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777 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Allogeneic Transplantation: Long-term Follow-up and Disease Recurrence I
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Biological therapies, Translational Research, Lymphomas, Clinical Research, T Cell lymphoma, Diseases, Therapies, Lymphoid Malignancies, Transplantation, Minimal Residual Disease
Monday, December 12, 2022: 11:00 AM

Chitra Hosing, MD1, Eric McLaughlin, MS2*, Zachary Braunstein, MD3*, Benigno C Valdez, PhD1, Lai Wei, PhD2*, Uday R Popat, MD1, Borje S Andersson, MD, PhD4, Sumithira Vasu, MBBS5, Karilyn T. Larkin, MD6, Samantha Jaglowski, MD, MPH7, Sam Penza, MD8, Ayman Saad, MD9, Hannah Choe, MD5, Sarah A Wall, MD, MPH10, Alex Cash11*, Robin Nakkula12*, Richard E Champlin, MD1, Marcos J.G. de Lima, MD13, Dean Anthony Lee, MD, PhD14 and Jonathan E Brammer, MD15

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Center for Biostatistics, The Ohio State University, Columbus, OH
3Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
4Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
5Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
6Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH
7The Ohio State University, Columbus, OH
8Hematology, The Ohio State University, Columbus, OH
9Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
10Division of Hematology, The Ohio State University, Columbus, OH
11Nationwide Children's Hospital, Columbus
12Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH
13Blood and Marrow and Cellular Therapy Program, Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH
14Center for Childhood Cancer, Abigail Wexner Research Institute, The Research Institute At Nationwide Children’S Hospital, Columbus, OH
15Division of Hematology, Department of Internal Medicine, The Ohio State University James Comprehensive Cancer Center, Columbus, OH

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.

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 (2nd 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.


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.


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.

Disclosures: 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; ASCO: Consultancy. 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.

*signifies non-member of ASH