scholarly journals Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e040467
Author(s):  
Seitaro Terakura ◽  
Takaaki Konuma ◽  
Masatsugu Tanaka ◽  
Yukiyasu Ozawa ◽  
Makoto Onizuka ◽  
...  
Keyword(s):  
Cord Blood ◽  
Study Protocol ◽  
Total Body Irradiation ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Blood Transplantation ◽  
Total Body ◽  
Randomised Controlled

IntroductionA better long-term quality of life after umbilical cord blood transplantation (CBT) is observed compared with transplants from other alternative donors, whereas graft failure and relapses after CBT are still major issues. To minimise graft failure and relapse after CBT, intensification of conditioning by the addition of high-dose cytosine arabinoside (CA) and concomitant continuous use of granulocyte-colony stimulating factor (G-CSF) are reported to convey a significantly better survival after CBT in some retrospective studies. To confirm the effect of G-CSF plus CA combination, in addition to the standard conditioning regimen, cyclophosphamide (CY)/total body irradiation (TBI), we design a randomised controlled study comparing CA/CY/TBI with versus without G-CSF priming (G-CSF combined conditioned cord blood transplantation [G-CONCORD] study).Methods and analysisThis is a multicentre, open-label, randomised phase III study that aimed to compare G-CSF+CA/CY/TBI as a conditioning regimen for CBT with CA/CY/TBI. Patients with acute myeloid leukaemia or myelodysplastic syndrome, aged 16–55 years, are eligible. The target sample size is 160 and the registration period is 4 years. The primary endpoint is the 2-year disease-free survival rate after CBT. The secondary endpoints are overall survival, relapse, non-relapse mortality, acute and chronic graft-versus-host disease, engraftment rate, time to neutrophil recovery, short-term adverse events, incidence of infections and causes of death.This study employs a single one-to-one web-based randomisation between the with-G-CSF versus without-G-CSF groups after patient registration. Combination of high-dose CA and CY/TBI in both groups is used for conditioning.Ethics and disseminationThe study protocol was approved by the central review board, Nagoya University Certified Review Board, after the enforcement of the Clinical Trials Act in Japan. The manuscripts presenting data from this study will be submitted for publication in quality peer-reviewed medical journals. Study findings will be disseminated via presentations at national/international conferences and peer-reviewed journals.Trial registration numbersUMIN000029947 and jRCTs041180059.

Phase II Multicenter Study of Busulfan-Fludarabine Conditioning Regimen for cord Blood transplantation in Pediatric Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1928-1928
Author(s):  
Hee Young Ju ◽  
Hyoung Jin Kang ◽  
Ji Won Lee ◽  
Hyery Kim ◽  
Kyung Duk Park ◽  
...  
Keyword(s):  
Cord Blood ◽  
Myeloid Leukemia ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Once Daily ◽  
Pediatric Acute Myeloid Leukemia ◽  
Blood Transplantation

Abstract Abstract 1928 Introduction. Cord blood transplantation (CBT) has become an alternative transplantation for various diseases. CBT has comparable efficacy with unrelated transplantation, but higher transplantation related mortality (TRM) rate upto 50% in early results has been a major obstacle. To reduce TRM, we studied reduced toxicity myeloablative conditioning regimen with busulfan and fludarabine for CBT in pediatric acute myeloid leukemia (AML) patients. Patients and methods. This study was a phase II prospective multicenter clinical trial (NCT01274195) and 27 patients were enrolled who underwent CBT with upto 2 HLA mismatch cord blood. Conditioning regimen was composed of fludarabine (40 mg/m2 once daily iv on days -8 ∼ -3), busulfan (0.8 mg/kg every 6 hours iv on days -6 ∼ -3) and rabbit thymoglobulin (2.5 mg/kg once daily iv on days -8 ∼ -6). For GVHD prophylaxis, cyclosporine and MMF were used. Results. Nine patients received single unit cord blood, and 18 patients received double unit cord blood. Median dose of nucleated cells and CD34+ cells were 4.23×107/kg (0.5–16.4) and 2.58×105/kg (0.33–6.77), respectively. Primary graft failure developed in 5 patients, and secondary graft failure occurred in 1 patient. Acute and chronic GVHD occurred in 16 patients (59.3%) and 10 patients (37%), respectively. TRM developed in 5 patients (cumulative incidence 22.2%), which included chronic GVHD-associated complication (n=1), post-transplantation lymphoproliferative disease (n=2), pneumonia (n=2), and diastolic cardiomyopathy (n=1). Relapse incidence was 30.9%. The 5-year overall and event-free survival were 46.3% and 40.0%, respectively. Patients who received single unit cord blood showed survival rate of 44.4%, and those who received double unit cord blood showed survival rate of 50%. Univariate analysis revealed that low nucleated cell count (P=0.011), low CD34+ cell count (P=0.002) were independent prognostic factor for survival. Conclusion. Reduced intensity conditioning regimen containing fludarabine and iv busulfan showed lower TRM rate than previous studies with myeloablative conditioning regimens. However graft failure and relapse rate were not satisfactory, and further study for optimization of conditioning regimen is warranted. Disclosures: No relevant conflicts of interest to declare.

Better Engraftment of Single-Unit Unrelated Cord Blood Transplantation in Patients with Acquired Severe Aplastic Anemia Not Respond to IST Using Conditioning Regimen without ATG

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5727-5727
Author(s):  
Wan Xiang ◽  
Baolin Tang ◽  
Huilan Liu ◽  
Xiaoyu Zhu ◽  
Kaidi Song ◽  
...  
Keyword(s):  
Body Weight ◽  
Graft Failure ◽  
Single Unit ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Cell Number ◽  
Blood Transplantation ◽  
Primary Graft Failure ◽  
Total Body ◽  
Unrelated Cord Blood

Background: Previous studies show that the use of single-unit unrelated cord blood transplantation (sUCBT) for severe aplastic anemia (SAA) has poor outcome because of high incidence of primary graft failure. Effective measures to completely prevent rejection in SAA remain to be identified, but higher cell dose, less HLA disparities and better conditioning regimen are known to improve the outcome. In this study we compare two conditioning regimens to determine which is better to facilitate engraftment after sUCBT. Patients and methods: We retrospectively analyzed the outcomes of 21 Chinese patients with acquired SAA who do not have HLA-matched siblings and do not respond to first-line immunosuppressive therapy with ciclosporin (CSA) and/or anti-thymocyte globulin (ATG) that received sUCBT were included beteween July 2016 and October 2018. Data collected as of June 2019 were analyzed. 6 patients (ATG group) used a conditioning regimen consisting of ATG (rabbit) 2.5 mg/kg (D-9 to D-7) with fludarabine 30 mg/m2 (D-9 to D-4), cyclophosphamide 60 mg/kg (D-3 to D-2) and total body irradiation (3 Gray) on D-1. Median age at time of sUCBT was 11 (5-20) years, median body weight was 34(18-53)kg. Waiting time from diagnosis to transplantation was 427(277-3407)days. The median total nucleated cell number and CD34-positive cell number at infusion were 3.57(2.77-9.36) × 107/kg and 2.5(1.02-3.99) × 105/kg, respectively. Another group (No-ATG) of 15 patients used a conditioning regimen without ATG consisting of fludarabine 40 mg/m2 (D-8 to D-4), cyclophosphamide 60 mg/kg (D-3 to D-2) and total body irradiation (4 Gray) on D-1. Median age at time of UCBT was 11 (3-42) years, median body weight was 35(13-70)kg. Waiting time from diagnosis to transplantation was 1664(160-2006)days. The median total nucleated cell number and CD34-positive cell number at infusion were 3.63(1.65-9.38)×107/kg and 2.5(0.69-5.61)×105/kg, respectively. CsA and MMF was given to both groups as prophylaxis for graft versus host disease (GVHD). Results: Primary graft failure was observed in 4 out of 6 patients in ATG group. All of these 4 patients received salvage transplantation with haploidentical related donor, 3 patients died after salvage transplantation due to grade IV GVHD in intestinal tract and infection. However, all of 15 patients in the No-ATG group had completely engraftment. The median time to neutrophil engraftment was 18 (13-27) days, platelet engraftment was 32 (17-112) days. 42-day cumulative incidence of engraftment is 100% compared to 33% in ATG group (P=0.008). During follow-up, 2 patients died before 1 year due to renal failure (n=1) and encephalorrhagia (n=1) in the No-ATG group. One-year survival rate is 86.7% in No-ATG group compared to 50% in ATG group (P=0.0598). Conclusion: sUCBT after a FLU-CY-TBI conditioning regimen was an effective and safe option for SAA patients, with better engraftment and survival. Pediatric and adult SAA patients who are younger than 50 years old, lack of HLA-matched sibling donor and refractory to immunosuppressive therapy should consider sUCBT. Table Disclosures No relevant conflicts of interest to declare.

Reduced Intensity Umbilical Cord Blood Transplantation(RI-UCBT) in Adult Patients with Graft Failure or Relapse after First Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5121-5121
Author(s):  
Kazuhiro Masuoka ◽  
Koichiro Yuji ◽  
Yuji Miura ◽  
Tomohiro Myojo ◽  
Daisuke Kato ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Blood Transplantation ◽  
Reduced Intensity ◽  
Neutrophil Engraftment

Abstract Background: Graft failure, graft rejection, or disease relapse post allogeneic hematopoietic stem cell transplantation(HSCT) is life-threatening and serious complication that necessitate consideration for a second transplantation. Graft failure has been more frequently reported in patients with aplastic anemia with T-cell depletion of the graft, in cord blood transplants, or when unrelated or HLA-mismatched related donors were used. In second allogeneic stem cell transplant setting, current questions include suitable stem cell source, additional conditioning, immunosuppression, and the use of a different donor, still remain unknown. We performed a feasibility study of reduced intensity umbilical cord blood transplantation (RI-UCBT) in adult patients with graft failure or disease relapse after first allogeneic transplantation. Patients and Methods: Nine patients (median age, 53 years; range 17–68) with advanced hematological diseases [AML (n=4), ALL (n=2), MDS (n=2), ATL (n=1)] who showed relapse or graft failure after first allogeneic transplantation underwent RI-UCBT with single cord blood unit at Toranomon Hospital between May 2003 and February 2004. Eight cases were in non-CR at transplant. A median time from first to second transplant was 226 days (range 31–475). The median number of mononuclear cells transfused was 2.3 x 107 /kg (range 1.8–3.5). HLA disparities were as follows; 5/6 in two cases, 4/6 in seven cases. Conditioning regimen mainly consisted of fludarabine 25 mg/m2 on days -7 to −3, melphalan 40mg/m2 (n=8) or busulfan 4mg/kg(n=1) day −3 to −2, and 4 Gy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis was composed of ciclosporin alone (n=6) and tacrolimus alone (n=3). Results: All of them achieved primary neutrophil engraftment (>500/μL) after a median of 22 days (range, 15–32) and achievement of donor T-cell chimerism was confirmed. Four cases developed grade II-IV GVHD, and one case developed limited chronic GVHD. Of all the nine cases received RI-UCBT, seven died from relapse (n=4), sepsis (n=2), and TMA (n=1). Two survived without relapse for +232 and +81 days, respectively. Discussion: Although the number of patients is small and the follow-up period is short, our results corroborate that RI-UCBT for graft failure or relapse post first transplant is tolerated and may be worth considering for further evaluation. Neutrophil engraftment was achieved, however, disease relapse rate and treatment-related mortality is high. The management of disease status and development of ideal conditioning regimen will be the focus of future investigation.

Multiple Unit Umbilical Cord Blood Transplantation with Total Body Irradiation, Etoposide and Antithymocyte Globulin for Adult Hematologic Malignancy Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4344-4344
Author(s):  
Ronald Sobecks ◽  
Edward Copelan ◽  
Matt Kalaycio ◽  
Medhat Askar ◽  
Lisa Rybicki ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Hematologic Malignancy ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Umbilical Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Multiple Unit ◽  
Total Body

Abstract Abstract 4344 Multiple unit umbilical cord blood transplantation (MU-UCBT) has become an acceptable alternative donor transplant approach for adult hematologic malignancy patients without a bone marrow or peripheral blood stem cell donor. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in MU-UCBT has not been well described. From 10/03-2/09 16 adult hematologic malignancy patients were enrolled on a clinical trial at our institution using this regimen prior to MU-UCBT. Patients were eligible if they did not have an HLA matched related or unrelated donor. They also were required to have at least a 4/6 HLA matched UCB unit with at least 0.5 × 107 nucleated cells/kg and a second UCB unit that was at least a 4/6 HLA match with the first UCB unit. The minimum required cryopreserved total nucleated cell (TNC) dose for the combined units was 1 × 107/kg or an infused CD34+ cell dose of 1.5 × 105/kg. Patients received TBI 1,320 cGy (fractionated over days -7 through -4), VP16 60 mg/kg (day -3) and antithymocyte globulin (ATG) 30 mg/kg (days -3 through +1). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. The median age was 47 yrs (range, 18-60) and diagnoses included: 8 AML, 3 CML-accelerated/blast phase, 2 MDS, 1 ALL, 1 CLL 1 NHL. Comorbidity index scores were 9 low, 6 intermediate and 1 high. The median time from diagnosis to UCBT was 8 mos (range, 1-89). HLA match results of the 1st UCB unit infused (UCB1) with the recipient included five 4/6, ten 5/6 and one 6/6 matches, and for the 2nd UCB unit (UCB2) with recipient there were one 3/6, five 4/6, and ten 5/6 matches. The median thawed TNC doses infused for UCB1 and UCB2 were 1.6 × 107/kg (range, 1.0-2.4 × 107/kg) and 1.2 × 107/kg (range, 0.8-2.4 × 107/kg), respectively; the thawed CD34+ cell doses were 0.6 × 105/kg (range, 0.01-2.4 × 105/kg) and 0.6 × 105/kg (range, 0.2-3.1 × 105/kg), respectively. Twelve were evaluable for engraftment analyses; 3 others had early deaths and 1 had graft failure and was rescued with infusion of cryopreserved remission autologous bone marrow. Sustained engraftment in the 12 was observed from a single UCB unit in all cases and the winning unit was UCB1 in 5 (42%). The winning unit had larger median CD8 (p=0.009) and thawed CD34+ cell (p=0.006) doses infused. The median time to achievement of T-cell complete donor chimerism was 30 days (range, 13-139). Median times to neutrophil and platelet engraftment were 20 days (range, 14-48) and 46 days (range, 29-86), respectively. Median time hospitalized was 39 days (range, 20-74). Grade 2-4 and 3-4 acute GVHD developed in 3 pts (19%) and 1 pt (6%), respectively. Chronic GVHD developed in 5 pts (31%) and 4 (25%) were extensive. Graft failure occurred in 2 pts. Six developed CMV infection and 15 developed other infections. There have been 2 (13%) relapses (1 MDS, 1 AML). Eight pts (50%) remain alive at a median follow-up of 15 mos (range, 5-35). Causes of death include 4 infections, 1 graft failure, 1 pulmonary toxicity, 1 CNS bleed, 1 relapse (AML). Incidence of death at 1 and 2 years are 45% (6% relapse, 39% non-relapse) and 59% (6% relapse, 53% non-relapse), respectively. We conclude that the TBI, VP16 and ATG conditioning regimen for MU-UCBT is effective in adult hematologic malignancy patients. Further strategies to enhance immune reconstitution and prevent infections post-transplant are clearly warranted. Disclosures: Off Label Use: Etoposide (VP16) may be considered off-label. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in multiple unit umbilical cord blood transplantation has not been well described. This abstract shares results of a novel trial with TBI/VP/ATG for multiple unit umbilical cord blood transplantation.

Unrelated Umbilical Cord Blood Transplantation for Hematological Malignancies Using Fludarabine/BUCY2 Conditioning Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4572-4572
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Liangquan Geng ◽  
Xingbing Wang ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Blood Transplantation

Abstract Abstract 4572 Cord blood transplantation (CBT) is largely used to treat patients affected by hematological malignant disorders. Myeloablative TBI-based conditioning appears to provide reliable engraftment after CBT for malignancies. However, the toxicity of TBI limits their widespread use. So far, a standard non-TBI based regimen has not been firmly established. In order to overcome graft failure, we investigated a strategy using Fludarabine (FLU)/BUCY2 regimen in CBT for patients with hematologic malignancies. Seventeen patients(children 16, adult 1) with hematologic malignancies who underwent single-unit CBT used a conditioning regimen comprising FLU 120 ‡r/‡u, intravenous busulfan (BU) 12.8‡r/kg and cyclophosphamide (CY)120 mg/kg (FLU/BUCY2). All patients were given a combination of cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Seventeen patients with acute leukemia (n=13), chronic myelogenous leukemia (n=4) were treated, thirteen of whom were high risk diseases and two were advanced-stage at CBT. Seventeen patients with a median age of 8 years (range,2.5–46 years) and a median weight of 32 kg (range, 12–55 kg)received the median number of nucleated cells and CD34+cells infused were 5.70× 107/kg (range: 3.15–9.60×107/kg) and 3.84× 105/kg (range:1.27–5.24 ×105/kg), respectively. The cumulative incidence of primary donor engraftment was 94% (16 patients); one patient had secondary graft failure. Median time to neutrophil≥0.5×109/L was 17 days (range 12–30) and platelet engraftment (≥20×109/L) was 35 days (range 14–56). Preengraftment syndrome (PES) developed in 71% of the patients at a median of 7days (range: 5–13).9 cases developed acute GVHD (56%), more than grade II in three cases. Two of fourteen patients who survived more than 100 days developed chronic GVHD. 12 cases are alive at a median follow-up of 7 months (range 3~ 11).The probability of overall survival at 100 days and 1 year are 88.2% and 67.9%, respectively. Two cases had extramedullary relapsed. Five cases died of severe GVHD (n=3), pulmonary toxicity (n=1) and secondary graft failure (n=1). Preliminary evidence of the small study suggests successful engraftment and decreasing relapse rate following FLU/BUCY2 regimen for CBT in patients with hematologic malignancies. But it had a tendency towards increasing the incidence of GVHD-related morbidity and mortality. Whether this regimen offers a survival benefit for patients with poor-risk leukemia has to be tested in larger prospective trials. Disclosures: No relevant conflicts of interest to declare.

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