scholarly journals Pretransplant active disease status and HLA class II mismatching are associated with increased incidence and severity of cytokine release syndrome after haploidentical transplantation with posttransplant cyclophosphamide

2019 ◽  
Vol 9 (1) ◽  
pp. 52-61
Author(s):  
Jacopo Mariotti ◽  
Daniela Taurino ◽  
Fabrizio Marino ◽  
Stefania Bramanti ◽  
Barbara Sarina ◽  
...  
Keyword(s):  
Disease Status ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Haploidentical Transplantation ◽  
Active Disease

scholarly journals Timing of Initiation of Calcineurin Inhibitors in Pediatric Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Effects on Survival, Relapse, and Cytokine Release Syndrome

2021 ◽  
Author(s):  
Vedat Uygun ◽  
Gülsün Karasu ◽  
Koray Yalçın ◽  
Seda Ozturkmen ◽  
Hayriye Daloğlu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Calcineurin Inhibitors ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Post Transplantation ◽  
Acceptable Alternative ◽  
Haploidentical Transplantation ◽  
Timing Of Initiation ◽  
Overall Survival Analysis ◽  
Matched Donor

Background: The use of unmanipulated haploidentical stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNI) used in combination with PTCY is increasingly becoming a topic of controversy. Method: We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-CY). Results: There were no significant differences in the overall survival analysis between the two groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p=0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group (p=0.04). The OS and EFS at 2 years in patients with and without CRS in the pre-Cy group were 42.9% vs 87.5% (p=0.04) and 38.1% vs 87.5% (p=0.04), respectively. Conclusion: Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNI before CY needs to be reconsidered.

T-Cell Replete Peripheral Blood Haploidentical Donor Transplant Is Frequently Associated with Cytokine Release Syndrome Which Responds to Anti-IL-6 Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3106-3106
Author(s):  
Ramzi Abboud ◽  
Jesse Keller ◽  
Michael Slade ◽  
Michael P. Rettig ◽  
Stephanie Meier ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Cytokine Profiles ◽  
Clinical Responses ◽  
Active Disease

Abstract Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Traditionally reserved for patients with an HLA-matched donor, advances in graft versus host disease (GVHD) prophylaxis utilizing post-transplant cyclophosphamide (PTCy) have expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). While overall outcomes for haplo-HCT appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. The immediate post-transplant course in T cell replete haplo-HCT is often complicated by symptoms including fever, hypoxia, hypotension and organ dysfunction resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics such as CAR T-Cells. IL-6 is thought to be a key mediator of CRS in patients receiving novel T-cell engaging therapies, and tocilizumab has been used with success in this setting. Here we aim to describe the nature and incidence of CRS in haplo-HCT recipients, as well as its potential implications on clinical outcomes. Additionally, prospective analysis of cytokine profiles of haplo-HCT recipients and clinical responses to tocilizumab therapy are presented. Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through April 2015. Patients were scored for symptoms of CRS based on established grading criteria (Lee et al, Blood 2014). Patients were stratified into three categories by grade of CRS experienced: none (grade 0), mild (grade 1-2) and severe (grade 3-4). Outcomes were assessed. A total of 84 patients were identified, 55% (46) were male, with a median age at transplant of 49 (19-73), and 49% (41) had active disease at the time of transplant. The most common diagnosis was AML (55 pts), followed by ALL (9 pts), MDS (5 pts) and NHL (2 pts). Among the patients, 26% (22 pts) had undergone prior transplant. In addition to the retrospective review, baseline and post- transplant cytokine levels were prospectively drawn in 10 patients who underwent haplo-HCT. A total of 7 additional patients who met criteria for CRS were treated prospectively with tocilizumab (dose: 4mg/kg-bw) and clinical responses were recorded. We recorded CRP levels in selected patients as part of clinical monitoring. Results: We found a high incidence, 85%, of CRS in our haplo-HCT patients. Among a total of 84 patients, 12 (14%) experienced severe CRS, 60 (72%) had mild CRS, and 12 (14%) patients had no evidence of CRS. The most common manifestations of severe CRS included: fever (100%), respiratory failure (75%), hypotension (83.3%), hepatic failure (25%) and renal failure (33.3%). The median maximum CRP (during post-transplant days 0 to 8) in all patients suffering from CRS was 155 mg/L. Of the twelve patients who suffered from severe CRS, nine (75%) died. Predicted median survival was 0.72 months for severe CRS, 12.7 months for patients with no CRS and was not reached for patients with mild CRS (fig 1). Rates of acute and chronic graft-versus-host disease did not differ by CRS status. The incidence of mild and severe CRS did not differ by ABO mismatch, age, CMV status, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS for patients in remission versus active disease at time of transplant. There were no differences in engraftment. Cytokine profiles in haplo-HCT recipients showed significant elevation in serum IL-6 levels, most significant in patients who suffered from severe CRS (fig 2). We administered tocilizumab to 7 patients with severe CRS symptoms early after haplo-HCT (median day of treatment was day +3) resulting in the resolution of their CRS symptoms within 48-72 hours. Over the same time period CRP levels dropped below 50% of the peak value. Summary: CRS is common after T-cell replete haplo-HCT and severe CRS is potentially associated with high risk of early mortality after transplant. Cytokine profiles suggest IL-6 is a key mediator of CRS in haplo-HCT patients. Tocilizumab appears to be an effective treatment for patients who develop severe CRS early after T-cell replete haplo-HCT. Future prospective studies are warranted in studying the role of tocilizumab in the treatment and potentially prevention of severe CRS in haplo-HCT patients. Disclosures Fehniger: Celgene: Research Funding. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Gerson Lehman Group: Consultancy.

Risk Factors for the Development of and Outcomes of Patients Who Develop Severe Cytokine Release Syndrome after Peripheral Blood Haploidentical Donor Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3419-3419
Author(s):  
Ramzi Abboud ◽  
Michael Slade ◽  
Wenners Ballard ◽  
Jesse Keller ◽  
John F DiPersio ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Patient Characteristics ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Active Disease ◽  
Related Mortality

Abstract Background:Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Following development of post-transplant cyclophosphamide (PTCy) regimens, the use of haploidentical hematopoietic cell transplantation (haplo-HCT) has expanded. While overall outcomes for haploidentical transplantation appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. We recently described occurrence of severe cytokine release syndrome (CRS) after haplo-HCT. We further reported that severe CRS was associated with poor clinical outcomes, including transplant related mortality (TRM), overall survival (OS), and neutrophil engraftment (Abboud et al, BBMT, 2016). However, the factors predicting the occurrence of and long-term outcomes of patients who develop severe CRS after haplo-HCT is currently not known. Objective: To describe our clinical experience with CRS in an expanded cohort of haplo-HCT patients, its implication on clinical outcomes and elucidation of possible risk factors for the development of severe CRS. Patients and Methods: We performed a retrospective review of patients who had undergone peripheral blood T-Cell replete haplo-HCT with PTCy from July 2009 through March 2016 at our institution. A total of 137 patients were identified, 51% (74) were male, with a median age at transplant of 52 (19-73), a total of 40% (57) had active disease at the time of transplant. The most common diagnosis was AML (93 pts), followed by ALL (16 pts) and MDS (15 pts). Thirty-one percent (44 pts) had undergone prior transplant. In grading CRS, we used our approach modified from by Lee et al (Blood, 2014). Twenty-two patient, donor and disease characteristics were examined to identify predictors for the development of severe CRS. Results:One hundred and twenty-four (90%) of patients met criteria for CRS, and 26 (19%) suffered from severe (grade 3-4) CRS. Virtually all patients (99%) with CRS suffered from fevers. Patients with severe CRS had a significant delay in neutrophil (p < 0.0001) and platelet (p < 0.0001) engraftment compared to the patients who developed mild or no CRS (Figure 1A and 1B). Severe CRS was also associated with a high early transplant related mortality; the rate of death before post-transplant day 28 was 6.9 times higher for patients with grade 3-4 CRS compared with those with mild CRS (p < 0.0001, Figure 1C). Consistent with these findings, the development of severe CRS was associated with extremely poor survival. Median survival was 3 months for grade 3-4 CRS, 15 months for grade 1-2 CRS, and 13 months for no CRS. One-year OS was 4% for grade 3-4 CRS, 55% for grade 1-2 CRS, and 50% for no CRS (Figure 1D). There was no difference in the cumulative incidence of relapse, acute graft versus host disease, and chronic graft versus host disease (data not shown). A total of nine patients received Anti-IL-6 Therapy with tociluzimab (4 mg/kg of actual body weight), 4 of which suffered from severe CRS. In terms of predictive factors, the development of severe CRS was associated with disease risk index (p=0.037), HCT-CI score (p=0.005) and presence of a previous transplant (p=0.026) by univariate analysis. Risk and severity of CRS did not differ by age, ABO mismatch, age, CMV status of donor, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS among patients in remission or with active disease at the time of transplant. Conclusions: Severe CRS after peripheral blood haplo-HCT is associated with high early TRM, poor OS and delayed neutrophil and platelet engraftment. Furthermore, patients with high DRI, high HCT-CI and prior HCT are at a higher risk for the development of severe CRS after haplo-HCT. We have previously shown the safety and potential efficacy of using anti-IL-6 therapy in these patients. Our current results suggest potential benefit to targeting this pathway prophylactically in patients at high risk for the development of severe CRS. Table Patient Characteristics Table. Patient Characteristics Figure CRS impacts neutrophil (A) and platelet (B) engraftment and is associated with high TRM (C) and poor OS (D). Figure. CRS impacts neutrophil (A) and platelet (B) engraftment and is associated with high TRM (C) and poor OS (D). Disclosures DiPersio: Incyte Corporation: Research Funding. Abboud:Gerson and Lehman Group: Consultancy; Merck: Research Funding; Teva: Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Alexion: Honoraria; Baxalta: Honoraria; Pharmacyclics: Honoraria; Takeda: Honoraria; Cardinal: Honoraria. Fehniger:Affimed: Consultancy; Celgene: Research Funding; Fortress Biotech: Consultancy.

scholarly journals Timing of Initiation of Calcineurin Inhibitors in Pediatric Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Effects on Survival, Relapse, and Cytokine Release Syndrome

2021 ◽  
Author(s):  
Vedat Uygun ◽  
Gulsun Karasu ◽  
Koray Yalçın ◽  
Seda Öztürkmen ◽  
Hayriye Daloglu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Calcineurin Inhibitors ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Post Transplantation ◽  
Acceptable Alternative ◽  
Haploidentical Transplantation ◽  
Timing Of Initiation ◽  
Overall Survival Analysis ◽  
Matched Donor

Abstract The use of unmanipulated haploidentical stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNI) used in combination with PTCY is increasingly becoming a topic of controversy. We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-CY). There were no significant differences in the overall survival analysis between the two groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p = 0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group. Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNI before CY needs to be reconsidered.

scholarly journals Cytokine Release Syndrome after Peripheral Blood T-Cell Replete Haploidentical Transplantation Is Not Prevented By Dexamethasone and Limits Its Full-Outpatient Conduction

2019 ◽  
Vol 25 (3) ◽  
pp. S136-S137
Author(s):  
Perla R. Colunga-Pedraza ◽  
Andrés Gómez-De León ◽  
Julia E. Colunga-Pedraza ◽  
Paola Santana-Hernández ◽  
Emmanuel Bugarín-Estrada ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Haploidentical Transplantation

scholarly journals Severe Cytokine Release Syndrome Is a Fatal Complication after PBSC, but Not after BM Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 665-665
Author(s):  
Jacopo Mariotti ◽  
Daniela Taurino ◽  
Stefania Bramanti ◽  
Barbara Sarina ◽  
Lucio Morabito ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Disease Status ◽  
Febrile Reaction ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Advisory Committees ◽  
Post Transplant ◽  
Grade 3 ◽  
First Time

Abstract Background: T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with high dose post-transplant cyclophosphamide (PT-Cy) represents an alternative option for patients with hematologic malignancies when a HLA identical sibling or a matched related donor is not available. Infusion-related febrile reaction and Cytokine release syndrome (CRS) were shown to occur within the first 24 hours and 14 days, respectively, after peripheral blood stem cell (PBSC) Haplo-SCT with PT-Cy. In particular, severe CRS is associated with an adverse outcome in terms of overall survival (OS) and non-relapse mortality (NRM) and appear to be mediated by a massive release of inflammatory cytokines, including IL-6, IFNγ, IL-2. Up to date, it is not known whether CRS is associated only with PBSC or may occur also after bone marrow graft. Moreover, no variable, either from the donor or the recipient, has been identified to be associated with the occurrence of CRS. Methods: We retrospectively analyzed 66 consecutive patients receiving Haplo-SCT with PT-Cy either form a BM (n=28) or PBSC (n=38) graft source between 2014 and 2015 at our institution. The two cohorts did not differ in terms of main patients' or donors' characteristics (median age of the recipient, pre-transplant disease status, CMV serostatus, HCT-CI, type of conditioning, donor age and type). CRS was identified and graded according to Abboud R, et al, BBMT 2016 and Lee DW, Blood 2014. Results: Grade 1 CRS characterized by febrile reaction was diagnosed in 34 out of 38 patients (89%) receiving PBSC and 20 out of 28 (71%) receiving BM Haplo-SCT with a median of 1 (0-7) and 2 (0-4) days, respectively, after transplant. By day 14 post-transplant CI of CRS grade ≥2 was 37% (95% CI: 19-45) after PBSC Haplo-SCT and 28% (95% CI: 8-52) after BM transplant (p=0.3). Interestingly, severe CRS grade ≥3 occurred only after PBSC transplant for a CI of 18% (95% CI: 3-44) vs 0% after BM Haplo-SCT (p=0.01) (Figure 1a). 1-year NRM did not differ between patients experiencing CRS ≥2 vs &lt;2 either after BM (5%, 95% CI: 0-22 vs 12%, 95% CI: 0-44) or PBSC (37%, 95% CI: 12-63 vs 26%, 95% CI: 10-46; p=0.5) Haplo-SCT. Similarly, 3-year OS was not significantly different between subjects with CRS ≥2 vs &lt;2: 52% (95% CI: 27-72) vs 65%(95% CI, 49-77) for the whole cohort (p=0.6). In marked contrast, recipients of PBSC Haplo-SCT experiencing grade ≥3 CRS had worse 1y-NRM compared with CRS &lt;3: 78% (95% CI: 6-98) vs 20% (95% CI: 8-37) (p=0.002, Figure 1b). Consistently, 3-years OS after PBSC Haplo-SCT was significantly affected by CRS grade ≥3: 3-y OS was 21% (95% CI: 1-58) for CRS ≥3 vs 53% (95% CI: 25-75) for CRS &lt;3 (p=0.01, Figure 1c). Within patients receiving PBSC Haplo-SCT, we were not able to identify any variable associated with the occurrence of severe CRS (data not shown). CRS ≥3 was the only variable associated with worse NRM both in univariate and multivariate analysis (HR: 4,7, 95% CI: 1,3-16,6, p=0.01). Pre-transplant disease status (CR vs PR vs PD/SD) and CRS ≥3 were associated with a worse 3-years OS both in univariate and multivariate analysis: disease status HR: 4,6, p=0.02; CRS≥3, HR: 13,4, 95% CI: 2,9-62,1; p=0.001. Conclusion: We have shown for the first time that CRS occurs not only after PBSC, but also BM Haplo-SCT with PT-CY. We have also found for the first time that severe CRS occurs only after PBSC transplant and confirmed that only CRS &gt;3 is associated with a worse outcome. Deepening our understanding of CRS biology, by analyzing not only the T cell, but also the macrophage compartment, is warranted in order to improve our chances to predict and abrogate CRS after T-cell-replete Haplo-SCT. Figure 1. Cumulative incidence (CI) of CRS and disease outcome after Haplo-SCT. A) CI of CRS ≥3 for subjects receiving PBSC vs BM graft; b) 1-year NRM of CRS ≥ 3 vs &lt;3 in recipients of PBSC Haplo-SCT; c) 3-year OS of CRS ≥ 3 vs &lt;3 in recipients of PBSC Haplo-SCT Disclosures Carlo-Stella: ADC Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy, Honoraria. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

scholarly journals HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment

2018 ◽  
Vol 2 (24) ◽  
pp. 3590-3601 ◽  
Author(s):  
Joseph Rimando ◽  
Michael Slade ◽  
John F. DiPersio ◽  
Peter Westervelt ◽  
Feng Gao ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Class Ii ◽  
Hla Class Ii ◽  
High Dose ◽  
Haploidentical Transplantation ◽  
Negative Effect ◽  
Novel Strategy ◽  
Risk Of Relapse

Abstract HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet–derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell–replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.

scholarly journals Peripheral Blood Grafts for T Cell–Replete Haploidentical Transplantation Increase the Incidence and Severity of Cytokine Release Syndrome

2018 ◽  
Vol 24 (8) ◽  
pp. 1664-1670 ◽  
Author(s):  
Renju V. Raj ◽  
Mehdi Hamadani ◽  
Aniko Szabo ◽  
Marcelo C. Pasquini ◽  
Nirav N. Shah ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Haploidentical Transplantation
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