KIR3DL2 MUTATION MAY DEFINE A HIGH RATE OF RESPONSE OF AITL TO TIPIFARNIB

Introduction: We have previously shown that Angioimmunoblastic T-cell Lymphoma (AITL) overexpresses CXCL12 and that patients (pts) with CXCL12-overexpressing T-lymphomas, including AITL, experience a high rate of response to the farnesyltransferase inhibitor tipifarnib (50% ORR, 90% clinical benefit rate, Witzig ASH 2018). Killer-cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed in NK and T cells that play regulatory functions, including roles in the regulation of chemokine/cytokine release (KIR3DL2) and angiogenesis (KIR2DL4). KIRs may be activatory (KIR-DS) or inhibitory (KIR-DL), interact with HLA and other ligands through extracellular D1-D3 loops, and signal intracellularly through ITAM (KIR-DS) or ITIM (KIR-DL) motifs. Methods: Twenty-seven pretreatment biopsies from pts with relapsed or refractory peripheral T-cell lymphomas enrolled in a multi-institutional, single-arm, open-label, phase 2 study of tipifarnib were investigated using next generation whole exome sequencing and single nucleotide variations (SNVs) analyzed according to the primary study endpoint of objective response. Tumor CXCL12 and CXCR4 expression were determined by RNA Seq. Pts had received at least one prior cytotoxic systemic therapy, were ≥18 years old, and with performance status of 0–2. Clinical trial information: NCT02464228. Results: A high rate of inhibitory KIR mutation (SNV of expected maximal population frequency <1%) was observed in the 11 AITL pts. The most notable mutations were found in the ITIM2 of KIR3DL1 and KIR2DL3 (3 subjects) and in the vicinity of the ITIM1 and CK2 phosphorylation sites of KIR2DL3 and KIR3DL2 (5 subjects). The latter mutations were associated with higher CXCL12/CXCR4 expression ratio (~3 fold) and susceptibility to response to tipifarnib. Two complete responses (CR), 2 partial responses and one disease stabilization (80% ORR) were observed in 5 AITL subjects carrying Q386E KIR3DL2. One additional CR was observed in 1 of 4 PTCL NOS pts with Q386E KIR3DL2. Nine of 27 PTCL samples (33%) carried Q386E. An additional 11 samples from tipifarnib treated pts and the overall incidence of KIR-DL mutation in PTCL and other lymphomas are being investigated. Conclusions: The high rate of inhibitory KIR mutation in AITL may contribute to the understanding of the hypervascularity and inflammatory phenotype of these tumors. The association of KIR3DL2 mutation with objective response may provide a robust method for the selection or stratification of AITL and other lymphoma pts who could benefit from tipifarnib therapy. Keywords: angioimmunoblastic T-cell lymphoma (AITL); chemokines; peripheral T-cell lymphomas (PTCL). Disclosures: Gualberto, A: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Scholz, C: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Mishra, V: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kessler, L: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Rodriguez, M: Research Funding: Kura Oncology. Piris, M: Research Funding: Kura Oncology. Witzig, T: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study).