scholarly journals A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment and Remission in Nonremission Myeloid Malignancies

2016 ◽  
Vol 22 (10) ◽  
pp. 1844-1850 ◽  
Author(s):  
Hisashi Yamamoto ◽  
Naoyuki Uchida ◽  
Mitsuhiro Yuasa ◽  
Kosei Kageyama ◽  
Hikari Ota ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Full Dose ◽  
Myeloid Malignancies ◽  
Blood Transplantation ◽  
Reduced Toxicity

A Novel Reduced-Toxicity Myeloablative Conditioningusing Full-Dose Busulfan and Melphalan For Cord Blood Transplantation Provides Durable Engraftment and Remission Without Increasing Non-Relapse Mortality In Advanced Myeloid Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2042-2042
Author(s):  
Hisashi Yamamoto ◽  
Naoyuki Uchida ◽  
Kousei Kageyama ◽  
Daisuke Kaji ◽  
Sachie Wada ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Rejection ◽  
Cumulative Incidence ◽  
Cord Blood Transplantation ◽  
Antitumor Effects ◽  
Full Dose ◽  
Myeloid Malignancies ◽  
Post Transplant ◽  
Blood Transplantation ◽  
Reduced Toxicity

Abstract Introduction Although cord blood transplantation (CBT) using reduced-intensity regimens has emerged as an effective therapy for elderly or patients with comorbidities, high relapse rate and non-relapse mortality (NRM) still remain to be resolved. Tointensify antitumor effects without increasing NRM, we have conducted a pilot study of a novel reduced-toxicity myeloablative conditioning for CBT in our institute. Methods The conditioning consisted of intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m2 and melphalan 80 mg/m2 followed by single CBT. Fifty-one patients with myeloid malignancies not in remission were included in this study between June 2007 and November 2012. All patients provided written informed consent, andmedical records were retrospectively reviewed. Results Their median age was 59 years (range, 19-70), with a median HCT-CI score of 3 (0-6). Underlying diseases were AML in 44, MDS (RAEB-2) in 3, and CML (AP/BC) in 4. All patients were not in remission including primary induction failure (n=19), relapse 1 (14), relapse>2 (7), and untreated (11). Tacrolimus (TAC) plus mycophenolate mofetil were used in 38 cases as GVHD prophylaxis, while TAC alone in 13. All patients received single cord blood unit with 2-mismatches (MM) to the recipient (n=47) and 1-MM (4). The median number of total nucleated cell and CD34+ cells infused at cryopreservation was 2.61 (range, 1.67-5.09) x 107/kg and 0.94 (range, 0.28-2.97) x 105/kg, respectively. Median observation period of survivors was 18.3 (range, 9-75.5) months. Overall survival (OS) and disease free survival (DFS) at 2 years were 62.4% and 55.1%, respectively (Figure 1). Eleven patients relapsed at a median of 5.2 months (range; 0.5-26.7). Cumulative incidences of relapse at 100 days and 2 years were 7.8% and 20.1%, respectively. Cumulative incidences of NRM at 100 days and 2 years were 11.8% and 21.7%, respectively. Causes of NRM were Infection (n=8), GVHD (2) and idiopathic pneumonia syndrome (1). Forty-six out of 51 achieved neutrophil engraftment at median of 19.5 days (range, 13-38) post-transplant, with a cumulative incidence of 90.2%. All patients who achieved engraftment showed complete remission with complete donor chimerism in bone marrow analysis performed at around 30 days post-transplant. Among 5 who failed to achieve neutrophil recovery, 3 experienced early disease progression and 2 died before engraftment, while no patients developed graft rejection. Cumulative incidence of grade II-IV and III-IV acute GVHD were 52.9% and 13.7%, respectively. Of the 42 patients who achieved engraftment and survived longer than 100 days post-transplant, 13 developed limited type of chronic GVHD, and 5 developed extensive type. Conclusion This study demonstrated that the novel conditioning regimen using full-dose busulfan and melphalan for CBT provides reliable engraftment without graft rejection and high OS and DFS rates without increasing NRM, even for relatively higher age population with myeloid malignancies not in remission. The promising results using the regimen deserve further evaluation in a multicenter prospective study. Disclosures: No relevant conflicts of interest to declare.

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.

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.

Intensified Myeloablative Conditioning Regimen without Antithymocytic (ATG) Results in Superior Patient Outcome Compared to Myeloablative Conditioning Regimen for Single-Unit Umbilical Cord Blood Transplantation in Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5837-5837
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Yue Wu ◽  
Changcheng Zheng ◽  
Baolin Tang ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cumulative Incidence ◽  
Single Unit ◽  
Hematological Malignancies ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Blood Transplantation ◽  
Group A ◽  
Neutrophil Engraftment

Abstract The superiority and safety of strengthening conditioning regimen for single- unit unrelated cord blood transplantation (sUCBT) in hematological malignancies remain controversial. We retrospectively analyzed the clinical data of 251 hematological malignancies undergoing sUCBT from Apr 2000 to Dec 2014 at Department of hematology in Anhui Provincial Hospital. Out of the 251 patients, 216 received the intensified myeloablative conditioning regimen (IMCR), and 35 received the myeloablative conditioning regimen (MCR). We evaluated the effect of IMCR without using Antithymocyte globulin (ATG) on patient outcomes. The cumulative incidence of myeloid and platelet engraftment of the IMCR group was significantly higher than that in the MCR group (96.98% vs. 82.81%, 85.89% vs. 51.79%, P=0.000 and 0.003, respectively). Corresponding incidences of transplantation-related mortality (TRM) by 180 days in the IMCR group and the MCR group were 19.50% vs. 41.67% (P=0.003), respectively. There were no differences in the incidence of grade II to IV acute GVHD (aGVDH), grade III to IV aGVHD and 2-year cumulative incidence of relapse. Up to Dec. 2015, with a median follow-up of 30 months, the estimated 3-year overall survival and disease- free survival in the IMCR group were both significantly higher than that of the MCR group (64.8% vs. 35.5%, 61.6% vs. 35.5%, P=0.000 and 0.001, respectively). This study is the first to show the superiority of intensified myeloablative regimen to conventional myeloablative regimen.A large-scale prospective study was needed. (A) (B) Figure 1 The cumulative incidence of neutrophil and platelet engraftment of the IMCR group and MCR group. (A)The cumulative incidence of neutrophil engraftment of the IMCR group was predominantly higher than that in the MCR group(96.98% vs. 82.81%, P=0.000). (B)The cumulative incidence of platelet engraftment of the IMCR group was also higher than that in the MCR group(85.89% vs. 51.79%, P=0.003). Figure 1. The cumulative incidence of neutrophil and platelet engraftment of the IMCR group and MCR group. (A)The cumulative incidence of neutrophil engraftment of the IMCR group was predominantly higher than that in the MCR group(96.98% vs. 82.81%, P=0.000). (B)The cumulative incidence of platelet engraftment of the IMCR group was also higher than that in the MCR group(85.89% vs. 51.79%, P=0.003). Figure 2 Comparison of the incidence of 3-year OS between the IMCR group and the MCR group.The incidence of 3-year OS of the IMCR group is predominantly higher than that of the MCR group(62.4% vs. 35.5%,P=0.001). Figure 2. Comparison of the incidence of 3-year OS between the IMCR group and the MCR group.The incidence of 3-year OS of the IMCR group is predominantly higher than that of the MCR group(62.4% vs. 35.5%,P=0.001). Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

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