Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

Abstract The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501; NCT00412360) randomized children with hematologic malignancy to one or two cord blood unit transplantation between December 2006 and February 2012. While the trial concluded that survival was similar regardless of number of units infused, results were generally better than those previously reported after single UCB transplant. The apparently improved survival in recipients of BMT CTN 0501 compared to prior studies in children transplanted with a single UCB unit prompted a comparison of trial versus non-trial treatment outcomes to determine 1) the generalizability of trial results and 2) whether survival was better for patients treated with the trial regimen. Using data reported to the Center for International Blood and Marrow Transplant Research during the trial period, 396 recipients of one UCB unit transplant met the broad eligibility criteria for BMT CTN 0501 (i.e. aged 1- 21 years, high-risk acute leukemia, performance score ≥70). Trial and non-trial patients were comparable in their HCT-CI score. Trial patients (n=100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Non-trial patients either received the same regimen as in the trial (N=62; non-trial TCF) or an alternative regimen (N=334; non-trial non-TCF regimen). Excluded were 13 patients on BMT CTN 0501 randomized to receive a single UCB unit for malignant diseases other than acute leukemia. Patient and disease characteristics of those treated on BMT CTN 0501 and others were similar except that those who received non-trial TCF regimen were more likely to report performance scores of 80 or 70 (24% versus 11%, p=0.04) and transplanted in relapse (18% vs. 5%, p=0.02) and those that received non-TCF regimens were more likely to 1-10 years of age (76% versus 53%, p<0.0001). Sixty-three percent of non-trial non-TCF regimens included TBI (≥1000 cGy) and the predominant non-TBI regimen was busulfan and cyclophosphamide. All patients received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis. Donor-recipient HLA-match, median infused total nucleated cells and median follow up times were similar across the groups. Three-year survival rates were similar between patients receiving TCF regimen either on (A) or off trial (B), Figure1A, p=0.83. Similarly, there were no differences in hematopoietic recovery, relapse or non-relapse mortality between trial and non-trial TCF. However, compared to TCF on trial (A), overall survival rates were significantly lower with non-TCF non-TBI (C) and TBI (D) containing regimens after adjusting for age, CMV serostatus, disease and disease status; Figure 1B, 68% versus 55% (p=0.001) and 68% versus 50% (p=0.04), respectively. Results of multivariate analysis are shown in Table 1. Compared to patients treated on trial (TCF regimen; 20% at 3-years) relapse rates were higher with non-TCF non-TBI (42%, p=0.003) but not TBI-containing regimens (25%, p=0.38) after adjusting for age, disease, disease status and CMV seropositivity. Among non-TCF patients, relapse risk was higher for non-TBI compared to TBI-containing regimens (hazard ratio [HR] 1.61, p=0.02) but not mortality risk (HR 0.93, p=0.74). Cytogenetic risk features were not associated with relapse or survival. There were no differences in hematopoietic recovery, acute and chronic GVHD. The results of BMT CTN 0501 appear generalizable to the population of trial eligible patients. The survival differences between the trial specified and other conditioning regimens support use of the TCF regimen to improve survival. It also indicates the importance of conditioning regimen for outcome and may serve as a stimulus to design trials to identify the optimal regimen for children with acute leukemia undergoing UCB transplantation. Disclosures No relevant conflicts of interest to declare.

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Comparison Between Related T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (TCD-Haplo) and Umbilical Cord Blood Transplantation (UCBT) in Pediatric Patients with Acute Leukemia, a Eurocord, PDWP-EBMT Study

Blood ◽

10.1182/blood.v124.21.1215.1215 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1215-1215

Author(s):

Franco Locatelli ◽

Myriam Labopin ◽

Gerard Michel ◽

Rupert Handgretinger ◽

Cristina Diaz de Heredia ◽

...

Keyword(s):

Multivariate Analysis ◽

Acute Leukemia ◽

Advanced Disease ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Disease Status ◽

Gvhd Prophylaxis ◽

Risk Of Relapse

Abstract Both TCD-Haplo and UCBT are used for treating children with either acute lymphoblastic (ALL) or myeloid (AML) leukemia in need of an allograft and lacking a suitable donor. Although both these types of HSCT have been shown to be effective in curing children with acute leukemia, to date, no study has compared the outcomes of these two types of transplant. We performed a retrospective registry-based study on children (less than 18 years) with either ALL or AML, receiving, after a myeloablative conditioning regimen, a TCD-Haplo (CD34+ cell positive selection, CD3+ negative or TCR alpha/beta+ cell depletion) or single unit UCBT. Patients given pharmacological graft-versus-host disease (GVHD) prophylaxis after graft infusion in haplo HSCT were excluded. Transplants were performed from 2001 to 2012 in EBMT centers; 1067 patients received single UCBT and 266 TCD-Haplo for AML (n=478) or ALL (n=855). Median follow up was 28 (range 1-150) and 20 (range 1-152) months for UCBT and TCD-Haplo, respectively. Compared to TCD-Haplo, UCBT recipients were younger (median age 5.96 years vs 9.6 years, p=<0.0001), were transplanted more frequently in CR1 (42% vs 24%, p=<0.001), less frequently in advanced disease (10% vs 21%, p=<0.001) and had more often negative cytomegalovirus (CMV) serology (45% vs 31%, p=<0.001). Conditioning regimen was mainly total body irradiation (TBI)-based, 56% versus 50% for TCD-Haplo and UCBT, respectively. For UCBT, patients CSA+steroids was the most commonly used (72%) GVHD prophylaxis. A higher proportion of patients transplanted with TCD-Haplo received ATG in the conditioning regimen (90% vs 74%, p=<0.001). Acute GVHD (grade II-IV) incidence was 16% and 28% (p<0.001) while that of chronic GVHD was 14% and 16%, (p=0.40) for TCD-Haplo and UCBT respectively. Since diagnosis was the most important factor influencing outcome, the analysis was performed separately for patients with ALL and AML. For ALL (n=855) in univariate analysis, the 2-year probability of leukemia-free survival (LFS) was 35% and 43% (p=0.08), for TCD-Haplo and UCBT, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 28% and 29% (p=0.57), and relapse incidence (RI) was 36% and 28% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=300), 2-year RI was 21% versus 20%, p=0.75; NRM 30% versus 24%, p=0.59; and 2- year LFS 49% versus 56%, p=0.87; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=478), 2-year RI was 34% versus 29%, p=0.75; NRM 28% versus 32%, p=0.29; and 2- year LFS 38% versus 39%, p=0.63, for TCD-Haplo and UCBT, respectively. For patients in advanced disease (n=77), 2-year LFS was 5% versus 8%, p=0.08 for TCD-Haplo and UCBT, respectively. For patients with AML (n=478), 2-year probability of LFS was 21% and 58% (p=<0.0001), for TCD-Haplo and UCBT, respectively. CI of NRM was 43% and 19% (p=<0.001), and RI was 36% and 23% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=207), 2-year RI was 31% versus 14%, p=0.06; NRM 45% versus 16%, p=0.002; and 2-year LFS 24% versus 69%, p=<0.001; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=180), 2-year RI was 28% versus 24%, p=0.49; NRM 44% versus 21%, p=0.004; and 2- year LFS 28% versus 55%, p=0.0005, for TCD-Haplo and UCBT, respectively. For patients in advanced disease status (n=91), 2-year LFS was 10% versus 22%, p=0.44 for TCD-Haplo and UCBT, respectively. In multivariate analysis adjusted for differences between the 2 groups, for patients with ALL, no statistically significant differences were observed according to the graft source. Disease status was the only factor associated with better LFS (HR 4.84, p<0.0001). TCD-Haplo was associated with greater risk of RI (HR 1.58, p=0.01). For AML, in multivariate analysis, TCD-Haplo was associated with greater risk of relapse (HR 1.67, p=0.05) and of NRM (HR= 1.94; p=<0.001), and worse LFS (HR 1.94, p=<0.001) when compared to UCBT. Advanced disease at transplantation (HR 2.89, p=<0.001) was the other factor associated with LFS and RI. This retrospective analysis demonstrates that children with ALL have comparable probability of LFS after either UCBT or TCD-Haplo. By contrast, in children with AML, UCBT is associated with lower risk of relapse and NRM than TCD-Haplo, this translating into better LFS. These results may help guide physician choices for transplanting children with acute leukemia. Disclosures No relevant conflicts of interest to declare.

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Ex Vivo T Cell-Depleted Haploidentical HCT for Children with Acute Leukemia after a Reduced-Intensity Preparative Regimen Containing Low-Dose TBI

Blood ◽

10.1182/blood.v128.22.4673.4673 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4673-4673

Author(s):

Yeon Jung Lim ◽

Ho Joon Im ◽

Sung Han Kang ◽

Hyery Kim ◽

Kyung-Nam Koh ◽

...

Keyword(s):

T Cell ◽

Acute Leukemia ◽

Low Dose ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Reduced Intensity

Abstract Background: Recent advances in haploidentical hematopoietic cell transplantation (HHCT) enabled this transplant using haploidentical family donor to be a viable option for pediatric patients lacking matched related or unrelated donor. In our center, HHCT using ex vivo T cell-depleted (TCD) grafts after reduced-intensity conditioning (RIC) was conducted since 2008. The safety and efficacy of this transplantation modality for pediatric with acute leukemia were investigated. Methods: Thirty-one pediatric patients with acute leukemia received ex vivo T cell-depleted HHCT at Asan Medical Center Children's Hospital between July 2008 and June 2016. Four patients received CD3-depleted grafts and 27 received TCRαβ-depleted stem cells. Among 31 patients, 9 had ALL (3 CR1, 6 CR2-3), 22 had AML (18 CR1-3, 4 NR). Seven patients had relapsed after previous allogeneic HCT. All 31 patients underwent a uniform RIC regimen consisting of low-dose total body irradiation (LD-TBI; 600 cGy), fludarabine (FLU; 180 mg/m2), cyclophosphamide (CY; 100 mg/kg), and rabbit anti-thymocyte globulin (r-ATG; 3 mg/kg). Results: The median age at HHCT was 14 years (range, 1-19). All 31 patients achieved sustained neutrophil engraftment at a median of 10 days (range, 9-17) post-transplant. The cumulative incidence of acute GVHD grade II-III and III were 30% and 21%, respectively. None developed grade IV. Two of 26 evaluable patients developed extensive chronic GVHD. As of July 2016, 18 of the 31 patients survive free of disease with a median follow-up of 26 months (range, 2-98 months). Ten patients have died. Causes of death were relapse (n=9) and disseminated tuberculosis (n=1). Only one patient died of non-relapse cause, leading to TRM of 5.3% at 1 year. EFS and OS at 2 years for all patients were 51% and 60%, respectively. Sixteen patients with AML who received a first HHCT in any CR showed a favorable outcome (EFS of 85%), whereas, 6 patients with ALL who received a first HHCT in CR showed a poor EFS of 28%. In addition, all patients (6 with AML and 3 with ALL) who received a subsequent HCT in CR or were not in remission developed relapse. Conclusions: This study demonstrated that our ex vivo T cell-depleted HHCT using RIC is a feasible therapy with low TRM for pediatric patients with acute leukemia. The outcome of patients with AML who received their first transplant in CR was excellent in this treatment modality. However, the outcome of ALL was poor suggesting that more intensified conditioning regimen may be required for those diseases. Furthermore, an innovative treatment strategy is warranted to improve the outcome for patients with relapsed or refractory acute leukemia. Disclosures No relevant conflicts of interest to declare.

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Risks and Benefits of Unrelated Donor Peripheral Blood Progenitor Cells (PBPC) in Children and Adolescents with Acute Leukemia.

Blood ◽

10.1182/blood.v112.11.977.977 ◽

2008 ◽

Vol 112 (11) ◽

pp. 977-977

Author(s):

Mary Eapen ◽

Olle Ringden ◽

Franco Locatelli ◽

Haydar Frangoul ◽

Mats Remberger ◽

...

Keyword(s):

Overall Survival ◽

Acute Leukemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Unrelated Donor ◽

Platelet Recovery ◽

Free Survival ◽

Grade 3

Abstract Although PBPC is an acceptable alternative to bone marrow (BM) for transplanting children with leukemia, there are no published studies describing outcomes after unrelated donor PBPC transplants. We compared the results of 385 unrelated donor BM transplants that were allele-matched (n=186) or mismatched (n=199) at HLA A, B, C, DRB1 and 110 PBPC transplants that were matched (n=60) or mismatched (n=50) at HLA A, B, C, DRB1 in patients younger than 18 years of age. All patients had acute leukemia and were transplanted in 2000–2006. Median follow up of surviving patients was 2 years in both treatment groups. There were no significant differences in patient and disease characteristics, transplant conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and donor-recipient HLA disparity by graft type. Though the early probability of neutrophil recovery (³500/ul) was faster after transplantation of PBPC (31% vs. 10% at day-14, p<0.001) the probability of recovery by day-28 was similar after PBPC and BM transplants (94% and 91%, p=0.391). In contrast, platelet recovery (³20,000/ul) was better after PBPC transplants (86% vs. 76% at day-60, p=0.022). Risks of grade 2–4 (hazard ratio [HR] 1.24, p=0.147) and grade 3–4 (HR 1.07, p=0.785) acute GVHD were similar after PBPC and BM transplants. The risk of developing chronic GVHD was significantly greater after PBPC transplants compared to BM transplants (HR 2.36, p<0.001). After adjusting for disease status, donor-recipient HLA disparity and age, the of transplant-related mortality (TRM) relapse, treatment failure (relapse or death from any cause; inverse of leukemia-free survival and overall survival were similar after PBPC and BM transplants. The Table below shows the day-100 probability of grade 2–4 acute GVHD and the 3-year probabilities of chronic GVHD, TRM, relapse, leukemiafree survival and overall survival by graft type. These results differ from transplantation of PBPC from HLA-matched siblings where higher chronic GVHD translated into higher TRM and lower LFS. It remains to be seen whether the observed higher chronic GVHD after PBPC transplants will eventually result in the long term in higher mortality or fewer leukemia recurrence. PBPC BM Grade 2–4 acute GVHD 53% 49% Chronic GVHD 58% 33% TRM 20% 24% Relapse 34% 28% Leukemia-free survival 46% 48% Overall survival 49% 49%

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

Blood ◽

10.1182/blood.v118.21.4572.4572 ◽

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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Comparison of PBSC Vs Cord Blood (CB) As Stem Cells Source for Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Adult Patients with Haematological Diseases: A Single Centre Analysis.

Blood ◽

10.1182/blood.v120.21.3108.3108 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3108-3108

Author(s):

Amandine Lebourgeois ◽

Marion Loirat ◽

Benoit Tessoulin ◽

Elsa Lestang ◽

Pierre Peterlin ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cord Blood ◽

Median Time ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Single Centre ◽

Stem Cell Source

Abstract Abstract 3108 Introduction: RIC regimens are increasingly used for allo-SCT in older patients or patients with co-morbidities. The FB2 regimen (Fludarabine 120–150 mg/m2 + I.V. Busulfan 6.4 mg/Kg + ATG 5 mg/Kg) using PBSC as stem cell source is currently the most widely used RIC regimen in many European centres. On the other hand, in patients without a suitable HLA-matched donor, the use of umbilical cord blood stem cells for allo-SCT (uCBT) is increasingly considered, especially using the RIC regimen developed by the Minneapolis group. Series comparing PBSC vs CB as stem cells source for RIC allo-SCT are still scarce and using various RIC regimens before allo-SCT. Patients and Methods: This retrospective single centre analysis compared two homogeneously treated cohorts of patients who had received between January 2007 and November 2010 in our department either a FB2/PBSC allo-SCT (n=52, males: 61%; median age: 59 years (range: 22–70)) or a FC-TBI/uCBT (Fludarabine 200 mg/m2 + Cyclophosphamide 50 mg/Kg + TBI 2 Grays regimen; n=39, males 49%; median age 56 years (range: 22–70). Except for age (p=0.03), there were no significant differences between the 2 groups regarding patients and diseases characteristics: gender (p=0.22), interval between diagnosis and transplant (PBSC: 9 months vs CB: 10 months, p=0.85), disease type (PBSC: myeloid disease 63% vs CB: 67%, p=0.75), status at transplant (complete remission PBSC: 77% vs CB: 67%, p=0.28), prior auto-SCT (PBSC: 35% vs CB: 33%, p=0.90). Donors in the PBSC group were as follows: sibling donors, n=30; HLA-MUD n=20, mismatched unrelated n=2. All patients from the CB group received 2 CB units (HLA matching 4/6 n=25; 5/6 n=53). As for GVHD prophylaxis, patients received cyclosporine (CsA) alone in case of an HLA-identical sibling donor, and CsA+ mycophenolate mofetyl in all other cases. None of the patients from the PBSC group received G-CSF after transplant, while it was administered to all CB recipients. Results: Median follow-up was respectively 19 and 20 months for the PBSC and the CB groups (p=NS). Engraftment and median time for neutrophils recovery were similar between the 2 groups: PBSC: 96% vs CB: 90%, p=0.22; and 17 days (range: 0–39) vs 16 days (range: 8–60), p=0.88, respectively. The median time for platelets recovery (>20000/mm3) was significantly higher in the CB group: 38 days (range: 13–150) vs PBSC: 0 days (range: 0–186) (p<0.0001). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were comparable between both groups: PBSC: 31% and 15% vs CB: 26% and 8% (p=0.72 and p=0.28) as also the 2-years incidence of chronic GVHD: PBSC: 35% vs uCBT: 25%, p=0.54. 2-years NRM was significantly higher after uCBT: 26% vs 6%, p=0.02. Finally, there were no differences between the two groups in terms of 2-years OS, DFS and Relapse Incidence: PBSC: 62.3% vs CB: 60.8% (p=0.51); 58.7% vs 50.4% (p=0.43) and 36% vs 23% (p=0.31). In multivariate analysis, the source of stem cells (CB) remains associated with NRM (HR: 0.16, 95%CI: 0.05–0.5, p=0.001) but was not predictable for survivals. Conclusion: Our study suggests that RIC uCBT is a valid alternative in patients lacking an HLA-matched related or unrelated donor and candidate for RIC allo-SCT. Prospective and randomized studies are warranted in order to establish the definitive role of uCBT, especially in patients with acute leukemia, where CB cells may offer a rapidly available source of stem cells in diseases with high tumor kinetics. Disclosures: No relevant conflicts of interest to declare.

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Are Outcomes After Myeloablative Conditioning Regimen in Double Cord Blood Transplantation (UCBT) Better Than Single UCBT for Adults with Acute Leukemia in Remission?.

Blood ◽

10.1182/blood.v120.21.3083.3083 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3083-3083

Author(s):

Annalisa Ruggeri ◽

Henrique Bittencourt ◽

Guillermo Sanz ◽

Alessandro Rambaldi ◽

Ibrahim Yakoub-Agha ◽

...

Keyword(s):

Multivariate Analysis ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Grade Ii ◽

Group 2

Abstract Abstract 3083 Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for patients (pts) with acute leukemia (AL) with poor-risk cytogenetics or refractoriness to chemotherapy. For adults requiring HSCT urgently, such as pts in first complete remission (CR1), a single (s) or double unit (d) UCBT is a valid stem cells source. In the sUCBT setting, type of conditioning regimen seems to be associated with better outcome (Sanz BMT 2012). With the aim to compare single vs double UCBT after myeloablative conditioning regimen (MAC) in a homogeneous series of pts, we analyzed 239 adults (>18years) with AL in CR1. Pts were transplanted with sUCBT (n=156) or dUCBT (n=83) from 2005–2011 in EBMT centers for ALL (n=101) and AML (n=138). Type of MAC was statistically associated with outcomes therefore pts were analyzed in 3 different groups: Group 1: pts receiving sUCBT with TBI-based+Cy (+Flu) (n=68) (performed in 42 transplant centers (TC)), Group 2: pts receiving sUCBT with Bu+Flu+Thiotepa (n=88) (performed in 23 TC) and Group 3: pts receiving dUCBT with Cy+TBI+Flu (n=83) (performed in 47 TC). No statistical differences were found among the 3 groups for pts and disease characteristics (diagnosis, risk, gender, weight, CMV status, year of UCBT and time from diagnosis to UCBT) however pts in group2 were older than in group1 and 3 (median age 38 vs 33 vs 31 years) (p=0.03). Cytogenetic at diagnosis was available for 176 pts, 39% of pts were classified in the intermediate risk and 56% in unfavorable risk group. Forty-two pts had t(9;22) and 26 FLT3/ITD mutation. No differences on cytogenetic were found among the 3 groups. Thirty one percent of CB units were identical to recipient or had 1 HLA disparity (antigen level typing for HLA-A and B and allelic level for DRB1) while 69% had 2–3 HLA disparities. There was no difference on HLA disparities among the 3 groups. Median infused TNC was 2.9×107/kg for group1, 3×107/kg for group2, and 3.7×107/kg for group3 (p=0.01) and median CD34 was 1.2×105/kg, 1.6×105/kg and 1.5×105/kg, respectively (p=0.32). ATG was part of conditioning regimen in 73% of pts. The use of ATG was different in the 3 groups (70%, 90% and 40% for group1, 2 and 3, respectively p<0.001). GVHD prophylaxis consisted either of CSA±MMF or CSA±steroids in 46% and 22% of pts, respectively. All groups had the same median follow-up time: 24 (range 3–74) months. For group1, group2 and group3, the cumulative incidence (CI) of 60 days neutrophil recovery was 82%, 89% and 87% (p=0.15), with median time of 27, 21 and 24 days, respectively (p<0.001). Chimerism analysis performed at day 100 showed full donor chimerism in 87% of pts (data available for 80% of pts who engrafted). No differences in chimerism status were found between the 3 groups (p=0.47). At day 100, CI of acute GVHD (grade II-IV) was 30% vs 20% vs 45% for group1, group2 and group3, respectively (p=0.001). Pts receiving a dUCBT who developed aGvHD (n=38), experienced mainly grade II aGvHD with skin involvement (grade II (n=25), grade III (n=10), grade IV (n=3)). CI of chronic GvHD at 1 year was 29%, with no differences in the incidence among the groups. At 1 year, CI of TRM was 44% for group1, 33% for group2 and 36% for group3 (p=0.46). In multivariate analysis, two factors were associated with higher TRM: diagnosis of ALL (p=0.048) and age>35 years (p=0.049). One-Hundred-six pts died and the causes of death were infection (n=38), GvHD (n=18), other transplant-related events (n=31) or relapse (n=18). CI of 2y relapse was 25% for group1, 18% for group2 and 16% for group3 (p=0.22). No factors were found to be associated with increase relapse incidence in multivariate analysis. The 2y probability of leukemia-free-survival (LFS) was 31% for group1 (sUCBT-TBI based), 48% for group2 (sUCBT-BuFluTT), and 47% for group3 (dUCBT) (p=0.03). No center effect was found for LFS. In multivariate analysis, use of sUCBT using TBI based MAC (HR=0.9, p=0.003), diagnosis of ALL (HR=0.69, p=0.04) and age>35years (HR=1.4, p=0.04) were independently associated with decreased LFS. In this retrospective based registry analysis, in the myeloablative setting for adults with AL in CR1, outcomes (TRM, RI and LFS) after dUCBT were not statistically different from sUCBT using iv-BuFluTT. However, compared to sUCBT using TBI-based MAC, dUCBT was associated with lower RI and better LFS rates. In the MAC setting, the combination of conditioning regimens and type of graft (single vs. double) may have different impact UCBT outcomes. Disclosures: No relevant conflicts of interest to declare.

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Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms

Blood ◽

10.1182/blood.v120.21.4545.4545 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4545-4545

Author(s):

Jorge Gayoso ◽

Mi Kwon ◽

David Serrano ◽

Pascual Balsalobre ◽

Javier Anguita ◽

...

Keyword(s):

High Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Allogeneic Transplantation ◽

High Dose ◽

Unrelated Donor ◽

Haploidentical Transplantation ◽

Gvhd Prophylaxis

Abstract Abstract 4545 Introduction: Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor. Patients and Methods: We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5. Results: From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated. Conclusions: HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution. Disclosures: No relevant conflicts of interest to declare.

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Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis

Blood ◽

10.1182/blood-2010-12-323824 ◽

2011 ◽

Vol 117 (24) ◽

pp. 6714-6720 ◽

Cited By ~ 87

Author(s):

Mukta Arora ◽

John P. Klein ◽

Daniel J. Weisdorf ◽

Anna Hassebroek ◽

Mary E. D. Flowers ◽

...

Keyword(s):

Overall Survival ◽

Risk Score ◽

Chronic Gvhd ◽

Disease Status ◽

Risk Groups ◽

Marrow Transplant ◽

Karnofsky Score ◽

Blood And Marrow Transplant ◽

Gvhd Prophylaxis ◽

Research Analysis

Abstract Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

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Different Approaches Of Allogeneic Stem Cell Transplantation For Acute Leukemias In Suzhou (China) Lead To Similar Outcome Compared With European Group For Blood and Marrow Transplantation (EBMT) Results: A Pair-Matched Analysis

Blood ◽

10.1182/blood.v122.21.2131.2131 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2131-2131

Author(s):

Jia Chen ◽

Yin Lu ◽

Myriam Labopin ◽

Depei Wu ◽

Mohamad Mohty ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Multivariate Analyses ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Acute Leukemias ◽

Significant Difference

Abstract The first affiliated hospital of Soochow University initiated a program of stem cell transplantation for hematological malignancies in 2001 and has done until December 2011 a total of 460 transplants. The EBMT presently handles a registry with information on more than 450 000 transplants including over 100 000 transplants for Acute Leukemias. In order to evaluate the outcome of patients transplanted in Suzhou and to compare it with results from the EBMT, we collected the necessary information on all patients transplanted in Suzhou and we did a pair matched analysis. In Suzhou, the patient population studied consisted of 382 first allografts (322 adults and 60 children less than 18 years old). There were 223 Acute Myelocytic Leukemias (AML), 148 Acute Lymphoblastic Leukemias (ALL) and 11 biphenotypic leukemias. The median age of the patients was 32 years (4-63). By cytogenetics, 9% of the patients were good risk, 57% intermediate risk and 34% poor risk. Molecular biology was not available. 286 patients were transplanted in first remission (CR1), 63 in CR2 and 30 in more advanced disease. Donors were identical siblings in 57%, unrelated in 30%, mismatched relatives in 13%. The source of stem cells was bone marrow (BM) (harvested after stimulation of the donor by GCSF) in 40%, Peripheral Blood (PB) in 36%, BM + PB in 17% , Cord Blood in 4% and other in 3%. 97% of the patients received myeloablative conditioning (MAC) with no Total Body Irradiation (TBI) in 76%, and 3% reduced intensity conditioning (RIC). 98% of the patients engrafted. Acute Graft versus Host Disease (aGVH) grade >=2 occurred in 43%. The cumulative incidence of chronic GVHD at 2 years was 26±2%. With a median follow up of 21 months (1-143), 2 year overall survival (OS), Leukemia free survival (LFS), Relapse Incidence (RI) and non Relapse Mortality (NRM) in patients allografted in CR1 were 76± 3, 65± 3, 18± 2 and 17 ± 2% and in CR2 52± 7, 36± 7, 37± 7 and 28 ± 6%. TBI in MAC was associated with poorer results (p< 0.01 for OS,LFS,RI). By multivariate analyses, The NRM was lower with PB (p=0.04) and PB+BM (p= 0.01) compared to BM and the OS higher ( p=0.05 and 0.01 respectively). In a pair matched analysis 246 adult patients from Suzhou transplanted in CR with BM and/or PB were matched with 484 patients from the ALWP EBMT registry. Matching factors were age, diagnosis (AML and ALL), disease status (CR1 or CR2), Cytogenetics and donor origin (identical siblings, unrelated, mismatched relatives). Patients from Suzhou were transplanted more recently ; the interval from diagnosis to transplant was shorter (138 days vs 154 days, p<0.0001). TBI was less frequently used for MAC both for AML and ALL (p< 0.0001 for each) and PB + BM was used in 17% of the cases versus 0% for EBMT (p < 0.0001). By univariate analyses the results were: Suzhou versus EBMT: OS 72 ± 3 vs 61 ±2 % (p= 0.05), LFS 62 ± 3 vs 55 ± 2% (p= 0.17), RI 19 ± 3 vs 22 ± 2% (p= 0.25), NRM 20 ± 3 vs 22 ± 2% (p = 0.67), incidence of chronic GVH 30± 3 vs 48 ± 2% (p< 0.0001). By multivariate analyses, there was no significant difference for OS (HR: 0.9 range 0.59-1.39), LFS (HR: 0.93, range 0.63-1.38), RI ( HR: 0.72, range 0.41-1.28) and NRM (HR: 1.21, range 0.70-2.10). We conclude that the results from Suzhou are identical to those obtained using the EBMT database, even though some approaches (GCSF stimulated BM, BM+PB, conditioning regimen) were different. Disclosures: No relevant conflicts of interest to declare.

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Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

Blood ◽

10.1182/blood-2011-06-363572 ◽

2012 ◽

Vol 119 (12) ◽

pp. 2949-2955 ◽

Cited By ~ 78

Author(s):

Juliana F. Fernandes ◽

Vanderson Rocha ◽

Myriam Labopin ◽

Benedicte Neven ◽

Despina Moshous ◽

...

Keyword(s):

Cord Blood ◽

Treatment Options ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Survival Rates ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Blood Transplantation ◽

Valuable Treatment

Abstract Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

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