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Sirolimus is an acceptable alternative to tacrolimus for graft-versus-host disease prophylaxis after haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide
Elmariah, H., Otoukesh, S., Kumar, A., Ali, H., Arslan, S., Shouse, G., Pourhassan, H., Nishihori, T., Faramand, R., Mishra, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus (TAC) and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor transplantation. A phase II study from Moffitt Cancer Center substituting sirolimus (SIRO) in place of TAC reported comparable rates of grade II-IV acute GVHD. Many centers have substituted SIRO for TAC in this setting based on a preferred side effect profile, though comparative data is limited. OBJECTIVE The objective of this study is to compare outcomes of haplo HCT with PTCy/SIRO/MMF versus PTCy/TAC/MMF. STUDY DESIGN We retrospectively compared haplo HCT outcomes with PTCy/SIRO/MMF versus PTCy/TAC/MMF. Included were all consecutive patients receiving haplo donor T cell replete peripheral blood stem cell graft HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. RESULTS A total of 423 patients were included, of which 84 (20%) received SIRO and 339 (80%) received TAC. Median age for all patients was 54 (range 18 to 78) years, and median follow-up for entire study cohort was 30 months. SIRO group had a higher proportion of patients ≥60 years (58% versus 34%, P = <.01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV acute GVHD (45% versus 47%, P = .6) at day +100 or chronic GVHD (47% versus 54%, P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better with TAC (OR = 0.30, CI 0.1 to 0.83, P = .02) with a median time to engraftment of 17 days versus 18 days for SIRO, but platelet engraftment was similar in both groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on acute or chronic GVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease free survival, or overall survival after peripheral blood haplo HCT. CONCLUSIONS These findings suggest that SIRO is a comparable alternative to TAC in combination with PTCy/MMF for GVHD prophylaxis, resulting in overall similar clinical outcomes despite delay in engraftment after peripheral blood haplo HCT. While TAC remains the standard of care, SIRO may be substituted based on the side effect profile of these medications with consideration of patient medical comorbidities at HCT.
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Tocilizumab for Cytokine Release Syndrome Management after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis
Yao, J. M., Otoukesh, S., Kim, H., Yang, D., Mokhtari, S., Samara, Y., Blackmon, A., Arslan, S., Agrawal, V., Pourhassan, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplant (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. OBJECTIVES In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplant cyclophosphamide- (PTCy-) based graft-versus-host disease (GVHD) prophylaxis. STUDY DESIGN Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (MAC vs RIC/NMA), and CRS grading (1, 2 vs 3-4). Instead of 22 controls, we chose 21 patients because there was only one control matched with one TOCI treatment patient in one stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (HR=3.4 or higher) in transplant outcomes using a two-sided 0.05 test. The power would be reduced to about 20-30% if the difference was moderate (HR=2.0) using the same test. RESULTS No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range: 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% CI: 0.28-1.06, P=0.08). Median time to platelet engraftment was 34 days (range: 20-81) in TOCI and 28 days (range: 12-94) in NO-TOCI group (HR=0.56; 95% CI: 0.25-1.22, P= 0.19). Cumulative incidences of day +100 acute GVHD grades II-IV (P=0.97) and grades III-IV (P=0.47) were similar between the two groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% vs 24%; P=0.05). Rates of NRM (P=0.66), relapse (P=0.83), disease-free survival (P=0.86), and overall survival (P=0.73) were similar at 1-year post-HCT between the two groups. CONCLUSIONS Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore, using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.
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3.
Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens
Yao, J. M., Yang, D., Clark, M. C., Otoukesh, S., Cao, T., Ali, H., Arslan, S., Aldoss, I., Artz, A., Amanam, I., et al
Bone marrow transplantation. 2021
Abstract
Post-transplant cyclophosphamide (PTCy) combined with tacrolimus (TAC) as graft-versus-host disease (GvHD) prophylaxis post-hematopoietic cell transplantation (HCT) is safe and effective. Optimal serum levels of TAC in this combination remain undetermined. We hypothesized that TAC at initial steady state (TISS) of <10?ng/mL could promote optimal transplant outcomes and prevent TAC-associated toxicities. We retrospectively analyzed a consecutive case series of 210 patients who received PTCy/TAC-based prophylaxis post-HCT from 1/2013-6/2018. Patients received HCT from haploidentical (n?=?172) or mismatched donors (n?=?38), and flat dose (FD) or weight-based dose (WBD) TAC. Twenty-four-month overall survival (OS), disease free survival (DFS), and relapse rate (RR) were 61%, 56%, and 22%, respectively, in TISS?10?ng/mL cohort (n?=?176), and 50%, 43%, and 35%, respectively, in TISS?=?10?ng/mL cohort (n?=?34) (OS, P?=?0.71; DFS, P?=?0.097; RR, P?=?0.031). OS, DFS, RR, non-relapse mortality, acute GvHD grade II-IV, grade III-IV or chronic GvHD by TISS were similar in multivariable analysis. TISS?=?10?ng/mL conferred increased risk of viral infection (P?=?0.003). More patients receiving FD vs. WBD had TISS?10?ng/mL (P?=?0.001). Overall, TISS?10?ng/mL early post HCT conferred similar survival outcomes and lowered risk of viral infection and toxicities compared to TISS?=?10?ng/mL.
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Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch
Al Malki, M. M., Gendzekhadze, K., Yang, D., Mokhtari, S., Parker, P., Karanes, C., Palmer, J., Snyder, D., Forman, S. J., Nademanee, A., et al
Transplantation. 2019
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Abstract
BACKGROUND While Tacrolimus/Sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor (URD) HCT (2005 - 2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range=2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95%CI: 43.0-52.0) and 43.6% (95%CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of non relapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% vs. 50.7% at 5 years, p=0.034), primarily due to greater risk of NRM (33.5% vs. 21.7%, p=0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% vs. 12.8%, p=0.022) and infection (33.0% vs. 18.1%, p<0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (HR= 2.21, 95%CI: 1.16-4.23; p<0.01) and mMUD (HR=1.55, 95%CI:.1.15-2.08; p=0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.
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Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.
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Influence of Absorption, Distribution, Metabolism, and Excretion Genomic Variants on Tacrolimus/Sirolimus Blood Levels and Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation
Khaled, S. K., Palmer, J. M., Herzog, J., Stiller, T., Tsai, N. C., Senitzer, D., Liu, X., Thomas, S. H., Shayani, S., Weitzel, J., et al
Biology of Blood & Marrow Transplantation. 2016;22(2):268-76
Abstract
Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 (P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.