Li, Hailun

Abstract Background We have previously reported and validated that the E-IPI, provided better discrimination of overall survival (OS) than the IPI for DLBCL patients > 60 years of age treated with R-CHOP (Advani et al., BJH 2010 and 12-ICML 2013 Abstract 222). Recent reports suggest that males > 60 years treated with R-CHOP have worse outcomes likely related to differences in rituximab clearance (Muller et al., Blood 2012). In this study, we explored if the addition of male sex to the E-IPI further improved risk stratification. Methods DLBCL patients > 60 years treated with R-CHOP on the E4494, RICOVER-60 and GELA 98-5 trials were included. A multivariate analysis was performed to assess whether male sex is an independent prognostic factor for OS in addition to the five E-IPI risk factors, E-IPI score, and E-IPI risk group. Male sex (S) was added as an additional risk factor to the E-IPI (S-EIPI, 0-6) and patients regrouped according to the number of risk factors: low (L)=0-1, low intermediate (LI)=2, high intermediate (HI)=3 and high (H)=4-6 based on the observed OS using Kaplan-Meier curves. C-statistic was used to compare the discrimination ability. The 5 year OS was estimated using the Kaplan-Meier method. Results 1079 patients (E4494, n=267; RICOVER-60, n=610; GELA 98-5, n=202) with a median follow-up of 8.9 years were included. In multivariate analyses, male sex was a significant independent predictor for OS adjusting for all five E-IPI factors, (HR 1.5, p < 0.0001), E-IPI score (HR 1.42, p < 0.001), and E-IPI risk group (HR 1.42, p < 0.001) (Table 1). C-statistic was 0.66 for S-EIPI and 0.64 for EIPI. Incorporation of sex into the E-IPI shifted 35% patients to higher risk groups, including 110 patients into the highest risk group (Table 2). The estimated 5 year OS for the S-EIPI L, LI, HI, and H risk groups was 87%, 70%, 58%, and 40%, respectively (Table 3). Compared to E-IPI, the 95% C.I. did not overlap among S-EIPI risk groups. Conclusion For DLBCL patients >60 years treated with R-CHOP, our results suggest the addition of male sex to the E-IPI may improve categorization of patients into well-defined clinically relevant risk groups. Patients with low risk S-EIPI have an excellent outcome (5 year OS 87%). Patients with high risk S-EIPI have a 5 year OS of only 40% and therapies beyond standard R-CHOP need to be explored. Disclosures: Horning: Genentech: Employment; Roche: Equity Ownership.

Abstract Background The international prognostic score (IPS) (Hasenclever et al., NEJM 1988) uses 7 factors (age> 45, male sex, hemoglobin<10.5, stage IV, leukocytosis > 15,000, and lymphopenia< 600) to predict a 5 year freedom from progression (FFP) of 42%-84% and overall survival (OS) of 56%-89% for patients with advanced HL. Constructed from a retrospective analysis of patients treated before 1992, the IPS continues to be the most commonly used risk stratification index for advanced HL. Recent studies suggest that the predictive range of the IPS has narrowed due to improved outcomes of patients treated with current therapy (Moccia et al. JCO 2012). In this report we prospectively evaluated the ability of the individual components of the IPS to predict outcome in patients enrolled on the US Intergroup trial E2496. Methods All seven IPS (IPS-7) variables were recorded for all patients at study entry. FFP was defined as the time from study entry to disease progression or relapse; deaths that occurred during remission that were not preceded by disease progression/relapse were censored. OS was defined as the time from study entry to death from any cause. Kaplan-Meier methodology was used to construct survival curves. Univariate and multivariate analysis (MVA) was performed using Cox proportional-hazards models. We subsequently constructed an alternative prognostic score utilizing the factors which were significant on MVA (PS-3). Results From 1996-2006, 854 patients with advanced HL, were randomized to treatment with either ABVD or Stanford V, with no significant differences in outcome (Gordon et al, JCO 2013). While the IPS-7 remained prognostic it did not stratify the lowest risk patients (0-1 risk factor) or patients with 3-5 risk factors, as its predictive range was narrowed due to improved clinical outcomes (Fig 1a and 2a). Table 1 shows the univariate and multivariate analysis for IPS-7 and outcomes. In contrast to the original IPS-7, on MVA, only two factors, hemoglobin and stage were significant for FFP, and three factors for OS: hemoglobin, stage, and age. We then evaluated a new 3 factor score (PS-3) utilizing variables significant on the MVA. The PS-3 was significant for both FFP (p=0.0001) and OS (p<.0001) and clearly separated patients into 4 distinct risk groups with either: 0, 1, 2 or 3 risk factors. The five year FFP was 83%, 74%, 68%, and 63% and OS was 95%, 85%, 75%, and 52% for patients with 0, 1, 2, and 3 risk factors, respectively (Table 2, Fig 1b and 2b). Conclusion In E2496, for patients with advanced HL, the PS-3 may stratify patients more clearly compared to IPS-7 and provide a simpler model to assess risk. Studies comparing PS-3 with IPS-7, and are ongoing. The incorporation of novel biomarkers and biologic factors into PS-3, as well as validation with other data sets is warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Rituximab in combination with chemotherapy has been shown to improve overall survival (OS) in pts with FL compared with chemotherapy alone. The effect of MR was evaluated in randomized clinical trials (RCTs) with conflicting results regarding OS. In a previous systematic review and meta-analysis of summary (aggregate) data we demonstrated an OS benefit of MR treatment in pts with relapsed or refractory FL and an improved progression free survival (PFS) in both untreated and relapsed refractory FL. However, pts' disease and treatment characteristics may interact with the effect of MR. To improve identification of sub-groups of pts who may benefit from MR treatment, and to evaluate factors that interact with the effect of MR we conducted an international IPD (raw data) meta-analysis of RCTs of MR for pts with FL. We present the first analysis of this meta-database. Methods In June 2014, we updated an electronic search in Pubmed and the Cochrane Library, conference proceedings and database of clinical trials for randomized trials comparing MR to observation. The investigators of eleven trials that fulfilled inclusion criteria were invited to cooperate. Results of one trial were not reported and this trial could not be included in the meta-analysis. Seven study groups participated in this collaborative project and contributed data on individual pts, including disease characteristics, past treatment, response, survival and adverse events. We examined the effect of pt, disease and treatment characteristics by performing a series of Cox regression analyses stratified by trial. In a sensitivity analysis we combined the assessed log hazard ratios (HR) using a log-rank test for each study and combined the results using a fixed effect meta-analysis. Results We obtained data for 2323 patients randomized in 7 trials of MR compared to observation after induction therapy. The median follow up ranged from 28-114 months. The median age was 57 years (23 - 85 years), and 41% were older than 60 years. 50% of pts were women, 97% had WHO performance status 0-1; 1195 (53%) pts received CHOP/RCHOP, 453 (20%) CVP/R CVP; 1755 (77%) received rituximab containing induction; 33% of pts received 1st induction, 67% ≥2nd. Overall, pts less than 60 years of age (vs. ≥60 years) (p < 0.0001), and women (p = 0.001) had a better prognosis. There was no interaction between sex and the effect of MR (p = 0.65). Pts treated with MR had an improved OS compared to observation (HR 0.76, 95% CI 0.62-0.93, p=0.008, Figure). This was demonstrated also in a sensitivity analysis of 10 studies fulfilling inclusion criteria. There was no statistically significant heterogeneity of treatment effect between trials (p=0.15). In an analysis by treatment line (1st vs. ≥2nd), the estimated effect of MR among patients who received ≥2nd induction was HR of 0.70 (95% CI 0.55 - 0.91), compared to 0.90 (95% CI 0.65 - 1.25) among patients who received 1st induction. However, this difference was not statistically significant (p=0.25). Analysis by the inclusion of rituximab in induction demonstrated among patients who received rituximab in induction a HR of 0.82 (95% CI 0.63 – 1.06), and among those who received induction without rituximab a HR of 0.68 (95% CI 0.49 – 0.93). This difference was not statistically significant (p= 0.35). Analysis by chemotherapy regimen demonstrated an estimated effect for MR among patients who received RCHOP/CHOP of 0.79, 95% CI 0.58 – 1.06, and after RCVP/CVP of 0.65, 95% CI 0.42 – 1.02, with no statistically significant difference between these sub-groups (p = 0.50). Conclusions This is the first report of the collaborative group of maintenance therapy for FL patients. Based on individual patient data, this study demonstrated an improved OS with MR therapy for patients with FL. A sensitivity analysis with all 10 eligible trials supported these results. Results support the effectiveness of MR among patients after their 1st induction as well as after ≥2nd induction, and irrespective of inclusion of rituximab in induction, and the chemotherapy regimen. These results are consistent with those of the summary data meta-analysis that was previously published. The wider CI and lack of statistical significance within sub-groups could be attributed to the sample size. Figure: Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Figure:. Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Disclosures Vidal: Roche: unrestricted grant Other. Shpilberg:Roche: Consultancy, Research Funding.

Abstract Abstract 687 Background: A persistently positive PET scan after just a few cycles of therapy is predictive of a poor clinical outcome in diffuse large B-cell lymphoma (DLBCL). Prior data suggested that about one third of patients remain PET positive after 2–4 cycles, with ≤ 20% 2 year progression-free survival (PFS) for such patients. A response-adapted strategy was studied in E3404 to test the hypothesis that an early treatment change to four cycles of R-ICE might reduce the treatment failure rate of patients whose PET scan remained positive after an initial 3 cycles of R-CHOP. Study Design: Previously untreated patients with DLBCL stage III, IV, or bulky II, with measurable disease, HIV negative, and with adequate organ reserve, were eligible. PET/CT scan was performed before treatment and again after 3 cycles of R-CHOP. A fourth cycle of R-CHOP was given while the scan was centrally reviewed and scored as either positive or negative for FDG-avid tumor by a single reviewer using criteria based on modifications of the Harmonization Criteria. Persistently PET-positive patients received 4 cycles of R-ICE, while PET-negative patients received 2 more cycles of R-CHOP, for a total of 6 cycles. PET/CT was performed again at the end of treatment. A ≥45% 2 year PFS for mid-treatment PET- positive patients was viewed as a promising result, with 88% power if 33 such patients were accrued. Total accrual of 99 patients was therefore planned. Results: Of 100 patients accrued, 78 were eligible; all but 1 ineligibility was based on central pathology review. Fifty-eight were male; median age was 62 years (20–74); 13% IPI 0–1, 31% IPI 2, 37% IPI 3, and 19% IPI 4–5. Seventy-four of 78 (95%) patients completed the first 3 cycles of R-CHOP. Of 72 patients continuing treatment, 67 (93%) completed protocol treatment: 83% of mid-treatment PET-positive and 93% of PET-negative patients. Of 74 patients undergoing mid-treatment PET scan, 12 (16%) were scored as positive, and 62 (84%) as negative. At the end of treatment, 13% were scored as positive, and 87% as negative. Two-year PFS, from the time of study entry, was 72% among all eligible patients. Two year PFS from the time of mid-treatment PET scan was 45% (90% CI, 21–67%) for patients scored as mid-treatment PET-positive, and 77% (90% CI 67–85%) for patients scored as mid-treatment PET-negative. The 80% confidence interval (corresponding to a test with a one-sided type I error of 10%) did not include the null hypothesis of 25%, implying that the results met the pre-specified threshold. Among all 78 eligible patients, 10 have died (13%); 5-year overall survival was 87% (90% CI 78–92%) Three-year overall survival was 67% (90% CI 40–84%) for mid-treatment PET-positive patients, and 93% (90% CI 85–97%) for mid-treatment PET-negative patients. Conclusions: The 2-year PFS for mid-treatment PET-positive patients met the threshold to be considered promising, but the confidence interval was wider than expected due to the small patient number. In addition, the inter-observer variability in the interpretation of mid-treatment PET scans as a binary variable in this study (studied and reported separately in Horning SJ et al. Blood 2010) implies that treatment modification based on early PET scanning should remain confined to clinical trials. Disclosures: Swinnen: Celgene: Consultancy; Genentech: Research Funding. Quon:Genentech: Research Funding. Advani:Pharmacyclics: Research Funding. Kahl:Roche/Genentech: Consultancy; Celgene: Consultancy; Cell Therapeutics: Consultancy; Janssen: Consultancy; GSK: Consultancy; Gilead: Consultancy. Horning:Genentech: Employment; Roche: stock, stock Other.

BACKGROUNDIn an ECOG‐ACRIN Cancer Research Group study (E1496), maintenance rituximab (MR) was reported to prolong progression‐free survival (PFS) in comparison with observation (OBS) alone in patients with indolent lymphoma after induction chemotherapy. Here the long‐term follow‐up of the same patient cohort is presented.METHODSPatients with indolent lymphoma received induction chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). Patients with stable disease or a better response were then randomized to weekly rituximab (375 mg/m2 × 4 doses) every 6 months for 2 years (MR) or to OBS. The primary endpoint was PFS; the secondary endpoints were overall survival (OS), response rate, and toxicities.RESULTSOf the 387 patients who initially received CVP induction, 158 were randomized to MR, and 153 were randomized to OBS. After a median follow‐up of 11.5 years, patients on MR had longer median PFS (4.8 years) than patients on OBS (1.3 years; hazard ratio [HR], 0.49; P < .0001). However, there was no difference in OS between MR and OBS (10‐year OS, 67% vs 59%; median OS, 13.5 years vs not reached; HR, 0.91; P = .69). Other than MR, only minimal residual disease after induction therapy was significantly associated with PFS on multivariate analysis (HR, 0.71; P = .02). A low initial tumor burden, minimal residual disease, follicular histology, a low Follicular Lymphoma International Prognostic Index score, and female sex were associated with longer OS. There was no increase in the rate of second primary malignancies with MR vs OBS.CONCLUSIONSWith long‐term follow‐up, MR did not influence OS. The PFS benefit was maintained. MR should be considered optional for patients with indolent B‐cell lymphoma. Cancer 2016;122:2996‐3004. © 2016 American Cancer Society.

We recently defined event‐free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age‐ and sex‐matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline‐based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c‐statistic = 0.671) in the validation dataset compared to the IPI (c‐statistic = 0.649) or the NCCN‐IPI (c‐statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12–88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps. Am. J. Hematol. 91:179–184, 2016. © 2015 Wiley Periodicals, Inc.

SummaryThe International Prognostic Score (IPS‐7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS‐7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS‐7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS‐7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS‐3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS‐3 outperformed the IPS‐7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS‐7 low risk patients were re‐classified as intermediate risk and 13% of IPS‐7 intermediate risk patients as low risk. For patients with advanced HL, the IPS‐3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

Summary A persistently positive positron emission tomography ( PET ) scan during therapy for diffuse large B‐cell lymphoma ( DLBCL ) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET ‐positive patients received four cycles of R‐ ICE , PET ‐negative patients received two more cycles of R‐ CHOP . A ≥45% 2‐year progression‐free survival ( PFS ) for mid‐treatment PET ‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET ‐positives and 76% (90% CI 65–84%) for PET ‐negatives. Three‐year overall survival ( OS ) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET ‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET ‐positive patients intensified to R‐ ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.