Myeloablative Conditioning with Pharmacokinetic-Targeted Intravenous Busulfan and Cyclophosphamide in Unrelated Cord Blood Transplantation for Myeloid Malignancies in Children

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1965-1965
Author(s):  
Henrique Bittencourt ◽  
Marc Ansari ◽  
Mohamed Aziz Rezgui ◽  
Samira Meziani ◽  
Marie-France Vachon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Platelet Recovery ◽  
Myeloid Malignancies ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Abstract Abstract 1965 Unrelated cord blood transplantation (UCBT) has been an increasingly used stem cell source in hematopoietic stem cell transplantation for myeloid malignancies in children when a related HLA-identical donor is unavailable. Advantages of UCBT include a less stringent HLA compatibility and prompt availability. Myeloablative regimens for UCBT use a combination of total body irradiation or Busulfan (Bu) with Cyclophosphamide (Cy) or other chemotherapy agent. Intravenous Bu has a more predictable bioavailability comparing with oral Bu. Nevertheless, there is still an important variation in Bu pharmacokinetics (PK) between patients. Dose modification of Bu based on its first-dose PK might decrease the risk of toxicity and graft rejection and increase its antitumoral effect. In order to analyse the role of a myeloablative conditioning regimen of PK-adapted Bu for myeloid malignancies we analyzed 30 consecutive first UCBT performed in children between dec/2000 and aug/2010. Median age at transplant was 6.3(0.6-17.3) years, 18 (60%) were male and median weight was 26.2 (6.9-81.1) kg. There were 18 acute myeloid leukemia (AML) and 12 myelodysplastic syndromes (MDS). Seven, nine, and two patients with AML were transplanted in first remission (CR1), second remission (CR2), or in advanced phase of disease (>CR2 or in relapse), respectively. Twenty-eight patients received a single UCBT. Seven, thirteen, and ten patients received a 6/6, 5/6 and 3–4/6 HLA-matched graft. Median infused nucleated cells (NC) and CD34+ cells were 5.28 × 107/kg and 2.07 × 105/kg of recipient body weight, respectively. Cyclosporin A and steroids were used as graft versus host disease (GvHD) prophylaxis. All patients received anti tymoglobuline. Conditioning regimen consisted of PK-adapted Bu (targeted steady-state concentration - Css - between 600–900 ng/ml) and Cy 200 mg/kg (n=27), Melphalan 135 mg/m2 (n=2) or Cy 120 mg/kg and etoposide 30 mg/kg (n=1). PK data were available for all but one patient. For five patients the initial prescribed dose of Bu was not changed, for two patients initial prescribed dose of Bu was decreased and for 22 patients the initial prescribed dose of Bu was increased (median increase of 24.8% - range: 5.3–56,3 %). Median follow-up was 53 months. Cumulative incidence (CI) of neutrophil (>0.5×109/L) at D+60 and platelet recovery (>50×109/L) at D+150 was 83% and 83%, respectively. Median time to neutrophil and platelet recovery was 20 days and 69 days, respectively. There was a single case of graft failure. CI of acute GVHD grade II-IV at D+180 was 14% (with one case of grade III aGvHD). There were two cases of VOD (one mild and one moderate). Two-years CI of transplant-related mortality (TRM) was 17% (three patients died due to infections and one due to graft failure). CI of relapse at 2 years was 30% (with all relapses occurring within two years of UCBT). Event-free survival (EFS) at 5 years was 53%. EFS for patients with MDS (67%) and AML (45%) were not significantly different (P=0.45). Overall survival (OS) at 5 years was 61%. There was a tendency to a better OS for patients with MDS vs AML (83% vs 49% - P=0.19). For AML, disease status did not influence survival. In conclusion, UCBT for myeloid malignancies is a viable option when a HLA-identical sibling donor is unavailable. PK study for ivBu is important as most patients needed Bu dose adjustment. PK-adapted BU seems to reduce acute toxicity and graft failure. However TRM due to infection and relapse remains a problem. New conditioning regimens associating fludarabine with PK-adapted Bu alongside with modification in GvHD prophylaxis to improve immunological recovery might contribute to further decrease TRM and relapse and improve UCBT results, especially for AML. Disclosures: No relevant conflicts of interest to declare.

Reduced-Intensity Unrelated Cord-Blood Transplantation (RI-UCBT) for Patients with High-Risk Myeloid Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Koichiro Yuji ◽  
Shigesaburo Miyakoshi ◽  
Shinsuke Takagi ◽  
Daisuke Kato ◽  
Yuji Miura ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Myeloid Malignancies ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Unrelated Cord Blood ◽  
Reduced Intensity

Abstract <Background>Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for advanced myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The therapeutic benefits are attributable to myeloablative radiochemotherapy and graft-versus-leukemia effect, whereas severe regimen-related toxicity (RRT) limits the efficacy of allo-HSCT to young patients without co-morbidities. Reduced-intensity stem-cell transplantation (RIST) using a non-myeloablative preparative regimen has been developed to decrease RRT, whilst preserving an adequate antitumor effect. RIST may be a curative treatment for heavily pretreated elderly patients with myeloid malignancies. Umbilical cord blood from unrelated donors has been used as an alternative stem cell source. We report the results of reduced-intensity unrelated cord-blood transplantation (RI-UCBT) in patients with advanced or high-risk myeloid malignancies. <Patients and Methods>Forty-eight patients (median age, 59 yr; range, 17–70) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy of total body irradiation from 2002 to 2004. Twelve-seven patients were classified as AML not otherwise categorized, 16 as AML with multilineage dysplasia, 4 as RAEB and 1 as RA. The disease status at transplant was 2 CR1, 5 CR2 or CR3, 3 untreated and 38 refractory. The median infused total cell dose was 2.8 (range, 1.8–4.5) x 107/kg. HLA match was 6/6 in 1, 4/5 in 8, and 4/6 in 39 cases. GVHD prophylaxis was composed of cyclosporine (n=25) or tacrolimus alone (n=23). <Results> Fourty-three patients achieved primary neutrophil engraftment after a median of 20 days. Twelve patients developed grade II–IV acute GVHD and 7 developed chronic GVHD. Fifteen patients achieved CR. Eleven patients experienced relapse. Thirty-one patients died as a result of relapse (n=10), GVHD-associated complications (n=10), or infection (n=11). With a median follow-up of 489 days (range, 192–768), 17 of 48 patients are alive, resulting in a 2-year overall survival rate of 31% (95% CI, 16% to 45%). GVHD prophylaxis influenced outcomes (p<0.05). <Discussion> These data suggest that RI-UCBT may be an effective option for patients with high-risk myeloid malignancies who lack an HLA-matched donor. RI-UCBT is associated with high TRM, providing a rationale for a larger clinical study, which should be modified to focus on enhancing any GVL effect, minimizing toxicities, and controlling infectious complications. Figure Figure Figure Figure

Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 223-223 ◽  
Author(s):  
Vanderson Rocha ◽  
Myriam Labopin ◽  
Annalisa Ruggeri ◽  
Marina Podestà ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Adult Patients ◽  
Myeloablative Conditioning ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

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 (&gt;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.

scholarly journals Outcomes of Unrelated Cord Blood Transplantation in Patients with Multiple Myeloma a Eurocord, CBC-Cellular Therapy & Immunobiology Working Party and Chronic Malignancies Working Party-EBMT Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3203-3203
Author(s):  
Annalisa Paviglianiti ◽  
Erick Xavier ◽  
Patrice Ceballos ◽  
Annalisa Ruggeri ◽  
Eric Deconinck ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Median Time ◽  
Cord Blood Transplantation ◽  
Working Party ◽  
Immunomodulatory Drugs ◽  
Myeloablative Conditioning ◽  
Blood Transplantation ◽  
Unrelated Cord Blood

Abstract Although outcomes for multiple myeloma (MM) have improved with the use of drugs such as bortezomib, thalidomide, lenalidomide and autologous stem cell transplantation (ASCT), it remains an incurable disease. Allogeneic stem cell transplantation (AlloSCT) is not a standard therapy for MM, but it potentially provides a graft versus myeloma effect. The use of reduced-intensity conditioning (RIC) and the autologous-allogeneic tandem transplantation have broadened the use of AlloSCT in patients (pts) with MM. Nevertheless, relapse incidence (RI) after AlloSCT remains high and investigation of this procedure in MM population is warranted. To date, few published reports describe outcomes of unrelated cord blood transplantation (UCBT) in MM pts. We retrospectively analyzed 95 pts, 85 with MM and 10 with Plasma cell leukemia, who underwent UCBT in EBMT centers from 2001 to 2013. Median follow-up was 41 (range 3.6-96) months. The Immunoglobulin (Ig) subtype was IgG in 41% of pts. Out of the 45 pts with available cytogenetic data, 32 had abnormal karyotypes including 11 with high risk alterations (e. g. t(4,14) and del17p). Eighty-two pts received proteasome inhibitors or immunomodulatory drugs before UCBT. The median age at UCBT was 53 years (yrs) and 36% of pts was at stage III ISS. Fifty-one pts were male (54%) and 53% of pts were CMV positive. Thirty-six pts (38%) received a single UCBT and 59 (62%) a double UCBT (dUCBT); 89 pts (96%) received at least one previous ASCT, 26 (30%) had a tandem auto-auto transplant while 18 (21%) had an auto-allotransplant. For those 18 pts, the median time between auto and UCBT was 3.4 (2-8) months. Disease status at UCBT was 1st complete remission (CR) in 10 pts, 2nd CR in 10 pts, very good partial response (VGPR) in 20 pts, partial response (PR) in 37 pts, stable or progressive disease in 14 pts and missing data in 4 pts. The majority of pts (85%, n=77) received a RIC and 17 a myeloablative conditioning. Among RIC, 78% of pts received cyclophosphamide+fludarabine+Total Body Irradiation (TBI) (2-6 Gy) and 23% received anti thymocyte globulin (ATG). Median number of infused total nucleated cells (TNC) was 3.3 x107/kg (0.8-7.82). Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 97±3% at 60 days and 72±5% at 180 days after UCBT with a median time for achievement of 20 and 33 days, respectively. Among 7 pts who failed neutrophil engraftment, 4 died in a median time of 21 months after UCBT and 2 underwent ASCT. CI of 100-day acute GvHD grade II-IV and grade III-IV was 41±5% and 16±4% respectively; aGVHD was lower in pts who received ATG (18% vs 48%, p=0.02) and in those who did not receive TBI (15% vs 49% p=0.0008). CI of chronic GVHD (cGVHD) at 2 years was 22±4%, (median time 188 days, 5/23 pts had extensive cGvHD). CI of cGVHD was higher after dUCBT (30% vs 9%, p=0.015). CI of relapse at 3 years was 47±5% and it was higher in chemoresistant MM (75% vs 45%, p=0.05). Non relapse mortality (NRM) at 3 years was 29±5%. ATG use, myeloablative conditioning and TBI were associated with higher incidence of NRM, in the univariate analysis. Sixty-three pts died: 30 of relapse and 33 of transplant related causes (infections, n=16, GvHD, n=5 and others causes, n=12). The 3-yr progression free survival (PFS) and overall survival (OS) were 24±5% and 40±5%, respectively. In multivariate analysis, the use of ATG was associated with decreased incidence of aGVHD (HR=0.16, 95%, CI=0.03-0.78, p=0.023), higher incidence of NRM (HR=6.9, 95% CI 2.06-23.38, p=0.002), decreased OS (HR=5.53, 95% CI=2.35-12.98, p<0.001) and decreased PFS (HR=3.39, 95% CI=1.50-7.67, p=0.003). Pts with good cytogenetic risk had lower RI (HR=0.28, 95% CI=0.09-0.88, p=0.03) and better OS (HR=0.35, 95% CI=0.145-0.82, p=0.016) and PFS (HR=0.38, 95% CI=0.16-0.89, p=0.027). cGVHD as time dependent variable was associated with higher PFS and OS (HR=2.64, 95% CI=1.33-5.25, p=0.006, and HR=2.43, CI=1.15-5.1, p=0.02, respectively). Three pts received maintenance with lenalidomide after UCBT. These results show that UCBT may be beneficial in approximately 25% of MM pts. The main reason of transplant failure is probably the relatively high risk of relapse in pts heavily pretreated and with high disease burden. UCBT progress might be obtained with better patient selection. The role of immunomodulatory drugs as maintenance therapy after UCBT needs to be further investigated in well-designed protocol for improving UCBT outcomes. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Early Engraftment of Unrelated Cord Blood Transplantation in Patients with Acquired Severe Aplastic Anemia Using Conditioning Regimen without Anti-Thymocyte Globulin

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2072-2072
Author(s):  
Wan Xiang ◽  
Huilan Liu ◽  
Baolin Tang ◽  
Xiaoyu Zhu ◽  
Yao Wen ◽  
...  
Keyword(s):  
Cord Blood ◽  
Immunosuppressive Therapy ◽  
Median Time ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Cell Number ◽  
Blood Transplantation ◽  
Primary Graft Failure ◽  
Unrelated Cord Blood

Abstract Background: Previous studies show that the use of unrelated cord blood transplantation (UCBT) 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 early engraftment after UCBT. Patients and methods : We retrospectively analyzed the outcomes of 35 Chinese patients with acquired SAA who received UCBT since September 2016. Eighteen patients (ATG group) used a conditioning regimen consisting of ATG (thymoglobulin) 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 UCBT was 9 (4-37) years. The median total nucleated cell number and CD34-positive cell number at infusion were 4.08 (1.74-9.36) × 107/kg and 2.13 (0.67-4.29) × 105/kg, respectively. Another group (No-ATG) of 17 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 14 (4-52) years. The median total nucleated cell number and CD34-positive cell number at infusion were 3.5 (1.07-7.87)× 107/kg and 1.7 (0.69-5.27) × 105/kg, respectively. Ciclosporin (CsA) and mycophenolate mofetil (MMF) was given to both groups as prophylaxis for graft versus host disease (GVHD). Results: Neutrophil recovery (>0.5×109/L) was observed in 11 patients of the ATG group and the median time to engraftment was 19 (13-35) days. The median time to platelet recovery (>20 × 109/L) was 40 (24-153) days. Primary graft failure was observed in seven patients. Only 1 out of 17 patients in the No-ATG group had primary graft failure. The median time to neutrophil engraftment was 17 (13-36) days. The median time to platelet engraftment was 31 (17-65) days. During follow-up, 7 patients died before 1 year due to non-engraftment (n=4), infection (n=2) and encephalorrhagia (n=1) in the ATG group. Four patients died in the No-ATG group due to infection (n=3) and IV grade acute GVHD in the skin and the intestinal tract (n=1, induced by discontinuing medicine). Furthermore, conditioning regimen without ATG shows even more superiority in patients refractory to immunosuppressive therapy with ATG and/or CsA (n=8), who had neutrophil engraftment completely within 20 days after cord blood infusion. Conclusi on: UCBT after a FLU-CY-TBI conditioning regimen without ATG for SAA patients is better than that with ATG, especially for patients refractory to immunosuppressive therapy. 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 UCBT. Table. Table. Disclosures No relevant conflicts of interest to declare.

Outcome Of Unrelated Umbilical Cord Blood Transplantation For Children With Osteopetrosis: An Eurocord and Inborn Errors Working Party (IEWP)-EBMT Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2100-2100 ◽  
Author(s):  
Robert Chiesa ◽  
Annalisa Ruggeri ◽  
Marco Zecca ◽  
Franco Locatelli ◽  
Marta Gonzalez-Vincent ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Cell Dose ◽  
Blood Transplantation

Abstract Osteopetrosis (OP) is a genetic disease characterized by increased bone density due to osteoclast dysfunction, leading to life-threatening multi-systemic complications in early childhood. Haematopoietic stem cell transplantation (HSCT) is the only curative approach for most children with OP and can effectively prevent serious complications such as blindness, bone fractures, hydrocephalus and cranial nerve compression. Since timing of transplant is critical in OP, umbilical cord blood is an attractive stem cell source, due to its prompt availability. We analysed the outcomes of unrelated umbilical cord blood transplantation (UCBT) in 45 children with osteopetrosis transplanted in EBMT centers between 1996 and 2012, using data reported to Eurocord. Median age at UCBT was 6 months (1.1 month - 7.4 years). Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allelic level) in 14 or HLA mismatched at 1 (n= 23) or 2 (n= 7) loci. Information on conditioning regimen was available for 42 patients; it was myeloablative (mostly busulfan-based) in 40 children and reduced intensity in 2 patients. GvHD prophylaxis consisted mainly of cyclosporine combined with either prednisolone (n= 20), or methotrexate (n=6), or mycophenolate mofetil (n=3). Anti thymocyte globulin (ATG) or alemtuzumab was given to 37/40 patients. Median number of infused total nucleated cell (TNC) and CD34+ was 13x107/kg and 3.4x105/kg, respectively. Median follow-up for survivors was 44 (range 4-144) months. Neutrophil recovery with donor chimerism was documented in 27/45 patients; 19/25 evaluable patients presented full donor engraftment, while 6 children presented mixed donor chimerism. Median time to neutrophil recovery was 20 (range 10-60) days. Eighteen patients experienced graft failure and 3/18 are alive at last follow up. Information on treatment post-graft failure was available 7/18 children: 6 patients underwent a second HSCT and 3 of them survived. Stem cell dose was associated with a trend for a better probability of donor engraftment: the cumulative incidence of donor engraftment was 46% in patients who received a CD34+ cell dose<2 x 105/kg, versus 71% in children receiving a CD34+ cell dose ≥2x105/kg (p = 0.09). Eleven patients developed grade II-IV acute graft-versus-host disease (aGvHD: n=6 grade II, n=4 grade III, n=1 grade IV) and 5 patients chronic GVHD (cGvHD: n=3 limited, n=2 extensive). Overall survival (OS) at 3 years was 45+8%. Twenty-four patients died after UCBT due to: infections (n=13), acute respiratory distress syndrome (n=2), veno occlusive disease (VOD), (n=2) hemorrhage (n=2), or other causes (n=5). VOD was observed in 7/26 evaluable patients. Stem cell dose and HLA disparity were the only predictors of superior outcome in univariate analysis. The 3-year probability of OS was 50% in patients who received grafts with a CD34+ cell dose >2x105/kg versus 0% in children receiving grafts with a CD34+ cell dose < 2x105/kg (p=0.001). According to HLA disparities, 3-year probability OS was 54% versus 58% versus 0% in patients receiving a 6/6, 5/6 and 4/6 HLA-mismatched graft, respectively (p=0.01). Interestingly, 4/4 children receiving a treosulfan-based myeloablative regimen achieved donor engraftment and 3 children are alive at last follow up. These data suggest that transplantation of unrelated UCB is a valid alternative for children with OP without a matched sibling or a suitable matched unrelated adult donor. The use of CB units mismatched at >1 HLA locus should be avoided due to worse survival. The incidence of primary graft failure was high and therefore the optimization of the conditioning regimen and/or the use of CB units containing a high TNC and CD34+ cell dose must be considered in this setting. The use of treosulfan-based conditioning regimens is worth further investigation, as well as the use of defibrotide prophylaxis to reduce the risk of VOD in this population of high risk patients. Disclosures: No relevant conflicts of interest to declare.

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