Durable Responses with Ipilimumab Plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Background: Prevention or treatment of relapsed lymphoid malignancies after SCT requires novel strategies. We previously reported on safety and early responses of ipilimumab combined with lenalidomide in 16 treated patients (pts.) (Khouri et al. Clin Cancer Res, 2018). Here, we update the published data on a larger cohort of pts. with a longer follow-up. In addition, we define immune phenotpyes that correlated with response. Patients andMethods: Pts. with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autologous SCT were included within 6 mos post-SCT if they were still in CR, but 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). Considering the favorable safety profile in the initial patients treated, number of cycles was amended to 8 cycles in 6/2017. PBMC's from 20 pts (12 responders and 8 non-responders) were analyzed by flow cytometry. Results: Twenty-two pts. were enrolled. Autologous group (n=11): Median age was 57 yrs (range, 33-68). Histologies included diffuse-large-B-cell lymphoma (DLBCL) [n=6; including 3 with double-hit lymphoma (DHL)], mantle cell lymphoma (MCL) (n=2; one with CNS involvement), Hodgkin's disease (n=2; with persistent PET+ post-SCT), and follicular lymphoma (n=1, PIF with response to 4^th line of therapy). Median time to enrollment after SCT was 3.8 months (range, 1.4-5.5). With a median follow-up duration of 23.4 months (range, 10.1- 48), median OS was not reached. Three pts. relapsed at a median of 6.7 months; 1 pt. died after developing T-cell lymph proliferative disorder 2 years after finishing treatment and ten pts. remain alive. The most common other AEs were 19 events of neutropenia (n=5, gr 4; n=2 gr 3, n=12 gr 2), two patients had thrombocytopenia gr 2, and one developed pulmonary embolism. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. AEs were similar in pts. who received 4 or 8 cycles (n=5). Allogeneic group(n=11): Median age was 55 yrs (range, 44- 66). Histologies included [Follicular (n=2), CLL (n=3), MCL (n=2), DLBCL (n=3; 2 of whom were DHL), and T-cell anaplastic lymphoma (n=1)]. Median number of therapies excluding the alloSCT was 3 (range 2-7). Two failed a prior autoSCT, one had 2 prior alloSCT, and three failed prior donor lymphocyte infusions, and one CLL pt. failed prior FCR, lenalidomide/ofatumumab, ibrutinib, idelalisib, CAR-T cell and venetoclax. Two pts. relapsed within 3 mos 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 liver and skin GVHD, which responded to steroids. Another pt. developed chronic GVHD after cycle 4 which precluded treatment with the pre-planned 8 cycles. No other cases of GVHD were noted. ORR rate was 73%. Five (45%) pts. had CRs (four of which were durable at 14+, 32+, 33+ and 34+ months; including the CLL pt. who failed small molecule inhibitors and CAR-T), and 3 (27%) had PR. With a median follow-up time of 30.8 mos (range, 3-45.1), 9 (82%) pts. remain alive. One PR pt. died secondary to cardiac complications after a hip replacement; and 1 died of progression. AEs included eight episodes of neutropenia (n=2, gr 4; n=2, gr 3; n =4, gr 2), anemia gr 2 (n=1), thrombocytopenia gr 2 (n=1), diarrhea (gr 2; n=1), nausea (gr 2, n=1), headache (gr 2; n=1), hypertension (gr 2; n=1), hypoalbuminemia (gr 2; n=1). All AEs resolved. Immune monitoring of 20 transplant pts showed a Th1 type anti-tumor immune response in responding pts. In the responders, there was a higher frequency of CD4+ICOS+PD-1+ and CD8+PD+1 T effector cells at baseline when compared to non-responding pts. In contrast, the non-responders had a Th2 type response with a higher frequency of CD4+GATA3+ T effector memory cells at baseline when compared to responders (Figure). Conclusions: Follow-up results demonstrate better than expected response rates that are durable in pts. with lymphoid malignancies who relapsed after alloSCT. Continuous remission duration was also observed after autologous SCT. Immune monitoring analysis suggests that CD4+GATA3+ T cells could be a potentially valuable biomarker for stratification of pts. for lenalodimide+ipilimumab combination therapy.

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