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4096 Clinicogenetic Risk Models in Patients Randomized to Receive Consolidative Autologous Stem-Cell Transplantation after Frontline R-CHOP for Advanced Follicular Lymphoma: An Analysis from the GLSG2000 Trial

Program: Oral and Poster Abstracts
Session: 621. Lymphoma—Genetic/Epigenetic Biology: Poster III
Hematology Disease Topics & Pathways:
Follicular Lymphoma, Diseases, Adult, Biological, Therapies, Non-Hodgkin Lymphoma, Technology and Procedures, Study Population, Lymphoid Malignancies, Clinically relevant, genetic profiling, transplantation, NGS
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Stefan Alig, MD1*, Alessandro Pastore2, Vindi Jurinovic1,3*, Sarah Häbe1*, Deepak Bararia, PhD1*, Verena Passerini, PhD1*, William Keay1*, Johannes Hellmuth4, Andreas Rosenwald5*, Wolfram Klapper, MD6*, Harald Stein, MD, PhD, Dr. h.c.7*, Alfred Feller8*, German Ott, MD9*, Annette M. Staiger, PhD9,10*, Heike Horn, PhD11*, Martin-Leo Hansmann12*, Christiane Pott13*, Roswitha Forstpointner1*, Wolf-Karsten Hofmann14, Norbert Schmitz, MD15*, Georg Hess16*, Michael Unterhalt17*, Martin H. Dreyling, MD, PhD1, Anna-Katharina Zoellner1*, Christian Schmidt, MD1*, Eva Hoster3,17*, Wolfgang Hiddemann1 and Oliver Weigert, MD1

1Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
2Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
3Institute for Medical Informatics, Biometry and Epidemiology, LMU Munich, Munich, Germany
4Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York
5Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany
6Department of Hematopathology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany
7Pathodiagnostik Berlin, Berlin, Germany
8Hämatopathologie Lübeck, Lübeck, Germany
9Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany
10Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
11Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart, and University of Tuebingen, Stuttgart, Germany
12Dr. Senckenberg Institute of Pathology and Reference and Consultant Center for Lymph Node and Lymphoma Pathology, Goethe University Hospital, Frankfurt am Main, Germany
13Department of Medicine II, University Hospital of Schleswig-Holstein, Kiel, Germany
14Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
15Medizinische Klinik A, University Hospital Münster, Münster, Germany
16Department of Hematology, Medical Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
17Department of Medicine III, Ludwig-Maximilians-University Hospital, Munich, Munich, Germany

Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore whether HDT/ASCT is an effective frontline therapy for patients identified to be high-risk by clinical (i.e., FLIPI) or clinicogenetic risk models (i.e., m7-FLIPI, POD24-PI).

Methods: We performed targeted DNA deep-sequencing of >150 genes in available diagnostic FL biopsies from 165 patients ≤60 years with advanced FL from the GLSG2000 trial who uniformly received R-CHOP as frontline treatment. Of these, 87 patients (53%) were randomized to receive consolidative HDT/ASCT, 78 (47%) were randomized to interferon maintenance. We performed intention-to-treat (ITT) survival and regression analyses to explore whether known clinical and clinicogenetic risk factors can be overcome by ASCT.

Results: The HDT/ASCT and no-HDT/ASCT cohorts were balanced regarding age (48 vs 50 years), sex (49% vs 64% male patients), high-risk FL International Prognostic Index (FLIPI; 25% vs 29%), Eastern Cooperative Oncology Group Performance Score >1 (6% vs 5%) and mutation status of EZH2 (23% vs 18%) and TP53 (3% vs 3%). The incidence of POD24 was not significantly lower in the HDT/ASCT cohort (8% vs 14%, p=0.32). After a median follow-up of 7.5 years, 5-year failure-free survival (FFS) rates in the HDT/ASCT and no-HDT/ASCT cohorts were 77% and 69% (HR 0.7, p=0.16), 5-year OS rates were 95% and 90% (HR 0.6, p=0.21), respectively.

The high-risk cohorts identified by FLIPI, m7-FLIPI, and POD24-PI comprised 27% (n=45), 18% (n=29) and 22% (n=37) of patients, respectively (Fig. A). The m7-FLIPI reclassified 10% (n=16) of patients from high-risk FLIPI to low-risk m7-FLIPI. The POD24-PI reclassified 5% (n=9) of patients from high-risk FLIPI to low-risk POD24-PI; one patient was reclassified from low-risk FLIPI to high-risk POD24-PI. Patients identified to be high-risk by all three indices had shorter FFS (FLIPI: HR 2.8, p=0.0002; m7-FLIPI: HR 3.0, p=0.0003; POD24-PI: HR 2.5, p=0.0013), but OS was not different (FLIPI: HR 1.4, p=0.47; m7-FLIPI: HR 1.5, p=0.45; POD24-PI: HR 1.5, p=0.47). The risk to develop POD24 was increased in high-risk patients (FLIPI: OR 4.4, p=0.007; m7-FLIPI: OR 4.8, p=0.005; POD24-PI: OR 4.3, p=0.008).

Consolidative HDT/ASCT did not prolong FFS in high-risk patients as defined by FLIPI (HR 1.2, p=0.67), m7-FLIPI (HR 1.2, p=0.70; Fig. B) and POD24-PI (HR 1.3, p=0.63; Fig. B). Similarly, OS was not significantly improved in all three high-risk cohorts (FLIPI: HR 0.2, p=0.13; m7-FLIPI: HR n/a, p>0.99; and POD24-PI: HR 0.3, p=0.22). In low-risk patients, HDT/ASCT was associated with a non-significant trend towards prolonged FFS (FLIPI: HR 0.5, p=0.061; m7-FLIPI: HR 0.6, p=0.16; POD24-PI: HR 0.5, p=0.068; Fig. B), but again OS was not significantly different (FLIPI: HR 0.8, p=0.69; m7-FLIPI: HR 0.8, p=0.66; and POD24-PI: HR 0.7, p=0.52).

Conclusions: Our ITT-analysis confirms that consolidative HDT/ASCT should not be offered to unselected cohorts of patients with previously untreated, advanced FL after R-CHOP. Also, our current clinicogenetic risk models are not optimized to select high-risk patients who may benefit from frontline HDT/ASCT. The fraction of patients identified to be high-risk by FLIPI, m7-FLIPI and POD24-PI is low when applied to younger, medically fit patients. Moreover, the fraction of patients being reclassified by integrating gene mutation data is low in this patient cohort. Therefore, we are developing specific stratification algorithms for younger, medically fit patients who are eligible for dose-intensified approaches.

Disclosures: Klapper: F.Hoffman-La Roche: Honoraria, Research Funding; HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schmitz: Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Hess: CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt: F. Hoffman-La Roche: Other: Travel support. Dreyling: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees. Schmidt: Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Hoster: F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Hiddemann: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Weigert: Roche: Research Funding; Novartis: Research Funding.

*signifies non-member of ASH