Acute Graft-Versus-Host Disease Following Umbilical Cord Blood Transplantation: Retrospective Survey Involving 2015 Japanese Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1070-1070
Author(s):  
Shigesaburo Miyakoshi ◽  
Takuhiro Yamaguchi ◽  
Masahiro Kami ◽  
Tomoko Matsumura ◽  
Koichiro Yuji ◽  
...  
Keyword(s):  
Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Event Free Survival ◽  
Free Survival ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Acute Graft

Abstract BACKGROUND Limited information is available on incidences and clinical features of acute graft-versus host disease (GVHD) after cord blood transplantation and large-sized researches have been awaited. METHODS We investigated the incidences and clinical features of acute GVHD in 2,015 patients reported to the Japan Cord Blood Bank Network, who underwent cord blood transplantation between June 1997 and August 2006. RESULTS Of 2,015 patients, 1481 patients (73%) achieved neutrophil engraftment at a median of day 22 (range, 6–81). Cumulative incidence of neutrophil recovery at day 100 was 0.74 (95%CI, 0.73–0.76). Of 2015 patients, 708 patients developed grade II-IV acute GVHD: grade II (n=423), grade III (n=237), and grade IV (n=48). The median onset was day 19 (range, 4–190). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 0.35 (95% CI, 0.33–0.37) and 0.14 (95% CI, 0.12–0.15), respectively. Skin and gastrointestinal acute GVHD was documented in 1,006 and 405 patients, respectively, whereas liver GVHD was diagnosed in 149 patients. Multivariate analysis identified the following predictors of grade II-IV acute GVHD: the number of infused nucleated cells, transplantation from female donors to female recipients, TBI-containing preparative regimens, methotrexate-containing GVHD prophylaxis, and tacrolimus-based GVHD prophylaxis. Overall survival rates at three years of patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer were 0.58 (95%CI, 0.53–0.63), 0.61 (95% CI, 0.54–0.67) and 0.40 (95%CI, 0.31–0.49), respectively. CONCLUSIONS Acute GVHD following cord blood transplantation is mild and has graft-versus malignancy effects. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation.

Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2023-2023
Author(s):  
Koji Kato ◽  
Ayami Yoshimi ◽  
Etsuro Ito ◽  
Kentaro Oki ◽  
Jun Hara ◽  
...  
Keyword(s):  
Cord Blood ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Disease Status ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
Cd34 Cells ◽  
Advanced Stages ◽  
Grade Ii

Abstract Cord blood transplantation (CBT) became one of the important alternatives in allogeneic stem cell transplantation for children with hematological malignancies. We have analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified risk factors of transplant outcome, when they had no prior transplant. From 1997 to 2006, total 332 children with ALL have undergone CBT from unrelated donor and 270 of them had no prior transplant. They are 0–15 yrs (median 5) and 4 to 60kg of body weight (median 18). Serological disparities of HLA for graft-versus-host disease (GVHD) direction were 0(n=54), 1(n=168) and 2(n=47), and disease status at transplant were 1st complete remission (CR) (n=120), 2nd CR (n=71), and more advanced stages (n=75). The median number of nucleated cells in cord blood unit was 4.93×107/kg (1.35–24.9), and that of CD34+ cells was 1.53×105/kg (0.17–15.0). As preconditioning, total body irradiation (TBI) was given in 194 patients and methotrexate (MTX) was given as GVHD prophylaxis in 159 patients. The neutrophil engraftment was achieved in 88.5% (95%CI: 84.1–91.8%) of patients and platelet engraftment (>50k) was obtained in 72.6% (95%CI: 66.8–77.7). The incidence of grade II–IV and III–IV acute GVHD was 45.6% (95%CI: 39.5–51.4) and 20.4% (95%CI: 15.8–25.4) respectively. Non-relapse mortality was observed in 22.6% (95%CI: 17.7–27.8) and 35.2% (95%CI: 29.2–41.3) of patients relapsed after CBT. The five year event free survival (EFS) of all patients was 38.1% (95%CI: 34.9–41.3); 47.4%(95%CI: 42.4–52.4) in 1st CR, 45.5%(95%CI: 38.9–52.1) in 2nd CR and 15.2%(95%CI: 10.8–38.9) in more advanced stages, respectively. The multivariate analysis revealed that the larger number of CD34+ cells (p<0.01) and administration of granulocyte colony stimulating factor after CBT (p<0.01) were associated with earlier neutrophil engraftment. Preconditioning with TBI (p<0.01) and absence of MTX (p=0.037) significantly affected the development of grade II-IV acute GVHD. Advanced disease at transplant was the most predominant factor for leukemic relapse (p<0.01). GVHD prophylaxis with MTX (p=0.042), less allele mismatches (p=0.013) and disease status of 1st and 2nd CR at transplant (p<0.01) were significantly associated with better EFS. Our results showed the favorable effect of MTX for the development of acute GVHD and EFS. In conclusion, GVHD prophylaxis including MTX is important in CBT for children with ALL.

Infliximab Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease After Reduced-Intensity Cord Blood Transplantation in Adults

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4553-4553
Author(s):  
Kazuya Ishiwata ◽  
Aya Nishida ◽  
Hikari Ota ◽  
Taichi Ikebe ◽  
Masanori Tsuji ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Infliximab Treatment ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Reduced Intensity ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Abstract 4553 Introduction Acute graft versus host disease (GVHD) remains the most frequent complication after allogeneic hematopoietic stem cell transplantation (SCT). In reduced intensity cord blood transplantation (CBT) previous studies have reported a lower incidence of severe acute GVHD compared with conventional allo-SCT. However, in these studies the incidences of grade II-IV acute GVHD varied widely from 26% to 51% (H.Narimatsu Stem cell int. 2011: 607569). In particular, post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. Infliximab, a chimeric monoclonal antibody against tumor necrosis factor alpha, has shown activity against steroid refractory acute GVHD. Patients and Methods We retrospectively reviewed 275 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from March 2007 to December 2011 at our institute. Patients in whom PIR or acute GVHD developed received methylprednisolone 1–2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to infliximab treatment. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. An antifungal drug, itraconazole or micafungin or voriconazole was used until all immunosuppressive drus were withdrawn. Results In this study we retrospectively evaluated 54 patients who had steroid refractory acute GVHD. Of these, 21 who received infliximab were analyzed. GVHD prophylaxis was with only tacrolimus(n=15) and mycophenolate mofetil+tacrolimus(n=6). All of them developed grade III to IV GVHD. Median follow-up time of survivors was 548 days (range, 222–1152). The overall response rate was 62% (n=13), and 9 patients (43%) experienced complete response (CR). 5 patients (24%) did not respond and 3 (14%) had progressive GVHD. The Kaplan-Meier estimate of overall survival was 31%, with no signs of chronic GVHD (n=2). Four patients who responded subsequently died, one of exacerbation of GVHD, three of infections. All the 8 unresponsive patients died of GVHD or infections. Five patients (21%) had non-Candida invasive fungal infections. Sixteen patients(79%) had bacterial infections. Conclusion Infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD even following reduced intensity cord blood transplantation. However, it is associated with a high rate of infections. Controlled studies to assess the pharmacokinetics and most effective dosing regimen of infliximab for the treatment of steroid refractory acute GVHD are warranted. Disclosures: No relevant conflicts of interest to declare.

Intensified Mycophenolate Mofetil (MMF) Dosing Every 8 Hours Is Safe From The Standpoint Of Engraftment and May Ameliorate Severe Acute Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (CBT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4600-4600 ◽  
Author(s):  
Doris M Ponce ◽  
Stephen J. Harnicar ◽  
Sean Devlin ◽  
Patrick Hilden ◽  
Katherine L Evans ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Cord Blood ◽  
Graft Versus Host Disease ◽  
Calcineurin Inhibitor ◽  
Cord Blood Transplantation ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Grade Ii ◽  
Grade Iii ◽  
Acute Graft

Background Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure. Methods We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those <12 years received 15 mg/kg/dose). From 9/2009, 91 patients (53%) received MMF at 1 gm IV q8 for patients both >12 years and ≥50 kg (or 15 mg/kg/dose if >12 years but <50 kg, or 20 mg/kg/dose if <12 years). The Gray's test compared the incidence of GVHD across the q12 and q8 dosing while the log-rank test was used to compare progression-free survival (PFS). Results Patient characteristics and infused viable CD34+ cell doses were similar in the q12 and q8 MMF groups. A comparison of transplant outcomes by MMF dosing is shown (Table). There were no differences in the time to neutrophil or platelet engraftment and the median time to count recovery was also similar. The incidences of grade II-IV aGVHD at day 100 were similar in the groups (46% vs 52%). However, there was a suggestion of decreased grade III-IV aGVHD at day 100 in the q8 MMF group (12%) versus the q12 group (21%), although this comparison did not reach significance. With a median follow-up of 41 months (range 3-94), the PFS in each dosing group was not significantly different. Conclusions We demonstrated that intensified q8 MMF dosing is safe from the standpoint of engraftment and toxicity. There was a suggestion of decreased severe grade III-IV aGVHD in recipients of 1 gm IV every 8 hours. While a larger analysis is needed to further investigate these findings, the results are encouraging. They suggest that, as with adult donor allografts, intensified q8 hour MMF dosing should be the dose investigated for the prevention of aGVHD in CBT recipients transplanted with CSA/ MMF prophylaxis without ATG. Finally, aGVHD prophylaxis could be further optimized in CSA/ MMF-based CBT by mycophenolic acid trough level drug monitoring, early post-transplant biomarker measurements such as ST2, and delayed taper post-transplant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2410-2415 ◽  
Author(s):  
Margaret L. MacMillan ◽  
Daniel J. Weisdorf ◽  
Claudio G. Brunstein ◽  
Qing Cao ◽  
Todd E. DeFor ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Umbilical Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Umbilical Cord Blood Transplantation ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Grade Ii ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) occurs less frequently after umbilical cord blood transplantation (UCBT). More recent investigations include the use of 2 partially human leukocyte antigen (HLA)–matched UCB units, or double UCB graft, to meet the minimum cell-dose requirement. The purpose of this analysis was to assess the relative risk of acute GVHD in 265 consecutive patients receiving transplants with UCB graft composed of 1 (n = 80) or 2 (n = 185) units. The incidence of grade III-IV acute GVHD was similar between cohorts. However, the incidence of grade II-IV acute GVHD was higher among double UCBT recipients (58 vs 39%, P < .01). Three risk factors for grade II-IV acute GVHD were identified in multiple regression analysis: use of 2 UCB units, use of nonmyeloablative conditioning, and absence of antithymocyte globulin in the conditioning regimen. Transplantation-related mortality (TRM) at 1 year, however, was significantly lower after double UCBT (24 vs 39%, P = .02) even if recipients had grade II-IV acute GVHD (20 vs 39%, P = .05). These data suggest that, despite a higher incidence of grade II acute GVHD in recipients of 2 partially HLA-matched UCB units, there is no adverse effect on TRM. This study is registered at http://www.clinicaltrials.gov under the identifiers NCT00305682 and NCT00309842.

scholarly journals Double Cord Blood Transplantation: Incidence, Organ Involvement and Risk Factors of Acute Graft Versus Host Disease. a Retrospective Analysis on Behalf of Eurocord, ALWP and Cqwp-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 187-187
Author(s):  
Erick Xavier ◽  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Didier Blaise ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Hla Mismatches ◽  
Grade Iii

Abstract Double umbilical cord blood transplantation (dUCBT) has extended the applicability of UCBT for hematologic disorders especially to adult patients (pts) for whom the low cellular content of a single unit is a limiting factor. However the use of dUCBT has been, recently, associated with a higher incidence of acute graft-versus-host disease (aGVHD) when compared with single UCBT (sUCBT). Moreover, several retrospective and prospective studies have addressed risk factors for aGVHD with some conflicting results. Whether the number of total nucleated cells, HLA disparities, type of conditioning regimen or GVHD prophylaxis have an impact on aGVHD incidence in dUCBT is yet to be established in a larger series of patients. With this background, this report analyzed 921 adult recipients who underwent dUCBT for hematologic malignancies from 2005-2012 in EBMT centers. Median age was 46 (range, 18-72) years (yrs) and 59% were males. Diagnosis was acute leukemia in 56%, MDS/CML in 19% and lymphoid malignancies in 25%; 22% of pts received at least one prior autologous HSCT. Reduced-intensity conditioning (RIC) was used in 68% of pts and the most common regimen for both myeloablative conditioning (MAC) and RIC was Cyclophosphamide-Fludarabine-TBI (TCF) (40% and 78%, respectively). ATG was used in 30% of pts. GVHD prophylaxis consisted of a MMF based regimen in 774 pts (84%); cyclosporine±steroids in 103 (11%) and MTX-based regimen in 44 (5%). HLA incompatibilities were classified using the cord blood unit bearing the highest degree of mismatch with the recipient: 1% were HLA matched 6/6, 25% were 5/6, 67% were 4/6, and 7% <4/6. Median TNC collected was 4.8x10e7/kg. With a median follow-up of 26 months (range, 3-98) aGVHD was absent in 418 patients (46%), 169 pts developed grade I (18%), 194 grade II (21%), 103 grade III (11%) and 37 grade IV (4%). One-hundred day cumulative incidence (CI) of aGVHD grade II-IV was 36%±2% and III-IV 15%±2%, with a median time of onset of 28 days (range, 4-97). Of those pts with grade II-IV aGVHD, 82% had skin, 66% gastro-intestinal tract (GIT) and 25% liver involvement. The most common organ involvement in pts with grade III-IV aGVHD was GIT (89%) followed by skin (71%) and liver (39%). Treatment of grade II-IV aGVHD was steroid alone in 91% of pts. For pts with grade III-IV aGVHD steroid was used alone in 77% of pts, 11% received steroid+monoclonal antibodies, 3% steroid+MTX and 9% other treatments (figure 1). At day 60, CI of neutrophil engraftment was 84%. Out of the 712 pts at risk, 218 developed chronic GVHD (cGVHD) with a CI at 2 yrs of 25%±5%. Of these, 102 pts (47%) had previous aGVHD grade II-IV and 116 (53%) had de novo cGVHD. CI of early NRM (at day 100) was 13%. At 2 yrs, the probability of PFS was 37%, NRM 35% and relapse 28%. In multivariate analysis, the following factors were associated with an increased incidence of grade II-IV GVHD: use of MAC (HR: 1.45 (1.12-1.91), p=0.005), absence of ATG (HR: 2.39 (1.78-3.30), p<0.001) and ≥2 HLA mismatches (HR: 1.35 (1.01-1.81), p=0.048) – figure 2; whereas advanced stage disease at transplantation (HR: 1.76 (1.10-2.80), p=0.02) and absence of ATG (HR: 2.54 (1.56-4.13), p<0.001) were associated with increased incidence of aGVHD grade III-IV. Presence of 2 or higher HLA mismatches was associated with increased incidence of cGVHD (HR: 1.5 (1.1-2.05), p=0.01). In a time dependent model the presence of grade II-IV aGVHD was associated with lower relapse risk (HR: 0.71 (0.54-0.94), p=0.02), higher NRM (HR: 1.4 (1.1-1.76), p=0.005) and increased incidence of cGVHD (HR: 1.92 (1.59-2.63), p<0.001). Despite previous analysis showing increased incidence of acute and chronic GVHD after dUCBT, our study demonstrated that the GVHD incidence remains relatively low in dUCBT setting when compared to published data on HLA matched adult donor. In pts developing grade II-IV aGVHD, skin was the most common organ affected, followed by GIT and liver. Steroid alone was the backbone treatment of aGVHD and the association of steroid and other therapies (mainly monoclonal antibodies) was mostly seen in pts affected by grade III-IV aGVHD. Acute GVHD grade II-IV seems to be influenced by the intensity of the conditioning regimen, the use of ATG, and HLA compatibility; therefore prospective trials evaluating the role of these factors in dUCBT should be addressed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low-Dose Methotrexate Could Reduce Severe Early Immune Reactions but Probably Increase Garft Failure in Umbilical Cord Blood Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5679-5679
Author(s):  
Liu Huilan ◽  
Xiaoyu Zhu ◽  
Kaidi Song ◽  
Xiang Wan ◽  
Guangyu Sun ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Versus Host Disease ◽  
Low Dose ◽  
Cord Blood Transplantation ◽  
Immune Reactions ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis

Early immune disorders, including preengraftment syndrome (PES)and acute graft-versus-host disease(aGvHD)are problematic in cord blood transplantation (CBT), and optimal prophylaxis has not been established. Here, we prospectively investigated whether intensive GvHD prophylaxis by adding low-dose methotrexate (MTX)at day 3 after CBThas a prognostic impact on CBT. 16 consecutive single-unit CBT recipients treated for high-risk hematologic malignancies (10 cases) and non-malignancies (6 cases) between February 2019 and March 2019. The patients, 6 female and 10 males, had a median age of 9 years (range 4-40) and a median weight of 26 kg (range 14-68). Myeloablative preparative regimen comprised fludarabine, busulfan and cyclophosphamide for malignancies and reduced-intensity-conditioning comprised fludarabine, cyclophosphamide and total-body irradiation (4 Gy) for non-malignancies. Graft-versus-host disease (GvHD) prophylaxis was cyclosporine and mycophenolate mofetil plus MTX 3 mg/m2 on day+3. 14 patients achieved engraftment at a median of day 19 and had more than 95% (complete) donor chimerism on day+14.Two patients without hematopoietic reconstitution were engrafted after a second CBT. PES was characterized by high-grade fever, rash, pulmonary edema, weight gain, liver and renal dysfunction developed on a median of day 8 in 11 of the 16 evaluable patients, including 2 who did not achieve engraftment. The PES patients received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 2 patients were requiredBasiliximab to improve clinical symptoms. Grade I to IV and aGvHD developed in 4 and only 1 patient developed severe aGvHD with Grade Ⅲ. Follow-up so far, one death occurred at day 103 because of pneumonia. 15 patients are alive well at a median follow-up of 135 days (131-163). Adding low-dose MTX at day +3 may be offer one optimal regimen to reduce severe early immune reactions and improve outcomes in CBT. Disclosures No relevant conflicts of interest to declare.

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