Abstract: Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma. Patients and Methods The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7. Results Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm. Conclusion Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%.

Abstract: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response–adapted treatment guided by early interim positron emission tomography (PET) –computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely. Methods An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma. Results A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods. Conclusion This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [ 18 F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.

Abstract: SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133–tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.

Abstract: The 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.

Abstract: Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐ HCT ) is effective for younger patients with mantle cell lymphoma ( MCL ). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyper CVAD / MTX / ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) ( RH ) versus rituximab plus bendamustine ( RB ) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III , IV , or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB , followed by auto‐ HCT . Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival ( PFS ) was 81% vs. 82% and overall survival ( OS ) was 87% vs. 88% for RB and RH , respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL . RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL .

Abstract: 8001 Background: Advanced follicular lymphomas (FL) are considered incurable with chemotherapy and there is no consensus on the best treatment. Outcomes are variable, but can be partially predicted by defined prognostic factors. SWOG and CALGB compared the safety and efficacy of 2 immunochemotherapy regimens in a Phase III trial enrolling 554 patients between 3/1/2001 and 9/15/2008. Methods: Patients were eligible if they had bulky stage II, III or IV FL and had not received prior therapy. Patients randomized to CHOP-R received 6 cycles of CHOP every 21 days + 6 doses of rituximab. Patients randomized to CHOP-RIT received 6 cycles of CHOP, followed by consolidative radioimmunotherapy with tositumomab/iodine I-131 tositumomab. A Cox proportional hazards multi-variable regression analysis assessed the prognostic impact of age, stage, LDH, LN size and number, performance status, hemoglobin, β2 microglobulin, BM involvement, and B symptoms.  The prognostic value of 3 multi-variable models were compared. Results: Outcomes were outstanding with either CHOP-R or CHOP-RIT (2 yr PFS: 76% vs 80% [ p =0.11] ; 2 yr OS: 97% vs 93% [p =0.08], respectively).  Subset analyses so far have not identified any subgroups clearly benefitting to a greater degree from CHOP-R or CHOP-RIT in terms of both PFS and OS. Cox multivariable regression analysis identified serum-β2M, LDH level, and FLIPI index as the strongest prognostic factors associated with worse PFS and OS. Conclusions: Both regimens produced outstanding PFS and OS, and no statistically significant differences between them were observed.  FLIPI, FLIPI2, and LDH + β2M models were all strong predictors of patient outcomes.  A combination of LDH + β2M was as good as the FLIPI index, and was simpler to apply.  (Supported in part by NCI grants CA32102 and CA38926 from the NCI and GlaxoSmithKline.) [Table: see text]

Abstract: Introduction: Aggressive induction chemotherapy followed by autologous stem cell transplant (ASCT) is effective for younger patients with mantle cell lymphoma (MCL). Among patients undergoing ASCT, cytarabine-based induction regimen induced higher rates of MRD-negativity compared to R-CHOP (Hermine et al, ASH 2012), and achievement of MRD-negative status was predictive of good outcome. R-bendamustine (RB) has superior efficacy compared to R-CHOP (Rummel et al, Lancet 2013; Flinn et al, Blood 2014) but, there are no data regarding its impact on MRD. S1106 (SWOG) was conducted to compare R-HyperCVAD/MTX/ARAC (RH) or RB to identify the better induction regimen followed by ASCT. We report the result of MRD analysis and updated 2 year PFS/OS. Method: S1106 was a US intergroup (SWOG/ECOG/CALGB), randomized phase II trial. The primary objective was to estimate 2 year PFS, with secondary objectives to assess response rates, OS, toxicities, and MRD status. Inclusion criteria were: untreated stage III, IV or bulky stage II MCL, Cyclin D1 +, age 〉 18 〈 65, and adequate organ function. Randomization was stratified by MIPI. Patients received either 4 cycles of RH or 6 cycles of RB, followed by ASCT. MRD was assessed at baseline and post induction. Genomic tumor DNA was extracted from FFPE tissue or bone marrow aspirate mononuclear cells. PCR amplification of IGH-VDJ, IGH-DJ, and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s) (Adaptive Biotechnologies). DNA from peripheral blood mononuclear cells (PBMC) and plasma was amplified and sequenced to determine lymphoma molecules per million diploid genomes. Results: A total of 53 patients were accrued out of planned 160. This study was closed prematurely based on predetermined criteria of stem cell mobilization failures on the RH arm. Table 1 shows patient characteristics. The ORR was 94% in RH vs. 83% in RB. The CR rates were 35% (RH) and 40% (RB). Only 4/17 patients on RH and 21/35 patients in RB underwent ASCT; the rest could not complete study (Table 1). RH induced significantly more grade 3/4 heme toxicities as compared to RB (Table 1). The median follow up was 29 months in RH and 26 months in RB. The estimated 2 year PFS was 81% (Fig 1) and OS was 87% for both arms. 27 patients consented to the optional MRD assessment, with 12 paired serial samples (baseline and post induction). 10 were in RB and 2 were in RH. Both patients in RH were MRD positive at baseline and achieved MRD negative status. 1/10 patient in RB was MRD negative at baseline and remained negative throughout treatment. 8/9 patients in RB with baseline MRD-positivity converted to MRD-negative status by the end of induction, and 3/8 did not go to ASCT. Three additional patients were missing baseline samples but were MRD negative at the end of RB. Overall, the estimated 2 year PFS was 100% for all 13 patients who achieved MRD negative status at the end of RB. Conclusions: RH is not an ideal platform for future transplant trials in MCL due to stem cell mobilization failures. RB achieved a 2 year PFS of 81%, higher than the planned target of 75%. It also achieved an 89% MRD negative rate on all the paired samples tested. Low CR on RB could be due to lack of mandatory PET. All patients with MRD negative status remain in remission, with some not having undergone ASCT. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD. However, this analysis suggests that RB can achieve a deep remission and could be a platform for future trials in MCL. Table 1. RH (n=17) RB (n=35) Age 59 (44-66) 57 (33-64) Male (p=0.003) Female 9 8 32 3 Performance status 0 1 11 6 26 9 Disease Stage III IV 1 16 3 32 B sx Yes No 6 11 10 25 BM involvement Positive Negative 14 3 31 4 Extranodal involvement Yes No 15 2 32 3 KI 67 〈 10% 10-30% 〉 30% 20% 60% 20% 14% 66% 20% MIPI Score Intermediate/High Risk Low Risk 6 11 13 22 Grade 3/4 Hematological toxicities (Induction only) Anemia 56% Neutropenia 63% Febrile neutropenia 31% Thrombocytopenia 69% Anemia 8.6% Neutropenia 34% Febrile neutropenia 14% Thrombocytopenia 17% Reasons for early off treatment or not going to ASCT Failure to collect stem cell 5 Thrombocytopenia 4 Pancytopenia 1 Others 2 Patient choice 4 Progressive disease 2 Failure to collect stem cell 1 Allergy 1 Seizure 1 Insurance denial 1 Others 3 Figure 1. Figure 1. Disclosures Chen: genentech: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Millennium: Consultancy, Research Funding, Speakers Bureau. Forman:Mustang Therapeutics: Research Funding. Cashen:Celgene: Speakers Bureau. Blum:cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Fenske:Pharmacyclics: Honoraria; Millennium/Takeda: Research Funding; Seattle Genetics: Honoraria; Celgene: Honoraria. Cheson:Celgene: Consultancy, Research Funding; Spectrum: Consultancy; Astellas: Consultancy; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; MedImmune: Research Funding; Ascenta: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Teva: Research Funding. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Faham:adaptive biotech: Employment, Other: stockholders. Wilkins:adaptive biotech: Employment. Leonard:teva: Consultancy; genentech: Consultancy. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy.