Outcomes Following Salvage Therapy in Primary Refractory Peripheral T-Cell Lymphoma (PTCL)
Authors: Zhang Janie Y , Briski Robert , Devata Sumana , Kaminski Mark S , Phillips Tycel , Mayer Tera , Bailey Nathanael G , Wilcox Ryan A 
Published: October 2019

Abstract
Background: Resistance to conventional anthracycline-based regimens (CHOP/CHOEP) and the emergence of primary refractory disease remains a clinical challenge in PTCL, and is observed in ≈25% of patients. Outcomes in the setting of primary refractory disease, particularly for those patients who fail to achieve a remission with second-line chemotherapy, are poorly described and the optimal therapeutic strategy for these patients remains uncertain.
Patients and Methods: We identified 159 patients with PTCL who received multi-agent, anthracycline-based treatment from 1988 to 2011 in the PTCL database at our institution. Primary refractory disease, defined as disease progression during initial therapy or relapse within 6 months of its completion, was observed in 58 (36%) of patients.
Results: The median age at diagnosis with primary refractory PTCL was 49 years (range, 18.8-77.1). Median follow up was 2.7 years among surviving patients (95% CI, 1.2-6.3). Median overall survival (OS) was 1.1 years (95% CI, 0.7-1.9). The median number of lines of therapy underwent by patients was 3 (range, 1-9). PTCL, NOS (n=24), angioimmunoblastic T-cell lymphoma (n=6), and ALK-positive anaplastic large cell lymphoma (n=7) accounted for the majority (63.8%) of these patients. No difference in OS was observed between patients who failed to respond to initial therapy and those who relapsed within 6 months after a first remission (median OS 0.9 [95% CI, 0.6-1.9] vs. 1.3 [95% CI, 0.5-6.3], p=0.6). After developing primary refractory disease, 48.3% of patients received aggressive, multi-agent salvage regimens (ICE, n=16; DHAP, n=3; ESHAP, n=6; other, n=3), 29.3% of patients received other systemic therapies (HDAC inhibitor, n=1; gemcitabine-based therapies, n=5; pralatrexate, n=3; other, n=8), and 22.4% of patients received no systemic therapies. Patients who received no systemic salvage therapy had reduced OS compared to both patients who received aggressive regimens and patients who received other types of systemic therapies (median OS 0.3 [95% CI, 0.2-1.1] vs. 1.7 [95% CI, 0.8-11.7] vs. 1.3 [95% CI, 0.4-8.6], respectively, p<0.001), but the difference in OS observed between patients who received conventional salvage regimens and other systemic therapies was not significant (p=0.3). Patients receiving aggressive, multi-agent salvage regimens were more likely to undergo autologous or allogeneic stem cell transplantation (SCT) compared to those receiving non-traditional regimens or no systemic therapy (53.6% vs. 23.5% vs. 0%, respectively, p=0.0003). Following second-line therapy, 32.8% of patients underwent high dose therapy followed by autologous SCT (ASCT) (n=5) or allogeneic SCT (allo-SCT) (n=15). Not surprisingly, consolidation with either ASCT or allo-SCT was associated with improved OS (median OS 2.3 [95% CI, 0.9-11.4] vs. 0.6 [95% CI, 0.4-1.3], p=0.0012). Among patients who underwent allo-SCT, 26.7% (n=4) relapsed; among those who underwent ASCT, 60% (n=3) relapsed. A median OS of 0.6 years (95% CI, 0.4-1.1) was observed in patients who failed to achieve a remission with first salvage therapy and did not undergo ASCT or allo-SCT (n=25). Overall, 77.6% of patients with primary refractory PTCL failed to achieve a remission following second-line therapy or relapsed within 3 months of transplant. Among patients who did not achieve remission with the first salvage therapy, a median of 1 subsequent line of therapy (range, 0-7) was utilized. Among these patients who did not achieve a remission with initial salvage therapy, 20.6% (n=7) achieved a partial or complete remission with further therapy.
Conclusion: Primary refractory PTCL is associated with dismal outcomes. The likelihood of achieving a remission and proceeding to transplant is ≈30% and with transplant, only 11 (19% of patients with primary refractory disease) achieved a durable remission. Improved understanding of resistance mechanisms in PTCL and the development of improved therapeutic strategies are needed. A significant survival benefit was not observed for patients receiving traditional salvage regimens compared to other systemic second-line regimens, with median survival <20 months. Therefore, participation in well-designed clinical trials should be encouraged in these patients.

Disclosures
No relevant conflicts of interest to declare.