Lenalidomide with Ipilimumab for Lymphoid Malignancies after Allogeneic or Autologous Stem Cell Transplantation (SCT)

Background: Prevention or treatment of relapse after SCT for lymphoid malignancies requires novel strategies. Targeting immune checkpoints could result in lasting responses but only in few patients. Combination strategies with targeted agents, such as lenalidomide, could result in the release of tumor antigens to tumor-specific T cells. These T cells would become activated but also upregulate inhibitory checkpoints such as CTLA-4. These can be blocked with the anti CTLA-4 antibody, ipilimumab, to permit enhanced anti-tumor T cell responses (Sharma P and Allison JP. Cell 2015). In addition, the release of tumor antigens may focus the activated immune response on tumor antigens rather than self-antigens, resulting in fewer adverse events (AEs). Patients andMethods: Patients (pts.) with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autoSCT were included within 6 months post-transplant, if they had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Lenalidomide dose reduction was permitted to 5 mg based on standard clinical practice. The primary objective was to evaluate safety and secondary objectives were to assess overall response rate (ORR) and survival. Results: Sixteen pts. were enrolled in the study. Autologous group (n=7): The median age was 55 yrs (range, 33 - 68). Lymphoma histologies included [Double-hit (DHL) (n=3), mantle cell (MCL) (n=3; including 2 with 2 prior transplants, one with CNS involvement), and Hodgkin's disease (n=1 with persistent PET+ post-SCT]. Median time to enrollment after SCT was 3.7 months. Median follow-up was 9.0 months (range, 5.3 - 27.1). All pts. remain alive. One DHL pt. transplanted during second remission relapsed at 1.6 months after just initiating cycle 2 of therapy. All others remain in complete remission (CR). The most common other AEs were 16 events of neutropenia (n=4, gr 4; n=2, gr 3, n=10, gr 2), thrombocytopenia (n=1, gr 2,) and one pt. developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one pt. (dermatitis, gr 2) after the second ipilimumab dose and resolved with steroids. Allogeneic group(n=9): The median age was 54 yrs (range, 44- 66). Histologies included [Follicular (n=3), CLL (n=2), MCL (n=2), DHL (n=1), diffuse large cell (n=1), and T-cell anaplastic lymphoma (n=1)]. The median number of therapies excluding the alloSCT was 3 (range 2- 7). Two failed a prior autoSCT, one had 2 prior alloSCT, and 3 failed prior DLIs. Two pts. relapsed within 2 months of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed GVHD, which responded to steroids and pt. is now off immunosuppression. All others finished planned treatment without GVHD. ORR was 75% (CR 37.5% and PR 37.5%). With a median follow-up time of 9.2 months (range, 3.0-20.9), all pts. remain alive. Three pts. had recurrent disease at a median time of 5.4 months (range, 4.6 -12.0) after stopping therapy. One is showing ongoing response to retreatment. AEs included seven episodes of neutropenia (n=1, gr 4; n=2, gr 3; n =4, gr 2), anemia (n=1, gr 2), diarrhea (n=1, gr 2), nausea (n=1, gr 2), headache (n=1, gr 2), hypertension (n=1, gr 2). All AEs resolved. There were no immune mediated AEs. Immunologic analyses: We conducted 17-color flow cytometric analyses on PBMC pre-, during and post-treatment time points. We observed ~1.5-2-fold increase in ICOS+ CD4+T cells after ipilimumab+lenalidomide combination therapy. We previously identified an increase in ICOS+ CD4+ T cells as a phamacodynamic biomarker of ipilimumab therapy (Ng Tang et al., Cancer Immunology Research, 2014). Although we expected significant differences in immunologic impact of ipilimumab therapy in allogeneic versus autologous transplant pts., our preliminary data indicate similar immune responses in the two groups.

Conclusions:Treatment with lenalidomide and ipilimumab after SCT for pts with lymphoid malignancies has a favorable toxicity profile. Our Immunological results, together with the fact that the frequency of AEs was not different between the allogeneic and autologous arms, suggest that combination therapy with lenalidomide and ipilimumab elicits measurable immunologic changes and clinical responses without inducing GVHD.