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1.
Autoimmune Limbic Encephalitis in Patients with Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide
Heo, B. Y., Lee, M. W., Choi, S., Jung, Y., Pham, T. T. D., Jang, Y., Park, J. H., Kang, S., Koh, J. S., Jo, D. Y., et al
Cells. 2023;12(16)
Abstract
Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with post-transplant cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflammatory biomarkers, and reconstitution of various T cell populations. Of 35 patients, 4 developed LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.
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2.
Cytokine profiling during conditioning in haploidentical stem cell transplantation and its prognostic impact on early transplant outcomes
Li, N., Zhao, C., Ma, R., Lou, R., Liu, X. J., Zheng, F. M., Wang, J. Z., Wang, Y., Huang, X. J., Sun, Y. Q.
Transplant immunology. 2023;78:101830
Abstract
Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival.
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3.
Double filtration plasmapheresis combined with rituximab for donor-specific antibody desensitization in haploidentical haematopoietic stem cell transplantation
Liu, L., Ji, X., Zhu, P., Yang, L., Shi, J., Zhao, Y., Lai, X., Yu, J., Fu, H., Ye, Y., et al
British journal of haematology. 2023
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical haematopoietic stem cell transplantation (Haplo-HSCT). Double filtration plasmapheresis (DFPP) avoids the unnecessary loss of plasma proteins and increases the efficiency of purification. To investigate the effectiveness of the desensitization protocol including DFPP and rituximab, we conducted a nested case-control study. Thirty-three patients who had positive DSA were desensitized by the protocol and 99 patients with negative DSA were randomly matched as control. The median DSA mean fluorescence intensity values before and after DFPP treatment were 7505.88 ± 4424.38 versus 2013.29 ± 4067.22 (p < 0.001). All patients in DSA group achieved haematopoietic reconstitution and the median neutrophils and platelets engraftment times were 13 (10-21) and 13 (10-29) days respectively. Although the cumulative incidence of II-IV aGVHD (41.4% vs. 28.1%) and 3-year moderate to severe cGVHD (16.8% vs. 7.2%) were higher in DSA cohort than in the control, no statistical significance was observed. The 3-year non-relapse mortality and the overall survival were 6.39% and 72.0%, respectively, in the DSA cohort, which were comparable to the negative control. In conclusion, DFPP and rituximab could be effectively used for desensitization and overcome the negative effects of DSA in Haplo-HSCT.
PICO Summary
Population
Adults with haematological malignancies receiving haploidentical transplant at a single centre in China (n=132)
Intervention
Patients who were positive for donor specific antibodies and received two sessions alternate day double filtration plasmapheresis (DFPP) plus a single dose of rituximab (DSA group, n=33)
Comparison
Matched controls who were negative for donor specific antibodies (control, n=99)
Outcome
All patients in DSA group achieved haematopoietic reconstitution and the median neutrophils and platelets engraftment times were 13 (10-21) and 13 (10-29) days respectively. Although the cumulative incidence of II-IV aGVHD (41.4% vs. 28.1%) and 3-year moderate to severe cGVHD (16.8% vs. 7.2%) were higher in DSA cohort than in the control, no statistical significance was observed. The 3-year non-relapse mortality and the overall survival were 6.39% and 72.0%, respectively, in the DSA cohort, which were comparable to the negative control.
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4.
Thrombopoietin level predicts the response to avatrombopag treatment for persistent thrombocytopenia after haploidentical haematopoietic stem cell transplantation
Fu, H., Lv, M., Liu, H., Sun, Y., Zhang, Y., Mo, X., Han, T., Wang, F., Yan, C., Wang, Y., et al
Bone marrow transplantation. 2023
Abstract
Persistent thrombocytopenia (PT) has an unsatisfactory response to therapy after haploidentical haematopoietic stem cell transplantation (haplo-HSCT). We retrospectively evaluated the safety and efficacy of avatrombopag treatment in 69 patients with PT following haplo-HSCT and assessed whether baseline thrombopoietin (TPO) levels could predict treatment response. Overall response (OR) and complete response (CR) were defined as increased platelet levels to over 20 × 10(9)/L or 50 × 10(9)/L independent of platelet transfusion during or within 7 days of the end of avatrombopag treatment, respectively. The incidences of OR and CR were 72.5% and 58.0%, with a median of 11 and 29 days to OR and CR, respectively. ROC analysis suggested that the optimally discriminant baseline TPO level threshold for both OR and CR to avatrombopag was ≤ 1714 pg/mL. In multivariate analysis, a lower baseline TPO level (P = 0.005) was a significant independent factor of response to avatrombopag. For patients resistant to other TPO receptor agonists (TPO-RAs), 9/16 (56.3%) exhibited a response after switching to avatrombopag. Avatrombopag was well tolerated, and responders achieved improved overall survival (79.0% vs. 91.1%, P = 0.001). In conclusion, avatrombopag is a potential safe and effective treatment for PT after haplo-HSCT, and lower baseline TPO levels predicted a better response.
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5.
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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6.
Poor graft function after haploidentical stem cell transplantation with post-transplant cyclophosphamide
Gómez-Centurión, I., Martin Rojas, R. M., Bailén, R., Muñoz, C., Sabell, S., Oarbeascoa, G., Fernández-Caldas, P., Carbonell, D., Gayoso, J., Martínez-Laperche, C., et al
Annals of hematology. 2023
Abstract
This is a retrospective cohort study of consecutive adult patients who received a haploidentical-SCT (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) in a single centre. Poor graft function (PGF) was defined as the occurrence of either persistent neutropenia (ANC < 0.5 × 10(9)/µL) with poor response to granulocyte colony-stimulating factors (G-CSF) and/or thrombocytopenia (platelets < 20 × 10(9)/L) with transfusion dependence, with complete donor chimerism and without concurrent severe GVHD or underlying disease relapse, during the first 12 months after transplantation. Forty-four (27.5%) out of 161 patients were diagnosed with PGF. Previous CMV reactivation was significantly more frequent in patients with PGF (88.6% versus 73.5%, p = 0.04) and the number of reactivations was also higher in these patients. Besides, early CMV reactivations in the first 6 months post-SCT were also significantly more frequent among patients with PGF (88.6% versus 71.8% p = 0.025). Thirty-two percent of patients with PGF were treated with increasing doses of thrombopoietin-receptor agonists (TRA) and 7 patients were treated with a donor CD34 + selected boost. In total, 93.2% of patients reached adequate peripheral blood counts in a median time of 101 days (range 11-475) after diagnosis. PGF is a frequent complication after haplo-SCT with PT-Cy. CMV reactivation might be the most relevant factor associated to its development. Even when most patients recover peripheral counts with support therapy, there is a group of patients with persistent cytopenias who can effectively be treated with TRA and/or a boost of CD34 + selective cells.
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7.
Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse
Shapiro, R. M., Kim, H. T., Ansuinelli, M., Guleria, I., Cutler, C. S., Koreth, J., Gooptu, M., Antin, J. H., Kelkar, A. H., Ritz, J., et al
Blood advances. 2023
Abstract
Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles the CRS after chimeric antigen receptor (CAR)-T therapy. We conducted this single-center retrospective study evaluating the association of post-haploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction, and graded according to established criteria. The development of post-haploidentical HCT CRS was associated with a lower incidence of disease relapse (p=0.024) but with an increased risk of chronic GVHD (p=0.01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor TNC dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (p<0.0005), CD4+ Tcon (p<0.005) and CD8+ T-cells (p<0.005) were increased at 1 month following HCT compared to those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells at 1 month post HCT was most notable among patients with CRS who received a bone marrow graft (p<0.005). The development of post haploidentical HCT CRS is associated with a reduced incidence of disease relapse and with a transient effect on post HCT immune reconstitution of T cells and their subsets. Validation of these observations in a multicenter cohort is required.
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"Incidence and significance of donor-specific antibodies in haploidentical stem cell transplantation"
Altareb, M., Al-Awwami, M., Alfraih, F., Alhayli, S., Ahmed, S. O., Shaheen, M., Chaudhri, N., Alsharif, F., Alkhabbaz, H., Albabtain, A. A., et al
Bone marrow transplantation. 2023
Abstract
PGF is a devastating complication after allogeneic transplant. We retrospectively analyzed our haploidentical transplant registry to report the incidence and impact of DSA and anti-HLA on engraftment. 107 patients were identified. Median recipient-age of 22, median donor-age of 31. Sixty-two patients had AML (58%), 29 had ALL (27%), 16 (15%) had other malignancies. Sixty-one recipients (57%) had positive anti-HLA, 56 of them had the DSA results available, of these 17 patients had DSAs (15% of the total number of patients, or 28% of patients who have anti-HLA antibodies). The median cumulative MFI was 2062. Sixty-three percent of the DSA were against class-II HLA antigens. The OS, CIR, aGvHD, and cGvHD did not differ between patients with and without anti-HLA antibodies, nor between patients with and without DSA. The gender of the recipient and donor, as well as the gender mismatch between recipient and donor, were statistically associated with the incidence of anti-HLA antibodies. Three patients only developed GF (2.8%), one was primary (0.9%) and the other two secondary GF (1.9%). None of the GF cases was in patients with anti-HLA antibodies or DSA. The presence of anti-HLA or DSAs did not affect the outcomes including the incidence of PGF.
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9.
Acute kidney injury in peripheral blood haploidentical hematopoietic stem cell transplantation: should attract enough attention
Liu, Y., Duan, Z., Li, F., Zhang, X., Chen, R., Lu, H., Qian, S., Wu, H., Chen, L., Zhu, Y., et al
Bone marrow transplantation. 2022
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10.
Clinical Significance of Haplo-Fever and Cytokine Profiling After Graft Infusion in Allogeneic Stem Cell Transplantation From Haplo-Identical Donors
Wang, L., Dai, B., Gao, W., Wang, J., Wan, M., Wang, R., Wang, L., Jiang, J., Blaise, D., Hu, J.
Frontiers in medicine. 2022;9:820591
Abstract
Allogeneic stem cell transplantation from haplo-identical donors (haplo-HSCT) has become a well-established therapeutic option for hematological malignancies. The fever of unknown origin (haplo-fever) early after the infusion of T cell repleted graft, which returned to normal right after post-transplantation cyclophosphamide (PTCy), is a unique clinical feature in patients undergoing haplo-HSCT. In the current study, the characteristics of haplo-fever and cytokine profiles during haplo-fever were retrospectively analyzed in a cohort of 37 patients undergoing T cell repleted haplo-HSCT with PTCy as graft versus host disease (GvHD) prophylaxis. In total, 33 patients (89.2%) developed haplo-fever from day 0 to day +7. Patients with high peak temperatures tended to have a lower incidence of chronic GvHD (cGvHD) (p = 0.07), moderate to severe cGvHD (p = 0.08), and superior GvHD and relapse-free survival (GRFS, p = 0.04). During the haplo-fever, there were significant increases in multiple cytokines, such as interferon gamma, interleukin (IL) 6, IL2, IL2 receptor, IL8, IL10, IL17, and tumor necrosis factor (TNF). The increases in IL2 receptor (p = 0.037) and TNF (p < 0.001) on day +4 were correlated with the lower risk of cGvHD. Increased TNF > 1.8055-fold on day +4 was the best predictive threshold for cGvHD, and was correlated with a lower incidence of cGvHD (p < 0.001), moderate to severe cGvHD (p = 0.003), and superior GRFS (p < 0.001). These observations may reflect the early reactivation of donor T cells after haplo graft infusion, which would potentially be eliminated by PTCy. Further studies with larger independent cohorts of patients are warranted, to clarify the clinical significance of haplo-fever, and day +4 TNF as a potential biomarker to predict GvHD and GRFS.