Maintenance Therapy with Ipilimumab Plus Lenalidomide after Autologous Stem Cell Transplantation for Patients with Lymphoma

Background: Relapse is the major cause of failure after autologous stem cell transplantation (autoSCT) for patients (pts) with lymphoma. Targeting immune checkpoints with ipilimumab (Ipi) could result in lasting responses but only in few pts. We have previously reported that combination strategies of Ipi with lenalidomide (LEN) 10 mg (Ipi+LEN) resulted in enhanced immune activity manifested by a significant increase in the numbers of ICOS⁺CD4⁺FoxP3^- T cells (Khouri I et al. Clin Cancer Res 2018:1011-1018). We have demonstrated proof-of-principle of this activity in one pt with refractory double hit lymphoma (DHL) (failed an autoSCT then relapsed after an allogeneic SCT) and another pt with CLL (failed ibrutinib, CART cell, and allogeneic SCT). Both pts then achieved complete remission with Ipi+LEN that has lasted 5+ and 4+ years, respectively. Hence, we have used Ipi+LEN to prevent relapse after autoSCT in pts with high-risk lymphoma, including double-expressor (DEL)/DHL who have been reported to have a 0% progression-free survival (PFS) rate at 4-years after autoSCT (Herrera et al. J Clin Oncol. 2017; 35:24-33). Patients and Methods: In this prospective trial, pts with lymphoma were enrolled within 6 months post-autoSCT. Inclusion criteria included: age 18 to 80 years; an ECOG PS 0-2; adequate liver (bilirubin and liver enzyme concentrations up to two times the upper limit of normal), renal (serum creatinine < 1.6 mg/dl) , cardiac (ejection fraction 45%), and pulmonary (diffusing capacity of the lung for carbon monoxide 40% of predictive value) function; no active infections; ANC ≥ 1.5x10⁹/L and a platelet count ≥ 75x10⁹/L. Treatment consisted of LEN 10 mg PO daily for 21 days (cycles 1) alternating with Ipi 3 mg/kg IV on day 1 (Cycle 2) for up to 8 cycles. LEN dose reduction was permitted to 5 mg based on standard clinical practice. Results: Twenty-three pts were enrolled in the study. The median age at autoSCT was 56 years (range, 33-74). Fifteen (65%) were males and 5 (22%) pts had an HCT-CI ≥ 3. The median # of prior chemotherapies excluding their SCT was 2 (range, 1-5). Two pts had failed a prior autoSCT and were enrolled after a second transplant. Histologies included [DEL/DHL (n=8, 35%), DLBCL nonDEL/nonDHL (n=6, 23%), mantle cell lymphoma (MCL) (n=4, 17%; including 2 with 2 prior transplants, 1 with CNS involvement, 2 had blastoid histology, 1 in partial response to induction chemotherapy), follicular lymphoma (n=1; 4%; 3 prior therapies) Hodgkin’s disease (n=2, 9%; including 1 with persistent PET+ post-transplant), angioimmunoblastic t-cell lymphoma (n=2, 9%). Most pts received R-BEAM (n=17, 74%) or BEAM (n=3, 13%) conditioning for their autoSCT. Median # of cycles of immunotherapy received after autoSCT was 5 (range, 2-8). Two pts are continuing their pre-planned treatment. Median follow-up duration was 35 months (range, 4-78 months). The 3-year rates of overall survival (OS) and PFS were 92% and 73%, respectively (Figure 1). Only 1 death was observed: this occurred in a pt with MCL who received 2 prior autoSCT and then developed post-transplant lymphoproliferative disorder without any evidence of MCL recurrence. The most common other grade 3-4 AEs were 10 events of neutropenia, anemia (1), perianal infection (1), and one developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. DEL/DHL group (n=8): This group was heavily pre-treated. The median # of prior chemotherapies excluding their SCT was 3 (range, 1-5). Five have failed DA-REPOCH, one had failed R-Hyper-CVAD and one was induced with R-CHOP. With a median follow-up of 35 months (range, 4-78months), all pts remain alive. One patient with DEL/DHL who was transplanted during second remission relapsed at 1.6 months after initiating therapy (just after finishing the cycle 2). All others remain in complete remission (Figure 2). Conclusions: Maintenance therapy with Ipi+LEN after autoSCT for high-risk lymphoma shows encouraging survival rates, including pts with DEL/DHL who usually have dismal outcomes. The treatment has favorable toxicity profile. These results warrant a randomized trial for confirmation.