Event-free Survival Benefit Research Articles

Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): An exploratory subgroup analysis of AEGEAN.

8011 Background: In the phase 3 AEGEAN study (NCT03800134), perioperative D + neoadj chemotherapy (CT) vs neoadj CT alone significantly improved the primary EPs of event-free survival (EFS) and pathological complete response (pCR; absence of residual viable tumor [RVT] in resection specimen, incl. primary tumor and sampled lymph nodes) with manageable safety in pts with R-NSCLC (modified ITT [mITT] population). Here, we report exploratory analyses of pts in AEGEAN with baseline N2 nodal status. Methods: Pts with Tx-naïve R-NSCLC (stage II–IIIB[N2]; AJCC 8th ed) were randomized (1:1) to 4 cycles of platinum-based CT plus D 1500 mg IV or placebo (PBO) Q3W before surgery (Sx), followed by D or PBO (Q4W, 12 cycles) after Sx. The mITT population excluded pts with known EGFR/ ALK alterations. Efficacy was assessed in an mITT subpopulation with baseline N2 nodal status (per investigator). Safety was assessed in all N2 R-NSCLC pts who had ≥1 Tx dose. Results: Of 740 pts in the mITT population, 366 (49.5%) had baseline N2 nodal status (D, n = 181; PBO, n = 185). In the N2 subgroup, 83.4% in the D arm and 84.9% in the PBO arm completed 4 cycles of platinum-doublet CT; 77.9% and 77.8%, respectively, had Sx; and 73.5% and 71.9% completed Sx. In the N2 subgroup, similar to the overall mITT population, EFS was prolonged in the D vs PBO arm (HR, 0.63 [95% CI: 0.43–0.90]); rates of pCR (16.6% vs 4.9%; difference, 11.7% [95% CI: 5.6–18.4]) and major pathological response (MPR, ≤10% RVT in primary tumor; 32.6% vs 15.1%; difference, 17.5% [95% CI: 8.8–26.0]) were higher in the D vs PBO arm. While EFS benefit in the D vs PBO arm was similar among pts with single- (HR, 0.61 [95% CI: 0.39–0.94]) or multi-station N2 (HR, 0.69 [95% CI: 0.33–1.38]), pCR benefit was less pronounced in multi-station pts (difference in pCR rate, 13.9% [95% CI: 6.6–21.7] for single-station N2 vs 3.8% [95% CI: –9.2–18.8] for multi-station N2). Among pts in the N2 subgroup who had Sx, similar proportions in the D and PBO arms had open (47.5% vs 50.0%) and minimally invasive procedures (50.4% vs 46.5%); 9.2% vs 11.1% had pneumonectomy (9.2% vs 9.6% in the overall mITT population). Of pts in the N2 subgroup who completed Sx, the proportion with R0 resection in the D vs PBO arm (94.7% vs 91.7%) was similar to that in the overall mITT population. Sx was delayed in a similar proportion who had Sx in the D vs PBO arm (19.9% vs 23.6%, respectively), most commonly for logistical reasons (e.g., scheduling issues). Among 394 pts who received Tx (N2 safety analysis subset; D, n = 200; PBO, n = 194), max grade 3/4 any-cause AEs occurred in 38.5% vs 41.8% in the D and PBO arm, respectively, similar to rates in the overall safety analysis set. Conclusions: With clinically meaningful improvement in efficacy, no adverse impact on Sx outcomes and a manageable safety profile, the addition of perioperative D to neoadj CT remains a potential new Tx option for pts with N2 R-NSCLC. Clinical trial information: NCT03800134 .

Neoadjuvant followed by adjuvant pembrolizumab in melanoma: time biases in the data analysis of the SWOG S1801 trial.

The SWOG S1801 trial investigated the role of pembrolizumab, an anti-PD1 immune checkpoint inhibitor, in the perioperative setting of stage III or IV melanoma. This phase 2 trial compared two groups: one receiving pembrolizumab both before and after surgery (neoadjuvant-adjuvant), and another receiving it only post-surgery (adjuvant-only), with event-free survival (EFS) as the primary endpoint. Neoadjuvant strategies, involving pre-surgical drug administration, potentially offer rapid tumor control and a unique opportunity to assess tumor response. However, they may expose to toxicity and delay or preclude surgery. The study met its primary endpoint, with a 72 % EFS rate in the neoadjuvant-adjuvant group, and 49 % in the adjuvant group. Here, we question the results' applicability with three potential limitations. Key concerns include an arbitrary rule in event assignment, possibly affecting the event distribution over time. Second, different rates of early censoring between groups introduce the possibility of informative censoring, which could have led to an artefactual benefit in EFS. Lastly, phase 2 trial results, by definition, carry risk of fluke results, and should be confirmed in phase 3 trial before wide adoption. Collectively, these factors must be integrated into a careful interpretation of the SWOG S1801 trial outcomes. More robust data are needed to fully appraise strengths and limitations of neoadjuvant pembrolizumab in melanoma treatment.

Abstract A22: Cost effectiveness of second line Axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma

Abstract Background In patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL), CAR T has been shown to be effective in patients with at least 2 prior lines of therapy. ZUMA-7 study demonstrated that axi-cel improved event free survival (EFS) compared to standard of care (SOC) salvage chemoimmunotherapy in primary refractory/early relapse DLBCL leading to its recent FDA approval in this setting. We evaluated the cost effectiveness of second line axi-cel. Methods We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapse DLBCL by developing a Markov model (20-year horizon) to model the cost-effectiveness of axi-cel in the second-line setting compared to SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-year (QALY). Results Assuming a 5-year EFS of 35% with second line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of 100,000 and 150,000 ($93,547/QALY). Axi-cel was no longer cost effective if its 5-year EFS was 26.4% or lower. One-way sensitivity analysis demonstrated that second-line CAR T is cost effective up to a cost of $972,061 at a WTP of $150,000. Second-line axi-cel was the cost-effective strategy in 73% of the 10,000 Monte-Carlo iterations at a WTP of $150,000. Conclusions If the absolute benefit in EFS is maintained over time, second line axi-cel for aggressive RR-DLBCL is cost effective when compared to SOC at WTPs of $100,000 and $150,000/QALY. However, its cost effectiveness is highly dependent on long-term outcomes. Routine usage of second-line CAR T would add significantly to healthcare expenditures even when used in a high-risk subpopulation. Further reductions in cost of CAR T are needed. Citation Format: Swetha Kambhampati, Monica Saumoy, Yecheskel Schneider, Lihua E. Budde, Alexey Danilov, Matthew Mei, Leslie Popplewell, Tanya Siddiqi, Jasmine Zain, Stephen Forman, Larry Kwak, Steven Rosen, Alex Herrera, Nikhil Thiruvengadam. Cost effectiveness of second line Axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A22.

Cost-effectiveness of second-line axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma

AbstractThe ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.

Anti-CD19 chimeric antigenic receptor T cell as a second-line therapy for patients with relapsed/refractory diffuse large B-cell lymphoma.

e19502 Background: Inconsistent results observed in recent trials (ZUMA-7, TRANSFORM, BELINDA) assessing chimeric antigenic receptor T (CAR-T) cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) prompted a meta-analysis to assess the available evidence and to compare the effectiveness of different CAR-T products. Methods: MEDLINE and EMBASE were searched to identify full-text or abstract publications of phase 3 randomized controlled trials (RCTs) assessing CAR-T in patients with R/R DLBCL compared to standard of care (SOC). Efficacy outcomes included event-free survival (EFS), progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and complete response (CR). CR rates were also compared between CAR-T and patients in SOC arm who received autologous stem-cell transplantation (ASCT). Safety outcomes included grade > 3 any adverse events (AE), cytokine release syndrome (CRS) and neurological toxicity (NT). A DerSimonian-Laird random-effects meta-analysis was conducted to pool effect estimates. Freeman-Tukey transformation method was used to estimate pooled proportion (PP) of safety events specific to CAR-T. Mixed treatment comparisons were computed using a frequentist network meta-analysis approach. Results: Of 1803 studies identified, three RCTs with 865 patients were included. Meta-analysis showed significant improvement in EFS (HR: 0.51; 95% CI: 0.27-0.97; I2: 92%), PFS (HR: 0.47; 95% CI: 0.37-0.60; I2: 0%) with CAR-T compared to SOC. OS was not significantly different between the two groups (HR 0.76; 95% CI: 0.56 to 1.03; I2: 29%). Higher objective response (RR: 1.49; 95% CI: 1.13-1.97; I2: 81%), and CR rates (RR: 1.55; 95% CI: 1.07-2.24; I2: 79%) were observed with CAR-T compared to SOC. However, CAR-T was associated with lower CR when compared to patients who underwent ASCT (RR: 0.65; 95% CI: 0.46-0.90; I2: 89%). The safety profile was not different between CAR-T and SOC. The incidences of grade ≥3 CRS (PP: 4.19; 95% CI: 1.60-7.80; I2: 57%) and grade ≥3 NT (PP: 7.57; 95% CI: 0.20-22.6; I2: 95%) were low. Mixed treatment comparisons showed significant EFS benefit with liso-cel (rank 1: HR: 0.37; 95% CI: 0.22-0.61) and axi-cel (rank 2: HR: 0.42; 95% CI: 0.29-0.61) compared to tisa-cel (rank 3). No significant differences were observed among different CAR-T products for PFS or OS improvement. The safety profile of CAR-T products was comparable with tisa-cel (rank 1) being the safest. Conclusions: CAR-T therapy, as a second line treatment, appears to be effective in achieving higher response rates and delaying the disease progression compared to SOC in R/R DLBCL. However, given lack of OS benefit coupled with lower response rates when compared to patients who received ASCT, we should exercise caution in adopting CAR-T as second line therapy for all patients with R/R DLBCL.

Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer.

Simple SummaryHigh stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR. In this study of 318 early-stage TNBC patients in a prospective clinical trial, event-free survival (EFS) in patients without a pCR was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). Therefore, high baseline sTILs do not confer a benefit in EFS in the absence of a pCR. RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS, suggesting the type of lymphocytes within the TIL fraction may be an important parameter to consider for de-escalation strategies. The implications of our findings in the setting of immune checkpoint inhibitor therapy remain to be investigated.High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses.

To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

Role of radiotherapy to bulky sites of advanced Hodgkin lymphoma treated with ABVD: final results of FIL HD0801 trial

AbstractThe role of consolidation radiotherapy (RT) for bulky lesions is controversial in patients with advanced-stage Hodgkin lymphoma who achieve complete metabolic response (CMR) after doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)–based chemotherapy. We present the final results of the Fondazione Italiana Linfomi HD0801 trial, which investigated the potential benefit of RT in that setting. In this phase 3 randomized study, patients with a bulky lesion at baseline (a mass with largest diameter ≥5 cm) who have CMR after 2 and 6 ABVD cycles were randomly assigned 1:1 to RT vs observation (OBS) with a primary endpoint of event-free survival (EFS) at 2 years. The sample size was calculated estimating an EFS improvement for RT of 20% (from 60% to 80%). The secondary end point was progression-free survival (PFS). One hundred sixteen patients met the inclusion criteria and were randomly assigned to RT or OBS. Intention-to-treat (ITT) analysis showed a 2-year EFS of 87.8% vs 85.8% for RT vs OBS (hazard ratio [HR], 1.5; 95% confidence interval [CI], 0.6-3.5; P = .34). At 2 years, ITT-PFS was 91.3% vs 85.8% (HR, 1.2; 95% CI, 0.5-3; P = .7). Patients in CMR randomly assigned to OBS had a good outcome, and the primary end point of a 20% benefit in EFS for RT was not met. However, the sample size was underpowered to detect a benefit of 10% or less, keeping open the question of a potential, more limited role of RT in this setting. This trial was registered at www.clinicaltrials.gov as #NCT00784537.

Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Abstract Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons <0.0001: Table 1 pCR BreastpCR Br/AxpCR Br/Ax or RCB IYes/No N (%)231 (52%)/212 (48%)207 (47%)/236 (53%)266 (60%)/177 (40%)EFS-HR0.33 (0.22-0.50)0.30 (0.19-0.46)0.29 (0.20-0.43)OS-HR0.28 (0.17-0.46)0.20 (0.11-0.36)0.21 (0.13-0.34) Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Table 2 CbBevN (Yes/No)225/218222/221EFS - HR0.84 (0.58-1.22) p=0.360.80 (0.55-1.17) p=0.25OS - HR1.15 (0.74-1.79) p=0.530.76 (0.49-1.19) p=0.23 Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-05.

Non-anthracycline-containing docetaxel and cyclophosphamide regimen is associated with sustained worse outcome compared with docetaxel, anthracycline and cyclophosphamide in neoadjuvant treatment of triple negative and HER2-positive breast cancer patients: updated follow-up data from NATT study.

ObjectiveA previous study demonstrated that non-anthracycline-containing docetaxel plus cyclophosphamide (TC) regimen was inferior to docetaxel, anthracycline and cyclophosphamide (TAC) in neoadjuvant treatment of triple-negative breast cancer (TNBC) and human epidermal growth factor receptor-2-(HER2)-positive breast cancer in a short-term follow-up. Herein, long-term follow-up survival outcomes have been investigated.MethodsTNBC or HER2-positive patients were randomized to receive 6 cycles of TC or TAC neoadjuvant treatment. The primary endpoint was pathological complete remission (pCR). Secondary endpoints included clinical response rate, event-free survival (EFS), and overall survival (OS).ResultsA cohort of 96 patients consisted of 45 in TC and 51 in TAC arm. With a median follow-up period of 53 (range, 8–76) months, the patients achieving pCR post neoadjuvant chemotherapy exhibited superior EFS and OS than patients without pCR (P<0.05). TAC treatment resulted in consistently better EFS than TC treatment: the estimated 5-year EFS was 66.1% vs. 29.8% (P=0.002). Moreover, the estimated 5-year OS was also in favor of TAC: 88.4% vs. 51.6% (P<0.001). Multivariable analysis demonstrated that the treatment regimen was an independent prognostic factor, and patients treated with TAC had a superior EFS [hazard ratio (HR), 0.48; 95% confidence interval (95% CI), 0.26–0.90; P=0.021] and OS (HR, 0.20; 95% CI, 0.08–0.60; P=0.003). ConclusionsThe updated long-term follow-up data demonstrated a sustained benefit in EFS and OS from anthracycline-containing TAC treatment, indicating that anthracycline is an essential and effective drug in this clinical trial.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS.Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data.Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009).Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32).Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS.Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion.Table 1Results of E1900 based on an EFS endpoint versus an OS endpoint.SubgroupNOS HR (DNR 90/DNR 45) & 95% CIWald PEFS HR (DNR 90/DNR 45) & 95% CIWald PDNR 45DNR 90Age< 50 yrs ³ 50 yrs188 142172 1550.66 (0.50, 0.85) 0.81 (0.62, 1.06)0.002 0.1180.64 (0.50, 0.82) 0.86 (0.67, 1.10)0.0004 0.23CytogeneticFavorable Intermediate Unfavorable38 141 5951 127 630.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16)0.027 0.012 0.2250.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05)0.32 0.001 0.09SubgroupNOS HR (MUT/WT) & 95% CIWald PEFS HR (MUT/WT) & 95% CIWald PFLT3-ITDWT MUT456 1471.62 (1.31, 2.01) <.00011.48 (1.21, 1.82) 0.0002DNMT3AWT MUT371 1191.30 (1.03, 1.65) 0.031.23 (0.98, 1.54) 0.07IDH1WT MUT465 360.88 (0.59, 1.33)0.550.91 (0.62, 1.34)0.64IDH2WT MUT451 500.63 (0.43, 0.93)0.020.68 (0.48, 0.97)0.03NPM1DNR 45 DNR 90245 2570.84 (0.61, 1.16) 0.60 (0.41, 0.89)0.30 0.010.90 (0.66, 1.22) 0.59 (0.41, 0.84)0.49 0.004 DisclosuresNo relevant conflicts of interest to declare.

Follicular Lymphoma: To Treat or Not to Treat Is No Longer the Question

Follicular lymphoma arises from germinal center B cells and is the most common indolent non-Hodgkin lymphoma (1). It has a widely variable clinical course but nearly always presents as advanced disease with asymptomatic lymphadenopathy and has a long median overall survival of 8-10 years or more (2). Treatment before the onset of symptoms or organ dysfunction related to disease progression has not been proven to improve disease-specific survival or overall survival (OS), although early treatment may result in higher complete response rates and may prevent prognos- tically significant histological progression (3,4). However, the introduction of rituximab as a therapy for this disease has changed the landscape of this debate (5). When treatment is indicated, a variety of combination chemotherapeutic regimens have proven efficacy, and although some result in improvements in progression- free (PFS) and event-free survival (EFS), none are superior with respect to OS. The addition of rituximab to these regimens, how- ever, has resulted in a statistically significant improvement in OS in this disease (6-9). Response rates to chemoimmunotherapy are high, but this disease remains, for the most part, incurable and will, with rare exception, relapse. Further attempts to improve PFS and OS have included maintenance therapy with rituximab or con- solidation high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) (10-15). In this issue of the Journal, Al Khabori et al. (16) report the results of a meta-analysis exploring the efficacy and toxicity of HDC-ASCT compared with conventional-dose chemotherapy or chemoimmunotherapy in patients with untreated, advanced-stage follicular lymphoma. Four studies, including 941 patients with a median follow-up of 5-9 years, were identified that met the eligibility criteria; and data regarding OS, EFS, treatment-related mortality, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and secondary malignancies were abstracted (12-15). Only one of these studies included rituximab in both arms (15). There was no difference in OS between HDC-ASCT and con- ventionally treated patients, but EFS was statistically significantly improved following HDC-ASCT compared with conventional treatment. Treatment-related mortality and the rates of sec- ondary solid tumor malignancies were not different between the two arms. The rate of MDS/AML was somewhat higher following HDC-ASCT, although the difference was not statisti- cally significant. In these prospective randomized controlled trials, the 4- to 7-year EFS and OS ranged from 38% to 61% and 76% to 84%, respectively, and were similar whether or not rituximab was part of the therapy in each arm. An EFS benefit despite the absence of an improvement in OS is not insignificant in a disease with a long clinical course, as time off therapy may have an important impact on personal productivity and quality of life. However, the lack of OS benefit seen following HDC-ASCT in untreated patients has often been attributed, in part, to an increased rate of sec- ondary MDS/AML and solid tumors, which have been reported to be as high as 16%-21% at 10 years following total body irradiation-containing regimens (17,18). The lower rate of both secondary MDS/AML (4%) and solid tumors (5%) following HDC-ASCT observed in this meta-analysis may be a reflection of conditioning regimens, as two of the four studies did not include total body irradiation, or it may reflect abbreviated follow-up. An investigation into the efficacy of HDC-ASCT in untreated follicular lymphoma is timely in light of the recent data showing the efficacy of maintenance rituximab in the ECOG1496 and PRIMA trials (10,11). The results of the studies included in this meta-analysis are similar to the 3-year PFS of 68%-75% seen in these two trials of maintenance rituximab. Given the risk of sec- ondary MDS/AML and solid tumors following HDC-ASCT and

Fractionated Doses of Gemtuzumab Ozogamicin (GO) Combined to Standard Chemotherapy (CT) Improve Event-Free and Overall Survival in Newly-Diagnosed De Novo AML Patients Aged 50–70 Years Old: A Prospective Randomized Phase 3 Trial From the Acute Leukemia French Association (ALFA)

Abstract 6 Aim.GO is a potent antibody-directed chemotherapy against CD33 antigen. Two MRC and SWOG Phase 3 studies have compared standard CT alone or combined with one single GO infusion (at 3 and 6 mg/m2, respectively) in younger adults with AML with contradictory results (Burnett, JCO 2011; Petersdof, Blood 2009). We have shown in relapsed AML Phase 2 studies that fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 was effective and might be safely combined to standard 3+7 DNR/AraC induction (Taksin, Leukemia 2007; Farhat, AJH, accepted). Here, we report the results of the prospective open label randomized multicentric Phase 3 ALFA 0701 trial (ClinicalTrial.gov ID, NCT00927498) designed to evaluate the efficacy and safety of adding this fractionated GO schedule to standard front-line chemotherapy in older AML pts. Methods.Eligible patients (pts) were adults aged 50–70 years old with previously untreated de novo AML. Pts were randomized to receive induction with DNR 60 mg/m2/d on day 1–3 and AraC 200 mg/m2/d CI on day 1–7, without (DA arm) or with GO at 3 mg/m2/d on day 1, 4 and 7(DAGO arm). Pts with persistent marrow blasts at day 15 received additional DNR 35 mg/m2/d on day 1–2 and AraC 1g/m2/12h on day 1–3. Pts achieving CR/CRp received two consolidation courses with DNR 60 mg/m2/d on day 1 and AraC 1 g/m2/12h on day 1–4, ± GO at 3 mg/m2/d on day 1 according to the randomization arm. The primary study objective was event-free survival (EFS). The study was designed to detect a 25% to 40% EFS gain at 3 years, (two-sided test, power 80%, type I error 5%). Secondary objectives were response rate, disease-free survival (DFS), overall survival (OS), and safety. Results.From March 2008 to November 2010, the required sample of 280 pts (median age, 62 years) was enrolled. Nine pts did not satisfy for inclusion criteria and were excluded from analysis. Cytogenetics was favorable (N=9), intermediate (N=177), adverse (N= 57), not done/failure (N=28). Overall, 52 pts had a favorable NPM1+ w/o FLT3-ITD genotype. The two treatment arms were well matched for all pre-treatment characteristics including age, sex, ECOG-PS, WBC, cytogenetics and molecular characteristics. CR+CRp was achieved in 220/271 pts (77%): 100/134 (75%) in the control DA arm versus 110/137 (80%) in the DAGO arm (P=0.31). There were 5/134 (4%) induction deaths in DA arm and 9/137 (6%) in DAGO arm (P=0.41). Primary resistant AML rate was 29/134 (22%) after DA versus 18/137 (13%) after DAGO (P=0.08). At 2 years, EFS was estimated at 15.6% in DA arm versus 41.4% in the DAGO arm (P=0.0018), while DFS was 18.1% in DA arm and 48.5% in the DAGO arm (P=0.0009). This significant benefit in EFS (primary objective) was observed in pts aged <65 years (P=0.035) as well as in older pts (P=0.019), and persisted after censoring the 39 pts who received allogeneic stem cell transplantation in first CR/CRp at transplant time (P=0.015). Subgroup analysis showed that EFS benefit persisted in pts with favorable/intermediate karyotype (P=0.0008) while not in those with adverse karyotype (P=0.25). Interestingly, EFS benefit was still observed when excluding favorable pts (favorable karyotype or genotype) from the comparison (P=0.0017). Finally, in the whole patient population, this gain in EFS translated into a longer OS (median, 25.4 versus 15.3 months in DAGO versus DA pts; P=0.037). Besides treatment arm, cytogenetics and favorable genotype were the only factors predictive of outcome. After adjustment on these factors, DAGO treatment remained significantly associated with longer EFS (P=0.009), DFS (P=0.003), but not OS (P=0.14). The rate of fatal adverse events at least possibly attributable to treatment was 9/134 (6.7%) in the DA and 12/137 (8.7%) in the DAGO arm (P=0.65). Prolonged grade ≥ 3 thrombocytopenia was observed in 19 DAGO pts, either after induction (N= 4) or first consolidation (N=15). Three liver VOD were observed in the DAGO arm (2 during induction, 1 during first consolidation), 2 being associated with a fatal issue. No difference was observed between both arms in the incidence of severe sepsis (DAGO 18.9%, DA 14%), as well as in the rate of intensive care unit admission during the course of therapy (DAGO 14.5%, DA 12.6%). Conclusion.The addition of fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) to standard CT significantly improves EFS and to a less degree OS in AML pts aged 50–70 years old. The main toxicity observed with GO was prolonged thrombocytopenia in 19 patients and 3 episodes of VOD. Disclosures:Castaigne:Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Gemtuzumab Ozogamicin is available in Europe as a compassionate treatment for relapsed AML. In this study patients GO was used in front-line treatment.

Clinical Significance of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) Achieved with Different Treatment Modalities Used As Frontline Therapy In Chronic Myeloid Leukemia (CML) Chronic Phase (CP)

Abstract 745▪FN2▪This icon denotes a clinically relevant abstract Background:Recent studies have shown that treatment of CML-CP with second generation tyrosine kinase inhibitors (2G-TKI) dasatinib and nilotinib result in a higher rate of CCyR and MMR and these responses are achieved earlier. Whether the same level of response at a given time-point achieved with different treatment modalities has the same implications for long-term outcome is unclear. Aim: To determine whether the early achievement of CCyR or MMR with different treatment modalities has similar long-term prognostic implications among patients with CML CP. Methods: The outcome of 485 patients treated in consecutive or parallel clinical trials of TKI’s as initial therapy for CML-CP were analyzed. Patients were treated with imatinib 400mg (IM400) (n=73), imatinib 800mg (IM800) (n=208), nilotinib (n=105), and dasatinib (n=99). Patients were followed uniformly with cytogenetics and PCR every 3 months for the first 12 months, then every 6 months. We reviewed the rates of CCyR and MMR at early time points, and analyzed the probability of long-term event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) according to the achievement of early responses. We then compared whether such outcome was similar for patients who achieved such response with different treatment modalities. For EFS an event was defined to include any of the following: loss of CCyR, in addition to standard IRIS definition of loss of complete hematologic remission (CHR), loss of major cytogenetic remission (MCyR), progression to accelerated phase (AC) or blast crisis (BC), or death due to any cause on treatment. Results: CCyR at any time was achieved by 94% of patients treated with nilotinib, 96% of those on dasatinib, 87% with IM400 and 91% with IM800. Rates of MMR (as defined by BCR-ABL/ABL ≤0.1% IS) of patients receiving nilotinib was 88%, dasatinib 86%, IM800 87% and IM400 73%. At six months, the rates of CCyR were 91%, 94%, 85%, 53% respectively. Corresponding rates at 12 months were 95%, 96%, 90% and 66%. The rate of MMR at 12 months was 86%, 74%, 81%, and 55%, respectively, and at 18 months 88%, 80%, 83%, and 67%. For patients taking nilotinib 9% had lost CCyR at 36mo, with dasatinib 6%, IM800 5%, and IM 400 13%. The median time to achieve MMR was 6 months for patients treated with nilotinib and dasatanib, compared to 6 months with IM800 and 9 months with IM400. For the total population, those achieving a CCyR at 6 months had a better EFS rate at 24 months (97%) compared to those not achieving this response (79%). Similarly, CCyR at 12 months correlated with a similar benefit in EFS (98% vs 72%). Achievement of CCyR and MMR at 18 months resulted in a 24 month probability of EFS of 98% compared to 87% for those with CCyR but no MMR and 71% for those with no CCyR. We then compared the results by treatment arm. Results are shown in Table 1. At two-year landmark, early achievement of CCyR by 6-mo was associated with higher EFS (but not OS) with all treatment modalities. Achieving MMR by 18 mo was a positive predictor of 24-mo EFS with IM and Dasatinib, but pts with Nilotinib so far had an excellent outcome regardless of 18-mo response. Conclusions: Time to achieving CCyR and MMR with frontline TKI’s in CML-CP, reflects similar prognostic implications regardless of the modality of frontline therapy used to achieve it. However, earlier achievement of CCyR with nilotinib or dasatinib results in a higher percentage of patients obtaining the long-term benefit associated with early responses. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Metaphase cytogenetic abnormalities (M-CA) in multiple myeloma (MM): Examining number of M-CA for survival in total therapy protocols (TT1, TT2, TT3).

8123 Background: Even in the era of gene expression profiling (GEP) providing superior risk discrimination, M-CA remains an independent adverse feature for overall survival (OS) and event-free survival (EFS). Here we examined whether the percentage of such M-CA (%M-CA) had additional prognostic implications. Methods: Among 1,324 patients enrolled in TT protocols, 441 (33%) had M-CA. The %M-CA was determined from the ratio of MM-typical M-CA and total metaphase count, typically 20. Analysis was done of OS and EFS, per protocol, according to tertiles of M-CA and in relationship to absence of M-CA. Results: We are confirming the superior outcome of absence of M-CA (OS; p<0.0001; EFS: p=0.02). Among those with M-CA, the 147 patients with low-tertile M-CA<15% fared better than the remainder with mid-tertile M-CA15%-<35% and top-tertile M-CA>35% (OS, EFS; both p<0.001). In TT1, only no M-CA stood out as being associated with superior OS and EFS (both p=0.003). For the control arm of TT2, there was a graded shortening of both outcomes with progressive M-CA% whereas, for TT2 plus thalidomide, only the top-tertile M-CA group had inferior OS/EFS (both p<0.001). With TT3, although overall further improved versus TT2+thalidomide, the major difference was between low- and mid-tertile groups (both p<0.0001). Considering all 1,324 patients including those without M-CA, M-CA>15% was the only surviving CA category affecting both OS and EFS adversely (p<0.001), also in the presence of GEP-defined high-risk available in 767 subjects, whereas TT2 and TT3 trials imparted significant OS and EFS benefit in comparison with TT1. Conclusions: While validating any M-CA as an adverse prognostic feature, only the high-tertile M-CA group survived the multivariate model, even in the presence of GEP-risk. Thus, %M-CA should be considered in prognostic models for MM. No significant financial relationships to disclose.

Recombinant interferon-α2b added to oral cyclophosphamide either as induction or maintenance in treatment-naive follicular lymphoma: final analysis of CALGB 8691

Recombinant interferon alpha-2b (IFN-α2) has direct and indirect antiproliferative effects in lymphoma, and may augment cytotoxicity when combined with chemotherapy. CALGB 8691 is a randomized study of daily oral cyclophosphamide (CPA) at 100 mg/m2 with or without IFN-α2 at 2 × 106 IU/m2 three times per week, followed by a second randomization between IFN-α2 maintenance (2 × 106 IU/m2 three times weekly) versus observation in treatment-naïve patients with follicular lymphoma (FL). Five hundred eighty-one patients were randomized to either CPA (n = 293) or CPA plus IFN-α2 (n = 288). One hundred five responding patients were randomized to observation and 99 to maintenance IFN-α2. With a median follow-up of 11.5 years, the median event-free and overall survival (OS) for CPA induction alone were 2.5 years (95% CI 2.2, 3.0) and 9 years (95% CI 7.7, 10.2), compared to 2.4 years (95% CI 2.1, 3.1) and 8.4 years (95% CI 7.5, 11.1) for the combination arm (p = NS). Patients with a partial response (PR) and randomized to observation had the worst outcome (event-free survival (EFS) 1.8 years versus 3.9 years; p = 0.002). Patients with a PR randomized to IFN-α2 had a similar EFS to compared to patients with complete response (CR), but this did not translate into a survival advantage. Myelosuppression was increased in IFN-α2-containing arms. Despite the small benefit in EFS in patients with PR randomized to IFN-α2 maintenance, we conclude that the addition of low dose IFN-α2 did not significantly improve the response rate, duration of response, event-free, or OS obtained with single-agent daily oral CPA in patients with previously untreated FL.

Early Stage Diffuse Large B Cell Lymphoma (DLBCL) in the CHOP-R Era: Does Involved Field Radiation Therapy (IFRT) Impact Outcome?.

Historically, patients (pts) with early stage DLBCL treated without consolidative IFRT more commonly relapsed in sites of initial disease. While event-free survival (EFS) was superior with IFRT after CHOP in the short-term in a large randomized trial (NEJM 339:21), prolonged follow-up demonstrated equivalent overall survival due in part to late relapses (Blood 98:724a). The optimal therapy for pts with early stage DLBCL in the rituximab-CHOP (R-CHOP) era has not been established. To determine the impact of IFRT after R-CHOP treatment on outcome of early stage DLBCL, we reviewed medical records of 67 consecutive pts with stage I and II DLBCL who were primarily treated with R-CHOP with or without IFRT between February 2001 and March 2006. Three to 8 cycles of R-CHOP were administered, and 30–45 Gy IFRT was administered for those irradiated. The Kaplan-Meier method was used for the estimates of outcome. EFS was measured from the date of diagnosis until first documented disease progression or death from any cause. Comparisons were adjusted for IPI by Cox proportional hazards regressions, and all tests were two sided. Median follow-up was 2.6 years (range 0.5–5.5). 45 (67%) of the pts were men. Median age at diagnosis was 60 years (range 20–92); 18 (27%) had ‘B' symptoms; bulky disease (defined as mass >10cm) was present in 15 (22%); 27 (40%) had stage I and 40 (60%) had stage II disease. Stage-adjusted IPI score distribution was: IPI 0, n=6 (9%); IPI 1, n=17 (25%); IPI 2, n=24 (36%); IPI 3, n=16 (24%); IPI 4, n=4 (6%). 39 (58%) pts had extranodal disease (23% soft tissue, 21% head & neck, 56% others). As expected, since the majority of pts had more than 1 IPI risk factor, the 2-year event-free survival (EFS) was 68% (median EFS not reached). 11 (16%) pts had primary refractory disease including 3 pts who died during treatment, and they were excluded from further analysis. Of the remaining pts, 34 (61%) received IFRT, and 22 were treated with R-CHOP alone. The IPI scores of the 2 groups were balanced, but as expected, stage II disease was more common in pts who received R-CHOP alone. The EFS at 2 years for pts treated with consolidative IFRT was 87%, and with chemotherapy alone was 72%. When controlling for IPI score and the presence of bulky disease, there was a significant benefit in EFS for patients treated with R-CHOP + IFRT compared with R-CHOP alone (p=0.027). Therefore, in pts with early stage DLBCL treated with R-CHOP, we find improved outcomes with a combined modality approach including consolidative IFRT compared with chemotherapy alone as was observed in the CHOP era. Our study has inherent biases due to its retrospective nature, and limited follow-up. However, to our knowledge, this is the first study that compare R-CHOP with and without IFRT in early stage DLBCL, and therefore has important implications on future clinical trial designs.