Outcomes for Patients with Relapsed and Refractory Peripheral T-Cell Lymphoma in the 21^st Century By Relapse Status, Salvage Therapy, and Receipt of Allogeneic Transplant

INTRODUCTION: Patients with relapsed or refractory (R/R) nodal-based peripheral T-cell lymphomas (PTCL) have historically poor outcomes. Series from the early 21^st century show short median survival times of less than one year; more recent reports show slightly prolonged survival, potentially reflecting increasing use of targeted therapies and wider availability of allogeneic hematopoietic stem cell transplant (alloHCT). To better refine our understanding of clinical outcomes in this context, we characterized a large cohort of patients with R/R PTCL to evaluate updated outcomes by relapse status, salvage therapy, and receipt of alloHCT.

METHODS: Through the Memorial Sloan Kettering Cancer Center patient database, we identified patients ≥ 18 years of age with histologically-confirmed PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), or anaplastic large cell lymphoma (ALCL) who were consecutively treated at our center between January 1, 2001 to October 1, 2021 at the time of initial diagnosis. Patients with < 6 months of followup in absence of progression, relapse, or death were excluded. Patients were categorized as primary refractory (having never achieved at least a partial response [PR] at end of therapy) or relapsed (achieved at least PR at end of therapy followed by subsequent disease progression). Retreatment regimens were categorized as cytotoxic or non-cytotoxic, which included brentuximab vedotin, histone deacetylase inhibitors (belinostat, romidepsin), and multiple other targeted therapies, including investigational agents. The primary objective was to determine the median progression-free (PFS) and overall survival (OS) of patients with R/R disease. Survival estimates were performed using the Kaplan-Meier method and compared for various features using the log-rank test, with p-value of ≤ 0.05 considered significant.

RESULTS: A total of 348 patients were identified; 193 (55%) had R/R disease (n=84 primary refractory; n=109 relapsed) (Table 1). Seventy-three patients had prior autologous transplant. The median time to relapse from end of initial therapy was 10.0 months (range: 0.7 months to 13.4 years). Thirteen patients were not treated at relapse/progression; 2 patients declined further treatment and all others died before treatment was initiated. Among those treated, first salvage included cytotoxic therapy (n=83), non-cytotoxic (n=89), other therapy (n=5), or radiation alone (n=3). Other therapies consisted of 4 patients treated with regimens consisting of cytotoxic therapy in combination with a non-cytotoxic agents and 1 patient treated with EBV-targeted cytotoxic T lymphocyte therapy. Among the entire R/R population, the median PFS and OS was 4.7 (95% CI 2.6-6.7) and 14.6 (8.5-20.6) months, respectively. Median OS for primary refractory versus relapsed was 7.7 versus 22.4 months, respectively (p=0.05). By histology, median OS for PTCL-NOS (n=92), AITL (n=73), anaplastic lymphoma kinase (ALK)+ ALCL (n=9), and ALK- ALCL (n=19), was 8.2, 22.4, not reached, and 30.4 months, respectively (p=0.06). Median OS for those not treated, treated with cytotoxic therapy, and treated with non-cytotoxic therapy was 0.9, 12.6, and 29.4 months, respectively (p<0.001). Overall 5-year survival for those who received an alloHCT after salvage therapy (n=41) versus those who did not (n=152) was 67% versus 17% (p<0.001). Specifically for those who achieved a complete response to initial salvage therapy (n=76), overall 5-year survival for those who subsequently received an alloHCT (n=25) versus those who did not (n=51) was 63% versus 35% (p=0.02) (Figure 1). Reasons for not receiving an alloHCT were varied. On multivariate analysis by era of diagnosis, histology, time to relapse, treatment modality, response to therapy, and transplant status, receipt of alloHCT conferred significantly decreased risk of death (HR 0.2, 95% CI 0.1-0.4, p<0.001).

CONCLUSIONS: R/R nodal-based PTCL remains common. In our cohort, patients with primary refractory disease had worse survival than those with relapse, as did those treated with cytotoxic therapy versus non-cytotoxic therapy as first salvage. Overall survival in this setting remains poor, though patients who achieve a complete response to salvage therapy followed by alloHCT can have prolonged, potentially curative remissions. Durable therapies in the non-transplant population are needed.

Sauter:BMS: Other: PI; Precision Biosciences: Other: PI; Genzyme/Sanofi: Other: PI; Gamida Cell: Consultancy; CSL Behring: Consultancy; Ono Pharmaceuticals: Consultancy; Kite Pharma Inc.: Consultancy; Karyopharm Therapeutics Inc.: Consultancy. Scordo:McKinsey & Company: Consultancy; Medscape, LCC (CME): Honoraria; Kite - A Gilead Company: Other: Ad-hoc advisory board (past); i3Health (CME): Honoraria; Amgen, Inc.: Research Funding; Omeros Corporation: Consultancy, Research Funding; Angiocrine Bioscience, Inc.: Consultancy, Research Funding. Shah:Janssen: Research Funding; Beyond Spring: Research Funding; Amgen: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Biegene: Research Funding; Miragen: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; SecuraBio: Research Funding; Affimed: Honoraria; Imbrium Therapeutics L.P./Purdue: Honoraria; Janpix Ltd: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Horwitz:C4: Research Funding; Seattle Genetics,: Research Funding; ONO Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kyowa Hakko Kirin: Consultancy; Daiichi Sankyo: Research Funding; Crispr Therapeutics: Research Funding; Celgene: Research Funding; ADC Therapeutics: Research Funding; Yingli Pharma Limited and Tubulis: Honoraria; Shoreline Biosciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem/SecuraBio: Research Funding; Millennium /Takeda: Research Funding; Cimieo Therapeutics: Honoraria; Kyowa Hakko Kirin: Research Funding; Affimed: Research Funding; Takeda: Consultancy; SecuraBio: Honoraria; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Affimed,: Consultancy.