scholarly journals Prognostic Impact of Gastrointestinal Involvement in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5400-5400
Author(s):  
David Kasouha ◽  
Nicola Lehners ◽  
Katharina Kriegsmann ◽  
Gerlinde Egerer ◽  
Anthony D Ho ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Elevated Serum ◽  
B Cell Lymphoma ◽  
Treatment Modalities ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Curative Intent ◽  
Large B Cell Lymphoma

Abstract Introduction: Involvement of >1 extranodal site is regarded as a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). It is necessary to clarify the prognostic impact of specific extranodal sites. Gastrointestinal (GI) involvement is one of the most frequently involved extranodal sites. Methods: Patients with newly diagnosed DLBCL treated at the University of Heidelberg between 06/2001 and 07/2015 were identified and included in this retrospective analysis. Data on clinical characteristics and treatment modalities were obtained by review of medical charts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of variables on PFS and OS was evaluated by univariate log-rank tests and by multivariate analysis using the Cox proportional hazards model. Results: A total of 1001 patients were identified of whom 119 (11.9%) presented with GI involvement. Median age of patients with GI involvement was 63.3 years [range 19.1-86.7], 71 (59.7%) were male. 92 patients had an available international prognostic index (IPI) score, 36 (39.1%) IPI 0-1, 33 (35.9%) IPI 2-3, and 23 (25%) IPI 4-5. The most frequently involved organs of GI were stomach (51.3%), small intestine (39.5%), colon (20.2%), and esophagus (2.5%). 107 (89.9%) patients were treated in curative intent and were further analyzed regarding the prognostic impact of several factors on outcome. 80.4% of them received CHOP-like therapies, 17.8% received chemotherapy more aggressive than CHOP, typically addition of etoposide or treatment with high-dose methotrexate in case of CNS involvement, 87.9% received additional rituximab, and 22.4% additional radiotherapy In DLBCL patients with GI involvement, we identified factors associated with worse OS (P<.05) by univariate analysis: B symptoms, elevated serum LDH, and involvement of more than two extranodal sites. On the contrary, age (>60 years), sex, Ann Arbor Stage (AAS) III/IV, and Performance Status of Eastern Cooperative Oncology Group (ECOG) more than one, and elevated serum sCD25 did not have any significant impact on OS. B symptoms were as well associated with decreased PFS (P<.05) by univariate analysis. Multivariate Cox Regression analysis revealed that patients with elevated serum LDH at diagnosis had significantly worse OS (P<.05), and patients with B symptoms had significantly worse PFS (P<.05). Regarding first-line treatment modalities, escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS in univariate analysis, not in multivariate analysis. Radiotherapy did not have any significant impact on OS or PFS. Regarding all DLBCL patients treated with curative intent, GI involvement did not have any significant prognostic impact on OS or PFS. Conclusions: In this retrospective registry analysis of patients with newly diagnosed DLBCL with GI involvement, B symptoms, elevated serum LDH, and involvement of more than two extranodal sites were identified as risk factors for inferior OS. Escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS. Further analyses are required as toward which treatment modalities might be best suited to improve prognosis of GI involvement. Disclosures Kriegsmann: Celgene: Research Funding; BMS: Research Funding.

scholarly journals Clonal Somatic Mutations Are a Biomarker for Inferior Prognosis in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Nicholas J. Boddicker ◽  
Pinkal Desai ◽  
Mithun Vinod Shah ◽  
Vivekananda Sarangi ◽  
Matthew J. Maurer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Large B Cell Lymphoma

Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma subtype with a 5-year survival of ~64%. While DLBCL is treated using immunochemotherapy (IC) with curative intent, 20%-40% of patients do not reach remission or relapse post IC. Clonal somatic mutations have been associated with aging, hematologic malignancies (predominately myeloid), and reduced OS in the general population. The objective of this study was to evaluate the association of clonal somatic mutations with event-free survival (EFS) and overall survival (OS). Methods We studied newly diagnosed DLBCL cases treated with IC who were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). Clinical and treatment data were abstracted from medical records and all patients were systematically followed for disease outcomes. Pre-treatment DNA was extracted from matched peripheral blood and paraffin-embedded tumor tissue, and whole exome sequencing was conducted at 100x coverage. From the peripheral blood, allele counts from GVCF files produced by HaplotypeCaller in GATK were extracted for 42 genes commonly associated with clonal hematopoiesis (e.g. DNMT3A, TET2, and ASXL1). Mutations were deemed clonal somatic if the population minor allele frequency was &lt;0.5% in ExAC and had a variant allele fraction (VAF) that deviated from 0.5 using a binomial distribution test at p&lt;0.001. Furthermore, mutations had to have a minimum alternate read count of at least 5 reads, a VAF greater than or equal to 10%, and met at least one of the following criteria: CAVA impact of "HIGH"; pathogenic/likely pathogenic per ClinVar; or reported in COSMIC at least 10 times. EFS was defined as time from diagnosis to disease progression, relapse, retreatment, or death due to any cause. The association of clonal somatic mutations with prognosis was estimated using Kaplan-Meier curves, and hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression. Associations were adjusted for age at diagnosis, sex, and the International Prognostic Index (IPI). Results The study consisted of 261 DLBCL patients treated with IC. The median age at diagnosis was 65 years (range 20-90) and 56% were male. With a median follow-up time of 5.1 years (range 0.1-15.0), there were 100 events and 80 deaths. A total of 17 (6.5%) patients had clonal somatic mutations, and16 patients were over the age of 60. A total of 8 (of 42) genes had clonal somatic mutations, with SF3B1, ASXL1, and TET2, being the most frequent (4 individuals per gene). VAFs ranged from 0.10 to 0.28 and none of the patients had multiple mutations. Additionally, the clonal somatic variants found in the peripheral blood were abscent in the tumor sample. Of the 17 patients with clonal somatic mutations, 12 had an event while 88 patients without a mutation had an event. In a univariate analysis, clonal somatic mutations were associated with inferior EFS (HR=2.55, 95% CI 1.39-4.68, p=0.002; Figure 1A). After adjusting for age, sex, and IPI, clonal somatic mutations remained associated with inferior EFS (HR=2.02, 95% CI 1.09-3.74, p=0.026). Clonal somatic mutations were also associated with inferior OS in the univariate analysis (HR=2.06, 95% CI 0.99-4.29, p=0.053), which attenuated after multivariate adjustment (HR=1.59, 95% CI: 0.76-3.34, p=0.22, Figure 1B). Although based on small numbers, mutations in SF3B1 were associated with inferior EFS (HR=3.25, 95% CI 1.16-9.12, p=0.025), but did not reach significance for OS (HR=2.56, 95% CI 0.78-8.38, p=0.120). Conclusions In this novel study of newly diagnosed DLBCL patients, clonal somatic mutations were identified in 6.5% of patients and were associated with inferior outcomes. Additional research is required at deeper sequencing to validate these findings and integration with tumor genomics is required to understand the prognosis of DLBCL patients with smaller clonal populations. Disclosures Shah: Dren Bio: Consultancy. Maurer:Celgene / BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Martin:Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Kite: Consultancy; Cellectar: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Teneobio: Consultancy. Witzig:AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; MorphSys: Consultancy. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding. Novak:Celgene/BMS: Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding.

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

Diffuse Large B-Cell Lymphoma with Testicular Involvement: Outcome and Risk of CNS Relapse in the Rituximab Era

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 780-780 ◽  
Author(s):  
David Telio ◽  
Diego Villa ◽  
Tamara Shenkier ◽  
Laurie H. Sehn ◽  
Richard Klasa ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Systemic Disease ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Stage Disease ◽  
Large B Cell

Abstract Abstract 780FN2 Background: Testicular involvement of diffuse large B-cell lymphoma (Te-DLBCL) is associated with a poor outcome and a high risk of central nervous system (CNS) relapse. Rituximab is now routinely used into the treatment of both limited (LIM) and advanced (ADV) stage disease but it is unclear if this can reduce the rate of CNS relapse given it's limited penetration of the blood brain barrier and frequent parenchymal relapses in Te-DLBCL. A recent phase II study by the IELSG using R-CHOP, contralateral testicular radiation (RT) and IT prophylaxis in LIM stage patients demonstrated improved survival rates and a lower rate of CNS relapse compared with historical series. Herein, we evaluated the impact of R-CHOP on the natural history in all patients with Te-DLBCL Methods: The Centre for Lymphoid Cancer Database was used to identify patients with Te-DLBCL who were treated with curative intent. LIM stage was defined as stage I/II without bulk (< 10 cm) or B symptoms and also included patients with discordant involvement of the bone marrow with a low grade lymphoma whose stage was otherwise limited stage, and ADV stage included all others. Results: 109 patients with Te-DLBCL treated between 1985–2011 were identified including 10 patients (11%) with discordant non-follicular low grade lymphoma in the bone marrow (9) or lymph node (1). Twenty-one patients were excluded: chemotherapy refusal (7), palliative (n=9), HIV + (2), peritesticular and not testicular involvement (2), clinical information N/A (1). Of the remaining 88 patients, 40 received CHOP-like chemotherapy and 48 received R-CHOP. The median age at diagnosis was 68 y (range 26–83 y) and half the patients had LIM stage disease. Most patients received either prophylactic contralateral testicular RT (59) or had bilateral orchiectomy (11) with few exceptions: refusal (3), PD or death on therapy (12), unknown (3). Five patients with CNS disease at presentation (R-CHOP n=4; CHOP n=1) also received HD methotrexate (HDMtx) and IT CHT. Only nine patients (7 ADV) received CNS prophylaxis (R-CHOP n=4; CHOP n=5) either IT (8) or IT + HDMtx (1) R-CHOP treated patients were more likely to have > 1 extranodal (EN) sites involved (p=0.030), and there was a trend to a greater proportion of patients with ADV disease (p=.087). With a median follow up of 60 mos, the 5 year TTP and OS for the CHOP and R-CHOP treated patients was similar (TTP 52% vs 67.5%, p=.181; OS 52.5% and 57%, p=0.262). However, an improved TTP (p=.025) and a trend to improved OS (p=.085) was observed in ADV stage patients but not LIM stage patients (TTP p=.617, OS p=.407) treated with R-CHOP. In univariate analysis, stage, EN sites > 1, IPI (0-2 v 3–5) and urinary tract (UT) involvement (kidney, adrenal or ureter) were prognostic for both TTP and OS. In multivariate analysis treatment with rituximab, > 1 EN sites and UT disease were prognostic for both TTP (rituximab p=.006, > 1 EN sites, p=.014, and a trend for UT disease p=.067) and OS (rituximab, p=.009, > 1 EN sites p=.025, UT disease p=.016) Excluding patients with CNS disease at diagnosis, there was no difference in the time to CNS relapse (TTCNS) in R-CHOP (5 y 27%) compared to CHOP treated patients (5 y 23%) (p=.789) in both LIM (5 y 16.5% vs 23.5%, p=.901) and ADV disease (5 y 27% vs 23%, p=0.386). In univariate analysis, the IPI, EN sites, PS and UT disease were associated with an increased risk of CNS relapse. In multivariate analysis, only UT disease (HR 9.18, p<.0001) was predictive of CNS relapse. CNS relapse in LIM patients (12) was typically late (≤ 2 years n=9), commonly parenchymal, (n=9 vs leptomeningeal (LM) n=2, both n=1) and usually in the absence of systemic disease (9). In contrast, CNS relapse in ADV patients (12) was usually early (< ∼ 1 year 10/12), preferentially involved the LM either alone (8) or in concert (3) with parenchymal lesions but also in the absence of systemic disease (10/12). Conclusion: Although survival has improved in Te-DLBCL patients since the introduction of rituximab, the benefit is likely primarily through systemic disease control as there remains an inherently high risk of CNS relapse. Patients with ADV stage disease and particularly with UT tract involvement, have frequent early leptomeningeal relapse and should be considered for up-front CNS treatment. Given the propensity for late parenchymal relapses in LIM stage patients, strategies to test agents with CNS penetration need further investigation. Disclosures: Villa: Roche: Research Funding. Shenkier:Roche: Research Funding. Sehn:Roche: Honoraria, Research Funding. Klasa:Roche: Research Funding. Gascoyne:Roche: Research Funding. Connors:Roche: Research Funding. Savage:Roche: Honoraria, Research Funding.

scholarly journals Management of Elderly Patients with Diffuse Large B-Cell Lymphoma in a Network of Community Oncology Practices in the United States

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4215-4215
Author(s):  
John M Burke ◽  
Jenny L Black-Shinn ◽  
Jamyia Clark ◽  
Jennifer Frytak ◽  
Janet Espirito ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Research Funding ◽  
Chart Review ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Chop Chemotherapy ◽  
Eligibility Criteria ◽  
Large B Cell Lymphoma ◽  
Community Oncology

Abstract Introduction: Treatment patterns and clinical outcomes in elderly patients with DLBCL treated outside of clinical trials are poorly characterized. A previous report from Medicare Claims data found that 28% of patients above the age of 66 were treated with rituximab monotherapy or were not treated at all, with corresponding median survival of 18 and 2 months, respectively (Hamlin PA et al., Oncologist 2014; 19:1249-57). We conducted a retrospective chart review of diffuse large B cell lymphoma (DLBCL) patients diagnosed and managed within a community oncology practice network to evaluate treatment patterns and corresponding clinical outcomes. Methods: This was a retrospective observational chart review study of patients aged 60 years and over with newly diagnosed DLBCL. Eligibility criteria required a diagnosis between 1/1/2011 and 12/31/2012, with follow up through 12/31/14, plus no prior therapy for DLBCL. Data were obtained via programmatic query of the US Oncology Network/McKesson Specialty Health electronic health record database. Manual chart review was then performed on a subset of patients (n = 301) to confirm initial findings and gather additional information. Structured data elements were evaluated in univariate and multivariable logistic regression analysis in the subset of patients with stage 2 to 4 disease in order to determine factors associated with treatment with standard R-CHOP. Overall survival (OS) and progression free survival (PFS) were estimated from treatment initiation using the Kaplan Meier (KM) method. Results: 1151 patients who fit the eligibility criteria were identified. Age significantly influenced frontline treatment selection. Table 1 lists the percentage of patients with stage 2 to 4 disease treated with various regimens by age cohorts. "R-CHOP Alternative" was defined as one of the following: less than 6 cycles of R-CHOP, < 80% of full doses of agents in R-CHOP, or use of an alternative regimen like R-CVP, R-CEOP, or bendamustine-R. In multivariable analysis, age (OR=4.07 for age 65-79 and OR=7.98 for age 60-64; p<0.0001), ECOG 0-1 (OR=2.44, p=0.1380), geographic practice region other than south (OR=1.96, p=0.0002), body mass index (OR=2.52 for underweight/normal and OR=1.93 for overweight, p<0.0001 compared to obese), increased albumin (OR=1.49, p=0.0046), and increased bilirubin (OR=0.56, p=0.0081) were identified as clinically relevant predictors of the likelihood of receiving standard R-CHOP chemotherapy. Patients with a documented history of cardiomyopathy, congestive heart failure, EF < 50%, chronic renal insufficiency, or diabetes had a reduced prevalence of receiving standard R-CHOP chemotherapy compared with patients with none of those risk factors (34.3% versus 51.2%, p = 0.0640). Median PFS in the R-CHOP, attenuated R-CHOP, and rituximab monotherapy groups was 51.5 months, 11.0 months, and 8.6 months, respectively. 12- and 24-month OS with standard R-CHOP, R-CHOP alternative, and rituximab monotherapy were 90% and 80%, 78% and 64%, and 74% and 47%, respectively. 2-year OS for patients with IPI 0-2 and IPI ≥3 was 80% and 58%, respectively. Conclusions: As patients with newly diagnosed DLBCL get older, fewer receive standard R-CHOP chemotherapy. Age, performance status, albumin, bilirubin, cardiac and renal function, and the presence of diabetes mellitus affect ability to receive standard R-CHOP. Aggressiveness of treatment correlates with clinical outcomes. Disclosures Burke: Incyte: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Black-Shinn:McKesson Specialty Health: Employment. Clark:McKesson Specialty Health: Employment. Frytak:McKesson Specialty Health: Employment, Equity Ownership. Espirito:McKesson Specialty Health: Employment. Sharman:Acerta: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Research Funding.

Prognostic Value of cMYC Gene Abnormalities in Diffuse Large B Cell Lymphoma Treated with Chemo-Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2664-2664 ◽  
Author(s):  
Ana Batlle López ◽  
Sonia Glez de Villambrosia ◽  
Santiago Montes-Moreno ◽  
Francisco Mazorra ◽  
Andrés Insunza ◽  
...  
Keyword(s):  
Cancer Research ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2664 Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas. Despite improvements in diagnostic and therapeutic procedures, DLBCL still represents a significant cause of morbidity and mortality. Two molecularly defined types of DLBCL have been recently described: the germinal center B-cell (GCB) and the activated B-cell (ABC) subtype. GCB type DLBCL has been shown to have a better OS and PFS than ABC-type in multiple series of DLBCL patients treated with chemoimmunotherapy. The processes involved in lymphomagenesis in both subtypes are not fully understood, but deregulated expression of various proto-oncogenes is observed, often as the result of chromosomal translocations leading to constitutive gene expression. The specific role of the cMYC gene abnormalities in the pathogenesis of these lymphomas is still a matter of debate. To address this question, the status of the cMYC gene was analyzed by interphase fluorescence in situ hybridization (FISH) using a break apart probe, in TMA arranged tissue samples from 241 patients with de novo DLBCL treated with chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). cMYC was rearranged in 15 cases out of 166 evaluable (9.26%). We did not find differences in the incidence of cMYC rearrangements between GCB and ABC-DLBCL subtypes (9/74 GCB and 6/82 ABC type) as classified according to extended immunohistochemical algorithms (Choi et al in Cancer Res. 2009). In our series, patients with DLBCL and cMYC rearrangements presented more frequently extranodal disease (p=0.007), higher IPI (p=0.037) and tended to have less than 60 years (p=0.053). cMYC gains were observed in 33 cases (21.85%). In the univariate analysis, cMYC abnormalities (gains and rearrangements) had no impact on the clinical outcome in the ABC subtype. However, whilst the cMYC gains did not identify a risk group in terms of OS or PFS the presence of cMYC rearrangements showed a significantly inferior progression-free survival (PFS) in the GCB-type group (p<0.006). However, the multivariate analysis showed that the only independent adverse predictors in these series of DLBCL cases were the presence of a high International Prognostic Index score (p=0.0028; RR=2.59 95% CI 1,34–4,99) and the ABC phenotype (p=0.0182; RR=2.16 95% CI 1,1–4,21). In summary, although cMYC rearrangements apparently do not provide additional prognostic information to the IPI score and/or GC-ABC classification in the whole DLBCL population, it identifies a subgroup of GCB-type DLBCL with very poor outcome. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Mollejo:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

miRNA Profiling Predicts Survival and Identifies a Novel Putative Oncomir in Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1548-1548
Author(s):  
Christoffer Hother ◽  
Ditte Reker ◽  
Konstantions Dimopoulos ◽  
Steen Knudsen ◽  
Thomas Jensen ◽  
...  
Keyword(s):  
Survival Analysis ◽  
B Cell ◽  
Alternative Treatment ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Treatment Modalities ◽  
Large B Cell Lymphoma ◽  
Robust Likelihood ◽  
Large B Cell

Abstract Abstract 1548 Introduction: The introduction of Rituximab as supplement to chemotherapy has significantly improved outcome in diffuse large B-cell lymphoma (DLBCL). Still, a fraction of patients are resistant or relapse shortly after treatment. Improved stratification of patients with DLBCL for standard immunochemotherapy or alternative treatment strategies is therefore urgently needed. Although DLBCL profiling based on mRNA expression may be helpful, this has not proven clinically efficient, and the prognostic value of immunohistochemical algorithms is controversial. In addition, novel therapeutic options are essential since the current alternative treatment modalities are often not curative. MicroRNAs (miRs) are particularly attractive molecules for clinical use since they are well conserved in formalin fixed paraffin embedded (FFPE) tissue, and novel data imply that they may be targeted directly in the patients. Materials and methods: RNA was extracted from diagnostic biopsies from DLBCL patients (n=97) treated uniformly with immunochemotherapy (R-CHOP n=80 or R-CHOEP n=17). GCB/non-GCB profiling was done by immunohistochemistry according to the Hans classification. MiR profiles were generated using Affymetrix microRNA version 1.0 arrays. Data analyses were performed using R/biocondutor and the webtool “SignS” that uses parallel computing for finding survival related genes and signatures from gene-expression datasets. Survival analysis was performed in R using the survival package. Univariate analysis was performed by comparing Kaplan-Meier survival estimates using Log-rank test. Cox proportional hazards regression model was used for multivariate analysis. Results and discussion: The median follow-up time for all patients was 3.4 years. The estimated 3-year over all survival probability was 82.8% (95% CI: 75.4%-90.9%). No difference in survivability was observed between the R-CHOP and the R-CHOEP treated cohort (P=0.145). High IPI (> 2) was significantly associated with inferior overall survival (OS, P = 0.038), but not progression free survival (PFS, P = 0.083). Univariate analysis showed that in this cohort the Hans classification was not prognostic (P=0.73; (52 GBC and 37 non-GCB subtypes; 8 NA)). Seven miRs were differentially regulated between GCB and non-GCB using a cutoff of P< 0.05. Five miRs were upregulated in non-GCB lymphomas: miR-625, miR-222, miR-221, miR-155 and miR-503, two were downregulated (miR-181a, miR-181b). For survival analysis, we initially applied a multivariate approach (Robust likelihood-based survival modeling, RBsurv), which identified a subset of miRs that significantly associates with poor survival. These include one upregulated miR, and four down regulated miRs. In order to obtain cross validated survival estimates, we applied three different algorithms; FCSM(SignS), TGD(SignS) and GLMboost(SignS) to the same sample set. These combined bioinformatic models identified a total of 17 deregulated miRs that significantly associate with survival. Among these, 9 are predicted by more that one algorithm, and interestingly, all 4 models identify a novel upregulated and potential oncogenic miR in patients treated by immunochemotherapy. When the cross-validated predictors were combined into a unified robust “miR-survival-predictor”, the performance is as good as, or even better, than the IPI. In addition, our model is a superior predictor of survival than the GCB/non-GCB classification according to Hans. Our data are currently being validated in a test set of 60 patients, and functional studies of the novel putative oncomiR are ongoing. Disclosures: No relevant conflicts of interest to declare.

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