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

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.

Download Full-text

The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽

10.1182/blood.v114.22.873.873 ◽

2009 ◽

Vol 114 (22) ◽

pp. 873-873

Author(s):

Andrea Toma ◽

Marie-Lorraine Balère-Appert ◽

Jean-Michel Boiron ◽

Pierre Bordigoni ◽

Gerard Socie ◽

...

Keyword(s):

Stem Cells ◽

Multivariate Analysis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity Conditioning Regimen ◽

Unrelated Donors ◽

Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

A Myeloablative Conditioning Regimen With Fludarabine Demonstrates Good Results In UCBT With Hematologic Malignancies, Especially Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v122.21.4575.4575 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4575-4575

Author(s):

Juan Tong ◽

Sun Zimin ◽

Liu Huilan ◽

Geng Liangquan ◽

Zheng Changcheng ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Good Survival ◽

Myeloablative Conditioning ◽

Blood Transplantation

Objectives We retrospectively analyzed the safety and efficacy of a myeloablative conditioning regimen without anti-thymocyte globulin (ATG) or total body irradiation (TBI) but with fludarabine (FLU) in unrelated cord blood transplantation (UCBT) for 30 patients with hematologic malignancies. Methods The myeloablative conditioning regimen consisted of FLU, busulfan (BU) and cyclophosphamide (CY). All of the patients received Cyclosporine (CSA) and mycophenolate mofetil (MMF) as graft versus host disease (GVHD) prophylaxis. Results With this conditioning regimen, we achieved high engraftment rates (96.7%) and rapid hematopoietic reconstitution. Acute GVHD occurred in 12 cases of the 29 engraftment patients (41.4%), and 6 cases (20.7%) were of grade III-IV. Chronic GVHD only occurred in 1 of 28 evaluable patients (3.6%). Twenty-three patients (76.7%) became infected, and 3 cases (10.0%) died of severe infections. Cytomegalovirus (CMV) reactivation occurred in 70.0% of the patients, but no CMV diseases were observed, nor did any patients die of CMV infection. The cumulative incidence of relapse (6.7%) was significantly reduced, and none of the acute lymphoblastic leukemia (ALL) patients relapsed. The 3-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 70.0%, respectively, representing satisfactory survival. The 3-year OS and EFS of the ALL patients was 75.0%. Discussion This conditioning regimen resulted in a high engraftment rate, rapid myeloid reconstruction and a low incidence of infection. Although there were many patients with high-risk disease and disease progression, the regimen resulted in low relapse rates and good survival. None of the ALL patients relapsed after UCBT, indicating that this conditioning regimen could be applied to more patients with ALL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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.

Download Full-text

Reduced Relapse and Similar Progression-Free Survival After Double Umbilical Cord Blood Transplantation (DUCBT): Comparison of Outcomes Between Sibling, Unrelated Adult and Unrelated DUCB Hematopoietic Stem Cell (HSC) Donors.

Blood ◽

10.1182/blood.v114.22.662.662 ◽

2009 ◽

Vol 114 (22) ◽

pp. 662-662 ◽

Cited By ~ 3

Author(s):

Claudio G. Brunstein ◽

Jonathan A Gutman ◽

Todd E. DeFor ◽

Ted Gooley ◽

Michael R Verneris ◽

...

Keyword(s):

Multivariate Analysis ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Hematologic Malignancies ◽

P Value ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Hematopoietic Recovery

Abstract Abstract 662 For patients with hematologic malignancies who lack a matched or mismatched unrelated donor, UCBT is an alternative. However, only a minority of larger adolescents and adults are able to find a single UCB with an adequate cell dose. Double UCB unit grafts (DUCB) have previously been shown to extend this HSC option. In order to understand the relative merits of each HSC source, we combined the datasets at the University of Minnesota and Fred Hutchinson Cancer Research Center. Between 2001- and 2008, 536 patients with leukemia (AML, n=211; ALL, n=236; CML, n=70 and MDS, n=19) were transplanted with HSC from a matched sibling (SIB, n=204), 8/8- (MUD, n=152) or 7/8-HLA (MMUD, n=52) matched unrelated donor or DUCB (n=128). All patients received myeloablative conditioning with cyclophosphamide 120 mg/kg and total body irradiation 1200-1320cGy with fludarabine 75mg/m2administered prior to DUCB. All patients received GVHD immunosuppression with a calcineurin inhibitor and either methotrexate (SIB, MUD and MMUD) or mycophenolate mofetil (DUCB). While patient weight and sex distribution and proportion with standard risk disease (STD, AML and ALL in CR1-2, and CML in CP1) were similar, DUCB pts were younger (median age 25 yrs, SIB 40 yrs, MUD 31 yrs, MMUD 31 yrs; p<.01). The proportion of AML and ALL was similar among groups, although more CML patients received a MUD or MMUD. Recipient CMV seropositivity was lower among MUD (44%; SIB 58%; MMUD 60; DUCB 62%, p<.01). The median follow-up of survivors was 3.1 yrs (0.3-8.1). The univariate point estimates at the stated timepoints and multivariate outcomes are summarized in the Table.Outcomes after SIB vs. MUD vs. MMUD vs. DUCBSIB* Ref.MUD* RR (95%CI)MVA p-value†MMUD* RR (95%CI)MVA p-value†DUCB* RR (95%CI)MVA p-value†Neutrophil Recovery at day 4598% 1.097% 0.62 (0.50-0.78). . <0.0198% 0.63 (0.46-0.86). . <0.0187%; 0.29 (0.23-0.37). . <0.01Platelet Recovery at day 10086% 1.081% 0.83 (0.64-1.09). . 0.1875% 0.71 (0.48-1.04). . 0.0845% 0.22 (0.17-0.29). . <0.01Grade II-IV aGVHD at day 10065% 1.080% 1.68 (0.32-2.14). . <0.0185% 2.17 (1.46-3.23). . <0.0160% 1.01 (0.76-1.35). . 0.94cGVHD at 2 year47% 1.043% 1.04 (0.75-1.46). . 0.8048% 1.24 (0.77-2.0). . 0.3726% 0.73 (0.47-1.13). . 0.16TRM at 3 years24% 1.014% 0.92 (0.53-1.60). . 0.7627% 1.83 (0.97-3.42). .0.0634% 2.86 (1.81-4.51). . <0.01Relapse at 5 years43% 1.037% 0.83 (0.58-1.19). . 0.3235% 0.68 (0.39-1.20). . 0.1915% 0.27 (0.16-0.47). . <0.01PFS at 5 years33% 1.048% 0.83 (0.62-1.11). . 0.2038% 1.04 (0.70-1.53). . 0.8551% 1.00 (0.73-1.37). . 0.99*Results are shown as pointwise estimates, relative risk (RR) and the 95% confidence interval. SIB group was the reference (Ref) group for the multivariate analysis (MVA).†P-value shown relates to multivariate analysis. In summary, after a Cy/TBI based myeloablation, DUCB is associated with slower hematopoietic recovery compared to other HSC sources. While incidence of acute GVHD was similar to that observed after SIB, DUCB was associated with less acute and trend toward less chronic GVHD relative to unrelated donors. Despite reduced risk of GVHD after DUCBT, risk of relapse was remarkably low while TRM was elevated, resulting in similar PFS. In the absence of a SIB donor, using either MUD or DUCB yield encouraging PFS and are promising donor options. These results support a) the front line use of HLA 0-2 antigen mismatched DUCB in patients with hematological malignancy, b) development of new strategies to enhance hematopoietic recovery after DUCBT, potentially reducing the risk of TRM, c) studies to understand why relapse rates are reduced with DUCBT and d) quality of life assessments long term between HSC groups, as there appears to be less risk of acute and chronic GVHD after DUCBT. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Is HLA-Haploidentical Hematopoietic Stem Cell Transplantation a Valid Alternative Option for Patients with Combined Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia (AA/PNH Syndrome)?

Blood ◽

10.1182/blood.v126.23.5535.5535 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5535-5535

Author(s):

Feng Chen ◽

Wu Depei ◽

Xiaowen Tang ◽

Miao Miao ◽

Chengcheng Fu ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Therapeutic Option ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem

Abstract Background In the era of eculizumab, indentifying patients with PNH who may benefit from allogeneic stem cell transplantation(SCT) is challenging, especially for those who have no HLA-matched donors. Several recent studies have shown that HLA-haploidentical SCT for patients with hematological malignancy can achieved comparable outcomes with HLA-identical sibling transplantation. There are very few reports on the use of HLA-haploidentical SCT for AA/PNH. The aim of the present study was to assess the long-term clinical outcome of HLA-haploidentical SCT in patients with AA/PNH. Methods Total of 9 AA/PNH patients received HLA-haploidentical SCT between Oct 2010 and Oct 2014 at our institution. The patients were aged 13 to 54(median 24 years). The median interval from the diagnosis to transplantation was 48 months (range 2-180). Of the 9 HLA-haploidentical donors, 3 were siblings, 2 fathers, 2 mothers, 1 son and 1 daughter. 8 patients received myeloablative conditioning regimen consisting of busulfan, cyclophosphamide and ATG (anti-thymocyte globulin), 1 patient who underwent salvage HLA-haploidentical SCT after the graft failure of double umbilical cord blood transplantation received conditioning including reduced-intensity total body irradiation, cyclophosphomide and ATG. G-CSF-mobilized bone marrow and peripheral blood stem cells were transplanted as graft. Prophylaxis for graft-versus-host disease(GVHD) consisted of cyclosporine or tacrolimus + mycophenolate mofetil + short-term methotrexate. Results All 9 patients were engrafted successfully. The median time of neutrophils (ANC) reached to 0.5×109/L and platelets (PLT) reached to 20×109/L were 12 (range 11-26) days and 15 (range 11-120) days, respectively. 2 patients developed grade Ⅱ acute GVHD, 2 patients developed limited chronic GVHD. After a median follow-up time of 14.0 (range 4.0-30.8) months, the 2-year OS probability was 72.9±16.5%. 2 patients died of treatment-related mortality, including severe pulmonary infection (n=1) and transplant-associated thrombotic microangiopathy (n=1),respectively. No patients were documented to have a recurrence of a PNH clone after SCT. Conclusion This study showed that long-term outcomes of HLA-haploidentical SCT in patients with AA/PNH were comparable to that of HLA-matched donor SCT ( the 2-year OS probability was 80.5±10.2%, P=0.02) at our institution. HLA-haploidentical SCT should be considered as a valid alternative therapeutic option for AA/PNH patients without HLA-matched donors. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Hematopoietic Stem Cell Transplantation (HSCT) as Curative Therapy for Fanconi Anemia (FA) Patients with Acute Leukemia or Advanced Myelodysplasia (MDS).

Blood ◽

10.1182/blood.v106.11.5464.5464 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5464-5464

Author(s):

Christopher J. Fraser ◽

John E. Wagner ◽

Margaret L. MacMillan

Keyword(s):

Acute Leukemia ◽

Hemorrhagic Cystitis ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Curative Therapy ◽

Disease Characteristics ◽

Gvhd Prophylaxis ◽

Preparative Regimen ◽

Total Body

Abstract Historically outcomes have been very poor for FA patients with advanced MDS or leukemia. It remains controversial as to whether HSCT is indicated for such patients and there is no consensus as to the optimal conditioning regimen in this setting. Traditionally, conditioning for FA patients has incorporated total body irradiation (TBI). Here, we report results of a pilot study in which we have substituted busulfan for TBI, designed for FA patients with one or more high risk features, identified following analysis of 42 previous consecutive URD FA transplants: advanced MDS or leukemia, age >18 years, or previous proven fungal or gram negative infection. Between 12/02–08/04 6 patients were enrolled, 5 with acute leukemia. Patient and disease characteristics are presented in Table 1. Conditioning consisted of busulfan (total 3.2mg/kg), cyclophosphamide (total 40mg/kg), fludarabine (total 140 mg/m2) and ATG (total dose 75mg/kg); GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. All patients received prophylactic voriconazole for one month prior to transplant. BM was T cell depleted with CD34 selection by Isolex 300i. Five out of six patients achieved neutrophil engraftment. Median time to an ANC>500 was 16 days (range: 11–20 days). One patient developed Grade I acute GVHD; no patient has developed chronic GVHD. The preparative regimen was well tolerated. Toxicities included Grade IV mucositis (n=1), VOD (n=2), hemorrhagic cystitis (n=1) and CMV pneumonia (n=1). Three patients are alive and in remission with a median follow-up of 575 days. Table 1 Age Diagnosis FANC group Remission status Donor source D+21 chimerism D+60 chimerism Vital status Patient and disease characteristics 5.9 ALL BRCA2 treated; CR 5/6 related BM 100% donor 100% donor alive d+894 21.7 AML A untreated 5/6 URD BM 99.1% donor 100% donor died resp. failure d+99 20.8 SAA A N/A 5/6 URD BM insufficient cells N/A died VOD d+24 6.6 ALL,MDS,Wilm’s BRCA2 ALL treated CR; MDS (7.5% blasts) 6/6 URD UCB 100% donor 100% donor alive d+575 7.1 AML A treated; refractory 4/6 UCB + 5/6 UCB 100% donor #2 54.7% #2; 45.3% recipient died AML relapse d+60 17.3 AML A treated; refractory 5/6 UCB x2 66.7% #1; 31.3% #2; 2% recipient 100% donor #1 alive d+423 These results suggest TBI is not required to achieve durable engraftment and leukemia control, busulfan 3.2 mg/kg is tolerable, and advanced MDS or acute leukemia does not preclude HSCT in FA patients.

Download Full-text

Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽

10.1182/blood.v114.22.661.661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 661-661

Author(s):

Jon J van Rood ◽

Cladd E Stevens ◽

Jacqueline Smits ◽

Carmelita Carrier ◽

Carol Carpenter ◽

...

Keyword(s):

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hla Antigens ◽

Human Leukocyte ◽

Hematologic Malignancies ◽

Hematopoietic Stem ◽

Leukocyte Antigens ◽

Grade Ii ◽

The Impact ◽

Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v120.21.1928.1928 ◽

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.

Download Full-text

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

Blood ◽

10.1182/blood.v128.22.1231.1231 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1231-1231 ◽

Cited By ~ 1

Author(s):

Mary Eapen ◽

Joanne Kurtzberg ◽

Mei-Jie Zhang ◽

Adam M. Mendizabal ◽

Ka Wah Chang ◽

...

Keyword(s):

Acute Leukemia ◽

Cord Blood ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Survival Rates ◽

Conditioning Regimen ◽

Disease Status ◽

Marrow Transplant ◽

Blood And Marrow Transplant ◽

Hematopoietic Recovery

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.

Download Full-text

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.

Download Full-text