Abstract: In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participating in a prospective trial, nine (8%) were interim PET positive and 19 (18%) had an IgM gammopathy. The monoclonal protein was not associated with distinguishing genetic features, and its light chain restriction was not always concordant with the light chain restriction of the lymphoma. The information provided by interim PET and IgM gammopathy was combined to dichotomize the population into sizeable high-risk (1–2 adverse factors) and low-risk groups (no adverse factor) with widely different outcomes (population size, 25% vs. 75%; 3-year risk of progression, 51% vs. 10%; 3-year overall survival, 64% vs. 95%). Multivariable analyses including established risk factors revealed the interim PET result and the IgM gammopathy status to be the only factors significantly associated with outcome. Information about interim PET response and IgM gammopathy may be useful in studies testing risk-adapted treatment strategies.

Abstract: Interim positron emission tomography (PET) using the tracer, [ 18 F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan that was evaluated using the ΔSUV max method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt’s lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606] ; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Abstract: There is no generally established prognostic index for patients with mantle cell lymphoma (MCL), because the International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been developed for diffuse large cell and follicular lymphoma patients, respectively. Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international prognostic index, MIPI) of overall survival (OS). Statistical methods included Kaplan-Meier estimates and the log-rank test for evaluating IPI and FLIPI and multiple Cox regression for developing the MIPI. IPI and FLIPI showed poor separation of survival curves. According to the MIPI, patients were classified into low risk (44% of patients, median OS not reached), intermediate risk (35%, 51 months), and high risk groups (21%, 29 months), based on the 4 independent prognostic factors: age, performance status, lactate dehydrogenase (LDH), and leukocyte count. Cell proliferation (Ki-67) was exploratively analyzed as an important biologic marker and showed strong additional prognostic relevance. The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.

Abstract: Introduction: Treatment results in diffuse large B-cell lymphoma (DLBCL) are heterogeneous. Established risk models like the International Prognostic Index (IPI) and molecular lymphoma features such as MYC translocations and the cell of origin (COO) subtype are prognostic of outcome. A positive iPET scan after 2 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has recently been shown to predict poor outcome independent of the IPI (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial [PETAL]; Dührsen et al., J Clin Oncol 36:2024, 2018). Another PET-derived parameter of potential prognostic significance is baseline MTV. This retrospective analysis of lymphoma biopsies from the PETAL trial investigated the relationship between molecular lymphoma features and PET parameters. Methods: Available lymphoma specimens were analyzed for COO by immunohistochemistry employing the Hans-classifier (HC) and by gene expression (GE) using the HTG EdgeSeq System (HTG Molecular Diagnostics). MYC and BCL2 and/or BCL6 translocations ("double-hit" [DH]) were assessed by fluorescence in situ hybridization (FISH). MTV was determined applying the 41% SUVmax segmentation method, and iPET was evaluated using the deltaSUVmax method. Association between iPET result and molecular lymphoma features was assessed by risk ratios (RR). Survival curves of time-to-event endpoints were compared using hazard ratios (HR) from Cox regression and the log-rank test. Results: Of 609 DLBCL patients treated in the PETAL trial, 63 had a positive iPET. 134 of 267 DLBCL biopsies available for HC analysis (50.2%) were classified as non-germinal center B-cell (non-GCB) and 133 (49.8%) as GCB. COO analysis by GE revealed an activated B-cell (ABC) type in 122 (51.1%) and a GCB type in 102 (42.7%) of 239 available biopsies (n=7 [2.9%] unclassified, n=8 [3.3%] failed quality control). Concordance between HC and GE was found in 165 of 197 biopsies studied by both methods (83.8%). MYC breaks were found in 27 (10.7%) and MYC amplifications in 48 (19.0%) of 253 cases studied by FISH. A DH lymphoma was diagnosed in 16 of 253 cases (6.3%). Complete information on HC, GE and DH status was available for 170 cases. The relationship is depicted in figure 1. COO classification by either HC or GE was not correlated with baseline MTV, iPET result, event-free (EFS) survival or overall (OS) survival. By contrast, DH status was correlated with positive iPET (RR 2.30 [95% CI, 0.76 to 6.96]) and inferior outcome as shown in figure 2 (EFS: HR 2.04 [95% CI, 1.02 to 4.07] ; p=.044; OS: HR 3.00 [95% CI, 1.34 to 6.71]; p=.007). There was no co rrelation between DH status and MTV. iPET-positive DLBCL harbored MYC breaks more frequently than iPET-negative DLBCL (RR 3.29 [95% CI, 1.40 to 7.77]). A similar trend was observed in 72 cases tested for BCL2 breaks (RR 1.30 [95% CI, 0.44 to 3.84] ) and 74 cases tested for BCL6 breaks (RR 1.85 [95% CI, 0.59 to 5.80]). Conclusion: HC and GE showed good concordance with respect to COO classification, but COO was not correlated with MTV, iPET, EFS or OS. By contrast, MYC-rearranged lymphomas with or without BCL2 or BCL6 breaks were statistically significantly associated with a positive iPET, and DH lymphomas were correlated with poor outcome. Yet, the unfavorable prognosis of iPET-positive DLBCL cannot solely be explained by MYC translocations because most iPET-positive lymphomas lacked this genetic anomaly. Our results strengthen the role of iPET as a prognostic tool, independent not only of IPI, but also of COO status and MYC translocation. Disclosures Richter: HTG Molecular Diagnostics, Inc.: Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Gärtner:HTG Molecular Diagnostics, Inc.: Employment. Duehrsen:Amgen: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Amgen: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

Abstract: Background. Anaplastic lymphoma kinase positive systemic anaplastic large cell lymphoma (ALK+ ALCL) represents an aggressive T-cell malignancy that primarily affects children and younger adults. Upon treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens its prognosis is relatively favourable compared to other aggressive T-cell lymphomas, however, the rare event of disease reoccurrence remains particularly challenging. ALCL is CD30 positive, and mono treatment with brentuximab vedotin (BrV) can achieve long term remissions in only few relapsed patients not receiving consolidating stem cell transplantation (Pro B. et al. Blood 2017). A subset of ALCL patients express platelet derived growth factor receptor (PDGFR) alpha or beta in their tumour cells which is induced by ALK via AP-1 transcription factor activation. We previously demonstrated that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is an effective treatment concept for ALK+ ALCL in experimental mouse models (Laimer D. et al. Nature Med. 2012). Here we aimed to assess the prognostic value of PDGFR expression and to probe the clinical value of its targeting by imatinib in ALK+ ALCL patients. Methods. The impact of PDGFR expression to predict clinical outcome was analyzed in samples of 98 ALK+ ALCL patients included in the studies NHL-BFM 90, 95 and ALCL99 between 1992 and 2006. Six patients (age 18-45) with chemo-refractory ALK+ ALCL were prospectively treated with imatinib plus (4) or minus (2) BrV. 33% (2/6) had previously received salvage treatment with stem cell transplantation (SCT). Three of the patients had been enrolled in a prospective single-arm study combining imatinib and BrV, a trial that was terminated due to poor patient recruitment (AGMT ALCL1 trial, EudraCT No.: 2013-003505-26, supported by Takeda®). PDGFR alpha and beta expression analyses were performed on tumour samples of treated patients. Results. ALK+ ALCL patients with high PDGFR expression on tumor cells (n=11) had a significantly lower event-free survival rate (EFS) at 5 years compared to patients with no or low expression (n=87) (27±13% versus 70±5%, respectively, p 〈 0.001, figure 1a). Four of the six patients with relapsed/ refractory ALK+ ALCL responded to imatinib +/- BrV with a rapid metabolic complete remission (CR). At a median clinical follow-up of 52 months (range 20 to108) all responding patients demonstrated an ongoing CR without SCT even after imatinib was discontinued with an average time on imatinib of 49 weeks (range 32 to 130; figure 1b). Half (2/4) of responding patients received no or only 1 infusion of BrV; both non-responding patients had received BrV. Importantly, despite the few patients that could be prospectively treated, PDGFR expression status had a significant impact on clinical course. All patients (4/4) who expressed either PDGFR alpha or beta in tumour cells and in the lymph node microenvironment responded with an ongoing metabolic CR, whereas the two patients whose lymphoma cells had negative PDGFR expression failed to respond (EFS: 4 versus 210 weeks, p = 0.018; figure 1c). Conclusions. 1) PDGFR expression is a poor risk factor in ALK+ ALCL. 2) Imatinib alone or in combination with BrV overcomes chemo-resistance conferred by PDGFR expression. 3) Imatinib treatment can be discontinued with ongoing CR. 4) These observations suggest that PDGFR expressing ALK+ ALCL patients might benefit from early treatment with imatinib. Disclosures Staber: Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Mayerhoefer:Siemens: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Greil:Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ratiopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; GSK: Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Boehringer Ingelheim: Honoraria; Mundipharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Imatinib - bcr-abl Inhibitor

Abstract: Introduction For patients (pts) with aggressive B-cell lymphoma immunochemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) represents the standard of care with curative intention. For elderly pts a dose-reduced R-mini-CHOP protocol is feasible. No standard of care exists for frail or very old ( 〉 80 yrs) pts not eligible for CHOP-like treatment. Here we present the final results of the prospective DSHNHL-phase-2 trial for old or frail pts receiving Rituximab/Bendamustine (RB) for 1st-line treatment of aggressive B-cell lymphoma. Our goal was to determine feasibility, toxicity of the BR regimen in this pt cohort, and to determine which pts groups might potentially benefit from this reduced-intensity approach. Methods The open-label, multicenter, prospective, non-randomized phase-II trial "Subcutaneous Rituximab and Intravenous Bendamustine in very Elderly Patients or Elderly Medically Non Fit Patients ("Slow Go") with Aggressive CD20-positive B-cell Lymphoma" (B-R-ENDA, DSHNHL 2010-1, EudraCT 2010-024004-98) included all pts aged ≥81 yrs or 61-80 yrs and elevated CIRS 〉 6, not qualifying for R- CHOP, with histologically confirmed CD20+aggressive lymphoma of any Ann Arbor-stage and IPI score, and ECOG 〈 4 as determined during or after a prephase treatment. During run-in-phase, 20 pts received a prephase treatment of Prednisolone 100mg p.o. d-7 to -1, followed by Rituximab 375mg/m² i.v. on d-3, again followed by 7 cycles of Rituximab 375mg/m² i.v. on d1,q21 and 6 cycles of Bendamustine 90mg/m² i.v. on d1 and 2,q21. After a safety analysis, subsequent pts received prephase treatment with Rituximab 375mg/m² i.v. followed by 7 cycles of subcutaneous (s.c.) Rituximab 1400mg on d1,q21 and bendamustine as above. Primary endpoints were 2-year-progression-free survival (PFS) for efficacy (expected at 30-50% in the 〉 80 yr cohort), and treatment-associated deaths, frequency of grade 3/4 adverse events and SAEs, adherence to the protocol, complete and partial remission rate, rate of primary progression and relapse, and quality of life assessed by geriatric assessment and EORTC-QLQ-C30 for feasibility. Results: From 2012 to 2016, 68 pts (22 male, 46 female) were recruited in 24 centers into the trial and included into this intent-to-treat analysis (ITT). The median age was 81 yrs with 21% of pts older than 85 yrs. The median CIRS score was 8 and 72% had a CIRS 〉 6. The IPI was 〉 2 in 59% of pts. The patient population was per protocol divided into two subgroups: pts 61 to 80 yrs old and medically non-fit (29 pts) and pts older than 80 yrs (39 pts). For the 61 to 80 yrs old medically non-fit patients median age was 77 yrs (64-80), median CIRS score was 10 (2-22), IPI was 〉 2 in 76% of pts, 66% of pts had stage 3 or 4 disease, and ECOG was 〉 1 in 52% of pts. For the subgroup of pts 〉 80 yrs, median age was 84 yrs (81-95), median CIRS score was 7 (1-17), IPI was 〉 2 in 46% of pts, 51% of pts had stage 3 or 4 disease, and ECOG was 〉 1 in 23% of pts. 49% of pts received the complete treatment as planned (61-80 yrs: 38%; 〉 80 yrs: 56%). Reasons for early termination of treatment were PD in 15% (17%; 13%) and toxicity in 24% (24%; 23%) of pts. 29% 95% Confidence interval 19-42% of pts (38%; 23%) had grade 3-5 infections. Treatment related mortality was 15% (17%; 13%). Overall response rate (ORR) was 41% (28%; 51%) with 31% CR (10%; 46%). Median observation time was 29 months for EFS, PFS and OS. 2-yrs EFS was 23% (10%; 37%), PFS was 40% (32%; 45%), OS was 42% (37%; 46%). In a multivariate analysis adjusted for IPI factors elevated LDH and ECOG 〉 1 constituted the most significant risk factors for poor outcome. Conclusions: We describe a frail patient cohort with a median CIRS score of 8, with 72% pts with a CIRS 〉 6, considerable comorbidities and a high percentage of high-risk IPI. The primary efficacy endpoint (2 yr PFS 〉 80 yrs 45%) was met; for R-mini-CHOP, this was reported at 47% (Peyrade et al., Lancet Haemat, 2011). The IPI predicts outcome in the 〉 80 yrs cohort reliably. The RB regimen is active even in very elderly and frail pts up to 90 yrs of age. Therefore, in pts not eligible for full- or reduced dose R-CHOP treatment, it represents a tolerable and efficient alternative, albeit with a limited curative potential preferably in IPI low/intermediate-risk pts. Biomarker, comorbidity and QoL data will be analysed subsequently. Disclosures Zettl: Roche: Other: travel grants, Research Funding; Mundipharma: Research Funding. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korfel:Mundipharma: Consultancy, Research Funding. Dreyling:Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: scientific advisory board; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Acerta: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Illmer:Roche: Other: travel support. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Poeschel:Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support; Astra Zeneca: Other: Travel support. Truemper:Takeda: Consultancy, Research Funding; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy.