Abstract 524
Understanding epigenetic mechanisms of gene regulation will provide an unprecedented opportunity for therapeutic intervention in cancer because, unlike genetic lesions, pathogenic ...changes to the epigenome are reversible. Non-Hodgkin Lymphoma (NHL), which strikes 70,000 Americans annually, is characterized by deregulated expression of large gene cohorts that mediate unchecked cell growth, the molecular basis of which remains poorly understood. Recently, recurrent somatic mutations were identified in chromatin modifier genes (EZH2, MLL2, EP300) in ∼30% of NHL, suggesting that epigenetic dysregulation may be a common mechanism for widespread gene expression changes. Indeed, previous studies have demonstrated evidence of aberrant DNA methylation in lymphoma. Moreover, NHL-specific regulatory elements are attractive candidates for therapeutic targeting, because reversal of their aberrant epigenetic profile would restore normal gene expression, while leaving normal cells intact.
In this study, we performed integrative epigenomic, genomic, and transcriptomic profiling of purified CD19+ B cells from excisional lymph node biopsies and peripheral blood (PB, when available and free of circulating lymphoma) in 84 patients with NHL (Diffuse Large B cell lymphoma (DLBCL) N=34, Follicular Lymphoma (FL) N=38, Marginal Zone/Mantle Cell/Chronic Lymphocytic Leukemia (MZL/MCL/CLL) N=12), 20 patients undergoing elective tonsillectomy (tonsil B cells), and 40 healthy volunteers (PB). To enrich for key changes in the NHL epigenome, crosslinked chromatin was subjected to formaldehyde-assisted isolation of regulatory elements (FAIRE), for highly active histone-depleted regions, and chromatin immunoprecipitation (ChIP) for several activating (H3K4me1, H3K27ac, H3K9/14ac), and repressive (H3K27me3) histone marks, followed by high throughput sequencing (FAIRE/ChIP-Seq). To identify genes regulated by putative NHL-specific regulatory elements, we profiled gene expression (mi/mRNA) by microarray and, in primary tumors, by RNA-Seq to detect novel isoforms, translocations, and mutations, such as those in epigenetic modifier genes.
In order to analyze this complex dataset, we created a global, integrative algorithm to evaluate the regulatory potential of a given epigenetic element, or set of elements, based on a step-wise approach. All regulatory elements were ranked according to several parameters, including distance to transcription start sites (TSS), gene expression level, chromatin state, distance to CTCF sites, genomic copy number, degree of sequence conservation, association with mutations in epigenetic modifiers, and most importantly, NHL-specificity and recurrence (number of samples). We first established the NHL-specificity of each regulatory element by comparison to matched PBB, if available, or to healthy donor B cells, identifying thousands of regulatory elements that are differentially enriched (“gained” or “lost”) in at least one primary NHL sample. We further assessed the likely role of each element by its genomic, epigenomic, and transcriptomic contexts. Gained elements were significantly associated with higher levels of gene expression in NHL compared to normal B cells (p<0.0001); and conversely, lost elements were significantly associated with decreased expression levels (p<0.0035). Subsequent to this global analysis, we ranked the NHL-specific elements as described above and identified a set of prioritized signatures, comprising a few dozen to hundreds of elements, depending on the type (gained/lost), chromatin state, and recurrence. As predicted, some of these signatures were associated with oncogenes, such as TP63, BCL2, and BCL6; however, others are intergenic and may be cis-elements coordinating expression of distal genes. Intriguingly, subsets of these chromatin signatures are specific for distinct NHL subtypes or grades. In summary, our findings establish a foundational dataset for surveying the epigenomic landscape of NHL, while identifying key chromatin signatures for the development of targeted epigenetic therapies.
No relevant conflicts of interest to declare.
Abstract 2686
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of HL (∼5%). This unique clinical entity is characterized by an indolent clinical course and unlike classical ...HL late relapses may occur. Standard treatment depends on stage and includes radiation therapy (RT) and/or chemotherapy which can be associated with an increased risk of treatment related late effects warranting investigation of other active agents. The malignant cells of NLPHL universally express CD20, therefore therapy with rituximab (R), the monoclonal anti-CD20 antibody, is a targeted option. We report our experience with R as front-line treatment for patients with NLPHL.
Patients with newly diagnosed NLPHL and measurable disease were treated with R at 375 mg/m2 administered weekly × 4 or, after protocol amendment (February 2003) with R followed by 4 doses of R maintenance (RM) administered every 6 months for 2 years. Restaging studies were performed at 1, 3 and 6 months and then every 6 months until progression. All pathology was centrally reviewed.
Nineteen patients were enrolled between May 1999 and September 2006. The median age at treatment was 45 years (range 17–63), stage I (n=6), stage II (n=7), stage III (n=6). Ten patients were treated with R alone and 9 with R+RM. The median follow-up for R patients is 8.8 years (5–11.4) and for R+RM patients is 5 years (2.5–7.6). At the end of induction therapy with R alone, the overall response rate was 100% complete response (CR) (n=10), CR unconfirmed (n=2) and partial response (n=7). The median progression free survival (PFS) for patients treated with R alone and R+RM is 50 months and 67 months, respectively (p=0.7; log rank test) and median overall survival (OS) not reached. The median follow up for patients without progressive disease at the time of this analysis was 6.9 years (range 2.5–11.5). The estimated PFS at 5 years is 51.7%, 95% CI 33.2–80.4 and at 10 years 35.4% 95% CI 17.7–70.8. There was no difference in median PFS between patients with stages I-II versus III (5.6 years and 4.15 years respectively, p=0.58 log rank test). The estimated OS at 5 years is 93.3%, 95% CI 81.5–100 and 10 years 76% 95% CI 55.4–100. Ten patients progressed (5 treated with R alone, 5 treated with R+RM) of whom 6 transformed to an aggressive B cell lymphoma (biopsy proven) at a median of 4.2 years range 0.9–8. Five of the 6 transformed patients had abdominal disease at initial diagnosis (stage III, n=4). Three patients died (2 aggressive NHL, 1 unknown).
Rituximab is an active single agent in the treatment of newly diagnosed NLPHL with a median PFS of 5.6 years. R+ RM resulted in a non-significant increase in PFS compared to R alone. In this series, abdominal involvement was associated with transformation to an aggressive B cell lymphoma underscoring the need for biopsy at relapse. These results demonstrate a pattern of late relapse following rituximab, at least as great as the historical data with RT or RT + CT. Although R alone achieved proof of concept for a targeted therapy, its use should remain investigational as primary therapy of NLPHL.
Advani:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab. Anti-CD20 agent that targets CD20 on NLPHL cells. Horning:Genentech: Employment, Equity Ownership.
Retrospective studies, mostly conducted in Western cultures, indicate that childhood cross-gender behaviors are strongly predictive of androphilia in adult men. To test the cross-cultural validity of ...these findings, we conducted a study of fa'afafine in Independent Samoa. Fa'afafine are a heterogeneous group of androphilic males, some of whom are unremarkably masculine, but most of whom behave in a feminine manner in adulthood. A total of 53 fa'afafine, 27 control men, and 24 control women participated. Participants were asked how often they engaged in female- and male-typical behaviors in childhood. Results demonstrated that fa'afafine and women recalled engaging in significantly more female-typical behaviors and significantly fewer male-typical behaviors in childhood compared to the men. Fa'afafine's recalled female-typical and male-typical behaviors did not differ significantly from those of women. These results suggest that the relationship in males between gender-atypical behavior in childhood and adult androphilia is not unique to Western societies and may be a cross-culturally universal pattern of psychosexual development shared by most males who are predominantly androphilic.
Mature T/NK-cell lymphomas comprise a subset of aggressive non-Hodgkin lymphomas. Some of these subtypes are known to express CD30, including systemic anaplastic large cell lymphoma (sALCL) where ...CD30 expression is pathognomonic. Few advances have occurred in the frontline treatment of sALCL and other T-cell lymphomas over the past 30 years, with treatment typically consisting of anthracycline-containing regimens such as CHOP. Overall outcomes with frontline therapy are poor, with a complete remission (CR) rate of 39–53% (Reimer 2009; D'Amore 2012) and a 5-year overall survival rate of 12–49%, depending on subtype (Vose 2008). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Efficacy was demonstrated in a pivotal phase 2 study of relapsed sALCL pts, where an objective response rate (ORR) of 86% and a CR rate of 57% were observed (Pro 2012).
A total of 39 pts were enrolled in this phase 1, open-label study designed to assess the safety and efficacy of brentuximab vedotin administered sequentially with standard-dose CHOP or in combination with CHP (CHOP without vincristine) (A+CHP) for the frontline treatment of sALCL and other CD30+ mature T/NK-cell lymphomas (ClinicalTrials.gov NCT01309789). ALK+ sALCL pts were required to have an IPI score ≥2. Pts in Arm 1 received sequential treatment (q3wk): 2 cycles of 1.8 mg/kg brentuximab vedotin followed by 6 cycles of CHOP. Arm 2 was designed to determine the recommended dose of brentuximab vedotin in A+CHP to be evaluated in Arm 3 (6 cycles q3wk). Responders were eligible to receive single-agent brentuximab vedotin (1.8 mg/kg q3wk) for 8–10 additional cycles (16 total cycles) in all 3 arms.
On Arm 1, 13 pts received sequential treatment with brentuximab vedotin and CHOP. Pts had a median age of 62 years (range, 23–81). All pts were diagnosed with sALCL (10 ALK–). Following initial treatment with single-agent brentuximab vedotin, 13 pts (100%) achieved an objective response (CR rate 38%). At the end of subsequent treatment with CHOP, 11 of 13 pts (85%) achieved an objective response (CR rate 62%). Treatment-emergent adverse events (TEAEs) (≥40%) included peripheral sensory neuropathy, nausea, fatigue, vomiting, dyspnea, constipation, and peripheral edema. TEAEs with a severity ≥ Grade 3 (≥10%) included febrile neutropenia, anemia, neutropenia, peripheral sensory neuropathy, constipation, and fatigue. Following sequential treatment, 12 of 13 pts remained on-treatment and received single-agent brentuximab vedotin. After a median observation time of 23 months, the 1-year PFS rate was 77% (95% CI 44, 92).
The remaining 26 pts received combination treatment with A+CHP on Arms 2 and 3. The median age of pts was 56 years (range, 21–82). sALCL was diagnosed in 19 pts (16 ALK–). Other diagnoses included peripheral T-cell lymphoma-NOS (n=2), angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and enteropathy-associated T-cell lymphoma (n=1).
The maximum tolerated dose of brentuximab vedotin in A+CHP was not exceeded at 1.8 mg/kg IV, based on 1 DLT (Grade 3 rash). 23 of 26 pts completed 6 cycles of A+CHP; 21 of these pts went on to receive subsequent single-agent brentuximab vedotin treatment. The median number of brentuximab vedotin cycles, including combination treatment and subsequent monotherapy, was 13 (range, 3–16). TEAEs (≥40%) included peripheral sensory neuropathy, nausea, fatigue, diarrhea, alopecia, and dyspnea. TEAEs with a severity ≥ Grade 3 (≥10%) included febrile neutropenia, anemia, and neutropenia.
All 26 pts were assessed for a clinical response at the end of treatment with A+CHP. The ORR was 100%, with a CR rate of 88%. All 7 non-ALCL pts achieved a CR. After a median observation time of 16 months, the 1-year PFS rate was 71% (95% CI 49, 85).
At a dose of 1.8 mg/kg, brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, exhibited manageable toxicity in the treatment of newly-diagnosed CD30+ mature T/NK-cell lymphomas. A+CHP exhibited substantial antitumor activity, with an ORR of 100% (CR rate 88%) and a 1-year PFS rate of 71%. A phase 3 study comparing A+CHP to CHOP in the frontline treatment of mature T-cell lymphomas is underway (ClinicalTrials.gov NCT01777152).
Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Davies:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Honoraria. Huebner:Takeda Cambridge US: Employment; Takeda: Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after ...frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented.
Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
In this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission CR or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity.
After a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152).
Display omitted
Pro:Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.
The role of body mass index (BMI) impacting clinical outcome among lymphoma patients is controversial. Two recent studies suggest that increased BMI is associated with significantly improved ...survival. In this study the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) was evaluated in three phase III Eastern Cooperative Oncology Group-led trials, among patients with DLBCL (E4494), follicular lymphoma (FL) (E1496) and Hodgkin's lymphoma (HL) (E2496).
537 patients with DLBCL, 730 patients with HD and 282 patients with FL were included in the analysis. BMI was calculated as weight (kilograms) divided by the square of height (meters), using data at study entry. BMI was analyzed both as continuous and categorical variables (underweight <18.5 kg/m2, normal weight: 18.5 to < 25 kg/ m2, overweight: 25 to < 30 kg/ m2, and obese :≥ 30 kg/ m2).The underweight group was excluded due to low (< 2%) prevalence. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. PFS was defined as the time from study entry to relapse, progression, or death. OS was measured from study entry to death of any cause. The log-rank test and Cox regression models was used to check the association. The association between BMI and FFS/OS was also independently assessed among patients treated with rituximab. A sensitivity analysis was performed excluding patients with significant weight loss at baseline.
Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have better prognosis at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome, with p-values of 0.89, 0.30 and 0.40 for FFS, and p-values of 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively (Figure 1). In multivariate analysis adjusting for other clinical factors, BMI remains an insignificant predictor for all three histologies (Table 1). When limiting to patients treated with rituximab, the association remains non-significant for both FL patients (p=0.92 for PFS, p=0.36 for OS) and DLBCL patients (Figure 2). A subset analysis of males with DLBCL treated on R-CHOP, which matched the study cohort used in a recent report (Carson et al, 2012), revealed no differences in FFS (p=0.48) or OS (p=0.58) (Figure 2). Sensitivity analysis excluding patients with weight loss at study entry resulted in similar findings.
Display omitted
Display omitted
Table 1Hazard ratio and 95% CIs for OS associated with BMI as continuous variable and categorical variables.DLBCLHLFLHazard ration (95% CI)PHazard ration (95% CI)PHazard ration (95% CI)PUnivariate AnalysisBMI –continuous0.99 (0.97, 1.02)0.591.01 (0.98, 1.04)0.581.02 (0.98, 1.06)0.44BMI groups0.640.670.09Overweight vs. Normal weight0.85 (0.61, 1.19)0.351.22 (0.76, 1.97)0.410.57 (0.33, 0.98)0.04Obese vs. normal weight0.89 (0.64, 1.26)0.531.01 (0.61, 1.07)0.960.95 (0.58, 1.56)0.84Multivariable AnalysisBMI -continuous+1.00 (0.97, 1.03)0.961.00 (0.97, 1.04)0.771.03 (0.98, 1.08)0.26BMI groups0.800.32Overweight vs. Normal weight0.89 (0.63, 1.26)0.521.09 (0.66, 1.78)0.740.71 (0.37, 1.33)0.28Obese vs. normal weight1.00 (0.69, 1.41)0.960.92 (0.55, 1.53)0.741.37 (0.74, 2.54)0.31List of factors adjustedAge, Sex, IPI, RCHOP/CHOP, B-symptom, SexAge, Sex, ABVD/Stanford V, IPS, B-symptomAge, Sex, B-symptom, FLIPI, maintenance treatment
BMI was not significantly associated with clinical outcomes among patients with DLBCL, HL or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.
Horning:Genentech: Employment.
Background: In diffuse large B-cell lymphoma (DLBCL), a MYC-rearrangement (MYC-R) is present in approximately 10% of cases and has been associated with an inferior outcome following R-CHOP ...chemotherapy. In a previous report that retrospectively analyzed the prognostic impact of a MYC-R on survival following DA-EPOCH-R, patients with a MYC-R had a similar outcome to MYC negative cases (4 year EFS of 83% versus 76% respectively: p=0.46 Ann Oncol 2011 (22) Suppl 4 # 71). We set out to prospectively validate these results in a multicenter study.
Methods: Patients were newly diagnosed with DLBCL or B-cell lymphoma unclassifiable (BCL-U) with features intermediate between DLBCL and Burkitt lymphoma (BL). Only cases that harbored a MYC translocation by fluorescent in-situ hybridization (FISH) or conventional cytogenetic testing were included in this report. Treatment consisted of 6 cycles of DA-EPOCH-R.
Results: 52 patients were included in this preliminary analysis. Characteristics were median (range) age 61 (29-80) years; male sex 37 (71%); stage III or IV disease 38 (73%); IPI score 0-2 in 35% versus 3-5 in 65%; HIV positive 4 (7%). Histologic diagnosis was DLBCL in 45 (86%) and BCL-U in 7 (14%). All cases had a MYC-rearrangement. BCL2 was rearranged in 14/31 (45%) and overexpressed by IHC in 24/43 (56%) cases tested. There were 3 deaths secondary to infectious complications and otherwise toxicities were similar to previous reports of the regimen. At a median follow-up time of 14 months, progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 79%, 86% and 77% respectively for all patients. PFS was 87% and 64% in cases that were FISH positive (double-hit) and IHC positive for BCL2 respectively.
Conclusions: Albeit short follow-up, DA-EPOCH-R in MYC-R DLBCL demonstrates promising activity in a multicenter prospective setting. Further analysis of this data is planned with central pathology review of cases and longer follow-up. The principal arm of this study testing the regimen in BL remains open to accrual (NCT01092182).
Display omitted
LaCasce:Seattle Genetics, Inc.: Research Funding.
Background: In patients with aggressive NHL, whole-body positron emission tomography/computed tomography (PET/CT) with 18Ffluorodeoxyglucose (FDG) performed after 2–4 cycles of front-line therapy has ...a reported positive predictive value (PPV) of 80–100% and a negative predictive value (NPV) of 70–100%. However, the studies reporting these results were primarily retrospective, contained a mixture of NHL subtypes and therapies, and did not apply the recently published consensus response criteria (J Clin Oncol 2007; 25:579). In addition, the interpretation of PET reports as positive or negative is often difficult for the treating oncologist.
Methods: In this study, patients with a new diagnosis of advanced stage diffuse large B-cell lymphoma (DLCL) received standard R-CHOP × 6 cycles. Patients had FDG-PET/CT scans performed after cycle 2 or 3 and at the completion of therapy. Two medical oncologists (AC, NB) reviewed the FDG-PET/CT reports and interpreted them as positive, negative, or equivocal. A nuclear medicine radiologist (FD) then reviewed the scans and applied the consensus response criteria to score each FDG-PET/CT as positive or negative. All patients provided written informed consent.
Results: Fifty patients (mean age 58 years, range 29–80) with stage III (n=15) or IV (n=35) DLCL were enrolled between March 2005 and May 2008 and treated with R-CHOP. All patients had a FDG-PET/CT performed after cycle 2 (n=47) or 3 (n=3), and 42 patients had FDG-PET/CT after 6 cycles. Median follow-up is 15 months. The medical oncologists interpreted the post-cycle 2 FDG-PET/CT reports as follows: 15 (30%) positive, 15 (30%) negative, 20 (40%) equivocal. Their NPV was 87% and the PPV was 27%. Patients with equivocal scans had outcomes similar to those with negative scans (80% free of relapse). After the radiologist's review, the equivocal scans were classified as negative (n=10, 50%) or positive (n=10, 50%). The reviewed post-cycle 2 PET/CT results did not significantly correlate with progression-free survival (PFS) (graph, log-rank test p-value=0.35), and NPV and PPV were 85% and 25%, respectively. At the completion of therapy, the medical oncologists called 5 (12%) FDG-PET/CT reports positive, 25 (60%) negative, and 12 (29%) equivocal. These results significantly correlated with PFS (logrank test p-value<0.001; NPV 92% and PPV 80%). Again, the equivocal scans predicted outcomes similar to negative scans (92% free of relapse). The final, radiologist-reviewed FDG-PET/CT results were also significantly associated with outcome (graph, log-rank test p-value<0.001).
Conclusions: In contrast to prior reports on the value of interim FDG-PET/CT, our results demonstrate that in DLCL patients treated with R-CHOP who are assessed prospectively, interim FDG-PET/CT does not predict PFS. However, end of therapy FDG-PET/CT does correlate strongly with PFS. It may be that the dichotomous consensus response criteria, which apply to end of therapy FDG-PET/CT, are not useful for interpretation of interim scans. In support of a more relative interpretation of interim FDG-PET/CT, we found that the subset of FDG-PET/CT reports that cannot be clearly designated as positive or negative predict outcomes similar to those of negative scans.
Display omitted
Background: The WHO recognizes a category of B-cell lymphoma unclassifiable with features intermediate between DLBCL and cHL, also known as GZL. This is a challenging disease entity to treat due to ...disease heterogeneity and lack of pathologic or clinical prognostic indicators as well as absence of standard management guidelines for untreated or relapsed/refractory patients (pts).
Methods: We performed a multicenter retrospective analysis of newly diagnosed GZL pts treated from 2001-2012 across 19 North American academic centers. Diagnosis was established by institutional expert pathology review. This work is an expansion and update of prior reported data (Evens AM et al, ASH 2013, #847) with 16 cases added to the original report. Additionally, new data were examined including histopathologic and IP analysis and detailed frontline and salvage therapy. Prognostic factors associated with survival on univariate and multivariate Cox regression analyses were examined.
Results: Characteristics of 112 GZL pts included: median age 39 years (19-86); M:F 1.8:1; ECOG PS 0-1 87%; B symptoms 40%; anemia 59%; hypoalbuminemia 30%; bulky disease (≥10cm) 24%; non-mediastinal presentation 57%; bone marrow pos 11%; Stage III/IV 52%; IPI 0-2 77%; and IPS 0-2 in 81%. The most prevalent tumor IPs were: 93% CD20+ (100/108), 91% CD30+ (98/108), 78% CD79+ (43/55), 97% Pax5+ (67/69), 97% Oct2+ (27/28), and 94% MUM1+ (32/32). CD15 (44%, 45/101) and CD45 (69%, 48/70) were variable. Only 13% and 24% of pts were CD10+ (4/30) and EBV+ (13/55), respectively. Notably, IP did not differ based on clinical presentation (ie, mediastinal vs non-mediastinal). The most common frontline treatments were R-CHOP n=52, ABVD +/- R n=34, and R-EPOCH n=11. 71% of CD20+ pts were treated with rituximab as part of frontline therapy. At 31-month median follow-up, 2-year PFS and OS for all pts were 40% and 88%, respectively. The only pathologic factor correlating with outcome was CD20 positivity (PFS: HR 0.34, 95% CI 0.16-0.73, P=0.006). Characteristics correlating with PFS were anemia (HR 0.51, 95% CI 0.29-0.91, P=0.022), low albumin (HR 0.57, 95% CI 0.32-1.00, P=0.05), and IPI (continuous: HR 1.48, 95% CI 1.19-1.82, P=0.0003). For therapy, 2-year PFS and OS for R-CHOP were 46% and 84%, respectively; ABVD+/-R 25% and 96%, respectively; and R-EPOCH 68% and 83%, respectively (Fig. 1). R-EPOCH predicted improved PFS (0.047), however this effect was abrogated after controlling for IPI, anemia and hypoalbuminemia (P=0.2). Pts who received rituximab with frontline therapy had improved 2-year PFS (51% vs 19%, respectively, P=0.012). Interestingly, the significance of CD20 persisted on Cox regression controlling for rituximab (rituximab HR 0.55, 95% 0.33-0.93, P=0.025; CD20 0.35, 95% CI 0.16-0.75, P=0.007). Furthermore, the effect of rituximab remained significant after controlling for IPI, anemia, and hypoalbuminemia (HR 0.35, 95% CI 0.18-0.69, P=0.002). Overall, 58% of pts relapsed with median time to relapse of 7 months (0-64); the mean number of salvage therapies was 3. Regimens at 1st relapse included: R-ICE (n=33), R-ESHAP (n=6), R-EPOCH (n=7), ABVD (n=1) and brentuximab vedotin (n=4). Beyond first relapse, the most common treatments were: brentuximab vedotin (n=7) and radiation (n=5). 61% of relapsed pts proceeded to stem cell transplantation (SCT) (38% allogeneic, 62% autologous). 20/27 (74%), 20/32 (63%), and 3/3 (100%) of pts who relapsed after frontline ABVD, R-CHOP and R-EPOCH, respectively, had SCT at relapse. 2-year OS was superior for pts who had SCT (88% vs 67%, P=0.014; Fig. 2), which persisted on multivariable regression (SCT: HR0.14, 95% CI 0.02-0.95, P=0.044; IPI continuous: HR 2.04, 95% CI 1.00-4.16, P=0.05; anemia: HR 2.40, 95% CI 0.32-18.25, P=0.4; low albumin: HR 5.54, 95% CI 1.08-28.44, P=0.04).
Conclusions: To the best of our knowledge, this represents the largest series of GZL reported to date. Presence of CD20 appeared to be an independent prognostic factor and treatment with a rituximab-based DLBCL-specific regimen for frontline therapy was associated with the most optimal PFS. In addition, pts who underwent SCT at relapse appeared to have superior OS, however caution should be given to this finding given likely selection bias. Continued examination of this unique lymphoma is warranted.
Display omitted
Display omitted
Bartlett:Seattle Genetics, Inc.: Other, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Advani:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Janssen Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding. Blum:Janssen, Pharmacyclics : Research Funding.
Abstract 3644
Use of interim PET in Hodgkin Lymphoma (HL) for risk-adapted treatment has been confounded by a lack of standardized criteria for interpretation. The International Harmonisation Project ...(IHP) criteria (JCO 2007;25:571) have been validated and are widely used for restaging following therapy. Our objective was to validate the IHP criteria for response evaluation based on PET after two cycles and correlate with the “London”criteria and diagnostic CT-based (dCT) lesion size changes.
Pts were accrued prospectively to CALGB 50203, a trial of doxorubicin, vinblastine and gemcitabine (AVG) for initial treatment of stage I-II non-bulky Hodgkin lymphoma (HL). All had FDG PET or PET/CT and a separate high-resolution dCT scan at baseline, after two cycles of AVG (PET-2 and dCT-2) and at the end of therapy. No treatment change was made based on the PET-2 results. Of 99 assessable pts, 88 had both PET-2 and dCT-2. The primary PET-2 interpretation was based on IHP criteria (uptake > mediastinal blood pool/background is positive), a secondary interpretation was performed using the 5 point London criteria (uptake > liver is positive). The percent decrease in the sum of the products of the diameter (%SPPD) was determined between baseline dCT and dCT-2. A receiver operator curve (ROC) analysis was performed to determine the best cut-off for %SPPD to define a positive and negative CT result. The PET-2 and dCT-2 (%SPPD change) data were correlated with progression free survival (PFS).
Sixty-four pts (73%) achieved a complete remission (CR)/CR unconfirmed (CRu), 23.9% a partial response (PR), and 3% had stable disease. After a median follow-up of 3.3 years (1.8–5.0 years), 23.9% of patients relapsed/progressed with an estimated 3-year PFS of 0.77 CI 68,84. Eleven of 24 (45.8%) PET-2 positive patients relapsed vs. 10 of 64 (15.6%) PET-2 negative patients (p=0.0004). The best cut-off determined from ROC analysis for %SPPD change was 65%. The comparative results for individual evaluation criteria are displayed in the Table. In the PET-2 positive group, a negative dCT-2 increased PFS by 27–35%, suggesting an influence from dCT-2 results. However, in the combinatorial analysis, some of the confidence intervals are large due to small number of patients in each individual group, particularly, when both PET-2 and dCT-2 were positive as well as when PET-2 was positive and dCT-2 was negative.
Interim PET/CT after two cycles of chemotherapy using either IHP or London criteria has a high NPV in early stage non-bulky HL. However, the PPV of interim PET needs to be improved to guide clinical management. Combining PET-2 with %SPPD decrease after 2 cycles improves prediction of PFS compared to each test alone. These data provide a proof of concept for risk-adapted clinical trials and further studies are underway to confirm these findings in a larger population.
TableFDG PET Evaluation with IHP and London Criteria, Dedicated CT and Combined AnalysisPatients N, (%)Progression N, (%)PPV 95%CINPV 95%CI2-year PFS 95%CIPET by IHP45.8% 26,6784.4% 73,92PET2−64 (72.7%)10 (15.6%)88% 77,93PET2+24 (27.3%)11 (45.8%)54% 33,71PET by London50.0% 25,7581.9% 71,90PET2−72 (81.8%)13 (18.1%)85% 74,91PET2+16 (18.2%)8 (50.0%)50% 25,71%SPPD change42.9% 26,6188.5% 77,95≥65% (negative)52 (59.8%)6 (11.5%)88% 76,95<65% (positive)35 (40.2%)15 (42.9%)63% 45,76Combined AnalysisNANAPET2−/≥ 65%42 (48.3%)3 (7.1%)93% 79,98PET2−/< 65%21 (24.1%)7 (33.3%)76% 52,89PET2+/≥ 65%10 (11.5%)3 (30.0%)70% 33,89PET2+/< 65%14 (16.1%)8 (57.1%)43% 18,66NA: not done, small samples
Bartlett:seattle genetics: Research Funding. Cheson:Celphalon: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.
PDF