scholarly journals Low day +100 serum epidermal growth factor levels are associated with acute GvHD after allogeneic hematopoietic cell transplantation

2016 ◽  
Vol 52 (2) ◽  
pp. 301-303 ◽  
Author(s):  
F He ◽  
M R Verneris ◽  
S Cooley ◽  
B R Blazar ◽  
M L MacMillan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Epidermal Growth

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

scholarly journals Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

2011 ◽  
Vol 208 (5) ◽  
pp. 1069-1082 ◽  
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Yvonne Saenger ◽  
Wing-Hong Kwan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Expansion ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

scholarly journals Causes and Effects of Methotrexate Dose Alterations in Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2460-2460 ◽  
Author(s):  
Radha Ramanan ◽  
Andrew Boon Ming Lim ◽  
Kate Mason ◽  
Jeffrey Szer ◽  
David Ritchie
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
World Health ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Grade 3

Abstract Aim To identify the causes and consequences of omission and/or reduction of methotrexate (MTX) doses in graft-versus-host disease (GVHD) prophylaxis used during allogeneic hematopoietic cell transplantation (alloHCT). Method We conducted a retrospective medical record review of 125 alloHCTs performed between the years 2011 and 2013 at our hospital where MTX (15, 10, 10, 10 mg/m2 intravenously on day [D] +1, D+3, D+6, D+11 respectively) is used with cyclosporine as GVHD prophylaxis. The association of MTX dose omission with overall survival (OS), non-relapse mortality (NRM) and acute GVHD, measured from a landmark of D+12, was evaluated with univariate and multivariate analysis. Results 116 patients (median age 48, range 17-67, 59% male) were eligible for analysis. Commonest indications for alloHCT were acute leukemia (47%) and chronic lymphoproliferative disorders (28%). Conditioning was myeloablative in 54%, donors were siblings in 53%, and grafts were peripheral blood in 87%. 85 patients (73%) received all four full doses of MTX. 22 patients had a dose omission at D+11, and two at both D+6 and D+11. 43 patients were given folinic acid rescue. Documented reasons for MTX alteration were mucositis (n = 22; World Health Organisation mucositis grade 4 in 16 patients, grade 3 in 4 patients and grade 2 in 2 patients), fluid overload (n = 10), liver impairment (n = 8, median bilirubin 83 micromol/L, range 19-204 micromol/L, normal < 21 micromol/L), renal impairment (n = 8, median creatinine 138 micromol/L, range 67-276 micromol/L, normal 45-90 micromol/L) and sepsis (1). MTX omission was associated with poorer OS (48% vs 90%; hazard ratio [HR] for mortality 5.4, 95% CI 2.5-11.7, P < 0.001, Figure 1) and higher NRM (39% vs 5%, HR 10.2, 95% CI 3.4-30.8, P < 0.001, Figure 2) at 12 months post landmark. A pattern of ongoing NRM was observed beyond day 100. Strikingly, those patients who received all four full doses of MTX had NRM of 0% at 100 days post landmark. There was no difference in rates of grade 2-4 (24% vs 22%, P = .950) or grade 3-4 (9% vs 11%, P = .662) acute GVHD, or relapse (20% vs 17%, P = .514), at day 100 post landmark. Conclusion MTX dose reduction has no significant impact on GVHD development, suggesting that MTX omissions or other adjustments of GVHD prophylaxis did not lead to enhanced T cell activation. However, it seems that the need to reduce MTX indicates an increased risk of NRM, likely reflecting ongoing organ dysfunction. Older patients or those with pre-transplant co-morbidities may be better served by strategies that lower the likelihood of organ toxicity, including reduced intensity conditioning and lower initial doses of MTX. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Disclosures No relevant conflicts of interest to declare.

scholarly journals HLA-mismatched donor and high ferritin level showed poor clinical outcomes after allogeneic hematopoietic cell transplantation in patients with advanced myelofibrosis

2020 ◽  
Vol 11 ◽  
pp. 204062072093693
Author(s):  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mismatched Donor ◽  
Grade Iii

Background: Preconditioning intensity, donor choice and graft- versus-host disease (GVHD) prophylaxis of allogeneic hematopoietic cell transplantation (allo-HCT) for advanced myelofibrosis (MF) have not been fully elucidated. Methods: Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling donors first, followed by matched or mismatched unrelated donors and familial mismatched donors. Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation ⩽400cGy. Results: All showed engraftments, but four showed either leukemic relapse or delayed graft failure. Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III–IV acute GVHD (eight grade III and four grade IV) was higher in human leukocyte antigen (HLA)-mismatched donor HCT compared with HLA-matched HCT (70% versus 20%). Chronic GVHD was observed in 16 patients, and a cumulative incidence of severe chronic GVHD was 33% in HLA-mismatched donor HCT and 7.7% in HLA-matched HCT. Significant hepatic GVHD was observed in nine patients (five acute, four chronic) and six of them died. Multivariate analysis revealed inferior OS in HLA-mismatched donor HCT (hazard ratio (HR) = 6.40, 95% confidence interval (CI) 1.6–25.7, p = 0.009) and in patients with high ferritin level at the time of pre-conditioning period (HR = 7.22, 95% CI 1.9–27.5, p = 0.004), which were related to higher incidence of hepatic GVHD with high NRM rate. Conclusion: RIC allo-HCT can be a valid choice providing graft- versus-fibrosis effect for advanced MF patients. However, HLA-mismatched donor and high pre-HCT ferritin level related to fatal hepatic GVHD should be regarded as poor-risk parameters.

A Retrospective Comparison of Tacrolimus Vs. Cyclosporine for Immunosuppression After Allogeneic Hematopoietic Cell Transplantation with G-CSF-Mobilized Blood Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2319-2319
Author(s):  
Yoshihiro Inamoto ◽  
Mary E.D. Flowers ◽  
Frederick R. Appelbaum ◽  
Paul A. Carpenter ◽  
H. Joachim Deeg ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Unrelated Donors ◽  
Total Body

Abstract Abstract 2319 Background: Graft-versus-host disease (GVHD) is a common immunologic complication after allogeneic hematopoietic cell transplantation (HCT). Cyclosporine or tacrolimus in combination with other agents represent widely accepted standards of care as immunosuppressive regimens after HCT. Results of open-label randomized prospective phase III studies have indicated that the risk of grades II-IV acute GVHD after bone marrow transplantation with related or unrelated donors is lower with the use of tacrolimus as compared to cyclosporine, in combination with methotrexate. The current study was carried out to compare results with tacrolimus versus cyclosporine after HCT with G-CSF-mobilized blood cells. Patients and methods: The study cohort included 510 consecutive patients who received a first G-CSF-mobilized blood cell graft from related or unrelated donors after high-intensity conditioning for treatment of hematological malignancies between 7/1/2003 and 2009 at our center. All patients received ursodeoxycholic acid from 2 weeks before conditioning until 90 days after HCT to prevent hepatic complications, and all patients received immunosuppression with either tacrolimus or cyclosporine in combination with methotrexate after HCT. Endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, end of treatment for chronic GVHD, overall survival, disease-free survival, recurrent malignancy and nonrelapse mortality. Multivariate Cox regression models were used to evaluate hazard ratios for these endpoints with tacrolimus as compared to cyclosporine. The models were adjusted for patient age, donor type, recipient and donor gender combination, disease type, disease risk category, use of total body irradiation in the conditioning regimen, and year of HCT. The analysis was carried out as of July, 2010. Results: The median age of patients was 47 (range, 1 to 66) years. Diagnosis at HCT was acute myeloid leukemia in 200 (39%) patients, acute lymphoblastic leukemia in 73 (14%), chronic myeloid leukemia in 49 (10%), myelodysplastic syndrome or myeloproliferative disorders in 160 (31%) and other lymphoid malignancies in 28 (5%). Total body irradiation was used for conditioning in 168 (33%) patients. Of the 510 patients, 277 (54%) had HLA-matched related donors, 203 (40%) had HLA-matched unrelated donors, and 30 (6%) had HLA-mismatched related or unrelated donors. Outcomes according to immunosuppression with tacrolimus or cyclosporine are shown in Table 1. Multivariate analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested (Table 2), although the results showed a trend suggesting that the risk of non-relapse mortality might be lower with tacrolimus as compared to cyclosporine. Conclusion: In this retrospective analysis, tacrolimus offered no statistically significant advantage over cyclosporine for preventing grades II-IV acute GVHD after HCT with G-CSF-mobilized blood cells, and results for other outcomes also showed no statistically significant differences. Although our data support the hypothesis that either regimen could be an acceptable standard of care for immunosuppression, the number of patients analyzed in this study is not sufficient to completely exclude clinically meaningful differences in outcomes with the two regimens. Disclosures: Off Label Use: Tacrolimus and cyclosporine for immunosuppression after allogeneic hematopoietic cell transplantation.

scholarly journals Encouraging Survival and High Rates of Toxicity: Allogeneic Hematopoietic Cell Transplantation after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Aggressive Lymphoma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 910-910
Author(s):  
Shalev Fried ◽  
Ivetta Danylesko ◽  
Ronit Yerushalmi ◽  
Noga Shem-Tov ◽  
Roni Shouval ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Aggressive Lymphoma ◽  
T Cell Therapy ◽  
Car T

Abstract Background Approximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience. Methods and patients A total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%. Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively. Results Median follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS. High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin &gt;3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa. One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them. Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis. Conclusion Allogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

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