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

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-Intenisty Unrelated Cord Blood Transplantation for Patients with Advanced Malignant Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5453-5453
Author(s):  
Naoyuki Uchida ◽  
Shigesaburo Miyakoshi ◽  
Tomoko Matsumura ◽  
Koichiro Yuji ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Cord Blood ◽  
Malignant Lymphoma ◽  
Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Risk Patients ◽  
Unrelated Cord Blood ◽  
Standard Risk ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation has been potentially curative approach for advanced malignant lymphoma. Unrelated umbilical cord blood cell has become a viable source of transplantation for those who lack suitable donors, but the outcome of the transplantation with reduced-intensity conditioning has not been clearly defined yet. We have therefore analysed the outcome of the patients with advanced malignant lymphoma who have undergone reduced-intensity unrelated cord blood transplantation (RI-UCBT). Thirty patients (median age, 47 years; range 27–69 years) underwent RI-UCBT with a preparative regimen consisting mainly of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy of total body irradiation since June 2002 to June 2005 with a mean follow-up of 353 days (59–621 days). The types of lymphoma included in this study were DLBCL (11 cases), PTCL (5), Hodgkin disease (5), Follicular lymphoma (5), AITL (2), ALCL (1), and nasal NK/T lymphoma (1). All the patients were heavily treated before proceeding to RI-UCBT, including 9 with prior autologous and 1 allogeneic transplantation. The median infused total cell dose was 2.71 x 107/kg (range, 1.76–4.76 x 107/kg). Graft-versus host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Twenty-four patients (80%) achieved primary neutrophil engraftment at a median of 23 days (12–33 days), and 18 (60%) achieved platelet engraftment at a median of 40 days (26–77 days). Fourteen patients (57.1%) developed grade II to IV acute GVHD at a median of 31 days (15–59 days). Five patients subsequently relapsed and all died within 2 years. Fifteen patients died of non-relapse causes such as infection (8), GVHD (3), IP (2), and others (2). Transplant-related mortality (TRM) within 100 days was 54%. The estimated 1-year probability of overall survival was 24% (95%CI: 1–46%). In subgroup analyses, standard risk patients (CR1, CR2, PR1, n=5) showed 80% while high risk (n=25) showed 13% overall survival at 1 year. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack HLA-matched donors. Although the patients in standard risk can expect reasonably good overall survival, the beneficial effect is only limited to small part of the high risk patients. To further improve the outcome, RI-UCBT should be investigated among patients with less advanced diseases in a well-designed clinical trial. Figure Figure

Reduced Intensity Conditioning Regimen in Single Unrelated Cord Blood Transplantation in Adults with Hematological Malignant Disorders. An Eurocord-Netcord and SFGM-TC Survey.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3143-3143 ◽  
Author(s):  
Vanderson Rocha ◽  
Bernard Rio ◽  
Federico Garnier ◽  
Marc Renaud ◽  
Anne Sirvent ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Blood Transplantation ◽  
Reduced Intensity Conditioning Regimen ◽  
Conditioning Regimens ◽  
Unrelated Cord Blood ◽  
One Year ◽  
Reduced Intensity

Abstract Results of reduced intensity conditioning regimen (RIC) in unrelated cord blood transplantation (UCBT) have been reported, however more frequently RIC was performed using double cord blood transplants. In order to study risk factors in single RIC-UCBT we have analyzed 65 patients with hematological malignancies (ALL=10, AML=37, Hodking and NHL=10, MDS=4, CML=3, Myeloma =1) transplanted from 1999–2005 and reported to Eurocord and SFGM-TC. The median follow-up was 8 months (3–26) and the median age was 47 years (16–76). At transplant, 49% of the patients had advanced phase of disease and 39% had received a previous autologous transplants. The conditioning regimen varied according diasease and centers: Fludarabine(FLU)+Endoxan (EDX) +TBI (2Gy) was given to 33 patients, FLU+(EDX or Melphalan) in 11, FLU+BU (<8mg/kg) associated or not to other drugs in 13, FLU+TBI(2GY) in 3 and other regimens in 5 patients. ATG/ALG was added in 26% of the cases. GVHD prophylaxis most commonly (55%) consisted of CsA and MMF; 87% received hematopoietic growth factors (<day 8). The median nucleated cell dose infused was 2.4 x107/kg and the graft was HLA identical (6/6) ( HLA A and B low resolution and DRB1 allelic typing) in 3 cases, 5/6 in 15, 4/6 in 37 and 3/6 in 10. Results: Median time to neutrophil recovery (>500/mm3) was 20 days (0–56) and 35 dyas for platelets recovery (>20.000/mm3). At day 60 probability of neutrophil recovery was 87± 7% of the 33 patients who received the Flu+End+TBI conditioning regimen and was 65±10% for patients receiving other regimens (p<0.01). Chimerism analysis was available in 71% of the patients at 3 months and was full donor in 67%, mixed chimerism in 9% and autologous reconstitution in 24%. Grade II aGVHD was observed in 13%, grade III in 7% and grade IV in 7%; the TRM was 45±7% overall, 50±15% in acute leukemia, 30±15% in lymphomas and 27±16% for other diagnoses. The TRM at one year for those receiving <2.4 x 107 TNC/kg was 53±9% and for those receiving >2.4 x107TNC/kg was 39±10% (p=0.07). For patients receiving Flu+End+TBI the TRM at one year was 24±10% and for those receiving other conditioning regimens was 60±9% (p=0.001). DFS at one year for lymphomas was 50±9%, for leukemias was 27±7% and for other diagnoses was zero. When the HLA compatibility was 6/6 or 5/6, DFS at one year was 42±12%, for 4/6 disparities DFS was 27±9% and for 3/6 disparities DFS was zero. DFS was 43±11% for those receiving Flu+End+TBI, and was 16±7% for patients receiving other conditioning regimens (p=0.005). For patients receiving >2.4 x 107TNC/kg the DFS was 31±12% and for patients receiving <2.4 x 107TNC/kg the DFS was 14±8% (p=0.05). In collusion, results of single RIC-UCBT are encouraging; cell dose and HLA remain important factors in this setting. The type of conditioning (Flu+End+TBI) seems to be associated with decreased TRM and better DFS, but a multivariate analysis with a higher number of patients is needed.

Reduced-Intensity Versus Myeloablative Conditioning for Unrelated Cord Blood Transplantation in Adults with Acute Leukemia: A Report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy & Immunobiology Working Party of the European Group for Blood and Marrow Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 155-155
Author(s):  
Frederic Baron ◽  
Ruggeri Annalisa ◽  
Eric Beohou ◽  
Myriam Labopin ◽  
Guillermo Sanz ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cord Blood ◽  
Research Funding ◽  
Cord Blood Transplantation ◽  
Working Party ◽  
Myeloablative Conditioning ◽  
Unrelated Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Reduced Intensity

Abstract BACKRGOUND. Non-relapse mortality (NRM) is the first cause of treatment failure after unrelated cord blood transplantation (UCBT) following myeloablative conditioning (MAC). In the last decade, reduced-intensity conditionings (RIC) for UCBT have been developed with the aim of reducing NRM and allowing older patients and those with medical comorbidities to benefit from UCBT. The aim of our retrospective registry study was to compare outcomes of acute leukemia (AL) adult patients given UCBT after either RIC or MAC regimens. Regimens were classified as MAC or RIC based on EBMT criteria. PATIENTS AND METHODS. Data from 1352 adult (> 18 yrs) patients with AL (acute myeloid leukemia [AML; n=894] or acute lymphoblastic leukemia [ALL; n=458]) given a first single or double UCBT from 2004 to 2013 at EBMT-affiliated centers were included in this retrospective study. RESULTS. 518 patients were given UCB after RIC, while 834 patients were administered MAC. The most frequently used conditioning regimens combined either TBI, cyclophosphamide and Flu (TCF regimen, given in 22% of MAC vs 75% of RIC recipients, P<0.001), or thiotepa, Bu and Flu (TBF, given in 32% of MAC vs 6% of RIC recipients, P<0.001). In comparison to MAC recipients, RIC recipients were almost 2 decades older (median age 52.5 vs 33.7 yrs, P<0.001), were more often transplanted for AML (80% vs 57%, P=0.001), received more frequently 2 cord blood units (61 vs 32%, P<0.001), received more frequently units with > or = 2 HLA-mismatches (69% vs 58%, P<0.001), received more TNC (median 3.5x10E7 vs 2.9x10E7, P<0.001), and received less frequently ATG in the conditioning (23% versus 57%). Disease status at UCBT was comparable in both groups (51% of patients in CR1 and 17% >CR). Median follow-up for survivors was 25 months. In univariate analyses, in comparison to patients given MAC, RIC recipients had a similar rate of neutrophil engraftment (89.5 vs 89%, P=0.7), and a similar incidence of grade II-IV acute (34% vs 29%, P=0.1) and chronic (22% vs 26%, P= 0.22) GVHD. In contrast, at 2-yr, RIC recipients had a higher incidence of disease relapse (41 vs 24%, P<0.001) but a lower NRM (19 vs 37%, P<0.001), translating to similar leukemia-free survival (LFS, 40% vs 38%, P=0.6) but better overall survival (OS, 47 vs 42%, P=0.01) than MAC recipients (Figure 1). Further, among ALL patients, the use of TCF regimen (n=159) was associated lower NRM (21 vs 40% at 2-yr, P<0.001), lower relapse incidence (24 vs 34%, P=0.07), and better OS (63 vs 34%, P<0.001) and LFS (55 vs 27%, P<0.001). We performed separate multivariate analyses (MVA) for patients with AML and ALL. In MVA for AML patients, the use of RIC regimen was associated with a higher incidence of relapse (HR=1.6, P=0.005) but a suggestion for lower NRM (HR=0.7, P=0.1) translating to similar OS (HR=1.0, P=0.9) and LFS (HR=1.1, P=0.3). Similarly, in MVA for ALL patients, the use of RIC regimen was associated with a higher incidence of relapse (HR=2.0, P=0.002) but a lower NRM (HR=0.6, P=0.04) translating to similar OS (HR=0.8, P=0.2) and LFS (HR=1.1, P=0.5). Further, interestingly, conditioning with TCF-based regimen was associated with a lower incidence of relapse (HR=0.5, P=0.004) translating into better OS (HR=0.6, P=0.013) and LFS (HR 0.6, P=0.002) in ALL patients in MVA adjusted for conditioning intensity (RIC vs MAC). CONCLUSIONS. These data suggest that LFS and OS might be as good with RIC than with MAC in adults AL patients offered UCBT. These observations could serve as basis for future prospective randomized studies. Figure 1. Unadjusted UCBT outcomes in patients transplanted following RIC versus MAC. Figure 1. Unadjusted UCBT outcomes in patients transplanted following RIC versus MAC. Disclosures Milpied: Celgene: Honoraria, Research Funding. Sierra:Amgen: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Mohty:Janssen: Honoraria; Celgene: Honoraria. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand.

Successful engraftment following reduced-intensity cord blood transplantation with fludarabine and oral busulfan for advanced hematologic diseases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7110-7110
Author(s):  
T. Azuma ◽  
M. Kami ◽  
E. Kusumi ◽  
Y. Sato ◽  
Y. Miura ◽  
...  
Keyword(s):  
Cord Blood ◽  
Disease Progression ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Hematologic Diseases ◽  
Blood Transplantation ◽  
Donor Type ◽  
Preparative Regimen ◽  
Primary Graft Failure ◽  
Reduced Intensity

7110 Background: Feasibility of reduced-intensity cord blood transplantation (RI-CBT) has been demonstrated in adult patients. Most researchers use preparative regimens containing total body irradiation (TBI) 2–4 Gy, while TBI causes considerable toxicities in elderly patients. We investigated the feasibility of RI-CBT using non-TBI regimen for the treatment of adult hematologic diseases. Methods: Nineteen patients (median age, 61, range, 38–74) with advanced hematological diseases were enrolled in this study. Fifteen patients had chemorefractory diseases at RI-CBT. Preparative regimen comprised fludarabine 180 mg/m2 and oral busulfan 8 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus. Engraftment was defined as an absolute neutrophil count > 0.5 × 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis occurring without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis occurring after primary engraftment. Endpoint of this study was engraftment. Median follow-up of surviving patients was 24.7 months (range, 21.6–25.8). Results: All the patients tolerated the preparative regimen. Median dose of infused nuclear cells was 2.7x10E7/kg (range, 1.9–4.6). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigen (n=3). Eleven patients achieved engraftment at a median of day 18 (range, 9–30). Chimerism analysis was conducted in six of these eleven patients, and complete donor-type chimerism was documented within 30 days of transplant in five patients. Primary graft failure was diagnosed in two patients. The other six patients died without engraftment due to diffuse alveolar hemorrhage(n=1) and disease progression(n=5). No patients developed acute GVHD. Five of the 11 patients who achieved primary engraftment developed secondary graft failure. As of December 2006, four patients survived in complete remission with complete donor-type chimerism. Estimated 1-year overall survival rate was 21.1%. Conclusions: This study demonstrated the feasibility of RI-CBT using non-TBI regimen; however, high incidences of disease progression before engraftment and secondary graft failure were significant problems. No significant financial relationships to disclose.

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