scholarly journals Randomized Trial of Tacrolimus and Methotrexate Versus Tacrolimus, Reduced Dose Methotrexate, and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease after Myeloablative Related and Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 99-99
Author(s):  
Betty K. Hamilton ◽  
Lisa A. Rybicki ◽  
Taylor Lucas ◽  
Donna Corrigan ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Toxicity Profile ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Reduced Dose ◽  
Grade 3

Abstract Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose ("mini")-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT. Methods: Patients <70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power. Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P<0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P<0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P<0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P<0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06). Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

scholarly journals Impact of Specific Adverse Cytogenetic Features on Outcomes after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome with Very Poor Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of EBMT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3953-3953
Author(s):  
Xavier Poiré ◽  
Diderik-jan Eikeman ◽  
Linda Koster ◽  
Johan A. Maertens ◽  
Jan J. Cornelissen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade Ii

Abstract INTRODUCTION: Myelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODS: We selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTS: A total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups. The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (<55: 45% (95% CI 31-59%); 55-65: 65% (95% CI 54-77%); >65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSION: MDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. Disclosures Byrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

scholarly journals Low Incidence of Chronic Graft-Versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Using Matched Related or Unrelated Donors: Phase II Study Interim Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1811-1811
Author(s):  
Najla H El Jurdi ◽  
Daniel O'Leary ◽  
Fiona He ◽  
Todd E. DeFor ◽  
Armin Rashidi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

scholarly journals Outcomes of Allogeneic Hematopoietic Cell Transplantation with Cord Blood Versus Mismatched Unrelated Donor with Post-Transplant Cyclophosphamide in Acute Myeloid Leukemia: An Analysis from the ALWP of the EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Bhagirathbhai Dholaria ◽  
Myriam Labopin ◽  
Jaime Sanz Caballer ◽  
Annalisa Ruggeri ◽  
Jan J. Cornelissen ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Matched Pair ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Matched Pair Analysis ◽  
Grade Ii

Background Haploidentical allogeneic hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) has greatly expanded potential donor options for patients (pts) without a fully HLA-matched donor. However, an HLA-mismatched unrelated donor (UD) or cord blood transplantation (CBT) are valid options for pts who do not have an haploidentical-related or a fully HLA-matched donor. The incorporation of PTCy with mismatched UD allo-HCT is associated with reduced risk of non-relapse mortality (NRM) and graft-versus-host disease (GvHD) (Jorge et al., BBMT, 2018). No previous study has compared outcomes of these two graft sources in contemporary era. In this study, we compared the outcomes of CBT versus (vs) single antigen-mismatched (HLA 9/10) UD allo-HCT with post-transplant cyclophosphamide (PTCy) in pts with acute myeloid leukemia (AML). Methods Pts with AML who underwent a first CBT without PTCy (N=902) or allo-HCT from a 9/10 UD with PTCy (N=280) between 2010 to 2019 were selected from The European Society of Blood and Marrow Transplantation (EBMT) registry. We excluded pts who had ex vivo T cell depletion. The median pt age was comparable between CBT and UD cohort [51 years (y) vs. 52 y, p=0.09]. The recipients of CBT had a longer median follow up (47 vs. 19 months, p<0.01) compared to UD. The cytogenetic risk category was good in 68 (6%), intermediate in 514 (46%), poor in 184 (16%) and unknown in 416 (35%) pts. Pre-HCT disease status was first complete remission (CR1) in 701 (59%), CR2 in 279 (24%) and advanced (non-CR1/CR2) in 202 (17%) pts. Myeloablative conditioning (MAC) was used in 47% of the total pts and the use of MAC was comparable between the study cohorts (p=0.21). In vivo T cell depletion was used more frequently with CBT compared to UD (40% vs. 26%, p<0.01). A Cox regression multivariate (MV) analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score based 1:1 matching of pts with known cytogenetic risk. Propensity score was based on pt age, gender, Karnofsky performance score, cytogenetic risk group, pre-HCT disease status and intensity of conditioning regimen. Results In the univariate analysis, day +180 incidence of grade II-IV acute GvHD was 36% vs. 32% (p=0.07) and grade III-IV acute GvHD was 15% vs. 11% (p=0.16) for CBT and UD cohorts, respectively. The 2-y incidence of total chronic GvHD was 26% vs. 32% (p=0.20) and extensive chronic GvHD was 12% vs. 12% (p=0.83), respectively. CBT was associated with higher incidence of graft failure (11% vs. 4%, p<0.01) and higher 2y NRM (30% vs. 16%, p<0.01) compared to UD. CBT resulted in lower leukemia free survival (LFS) (43% vs. 61%, p<0.01), overall survival (OS) (47% vs. 63%, p<0.01) and GvHD-free, relapse-free survival (GRFS) (34% vs. 47%, p<0.01). There was no difference in 2y relapse incidence (RI) between study cohorts (28% vs. 23%, p=0.24). There were more infection-related deaths in CBT compared to UD allo-HCT recipients (31% vs. 24% of total reported deaths). Among CBT recipients, 3 pts died from graft failure and 5 pts died from lymphoproliferative disorder. In the MV analysis (Table 1), CBT was associated with higher risk of grade II-IV acute GvHD [hazard ratio (HR)=1.32, 95% confidence interval (CI):1-1.74,p<0.05], NRM [HR=2.09, 95% CI:1.46-2.99, p<0.0001], and RI [HR=1.35, 95% CI: 1-1.83, p=0.05] which resulted in inferior LFS [HR=1.68, 95% CI:1.34-2.12,p<0.0001], OS [HR=1.7, 95% CI:1.33-2.17, p<0.0001] and GRFS [HR=1.49, 95% CI:1.21-1.83,p<0.0001] compared to UD. The chronic GvHD did not differ between the study cohorts [HR=0.94, 95% CI: 0.68-1.3, p=0.69]. Older age and advanced disease status were associated with poor OS. These results were confirmed in a matched-pair analysis, which compared 177 pairs of CBT vs. 9/10 UD allo-HCT pts. CBT was associated with higher 2y NRM (HR=1.96, p<0.01), RI (HR=2.01, p<0.01), and lower LFS (HR=1.98 p<0.01), OS (HR=1.82, p<0.01) and GRFS (HR=1.77, p<0.01) (Figure 1). Grade II-IV acute (HR=1.33, p=0.13) and total chronic (HR=1.02, p=0.93) GvHD rates were comparable between the cohorts. Conclusions In this large registry-based observational study, CBT was associated with inferior LFS, OS and GRFS due to higher NRM and RI compared to 9/10 UD allo-HCT with PTCy. In the absence of a fully matched or haplo donor, 9/10 UD allo-HCT with PTCy may be preferred over CBT in pts with AML. A prospective study is needed to validate our findings. Disclosures Dholaria: Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&J: Research Funding; bms: Research Funding. Labopin:Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T Cells (Treg) After Allogeneic Hematopoietic Cell Transplantation (HCT), and Is More Effective Than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft Vs. Host Disease (GVHD) and Moderate to Severe Chronic Gvhd

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 323-323 ◽  
Author(s):  
Joseph Pidala ◽  
Jongphil Kim ◽  
Heather Jim ◽  
Hugo F. Fernandez ◽  
Marcie Tomblyn ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Graft Vs Host Disease ◽  
Grade Ii

Abstract Abstract 323 Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T cells (Treg) after Allogeneic Hematopoietic Cell Transplantation (HCT), and is More Effective than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft vs. Host Disease (GVHD) and Moderate to Severe Chronic GVHD Background: Clinical translation of the Treg suppressive potential will require definition of a pharmacologic immune suppressive platform conducive to preferential Treg reconstitution post-HCT. Sirolimus has differential impact on Treg and conventional T cells. Patients and Methods: We performed a prospective, randomized phase II trial of sirolimus (SIR) and tacrolimus (TAC) vs. methotrexate (MTX) and TAC. From 9/2008 to 5/2011, a total of 74 patients were randomized 1:1 to SIR/TAC vs. MTX/TAC, stratified by age (> or ≤ 50) and donor relation (related vs. unrelated). SIR was administered as a 9 mg oral loading dose on day -1, followed by maintenance with 4 mg daily adjusted to target 8–12 ng/ml; SIR was continued for at least 1 year. MTX was 15 mg/m2 on day +1, then 10 mg/m2on days +3, 6, and 11. TAC was administered at 0.02 mg/kg/day IV or equivalent oral dosing starting on day -3. Target TAC levels were 3–7 ng/ml for the SIR arm versus 10–15 ng/ml for the MTX arm and were maintained through day 60. TAC was tapered thereafter in the absence of acute GVHD. Patient age for the whole study was 23 to 69 (median 49) years, and disease diagnoses included AML (23), ALL (15), MDS (9), MM (8), NHL (8), CLL (7), CML (2), and MPD (2). Patients received peripheral blood mobilized stem cells from HLA-A, B, C, and DRB1 matched sibling (n=35) or unrelated donors (n=39). Age, diagnosis, disease risk and donor relation were balanced across the two study arms. Serial peripheral blood samples were obtained at baseline pre-HCT, day 0, and days 30, 90, 180, and 360 post-HCT. Treg were defined by the surface CD4+CD25brightCD127negative phenotype. The reciprocal relationship between negative surface CD127 and high intracellular FoxP3 expression was confirmed in a subset (n=15) of day 30 patient samples (r=0.94). Results: Median percent Tregs among blood CD4 T cells at day 30 was 16.3 (range 12.5–17.9) for SIR versus 9.9 (8.6–13.5) for MTX, p < 0.0001, and 14.6 (10.8–18.1) for SIR and 9.7 (7.5–11.6) for MTX at day 90 post-HCT, p = 0.0009. SIR-treated patients had increased absolute numbers of Treg, and decreased absolute numbers of non-Treg CD4+ cells on days 30 and 90. The 100-day cumulative incidence of grade 2–4 acute GVHD for SIR was 43% (95% CI 30–63%), and 89% (95% CI 80–100%) for MTX, p<0.0001. Grade 3–4 acute GVHD for SIR was 16% (95% CI 7–36%) and 13% (95% CI 5–33%) for MTX, p=0.16. The incidence of any grade chronic GVHD for SIR was 51% (95% CI 34–78%) and 67% (95% CI 52–85%) for MTX, p=0.56. The cumulative incidence of NIH consensus-defined moderate to severe chronic GVHD was 20% (95% CI 9–43%) following SIR, and 63% (95% CI 47–83%) for MTX, p=0.013. Median time to neutrophil engraftment was comparable (SIR 16, range 11–22 days; MTX 16, range 12–28, p=0.57), and platelet engraftment was improved with SIR (SIR 12, range 6–20; MTX 16, range 10–33, p=0.012). No significant differences in peak mucositis, hepatic veno-occlusive disease (VOD), or thrombotic microangiopathy were observed between SIR and MTX. Overall survival did not significantly differ, log-rank p=0.55. Causes of death in SIR included relapse (n=2), and non-relapse death (septicemia 2, acute GVHD 1, chronic GVHD 1, influenza pneumonia 1, RSV pneumonia 1, VOD 1, multi-organ failure 1). Causes of death in the MTX arm were relapse (n=7), and non-relapse death (diffuse alveolar hemorrhage 1, GVHD 1). We performed serial assessment of patient-reported quality of life (QOL) with the FACT-BMT. While those patients in the MTX group had significantly better mean FWB and FACT-G scores at baseline pre-HCT, we did not detect significant differences in any FACT-BMT domain or summary score at day 30 or 90 post-HCT. Further follow up is needed to study longer term recovery of QOL in SIR and MTX treated patients. Conclusions: These results of a randomized, controlled study provide evidence that the combination of SIR/TAC favors Treg recovery and more effectively prevents acute GVHD and moderate to severe chronic GVHD after allogeneic HCT. Disclosures: Alsina: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

Minor Histocompatibility Antigen Mismatch and Incidence of Graft Versus Host Disease, Event-Free, and Overall Survival in Patients Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4201-4201
Author(s):  
Brian C Shaffer ◽  
Christine Tremblay ◽  
Daniel Peaceman ◽  
Jennifer Hsu ◽  
Seth M. Steinberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Histocompatibility Antigen ◽  
Unrelated Donor ◽  
Minor Histocompatibility Antigen ◽  
Graft Versus Host

Abstract Abstract 4201 Graft versus Host Disease (GvHD) is a potentially devastating complication of allogeneic hematopoietic cell transplantation (HCT) initiated in part due to donor-recipient disparities in immunoreactive proteins, or minor histocompatibility antigens (mHAgs). There are no established prognostic tools to predict which patients will get acute or chronic GvHD. Analysis of mHAg mismatch is a potential predictive tool for GvHD; however, previous studies attempting to establish a relationship between mHAg mismatch and GvHD have been largely equivocal. Here we tested the hypothesis that analysis of an expanded set of mHAgs for mismatch in the GvH direction can be predictive of acute or chronic GvHD by NIH criteria. We additionally analyzed event-free (EFS) and overall survival (OS) in the mHAg matched and mismatched subgroups. Recipient/donor pairs from 45 HLA-A, -B, -C, and DRB1 matched unrelated donor transplants from 2007–2011 were retrospectively typed for 19 mHAgs using an SSP-PCR typing kit (Minor Histocompatibility Antigen Typing Kit; Life Technologies, Carlsbad, CA). Genomic DNA was obtained from peripheral blood mononuclear cells. EFS and OS were estimated using the Kaplan-Meier method. The relationship between mismatch and acute or chronic GvHD was described using Fischer's Exact Test. Cumulative incidence of treatment related mortality (TRM) was calculated using the Gooley Method. Two patients expired of early TRM and were excluded from the GvHD analyses. The rate of acute GvHD grades II-IV was 6 of 14 in those without a mHAg mismatch and 21 of 29 in those with a mismatch (43% versus 72%, P = 0.062). The rate of chronic GvHD was 8 of 14 in those without a mismatch and 10 of 29 in those with a mismatch (53% versus 34%, P = 0.140). The presence of a mismatch did not significantly impact EFS (P = 0.42) or OS (P = 0.26). The cumulative incidence of TRM at 24 months post transplantation was greater in patients with a mismatch (36% versus 13%). Two year OS was superior in patients who were conditioned with alemtuzumab (N = 24) and had a lower degree of mismatch (0–1 mismatch = 72% versus 2+ mismatches = 38%, P = 0.038). This study suggests the possibility of a relationship between mHAg mismatch and acute GvHD and TRM. Further study using this expanded mHAg analysis on a larger cohort of individuals would more adequately define the potential benefit of mHAg mismatch analysis in the context of unrelated donor HCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2141-2148 ◽  
Author(s):  
Junya Kanda ◽  
Masakatsu Hishizawa ◽  
Atae Utsunomiya ◽  
Shuichi Taniguchi ◽  
Tetsuya Eto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Leukemia ◽  
Graft Versus Host ◽  
Adult T Cell Leukemia ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.

scholarly journals First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4885-4885
Author(s):  
Thomas A Gagliardi ◽  
Jordan Milner ◽  
Cassey Paula ◽  
Mehmet Ozkayank ◽  
Oya Levendoglu-Tugal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lung Biopsy ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Case Series ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD. Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172. Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved. Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option. Disclosures Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.

scholarly journals Gvhd and Relapse Free Survival (GRFS) after Allogeneic Transplantation for Idiopathic Severe Aplastic Anemia: An Analysis from the Saawp Data Quality Initiative Program of EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Raynier Devillier ◽  
Dirk-Jan Eikema ◽  
Paul Bosman ◽  
Carlo Dufour ◽  
Mahmoud Aljurf ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Cox Model ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3

Background Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved over past 20 years, approaching 75% at 5 years. However, beyond survival, a SAA-adapted composite endpoint GVHD and relapse free survival (GRFS) may more accurately assess patient outcomes, becoming a meaningful study endpoint. We analyzed GRFS aiming to identify risk factors and specific causes of GRFS failure. Methods This retrospective analysis from the SAAWP Data Quality Initiative (DQI registry database) program of EBMT included patients with: diagnosis of idiopathic SAA; first Allo-HSCT from 2005 to 2016; and matched related (MRD) or unrelated donor (UD) (no cord blood). Relevant events for Kaplan-Meier calculation of GRFS were: relapse (including primary and secondary graft failure); grade 3-4 acute GVHD; extensive chronic GVHD; and death. In addition, we used a competing-risk model to analyze cumulative incidences of specific causes of GRFS failure. Results We analyzed 580 patients (385 adults and 195 younger than 18 years), with a median age of 23 years (&lt;0.1-77). Donor was matched related and unrelated in 337 and 243 patients, respectively. Median time from diagnosis to Allo-HSCT was 6 months (IQR: 2-15) and 310 (53%) patients underwent Allo-HSCT without prior treatment. GRFS at 5 years was 69% (65-73) in the whole cohort. Median follow up was 61 months (95%CI: 56-67). Multivariate cox model including age (continuous), graft source, conditioning intensity, sex mismatch, CMV-serostatus, donor type, time from diagnosis to Allo-HSCT (&lt; vs. &gt; 6 months) and previous treatment before Allo-HSCT showed that age (HR=1.02, [1.01-1.03], p&lt;0.001) and CMV serostatus other than negative-donor to negative-recipient [D-/R-] (HR=1.51, [1.02-2.23], p=0.041) were the only independent factors associated with worse GRFS. Using cause specific cox model, we analyzed the risk of the different causes of GRFS failure and found that CMV-serostatus other than D-/R- was associated with higher risk of graft failure/relapse (HR=2.88, [1.12-7.38], p=0.028) while age influenced the risk of grade 3-4 acute GVHD (HR=1.03, [1.00-1.05], p=0.043), extensive chronic GVHD (HR=1.03, [1.01-1.06], p=0.008) and death without prior failure (HR=1.03, [1.01-1.04], p&lt;0.001). Among the 209 patients who underwent upfront Allo-HSCT from a MRD, 5-year GRFS was 77% (71-84). In multivariate analysis, time from diagnosis to Allo-HSCT (HR=2.64, [1.38-5.03], p=0.003) and age (HR=1.03, [1.00-1.05], p=0.039) independently influenced GRFS. When investigating the causes of GRFS failure in this subset of patients who underwent upfront MRD Allo-HSCT, time from diagnosis to Allo-HSCT was the only remaining factors significantly associated with the risk of death without prior failure (HR=0.29, [0.10-0.84], p=0.022). No factor was found specifically associated with any other causes of GRFS failure. Conclusions We observed 5-year GRFS of 69%, meaning that most of patients who underwent Allo-HSCT for idiopathic SAA are cured without experiencing severe forms of acute and chronic GVHD. In the context of upfront MRD Allo-HSCT, GRFS was even more promising (77%). In this particular setting, time from diagnosis to Allo-HSCT was the most important factor influencing GRFS, suggesting the need to proceed to Allo-HSCT as quick as possible when a MRD is available. Disclosures Ganser: Novartis: Consultancy; Celgene: Consultancy. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals A Single-Arm, Open-Label, Pilot Study of the JAK1 Selective Inhibitor Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome in T-Cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 100-100
Author(s):  
Ramzi Abboud ◽  
Feng Gao ◽  
Michael P. Rettig ◽  
Jeremy Eisele ◽  
Leah Gehrs ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Peripheral Blood ◽  
Intracellular Signaling ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Ki 67 ◽  
Graft Versus Host ◽  
Engraftment Failure

Abstract Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report the clinical outcomes from our pilot study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100, followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS (graded by Lee criteria). Peripheral blood and serum samples were banked prior to conditioning and on days -1, 1, 3, 7, 14, 28, 60, 100, end of treatment, and time of diagnosis of acute GVHD. Matched control samples were collected from patients undergoing haplo-HCT off clinical trials. Correlative studies include flow cytometry (FACS) with five 28-color panels for cellular subsets, mass cytometry (CyTOF) with 40-colors for intracellular signaling events, single cell RNA sequencing, and serum cytokine and chemokine measurements. Results: Twenty of a planned 20 patients completed enrollment and underwent haplo-HCT between 11/2019 and 3/2021. Median age at transplant was 49 (21-74). Diagnoses were AML (13), ALL (5) and NHL (2). Median follow up is 319 days, with 18/20 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment (historical 16 and 25 days, respectively). There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD on day 100 was 15%. Two patients developed grade I-II skin acute GVHD during itacitinib taper and responded to resumption of a higher dose. There were no cases of extensive chronic GVHD. There were no cases of severe CRS (historical rate 17%), with 90% of patients having grade 1 CRS and 10% having no CRS. Furthermore, no anti-IL6R or steroid therapy was used. Overall survival at day 180 was 90% (95% CI 75-100%) by Kaplan-Meier estimate. Incidence of relapse at 180 days was 5.5% (95% CI 0-15.6%). Refined GVHD and relapse-free survival at 180 days was 83% (95% CI 68-100%). All patients had full donor engraftment and &gt;95% chimerism at day 100. FACS and CyTOF have been performed and analyzed for the day 28 time point from 14 patients and four controls. Flow cytometry revealed no difference in cell subset numbers between controls and patient samples. CyTOF revealed differences in intracellular signaling molecules between itacitinib and control patients - including higher Ki-67, pNF-κB, and Caspase3 in controls. Phospho-Stat1 and pStat3 were lower CD4 T subsets. FACS and CyTOF at remaining time points, single cell RNA sequencing, and serum cytokine and chemokine measurements are underway and will be presented at the ASH 2021 meeting. Conclusions: Itacitinib with PB haplo-HCT was safe with no engraftment failure and prompt engraftment. Rates of acute and chronic GVHD were low, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. Flow cytometry demonstrated comparable immune reconstitution in terms of cell lineage and number between treated patients and controls. Mass cytometry revealed lower Ki-67, pNF-κB, and caspase3 levels, among other markers, which suggest lower immune cell activity, proliferation, and apoptosis. An extension cohort of 20 additional patients is enrolling. Multi-platform correlative studies are underway, comparing samples from haplo-HCT patients treated with and without itacitinib. Figure 1 Figure 1. Disclosures Uy: Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; Agios: Consultancy; Jazz: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Macrogenics: Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Pusic: Syndax: Other: Advisory Board. Schroeder: Equillium Inc: Honoraria; Janssen: Honoraria; Sanofi Genzyme: Honoraria.

scholarly journals Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 256-256 ◽  
Author(s):  
Uday Popat ◽  
Rohtesh S. Mehta ◽  
Roland Bassett ◽  
Amanda L. Olson ◽  
Julianne Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Very High

Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was &gt;3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (&gt; 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

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