Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As
F-fluorodeoxyglucose (
F-FDG) ...positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (
< .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio HR, 2.11; 95% confidence interval CI, 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.
Background. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently considered as the standard of care for patients with newly diagnosed diffuse large B-cell ...lymphoma (DLBCL). However, three-year progression-free survival (PFS) and overall survival (OS) rates remain at 60% and 70%, respectively. We recently reported a new tool to help the early identification of ultra-high risk DLBCL patients1. This tool was identified in a cohort of 301 patients included in the REMARC study, responders to R-CHOP, and was based on a combination of 2 factors at baseline: 1/ total metabolic tumor volume (TMTV) above 220cm3 measured on baseline 18FDG-PET and 2/ elevated ECOG PS ≥2. Here, we validated this combination in multiple cohorts including two large clinical trials and in real world.
Methods: We evaluated the combination TMTV-PS in a series of 2306 patients with DLBCL including patients treated in clinical trials in Europe and the United States; PETAL (n= 510) and GOYA (n=1315) and 481 patients treated in Real world (RW) across multiple centers in Europe (France, Poland, Portugal, UK). All patients were treated with a combination of immuno-chemotherapy with curative intent (Rituximab (R) or Obinutuzumab (0)-CHOP (R-CHOP n= 70%%, O-CHOP n= 29 %, and intensified regimen n=1%). Patients in PETAL were treated by a PET-guided strategy. Associations of TMTV and ECOG PS at baseline were explored with the International Prognostic Index (IPI) and outcome.
Results. For the PETAL, GOYA, and RW series, the median age was 62 (18-80), 62 (18-86), and 65 (17-92), and 55%, 58%, 60%, were > 60y respectively. ECOG PS>2 was present in 11%, 12%, 23% of the patients; IPI 3-5 in 38%, 44%, 51%; TMTV>220 in 45%, 61%, 44%, respectively. The combination of TMTV>220cm3 and ECOG PS>2 defined in PETAL, GOYA, and RW, patients with no risk factor representing 53%, 37% and 49% of the patients, one risk factor (either TMTV> 220cm3 or ECOG PS>2) representing 38%, 53.5%, 35% of the patients, and two risk factors representing 9%, 10%, and 16%, respectively. Patients with 2 risk factors had a significantly worse PFS than patients with 0 or 1 risk factor in the PETAL, GOYA and RW series, HR=3.32 (95% CL: 2.0-5.5); HR=2.68 (95% CL: 2.0-3.6), HR=4.06 (95% CL : 2.7-6.1), respectively. Overall survival was also significantly worse in patients with 2 risk factors than patients with 0 or 1 risk factor, HR=3.85 (95% CL: 2.2-6.8); HR=3.16 (95% CL: 2.2-4.5), HR=5.23 (95% CL: 3.4-8.1), respectively. The combination of TMTV-PS performed better than IPI with a positive C-Index for PFS and OS across all the series, PETAL, GOYA, and RW (figure 1)
Conclusion. The combination of TMTV and ECOG PS improves risk stratification for patients with DLBCL treated in frontline by standard treatment or intensified immuno-chemotherapy. This observation meets an unmet need for early and better identification of ultra-high risk DLBCL patients.
Display omitted
Thieblemont:Cellectis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Dührsen:Gilead/Kite: Consultancy, Honoraria; Alexion: Honoraria; CPT: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: travel, accomodations, expenses; Janssen: Consultancy, Honoraria, Other: travel, accomodations, expenses. Vitolo:Roche: Honoraria, Other: travel, accomodations, expenses; Jansen: Honoraria. Zaucha:Cellgene: Other: travel, accomodations, expenses; Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; BMS: Consultancy; Novartis: Consultancy. Maria:Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Other: travel, accomodations, expenses; MSD: Consultancy; BMS: Consultancy; Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses. Decazes:Bayer: Other: travel, accomodations, expenses. Tilly:BMS: Honoraria. Casasnovas:MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Amgen: Consultancy, Honoraria. Hüttmann:University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy; Gilead: Honoraria; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses. Schmitz:Abbvie: Other: travel. Paulson:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).
Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum ...intensity projection (MIP) images from
F-fluorodeoxyglucose (
F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL
F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmax
was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL.
Introduction
Diffuse large B-Cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Up to one third of patients relapse or fail to achieve complete remission, with poor ...prognosis. and low response rates to salvage treatments. Early identification of patients unlikely to be cured with R-CHOP might improve their chance of cure and quality of life. Interim 18FFDG PET (I-PET) measures the pattern of response during treatment, which might add important prognostic value. These measures could be used for I-PET guided treatment for both patients with a good response and patients with a poor response. At this moment it is unclear what the influence of timing and PET positivity criteria is on the prognostic value of I-PET. Therefore, the aim of this individual patient data (IPD) meta-analysis was to determine the optimal timing and optimal PET positivity criteria for I-PET to predict response in DLBCL patients.
Methods
Individual patient data from 1977 de novo DLBCL patients were obtained from the PETRA database (www.petralymphoma.org). These patients had been enrolled in 9 clinical studies and treated with R-CHOP14, R-CHOP21 or DA-EPOCH-R. All patients had an I-PET following one to four cycles of therapy. Progression free survival (PFS) was the primary endpoint. We used the Deauville score (DS) as a visual assessment of the I-PET with two different cut-offs for PET-positivity: DS 4-5 positive and DS 5 positive. Relative reductions (Δ) of Standardized Uptake Values (SUV) were used for semi-quantitative scoring of I-PET. A cut-off of 66% reduction was used for I-PET scans after 1,2 or 3 cycles and a cut-off of 70% was used for I-PET after 4 cycles. DS were available for 1828 patients and ΔSUV data for 1632 patients. Multilevel Cox proportional hazards models were used to study the effects of timing and PET positivity criteria on 2-year PFS, with I-PET after 2 cycles as reference.
Results
After correction for Ann Arbor stage and age, there were no significant differences in PFS between the 9 studies. I-PET1 was not able to significantly discriminate between responders and non-responders. I-PET2 and I-PET4 were able to significantly discriminate responders and non-responders, with higher hazard ratios (HR) for I-PET4. HR were 1.65 and 2.36 for DS4-5 positive, 3.69 and 5.28 for DS5 positive and 2.36 and 3.67 for ΔSUV criteria for I-PET2 and I-PET4 respectively. I-PET3 was able to significantly discriminate responders and non-responders only for DS5 positive criteria (HR: 7.92) (Table 1). However, there were few patients with I-PET1 and I-PET3 scans. Regarding I-PET negative patients, there were no significant differences in PFS using any of the response criteria at the 4 timepoints assessed. Regarding I-PET positive patients, there was a significantly lower PFS at I-PET4 than at I-PET2 , using the DS4-5 positive criteria (p = 0.009, HR = 1.52 (95% BI 1.11 - 2.09)) and ΔSUV criteria (p = 0.05, HR = 1.68 (95%BI 1.00-2.82)) but no other significant differences using other criteria or timepoints (Table 2).
Conclusions
I-PET is able to significantly discriminate between responding and non-responding patients after 2, 3 or 4 cycles of chemotherapy. The optimal timing to identify responders is after 2 cycles, as there is no significant increase in survival at later times, regardless of PET criteria. As the PFS of I-PET4 positive patients is significantly lower than that of I-PET2 patients, I-PET4 might be the optimal timing to identify non-responders. We suggest to perform an I-PET4 scan to identify poor-responding patients. The worst prognostic subgroup is best identified using the DS 5 positive or ΔSUV criteria. Based on these data, I-PET could be used to design response adapted trials for patients with good and poor responses respectively.
Display omitted
Barrington:Roche: Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Speakers Bureau. Dührsen:Alexion: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Teva: Honoraria; CPT: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Research Funding. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zucca:Janssen: Research Funding; AstraZenaca: Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Abbvie: Other: Travel Grant. Higley:FNIH: Research Funding; CCS associates: Employment; NCIS/Leidos: Research Funding. Hutchings:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Lugtenburg:Celgene: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Janssen Cilag: Honoraria; Servier: Consultancy, Honoraria, Research Funding; BMS: Consultancy; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding. Zijlstra:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.
Summary
Involvement of the internal female reproductive organs by diffuse large B‐cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 ...female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab‐containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression‐free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09–39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL.
PDF
