scholarly journals Diffuse Large B-Cell Lymphomas Transformed from or with Concurrent Follicular Lymphoma Demonstrate Similar Clinical Outcomes As De-Novo Diffuse Large B-Cell Lymphomas, Except for Cases Harboring Double Hit Rearrangements

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 828-828
Author(s):  
Amir Behdad ◽  
Craig Boddy ◽  
Angela Fought ◽  
Timothy Taxter ◽  
Marissa Falkiewicz ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Burkitt Lymphoma ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Double Hit ◽  
Large B Cell

Abstract Introduction: Follicular lymphoma (FL) is characterized by an indolent clinical course, but patients with this disease bear a risk of transformation to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). DLBCL transformed from FL (tDLBCL) traditionally has been associated with an aggressive course and a post-transformation survival of 0.6-1.7 years. However, a more recent study showed longer survivals in these patients, challenging the notion that transformation universally portends a poor prognosis in the immunotherapy era. Presence of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) also raises the possibility of transformation, but its clinical significance has not been elucidated in the literature. In this study, we analyzed and compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL. We also characterized the prevalence of MYC/BCL2/BCL6 gene rearrangements in tDLBCL and cDLBCL/FL cohorts and evaluated the impact of dual rearrangements (double hit, DH) on clinical outcomes. Methods: Patients diagnosed with DLBCL or B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma, also known as HGBL (BCLU/HGBL), treated at Northwestern University or University of Pennsylvania from 1/2010 to 7/2016 were included. Patients with Burkitt lymphoma, primary CNS and HIV-associated lymphoma were excluded. Transformation was defined as presence of DLBCL/ BCLU/HGBL in cases with an antecedent diagnosis of FL by at least 6 months. We divided our cohort into three groups: 1. De novo DLBCL or BCLU/HGBL with no prior history of FL (dDLBCL) 2. Transformed FL (tDLBCL) and 3. DLBCL or BCLU/HGBL with concurrent FL (cDLBCL/FL). Progression free survival (PFS) was defined as time from diagnosis to radiographic progression, regimen change, death or last follow-up. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Kaplan-Meier (KM) survival analyses, using a log-rank p-values were performed for PFS and OS to compare the three diagnosis groups (dDLBCL, tDLBCL, and cDLBCL; alpha=0.05) and pairwise comparisons of combinations of diagnosis (dDLBCL and tDLBCL+cDLBCL) and double hit status (accounting for multiple comparisons with a Bonferroni corrected alpha=0.013). Fluorescence in situ hybridization for MYC, BCL2 and BCL6 rearrangements was performed using break-apart probes per the policy of each institution. Results: A total of 293 pts, including 233 dDLBCL, 37 tDLBCL, and 23 cDLBCL/FL were included. 50% of the tDLBCL received at cytotoxic chemotherapy before transformation for precedent FL. Age and sex distribution, as well as clinical characteristics including stage, ECOG performance status, IPI score, and primary refractoriness were similar amongst the three groups. LDH was more likely to be elevated in dDLBCL (75%), as compared to tDLBCL(63%) and cDLBCL/FL (47%)( p=0.02%). Additionally, non-bone marrow extra-nodal disease was seen more often in dDLBCL (72%), as compared with tDLBCL (53%) and cDLBCL/FL (43%)( p <0.01). DH were seen more often in tDLBCL(32%) and cDLBCL/FL (30%), compared with the dDLBCL (11%)( p <0.01). The cell of origin was germinal-center type in 92% of the tDLBCL and 91% cDLBCL/FL, compared with 64% of dDLBCL (p <0.01). Intensive chemotherapy regimens (R-EPOCH or R-hyperCVAD) and autologous stem cell transplantation was used more often in tDLBCL (43% and 19%, respectively), compared with dDLBCL (30% and 3%, respectively) and cDLBCL/FL (28% and 8% respectively). For all pts, the median length of follow-up was 13.8 months (range 0.2-59.2). OS and PFS were similar in the three subgroups (p=0.90 and p=0.77, respectively; Figure 1). We then analyzed the survival based on the presence of DH in two separate subgroups: 1) dDLBCL and 2) tDLBCL + cDLBCL/FL (combined as one group given low number of cases). OS was significantly shorter in lymphomas with DH, compared to non-DH in both subgroups (p <0.001 for dDLBCL and p=0.004 for tDLBCL + cDLBCL/FL). Comparison of the OS in DH of dDLBCL versus DH of tDLBCL + cDLBCL/FL showed no statistical difference (p=0.15), similar to the OS of non-DH cases the two groups( p=0.31). Conclusions: DLBCLs transformed from FL or with concurrent diagnosis of FL (composite lymphoma) demonstrated similar clinical outcomes in our study. However, dual rearrangements are more prevalent in these patients and drive inferior survival similar to DH status in de novo DLBCL. Figure 1 Figure 1. Disclosures Landsburg: Curis: Consultancy, Research Funding; Takeda: Research Funding. Winter: Merck: Research Funding; Glaxo-Smith-Kline: Research Funding. Pro: Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gordon: Janssen: Other: Data Monitoring Committee. Karmali: Celgene: Speakers Bureau. Kaplan: Millennium: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding.

scholarly journals Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3885-3885
Author(s):  
Luis Porrata ◽  
Kay Ristow ◽  
Ellen D. McPhail ◽  
William Macon ◽  
Matthew J Maurer ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocyte To Monocyte Ratio ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

The Impact of Relative Dose Intensity (RDI) of CHOP on Outcome of Diffuse Large B-Cell Lymphoma: Results of a Single Center Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4456-4456
Author(s):  
Yoshiki Terada ◽  
Hirohisa Nakamae ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
Yasunobu Takeoka ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Cell Lymphoma ◽  
Dose Intensity ◽  
B Cell Lymphoma ◽  
Relative Dose Intensity ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Introduction: The achievement of a clinical response to the first induction chemotherapy has been considered for predicting survival in patients (pts) with aggressive non-Hodgkin lymphoma (NHL). Reduced dose intensity of chemotherapy has been likely to compromise long-term outcome of the patients with aggressive NHL treated with a standard chemotherapy of cyclophosphamide (CY), doxorubicin (ADR), vincristine and prednisone (CHOP). In particular, recent studies have revealed the relevance of relative dose intensity (RDI) to clinical outcomes, with reduced RDI leading to a poor survival, as well as the impact of RDI<85% for aggressive NHL with detailed analysis of risk factors influencing reduce RDI<85% (Gary H. Lyman, J. Clin Oncol22: 4302, 2004). This study was conducted to investigate the impact of RDI<85% of CHOP on outcomes of the pts with diffuse large B-Cell lymphoma (DLCL). Methods: Data were retrospectively collected on 100 pts with DLCL who had been initially treated with more than 3 courses of CHOP (n=70) or CHOP plus rituximab (CHOP-R, n=30) at our institution between 1995 and 2006. We evaluated whether RDI might affect clinical outcomes, including complete response (CR) and event free survival (EFS). The average RDI derived from CY and ADR (referred to as RDI-CY/ADR) was determined for each patient, with classified into 2 populations according to the differences from the value of 85%, including RDI-CY/ADR<85% (n=60), and RDI-CY/ADR≥85% (n=40). Results: The median age of the study population was 54 years (range, 17 to 76), with 36 pts older than 60 years (yrs) of age. According to International Prognostic Index (IPI) score, pts were classified into 2 groups of low/ low-intermediate (n=46) and high/ high-intermediate (n=54). The overall CR rate reached 62%, and the probability of overall survival (OS) or EFS at 5 years estimated 77% or 43%, respectively with a median follow-up of 13.3 months. Multivariate analysis identified RDI-CY/ADR<85%, as well as IPI score to be associated with CR rate and EFS. Thus, RDI-CY/ADR<85% and IPI score of high/ high-intermediate were significant factors for lower CR rate (as RDI-CY/ADR≥85%, HR=0.3, 95% CI 0.1 to 0.7, p=0.009, and HR=5.5, 95% CI 2.2 to 14, p<0.001, respectively), and for reduced EFS (HR=1.9, 95% CI 1.0 to 3.7, p=0.048, and as IPI score of low/ low-intermediate HR=0.3, 95% CI 0.2 to 0.6, p<0.001, respectively). Furthermore, logrank analysis revealed that CY/ADR-RDI<85% was the significant factor for reduced EFS in non elderly pts (≤60 yrs of age), or in pts with IPI score of low/ low-intermediate (p=0.01, p=0.02, respectively). Conclusion: These data thus suggested the impact of RDI-CY/ADR<85% in influencing outcomes of the pts with DLCL, in terms of CR rate and EFS. Further investigation is currently planned to confirm this promising results with longer follow-up in larger numbers of pts with NHL.

Outcome Of Patients With Double-Hit Lymphomas Treated With CODOX-M/IVAC + R Followed By Hematopoietic Stem Cell Transplantation In British Columbia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1788-1788 ◽  
Author(s):  
Haowei (Linda) Sun ◽  
Kerry J. Savage ◽  
Aly Karsan ◽  
Graham W. Slack ◽  
Cynthia L. Toze ◽  
...  
Keyword(s):  
British Columbia ◽  
B Cell ◽  
Cell Transplantation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Definitive Treatment ◽  
High Grade ◽  
Double Hit

Abstract Background Double-hit (DHIT) lymphoma is a heterogeneous group of non-Hodgkin lymphomas characterized by concurrent translocations involving MYC and BCL2 and typified by aggressive behavior and poor prognosis with only rare long-term survivors. There is no established treatment for DHIT lymphoma. Since 2003, the British Columbia Cancer Agency (BCCA) has adopted the use of intensive chemotherapy CODOX-M/IVAC combined with rituximab (R) followed by high-dose chemotherapy and hematopoietic cell transplantation (HSCT) as definitive treatment for DHIT lymphoma. In younger patients, an ablative matched sibling donor allotransplant (AlloSCT) is preferred over an autotransplant (AutoSCT). For all patients over the age of 60 years only AutoSCT is offered. Total Body Irradiation (TBI) is used as a part of the conditioning regimen for patients younger than 60 years of age. Here we report our provincial experience with this strategy, focusing on the ability to deliver this treatment and survival outcomes. Methods The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with non-Hodgkin lymphomas with concurrent translocation of MYC and BCL2 (DHIT lymphoma) diagnosed between January 2003-September 2012. Results 27 cases of DHIT lymphoma were identified with the following characteristics: median age at diagnosis was 55.8 years (range 35.5-70.9 years); 19 (70%) were male; 26 (96%) patients had stage 3/4 disease; 16 (59%) had bone marrow involvement. All cases were HIV negative. Histological diagnosis based on the WHO 2008 classification were: diffuse large B-cell lymphoma (DLBCL) n=8 (30%); B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCL-U) n=17 (63%); B-cell acute lymphoblastic lymphoma (ALL) n=1; high-grade B-cell lymphoma, not otherwise specified (NOS) n=1. 13 cases (48%) were transformed from an underlying indolent B-cell lymphoma (12 follicular lymphoma, 1 low-grade B-cell lymphoma NOS). CODOX-M/IVAC + R was administered in 20 patients (74%). 7 patients received alternative chemotherapy regimen (5 R-CHOP, 1 R-CVP, 1 R-ICE) due to patient and/or physician preference. 14 patients (52%) underwent HSCT (7 AutoSCT, 7 AlloSCT), including 11 patients treated CODOX-M/IVAC + R pre-transplant, and 3 patients who received other therapy. 13 patients did not undergo HSCT: primary refractory disease n=7; patient preference n=2; deconditioning n=1; age > 65 and poor performance status n=3. The clinical status at time of transplantation was CR in 5 patients (19%), PR in 8 (30%), progressive disease in 1 (4%). The conditioning regimens included: cyclophosphamide/TBI n=6, VP-16/cyclophosphamide/TBI n=4, BEAM n=3, busulfan/cyclophosphamide n=1. At last follow-up, 15 (56%) patients have died, 14 from disease progression and 1 from complications of AlloSCT. 10 (37%) patients are alive and in remission and 2 patients are alive but have relapsed. 8 of 14 HSCT recipients (6 AutoSCT, 2 AlloSCT) remain alive and free of disease compared with 2 of 13 patients who did not receive HSCT; both disease free survivors received CODOX-M/IVAC + R. Median follow-up for living patients was 31 months (range 6.5-67.3 months). 2-year EFS and OS from the diagnosis of all DHIT lymphoma patients were 35% (95% CI 16%-54%) and 45% (95% CI 20%-65%), respectively. For patients who received CODOX-M/IVAC + R, the 2-year EFS was 37%. For patients who received CODOX-M/IVAC + R followed by SCT, the 2-year EFS was 43%. Patients with BCLU/ALL/High-grade lymphoma NOS had a 2-year EFS of 27% and patients with DLBL had a 2 –year EFS of 50%. Conclusion Patients with DHIT lymphoma treated with CODOX-M/IVAC + R followed by SCT can have durable remissions. Regardless, progression during initial therapy prior to SCT remains a significant problem. Patients with DLBCL histology may have a more favorable outcome than those with BCLU. Disclosures: Savage: Eli-Lilly: Consultancy. Toze:Roche Canada: Research Funding; F Hoffmann-La Roche: Research Funding. Sehn:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Gerrie:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Sutherland:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Villa:Roche: Honoraria, Research Funding; Lundbeck: Honoraria; Celgene: Honoraria. Song:Roche: Research Funding.

scholarly journals Genomic Characterization of Diffuse Large B-Cell Lymphoma Transformation from Nodular Lymphocyte Predominant Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1486-1486
Author(s):  
Joo Y. Song ◽  
Caoimhe Egan ◽  
Alyssa Bouska ◽  
Weiwei Zhang ◽  
Qiang Gong ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma ◽  
Pi3k Pathway ◽  
Large B Cell Lymphoma ◽  
Frequent Mutations ◽  
Large B Cell

Introduction: Transformed nodular lymphocyte predominant Hodgkin lymphoma (tNLPHL) with a typical diffuse large B-cell lymphoma (DLBCL) pattern is rare and not well studied by genomic analysis. We employed next generation sequencing and copy number analysis (CNA) to examine the pathogenesis of these tumors. Methods: We identified 19 cases of tNLPHL with DLBCL morphology and sheet-like growth from three institutions. NLPHL preceded transformation in 5 patients and was concurrent with transformation in 11. All cases of tNLPHL were sequenced using a targeted sequencing panel of 356 genes that included commonly mutated genes associated with lymphoma. We had 8 cases with matched germline DNA. We also performed CNA using Oncoscan on 18 cases of tNLPHL. Library preparation with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to three large series of de novo DLBCL. Results: The CNA showed frequent gains in REL and loss of CDKN2A. Mutation analysis showed frequent mutations of genes associated with the PI3K pathway such as SGK1 (26%), ZFP36L1 (16%), PIK3R1 (11%), and IL7R (11%), the NF-kB pathway such as CARD11 (21%), JUNB (21%), BCL10 (11%), NFKBIA (11%), TNFAIP3 (11%), histone/DNA modification such as KMT2D (26%), EP300 (21%), TET2 (11%), TET3 (11%), and the NOTCH pathway such as NOTCH2 (16%), NOTCH1 (1 case), CTBP2 (11%). Mutations in genes involved in immune surveillance and TP53 abnormalities were infrequent. Compared to de novo DLBCL, mutations in IL7R (10.5% vs 0.6%, p=0.03), JUNB (21% vs 4.2%, p=0.01), and SMARCAL1 (11% vs 0%, p=0.01) were significantly higher in tNLPHL than in germinal center B-cell (GCB) subtype of DLBCL. Conclusion: The mutational spectrum of tNLPHL resembles the DLBCL Cluster 4 of Chapuy et al (Nat Med, 2018), which were primarily GCB-DLBCL with frequent mutations in the PI3K pathway (SGK1), NF-kB pathway (CARD11, JUNB), and histone modification. The mutational spectrum is also distinctive in having frequent mutations that are not often seen together in DLBCL, such as TET2, JUNB and NOTCH2. Distinct from transformed follicular lymphoma, TP53 abnormalities and mutations affecting immune surveillance are uncommonly observed. This study provides new insights into the biology of tNLPHL and may highlight potential targets for therapy in the future. Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding.

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Composite Histology Have Improved Early Outcome Compared to De Novo DLBCL When Treated with R-CHOP

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2819-2819
Author(s):  
Matthew J. Maurer ◽  
Thomas E. Witzig ◽  
William R. Macon ◽  
Sergei I. Syrbu ◽  
James R. Cerhan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Follicular Lymphoma ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: A significant percentage of DLBCL patients present with a composite histology, often seen as a node containing both follicular lymphoma and DLBCL or DLBCL in the node and discordant indolent lymphoma in the bone marrow. Literature from the pre-rituximab era suggests DLBCL patients with transformed lymphoma or composite histology have worse outcome than de novo DLBCL. Here we report on early events in a cohort of R-CHOP treated patients. Goal: To determine whether patients with composite lymphoma have an inferior event free survival (EFS) and overall survival (OS) compared to de novo diffuse large B-cell lymphoma when treated with R-CHOP. Methods: Newly diagnosed patients treated with an R-CHOP containing regimen were prospectively enrolled in our Lymphoma SPORE registry from 9/2002 through 6/2007. Pathology was centrally reviewed. All patients were followed for retreatment, disease progression, and death. Results: 401 DLBCL patients were enrolled; 14% (57/401) had a composite histology. 33 patients had DLBCL and another histology, predominantly follicular lymphoma (n=29), in the same node. 20 patients had a non-DLBCL histology in a distinct location from the DLBCL; this was primarily indolent lymphoma in the bone marrow (n=15). 4 patients had both. 19% (75/401) of patients died during follow-up and 30% (121/401) had an event (death due to any cause, progression, or retreatment). Median follow-up for living patients was 34 months (range, 5–73). Composite DLBCL patients had higher event-free (3 year EFS = 79%) and overall (3 year OS = 93%) survival then de novo DLBCL (3 year OS = 66%, 3 year EFS 79%), p=0.05 and p=0.005 respectively. These differences remained statistically significant after adjusting for the International Prognostic Index (IPI): EFS HR = 0.53, 95% CI: 0.29–0.97, p=0.02; OS HR=0.28, 95% CI: 0.10–0.76, p=0.002. OS and EFS for composite DLBCL more closely resembled R-CHOP treated grade III follicular lymphoma (A,B) from the same cohort (3 year EFS = 81%, 3 year OS = 93%). Improved outcome for composite DLBCL was consistent whether the additional histology was in the same node or distinct from the DLBCL. Conclusions: R-CHOP treated DLBCL patients with indolent discordant bone marrow involvement or other composite histology have improved early OS and EFS compared to de novo DLBCL. Further follow-up is needed to assess the long-term prognosis of composite DLBCL in the rituximab era. Histology N Age &gt; 60 Stage III/IV LDH &gt; ULN PS &gt; 1 &gt;2 EN Sites 3 YR EFS 3 YR OS * Denotes statistically significant difference at p=0.05 de novo DLBCL 344 58% 56% 56% 17% 22% 66% 78% Composite DLBCL 57 65% 77%* 34%* 18% 32% 79%* 93%* Figure Figure

Radiation Therapy Significantly Improves Survival Of Patients With Diffuse Large B-Cell Lymphoma Associated With MYC Translocation: A Report From The International DLBCL Rituximab-CHOP Consortium Program

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 213-213
Author(s):  
Zijun Y. Xu-Monette ◽  
Bouthaina S. Dabaja ◽  
Alexander Tzankov ◽  
Carlo Visco ◽  
Roberto N. Miranda ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinicopathologic Features ◽  
First Line ◽  
Large B Cell Lymphoma ◽  
Double Hit Lymphoma ◽  
Double Hit ◽  
Large B Cell

Abstract Context and objective Approximately 5-10% of diffuse large B-cell lymphoma (DLBCL) patients carry MYC gene translocations (MYC-translocation+) with a poor prognosis after standard chemotherapy. MYC-translocation+ DLBCL patients carrying BCL2 translocations (MYC+/BCL2+ double-hit lymphoma) have a worse survival. The efficacy of adjuvant radiotherapy in this setting is unknown. The purpose of this study is to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL. Patients and methods From the International DLBCL R-CHOP consortium program, we selected 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy (diagnosed and treated from 2000 to 2010). We excluded patients with transformed DLBCL, primary mediastinal, cutaneous, testicular or central nervous system large B-cell lymphomas, patients with HIV infection, and patients not treated with R-CHOP. The median follow-up was 54.9 months. Fluorescence in situ hybridization assessing MYC was performed for all the patients (n=581) and results were correlated with available clinical data to identify clinicopathologic features associated with MYC translocation, and to evaluate the prognostic significance of MYC translocations regarding overall survival (OS, from the time of diagnosis to death from any cause) and progression-free survival (PFS, from the time of diagnosis to relapse or death from any cause). In the MYC-translocation+ DLBCL group, 38 patients received chemotherapy alone and 21 patients received chemotherapy with adjuvant radiation therapy. The clinicopathologic features and survival of MYC-translocation+ DLBCL patients treated with (n=21) and without radiotherapy (n=38) after immunochemotherapy were compared to in order to evaluate the radiotherapy efficacy and other confounding factors. Results MYC translocations were detected in 59 DLBCL patients (10.2%). Patients with MYC-translocation+ DLBCL more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.20 - 3.35, P= .0083) and PFS (HR: 1.96, 95% CI: 1.22 - 3.13, P= .0005) independent of the International Prognostic Index score. Poor survival was primarily attributable to patients with MYC+/BCL2+ double-hit DLBCL who were predominantly of germinal center B-cell subtype. Among MYC-translocation+ DLBCL patients, a better survival was achieved in patients who received radiotherapy (for OS, HR: .32, 95% CI: .15 - .71, P= .0049; for PFS, HR: .35, 95% CI: .17 - .73, P= .0043). Conversely, radiotherapy abolished the adverse impact of MYC translocations. In addition, radiotherapy was associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma (P = .017 for OS, and P = .05 for PFS). However, owing to the common use of radiotherapy as consolidation therapy, the favorable prognoses in the group of patients who received radiotherapy could also be attributed to limited-stage disease and more frequent complete remission (CR) after first-line treatment and therefore these factors confound interpretation of the data. To address these issues, we evaluated radiotherapy efficacy in separate patient groups: patients who achieved CR, non-CR (PR/SD/PD) patients, and patient with stage I/II, or stage III/IV disease. The efficacy of radiotherapy appeared more apparent in patients with advanced disease who did not achieve CR after first-line chemotherapy. Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 - .80, P= .015) of MYC-translocation+ DLBCL patients. Conclusions The presence of MYC translocations in DLBCL is an important biomarker that facilitates prognostic prediction and treatment stratification independent of the IPI score. For chemoresistant MYC-translocation+ DLBCL patients, radiotherapy seems to be an effective adjuvant regimen likely due to the higher frequency of extranodal involvement and bulky disease in MYC-translocation+ DLBCL patients. Our results provide a rationale for larger scale studies to assess the potential role of radiotherapy in the management of MYC-translocation+ DLBCL patients, particularly patients with MYC+/BCL2+double-hit DLBCL. Disclosures: Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.

Clinical Significance of Co-Expression of MYC and BCL2 Protein in Advanced Diffuse Large B-Cell Lymphoma Treated with a Dose-Intensified Immunochemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3940-3940
Author(s):  
Hiromichi Takahashi ◽  
Sumiko Kobayashi ◽  
Katsuhiro Miura ◽  
Daisuke Kurita ◽  
Yoshihiro Hatta ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intermediate Risk ◽  
Chugai Pharmaceutical ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

Abstract Background Recent studies have shown that the concurrent expression of MYC and BCL2 protein evaluated by immunohistochemistry (IHC) in patients with de novo diffuse large B-cell lymphoma (DLBCL) is associated with worse survival when treated with standard R-CHOP, but the effect of intensive chemotherapies for such patients is unknown. Thus, we evaluated the impact of the co-expression of MYC and BCL2 protein among patients with advanced DLBCL, who were treated with a dose-intensive immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). Patients and Methods This is a retrospective analysis of patients with de novo DLBCL, who were categorized into high/high-intermediate risk by the age-adjusted International Prognostic Index (aaIPI). They were consecutively treated with the R-Double-CHOP regimen, consisting of rituximab (375 mg/m2, day -2), cyclophosphamide (750 mg/m2, day 1, 2), doxorubicin (50 mg/m2, day 1, 2), vincristine (1.4 mg/m2 [maximum 2.0 mg/body], day 1) and prednisolone (50 mg/m2, day 1-5) followed by consolidative high-dose chemotherapies at our institution from 2001 to 2013. MYC and BCL2 protein were measured by IHC assay using formalin-fixed paraffin-embedded tissue specimens for all available cases. Cut-off values of positivity for MYC and BCL2 protein were set as 40% and 50% of stained tumor cell, respectively. Lymphomas showing concurrent positivity for MYC and BCL2 protein were defined as "Double expressor lymphoma (DEL)". Results A total of 40 patients with a median 53-years (range 19-68) of age were analyzed. Twenty-one patients were at high risk and the other 19 patients were at high-intermediate risk by aaIPI. Cell of origin (COO) subtypes classified by Hans algorithm consisted of 14 germinal center B-cell (GCB) type and 26 non-GCB type. Totally, 10 (25%) patients were categorized into DEL. The overall response (OR) and the complete response (CR) rates to R-Double-CHOP for all patients were 93% and 83%, respectively. The OR and the CR rates were not significantly different between the DEL group and the non-DEL group (100% vs 90%, and 80% vs 83%, respectively). The proportion of patients proceeding to ASCT was not significantly different among these groups (50% vs 60%). With a median 52 months (range 3-155) of follow-up, the 3-year progression-free survival (PFS) and the overall survival (OS) rates for all patients were 55% and 72%, respectively (Figure a, b). Both the PFS and the OS were significantly worse in the DEL group than in the non-DEL group (Figure c, d). As for aaIPI and COO subtyping, either high/high-intermediate risk or GCB/non-GCB subtype were not significantly associated with the outcome of PFS or OS. Conclusion The concurrent expression of MYC/BCL2 protein in advanced DLBCL was associated with shorter remission duration and worse survival despite similar susceptibility to the treatment when a dose-intensive immunochemotherapy was applied. Our findings suggest that patients with advanced DEL may not benefit from dose-intensified therapies, and therefore need highly discrete strategies. Disclosures Miura: Astellas Pharma Inc.: Honoraria; Celgene K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Meiji Seika Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Hatta:Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Celgene K.K.: Honoraria. Iriyama:Brystol-Myers K.K.: Honoraria. Takei:Kyowa Hakko Kirin CO., Ltd, Japan: Research Funding; Bristol-Myers K.K.: Research Funding; Nippon Kayaku Co.: Research Funding; Shionogi & Co.: Research Funding; Meiji Seika Pharma: Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; TEIJIN PHARMA LIMITED: Research Funding; CSL Behring K.K: Research Funding; Japan Blood Products Organization: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; TORII, PHAMACEUTICAL CO: Research Funding; Alexion Pharmaceuticals: Research Funding; YAKULT HONSHA CO., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO. LTD: Research Funding.

Prevalence and Clinico-Pathological Attributes of c-MYC Rearranged High-Grade B-Cell Non Hodgkin Lymphomas (NHL): Single Centre Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5031-5031
Author(s):  
Manju Sengar ◽  
Sridhar Epari ◽  
Hasmukh Jain ◽  
Tanuja Shet ◽  
Sumeet Gujral ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
High Grade ◽  
Ki 67 ◽  
Large B Cell ◽  
Who 2008

Abstract Introduction: MYC rearrangement in high-grade B-cell NHL(non-burkitt), either as single hit or double hit, has significant prognostic and therapeutic implications. There is remarkable paucity of data on frequency and clinico-pathological features of MYC-rearranged large B-cell lymphomas from developing world. Method: This study included de-novo high grade B-cell NHL cases (>15 years of age) registered at Tata Memorial Centre between January 2013- December 2014. Demography details, clinical features (stage at presentation, bone marrow involvement, presence and extent of extranodal involvement, B-symptoms, international prognostic index),original histopathological diagnosis, chemotherapy and radiotherapy details were recorded from electronic medical or paper case records. Response to therapy, relapses or death if any, status at last follow up, dates of relapse and/or death and last follow up were recorded. All cases were reviewed by expert hematopathologists to categorize the high grade B-cell NHL as per the WHO-2008 classification of hematopoietic malignancies. All cases with adequate formalin-fixed paraffin embedded (FFPE) blocks were evaluated by FISH for c-MYC , BCl-2 and BCl-6 using Vysis dual colour break apart probes. Cases which showed >10% cells with split signal were considered to harbor rearrangement. Result: A total of 114 cases of de-novo high-grade B-cell NHL with adequate FFPE blocks were evaluated. Based on WHO 2008 classification, 112 cases were classified as diffuse large B-cell lymphoma (DLBL)) and 1 each as Burkitt's (BL) and B- cell lymphoma unclassifiable -intermediate between DLBL and BL(BCLU). A total of 9/112 (8%) cases of DLBL showed MYC rearrangement. One of these 9 cases had both MYC and BCl-2 rearrangement. BCLU did not demonstrate MYC or BCl-2 rearrangement. The Ki-67 index was variable (40-95%)in MYC rearranged cases. The median age of the c-MYC rearranged cases was 55 year (range-23-79 years). 88% were males. Advanced stage disease, bulky mass and extranodal disease was seen in 67%, 44% and 55% of cases respectively. All but one patient had high LDH, however none of the patients had elevation more than 2XULN. These patients received rituximab based chemoimmunotherapy (RCHOP-4,RCEOP-4, REPOCH-1) and 77% achieved complete response. At median follow up of 5 months, 1 year-overall survival and progression free survivals were 80% and 75% respectively. There were no significant differences in clinical features (except higher proportion of males in the c-MYC rearranged subset), LDH levels, ki-67 index , response to therapy and survival between DLBL with or without c-MYC rearrangement Conclusion: In our study 8% of all DLBL cases showed c-MYC rearrangement. The frequency of double hit lymphoma was less than 1% (0.8%). Disclosures No relevant conflicts of interest to declare.

scholarly journals Upregulation of CD47 Expression in De Novo Diffuse Large B-Cell Lymphoma Is More Frequent in Activated B-Cell Type

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3507-3507
Author(s):  
Winston Y Lee ◽  
Anamarija M. Perry ◽  
Vero Azcutia ◽  
Alex F. Herrera ◽  
Pamela Skrabek ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Surface Receptor ◽  
Large B Cell Lymphoma ◽  
Frequent Mutations ◽  
Large B Cell

Abstract CD47 is a marker of self that provides a "don't-eat-me-signal" through activation of signal-regulatory protein alpha (SIRPa), a cell surface receptor expressed on monocytes/macrophages and granulocytes. This interaction negatively regulates effector functions such as, phagocytosis, migration, and superoxide production. Upregulation of CD47 expression in cancer, including diffuse large B-cell lymphoma (DLBCL), has emerged as a mechanism to escape innate immune surveillance. Using conventional immunohistochemical detection, we assessed CD47 expression in DLBCL and interrogated its association with clinicopathologic features. Patients with de novo DLBCL were identified from two large institutions and were uniformly treated with R-CHOP and had sufficient material for study. Immunohistochemical stains (IHC) were performed on FFPE tissue (Hans algorithm, BCL2, MYC, and CD47) and scored semi-quantitatively from no reactivity (0) to strong (2 and 3; Figure 1). Mutational analysis using a 334 gene target sequencing panel, gene expression profiling using Lymph2Cx to determine the cell of origin (COO), and FISH analysis for MYC, BCL2, and BCL6 translocations, were performed. The Lymphgen tool (Wright et al, 2020) was also used to determine the DLBCL group. Fisher's exact test and Kaplan-Meier survival analysis for overall survival (OS) were performed and P &lt;0.05 was considered significant. CD47 expression was assessed by IHC in a cohort of 152 cases of de novo DLBCL, including 107 cases of germinal center B-cell (GCB) type (70%), 37 cases of activated B-cell (ABC) type (24%), and 8 cases of intermediate type (5%). A total of 17 cases (11%) showed strong and diffuse CD47 expression with IHC scores of 2 or above (CD47hi). CD47hi cases were significantly more frequent in ABC DLBCL (24%, 9/37) than GCB DLBCL (6%, 6/107; P=0.003). The remaining 2 CD47hi cases were in the intermediate DLBCL group (25%, 2/8). ABC DLBCL with CD47hi showed more frequent mutations with TET2 (33% vs 7%; P=0.08) and ZFP36L1 (22% vs 0%; P=0.05) compared to cases with low expression of CD47 with IHC scores of less than 2 (CD47low). ABC DLBCL with CD47low showed more frequent mutations of NOTCH2 (18% vs 0%; P=0.31) and MYD88 (29% vs 11%; P=0.4) compared to CD47hi. GCB DLBCL with CD47hi showed frequent mutations of TP53 (67% vs 21%; P=0.026) and CCND1 (33% vs 0%; P=0.003) compared to CD47low. None of the 13 cases with double- or triple-hit for MYC, BCL2 and/or BCL6 showed CD47 expression. The Lymphgen tool showed that cases of DLBCL with CD47hi were mostly in the 'other' group (50%), with other groups represented such as ST2 (21%), EZB (14%), MCD and BN2 (1 case each). There was no difference in overall survival (OS) between CD47hi and CD47low DLBCL (5-year OS, 75% vs 72%; P=0.57), or with the GCB or ABC subtypes. Strong expression with CD47 is more frequent in ABC DLBCL and is seen in a subset of GCB DLBCL with mutations in TP53 and/or CCND1. The level of CD47 expression does not appear to predict OS in patients with DLBCL treated with R-CHOP. This study demonstrates that conventional immunohistochemical methods can readily identify DLBCL with high CD47 expression, and these patients may benefit from the use of anti-CD47 therapy. Figure 1 Figure 1. Disclosures Herrera: Gilead Sciences: Research Funding; Takeda: Consultancy; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding.

scholarly journals Lenalidomide Plus Rituximab for Relapsed or Refractory Diffuse Large B-Cell, Follicular and Transformed Lymphoma: Final Data Analysis of a Phase 2 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3969-3969 ◽  
Author(s):  
Yucai Wang ◽  
Nicolaus Wagner-Bartak ◽  
Shouhao Zhou ◽  
Nathan Fowler ◽  
Maria Lourdes Dela Rosa ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Final Data ◽  
Transformed Lymphoma ◽  
Large B Cell

Abstract Background: We have previously reported the favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), grade 3 follicular lymphoma (FLG3) and transformed lymphoma (TL) (Wang et al, Leukemia 2013). Here we report results of the final data analysis of this phase 2 trial after an extended follow-up. Methods: Patients with R/R DLBCL, FLG3 and TL were enrolled in this single arm trial. Lenalidomide (20 mg daily) was administered orally on days 1-21 of each 28-day cycle, and rituximab (375 mg/m2 weekly) was administered intravenously during the first cycle only. Treatment was continued with dose-reduction allowance until disease progression, stem-cell transplantation or severe toxicity. The primary endpoint was overall response rate (ORR), and the secondary endpoint was survival. Analysis was by intention to treat. Results: In total, 45 patients were enrolled, with 32 DLBCL, 4 FLG3 and 9 TL. 29 were male and 16 were female. The median age was 66 years (range 23-84). Median ECOG PS was 1 (range 0-3). 41 patients (91.1%) were stage 3-4. Median number of prior lines of therapy was 3 (range 1-4). The median follow-up time was 9.8 months (range 0.8-77.7). Overall, 10 patients (22.2%) achieved CR, and 5 patients (11.1%) achieved PR, with an ORR of 33.3%. An additional 11 patients (24.4%) achieved SD. The ORR was 28.1% for DLBCL, 25.0% for FLG3, and 55.6% for TL. In Chi-square test, lower IPI score (0-2) was associated with higher ORR (P = 0.043). Patients with fewer prior lines of therapy tended to respond better (P = 0.118). In multivariate logistic regression, lower IPI was predictive of better ORR (P = 0.023). Median time to initial and best response was 1.8 months (range 0.8-2.1) and 1.8 months (range 0.8-20.1), respectively. Median duration of response was 10.2 months (95% CI 0.0-24.7). The median progression-free survival (PFS) was 3.7 months (95% CI 1.8-5.6), and the median overall survival (OS) was 10.8 months (95% CI 6.5-15.1). The 6- and 12-month PFS rates were 22.5% and 11.3%, respectively. The 1-, 2- and 5-year OS rates were 43.5%, 38.9% and 15.4%, respectively. Median OS was 50.3 months (95% CI 42.8-57.8) in responders and 6.6 months (95% CI 4.0-9.1) in non-responders (P < 0.001). In multivariate Cox regression, lower IPI was significantly predictive of longer OS (HR = 0.323, 95% CI = 0.157-0.668, P = 0.002) and showed a clear trend in predicting longer PFS (HR = 0.495, 95% CI 0.234-1.048, P = 0.066). Gender, Ki67 at registration and number of prior lines of therapy were not predictive of PFS or OS. Conclusions: Lenalidomide plus rituximab is an efficacious treatment regimen for relapsed or refractory aggressive B-cell lymphoma. IPI is strongly predictive of ORR and OS in this setting. Ki-67 and number of prior lines of therapy are not predictive of ORR, PFS or OS. Disclosures Neelapu: Celgene: Consultancy, Research Funding. Shah:Celgene: Consultancy, Research Funding. Thomoas:Celgene: Research Funding. Wang:Celgene: Research Funding.

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