Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with Aggressive T-Cell Malignancies in a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with FluBu conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT in the context of clinical results.

Methods: This is a phase I/II clinical trial of patients with T-leukemia/lymphoma in at least a partial remission requiring an allo-SCT, <70 years of age, with a MRD/MUD donor. Patients received BuFlu (AUC 20000 or 16000) with rom, followed by tacrolimus/methotrexate GVHD prophylaxis with ATG for MUDs. An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2^nd year optional), with built in dose reductions for toxicity. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=10) versus those who did not receive m-Rom (n=5). Cells were targeted against K562 and T-cell lymphoma targets using the calcein-AM assay. Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups.

Results: To date, 28 patients have been enrolled, with a median age at transplant of 55, 50% female, 75% received MUD donor, and 68% utilized PB marrow source with 32% receiving BM. 16/28 (57%) had a diagnosis of T-cell leukemia, while 12/28 (42%) had a diagnosis of lymphoma. These included: T-ALL (18%), ETP-ALL (14%), ATLL (4%), T-PLL (21%), CTCL (7%), and PTCL (36%). 18% of patients entered transplant in a PR, while the remaining entered transplant in CR1 (61%) or CR2+ (21%). With a median follow-up time of 12 months, the median OS is 40 months (95% CI: 7.5-not reached), with a 1 and 3 year OS probability of 67% and 56%. The median PFS is 28.2 months (95% CI: 6.5-not reached), with 1 and 3-year PFS of 58% and 32%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 15.6% and 19.8%. CI of grade II-IV aGHVD and extensive cGVHD were 42.9% and 19.1%. The CI of relapse (CIR) was 22.2% at 1 year (95% CI: 7.7-41.3%). There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.71), and no difference in 1-year CIR (p=0.83). PFS at 1 year was substantially better in the lymphoma versus leukemia patients (78% vs 44%, p=0.02), though CIR at 1 year was not significantly different (13% vs 29%, p=0.12). No patients with PTCL relapsed, and 4/6 patients with T-PLL are alive, disease free.

16/28 (57%) of patients received m-rom with a median number of 12 cycles (range 1-39). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). NK-cytotoxicity was significantly higher at each time point in patients who received m-rom compared to those who did not (p<0.01). Further, when NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p<0.0001) (Figure). Studies evaluating NK-cytotoxicity against patient T-cells are ongoing and will be presented at the ASH meeting.

Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. These results suggest long-term romidepsin past one year may decrease late relapse. Long-term follow-up is needed to evaluate these results, but these results suggest the BuFluRom regimen with m-rom should be strongly considered in patients receiving allo-SCT for T-cell malignancies to mitigate relapse.

Popat:Iovance: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Bayer: Research Funding. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Travel support. Larkin:Gilead: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite: Consultancy, Research Funding; Gamida: Consultancy; Novartis: Research Funding; CRISPR Therapeutics: Consultancy. Choe:Abbvie: Other: independent endpoint review committee for trial. Champlin:Omeros: Consultancy; General Oncology: Other: Data Safety Monitoring Board; Actinium: Consultancy; Kadmon: Consultancy; Cell Source Inc.: Research Funding; Bluebird: Other: Data Safety Monitoring Board; Johnson &Johnson: Consultancy. de Lima:Amgen: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Brammer:Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy; DrenBio: Consultancy; Bristol-Myers Squibb: Research Funding.