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Purpose: Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18 F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic., Methods: Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers NCT02257567, NCT02500407; 20% holdout in ClinicalTrials.gov identifier NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review., Results: The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses., Conclusion: These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.

Purpose: Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)-adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET-) disease and intensifying treatment in patients with PET-positive (PET+) disease., Methods: Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2-, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation., Results: Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2- and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2- and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2- was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04)., Conclusion: Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Purpose: Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL., Patients and Methods: Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS)., Results: Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell-like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1., Conclusion: In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL., Competing Interests: Grzegorz S. NowakowskiConsulting or Advisory Role: Celgene/BMS, MorphoSys, Genentech, Roche Selvita, Debiopharm Group, Kite/Gilead, Karyopharm TherapeuticsResearch Funding: Celgene/BMS, NanoString Technologies, MorphoSys Roche, Seattle Genetics Fangxin HongConsulting or Advisory Role: Merck Sharp & Dohme David W. ScottConsulting or Advisory Role: Celgene/BMS, Janssen, AbbVie, AstraZenecaResearch Funding: Janssen, Roche/Genentech, NanoString TechnologiesPatents, Royalties, Other Intellectual Property: Named inventor on a pending patent describing gene expression profiling in prognostication in classical Hodgkin lymphoma, As a member of the LLMPP I am potentially a named inventor on a pending patent on the use of gene expression profiling to assign cell-of-origin in diffuse large B-cell lymphoma, I am a named inventor on a pending patent on the use of gene expression profiling to determine the proliferation signature in mantle cell lymphoma, Named inventor on a pending patent describing using gene expression profiling to identify molecular subtypes of GCB-DLBCL Rebecca L. KingResearch Funding: Celgene/BMS Thomas M. HabermannConsulting or Advisory Role: Celgene/BMS, Kite/Gilead Nina Wagner-JohnstonConsulting or Advisory Role: ADC Therapeutics, Bayer, Regeneron, Calibr, Verastem, Gilead SciencesResearch Funding: Merck, Novartis/Pfizer, Genentech, Astex Pharmaceuticals, Juno Therapeutics, Regeneron, Acerta Pharma, ADC Therapeutics Carla CasuloHonoraria: Gilead SciencesResearch Funding: Celgene/BMS, Verastem, Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences, Roche James L. WadeEmployment: Johnson & JohnsonStock and Other Ownership Interests: Celgene/BMS, Abbott, GlaxoSmithKline, Johnson & Johnson, NovartisConsulting or Advisory Role: New Century Health Jonathon B. CohenConsulting or Advisory Role: Celgene/BMS, Seattle Genetics, Abbvie, Janssen, Loxo, Kite/Gilead, AstraZeneca, Cellectar, Aptitude MedicalResearch Funding: Bristol-Myers Squibb, Janssen, Novartis, Takeda, AI Therapeutics, Genentech, ASH, Lymphoma Research Foundation, Loxo, Bioinvent, AstraZeneca Nadia KhanHonoraria: JanssenConsulting or Advisory Role: IncyteResearch Funding: Bristol-Myers Squibb Jennifer E. AmengualHonoraria: Janssen, Daiichi Sankyo, Karyopharm TherapeuticsResearch Funding: Appia PharmaceuticalsTravel, Accommodations, Expenses: Epizyme John P. LeonardConsulting or Advisory Role: Celgene/BMS, Bristol-Myers Squibb, Gilead Sciences, Epizyme, Bayer, Genentech/Roche, ADC Therapeutics, MEI Pharma, AstraZeneca, Merck, Morphosys, Nordic Nanovector, Karyopharm Therapeutics, Sutter Medical Group, Miltenyi Biotec, Regeneron, Bayer, Akcea Therapeutics, Sandoz, Nordic Nanovector, Genmab, Abbvie, IncyteResearch Funding: Research Funding: Celgene/BMS, Alliance for Clinical Trials in Oncology, Takeda, Pfizer, National Cancer Institute, Janssen Oncology, EpizymeTravel, Accommodations, Expenses: BeiGene Jonathan W. FriedbergConsulting or Advisory Role: Astellas Pharma, NovartisResearch Funding: Seattle GeneticsPatents, Royalties, Other Intellectual Property: Patient on bone marrow microenvironment signals Lale KostakogluConsulting or Advisory Role: Roche/Genentech Brad S. KahlConsulting or Advisory Role: Celgene/BMS, Juno Therapeutics, Abbvie, Pharmacyclics, Acerta Pharma, ADC Therapeutics, Pharmacyclics, Genentech, Roche, AstraZeneca, BeiGene, Bayer, MEI Pharma, TG Therapeutics, Kite/Gilead, MorphoSys, JanssenResearch Funding: Genentech, Acerta Pharma, ADC Therapeutics, Celgene/BMSTravel, Accommodations, Expenses: Celgene/BMS, Juno Therapeutics, Genentech/Roche, Abbvie, Millennium, Seattle Genetics Thomas E. WitzigConsulting or Advisory Role: Karyopharm Therapeutics, Abbvie/Genentech, Seattle Genetics, Celgene/BMS, Incyte, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, MorphoSys, ADC TherapeuticsResearch Funding: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm TherapeuticsPatents, Royalties, Other Intellectual Property: T.E.W. is co-inventor on a patent application filed by Mayo Clinic and pending on the combination of CRM1 inhibitors with salicylates.No other potential conflicts of interest were reported.

Purpose: 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 [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials., Competing Interests: Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Purpose: Negative [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2)., Patients and Methods: All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years., Results: A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive., Conclusion: PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment., (© 2014 by American Society of Clinical Oncology.)

Purpose: Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response., Patients and Methods: Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues., Results: Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment., Conclusion: Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

Purpose: To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials., Methods: An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted., Recommendations: PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Purpose: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma., Patients and Methods: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab., Results: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT., Conclusion: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.

Purpose: To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of (177)Lutetium-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((177)Lu-J591) in patients with androgen-independent prostate cancer (PC)., Patients and Methods: Thirty-five patients with progressing androgen-independent PC received (177)Lu-J591. All patients underwent (177)Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments., Results: Thirty-five patients received (177)Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m(2), and the 70-mCi/m(2) dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m(2) was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m(2) could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing >or= 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months)., Conclusion: The MTD of (177)Lu-J591 is 70 mCi/m(2). Multiple doses of 30 mCi/m(2) are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.

Purpose: To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ((90)Y-J591) in patients with androgen-independent prostate cancer (PC)., Patients and Methods: Patients with androgen-independent PC and evidence of disease progression received indium-111-J591 for pharmacokinetic and biodistribution determinations followed 1 week later by (90)Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m(2). Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory., Results: Twenty-nine patients with androgen-independent PC received (90)Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m(2), with two patients experiencing thrombocytopenia with non-life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m(2) dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization., Conclusion: The recommended dose for (90)Y-J591 is 17.5 mCi/m(2). Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of (90)Y-J591 in the treatment of patients with PC.