Background: PTCL are aggressive malignancies associated with poor prognosis when treated with cytotoxic chemotherapy. Novel agents, such as HDAC inhibitor romidepsin and immunomodulatory agent lenalidomide, have shown clinical activities as single agents and in combination in R/R PTCL. We hypothesize that upfront treatment with these agents is an effective and well-tolerated option to defer chemotherapy, particularly in patients who are not candidates for intensive approach. We report the findings of the first chemo-free combination of romidepsin plus lenalidomide as initial treatment for PTCL (ClinicalTrials.gov-NCT02232516). Methods: Patients with untreated PTCL who were over 60 or noncandidates for chemotherapy based on comorbidity CIRS score were eligible. Treatment was initiated with romidepsin 10 mg/m2 IV on d 1, 8, 15, and lenalidomide 25 mg PO on d 1-21 of 28-day cycle for up to 1 year, unless discontinued prior due to POD, toxicities, or withdrawal of consent. The primary objective was to evaluate ORR per Cheson criteria. Secondary objectives included safety, PFS, OS, DOR, and delay to chemotherapy. The sample size was 20 evaluable patients, which allows to estimate the underlying true response rate with the margin of error of an approximate 95% confidence interval equal to 0.22, assuming the true ORR = 0.5. Results: The study enrolled 29 subjects at 3 US centers, including 16 (55%) AITL, 11 (38%) PTCL-NOS, 1 ATLL and 1 EATCL. The median age was 75 (range 49-84), and M:F ratio was 1:1. Nineteen (66%) had stage III/IV disease, 23 (79%) had elevated LDH, and 9 (31%) had IPI 3-5. Treatment was well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%) and anemia (28%). Grade 3-4 non-hematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), lung infection (10%) and sepsis (10%). At a median follow-up of 8 months, 20 subjects were evaluable with at least one response assessment, and received a median treatment of 6 cycles. The ORR was 75% (95%CI: 50.9%, 91.3%) with CR at 30% (11.9%, 54.3%). For AITL, the ORR was 85% (54.6%, 98.1%) with CR at 38% (13.9%, 68.4%). Median DOR was 4.2 months for all responders, and 14.3 months for CR patients. The estimated 1-yr PFS was 54.3% with 3-yr PFS at 36.2%, and the estimated 1-yr OS was 76.0% with 3-yr OS at 51.3%. Two subjects moved onto consolidative ASCT in remission, and 4 received additional cytotoxic chemotherapy after progression. Conclusions: This study provides the first demonstration that chemo-free biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL patients who are not candidates for cytotoxic chemotherapy. These data justify further evaluation of such novel agents as a frontline strategy. Clinical trial information: NCT02232516