Gordon, Leo I.

Abstract Twenty-eight patients with relapsed or refractory CD20+ NHL have been enrolled in an ongoing phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose is patient-specific based on dosimetry. 90YZ doses are calculated to deliver cohort-defined radiation doses (100, 300, 500, ... cGy) to critical organs (liver, lung or kidney), with 3–6 patients per group. On D -22, rituximab (R) 250 mg/m2 is infused followed by the imaging dose of 111In Zevalin® (5 mCi). Imaging is performed immediately post-injection and at 4, 24, 72, and 144 hours; dosimetry is performed on D -15. On D -14, R 250 mg/m2 is administered followed immediately by 90YZ at the dose calculated to deliver the cohort-prescribed absorbed radiation dose to the critical organ. On D -6 through -1, patients receive high-dose BEAM. On D0, a minimum of 2.0 X 106 CD34+ cells/kg is infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–72) years. NHL histologic subtypes were as follows: mantle cell 5, diffuse aggressive 13, low grade 5, and transformed 5. Most had received 3 or more treatment regimens, including R. The toxicity profile was similar to that associated with high-dose BEAM and included a decrease in DLCO for most patients with one patient at the 500 cGy dose level experiencing a transient decline to below 50% of the predicted value corrected for hemoglobin. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea, hemorrhage, and edema. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Engraftment occurred at a median of 10 days (range:8–18) to granulocytes ≥ 500/μL, and 21 days (range:13–40days) to platelets ≥20,000/μL . With a median follow-up of one year, the 3 year overall and progression-free survivals are 60% and 50%, respectively. Figure Figure 90-Y Zevalin Dosing by Cohort (median; range) Cohort (cGy) Total Dose (mCi) mCi/kg 100 (n=3) 5 (2–14) .06(.05–.12) 300 (n=7) 22(14–57) .25(.18–.63) 500 (n=6) 31(16–48) .40(.14–.63) 700 (n=6) 37(26–55) .38(.27–.73) 900 (n=3) 28(27–37) .32(.27–.44) 1100 (n=3) 48(29–65) .57(.50–.75) The liver was the critical organ in nearly all cases. Patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable suggesting that dosing based on weight and not dosimetry is likely to result in a wide range of absorbed dose to critical organs. In the context of this study, 90YZ has been administered to eight patients at doses of .5 mCi/kg or greater. We conclude that with careful dosimetry, 90YZ doses higher than the conventional .4 mCi/kg may be safely combined with BEAM and autotransplant. Accrual continues at the 1300 cGy dose level.

Abstract Background: As the first radiolabled monoclonal antibody approved for the treatment for the treatment of cancer, yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) achieves both high response rates and durable remissions in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. Because of the stability of 90Y ibritumomab tiuxetan and its favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation), dosing is based on patient weight and platelet counts. Yttrium 90 ibritumomab tiuxetan is typically delivered at a dose of 0.4 mCi/kg (in patients with platelets >150,000/mm3) or 0.3 mCi/kg (in patients with platelets ≤150,000/mm3) to a maximum recommended dose (MRD) of 32 mCi. However, patients >80 kg with platelet counts exceeding 150,000/mm3 may receive a lower drug concentration (ie, <0.4 mCi/kg 90Y) as a result of dose capping. We evaluated whether the 32 mCi dose cap influences the safety or efficacy of ibritumomab tiuxetan therapy in patients >80 kg. Methods: Efficacy and safety data were collected for patients from 3 registrational trials that received either 0.4 mCi/kg 90Y (patients ≤80 kg) or 32 mCi 90Y (patients >80 kg). Results: Clinical responses in 170 patients were evaluated. Patients ≤80 kg (n = 103) had a median weight of 70 kg (range, 45–80 kg) versus a median weight of 95 kg (range, 81–159) for patients >80 kg (n = 67). Gender (41% M vs 73% M, respectively; P <.01) was the only significantly different baseline characteristic between the ≤80 kg and >80 kg groups. Similar efficacy and safety results were reported for both subsets of patients. Overall response rates of 79% and 70% were observed for patients ≤80 kg and >80 kg, respectively (P =.27); and no significant differences were seen in complete response rates (28% vs 34%, respectively; P =.40). Median TTP (8.9 months vs 9.5 months; P =.53) and median DR (8.5 months vs 11.5 months; P =.34) were equivalent between the 2 weight-based groups. In addition, there were no statistically significant differences in safety measures including grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia. Conclusions: As a consequence of dose capping at an MRD of 32 mCi, 39% of patients received a lower dose/kg of 90Y ibritumomab tiuxetan. However, despite the difference in dose administered on a unit of body weight basis, the efficacy and safety results were similar between patients ≤80 kg and >80 kg. We conclude that the 32 mCi dose cap does not influence the efficacy or safety profile of 90Y ibritumomab tiuxetan for patients >80 kg.

AbstractAggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P‐MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi‐institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P‐MCL, using next generation sequencing and SNP‐array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C‐MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P‐MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C‐MCL showed monoallelic CDKN2A/B loss. In B/P‐MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P‐MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P‐MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.

8004 Background: To determine optimal induction and the role of maintenance, the E1496 study randomized patients (pts) to induction CVP (cyclophosphamide, vincristine, prednisone) versus CF (cyclophosphamide 1 G/m2 d1, fludarabine 20 mg/m2 d1–5 every 28 d) for 2 cycles beyond best response (maximum 8). Responding and stable pts were secondarily randomized to MR (375 mg/m2 weekly × 4 every 6 months for 2 years [yr]) or observation (OBS). Methods: Due to early deaths the CF arm was closed to accrual with 115 pts randomized to CF and 119 pts to CVP (thereafter all pts were assigned to CVP prior to maintenance randomization). The results presented here compare the outcome of CF patients with the subset of E1496 pts randomized to CVP (CVPR). Results: Median follow-up on pts randomized to induction is 6.5 yr. Toxic deaths occurred in 8 (7%) CF pts during induction and 4 additional deaths (1 OBS, 3 MR) occurred among the 69 (6%) CF pts randomized to MR or OBS. Causes of death were infection (9), liver failure (2), CNS gliosis (1). CF pts received a median of 5 cycles compared to 7 cycles for CVPR. The CR rate was 51% vs 22% (p=0.00001) and the PR rate was 35% vs 55% for CF vs. CVPR, respectively. Four-yr PFS for CF vs. CVPR was 49% vs 45% (p=0.19) and OS was 66% vs. 81% (p=0.12), respectively. Of 45 CF deaths, 23 (51%) occurred without lymphoma progression compared to 5 (13%) of 38 CVPR deaths (p=0.0004). More than 90% of CF patients randomized to maintenance achieved protocol-defined minimal residual disease compared with 64% CVPR pts. Maintenance therapy had no impact on 2 yr PFS for the 67 evaluable randomized CF pts, which was 74% for MR vs. 73% for OBS (p=0.19). In contrast, 2 yr PFS was 73% for MR and 42% for OBS in randomized CVPR pts (p=0.004). Survival at 2 yr for MR vs OBS was: CF 79% vs 91% (p=0.19) compared with CVP 98% vs 93% (p=0.21). Conclusions: Induction with CF results in higher CR and miminal residual disease rates than CVP. However, gains in remission quality with CF (in the dose and schedule used here) were offset by early and late deaths in the absence of progressive lymphoma. In E1496, the benefit of MR was influenced by the induction chemotherapy. [Table: see text]

Abstract Introduction 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). Patients and Methods 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. Results 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. Conclusion 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. Disclosures: Horning: Genentech: Employment.

Abstract Abstract 94 Background: Lymphoma diagnosed during pregnancy is a rare occurrence. Further, there is heterogeneity in clinical presentation and a range of lymphoma histologies resulting in a continued deficiency of lymphoma-specific data in the literature regarding prognosis, optimal therapy, maternal complications, and fetal outcome. Methods: A comprehensive retrospective analysis was completed for patients (pts) diagnosed (dx) with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy at 9 large U.S. academic centers over a 13-year period (1998–2011). The vast majority of cases were co-managed with high-risk maternal fetal medicine. Data on maternal disease characteristics, treatment details, obstetric complications, and fetal outcomes were analyzed. Results: 88 cases were identified with complete data available in 82. The median age of pts was 31 yrs (18–40). Lymphoma dx occurred at a median of 24 weeks (wks) gestation (5–40). 15% of pts were dx during the 1st trimester, 46% during the 2nd trimester, 35% during the 3rd trimester, while 4% (n=3) of pts had a pre-existing NHL dx (follicular lymphoma (FL)). 52% (n=43) of pts had NHL and 48% (n=39) HL. Of NHL cases, 83% (n=33) were B-cell and 17% (n=10) T-cell. B-cell histologies were DLBCL n=23 (including 2 primary CNS and 1 'double hit' NHL), FL n=5 (including 1 leukemic phase FL), Burkitt's lymphoma n=3, and mixed histology n=1; T-cell histologies were anaplastic large cell n=6, PTCL not otherwise specified n=2, and T-cell/NK NHL n=2. Pts with B-cell NHL and HL were dx at a median age of 29 yrs (range, 18–40), while T-cell NHL pts were dx at a median of 34 years (19–37). MRI without gadolinium was the most common imaging modality utilized for staging. 63% of NHL and 19% of HL pts had stage III/IV disease (25% of HL with stage IIB). Pregnancy was terminated in 6 pts (n=4 aggressive NHL and n=2 HD) to enable immediate chemotherapy (five in the 1st trimester [at 5, 8, 10, 10, and 12 wks] and 1 pt in the early 2nd trimester who required high-dose methotrexate). 48 pts (63%) initiated anti-lymphoma therapy at a median of 25 wks gestation (range, 13–37) with 79% of pts initiating therapy in the 2nd trimester (see Table 1). The median gestation at time of lymphoma dx for pts who received intra-partum treatment was 20 wks vs 34 wks for pts who had therapy deferred to post-delivery (p<0.0001). The overall response rate among pts who received therapy was 87% (74% complete remission). Notably, gestation went to full-term in 54% with delivery occurring at a median of 37 wks (31–40). Therapy was deferred until post-delivery in 28 pts (37%) and the majority of these pregnancies were also carried to term (median delivery at 38 wks). At a median follow-up of 41 months (6–157), the 3-year PFS and OS for all pts were 79% and 89% respectively. Histology-specific 3-year PFS and OS were: B-cell NHL: 73% and 82%, respectively; T-cell NHL: 50% and 90%, respectively; and HL: 90% and 95%, respectively (Figure 1). Detailed obstetrical information was available in 59 pts. There were minimal pre-term complications, the most common being induction of labor in 45%. Perinatal events included spontaneous rupture of membranes in 5% and pre-eclampsia in 8%. Further, there were no differences in these events detected among pts who received intra-partum treatment vs deferred therapy. No episodes of chorioamnionitis or endometritis were noted. There was 1 stillbirth that occurred at 19 wks gestation in a 34-year-old pt with double-hit NHL following 1 cycle of R-CHOP. The median birth weight of infants was 2427 grams (1005–5262) with no difference among pts who received intra-partum chemotherapy vs not (2637 grams vs 2212 grams, respectively; p=NS). Microcephaly was reported in 1 case following 4 intra-partum cycles of CHOP for DLBCL; there were otherwise no malformations detected. Conclusions: To our knowledge, this represents one of the largest experiences reported of lymphoma in pregnancy. Our data show that standard NHL and HL chemotherapeutic regimens (without anti-metabolites) administered during the 2nd and 3rd trimester, including as early as 13 wks gestation in select cases, is associated with minimal maternal complications or fetal detriment. In addition, pts with low risk clinical scenarios (e.g., indolent NHL and/or late gestational dx) had therapy safely deferred to post-partum. In our experience, this approach was associated with overall expected lymphoma-related survival. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized. Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients. Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates. Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

Abstract Abstract 1603 Background: We have previously reported similar outcomes for patients with bulky stage I or II mediastinal HL treated with combined modality therapy either with ABVD + radiotherapy or the Stanford V regimen in the North American Intergroup trial E2496 (Advani et al, ASH 2010 abstract 416). In the current analysis, we compare the patterns of failure between the two groups. Methods: Patients with stage I/II bulky mediastinal HL (maximum mediastinal mass width > 1/3 of intrathoracic diameter) were randomized to receive chemotherapy (CT) on either Arm A (ABVD x 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V administered weekly). Two-3 weeks after completion of chemotherapy all patients received modified involved field radiotherapy (RT) (36 Gy) delivered to the mediastinum, hila, and supraclavicular regions. Patients on Stanford V arm also received involved field RT to any other sites ≥ 5 cm at diagnosis. Patients were assessed 3, 6 and 12 months after completing RT with computed tomography scanning and then every 6 months for 5 years. The primary end points were failure free survival (FFS) and overall survival (OS). Disease progression was defined as 'in-field', 'distant' or both relative to the radiation fields prescribed in the E2496 protocol. Distant sites of failure were further characterized as intra-thoracic, intra-abdominal or other (bone, bone marrow and axillae, if not previously irradiated). Results: Two hundred and sixty-seven patients were randomized: 136 on the ABVD arm and 131 on the Stanford V arm. Patient characteristics were well matched with no differences between two arms in overall response rates (ORR), FFS and OS. (Advani et al ASH 2010 abstract 416). At a median follow up of 5.5 years 40 patients have relapsed with no difference in ABVD (n=18, 13%) versus Stanford V (n=22, 17%) (p=0.49). Central review of RT fields available in 37/40 patients found major violations with under treatment of tumor noted in 7/37 (19%). Patterns of failure are shown in Table 1. There were no differences in patterns of relapse for the two study arms. In-field relapses occurred in <10% in both study arms. Conclusion: For patients with stage I/II bulky mediastinal HL, combined modality therapy with either ABVD +RT or the Stanford V regimen results in excellent disease control. In-field relapse was uncommon. These results set a benchmark for assessing ongoing trials omitting RT in patients with stage I/II bulky mediastinal HL. Future research efforts should focus on risk stratification to identify the small subset of patients who are likely to fail standard upfront therapy. US cooperative group efforts in this subset of patients are ongoing that use interim PET-CT imaging based risk-adapted strategies. Disclosures: Horning: Genentech: Employment, Equity Ownership.

Motexafin gadolinium (MGd, Xcytrin®) is a novel anti-cancer drug that selectively concentrates in cancer cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd has been shown to generate reactive oxygen species and induce apoptosis in tumor cells. We initiated a study to evaluate the safety and efficacy of MGd in two B-cell malignancies, relapsed/refractory LG and relapsed/refractory CLL or CLL/small lymphocytic lymphoma (CLL/SLL). MGd was given intravenously (IV) at 6mg/kg/day for 3 days q 2 weeks for LG and 5mg/kg/day for 10 days q 3 weeks for CLL/SLL. Ten patients (pts) with LG (2 grade 1, 5 grade 2, 1 grade 3 follicular, 2 marginal zone), 2 pts with CLL/SLL and 1 pt with CLL have been enrolled. Median age was 64.5 yrs (range 44–77), median prior treatment regimens was 3.5 (range 1–6) and median time from diagnosis to treatment was 52 mo. Many LG pts had failed prior aggressive treatment regimens including: CHOP (4), ICE (1), HyperCVAD(1), auto-bone marrow transplant (1); all failed rituxamab and 6 failed Zevalin. CLL/SLL and CLL pts had failed rituxamab (3), fludarabine (2), and R-CHOP (1). MGd related adverse events included skin and urine discoloration (6 and 4 pts), diarrhea, nausea, vesiculobullous rash, peripheral neuropathy (3 pts each). MGd related ≥gr 3 adverse events included skin rash (3 pts), fatigue, neuropathy, photosensitivity (1 pt each). Importantly, no MGd-related myelosuppression was observed. In 12 evaluable pts, there have been three PRs of 2+, 5+ and 8 months duration (2 follicular, 1 CLL). Two pts had SD (follicular, SLL) one of these had resolution of lymphoma related autoimmune hemolytic anemia. Responses occurred after ≤2 cycles of therapy and were seen in patients after extensive prior treatment (mean 4.3 prior regimens, range 3–7). MGd is a non-myelosuppressive drug with single agent activity in LG and CLL/SLL.

Abstract Abstract 415 Background: The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives: The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method: Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass > 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or >/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had <6 C) + 36 Gy (only in pts with BMD) or Stanford V × 12 weeks (95% had 12 weeks) + 36 Gy (for sites >5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results: 854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was <1% in both groups. There was, however, more Grade 3 lymphopenia in Stanford V (78% vs. 42%, p< 0.0001) and more Grade 3 +4 sensory neuropathy in Stanford V (10%) than in ABVD (3%) (p< 0.0001). A total of 26 second primary cancers developed, 12 after ABVD and 14 after Stanford V (p=NS). FFS and OS. For 812 eligible patients, with a median follow up of 5.25 years, 5-year FFS was 73% for ABVD and 71% for Stanford V (p=0.29 by log rank) (Figure left); 5-year OS was 88% for ABVD and 87% for Stanford V (p=0.87 by log-rank, HR=0.97, 95% CI: 0.65 to 1.44) (Figure right) indicating no significant difference in either FFS or OS between the 2 arms. Conclusion: In the largest Phase III intergroup trial of HL in North America, there was no significant difference in RR, FFS, OS, and 5-year toxicity when ABVD (+ RT for BMD) is compared with Stanford V (+RT for nodal sites >5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p< 0.0001) and more Grade 3 + 4 sensory neuropathy (p< 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. Disclosures: Friedberg: Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.