Colchicine Can be an Effective Adjunctive Treatment for Extensive Refractory Chronic-Graft-Versus-Host Disease

Abstract Chronic extensive, severe graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality following an allogeneic hematopoietic stem cell transplant (HSCT). Patients with progressive chronic GVHD (cGVHD) following standard treatments have limited options. Patients with extensive refractory cGVHD have a decreased performance status (PS) and an increased non-relapsed mortality. Extensive sclerodermatous cGVHD responds poorly to standard treatments. Colchicine is a well-known anti-inflammatory drug that has been used in the treatment of many inflammatory disorders (1). We report a series of 8 patients with extensive cGVHD who were refractory to multiple lines of therapy and then were treated with colchicine. All patients had improvements in ECOG PS, skin GVHD and/or oral GVHD after starting colchicine. All patients were able to decrease their immunosuppressive therapies (IST) after starting colchicine. We retrospectively examined 8 patients with refractory extensive cGVHD, treated with colchicine (0.6 mg QD or BID). IST for cGVHD was defined by the following: steroids, extracorporeal photopheresis (ECP), imatinib, mycophenolate mofetil (MMF), tacrolimus, bortezomib, montelukast, cyclophosphamide (Cy), pentostatin, and rituximab. National Institutes of Health 2014 cGVHD consensus criteria (2) were used to grade the cGVHD prior to colchicine and at the time of best response after colchicine was started. Baseline patient characteristics are listed in Table 1. Conditioning regimen for allogeneic HSCT consisted of PPT (ECP, pentostatin, TBI) (4/8), busulfan/Cy (2/8), Cy-TLI (1/8), or Cy/TBI (1/8). GVHD prophylaxis involved CSA/MTX (7/8), tacrolimus/MTX (1/8) and ATG in addition to CSA/MTX (1/8). Median number of organs involved in cGVHD was 4.5 (range 2-5). All patients had extensive cGVHD with skin (8/8), oral (8/8), eye (8/8), GI (7/8), lung (6/8), liver (2/8), and/or genital (2/8) involvement. Median number of failed IST was 3.5 (range 1-6). Patients failed steroids (7/8), ECP (6/8), MMF (5/8), imatinib (3/8), cyclophosphamide (2/8) and bortezomib (1/8). Median number of IST immediately before colchicine was 2.5 (range 1-6). Most patients required twice daily dosing of colchicine (5/8). Median follow-up since beginning colchicine was 11 weeks (range 3-67 weeks). At best response with colchicine, all patients had clinical improvement of chronic GVHD (Figure 1). Patients with extensive cGVHD of the skin, including all patients with extensive sclerodermatous changes, responded to the addition of colchicine, and had steroid and MMF doses lowered, and/or were stopped on IST. Median number of IST fell to 2 (range 0-5). Four patients had a reduction in the number of IST. One patient was taken off 4 IST (ECP, imatinib, Cy and MMF). Another patient was able to stop ECP. Five patients had a reduction in prednisone with median reduction of 5mg (range 5-40 mg), while 2 had reductions in the total daily dose of MMF. Adverse events were uncommon and included 2 patients with grade 1-2 diarrhea. The most severe adverse event was grade 2 diarrhea in one patient that led to eventual discontinuation of colchicine. No hematologic toxicity was observed. The rest (7/8) continued on colchicine therapy. In conclusion, patients with extensive cGVHD involving the skin and mouth, refractory to multiple lines of IST, experienced clinical improvement on colchicine. Toxicity was limited to mild GI side effects. These observations need to be validated in a prospective clinical trial. References (1) Slobodnick et al. Am J Med. 2015 May;128(5):461-70. (2) Jagasia et al. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. Epub 2014 Dec 18. Table 1. Baseline Characteristics Variable Frequency (%) Age, median (range), yr 57 (30-65) Donor/recipient gender Sex-mismatched female/male 1 (13%) Sex-matched 7 (88%) Race White/Caucasian 7 (88%) Disease category Acute myeloid leukemia 4 (50%) Myelofibrosis 2 (25%) Aplastic anemia 1 (13%) Lymphoblastic lymphoma 1 (13%) Remission status at transplantation CR 8 (100%) Graft source BM 1 (13%) PBSC 7 (88%) Donor type Matched sibling 4 (50%) Matched unrelated 3 (38%) Mismatched 1 (13%) GVHD type Progressive 3 (38%) Overlap syndrome 2 (25%) De novo 3 (38%) Figure 1. Figure 1. Disclosures Off Label Use: Colchicine will be discussed as treatment for GVHD. Comenzo:Karyopharm: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Janssen: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Roberts:Millenium: Speakers Bureau. Miller:Biogen Idec: Consultancy; AbbVie: Speakers Bureau; Millennium: Speakers Bureau; Onynx: Speakers Bureau.

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Chronic Graft Versus Host Disease Burden and Relapse Rates Are Lower with Comparable Overall Survival and Graft Versus Host Disease Free, Relapse Free Survival Following Adult Umbilical Cord Blood Compared to Matched Sibling Peripheral Blood Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-119690 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4660-4660

Author(s):

Prashant Sharma ◽

Enkhtsetseg Purev ◽

Bradley M. Haverkos ◽

Daniel A Pollyea ◽

Clayton Smith ◽

...

Keyword(s):

Board Of Directors ◽

Graft Versus Host Disease ◽

Research Funding ◽

Chronic Gvhd ◽

Transplant Recipients ◽

Advisory Committees ◽

Host Disease ◽

Graft Versus Host ◽

Relapse Rates ◽

Donor Source

Abstract Background: Although matched related donors (MRD) are the preferred source of stem cells for allogeneic hematopoietic cell transplantation, umbilical cord blood (UCB) is a well-established donor source in patients without a MRD or matched unrelated donor (MUD). Prior studies (Eapen et al, Lancet Oncology 2010; Rocha et al, NEJM 2004) have shown similar overall survival and relapse rates after umbilical cord blood transplant (UCBT), and our group (Gutman et al, BMT 2016) has shown lower chronic graft-versus-host-disease (GVHD) when compared to MUD transplant. Based on these data, our preferred donor source is MRD followed by UCB. Here, we evaluate our data comparing transplant outcomes in UCBT recipients versus MRD recipients. Methods: We compared outcomes in all consecutive adult patients undergoing first MRD transplant versus first double UCBT from January 2010 to December 2017. Patient selection, graft-versus-host disease prophylaxis and transfusions were per institutional standards. Graft-versus-host-disease free, relapse free survival (GRFS) was defined by events that includedgrade 3-4 acute GVHD, moderate to severe chronic GVHD, relapse or any death. Results: Of the 296 patients studied, 187 underwent UCBT and 109 received MRD transplant. Graft failure occurred in 6 (3%) UCBT recipients (5 of whom received reduced intensity conditioning) and did not occur in any MRD transplant recipients. While the incidence of grade 2-4 acute GVHD was higher in UCBT recipients (p= 0.006), grade 3-4 acute GVHD was comparable (p= 0.36) between the two groups. Any chronic GVHD (p= 0.0000001) and moderate to severe chronic GVHD (p= 0.00011) was significantly higher in MRD transplant recipients (figure 1a and 1b). There were significantly lower disease relapses in UCBT recipients (n= 51, 27% versus n= 46, 42%; p= 0.0036) compared to MRD transplant recipients. Transplant related mortality was higher in UCBT recipients (n= 33, 42% versus n= 11, 23% in MRD transplant recipients; p= 0.03). There was no difference in GRFS (p=0.15, figure 1c) and overall survival (OS) in the 2 study cohorts (p=0.31, figure 1d). Conclusions: UCBT recipients as compared to MRD recipients had lower chronic GVHD and lower relapse rates with no difference in OS and the composite endpoint of GRFS. Based on these results, UCB remains an appropriate alternative donor source for hematopoietic cell transplantation and might result in improved quality of life by virtue of lower incidence of chronic GVHD in long-term transplant survivors. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pollyea:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Kamdar:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Mark:Janssen, Takeda, Celgene, Amgen: Consultancy; BMS, Celgene: Research Funding; Celgene: Honoraria.

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Treatment of Corticosteroid-Refractory Graft-Versus-Host Disease with Ruxolitinib in 95 Patients

Blood ◽

10.1182/blood.v126.23.858.858 ◽

2015 ◽

Vol 126 (23) ◽

pp. 858-858 ◽

Cited By ~ 1

Author(s):

Robert Zeiser ◽

Andreas Burchert ◽

Claudia Lengerke ◽

Mareike Verbeek ◽

Kristina Maas-Bauer ◽

...

Keyword(s):

Board Of Directors ◽

Graft Versus Host Disease ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

The United States ◽

Outcome Data ◽

Cell Transplant ◽

Advisory Committees ◽

Host Disease ◽

Graft Versus Host

Abstract Background: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematological malignancies. However a fraction of patients will develop corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) which both cause a high mortality and impaired quality of life. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib by modification of T cells and dendritic cells. Methods: In this retrospective analysis, 19 stem cell transplant centers in Europe and the United States reported clinical outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGvHD (1-10). The median follow-up times were 26.5 (3-106) for SR-aGVHD and 22.4 (3-135) weeks for SR-cGVHD-patients. Results: The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). The median time to response was 1.5 (1-11) and 3 (1-25) weeks after initiation of ruxolitinib treatment in SR-aGVHD and SR-cGVHD, respectively. Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%-90.7%,95% CI) and 97.4% (92.3%-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Relapse of the underlying malignancy occurred in 9.3% (5/54) and 2.4% (1/41) of the patients with SR-aGVHD or SR-cGVHD, respectively. Conclusion: Ruxolitinib constitutes a promising new treatment option for SR-aGVHD and SR-cGVHD. Its activity in SR-aGVHD and SR-cGVHD should be validated in a prospective trials in both, SR-aGvHD and cGvHD. Disclosures Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding.

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Predictors and Outcomes of Flares in Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood-2020-136479 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Grigori Okoev ◽

Daniel J. Weisdorf ◽

John E Wagner ◽

Bruce R. Blazar ◽

Margaret L. MacMillan ◽

...

Keyword(s):

Regression Analysis ◽

Board Of Directors ◽

Graft Versus Host Disease ◽

Research Funding ◽

Time Dependent ◽

Advisory Committees ◽

Graft Versus Host ◽

Day Range ◽

Similar Risk ◽

Fund Research

Introduction: Chronic Graft-versus-Host Disease (cGvHD) frequently requires prolonged immune suppressive therapy (IST) with > 50% still on IST at 5 years. The IST typically involves a slow taper of steroids often with flare of cGvHD, necessitating augmentation of previous therapy or addition of new IST. Studies describing cGvHD flares are limited. We analyzed patients with cGvHD who flared during the treatment with systemic IST, their overall survival (OS) and non-relapse mortality (NRM). Methods: This study included all adult patients with cGvHD (n=145) following an allogeneic transplant (2010 - 2017) from a matched sibling donor peripheral blood stem cell transplant (MSD, n=104 (72%) or double/single umbilical cord blood transplant (UCBT, n=41 (28%). The 2014 NIH Consensus Criteria were used to classify organ/overall cGvHD severity. Flare of cGvHD was defined as progression in cGvHD manifestations (after initial response), which was less severe than at diagnosis. Multivariate regression of flares was based on the Prentice, Williams and Peterson model for ordered multiple events (flares). Time-dependent effects on OS and NRM were analyzed by Cox and Fine and Gray regression with propensity scoring to control for confounding. Results: Flares occurred in 87 patients; the cumulative incidence of flares was 60% (95% CI: 51-70%) at a median of 188 days (range 16-751) after diagnosis of cGvHD. The median dose of prednisone was 1 mg/kg/day (range 0-4.2) at diagnosis of cGvHD. At the diagnosis of flare, 36 (41%) of the patients were off prednisone, 50 (57%) were receiving 0.1-0.5 mg/kg /day, and 2 patients > 0.5 mg/kg /day. Thirty two of the 87 (36%) patients experienced multiple flares (2 to 4). The most common organs involved at cGvHD flare were skin (n=45; 51%), mouth (n=27; 31%), GI tract (n=22; 25%) and liver (n=12; 14%); often in combinations of skin/mouth in 11 cases (13%), skin/GI in 6 (7%) and liver/mouth in 4 (5%) cases. Treatment for flare was mostly increase in dose of prednisone to 0.5 mg/kg/day (range 0.3-1.0) in 77 patients (88%) plus the addition of another line of IST in 48 patients (55%). In multiple regression analysis, only donor type was significant predictor of flare in cGvHD. UCBT was associated with 2-fold lower probability of flaring (HR 0.5; 95% CI: 0.3-0.9; p=0.03) compared to MSD. cGvHD severity, organ involvement, platelet count at diagnosis and type of onset were not significant predictors of cGvHD flares. At 2 years after the initial flare, the OS was 77% (95% CI: 66-84%) and NRM 19% (95% CI: 11-28%). Multiple regression analysis evaluating OS and NRM from onset of cGvHD comparing flare to non-flare were performed using flare as a time dependent variable. Compared to cGvHD patients without flare at 2 years, those with flare of cGvHD had a similar risk of NRM (HR 1.2; 95% CI: 0.2-6.1, p=0.86) and OS (HR 0.9; 95% CI: 0.4-2.3, p=0.85). At 2 years from cGvHD onset, the cumulative incidence of resolved cGvHD (durable discontinuation of steroids for ≥ 6 consecutive months) was 31% (95% CI: 21-41%) in those who flared vs. 86% (95% CI: 75-96%) in those without flare. Conclusions: Though cGvHD patients with flare had similar risk of NRM and OS as those without a flare, patients with flare required extended steroids, along with clinical monitoring and intensified IST. cGvHD after UCBT was associated with significantly lower risk of flaring compared to MSD. The ongoing burden of IST, risk of infection and morbidity of cGvHD is substantial and needs better approaches than chronic slow taper of steroids. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Wagner:Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Magenta Therapeutics: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Blazar:Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. MacMillan:Mesoblast: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Talaris Therapeutics, Inc: Consultancy; Fate Therapeutics, Inc.: Consultancy. Holtan:Generon: Consultancy; BMS: Consultancy; CSL Behring: Other: Clinical trial data adjudication; Incyte: Consultancy. Brunstein:AlloVir: Other: Advisory board; Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Bachanova:FATE: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Arora:Fate Therapeutics: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding.

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A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

Blood ◽

10.1182/blood-2020-141243 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-29

Author(s):

Walter Hanel ◽

Beth A. Christian ◽

Kami J. Maddocks ◽

Narendranath Epperla ◽

Basem M. William ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Response Rate ◽

Immune Escape ◽

Chronic Gvhd ◽

Complete Response ◽

Median Number ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Classical Hodgkin's Lymphoma (cHL) is characterized by an extensive inflammatory infiltrate with abundant Th2 and Treg cells which facilitate immune escape of Reed Sternberg (RS) cells and provides a growth promoting microenvironment by cytokine secretion and CD40/CD40L engagement. Our group previously show that ibrutinib irreversibly inhibits both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), a kinase important in Th2 signaling (Dubovsky et al Blood 2013). We hypothesized that the addition of ibrutinib to nivolumab would lead to deeper and more durable responses in cHL by normalizing the Th1/Th2 balance thus reversing immune escape of RS cells. We present results of a planned interim analysis of the first 10 patients enrolled with a data cutoff of June of 2020. Methods: This is a single arm, phase II, single institutional clinical trial testing the clinical activity of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who have received at least one prior line of therapy and who were either not candidates for or had a prior autologous stem cell transplant (ASCT). Prior treatment with nivolumab was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for 16 cycles. The primary objective was complete response rate (CRR) prior to cycle 7 assessed per Lugano criteria. Adverse events (AEs) were reported using CTCAE Version 4.0. Results: Of the first 11 cHL patients enrolled, one patient withdrew consent prior to initiating therapy. Of the remaining 10 patients, the median age was 41 years (range 20-84) and 4 patients (40%) were male. The median number of prior lines of treatment was 4.5 (range 1-11), 5 patients (50%) had prior ASCT, 8 patients (80%) had prior brentuximab, and 5 patients (50%) had prior nivolumab. Four of the five patients with prior nivolumab had progressed while receiving therapy while the remaining patient had stable disease upon completing nivolumab with a median time from the last nivolumab treatment of 15.6 months (range 0.7-23.2). Of the 10 patients who received treatment, one patient came off study after two cycles due to persistent grade 2 transaminitis lasting for several weeks attributed to nivolumab requiring high dose oral steroids. One patient came off study after cycle 9 due to grade 3 hematuria attributed to ibrutinib and another came off study due to a pericardial effusion after 8 cycles of ibrutinib maintenance. In the remaining patients, treatment was generally well tolerated with most AEs being grade 1-2 (Table 1). The median number of total cycles received was 9 (range 2-22). Of the 9 patients evaluable for response, 6 patients responded (ORR = 66%), 4 of whom had a complete response (CRR = 44%) with a median time to response of 2 months (Table 2, Fig.1). In intention-to-treat analysis, the ORR was 60% and CRR was 40% meeting our prespecified interim efficacy endpoint of a 30% CRR for trial continuation. Notably, of the 5 patients with prior nivolumab, 3 responded to nivolumab + ibrutinib (ORR = 60%), with one having a CR (CRR = 20%). Overall, at a median follow up of 9.5 months, both the median PFS and duration of response have not yet been reached, with 3 patients remaining in CR at the time of data cutoff. Three of 4 patients discontinued trial treatment to undergo SCT [2 allogeneic; 1 autologous]. Of the 2 allogeneic SCT patients, the first one underwent SCT 3 weeks after the last nivolumab infusion and developed multi-organ acute graft-versus-host disease (GVHD) followed by severe chronic GVHD requiring extracorporeal photopheresis. The second patient underwent allogeneic SCT 2 months following the last nivolumab infusion and had no acute GVHD and experienced only mild chronic GVHD which was medically managed. Conclusions: Although the numbers are small and further recruitment is ongoing (target n=17), the combination of ibrutinib and nivolumab was generally well tolerated and with high response rate with more than half of responding patients achieving a CR. In addition, responses were seen in patients with prior nivolumab treatment. Our results suggest a possible novel role for BTK inhibition in reversing nivolumab resistance in cHL, at least in some cases. Correlative studies including peripheral blood and tumor immune subset analyses are ongoing and the latest results will be presented at the meeting. Disclosures Christian: Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Maddocks:Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. William:Incyte: Research Funding; Dova: Research Funding; Celgene: Consultancy, Honoraria; Seattle Genetics: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Guidepoint Global: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy. Bond:Seattle Genetics: Honoraria. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: This trial uses ibrutnib in cHL to augment the responses of concurrent nivolumab administration.

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Graft-Versus Host Disease Prophylaxis with Postransplantation Bendamustine in Refractory Leaukemia Patients

Blood ◽

10.1182/blood-2019-125570 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5746-5746

Author(s):

Ivan S Moiseev ◽

Sergey N. Bondarenko ◽

Elena I Darskaya ◽

Aleksandr Alyanski ◽

Evgeniya Borzenkova ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Immunosuppressive Agents ◽

Single Agent ◽

Median Number ◽

Infectious Complications ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Background There was a limited improvement in the results of allogeneic hematopoietic stem cell transplantation (HSCT) in refractory leukemia over the last decades. The major reason of poor results is the relapse of the underlying malignancy. Thus the technologies to augment graft-versus-leukemia (GVL) effect is required for this group of patients. The preclinical study by Stokes et al. (British Journal of Haematology, 2016) indicated prolonged survival in the leukemia mouse model with substitution of posttransplantation cyclophosphamide (PTCy) with bendamustine (PTBenda). Also a small study evaluated the combination of PTCy and PTBenda in young patients and children (Katsanis E et al., 2018). We conducted the prospective study of postransplantation bendamustine as graft-versus-host-disease prophylaxis. Methods Single-center prospective dose-ranging de-escalation study (NCT02799147) evaluated safety and efficacy of PTBenda as GVHD prophylaxis. PTbenda was administered in doses 140, 100 and 70 mg/kg on days +3,+4. Myeloablative conditioning with fludarabine and busulfan was performed. First patients enrolled received single-agent PTbenda and subsequent- combination with other immunosuppressive agents. Inclusion criteria were acute myeloblstic (AML) or lymphoblstic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and more than 5% clonal blasts in the bone marrow. Twenty three patients were enrolled, 7 in the 140 mg/kg cohort, 10 in 100 mg/kg and 6 in 70 mg/kg, including 18 with AML and 5 with ALL. 35% of patients had primary refractory disease, and the rest - second or subsequent relapses, 61% had high-risk cytogenetics, 35% - complex karyotype, 17% - secondary AML, 30% - extramedulary disease. Median number of induction courses was 2 and 39% received target antibodies. Median number of blasts at transplant was 18% (range 6-97%). Two patients had matched related donor (MRD), 15 - unrelated (MUD), 6- haploidentical. Results Median follow-up was 10 months. The 140 mg/kg cohort was closed prematurely due to severe infectious complications. Ninety one percent of patients engrafted. Median time to engraftment was 16 days. Among the engrafted patients CR rate was 95%, and 67% had MRD(-) status. Relapse was documented in 10% of patients with CR. We have observed that PTBena induces a specific cytokine-release syndrome (CRC) with fever, vasculitis-like skin rush, oral mucositis, enteritis, hepatitis and pancreatitis. CNS signs, hypotension and respiratory failure were observed only in a few patients. CRC was observed in 78% of patients, including grade 1-2 in 17%, grade 3 in 26%, grade 4 in 22% and grade 5 in 3 patients. Median level of ferritin during CRC was 15 000 ng/ml and IL-6 levels were also increased (74 vs 8 ng/ml, p=0.036). Tocilizumab was administered to 13 patients and 10 responded. Classical grade II-IV GVHD was observed in 39% of pts and 60% of long-term survivors developed severe chronic GVHD. Non-relapse mortality was 48% with CRC, infectious complications and chronic GVHD as major causes. 1-year overall survival was 35%. Conclusion PTbenda even as a single agent has a significant potential to prevent acute, but not chronic GVHD. Moreover GVHD prophylaxis with PTbenda is a completely novel approach to induction of GVL, but optimal combination of immunosuppressive agents and supportive care should be determined to control the CRC and chronic GVHD. The optimal dosing regimen of PTbenda will be determined after enrollment in the last cohort will be completed. Figure Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants. OffLabel Disclosure: Bendamustine used for graft-versus-host disease prophylaxis.

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The Blood Microbiome Predicts Acute Graft-Versus-Host Disease after Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-129272 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4513-4513

Author(s):

Lily Blair ◽

Jonathan U. Peled ◽

Paul A Giardina ◽

John B. Slingerland ◽

Ann E. Slingerland ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Graft Versus Host Disease ◽

Research Funding ◽

Clinical Factors ◽

Barrier Dysfunction ◽

Advisory Committees ◽

Graft Versus Host ◽

Stool Samples

Introduction Translocation of intestinal bacteria across impaired mucosal barriers has long been believed to occur following exposure to chemotherapy. Consistent with this, we and others have previously reported that expansions of potentially pathogenic bacteria within the gastrointestinal microbiome precedes bloodstream infection. While the blood microbiome represents a rich area for investigation, detailed unbiased characterization of the blood microbiome has not previously been possible. Here, we sought to investigate the relationship between the blood and stool microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) who are at high risk for gut barrier dysfunction, severe infection, and the immunological complications of transplantation including graft-versus-host disease (GVHD). We show preliminary data suggesting that the blood microbiome may hold biomarkers for gut integrity. Subsequently, it may offer microbiological data supporting causative organisms in "culture-negative" fevers, or in itself, perform an immunomodulatory role acting as a damage/pathogen associated molecular pattern (DAMP/PAMP). Methods We sequenced serially-collected plasma and stool samples (n = 61 unique samples of each type) from a cohort of 19 patients who underwent allogeneic HCT at our center. Microbial cell-free DNA (mcfDNA) was extracted from plasma and sequenced using a next generation sequencing assay (Karius, Inc, Redwood City, CA). After sequences are processed, mcfDNA abundances are reported in molecules per microliter. Stool samples underwent were profiled using 16S-targeted sequencing (V4-V5 region) on the Illumina MISEQ platform and analyzed using the DADA2 pipeline. Association of blood microbial burden with clinical factors was assessed using a Wilcoxon rank sum test. Results We confirmed a high sequence homology between the DNA found in plasma and stool samples, thus demonstrating that circulating mcfDNA is gut-derived in these patients. By comparing microbial sequences from paired plasma and stool samples collected equivalent time points during the neutropenic nadir after HCT, we observed a correlation between the abundance of bacterial mcfDNA in plasma and DNA from the same microbes in stool. Of note, this occurred independently of conditioning regimen intensity, and was observed in patients who had received myeloablative, non-myeloablative and reduced intensity therapy. We assessed the association of bacterial mcfDNA burden (only considering sequences common to stool sequences) with various clinical factors. Translocation was significantly higher in patients who experienced pre-engraftment mucositis (any observed grade) compared with those who did not (p = 0.02, n = 5 in the mucositis group, any grade, and 12 in the mucositis-free group), but there was no relationship between the degree of translocation and HCT-CI, conditioning intensity, donor type, age or pre-engraftment fevers. We next asked whether translocation events were associated with acute GVHD (aGVHD) by assessing a subgroup of patients who received unmodified grafts (peripheral blood stem cell or bone marrow; n = 10) and tracked the degree of translocation from the gut to the blood stream pre-transplant, during the neutropenic nadir, and following engraftment. As shown in Figure 1, we observed low pre-transplant translocation (as quantified by the total bacterial DNA abundance in plasma where sequences were also shared in stool samples), and a marked increase during neutropenic nadir. Remarkably, even in this small cohort, we observe a higher burden of translocation in the post-engraftment period in patients who subsequently develop aGVHD, while it decreased to baseline levels in those who do not (n = 7 in the aGVHD group; n = 3 aGVHD-free; p = 0.05). Conclusions Here we demonstrate the first use of a culture-free molecular assay to track the blood microbiome and identify features of the circulating mcfDNA that correlate with the microbial DNA in stool samples. Despite the small sample size, these data suggest that the maintenance of a high mcfDNA-burden beyond the neutropenic nadir is associated with subsequent GVHD development, and provides some evidence for early gut barrier dysfunction that permits translocation in these patients. Disclosures Blair: Karius, Inc: Employment. Peled:Seres Therapeutics: Other: IP licensing fees, Research Funding. Giardina:Seres Therapeutics: Other: Salary funding. Slingerland:Seres Therapeutics: Other: Salary supported by Seres funding. Hollemon:Karius, Inc: Employment. Ho:Karius, Inc: Employment. Bercovici:Karius, Inc: Employment. Ahmed:Karius, Inc: Employment. Hong:Karius, Inc: Employment. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. van den Brink:Therakos: Consultancy, Honoraria; Merck & Co, Inc.: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Acute Leukemia Forum (ALF): Consultancy, Honoraria; Magenta and DKMS Medical Council: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Flagship Ventures: Consultancy, Honoraria; Juno Therapeutics: Other: Licensing; Evelo: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

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The Novel Combination of Sirolimus and Bortezomib Prevents Graft-Versus-Host Disease but Mantains the Graft-Versus-Leukemia Effect After Allogeneic Transplantation.

Blood ◽

10.1182/blood.v116.21.3738.3738 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3738-3738

Author(s):

Teresa Caballero-Velazquez ◽

Luis Ignacio Sanchez-Abarca ◽

Belen Blanco ◽

Carmen Herrero ◽

Silvia Gutierrez-cosio ◽

...

Keyword(s):

T Cells ◽

Synergistic Effect ◽

Board Of Directors ◽

Graft Versus Host Disease ◽

Allogeneic Transplantation ◽

Advisory Committees ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Abstract Abstract 3738 Graft-versus-host disease (GVHD) represents a major challenge and the main cause of morbidity and mortality after allogeneic transplantation. Using the standard GVHD prophylaxis based on a calcineurin inhibitor plus methotrexate (MTX). The incidence of acute GVHD is in the range of 30–60%, so that new strategies are required in order to decrease GVHD without hampering GVL. Sirolimus, an mTOR inhibitor, allows to decrease the risk of GVHD and increases the number of Treg after transplantation. Unfortunately, its use may increase the risk of microangiopathy and, moreover, its combination with calcineurin inhibitors blocks the development of Treg. Bortezomib is a proteosome inhibitor and blocks the nuclear translocation and activation of NF-kB. It induces depletion of alloreactive T and allows the expansion of T-cells with suppressive properties. Accordingly, both drugs could favour the development of a tolerogeneic immune response after transplantation. In the current study we have analyzed the synergistic effect of sirolimus together with bortezomib. Bortezomib 100 nM plus sirolimus 5nM synergistically inhibited T-cell activation as assessed by the expression of CD25, production of IFNg and expression of CD40L as well as proliferation assessed as expression of PKH. Remain vibility, these effects could not be attributed to a decreased viability of T-cells, as assessed by 7-AAD, at the concentrations evaluated. As compared to each drug alone, the combination significantly decreased the production of Th1 cytokines (IFNg, IL-2 and TNF) while regarding TH2 cytokines, only IL-6 significantly decreased upon combining both drugs. Concerning the mechanisms involved in this synergistic effect, the combination of both drugs resulted in an inhibition of the Akt and Erk ½ phophorylation, thus indicating that sirolimus inhibit pathways which could allow T-cells to escape from the effect of bortezomib at the doses used in the current experiment. In order to confirm in vivo the synergistic effect of sirolimus and bortezomib, a GVHD mouse model (C57/BL6-Balb/c) was carried out. Mice receiving both drugs (Bortezomib 1μg/day intravenous on days 0, +1, +2 postransplantat and sirolimus 0.25mg/Kg intra-peritoneal on days 0 to 12) has a significantly lower incidence of GVHD and longer survival as compared to each drug alone. We also wanted to evaluate whether the immunosuppressive effect of the combination was unspecific or, by contrast, it allowed induce specific immune tolerance against host but maintaining the immune response against other antigens. For this purpose a haematopoietic cells of Balb/c mice which were C57/BL6 complete chimeras were infused to NOD-SCID mice. While none of the donors had developed GVHD after transplantation plus sirolimus and bortezomib postransplant, the NOD-SCID mice succumbed due to GVHD. Furthermore, we infused WEHI cells to BALB/c after total body irradiation and we observed that, while all BALB/c mice receiving WEHI plus C57BL/6 donor BM cells died due to leukemic infiltration, none of those receiving WEHI cells plus C57BL/6 donor BM cells plus splenocytes (and GVHD prophylaxis with sirolimus and bortezomib) did develop leukemic infiltration, thus confirming that, using this approach, we were able to separate GVHD and GVL effect. In conclusion, the current study shows a potent synergistic effect between sirolimus and bortezomib in vitro and in vivo which prevent GVHD while maintaining GVL. Disclosures: Cañizo: CELGENE: Membership on an entity's Board of Directors or advisory committees. San Miguel:JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; MILLENNIUM: Membership on an entity's Board of Directors or advisory committees. Off Label Use: sirolimus and bortezomib are not approved for use in prophylaxis of graft versus host disease.

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The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Blood ◽

10.1182/blood.v128.22.1063.1063 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1063-1063 ◽

Cited By ~ 3

Author(s):

Maximilian Stahl ◽

Nikolai A Podoltsev ◽

Michelle DeVeaux ◽

Sarah Perreault ◽

Raphaël Itzykson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Regression Models ◽

Median Number ◽

Chromosome 7 ◽

Advisory Committees ◽

Logistic Regression Models ◽

Best Response ◽

Line Of Therapy

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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Invariant Natural Killer T Cell Subsets Have Diverse Functions: iNKT2 and iNKT17 Protect from Graft-Versus-Host-Disease, Whereas iNKT1 Have Antitumor Potential

Blood ◽

10.1182/blood-2018-99-113673 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 475-475

Author(s):

Kristina Maas-Bauer ◽

Federico Simonetta ◽

Toshihito Hirai ◽

Arielle Wenokur ◽

Furqan Fazal ◽

...

Keyword(s):

T Cells ◽

Natural Killer ◽

Board Of Directors ◽

Graft Versus Host Disease ◽

Survival Benefit ◽

Inkt Cells ◽

Advisory Committees ◽

Host Disease ◽

Graft Versus Host ◽

Invariant Natural Killer

Abstract Invariant natural killer T (iNKT) cells are an interesting subpopulation of T cells that can potently inhibit graft-versus-host-disease (GVHD) through the production of Interleukin 4 (IL-4), while also carrying anti-tumor potential (Leveson-Gower et al. Blood. 2011;117:3220-9; Schneidawind et al. Blood. 2014;124:3320-8). Murine iNKT cells differentiate during thymic development into three distinct sublineages, named according to the classification of conventional T cells: Th1-like iNKT (iNKT1) cells, Th2-like iNKT (iNKT2) cells, and Th-17 like iNKT (iNKT17) cells (Brennan et al. Nat Rev Immunol. 2013; 13:101-1). In this study we investigated the immune regulatory and anti-tumor potential of iNKT1, iNKT2 and iNKT17 cell subsets. Thymic iNKT1 cells, iNKT2 cells and iNKT17 cells were isolated from 8-10 week-old FVB/NJ mice by flow cytometry based on PBS-57-CD1d-Tetramer and a combination of cell surface molecules (iNKT1: ICOS- PD1- CD27+ CD24-; iNKT2: ICOS+ PD1+ CD27+ CD4+ CD24-; iNKT17: ICOS+ PD1+ CD4- CD27- CD24-) and purity was confirmed by intra-nuclear staining for the transcription factors PLZF and RORγT. RNA sequencing analysis determined that iNKT1 cells were the main subset expressing proinflammatory and cytotoxic genes, such as Interferon gamma (IFN-γ), Fas Ligand (FasL), Perforin, and Granzyme B (Gzmb), whereas IL-4 was expressed by iNKT2 cells and, at a lesser extent, by iNKT17 cells. To assess the immuno-regulatory potential of the three iNKT sublineages, we employed a murine major histocompatibility complex (MHC)-mismatched bone marrow transplantation model. BALB/c (H-2Kd) recipients were lethally irradiated with 8.8 Gy; on the same day, 4 x 106 TCD-BM cells and 1 x 106 conventional CD4 and CD8 T cells (Tcon) from FVB/NJ (H-2kq) mice were injected intravenously. Additionally, 5 x 104 purified iNKT1, iNKT2 or iNKT17 cell subsets from FVB donors were injected. A significant survival benefit was observed when iNKT2 (p=0.017) and iNKT17 (p=0.033) cells were adoptively transferred compared to mice that only received TCD-BM and Tcon, whereas there was no survival benefit in the group that received iNKT1 cells. In addition, body weight was improved in mice that received iNKT2 (day +41: p=0.009, day +49: p=0.005 and day +59: p= 0.005) or iNKT17 (day +59: p= 0.006) compared to mice that received iNKT1 cells. Clinical GVHD scores were also improved in mice that received iNKT2 (day +41: p= 0.012, day +51: p= 0.005) or iNKT17 (day +28: p=0.05, day +51: p=0.007) compared to mice that received iNKT1 cells. Interestingly, we found that even 1 x104 iNKT2 (p= 0.008) and iNKT17 (p= 0.04) significantly suppressed GVHD. As iNKT1, iNKT2 and iNKT17 have a very different gene expression profile, we tested the ability of the sublineages to kill a B-cell lymphoma cell line transduced to express high levels of CD1d (A20-CD1d) in vitro and found that iNKT1 cells killed A20-CD1d cells significantly better than iNKT2 (p=0.006) or iNKT17 (p=0.0001) cells. These findings are in line with the sequencing data mentioned above, showing that iNKT1 cells express a more inflammatory phenotype. In summary, we demonstrate here that only iNKT2 and iNKT17 cells protect from GVHD, whereas iNKT1 cells have cytotoxic function. To our knowledge, this is the first study to show functional differences between the iNKT sublineages, suggesting that iNKT1, iNKT2 and iNKT17 cells have diverse functions. Therefore, these data provide new biological insights, which will be useful for developing iNKT cell-based cell therapy. Disclosures Chang: Spring Discovery: Membership on an entity's Board of Directors or advisory committees; Epinomics and Accent Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Donor Lymphocyte Infusions for Relapsed Hematological Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Experience

Blood ◽

10.1182/blood-2018-99-120202 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4673-4673

Author(s):

Gunhan Gurman ◽

Guldane Cengiz Seval ◽

Sinem Civriz Bozdag ◽

Selami Kocak Toprak ◽

Meltem Kurt Yuksel ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematological Malignancies ◽

Median Number ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Support Research

Abstract Introduction:Donor lymphocyte infusion (DLI) is one of the therapeutic options for patients with relapsed or refractory hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). DLI can augment the graft-versus-tumor (GVT) effect; however, it can sometimes induce severe graft-versus-host disease (GVHD) and infectious complications induced by bone marrow aplasia or immunosuppressive therapy. In this study, we wanted to assess the risk factors for GVHD and transplant-related mortality (TRM) as well as disease outcomes according to the reason for DLI in patients who received DLI after allo-HSCT. Patients and Methods:We retrospectively analyzed 152 patients with various hematological malignancies who received a total of 250 DLI in our center between March 1991 and July 2018 for disease relapse and at different intervals after allo-HSCT. We used our institutional database to evaluate details and characteristics of patients and DLI outcomes. The probabilities of overall survival were calculated from the day of transplantation with Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. Results:Median patient age was 34 years (range, 14-67 years); the patient cohort included 96 males (63.2%) and 36.8 female (56%). Patients evaluated in this study were adult patients with acute myeloid leukemia (n=64), chronic myeloid leukemia (n=36), multiple myeloma (n=6), non-hodgkin lymphoma (4), primary myelofibrosis (n=6), myelodisplastic syndrome (n=3), and severe aplastic anemia (n=3). One hundred thirty-six (10.5%) and sixteen (10.5%) patients had sibling (SD) and unrelated donors (UD), respectively. The stem cell source was peripheral blood stem cells (PBSC) in 116 patients (76.3%) and the other 36 patients (23.8%) received bone marrow stem cells (BMSC). Patients underwent an allo-HSCT with a MAC (n= 109) or RIC (n=43) regimens at a median of 12.5 months from diagnosis. Cyclosporine and methotrexate were used as the main graft versus host disease (GVHD) prophylaxis in our cohort. All patients received DLI for relapse or progression. Median number of DLI was 1 (range, 1-5), the median interval between transplant and first DLI was 6 months (range, 3-86 months), median number of infused CD3+cells x 106/kg of recipient body weight was 1.5x107(range, 0.5x107- 11.1x107). The median time from relapse to the first DLI was 1.9 months (range, 0.1-32.7 months). Thirty-one patients (21%) developed acute grade II to IV GVHD and 10 patients (7%) developed extensive chronic GVHD. We could not demonstrate the higher CD3+ cell dose of DLI associated with an increased risk of GVHD. Furthermore, none of our patients presented graft hypoplasia after DLI. At a median follow-up from transplantation interval of 16.3 months (range, 0.5-188.2 months), 35 patients were still alive (%60). The OS at 1 and 3 years was 63.4±0.4 and 28.2±0.4, respectively (Figure 1). The primary cause of death was relapse of the original disease in most of the patients, whereas 14 patients died of TRM (15.3%). Discussion:Various modifications of DLI have been investigated in combination with molecular-targeted agents to enhance the antitumor effect while minimizing GVHD. Therefore, further studies of larger randomized cohorts with high quality data management are required to clarify the role of DLI in relapsed hematological malignancies. Figure. Figure. Disclosures Civriz Bozdag: TAKEDA: Consultancy; MSD: Research Funding; NOVARTIS: Consultancy. Özcan:MSD: Other: travel support, Research Funding; Jazz: Other; Janssen: Other: Travel Support, Research Funding; Novartis: Research Funding; Archigen: Research Funding; Jazz: Other: Travel support; Bayer: Research Funding; Abbvie: Other: Travel payment; Celgene: Other: Travel support, Research Funding; BMS: Honoraria; Roche: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; MSD: Research Funding. Ilhan:Roche: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau. Beksac:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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