel ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
B Cell ◽  
Lipid Rafts ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Receptor Activation ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Recent evidence suggests that classical Hodgkin lymphoma (cHL) and primary mediastinal diffuse large B-cell lymphoma (PMLBL) have similarities that span clinical, histopathologic, and molecular genetic features. MAL is a gene that encodes a protein associated with lipid rafts in T-cells and epithelial cells. In T-cells, it is involved in the reorganization of lipid rafts during T-cell receptor activation and signaling. MAL is overexpressed in PMLBL and in a minority of cHL cases; however, data on its expression in a large series of cHL with clinical follow-up is lacking. In order to determine whether there might be some clinical significance associated with MAL expression, we evaluated MAL expression in a series of cHL by immunohistochemistry. Clinical information including age, sex, stage, bulky tumors (≥ 1/3 of the thoracic diameter or mass ≥ 10cm), hemoglobin, WBC, lymphocyte count, albumin, and outcome were collected for the cHL patients. Tissue microarrays containing diffuse large B-cell lymphoma (n=33), PMLBL (n=41), and cHL (n=87) were stained for MAL. 54% of PBLBL, 17% of cHL, and 3% of non-mediastinal diffuse large B-cell lymphomas were found to express MAL. Focussing on cHL, MAL expression correlated with the nodular sclerosis histologic subtype (P=0.03, Fisher exact). Overall, 22 HL patients have failed (relapse or death) and 15 patients have died. Median follow-up of patients alive and free of disease is 6.7 years (range 1.0–16.9 years). The 5-year failure-free and overall survival are 75 +/− 5% and 85 +/−4%, respectively. Using P&lt;0.1 as significant, univariable analysis (Wilcoxon rank sum) showed that the following factors were associated with shorter failure free survival and overall survival: age ≥ 45 (P=0.01 and P&lt;0.001, respectively), stage III/IV (P=0.09 and P=0.03, respectively), and MAL expression (P=0.05 and P=0.01, respectively). Cox proportional hazards modeling showed that the following were independent predictors of both time to treatment failure and overall survival: age (P=0.03 and 0.01, respectively), stage (P=0.06 and 0.04, respectively), and MAL expression (P=0.06 and 0.02, respectively). These data suggest that MAL expression in cHL identifies a biologically different subset of cHL compared to those cases that lack MAL and that MAL expression is a predictor of adverse outcome.

scholarly journals Elevated Serum Free Light Chains Are Associated With Event-Free and Overall Survival in Two Independent Cohorts of Patients With Diffuse Large B-Cell Lymphoma

2011 ◽  
Vol 29 (12) ◽  
pp. 1620-1626 ◽  
Author(s):  
Matthew J. Maurer ◽  
Ivana N.M. Micallef ◽  
James R. Cerhan ◽  
Jerry A. Katzmann ◽  
Brian K. Link ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Light Chains ◽  
Reference Ranges ◽  
Serum Free ◽  
Large B Cell Lymphoma ◽  
Large B Cell

PurposeThe serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies.Patients and MethodsThe association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio.ResultsElevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components.ConclusionIncreased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.

scholarly journals Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients

Blood ◽  
2013 ◽  
Vol 122 (19) ◽  
pp. 3251-3262 ◽  
Author(s):  
Stefan K. Barta ◽  
Xiaonan Xue ◽  
Dan Wang ◽  
Roni Tamari ◽  
Jeannette Y. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Pooled Analysis ◽  
Factors Affecting ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Large B Cell

Key Points Rituximab use is associated with significant improvement in all outcomes for patients with HIV-associated CD20-positive lymphomas. Infusional EPOCH chemotherapy is associated with better overall survival in patients with AIDS-related diffuse large B-cell lymphoma (DLBCL).

scholarly journals C-MYC Protein Expression and High Ki-67 Proliferative Index are Predictives of Disease Relapse in Diffuse Large B Cell Lymphoma

2021 ◽  
Vol 6 (1) ◽  
pp. 15-20
Author(s):  
Mahmoud Tag El-Hussien ◽  
Nadia Mokhtar ◽  
Eman Naguib Khorshed
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Statistical Prediction ◽  
Proliferative Index ◽  
Ki 67 ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Objective: To evaluate the status of C-MYC protein expression and Ki-67 proliferative index and to clarify their role in predicting relapse of diffuse large B cell lymphoma (DLBL). Materials and Methods: A retrospective study conducted on 50 cases diagnosed as DLBL in a 3 years’ time period from January 2014 till December 2016, collected from the archive of Pathology Departments of the National Cancer Institute Cairo - Egypt, Misr University for Science and Technology and private labs of authors. The diagnosis of DLBL for all cases, both nodal and extranodal, was confirmed by histopathologic examination and immunophenotyping. Automated immunohistochemical staining using antibodies against C-MYC protein and MIB-1 was used to evaluate the C-MYC expression in tumor cells and to assess their proliferative ability by calculating Ki-67 labelling index. The relation between the percentage of C-MYC protein expression, Ki-67 proliferative index, clinical data and the relapse status during the follow up period were analyzed. Results: A total of 50 cases of DLBL in both nodal and extra-nodal sites were included. Twenty-three cases (46%) were expressing the C-MYC protein, and 29 cases (58%) showed high Ki-67 proliferative index. Twenty-two cases (44%) relapsed during the follow-up period. Positive C-MYC protein expression was significantly associated with high Ki-67 proliferative index. C-MYC protein expression and high Ki-67 proliferative index were independently associated with disease relapses in 81.8% and 86.4% of cases respectively. Cases with combined C-MYC protein expression and high Ki-67 proliferative index showed statistical prediction of relapse in 81.8% of cases. Conclusion: C-MYC protein expression and high Ki-67 proliferative index were independently associated with relapse of diffuse large B cell lymphoma. Furthermore, the combined positive C-MYC protein expression and high Ki-67 proliferative index is better than a single positive test in predicting relapses among DLBL patients.

scholarly journals Single Centre Retrospective Analysis: Transformation of Waldenström's Macroglobulinemia to Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Bert Heyrman ◽  
Nikki Granacher ◽  
Ka Lung Wu
Keyword(s):  
B Cell ◽  
Retrospective Analysis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Single Centre ◽  
The Past ◽  
Large B Cell Lymphoma ◽  
End Of Treatment ◽  
Large B Cell

Introduction: The incidence and outcome of Waldenström's macroglobulinemia (WM) patients with transformation to diffuse large B-cell lymphoma (DLBCL) are unclear. We performed a retrospective analysis to determine the incidence, clinicopathological characteristics and treatment outcome of WM patient with histologic transformation to DLBCL in our centre. Methods: Single centre chart review of WM patients in the past 10 years. Patients with histologic diagnosis of DLBCL after the diagnosis WM were included in our analysis. Results: Three of the 79 WM patients had histological transformation to DLBCL, two male and one female. Mean age at DLBCL development was 76,6 years. The mean time to transformation since diagnosis of WM was 8,3 years (14, 8 and 3 years). All three patients received at least one prior line of treatment in relation to WM (2, 1 and 3 prior lines). Different regimens used were cyclophosphamide/dexamethasone, rituximab/bendamustin, chlorambucil monotherapy, fludarabine monotherapy, R-CVP and ibrutinib monotherapy. The patients were in clinical CR from WM at the time of transformation, two patients were still on treatment. All three patients presented with advanced disease (stage IIIB, IVB, and IVA) non-GCB subtype DLBCL with at least 2 extra nodal sites. R-IPI scores were 4,5 and 4. Two patients were treated with R-miniCHOP, one patient received R-CHOP. The first patient achieved a CR at the end of treatment and is now 1,5 years in follow-up. The second patient died from pneumonia one year after achieving a CR. The third patient is in follow op since 3 months after reaching a CR at the end of treatment. Conclusion: Over the past decade transformation of WM to DLBCL was 3.7% in our centre. This is in accordance with previous data suggesting an 2.4% risk of transformation over 10 years.Time to transformation varies and no association with prior WM therapy and response to treatment can be found.All patients presented with more aggressive DLBCL in an advanced stage.All three patients achieved a CR following treatment for DLBCL, one patient died from pneumonia, two others are now in follow-up 1,5 years and 3 months respectively. Disclosures Heyrman: Celgene:Research Funding.

scholarly journals Systematic Literature Review of the Clinical Evidence in Relapsed/Refractory (R/R) Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5821-5821
Author(s):  
David G. Maloney ◽  
Fei Fei Liu ◽  
Lisette Nientker ◽  
Cathelijne Alleman ◽  
Brian Hutton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Frontline treatment is curative in ~60% of patients (pts); however, ~30% of pts relapse and ~10% are refractory to frontline treatment. Treatment options for pts with relapsed/refractory (R/R) disease, especially in the third-line or greater (3L+) setting, have been primarily salvage chemotherapies (CTs). Recently, 2 CAR T cell products, axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®), and the antibody-drug conjugate, polatuzumab vedotin (Polivy®), were approved in the 3L setting. A systematic literature review (SLR) of R/R LBCL was conducted to identify relevant evidence on clinical outcomes in LBCL pts, including these new therapies, within the second-line and greater (2L+) or 3L+ setting, and to define the unmet medical need. Methods: This SLR was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements. The review identified randomized and nonrandomized/observational studies within R/R LBCL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma grade 3B (FL3B), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL transformed from indolent lymphomas, and R/R DLBCL with secondary central nervous system (SCNS) involvement. Sources were EMBASE, MEDLINE, The Cochrane Library, and clinical conferences (ASCO, ESMO, EHA, ASH, ICML, AACR, and EORTC) from Jan 2000 to Apr 2019. Results : Following screening of 8683 database records and additional sources, 103 publications covering 78 unique studies were identified. Studies identified were characterized by line of treatment and R/R LBCL subtype (Figure). OS, PFS, DOR, OR, and safety observed from the identified studies were described. Disease subtypes, pt eligibility criteria, and length of follow-up varied notably across studies. In the 3L+ population, 11 salvage CT and 2 CAR T cell therapy studies reported survival outcomes. With salvage CT, the reported ORR across studies ranged from 0% to 54%, while CR ranged from 5.6%-31%. Median OS (mOS) ranged between 3-9 months, with one outlying study reporting mOS at 20 months. Median PFS (mPFS) reported within the salvage CT studies ranged from 2-6 months. Among CAR T cell therapies, pts treated with axicabtagene ciloleucel (n=101) reported a CR rate of 58% and median DOR (mDOR) was 11.1 months after a median follow-up of 27.1 months. mPFS was 5.9 months and mOS was not reached. At a median follow-up of 19.3 months, pts treated with tisagenlecleucel (n=115) had a CR of 40% but the mDOR was not reached. mOS was 11.1 months for all infused patients. In the 2L+ transplant-eligible population (36 studies), pts who received high-dose CT + HSCT achieved mOS between 9 months to 5 years. In the transplant noneligible population, 16 studies reported mOS between 3-20 months. Studies involving mixed transplant-eligible and noneligible populations (30 studies) reported mOS of 1-17 months. A few studies with limited sample sizes were found to report outcomes in LBCL subtypes (eg, PMBCL, SCNS lymphoma, DLBCL transformed from non-FL indolent lymphoma, FL3B). In the 3L+ setting, 1 study reported that mOS was not reached after a median of 6.6 months. In the 2L+ setting, 4 studies reported mPFS and mOS outcomes ranging between 2-9 months and 10-16 months, respectively. Among studies assessing safety of salvage CTs in R/R LBCL, neutropenia, leukocytopenia, thrombocytopenia, and infections were the most commonly reported adverse events (AEs), with neutropenia being the most reported. Among the 3 studies reporting safety outcomes of CAR T cell therapy, data suggest that hematologic AEs (possibly related to lymphodepleting CT), cytokine release syndrome, and neurotoxicity are the most reported. Conclusions : Despite the availability of new therapies for 2L+ and 3L + LBCL, examination of the current evidence has shown that there exists a high unmet need for additional therapeutic options that provide favorable benefit/risk and durable response for these patients. Furthermore, limited data are available for the rarer subtypes of LBCL. Both findings represent important treatment gaps for R/R LBCL that must be addressed in future research geared toward improvement of the current treatment landscape. Disclosures Maloney: Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Liu:Celgene Corporation: Employment. Nientker:Celgene Corporation: Consultancy; Pharmerit Cöoperatief U.A.: Employment. Alleman:Pharmerit Cöoperatief U.A.: Employment; Celgene Corporation: Consultancy. Garcia:Celgene: Employment, Equity Ownership.

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