PS1308 TARGETING T‐CELL RECEPTOR SIGNALING PATHWAY BY DASATINIB IN RELAPSED/REFRACTORY ANGIOIMMUNOBLASTIC T‐CELL LYMPHOMA
Authors: Kiyoki Y. , Sakata‐Yanagimoto M. , Nguyen T.B. , Fujisawa M. , Nannya Y. , Ishitsuka K. , Momose H. , Sukegawa S. , Shinagawa A. , Suyama T. , Sato Y. , Nishikii H. , Obara N. , Kusakabe M. , Kato T. , Yokoyama Y. , Kurita N. , Hasegawa Y. , Ogawa S. , Chiba S. 
Published: June 2019

Background:

Angioimmunoblastic T‐cell lymphoma (AITL) is an intractable T‐cell lymphoma. The recurrent hotspot (p.Gly17Val) mutations in RHOAencoding a small GTPase, together with the loss‐of‐function mutations in TET2encoding an epigenetic regulator, are the genetic hallmark in AITL. We previously identified that the p. Gly17Val RHOA mutant hyperactivates T‐cell receptor (TCR) signaling through direct binding to VAV1, a component of the TCR pathway. VAV1mutations were also found in RHOA‐negative AITL cases. The phosphorylation of VAV1 induced by the RHOA binding or its own amino acid changes was effectively inhibited by dasatinib at low concentrations. Dasatinib also prolonged the survival of AITL model mice (ASH 2017).

Aims:

Here, we performed a phase I clinical trial of dasatinib monotherapy in relapsed/refractory AITL patients.

Methods:

Five patients (one male and four females; 51–72 y/o; median, 65 y/o) being diagnosed with AITL were enrolled. Written informed consent was obtained from all the patients.

Results:

The median number of prior chemotherapies was 2 (range, 1–5). Two patients (Patient 1 and 2) were refractory to the latest chemotherapies. One patient (Patient 3) relapsed after the autologous transplantation. The performance status was 0‐ 2 (Table 1). Dasatinib was started at a dose of 100 mg/body q.d. and continued until days 10–78 (median day 58). Patient 2 withdrew the consent on day 10 and thus the response was not evaluable. In the remaining four patients, dasatinib was continued until day 54 or later and the response evaluation was possible. The trial was ultimately discontinued due to further treatment with allogeneic hematopoietic stem cell transplantation, disease progression, or severe adverse event in these four patients. Grade3/4 adverse drug reactions were observed in one case (Patient 5). The other adverse events were attributable to exacerbation of the diseases. There were no new safety concerns other than reported in BCR‐ABL‐positive chronic myelogenous leukemia/acute lymphoblastic leukemia. The maximum response was partial responses (PR) in all these four patients. The response at the discontinuation of trial was PR in two (Patient 1 and 5) and progressive disease (PD) in two (Patient 3 and 4).

Targeted sequencing using a panel for 427 genes identified 34 candidate mutations including 22 nonsilent single nucleotide variants (SNVs), 2 nonsense mutations, 3 frameshift deletions, 2 frameshift insertions, 2 nonframeshift deletions, and one nonframeshift insertion. Two TET2 mutations were found in 4 samples (PAT1, PAT2, PAT4, and PAT5). The Gly17Val RHOA mutations were found by targeted sequencing in 2 samples (PAT3 and PAT4). VAV1 mutations were found in 2 samples (PAT2 and PAT5). Additionally one tandem duplication involving VAV1 locus was also identified by manual inspection of Integral Genome Viewer (IGV) in PAT5.

Summary/Conclusion:

AITL is highly dependent on TCR signaling, and dasatinib appears to be a promising candidate treatment modality in AITL.