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

Abstract

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.

• Authors: Amy K Erbe, Wei Wang, Lakeesha Carmichael, Anna Hoefges, Bartosz Grzywacz, Patrick K Reville, Erik A Ranheim, Jacquelyn A Hank, KyungMann Kim, Songwon Seo, Eneida A Mendonca, Yiqiang Song, Vaishalee P Kenkre, Fangxin Hong, Randy D Gascoyne, Elisabeth Paietta, Sandra J Horning, Jeffrey S Miller, Brad Kahl, Paul M Sondel
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 7 Issue 1 Pg. 70 (03 12 2019) ISSN: 2051-1426 [Electronic] England
• PMID: 30871628 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-B Antigens
• HLA-Bw4 antigen
• HLA-C Antigens
• KIR2DL2 protein, human
• KIR3DL1 protein, human
• Receptors, KIR2DL2
• Receptors, KIR3DL1
• Rituximab

Topics

• Female
• Genotype
• HLA-B Antigens (genetics)
• HLA-C Antigens (genetics)
• Humans
• Lymphoma, Follicular (drug therapy, genetics)
• Maintenance Chemotherapy
• Male
• Proportional Hazards Models
• Receptors, KIR2DL2 (genetics)
• Receptors, KIR3DL1 (genetics)
• Rituximab (administration & dosage, therapeutic use)
• Treatment Outcome