Ten-Year Results of a Phase II Clinical Trial Evaluating Ipilimumab Plus Lenalidomide Combination after Autologous Hematopoietic Cell Transplantation in Patients with Lymphoma
Authors: Jabbour Joseph E. , Milton Denái R. , Gulbis Alison M. , Wang Bofei , Haddad Fadi G. , Ledesma Celina , Champlin Richard E. , Sharma Padmanee , Young Ken H. , Khouri Issa F. 
Published: December 2024

Background: We have previously reported a favorable safety profile of combining the checkpoint inhibitor ipilimumab (Ipi) with lenalidomide (LEN) given after autologous hematopoietic cell transplantation (HCT) to harness anti-lymphoma immunity (Clin Cancer Res 2018). The long-term efficacy of this strategy remains unknown.

Patients and Methods: In this prospective trial, patients with lymphoma were enrolled within 6 months after HCT. Inclusion criteria included: age 18 to 80 years; ECOG performance status 0-2; adequate liver (bilirubin and liver enzyme concentrations up to 2 times the upper limit of normal), renal (serum creatinine &lt; 1.6 mg/dL), cardiac and pulmonary function; no active infections; absolute neutrophil count ≥ 1.5x109/L; and platelet count ≥ 75x109/L. Treatment consisted of a cycle of LEN (10 mg orally daily for 21 days; cycle 1), followed by Ipi (3 mg/kg intravenously on day 1 of a 28-day cycle; cycle 2), for up to 8 alternating cycles (4 cycles per drug). LEN dose reduction to 5 mg was permitted based on standard clinical practice. Toxicity and survival duration were evaluated. We performed univariate assessment of probability of lymphoma-free status based on demographic and clinical characteristics, including alterations in CMYC/BCL2.

Results: Twenty-five patients were enrolled in the study. The median age at HCT was 56 years (range, 33-74). Seventeen (68%) were males, and 6 (24%) patients had HCT-specific Comorbidity Index (HCT-CI) ≥ 3. The median number of prior chemotherapy regimens excluding the transplant was 2 (range, 1-7). Three patients had had a prior unsuccessful HCT. Ten patients (40%) had diffuse large B-cell lymphoma (DLBCL) with CMYC/BCL2 alterations (8 were double-hit [DHL] and double-expressor [DEL] lymphomas, 1 DEL only, and 1 DHL that was not assessed for DEL). Other lymphoma histologies were non-DEL/non-DHL DLBCL (n=6, 24%); mantle cell lymphoma (n=4, 16%; including 2 with 2 prior transplants, 1 with central nervous system involvement, 2 with blastoid histology, and 1 who had partial response to induction chemotherapy); follicular lymphoma (n=1; 4%; 3 prior therapies); Hodgkin lymphoma (n=2, 8%; including 1 with persistent positron emission tomography positivity after transplant); and angioimmunoblastic T-cell lymphoma (n=2, 8%). Most patients received rituximab plus BEAM (n=18, 72%) conditioning for their HCT. Median time from HCT to starting immunotherapy maintenance with Ipi+LEN was 3.3 months (range, 1.4-5.5 months). Median number of cycles of immunotherapy received after HCT was 5 (range, 3-8). Median follow-up duration was 73 months (range, 12-123 months). Three patients developed immune-mediated toxicity (2 colon, 1 skin); they all responded to therapy with steroids. Three patients died, 1 of progressive lymphoma and 2 with secondary acute myeloid leukemia. Overall survival rates at 3-year and at last follow-up were 96% and 71%, respectively. In univariate assessment of 3-month landmark analysis of probability of lymphoma-free status, we found no significant difference by age (≤60 vs &gt;60 years; P = .82), male gender (P = .20), stage at diagnosis (P = .36), HCT-CI (&lt;3 vs ≥3; P =.90), or total lines of therapy before HCT (&lt;3 vs ≥3; P = .30). The 10 patients whose lymphoma had CMYC/BCL2 alterations had a better probability of being lymphoma-free at their last follow-up than the other patients (90% vs 27%; P = .07). One of the patients with CMYC/BCL2 alteration had a relapse after autologous HCT, then underwent allogeneic HCT and experienced a relapse 2 months later, so had refractory disease at the time of initiating Ipi+LEN; this patient continues to be in remission 10 years after finishing his therapy without any further intervention. The expected 5-year survival in these patients is 0-25% without immunotherapy.

Conclusions: The use of Ipi+LEN after HCT for high-risk lymphoma shows encouraging long-term survival rates. The favorable outcome in patients with MYC/BCL2 DEL/DHL needs to be verified in a larger number of patients. The lower dose of LEN used every other month in our trial makes it unlikely that the responses observed were due to LEN; rather, they likely were due to immunomodulation from immunotherapy with Ipi. In the era of CAR-T and targeted therapy, the combination of Ipi+LEN could be studied in patients who do not achieve complete response to those treatments.