End of Treatment Peripheral Blood T-Cell Receptor Gene Rearrangement Evaluation for Minimal Residual Disease Evaluation in Peripheral T-Cell Lymphomas
Authors: Mehta-Shah Neha , Fehniger Todd A , Jacobsen Eric D , Peterson Katrina , Kahl Brad S. , Bartlett Nancy L. , Cashen Amanda F , Ghobadi Armin , Fischer Anne , Reagan Beth , Moskowitz Alison J. , Wan Fei , Huang Ying , Hutt Kasey , Vigil Edgar , Olson Meredith , Jacobsen Austin , Horwitz Steven M. 
Published: February 2021

Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas with an overall response rate to CHOP-based therapy of 80% but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CT is prognostic (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response suggests that more sensitive determinants of minimal residual disease may have prognostic and even therapeutic importance. T-cell receptor gene rearrangement (TCR) by next generation sequencing is able to detect a known TCR clonotype at 10-5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of peripheral blood TCR by next generation sequencing in quantifying minimal residual disease in peripheral T-cell lymphoma. (NCT03297697) Here we report the results of TCR evaluation at the end of CHOP-based therapy.
Methods: Patients with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL;, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TCR gamma, TRG, or TCR beta, TRB) clonotype was established from baseline diagnostic tumor tissue. Peripheral blood (10cc) was collected in Streck tubes for TCR clonotype at each cycle of therapy, after completion of CHOP-based therapy, every 6 months for two years, at progression and in the stem cell product (if collected). TCR clonality was assessed and tracked using the LymphoTrack® TRG/TRB Assays-MiSeq® (Invivoscribe, San Diego, CA).
Results: 39 patients were enrolled in the study (16 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 1 MEITL). One patient was enrolled with PTCL-NOS but was withdrawn after confirming a diagnosis of T-ALL. One patient with ALK- ALCL withdrew consent prior to sample collection. 19 patients have completed frontline therapy and have end of treatment TCR analysis available. The remaining 18 patients either have not yet completed treatment or did not have samples analyzed at the time of submission. Patients received CHOEP (n=10), BV-CHP (n=4), CHOP (n=32), CEOP (n=1) and CHOP+azacitidine (n=1). Median age was 61 (range: 22-80). Sixteen completed 6 cycles of therapy and of these, 7 underwent consolidation with an autologous transplant. One stopped due to intolerance after 5 cycles and remains in complete remission. 2 had progression of disease prior to completion of 6 cycles of therapy. At end of treatment evaluation by PET/CT, 13/19 (68%) had complete remission, 1/19 (5%) had partial remission and 5/19 (26%) had progressive disease.
Of the 19 patients, 15 (78.9%), including 1 with leukemic disease, had TCR clonotype identifiable in the baseline diagnostic tissue, and 4 (21.1%) did not have a TCR clonotype identified (3 PTCL NOS, 1 ALK+ ALCL) in tumor tissues at baseline. Two of 15 patients had undetectable TCR clonotype in the blood at end of treatment and neither of them has relapsed. Thirteen of the 15 patients had detectable TCR clonotype at end of treatment. Of the 10 patients in complete remission by PET/CT at the end of treatment with known clonotype, 8 had a detectable TCR clonotype and 2 had undetectable TCR at the end of CHOP-based therapy. Five of 6 patients with PD or PR at end of treatment had detectable TCR clonotype in the blood and 1 lacked clonotype in baseline samples. At a median follow up of 13.1 months, only one patient has relapsed and this patient had positive peripheral blood TCR at end of treatment despite PET CR. We will present the end of treatment evaluation for all patients on the study at the time of the meeting.
Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in PTCL using next generation sequencing with a known tumor clonotype. Lack of radiographic CR was highly correlated with detectable TCR, but detectable TCR was also frequently seen in complete remission by PET/CT. Longer follow up, including analysis of TCR following autologous transplant, is required to determine if TCR clonotype at the end of CHOP-based therapy predicts likelihood of relapse and to evaluate the dynamics of TCR clonotype during and after completion of treatment.
This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society.

Disclosures
Mehta-Shah: Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Innate Pharmaceuticals: Research Funding; Genetech/Roche: Research Funding. Fehniger:Indapta: Consultancy; Nkarta: Consultancy; Kiadis: Consultancy; HCW Biologics: Research Funding; Compass Therapeutics: Research Funding; ImmunityBio: Research Funding; Orca Biosystems: Consultancy; Wugen: Consultancy. Jacobsen:Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Kahl:AbbVie: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Laboratories Inc: Consultancy; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; BTG: Consultancy; Janssen: Research Funding; BMS/Celgene: Research Funding; Immune Design: Research Funding; Kite, a Gilead Company: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Roche/Genentech: Consultancy, Research Funding; Autolus: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; WuGen: Consultancy; EUSA: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy. Huang:Invivoscribe: Current Employment. Hutt:Invivoscribe: Current Employment. Vigil:Invivoscribe: Current Employment. Olson:Invivoscribe: Current Employment. Jacobsen:Invivoscribe: Current Employment. Horwitz:GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; Myeloid Therapeutics: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Affirmed: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; C4 Therapeutics: Consultancy.