Immunoglobulin M Heavy/Light Chain Pair Measurement Independently Predicts Clinical Outcome and Refines Prognostic Information Provided By Interim PET in Patients with Aggressive Lymphomas
Authors: Johansson Patricia , Dürig Jan , Rekowski Jan , Müller Stefan P , Hertenstein Bernd , Franzius Christiane , Kroschinsky Frank , Kotzerke Jörg , Mesters Rolf , Weckesser Matthias , La Rosée Paul , Freesmeyer Martin , Wilop Stefan , Krohn Thomas , Dührsen Ulrich , Hüttmann Andreas 
Published: October 2019

Abstract
Introduction: We recently reported the first results of the large multicenter phase III PETAL trial (EudraCT 2006-001641-33, NCT00554164) showing that 18-fluorodeoxyglucose interim PET (iPET) performed after two cycles of chemotherapy is highly predictive of clinical outcome in patients with aggressive lymphomas. Here, the study`s biobank was utilized to exploratively investigate the prognostic value of immunoglobulin M heavy/light chain pair (HLC-M) abnormalities in this patient cohort.
Methods: HLC-M κ and λ were measured in pre-treatment serum samples of a representative subset (N=187, 22%) of patients employing the Hevylite® assay (The Binding Site Ltd, Birmingham, UK). Normal HLC-M ratios and concentrations were defined according to the manufacturer`s recommendations. For statistical analysis standard time-to-event methodology (Kaplan-Meier method, Log Rank test, Cox regression) was used.
Results: Median age of the 187 pts was 57 years (range 18-80), whereof 92 (49%) were male, and 95 (51%) were female. 174 pts. had CD20-positive B cell lymphomas (73% diffuse large B cell, 13% other aggressive B cell lymphomas, 7% follicular lymphoma grade 3), 13 had peripheral T cell lymphomas (7%). Normal HLC-M were observed in 150 patients (75.8%). 37/187 (20%) of the patients exhibited a monoclonal IgMκ/IgMλ ratio, where 17 (46%) showed a ratio below and 20 (54%) above the reference range. HLC-M abnormalities were significantly associated with adverse clinical characteristics including advanced Ann Arbor stage (p=0.005), high international prognostic index (IPI, p=0.001) and extranodal disease (p=0.003). Patients with abnormal HLC-M ratios had inferior time to treatment failure (TTTF, Figure 1) and overall survival (OS, Figure 2) as compared to their counterparts with normal HLC-M ratios. Of note, subgroup analyses revealed that the prognostic value of HLC-M abnormalities was limited to patients with a favorable iPET and low-intermediate IPI score. In multivariate analysis with the cox model and controlling for the IPI factors (including age), histology, sex as well as FLC κ and λ, monoclonal HLC-M remained predictive for a shorter TTTF (p=0.0181, covariate-adjusted hazard ratio (aHR) 2.195, 95% CI [1.144;4.214]) and OS (p=0.0034, aHR 3.844, 95% CI [1.559;9.476]).
Conclusions: Monoclonal HLC-M is an independent predictor of survival in patients with aggressive lymphoma and refines prognostic information provided by iPET and IPI.
Figure 1. Figure 1.

Disclosures
Dürig: The Binding Site: Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy, Other: Travel support, Speakers Bureau; Aicuris: Consultancy; Celgene: Consultancy, Other: Travel support, Speakers Bureau. La Rosée:Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; CTI Lifesciences: Honoraria; Janssen-Cilag: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Research Funding; Mundipharma: Other: Travel support; Takaeda: Consultancy, Honoraria, Other: travel support; Celgene: Honoraria. Dührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Hüttmann:Amgen: Consultancy, Research Funding; Gilead: Consultancy; Takeda: Consultancy, Other: Travel support; Roche: Research Funding; Celgene: Other: Travel support, Speakers Bureau.