International Harmonization Project Research Articles

Harmonica consensus, controversies, and future directions in radiotherapy for pediatric Wilms tumors.

Radiotherapy (RT) is essential for multimodality treatment of pediatric renal tumors, particularly in higher-risk and metastatic disease. Despite decades of use, particularly for Wilms tumor, there remain controversies regarding RT indications, timing, dose, and targets. To align global management, we address these issues in this international HARMONIsation and CollAboration (HARMONICA) project. There are multiple knowledge gaps and opportunities for future research including: (1) utilization of advanced RT technologies, including intensity-modulated RT, proton beam therapy, combined with image-guided RT to reduce target volumes; (2) impact of molecular biomarkers including loss of heterozygosity at 1p, 16q, and 1q gain on RT indications; (3) mitigation of reproductive toxicity following RT; (4) promotion of RT late effects research; and (5) support to overcome challenges in RT utilization in low- and middle-income countries where 90% of the world's children reside. Here, we outline current status and future directions for RT in pediatric renal tumors.

The value of FDG PET/CT imaging in outcome prediction and response assessment of lymphoma patients treated with immunotherapy: a meta-analysis and systematic review

PurposeTreatment strategies of lymphoid malignancies have been revolutionized by immunotherapy. Because of the inherent property of Hodgkin lymphoma and some subtypes of non-Hodgkin lymphoma as a highly FDG-avid tumor, functional 18F-FDG PET/CT imaging is already embedded in their routine care. Nevertheless, the question is whether it is still valuable in the context of these tumors being treated with immunotherapy. Herein, we will review the value of 18F-FDG PET/CT imaging lymphoid tumors treated with immunotherapy regimens.MethodsA comprehensive literature search of the PubMed database was conducted on the value of the 18F-FDG PET/CT for immunotherapy response monitoring of patients with malignant lymphoma. The articles were considered eligible if they met all of the following inclusion criteria: (a) clinical studies on patients with different types of malignant lymphoma, (b) treatment with anti-CD20 antibodies, immune checkpoint inhibitors or immune cell therapies, (c) and incorporated PET/CT with 18F-FDG as the PET tracer.ResultsFrom the initial 1488 papers identified, 91 were ultimately included in our study. In anti-CD20 therapy, the highest pooled hazard ratios (HRs) of baseline, early, and late response monitoring parameters for progression-free survival (PFS) belong to metabolic tumor volume (MTV) (3.19 (95%CI: 2.36–4.30)), maximum standardized uptake value (SUVmax) (3.25 (95%CI: 2.08–5.08)), and Deauville score (DS) (3.73 (95%CI: 2.50–5.56)), respectively. These measurements for overall survival (OS) were MTV (4.39 (95%CI: 2.71–7.08)), DS (3.23 (95%CI: 1.87–5.58)), and DS (3.64 (95%CI: 1.40–9.43)), respectively. Early and late 18F-FDG PET/CT response assessment in immune checkpoint inhibitors (ICI) and immune cell therapy might be an effective tool for prediction of clinical outcome.ConclusionFor anti-CD20 therapy of lymphoma, the MTV as a baseline 18F-FDG PET/CT-derived parameter has the highest HRs for PFS and OS. The DS as visual criteria in early and late response assessment has higher HRs for PFS and OS compared to the international harmonization project (IHP) visual criteria in anti-CD20 therapy. Early changes in 18F-FDG PET parameters may be predictive of response to ICIs and cell therapy in lymphoma patients.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study

Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. F Hoffmann-La Roche and Genentech.

Prognostic value of interim FDG PET-CT in patients older than 60 years with diffuse large B-cell lymphoma treated by PMitCEBO plus rituximab. Comparison between Deauville 5-point scale and International Harmonization Project criteria.

Advanced age is an independent poor prognostic factor of diffuse large B-cell lymphoma (DLBCL). PMitCEBO (mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone) is an alternative to the cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen to decrease side effects in elderly patients. Many studies have shown prognostic value of an interim FDG PET-CT to predict survival. A recent consensus (ICML, Lugano 2013) has suggested using the 5-point scale Deauville criteria instead of those of the International Harmonization Project (IHP) to visually assess the response on interim PET. The objective of this study was to evaluate the prognostic value of an interim FDG PET-CT in patients older than 60 with treated DLBCL and to compare IHP and 5-PS Deauville visual interpretation to predict survival. Forty-eight patients (mean age 73.2±5.2 years) treated by R-PMitCEBO for DLBCL undergoing FDG PET-CT before and after 3 cycles of treatment were retrospectively included. Event-free survival and overall survival were determined by Kaplan-Meier method and compared with interim PET-CT results using IHP and 5-PS Deauville criteria. Interim PET results using 5-PS Deauville criteria were significantly correlated with EFS (P<0.0001) and OS (P=0.001) whereas they were moderately correlated with EFS (P=0.046) and not with OS (P=0.106) using IHP criteria. Two-year EFS and OS rates were 86.5% and 89.2%, respectively, for patients in 1-3 score group, and 27.3% and 36.4%, respectively, for patients in ≥4 score group using the Deauville criteria. Our results confirmed the prognostic value of an interim PET-CT in elderly patients with DLBCL and the better performance of the 5-PS Deauville criteria.

Research on the midterm efficacy and prognosis of patients with diffuse large B-cell lymphoma by different evaluation methods in interim PET/CT

PurposeTo investigate the midterm efficacy and prognostic evaluation of patients with diffuse large B-cell lymphoma (DLBCL) by three image analysis methods: International Harmonization Project (IHP), Deauville 5-Point Scale (5-PS) and Δ SUVmax criteria in 18F-FDG PET/CT. MethodsThis was a retrospective analysis of 141 patients with DLBCL. All patients were given 3–4 cycles of chemotherapy and 18F-FDG PET/CT. According to three criteria, the patients were divided into negative and positive groups, respectively. Statistical methods were used to assess the midterm efficacy and prognosis factors. ResultsDuring the midterm follow-up, a total of 109 people achieved CR. Three methods showed statistically significant differences in OS and PFS for the interim PET/CT, and Δ SUVmax criterion was an independent risk factor for the prognosis of DLBCL patients. ConclusionIn our research, IHP, 5-PS and Δ SUVmax criteria all had a significant predictive value, while Δ SUVmax criterion had more advantages in evaluating the midterm efficacy and predicting prognosis for patients with DLBCL in interim PET/CT. But it should be noticed that Δ SUVmax criterion needs more strict guidelines in multicenter trials. The optimal cutoff value of Δ SUVmax% we recommended was 81.54%, which helped to judge the midterm efficacy.

Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p&lt;0.0001), IHP (Χ2=49.078, p&lt;0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Long-Term Follow-up of a PET-Guided Approach to Treatment of Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) in British Columbia (BC)

Background: Treatment practices for patients with limited-stage DLBCL are varied and include combined-modality treatment (3 cycles immunochemotherapy + radiation therapy) or immunochemotherapy alone. Since 2005, patients (pts) in BC with limited-stage DLBCL (stage I/II, no B-symptoms, mass &amp;lt; 10cm) have been treated according to a PET-guided algorithm. Following 3 cycles of R-CHOP, pts undergo FDG-PET/CT scan; PET-negative pts receive one additional cycle of R-CHOP, while PET-positive pts receive involved-site radiation therapy (RT). We present long-term follow-up of this population-based experience. Methods: Using the BC Cancer Lymphoid Cancer Database we identified all pts who were diagnosed with limited-stage DLBCL from Mar 2005 to February 2019 and underwent a PET/CT after 3 cycles of curative-intent R-CHOP, in keeping with the PET-guided policy. Pts with primary CNS, primary testicular, PMBCL, PTLD, and transformed/discordant/composite lymphoma were excluded. Pts with evidence of progressive disease prior to or on mid-treatment PET/CT were also excluded. All PET/CT scans were performed and reviewed centrally. Prior to 2014, interpretation was based on the International Harmonization Project (IHP) criteria, and subsequently according to Deauville criteria. Importantly, uptake greater than the mediastinal blood pool was consistently used to determine PET-positivity (ie. PET-positive by IHP, or D3-5 by Deauville). Results: Clinical characteristics of the 319 pts identified are as follows: median age, 68 y (range 19-92); 48%, male; 59%, stage I; 41%, stage II; 8%, PS&amp;gt;1; 13%, elevated LDH; 52%, at least 1 extranodal site; 37%, mass size ≥ 5cm. Stage-modified IPI risk score: 19%, 0; 45%, 1; 27%, 2; 9%, 3-4. Median follow-up is 6.25 yrs (range 0.42-14.25). After 3 cycles of R-CHOP: 254 pts (80%) were PET-negative; 59 pts (18%) were PET-positive; and 6 pts (2%) were considered PET-indeterminate (by IHP). Elevated serum LDH (p&amp;lt;0.001), mass size ≥ 5cm (p=0.008) and stage-adjusted IPI (p=0.025) were predictive of PET-positive status. Of the 254 PET-negative pts, 234 (92%) completed treatment with one additional cycle of R-CHOP, 7 (3%) stopped treatment after 3 cycles R-CHOP and 13 (5%) received RT due to poor chemotherapy tolerance or physician choice. 21/254 PET-negative pts have relapsed and 2/254 died of treatment-related toxicity. 8/21 (38%) PET-negative relapses were late, occurring more than 4 years post initial diagnosis. 55/59 (93%) PET-positive pts received RT, 2 pts refused RT and received only 3 cycles R-CHOP, and 2 pts received 1 additional cycle of R-CHOP alone due to physician preference. 13/59 PET-positive pts have relapsed, only 2/13 (15%) relapses were late &amp;gt;4 years from diagnosis. Of the 6 PET-indeterminate patients, 2 received RT and 3/6 have relapsed. Overall 5-year time-to-progression (TTP) censoring deaths from unrelated causes is 89% (92% for PET-negative and 80% for PET-positive pts). Overall 5-year PFS is 84% (88% for PET-negative and 74% for PET-positive pts) and 5-year OS is 87% (90% for PET-negative and 77% for PET-positive pts). On univariate analysis, age&amp;gt;60, PS&amp;gt;1, stage-modified IPI, and PET status were significant predictors of TTP. On multivariate analysis controlling for age&amp;gt;60, stage, PS, LDH, presence of extranodal involvement, mass size ≥ 5cm, and PET status, only age (p=0.002) and PET status (p=0.004) remained independent predictors of TTP. Conclusion: Using a PET-guided approach to treatment, the majority of patients with limited-stage DLBCL have negative PET scans after 3 cycles of R-CHOP. Patients with negative PET scans have an excellent outcome when treated with 4 cycles of R-CHOP alone, without exposure to radiation. Patients with a positive PET scan who complete treatment with radiation therapy have a slightly less favorable outcome, and may be appropriate for alternative approaches. A detailed analysis of patterns of relapse, as well as efforts to identify clinical factors, PET parameters and biomarkers associated with poor outcome and delayed relapse are ongoing. Figure Disclosures Sehn: Acerta: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria. Scott:NanoString: Patents &amp; Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Freeman:Seattle Genetics, Janssen, Amgen, Celgene, Abbvie: Consultancy, Honoraria. Pickles:TarSera: Honoraria, Other: Participated in advisory board meeting; Abbvie, Sanofi: Consultancy, Honoraria; Astellas Inc.: Research Funding. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria.

Outcome of Limited Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) and Evaluation of a PET-Adapted Approach

Outcome of Limited Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) and Evaluation of a PET-Adapted Approach

Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL

Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL

Enriching Personalized Endometrial Cancer Research with the Harmonization of Biobanking Standards.

Endometrial cancer is the commonest gynecological cancer, with an incidence predicted to escalate by a further 50–100% before 2025, due to the rapid rise in risk factors such as obesity and increased life expectancy. Endometrial cancer associated mortality is also rising, depicting the need for translatable research to improve our understanding of the disease. Rapid translation of scientific discoveries will facilitate the development of new diagnostic, prognostic and therapeutic strategies. Biobanks play a vital role in providing biospecimens with accompanying clinical data for personalized translational research. Wide variation in collection, and pre-analytic variations in processing and storage of bio-specimens result in divergent and irreproducible data from multiple studies that are unsuitable for collation to formulate robust conclusions. Harmonization of biobanking standards is thus vital, in facilitating international multi-center collaborative studies with valuable outcomes to improve personalized treatments. This review will detail the pitfalls in the biobanking of biosamples from women with cancer in general, and describe the recent international harmonization project that developed standardized research tools to overcome these challenges and to enhance endometrial cancer research, which will facilitate future development of personalized novel diagnostic strategies and treatments.

Prognostic values of baseline, interim and end-of therapy 18F-FDG PET/CT in patients with follicular lymphoma.

PurposeIn the present study, we aimed to investigate the role of baseline, interim and end-of treatment positron emission tomography/computed tomography (PET/CT) in assessing the prognosis of follicular lymphoma (FL).MethodsA total of 84 FL patients were retrospectively analyzed in this study. Baseline (n=59), interim (n=24, after 2–4 cycles) and end-of treatment (n=43) PET/CT images were re-evaluated, and baseline maximum standardized uptake value (SUVmax), total metabolic tumor volume (tMTV) and total lesion glycolysis (TLG) were recorded. Interim (I-PET) and end-of treatment (E-PET) PET/CT responses were interpreted by Deauville five-point scale (D-5PS) and International Harmonization Project criteria (IHP). Survival curves were calculated by Kaplan-Meier curves, and differences between groups were compared by log-rank test.ResultsThe 2-year progression-free survival (PFS) of the high- and low-TLG groups was 57.14% and 95.56%, respectively (p=0.0001). The 2-year overall survival (OS) of the high- and low-TLG groups was 62.50% and 100%, respectively (p<0.0001). Multivariate analysis showed that TLG was an independent prognostic factor for PFS (p=0.001, HR=6.577, 95% CI=2.167–19.960) and OS (p=0.030, HR=19.291, 95% CI =2.689–137.947). Besides, Eastern Cooperative Oncology Group (ECOG) was the independent prognostic factor for OS (HR=8.924, 95% CI=1.273–62.559, p=0.028). Interim PET results based on D-5PS or IHP criteria were not significantly correlated with PFS (all p>0.05). However, E-PET results using D-5PS and IHP criteria were statistically significant (p=0.0001 and p=0.006). The D-5PS showed stronger prognostic value compared with IHP criteria. The optimal cutoff value of ΔSUVmax% was 66.95% according to I-PET and 68.97% according to E-PET. However, only the ΔSUVmax% from the baseline to the end-of therapy yielded statistically significant results in the prediction of PFS (p=0.0002).ConclusionOur findings indicated that the baseline TLG and E-PET results were significantly associated with prognosis in patients with FL.

Outcomes of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Included in Phase I Clinical Trials

INTRODUCTIONThe phase 1 selection for clinical trials of patients with relapsed or refractory Diffuse Large-B cell lymphoma (R/R DLBCL) with a potentially rapid tumor growth is a challenge. Prognostics' factors identification could help to better orient patients in appropriate clinical trials. This study is focused on DLBCL to evaluate their outcomes in phase I clinical trials. Our main objectives were to identify prognostic factors, attest the investigational drugs' safety and perform a preliminary assessment of drugs' efficacy.METHODAll consecutive patients with R/R DLBCL included in phase I clinical trial at a single cancer center in France between 2008 and 2017. If a given patient had participated in several phase I clinical trial, only the data from his first trial were examined. The patients' and DLBCL characteristics, the safety data and the efficacy outcomes were recorded. Reponses were assessed according to the International Harmonization Project in Lymphoma Cheson 2007 criteria. Overall responses rates (ORR) included partial responses (PR) and complete response (CR) and tumor control rates included overall responses and stable disease (SD).RESULTSA total of 101 patients (males: 63,4%) with R/R DLBCL were included in a panel of 21 clinical trials. The median age was 64 (range 21-86). Before their inclusion in a phase I trial, patients had received a median of 3 (1-7) lines of treatment and 25,7% of patients had undergone an autologous stem cell transplantation. At the cute-off date, 5 of the 101 patients (4,95%) were still taking the investigational drug. The median progression-free survival and overall survival (OS) were 1,8 and 9,7 months. High-grade toxicity (grade 3 or higher) occurred in 47 of the 101 patients (46,5%), and was related to the investigational drug in 29 of these cases (61,7%). The most important drugs-related toxicity was a hematological toxicity (neutropenia and thrombocytopenia) for 79,3% of patients, other toxicities were digestive toxicity (5,9%), cutaneous toxicity (2,9%), hepatotoxicity (2,9%) and pneumopathy (2,9%). Dose-limiting toxicity (DLT) was experienced by 7 (6,9%) of the 101 patients. The time from D1C1 (day 1, cycle 1) to the occurrence of high-grade toxicity was 1,2 months (range 0,2-9,5). High-grade toxicity occurred during the DLT period (< 6 weeks) for 27 of the 46 patients (58,7%) and after the DLT period in the remaining 19 (41,3%) patients.Factors associated with poor overall survival (overall survival inferior to the median OS) were Ann Arbor staging (73.6% of poor OS patients (< 9.7 months) with a performance status at 4), serum albumin (30.2% of poor OS patients with a low rate of serum albumin ≤ 35 g/L), serum LDH (79.2% of poor OS patients with a high rate of serum LDH > 250 U/L) and progressive disease (90.6% of poor OS patients had a trial withdrawal because of progression). The overall objective response and disease control rates were 25% and 43%. The median trial duration was 1.9 months and were respectively 12,1 and 5,5 months for responders (PR and CR) and controlled patients (PR and CR and SD). 36.6% of patients were prematurely withdrawing of study (before weeks 6). Factors associated with premature withdrew were performance status at baseline (67.6% of early withdrawal patients at performance status 1); Ann Arbor staging (67.6% of early withdrawal patients at Ann Arbor stage 4); serum LDH (73% of early withdrawal patients with a high rate of serum LDH > 250 U/L) and serum albumin (35,1% of early withdrawal patients with a low rate of serum albumin ≤ 35 g/L).CONCLUSIONHigh-grade toxicity occurred after the DLT period in 41.3% of patients with R/R DLBCL, suggesting that the conventional concept of dose-limiting toxicity should be redefined in the era of modern cancer therapies. Besides, even if the phase 1 selection for clinical trials is very selective, it's necessary to better orient patients in hematology. In fact, 36.6% of patients were prematurely withdrawing of study which could be anticipated thanks to the identification of prognostics' factors. Although the objective response is only a secondary endpoint in phase I clinical trials, the median duration of participation in trials (almost one year for responders and 5.5 months for controlled patients) are relevant for some new possibilities of therapeutics in the field of early drugs clinical trials. [Display omitted] DisclosuresRibrag:NanoString Technologies: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; MSD: Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Amgen: Research Funding; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; argenX: Research Funding.

PD-1 Blockade for Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation

PD-1 Blockade for Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation

PD-1 Blockade with Pembrolizumab for Classical Hodgkin Lymphoma after Autologous Stem Cell Transplantation

PD-1 Blockade with Pembrolizumab for Classical Hodgkin Lymphoma after Autologous Stem Cell Transplantation

Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial.

Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001). Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. F Hoffmann-La Roche.

The use of Deauville criteria in follow-up assessment of response to therapy in extra-nodal Non-Hodgkin's lymphoma

ObjectiveOur aim was evaluate the role the PET/CT in the assessment of response to therapy in patients with Non-Hodgkin extra-nodal lymphoma: in particular, a five-point scale (Deauville criteria), which can be employed for early- and late-therapeutic response assessment. MethodsSixty patients with pathologically confirmed Non-Hodgkin lymphoma (NHL) were enrolled in this prospective study. All patients underwent the following PET/CT examinations: initial PET/CT for staging, interim PET/CT and end of treatment PET/CT. Response assessment was done using new Cheson’s guidelines and five-point scale (Deauville criteria). ResultsAll patients were evaluated for response to therapy in the early interim, followed by late interim, as well as end treatment assessment for the overall response. We found good concordance of response assessment according to the Deauville criteria classification with International Harmonization Project (IHP) classification. After early interim 48/60 patients had concordant designations (91.7%, 83.3%, 70%, and 33.3%) and 12 patients had discordant designations. After late interim, 56/60 patients had concordant designations (100%, 100%, 80%, and 50%) and four patients had discordant designations. After end of treatment, 54/60 patients had concordant designations (100%, 100% and 71.4%) and six patients has discordant designations. ConclusionResponse assessment according to the Deauville criteria classification showed good concordance with IHP classification. According to our findings, we recommend the use of Deauville criteria in reporting of PET/CT for staging and assessment of response to treatment.

FDG-PET/CT at the end of immuno-chemotherapy in follicular lymphoma: the prognostic role of the ratio between target lesion and liver SUVmax (rPET).

To retrospectively investigate the prognostic role of the ratio between target lesion and liver SUVmax (rPET) in patients with follicular lymphoma (FL) submitted to FDG-PET/CT at the end of immuno-chemotherapy (PI-PET), and to compare rPET with International Harmonization Project criteria (IHP), Deauville Score (5p-DS) and FL International Prognostic Index at diagnosis (FLIPI). Eighty-nine patients with FL undergoing PI-PET were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cut-point of rPET with respect to 5-years progression free survival (PFS). The prognostic significance of rPET was compared with IHP, DS and FLIPI. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of adverse events as gold standard. The ROC analysis for rPET as predictor of progression showed an optimal rPET cut-point of 0.98. Patients with positive values of IHP, DS and rPET had a PFS of 50, 30 and 31%. PPV were of 56, 80 and 80%, NPV of 83, 86 and 88%, respectively. DS and rPET differed only in two patients. FLIPI was not predictive of progression and relapse. rPET is a prognostic factor in patients with FL submitted to PI-PET. Although it has a similar prognostic power as DS, it can have methodological advantages over visual analysis. PI-PET with different evaluation systems has a stronger prognostic power than FLIPI at diagnosis, so it could be useful to identify patients with FL at risk for early relapse after immuno-chemotherapy.

Kinetics and nadir of responses to immune checkpoint blockade by anti-PD1 in patients with classical Hodgkin lymphoma

BackgroundWe aimed to define the depth and time of maximal anti-tumour response to programmed death-1 blockade antibodies (anti-PD1) in heavily pre-treated patients with classical Hodgkin lymphoma (HL). To this end, we evaluated the kinetics of response for up to two years. Materials and methodsThe 18F-FDG positron-emission tomography (PET) and contrast-enhanced computerised tomography (CECT) data of all relapsed or refractory HL treated at Gustave Roussy, Villejuif, France, from 2013 to 2015 were retrospectively reviewed according to the International Harmonisation Project Cheson 2014 criteria and the LYmphoma Response to Immunomodulatory therapy Criteria (LYRIC). ResultsSixteen patients were included. The median (range) treatment duration was 18.4 (2.8–23.7) months. Fifty-six percent of patients (9/16) achieved an objective response at 3 months, including 19% (3/16) of complete response. Seventeen percent (1/6) of partial responders at 3 months were converted in a complete response. 22% (2/9) of responders at 3 months relapsed before one year. The nadir was reached at 12.7 (3.0–23.0) months. The median (range) depth of response at nadir was −77% (−50% to 100%). ConclusionWe concluded that complete metabolic responses occurred within 6 months, a minority of partial responses were converted in complete response, and the median nadir was observed one year after treatment initiation. These data could help to better define the optimal treatment strategy by PET or CECT-directed approaches.

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1–2 trial

SummaryBackground:The major objective of this study was to explore the safety and clinical activity of Brentuximab vedotin (Bv) and bendamustine in combination in patients with relapsed or refractory Hodgkin Lymphoma. Bv produces high response rates and durable progression-free survival (PFS) in CD30-expressing lymphomas and is approved for the treatment of relapsed Hodgkin lymphoma (HL) and relapsed ALCL. Bendamustine (B) is active agent across the lymphoproliferative malignancies, though the PFS among patients with HL and PTCL is modest.Methods:This was an international, multicenter, single-arm, Phase 1–2 study of BvB in patients with relapsed or refractory HL and ALCL. Eligible patients were required to have relapsed/refractory CD30+ biopsy proven HL or ALCL and an ECOG Performance Status ≤2. In the Phase 1, HL patients were deemed eligible if they developed progressive disease following or after declining ASCT, or had at least 2 prior multi-agent chemotherapy regimens. In the Phase 2, patients with HL were eligible if they had relapsed or refractory disease after one line of therapy. Eligible ALCL patients were required to have relapsed after at least one prior multi-agent chemotherapy regimen and if they were not eligible for or have declined ASCT. The primary objective of the Phase I portion of this study was to identify the maximum tolerated dose (MTD) and dose limiting toxicity (DLT). The primary endpoint of the Phase 2 portion was to determine the overall response rate (ORR; complete response [CR] plus partial response [PR])) based on an intention to treat analysis (ITT). Secondary objectives of Phase 1–2 included assessing for duration of response, progression free survival and overall survival. Response was evaluated using International Harmonization Project Group 2007 Revised Response Criteria. Bv was escalated from 1.2mg/kg Day 1, and B from 70mg/m2 Days 1 and 2 every 21 days until the MTD or recommended phase 2 dose (RP2D) was reached. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov number NCT01657331.Findings:65 patients (only 1 ALCL) were treated, 28 on the Phase 1 and 37 on the phase 2. While the MTD of the combination was not reached, the single agent MTD of Bv (1.8mg/kg Day 1) and RP2D of B (90mg/m2 Days 1 and 2) were identified as the RP2D of the combination. Patients were heavily treated, 65% (42 of 65) had an autologous or allogeneic stem cell transplant or both. The Phase 1 revealed modest toxicity. The major Grade 3/4 toxicities included Grade 3 lung infection in 5 (14%) patients in the Phase 2, and Grade 3/4 neutropenia in 13 (24%) patients across the Phase 1 and 2. The Phase 1 and 2 overall response rates (ORR) were 61% and 78% respectively, with 43% (16 of 27) patients treated in the Phase 2 attaining a complete remission (CR). In the Phase 2, the median PFS has not been reached and duration of response (DOR) was 3.4 months. There was a total of 23 deaths with 21 due to progression of disease, 2 occurring after being transplanted, and none of which were treatment related.Interpretation:This demonstrates that BvB might be an effective salvage regimen for patients with HL, with a favorable safety profile.Funding:Seattle Genetics, The Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873 provided support for this investigator initiated sponsored trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Predictive value of interim PET/CT visual interpretation in the prognosis of patients with aggressive non-Hodgkin's lymphoma.

ObjectiveThe objective of the study was to evaluate the prognostic value of positron emission tomography (PET)/computed tomography (CT) visual interpretation in patients with aggressive non-Hodgkin’s lymphoma (NHL) using a meta-analysis and systematic review.MethodsUsing the PubMed, Embase, and Web of Science databases, we performed a systematic review of the use of visual evaluation mid-chemotherapy to evaluate the prognosis of aggressive NHL in studies published up to May 2017. Prospective and retrospective studies assessing progression-free survival (PFS) and overall survival (OS) were included. We used hazard ratio (HR) to determine the value of Deauville criteria and International Harmonization Project (IHP) criteria for measuring survival. Subgroup analysis was performed based on the number of chemotherapy cycles before the mid-term evaluation as well as the visual evaluation method.ResultsA total of 11 studies were included. PFS (HR =2.93, 95% confidence interval [CI]: 2.93–3.90, p<0.0001) and OS (HR =2.55, 95% CI: 1.76–3.68, p<0.0001) of PET/CT-positive patients were significantly lower when determined by the visual method. In subgroup analysis, IHP, Deauville criteria, and having no standard interpretation groups were factors able to predict PFS; IHP and having no standard interpretation group were able to predict OS. With PET/CT, IHP, and Deauville 5-point criteria, the PFS of patients receiving 2–4 cycles of chemotherapy before PET/CT was significantly lower than that of PET/CT-negative patients. No significant difference in OS was observed when patients received 3 or fewer cycles of chemotherapy before PET/CT, though OS was significantly lower in patients receiving more than 3 chemotherapy cycles.ConclusionIHP and Deauville criteria are commonly used for PET/CT visual evaluation at present. Interim PET/CT analysis after 3–4 chemotherapy cycles is capable of predicting disease prognosis. Large-scale prospective clinical trials are needed to confirm whether PET/CT analysis can be used as an indication for changing a treatment strategy.