Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab.

Autor: Erbe AK; Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Wang W; Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Carmichael L; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA., Hoefges A; Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Grzywacz B; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Reville PK; Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Ranheim EA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Hank JA; Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Kim K; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA., Seo S; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA., Mendonca EA; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA.; Department of Pediatrics, University of Wisconsin, Madison, WI, USA., Song Y; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA., Kenkre VP; Department of Medicine, University of Wisconsin, Madison, WI, USA., Hong F; Department of Biostatistics, Harvard University, Dana Farber Cancer Institute, Boston, MA, USA., Gascoyne RD; Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Paietta E; Montefiore Medical Center-North Division, Albert Einstein College of Medicine, Bronx, NY, USA., Horning SJ; Department of Medicine, Stanford University, Stanford, CA, USA., Miller JS; Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Kahl B; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Sondel PM; Department of Human Oncology, University of Wisconsin, Madison, WI, USA. pmsondel@humonc.wisc.edu.; Department of Pediatrics, University of Wisconsin, Madison, WI, USA. pmsondel@humonc.wisc.edu.; University of Wisconsin-Madison, 1111 Highland Avenue, 4159 WIMR Bldg, Madison, WI, 53705, USA. pmsondel@humonc.wisc.edu.
Jazyk: angličtina
Zdroj: Journal for immunotherapy of cancer [J Immunother Cancer] 2019 Mar 12; Vol. 7 (1), pp. 70. Date of Electronic Publication: 2019 Mar 12.
DOI: 10.1186/s40425-019-0538-8
Abstrakt: Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes.
Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage.
Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance.
Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.
Databáze: MEDLINE
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