scholarly journals Young High Risk Patients with MYC/BCL2 Double Hit Lymphoma, BCL2+ and/or Germinal Centre B-Cell like Diffuse Large B-Cell Lymphoma Benefit from Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis: Analysis of Data from the Nordic Lymphoma Group CRY-04 and Chic Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2955-2955 ◽  
Author(s):  
Sirpa Leppa ◽  
Judit Jørgensen ◽  
Leo Meriranta ◽  
Klaus Beiske ◽  
Jan M.A. Delabie ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Dose Dense ◽  
In The Beginning ◽  
Large B Cell

Abstract Background. Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these trials to compare clinical outcome and biological prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) versus at the end (CRY-04) of therapy. Patients and methods. In CRY-04 study, patients were treated with six courses of R-CHOEP14 followed by HD-Mtx and HD-Ara-C. In CHIC trial, treatment started with two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP-14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. For the correlative studies, formalin fixed paraffin embedded pretreatment tumor samples were analyzed by fluorescent in situ hybridization for BCL2 and c-MYC breakpoints and by immunochemistry for CD10, BCL6, MUM1, MYC and BCL2 expression. Germinal center B-cell-like (GCB)/non-GCB) subclassification was performed according to Hans algorithm. Results. Among 303 patients enrolled in the trials (CRY-04, n=160 and CHIC, n=143), 295 (CRY-04, n=154 and CHIC, n=139) were evaluable for baseline characteristics and outcome. Median age (54 and 56 years, p=0.222), male/female ratio, stage, and aaIPI scores were comparable in the two cohorts. CHIC regimen improved outcome over CRY-04; the findings included 4-year estimates of PFS (81% vs 66%, p=0.003), OS (83% and 79%, p=ns) and cumulative incidence rates of CNS progression (2.4% and 5.0%, p=ns). Treatment with the CHIC regimen reduced the risk of systemic progression (aaIPI adjusted RR=0.489, 95%CI 0.308-0.777, p=0.002). PFS benefit with CHIC over CRY-04 was observed across pre-specified subgroups, and particularly in patients less than 60 years old (p=0.008). In the entire study population, dual protein expression (DPE) of BCL2 and MYC was the only parameter to be significantly correlated with a worse PFS (4-y PFS 77% vs 50%, p=0.024; RR=2.300, 95% CI 1.088-4.860, p=0.029). Neither any single immunohistochemical marker nor the GCB/non-GCB subtype or MYC/BCL2-translocations significantly affected outcome. However, when treatment interaction was tested, MYC/BCL2 double hit status (DHL; 13%) predicted poor outcome among patients treated with CRY-04 regimen compared with patients who received CHIC regimen (4-y PFS; 38% vs 78%, p=0.086). GCB subtype and BCL2 positivity were also associated with better outcome in the CHIC cohort (4 y PFS; 63% vs 84%, p=0.011 and 61% vs 80%, p=0.007, respectively), whereas there were no significant survival differences between these regimens among the patients with non-GCB subtype, BCL2 negative DLBCL or DPE lymphomas. Conclusions. Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. The survival benefit related to CHIC regimen over CRY-04 is due to better systemic control of the disease, and at least partly linked to improved survival among patients with GCB subtype, BCL2 positivity and DHL. Disclosures Leppa: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding.

scholarly journals Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma

Cancer ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 4283-4290 ◽  
Author(s):  
Jeremy S. Abramson ◽  
Matthew Hellmann ◽  
Jeffrey A. Barnes ◽  
Peter Hammerman ◽  
Christiana Toomey ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Large B Cell

Dose-Dense CHOP plus Rituximab (R-CHOP14) for the Treatment of Elderly Patients with High-Risk Diffuse Large B Cell Lymphoma: A Pilot Study

2006 ◽  
Vol 115 (1-2) ◽  
pp. 22-27 ◽  
Author(s):  
Luigi Rigacci ◽  
Luca Nassi ◽  
Renato Alterini ◽  
Valentina Carrai ◽  
Giovanni Longo ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Elderly Patients ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Dose Dense ◽  
Large B Cell

A Phase II Randomized Study of Lenalidomide or Lenalidomide and Rituximab As Maintenance Therapy Following R-CHOP Chemotherapy for Patients with High Risk Diffuse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3668-3668
Author(s):  
Nishitha M. Reddy ◽  
Rhea M Simons ◽  
Meghan E Caldwell ◽  
Heidi Chen ◽  
Madan Jagasia ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Large B Cell Lymphoma ◽  
One Year ◽  
Large B Cell

Abstract Abstract 3668 Background: Diffuse large B-cell lymphoma (DLBCL) patients with an intermediate/high to high risk international prognostic index (IPI) score are at an increased risk of disease relapse in the first year after completion of standard therapy with R-CHOP. Lenalidomide (LEN), an immunomodulatory drug, enhances the natural-killer cell mediated antibody-dependant cellular cytotoxicity of rituximab in lymphoma cell lines, inhibits angiogenesis, alters cytokine production, and has been shown to have clinical activity against B-cell lymphoma including relapsed DLBCL. Methods: DLBCL patients with high risk features (IPI scores of 3 or greater) who achieved CR after R-CHOP were randomized to LEN (arm A) alone or LEN and rituximab maintenance therapy (arm B) within 12 weeks of last dose of R-CHOP. The primary endpoint of the study was to assess the one year relapse-free survival. We expected that a 25% difference of relapse compared with current standard therapy will have clinical significance. Patients in arm A received LEN at a dose of 25 mg daily for 21 days of 28 days. Patients in arm B received LEN at a dose of 20mg daily for 21 days of 28 days along with rituximab (375mg/m2) on day 8 of even cycles. Treatment on both arms was continued for one year. Treatment was discontinued for disease progression. LEN dose adjustments were incorporated in the protocol. Results: Thirty five patients, 19 arm A/16 arm B, 20 female/15 male, with a median age of 59 yrs were enrolled. The median IPI was 3 for all patients. For patients over the age of 60 the median IPI score was 4 and the median aa-IPI was 3. Two patients received XRT to areas of bulky disease at the completion of R-CHOP prior to start of maintenance. At a median follow up of 22 months, the 2 yr PFS and DFS was 86% and 96% respectively. For patients in arm A and arm B the 2 yr PFS was 92% vs.77% and the 2 yr DFS was 100% vs. 92% respectively (p=0.52). Two patients discontinued treatment due to adverse events. Grade 3–4 toxicities include neutropenia (25%), fatigue (17%), diarrhea (8%), DVT (3%), rash (3%), febrile neutropenia (3%). Related grade 1–2 toxicities include hypothyroidism (11%) and rash (47%). There were no treatment related deaths. Conclusions: Lenalidomide as maintenance therapy demonstrates encouraging clinical activity following standard chemotherapy and results in superior survival outcomes in DLBCL patients with high risk prognostic features. The 2-yr OS was 90% in our study as compared with historical controls of 70%. Our study suggests that maintenance strategy with lenalidomide based therapy may increase cure rate and needs to be prospectively evaluated in a phase III study. Disclosures: Reddy: Celgene: Research Funding. Off Label Use: Lenalidomide in Lymphoma. Park:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding.

scholarly journals Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 398
Author(s):  
Heli Vajavaara ◽  
Julie Bondgaard Mortensen ◽  
Suvi-Katri Leivonen ◽  
Ida Monrad Hansen ◽  
Maja Ludvigsen ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Immune Escape ◽  
Risk Of Death ◽  
Poor Outcome ◽  
Large B Cell Lymphoma ◽  
Dose Dense ◽  
Large B Cell

Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.

Dose-Dense Chemoimmunotherapy and Early Central Nervous System Prophylaxis For High-Risk Diffuse Large B-Cell Lymphoma. –Preliminary Results From a Nordic Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 849-849 ◽  
Author(s):  
Sirpa Leppa ◽  
Anne Maria Tierens ◽  
Judit Jorgensen ◽  
Mats Jerkeman ◽  
Magnus Bjorkholm ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Progression Rate ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Background Despite the advent of rituximab (R)-based chemoimmunotherapy, outcome for patients with high-risk diffuse large B-cell lymphoma (DLBCL) continues to be suboptimal, and the risk of central nervous system (CNS) progression is high. In a previous Nordic phase II study with dose-dense chemoimmunotherapy followed by systemic CNS prophylaxis, the CNS progression rate was lower than expected (4.5%), but all events occurred within 6 months after initiation of therapy (Holte et al., Ann Oncol 2013). Hence, in the present study, systemic CNS prophylaxis was moved to the beginning of therapy and CNS targeted therapy was further intensified by adding intrathecally administered liposomal AraC. Methods Inclusion criteria are age 18-65 years, primary DLBCL or grade 3B follicular lymphoma without clinical or radiological signs of CNS disease and cytology negative cerebrospinal fluid (CSF), age adjusted IPI 2-3, WHO performance score ≤3, and/or site specific risk factors for CNS recurrence. Treatment consists of two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5. All courses are administered with support of pegfilgastrim. Indications for radiotherapy are bulky masses at diagnosis and localized PET positive residual disease not eligible for biopsy. Primary endpoints are failure-free survival at 3 years, and CNS progression rate at 18 months. A secondary aim is to elucidate if CSF cytology negative/flow cytometry (FC) positive cases carry an increased risk of CNS progression with the present regimen. Results Of the accrued 84 patients by July 22, 2013, 70 had a complete set of baseline data. Median age was 55 years (range 20-64). The majority presented with DLBCL (96%), advanced-stage disease (94%), elevated LDH (94%), B-symptoms (67%), and 49% with >1 extranodal site. Seven CSF-samples were FC positive. Data on toxicity, response and relapse rates were registered for 45 patients. One toxic death due to pneumonia was reported. Grade 4 hematological toxicity and infections were observed in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients. CR, CRu, PR and PD rates at the end of chemoimmunotherapy were 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations. Conclusions Preliminary results indicate highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem feasible and safe. ClinicalTrials.gov Identifier: NCT01325194 Disclosures: Leppa: Amgen: Research Funding; Mundipharma: Honoraria, Research Funding. Holte:Mundipharma: Honoraria, Research Funding; Amgen: Research Funding.

Risk Stratification Combining MYC Immunohistochemistry with Standard IPI Has Utility in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2656-2656
Author(s):  
David Simon Kliman ◽  
Louise Imlay-Gillespie ◽  
Kirsten McIlroy ◽  
Anthony Gill ◽  
Christopher Arthur ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Significant Difference ◽  
Large B Cell

Abstract Background Though the majority of patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) are curable with R-CHOP chemotherapy, a significant proportion will relapse or have refractory disease. The most commonly used clinical tool is the international prognostic index (IPI), though this cannot fully capture the heterogeneity of cases seen in practice. In recent years biomarkers such as MYC are entering clinical use. Pts with lymphomas demonstrating dual abnormalities of MYC in association with BCL2 and/or BCL6-known as 'double-hit' lymphomas are consistently shown to have poorer disease free and overall survival. While Fluorescence in-situ hybridization (FISH) for MYC translocation is the gold-standard, immunohistochemistry (IHC) is faster and significantly cheaper. Studies in recent years have confirmed the prognostic significance of increased MYC expression by IHC. Due to significant inter-laboratory variability however, internal validation is required. Methods Tissue samples of pts treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012 were retrospectively assessed. Pts were included if they were transplant eligible (age <70 years), and had been treated for de novo DLBCL with a rituximab containing regimen. Samples were scored for MYC IHC as well as BCL2 and BCL6. Clinical data including IPI score, treatment and outcomes were also collected. Treatments were stratified into standard R-CHOP-like versus more intensive regimens including R-Hyper-CVAD and dose-adjusted R-EPOCH. A significant cut-off for MYC staining was determined using X-Tile (Rimmlab, New Haven, CT) and confirmed with the log-rank test. Estimation of OS and EFS was performed using the Kaplan-Meier method. Pt characteristics were compared using Chi-squared test. Statistical analysis was performed using MedCalc 15.4 (MedCalc software, Ostend, Belgium). Ethics approval was received for a retrospective study. Results 105 patients met study criteria. The 5 year OS and EFS was 86% and 77% respectively (Figure 1 and 2). The optimal cut-off for positive MYC IHC was >70%. This was seen in 23% of samples. From the 13 cases with MYC FISH results, the positive and negative predictive values of positive MYC IHC were 50% and 92% respectively. There was no significant difference between the MYC positive and negative groups with respect to demographics or IPI score (Table 1). Significantly more patients with MYC positivity received intensive treatment (37% versus 16%, p=0.047). Despite this, 5 year OS was significantly poorer at 51% versus 87% at median follow-up of 40 months (P=0.0025, Figure 3). There was a trend towards worse EFS at 61% versus 75% though this did not reach statistical significance (P=0.242). On multivariate analysis, MYC IHC and IPI score were the only independent prognostic factors. Based on the relative odds ratio, a combined scoring system was designed, attributing 1 point for positive MYC IHC and/ or IPI intermediate-high risk, and 2 points for IPI high risk. This resulted in 4 risk groups with significantly different 5 year OS of 94%, 78%, 45% and 0% (P<0.0001). Discussion MYC IHC is of independent prognostic significance. Due to significant variability between laboratories, local validation is required. A composite score combining IPI and MYC IHC is simple to calculate and may provide better prognostic utility than either factor alone. Ongoing prospective studies investigating the role of clinical risk stratification and newer biomarkers are required to identify patients likely to need more intensive or novel therapies. Figure 1. Figure 1. Disclosures Imlay-Gillespie: Novartis: Honoraria. Arthur:Amgen: Honoraria; Novartis: Honoraria; BMS: Honoraria. Mackinlay:Roche: Research Funding; Sanofi Aventis: Research Funding. Mulligan:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding.

Phase II Randomized Study Of Lenalidomide Or Lenalidomide and Rituximab As Maintenance Therapy Following Standard Chemotherapy For Patients With Intermediate-High/High Risk Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3061-3061 ◽  
Author(s):  
Nishitha M. Reddy ◽  
David S. Morgan ◽  
Steven I. Park ◽  
John P Greer ◽  
Kristy L. Richards
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Standard Chemotherapy ◽  
Large B Cell Lymphoma ◽  
One Year ◽  
Large B Cell

Background DLBCL patients (pts) with an intermediate/high to high risk international prognostic index (IPI) are at an increased risk of disease relapse rate in the first year after completion of standard therapy with R-CHOP. Lenalidomide (len), an immunomodulatory drug, has activity in relapsed diffuse large B cell Lymphoma. Len enhances the natural-killer cell mediated antibody-dependant cellular cytotoxicity of rituximab in lymphoma cell lines and inhibits angiogenesis as well as alters cytokine production. Lenalidomide received FDA approval based on its clinical activity in relapsed mantle cell lymphoma. Methods Intermediate-high/high risk IPI pts with DLBCL were randomized to len (arm A) alone or len and rituximab (arm B). The primary endpoint of the study was to assess the one year disease-free survival. We expected that a 25% difference of relapse will have clinical significance when compared with current standard therapy. Pts in arm A received len at a dose of 25 mg daily for 21 days of 28 days. Patients on arm B received len at a dose of 20mg daily for 21 days of 28 days along with rituximab on day 8 of even cycles. Treatment on both arms was continued for one year. Treatment was discontinued for disease progression. Len dose adjustments are incorporated in the protocol. Results Forty three pts, 21 arm A/ 22 arm B, 21 female/22 male, with a median age of 59 yrs were enrolled. The median IPI was 4 for pts over the age of 60 and the median aa-IPI was 3. Three pts received XRT to areas of bulky disease. At a median follow up of 27 months, the 2 yr DFS and OS was 88%. For patients in arm A and arm B the 2 yr DFS was 90% vs. 86% (figure 1) and the 2 yr OS was 95.2% vs. 81% (figure 2), respectively (P=NS). Two pts discontinued treatment due to adverse events. Grade 3-4 toxicities include neutropenia (28%), fatigue (16%), diarrhea (6%), DVT (3%), rash (3%), febrile neutropenia (3%). Related grade 1-2 toxicities include hypothyroidism (15%) and rash (54%). Conclusions Len as maintenance therapy demonstrates clinical activity following standard chemotherapy and improves DFS and OS in DLBCL patients with high risk prognostic features as compared with historical controls. This trial is registered with NCI- #NCT00765245 Disclosures: Reddy: Celgene: Research Funding. Off Label Use: lenalidomide in diffuse large B cell lymphoma. Park:TEVA: Research Funding; Seattle Genetics, Inc.: Research Funding.

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