Reduced-intensity Cord Blood Transplantation Research Articles

Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children.

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180mg/m2, melphalan (MEL) 210mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

Impact of NK Cell Reconstitution and Recipient HLA-C Typing on Clinical Outcome after Reduced Intensity Cord Blood Transplant: Results of a Prospective Phase II Multicentric Trial on Behalf of Societe Francaise De Greffe De Moelle Osseuse Et Therapie Cellulaire (SFGM-TC) and Eurocord

Background:Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly and unfit patients without an HLA identical donor. KIR ligand incompatibility between donor and recipient might favor Natural Killer (NK) cell alloreactivity after UCBT in AML patients (Wilhemze et al, 2009), although contradictory results were reported (Brunstein et al, 2009). We previously reported the results of the biological NK cell reconstitution after RIC-UCBT in a French prospective phase II multicentric trial (Rio et al, 2015). We showed that NK cells generated from RIC-UCBT exhibited features of transient immaturity and stable activation, correlating with a high ability to produce IFN-γ and a quick restoration of the ability both to produce TNF-α and degranulate (Souchet et al, ASH 2013). The aim of the present study is to analyze the impact of KIR ligand incompatibilities and NK cell reconstitution on OS, DFS and TRM after RIC-UCBT in a prospective trial.Materials and methods:Seventy-six patients with a de novo or secondary AML in complete remission were enrolled in 23 centers from Oct. 2007 to Sept. 2009. Peripheral blood samples were collected during the first year following UCBT in order to realize an extensive prospective phenotypic and functional study of NK cells. DNA samples were also collected in recipient and cords blood to perform KIROTYPE and HLA-C allelic typing. NK biological data were available at M1 for 54 patients. The inhibitory Killer-Immunoglobin Receptors (KIR) KIR2DL1, and KIR2DL2/3 bind KIR ligand C2 and C1 respectively, resulting in inhibition of NK-cell mediated lysis. Recipients and UCB were classified into C1 or C2 family depending on their HLA-C typing (C1-C1, C1-C2 or C2-C2).Results:Among the 54 patients, 35 events occurred (relapse or TRM). Median EFS and OS were 13.2 and 18.3 months, respectively. Recipients C2-C2 had a significant worse EFS and OS than C1-C1 or C1-C2 (median EFS C2-C2=3.8 month vs 15.1 month for C1-x; p=0.002); median OS C2-C2 3.8 months vs 29.9 months for C1-x; HR=6.12, IC95% [2.069; 18.113], p=0.001). High intracellular staining of CD107a, reflecting the capacity of NK degranulation with HLA negative K562 target, correlated with better OS. CD107a expression was divided in 2 groups at median (=51%). Median OS of CD107 (0-50%) was 12.8 months vs 20.9 months for CD107a (51-66); p=0.029. Relapse risk was highly increased in recipients C2-C2 (HR=5.04 (IC 95% [1.23; 20.56], p=0.02). Low expression of CD16 (HR=0.97, IC95% [0.937; 0.999], p=0.043), high expression of HLA-DR (HR=1.08, IC95% [1.031; 1.123], p=8e-04) on NK cells, and recipients C2-C2 (HR=9.44, IC95% [1.311; 67.882], p=0.026) significantly increased the risk of TRM. The inhibitory KIR2DL1 receptor binds to C2 ligands. Of interest, KIR2DL1 was significantly decreased on C2-C2 recipients NK cells at M1, as compared to C1-x recipients NK cells. On the contrary, KIR2DL2/3 and KIR3DL1 restored promptly, suggesting a sequential expression of KIRs. As interaction between inhibitory KIRs and their ligands are essential for NK cells to become functional ("licensing" process), we can hypothesize that the weaker expression of KIR2DL1 on C2-C2 NK cells alters the licensing process, rendering the NK cells hypo-responsiveness.Conclusion:Recipient C2-C2 is correlated with a worse outcome (EFS, OS, relapse, TRM) after RIC-UCBT in a prospective trial for AML patients. Weak capacity of degranulation and low expression of CD16 are associated with worse OS and increased TRM, respectively. These features can reflect an alteration of the NK licensing process and might have impact on clinical outcome after UCBT. DisclosuresNo relevant conflicts of interest to declare.

Reduced-intensity cord blood transplantation following a regimen using fludarabine and busulfan in adult patients with advanced hematologic malignancies.

7036 Background: Cord blood transplantation has grown as an effective alternative therapy for treating patients with advanced or high-risk hematologic malignancies who have no suitable related or u...

Impact of HLA Disparity with High-Resolution HLA Typing at HLA-a, -B, -C, and –DRB1 on Engraftment after Reduced Intensity Cord Blood Transplantation in Adults

Impact of HLA Disparity with High-Resolution HLA Typing at HLA-a, -B, -C, and –DRB1 on Engraftment after Reduced Intensity Cord Blood Transplantation in Adults

Infliximab Versus Rabbit Anti-Thymocyte Globulin As a Salvage Treatment For Steroid-Refractory Acute Graft-Versus-Host Disease After Reduced-Intensity Cord Blood Transplantation In Adults

Introduction In reduced intensity cord blood transplantation (CBT) post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. There is no consensus on the optimal salvage treatment of steroid-refractory acute GVHD. Patients and Methods We retrospectively reviewed 388 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from June 2008 to October 2012 at Toranomon Hospital. Patients who were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. Patients in whom acute GVHD developed received methylpredonisolone 1-2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to salvage treatment with infliximab or ATG. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. ATG was given at 1mg/kg/day once weekly for at least 1 course. An observational study compared response and survival rates in all consecutive patients receiving 1 of these 2 treatments. Results 52 patients among this group developed steroid refractory acute GVHD. Infliximab group (n=31) had a higher proportion of patients with grade III-IV GVHD (69% VS 59%, p=0.18). ATG group (n=21) had a higher proportion of patients with stage 3-4 liver GVHD (28% VS 5%, p<0.01). Infliximab or ATG therapy was initiated after a median of 12 days (range, 2 to 85 days; 10 days for infliximab group VS 22 days for ATG group; p<0.01) of steroids for primary therapy for GVHD. Both overall response (PR+CR) were significantly higher in the infliximab group compared with the ATG group (54.8% VS 33.3%, p=0.015 ). In multivariate analysis, time from first-line therapy (days<10) was an independent predictor of response (HR, 3.91; 95%CI, 1.10-13.8; p=0.034), infliximab therapy was not significant, (HR, 1.30; 95%CI, 0.42-3.99; p=0.18). Median follow-up of surviving patients from the date of initiation of salvage treatment was 21.6 months (range, 5.5-57.9 months).Overall, median survival was 2 months after salvage treatment (95% CI, 1-3), with 25% of patients surviving at 12 months (95%CI, 11-20). Patients who achieved a CR have better survival rates. GVHD was the main cause of death (50%). When comparing survival according to salvage treatment, better OS with infliximab (33.9% VS 22.8, p=0.08) in univariate analysis was not confirmed in multivariate analysis. In multivariate analysis, grade IV GVHD at steroid refractory GVHD onset (HR,7.1; 95% CI, 1.29-38.7; P=0.021), and gut involvement with bleeding (HR, 7.65; 95% CI, 1.35-43.2; P=0.024) were significantly associated with worse survival. Conclusion We conclude that infliximab has more activity than ATG in the treatment of severe steroid-refractory GVHD, and earlier initiation of salvage therapy may give better response. But outcomes remain poor. New methods to prevent and treat GVHD are needed. Disclosures: No relevant conflicts of interest to declare.

Moving Average Of Immature Platelet Fraction Predict Late Platelet Engraftment After Reduced-Intensity Cord Blood Transplantation: A Single-Institutional Study

Introduction Platelet engraftment is an important marker of successful allogeneic stem cell transplantation and platelet is the last to be regenerated in bone marrow after stem cell transplantation. Especially, platelet engraftment is far slower in reduced-intensity conditioning regimen(RIC) in cord blood transplant(CBT). Early prediction of platelet engraftment in RIC-CBT can be helpful to proper treatment. Recent retrospective studies suggested immature platelet fraction(IPF) can be useful to predict platelet engraftment. However, the role of IPF in RIC-CBT is not be sufficiently investigated. In addition, these studies included patients undergoing bone marrow or peripheral blood transplantation. Therefore, we analyzed cases in our database to evaluate the impact of IPF and Reticulocyte count(RET%) on the outcome of platelet engraftment in consecutive patients who were treated with RIC-CBT over the past 4 years at our institution in Tokyo, Japan. Patients and Methods We included 53 consecutive patients treated at our institution between April 2008 and May 2013. The study population consisted of 29 male and 23 female patients with a median age of 57 years old (range: 36-69). Patient in this cohort underwent RIC-CBT as a part of therapy for myeloid malignancies(N=28) and lymphoid malignancies (N=24). 21 patients were treated with Flu+Cy+TBI(2gy), and 31 patients were treated with Flu+Bu+TBI(2Gy). All patients received calcineurin inhibitor plus MMF for GVHD prophylaxis. Due to the influence of blood transfusion on IPF and RET% and overall estimation of IPF and RET% movement, IPF and RET% were assessed by using the 5-day moving average ,and then we compared movement of the fifth moving average between patients with platelet engraftment and patients without platelet engraftment. The fifth moving average was calculated from the time of day4 after transplantation until the date of platelet engraftment or death from any cause or the date on which the patient was received next chemotherapy. Platelet engraftment was defined as independent from platelet transfusion. Result Among 53 patient, 29 patieunt achieved platelet engraftment. The median time of platelet engraftment was day +42 (range:24-203day), and median time of follow up periods of patients without platelet engraftment was 47 days. 16 patients achieved platelet engraftment after day +40. Baseline characteristics according to patients who achieved platelet engraftment, or did not achieve were similar among RIC-regimen, patient diagnosis. Patients' age, sex, total cell count andCD34 cell count in donor cord blood has no impact on pletelet engraftment. Maximum value of IPF did not have significant impact on platelet engrafment. As shown figure 1, The mean of the 5-day moveing average in IPF show similar curve from day +4 to day +30 between patient with platelet engraftment and without, and after +30 days the curve of patient with platelet engraftment gradually highter than the curve of patient without platelet engraftment. The difference of these curves was larger after day +50. In the RET% case, it was almost same. the 5-day moveing average of IPF and RET% in platelet engraftment patient were raising after day +40, while those in non-engraftment patient were decreasing in this period. Provided the 5-day moving average of IPF are blow 6.0 from day +40 to day +50, It is highly likely that platelet engraftment can't be expected (p=0.001 in univariate analyses). Likewise, provided the 5-day moving average RET% are blow 1.5 from day +40 to day +50, platelet engraftment significantly can't be expected (p=0.002). Conclusion The results of the present study highlighted the importance of the fifth-moving average of IPF and RET% after day +40, and IPF and RET% can be useful tools to predict platelet engraftment in RIC-CBT. Disclosures: No relevant conflicts of interest to declare.

Impact of HLA Haplotype Matching On Engraftment in Reduced Intensity Cord Blood Transplantation.

Abstract 3043 IntroductionHLA-mismatched unrelated cord blood transplantation (UCBT) is feasible and, in retrospective comparative analyses, allows survival rates similar to conventional unrelated HLA-matched adult-derived grafts. Although it is clear that the degree of UCB HLA mismatch in patients has a negative effect on outcomes, the biologic implications of HLA haplotype itself have not been explored for UCBT. In unrelated bone marrow transplantation, an effect of HLA haplotype matching on GVHD has been clarified. (S.Morishima. et al. Blood 2010). This study was conducted to determine the impact of HLA haplotype matching in reduced intensity UCBT. Patients and MethodsTo determine the impact of HLA haplotype matching with outcomes after UCBT, We retrospectively reviewed patients with hematologic malignancies who underwent reduced intensity CBT at Toranomon Hospital from August 2006 and December 2010 consecutively. Patients who had prior history of transplantation, were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. Then, the remaining 164 consecutive patients were reviewed. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. DNAs of 164 pairs were analysed for HLA-A, -B, and -DRB1 based on High Resolution typing, and we have determined the HLA haplotype based on Japanese common HLA haplotypes referred from the previous reports. ResultsFor A, B, DR based on high resolution typing the following mismatch occurred: no mismatch 3(2%), one mismatch 12(7%), two mismatch 58(35%), three mismatch 60(37%), four mismatch 28(17%), five mismatch 3(2%) in the GvH direction, and: no mismatch 2(1%), one mismatch 16(10%), two mismatch 55(34%), three mismatch 56(34%), four mismatch 32(20), five mismatch 3(2%) in the HvG direction. Then 37 among 164 pairs were defined as the HLA haplotype matched group. The number of total nucleated cells and CD34+ cells were not significantly different between HLA haplotype matched group and non-matched group. The cumulative incidence of neutrophil recovery was higher in HLA haplotype matched group than in non-matched group.( 94.6% vs. 80.3% up to day 60, p=0.0027). Lower incidence of pre-engraftment immune reaction(PIR) and acute GVHD were observed in haplotype matched group (37.8 % vs. 47.9 % up to day 60 post-transplant, P = 0.32), III to IV acute GVHD( 18.9% vs. 27.7% up to day 100 post-transplant, p=0.29). The cumulative incidences of relapse tended to be lower in haplotype matched group than in non-matched group (21.5% vs. 31.5%, P=0.28).Overall survival (OS) was estimated as 36.0 % at 3 years post-transplant. There were no significant differences between mathed and non-matched group in the cumulative incidence of OS (36.8 % vs. 34.3% at 3 years post-transplant, P = 0.84). ConclusionHLA haplotype matching in UCBT was found to have a significant impact on engraftment in this analysis. Disclosures:No relevant conflicts of interest to declare.

Infliximab Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease After Reduced-Intensity Cord Blood Transplantation in Adults

Abstract 4553 IntroductionAcute graft versus host disease (GVHD) remains the most frequent complication after allogeneic hematopoietic stem cell transplantation (SCT). In reduced intensity cord blood transplantation (CBT) previous studies have reported a lower incidence of severe acute GVHD compared with conventional allo-SCT. However, in these studies the incidences of grade II-IV acute GVHD varied widely from 26% to 51% (H.Narimatsu Stem cell int. 2011: 607569). In particular, post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. Infliximab, a chimeric monoclonal antibody against tumor necrosis factor alpha, has shown activity against steroid refractory acute GVHD. Patients and MethodsWe retrospectively reviewed 275 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from March 2007 to December 2011 at our institute. Patients in whom PIR or acute GVHD developed received methylprednisolone 1–2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to infliximab treatment. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. An antifungal drug, itraconazole or micafungin or voriconazole was used until all immunosuppressive drus were withdrawn. ResultsIn this study we retrospectively evaluated 54 patients who had steroid refractory acute GVHD. Of these, 21 who received infliximab were analyzed. GVHD prophylaxis was with only tacrolimus(n=15) and mycophenolate mofetil+tacrolimus(n=6). All of them developed grade III to IV GVHD. Median follow-up time of survivors was 548 days (range, 222–1152). The overall response rate was 62% (n=13), and 9 patients (43%) experienced complete response (CR). 5 patients (24%) did not respond and 3 (14%) had progressive GVHD. The Kaplan-Meier estimate of overall survival was 31%, with no signs of chronic GVHD (n=2). Four patients who responded subsequently died, one of exacerbation of GVHD, three of infections. All the 8 unresponsive patients died of GVHD or infections. Five patients (21%) had non-Candida invasive fungal infections. Sixteen patients(79%) had bacterial infections. ConclusionInfliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD even following reduced intensity cord blood transplantation. However, it is associated with a high rate of infections. Controlled studies to assess the pharmacokinetics and most effective dosing regimen of infliximab for the treatment of steroid refractory acute GVHD are warranted. Disclosures:No relevant conflicts of interest to declare.

臍帯血ミニ移植が奏効した完全4倍体(92, XXXX)白血病

臍帯血ミニ移植が奏効した完全4倍体(92, XXXX)白血病

Reduced-intensity cord blood transplantation without prior remission induction therapy induces durable remission in adult patients with relapsed acute leukemia after the first allogeneic transplantation

Reduced-intensity cord blood transplantation without prior remission induction therapy induces durable remission in adult patients with relapsed acute leukemia after the first allogeneic transplantation

Feasibility of Reduced-Intensity Cord Blood Transplantation as Salvage Therapy for Graft Failure: Results of a Nationwide Survey of Adult Patients

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

Rapid Switch To Donor-Type Dominant Chimerism And Early Lymphocyte Recovery Following Reduced-Intensity Cord Blood Transplantation

Rapid Switch To Donor-Type Dominant Chimerism And Early Lymphocyte Recovery Following Reduced-Intensity Cord Blood Transplantation

Early relapse of hemophagocytic syndrome after reduced-intensity cord blood transplantation for relapsed acute lymphoblastic leukemia

Early relapse of hemophagocytic syndrome after reduced-intensity cord blood transplantation for relapsed acute lymphoblastic leukemia

Impact of ABO Imcompatibility On Acute GvHD and Thrombotic Microangiopathy After Reduced-Intensity Cord Blood Transplantation.

Abstract 2298Poster Board II-275 Introduction:Althouth ABO blood type is one of two antigen system for transplantation, the effect of ABO incompatibility on transplantation outcome still remains controversy. Furthermore, there is little data about ABO incompatibility on the outcome of unrelated cord blood transplantation following reduced-intensity conditioning (RI-CBT). Design and Methods:We retrospectively analyzed data of 155 patients who underwent RI-CBT performed at Toranomon Hospital from January 2005 to December 2008. The patients include 45 ABO-identical, 47 minor, 43 major, and 20 bidirectional ABO mismatched. All patients were performed using fludarabine-based reduced-intensity conditioning, and 114 patients (74%) were performed using TBI-containing regimen. Median age were 57 years-old and 94 patients (61%) were over 55 years-old. We evaluated the association between ABO incompatibility and neutrophil engraftment, one-year overall survival (OS) ; one-year non-relapsed mortality (NRM) ; and one-year relapse rate. We also analyzed the incidence of pre-engraftment immune reaction (PIR), acute graft-versus-host disease (GvHD) including severity, and thrombotic microangiopathy (TMA). Results:There were no significant differences in neutrophil-engraftment time, reticulocyte-engraftment time, and the incidence of PIR. The incidence of acute GvHD and grade 2-4 acute GvHD were significantly higher in major/bidirectional ABO-incompatible group than ABO-identical/minor ABO-incompatible group (respectively P=0.0008 and P=0.0116). The incidence of TMA tended to be higher in minor/bidirectional ABO-incompatible group than ABO-identical/major ABO-incompatible group (P=0.0637). There were no significant differences in one-year OS, NRM, and relapse rate. In multivariate analysis, risk factors of acute GvHD were age over 55, TBI-containing regimen, CD34-positive cells>0.7×10e5/kg, and major/bi-directional ABO incompatibility, and those of TMA were grade 3-4 acute GvHD and minor/bi-directional ABO incompatibility. Discussion:This study showed major-directional ABO incompatibility setting increased the incidence of acute GvHD. Sex incompatibility and HLA incompatibility were not significantly influenced the incidence of acute GvHD. The use of steroid for severe GvHD and the expression of ABO antigen on the surface of vascular endothelial cell may influence pathogenesis of TMA. Further studies including larger patients numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of RI-CBT. Disclosures:No relevant conflicts of interest to declare.

Clinical Characteristics and GVL Effect of Chronic Graft-Versus-Host disease Following Reduced-Intensity Umbilical Cord Blood Transplantation (RICBT).

Abstract 1162Poster Board I-184 BackgroundsUmbilical cord blood can be an alternative stem cell source for the patients of hematological diseases. However, little is known about chronic GVHD (cGVHD) and graft versus leukemia/lymphoma (GVL) effect in reduced-intensity cord blood transplantation (RICBT). We had been demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Here, we analyzed the clinical picture of chronic GVHD following RICBT and the GVL effect. MethodsWe reviewed medical records of 192 patients with hematological diseases who had received CBT between Jan. 2004 and Dec. 2008 who had been free from disease progression for more than 100 days after RICBT at Toranomon Hospital, Tokyo, Japan. Median age was 54 years (17-82). Most of them had diseases in advanced status (n=168). Most of the pre-transplant conditioning were reduced intensity consisted of fludarabine, melphalan and TBI 4Gy (n=157). GVHD prophylaxis were tacrolimus (Tac) alone (n=99) and Tac plus mycophenolate mofetil (MMF) (n=93). HLA disparities were as follows; 6/6 (n=9), 5/6 (n=38), 4/6 (n=142), and 3/6 (n=3). Underlying diseases were AML (n=58), myelodysplastic syndrome (n=36), ALL (n=23), lymphoma (n=64) and others (n=11). ResultsThe Median observation period after the transplantation was 924 days (range, 109–1944). Chronic GVHD was admitted in 114 patients (59.4%) consisted of limited type 88 (45.8%) and extensive type 26 (13.5%) in classical criteria, and mild type 96 (50.0%), moderate type 15 (7.8%), and severe type 3 (1.6%) in NIH consensus criteria of cGVHD. The target organs of cGVHD were skin 87.5%, liver 40.6%, and mouth mucous membranes 32.8 %, eye 23.4%, and the lungs only 7.8% (COP3 and BOS2). Except 21 cases ( 10.9%) required systemic steroid or MMF therapy. The median of Karnofsky score of cGVHD was 90%(40-100). During observation period, no patients except one patient caused by heart failure were died of cGVHD. In multivariate analysis, high-risk disease (p=0.019) and preceding acute GVHD (p=0.026) are related to the occurrence of cGVHD, and cGVHD increased overall survival (p<0.01) and suppressed recurrence of the disease (p<0.01). ConclusionAlthough the frequency of cGVHD was not low, the severity was mild, and the death related to cGVHD is rare in RICBT. NIH consensus criteria is useful for the evaluation of cGVHD severity. Some effect of GVL may play a role on better survival and lower relapse rate in RICBT. DisclosuresNo relevant conflicts of interest to declare.

Reduced-Intensity Cord Blood Transplantation without Preceding Remission Induction Therapy Induces Durable Remission in Patients with Relapsed Acute Leukemia After the First Allogeneic Stem Cell Transplantation.

Abstract 4341Relapses in acute leukemia (AL) following allogeneic stem cell transplantation (allo-SCT), particularly those relapses within 1 year after transplantation, are often refractory to induction chemotherapy. Patients with this type of relapse rarely achieve long-term remission even after the second SCT. Cord blood transplantation, performed in a timely manner, may improve treatment outcomes in these patients. To assess the effectiveness of second cord blood transplantation (CBT) with a reduced intensity conditioning (RIC) regimen early after the diagnosis of leukemia relapse, we retrospectively analyzed outcomes from RIC-CBT without preceding remission induction therapy in 11 consecutive patients.Between 2007 and 2009, we performed CBTs with a RIC regimen for 11 patients with AL who relapsed after allo-SCT. Seven patients were diagnosed with acute myeloid leukemia and four with acute lymphoblastic leukemia. Median duration between the first and the second SCT was six months (range: 3-24 months). Median duration between the relapse and the second SCT was 39 days (range: 22-60 days). All but one patient didnot receive induction chemotherapy due to the low probability of achieving complete remission (CR),and another patient didnot receive induction chemotherapy due to low blast percentage in bone marrow. Mean blast counts in bone marrow and peripheral blood were 39.3% and 22.1%, respectively. All but one patient were conditioned with fludarabine (25 mg/m2/day) from Day -8 to Day -4, with L-PAM (40 mg/m2/day) from Day -3 to Day -2, and with TBI (4Gy) on Day -1. Only FK506 was administered to patients as a graft versus host disease (GVHD) prophylaxis. Mean concentrations of FK506 during the first, second, third, and fourth 10-day period after CBT were 8.9, 8.9, 10.2, and 9.8 ng/ml, respectively. Median follow-up period was 12 months after transplantation in patients who survived.Six patients were alive at the last follow-up with a 1-year and 2-year OS rate of 72.7% and 36.4%, respectively. Five of these 6 patients have been maintaining CR. Four of the 5 patients maintaining CR were considered to be at an extremely high risk for relapse because they relapsed within 8 months (median: 5.5 months, range: 5 to 8 months) after the first SCT. These 4 patients have maintained CR with a median follow-up of 12 months (range: 7 to 32 months). The 2-year probabilities of transplant-related mortality (TRM), relapse-free survival (RFS), and relapse were 27.3%, 40.9%, and 42.9%, respectively. RIC-CBT without preceding remission induction therapy using a relatively low concentration of FK506 as a GVHD prophylaxis may be a promising therapeutic option for patients with AL who relapse shortly after the first transplantation.Age/SexDiseaseDonor type of 1st SCTPreparative regimen of 1st SCTTime (months) from 1st SCT to relapseTime (days) from relapse to 2nd SCTBlast BMBlast PBStatus last follow upOverall Survival (months)53/FAMLMUDTBI-CY124231.8%3%death no relapse342/MAMLCBTBI-CY53749.4%6%alive CR3240/FAMLCBBU-CY-TBI53229.0%81%death relapse1538/MAMLMUDTBI-CY212864.8%80%death no relapse228/FAMLSIBFlu-Mel-TBI24606.4%1%alive CR2319/MALLSIBTBI-CY83550.0%49%death relapse1521/MALLMUDTBI-CY82273.8%1%alive CR750/MAMLMUDTBI-CY5399.0%2%alive CR945/FALLSIBTBI-CY64157.8%4%alive CR1555/FALL(Ph1)SIBTBI-CY44151.2%16%alive relapse621/FAMLRelatedTBI-CY6429.2%0%death no relapse3 Disclosures:No relevant conflicts of interest to declare.

Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation

AbstractDelayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34+ cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.

Reduced-Intensity Cord Blood Transplantation for Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome

Reduced-Intensity Cord Blood Transplantation for Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome

Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced-intensity conditioning cord blood transplantation

The prognosis of multisystem LCH in children with risk organ involvement is extremely poor when they fail to respond to conventional chemotherapy. In such patients, allogeneic SCT may produce complete and sustained remission; however, high-dose myeloablative regimens are frequently associated with treatment-related morbidity and mortality. More recently, allogeneic SCT following an RIC regimen has been performed as an alternative salvage approach. We describe a nine-month-old boy with refractory multisystem LCH with pulmonary aspergillosis who was successfully treated with reduced-intensity cord blood transplantation.

Reduced-Intensity Unrelated Cord Blood Transplantation in Adult – a Single Center Analysis of 318 Transplants.

Objective: Cord blood is widely used as a third possible stem cell source for allogeneic transplantation following bone marrow and peripheral blood. CBT has unique characteristics such as allowing 2 loci mismatch and emergency use or ready to use transplantation. Reduced-intensity transplantation also has been widely accepted to offer opportunities for allogeneic transplant for older and poor overall status patients. We previously showed the feasibility of reduced-intensity cord blood transplantation (RI-CBT) in 30 patients with advanced hematological diseases. Then performed more than 300 time RI-CBT to those whom needed urgent transplantation without suitable HLA matched donors.Methods: We retrospectively analyzed medical records of 318 times and 287 cases of RI-CBT from 1/1/2004 to 5/7/2008 in Toranomon Hospital. Disease distribution of 287 studied patients was as follows; acute myeloblastic leukemia/myelodysplastic syndrome was 136 cases, malignant lymphoma 58, acute lymphoblastic leukemia 42, adult T cell leukemia/lymphoma 25, severe aplastic anemia 8 and others 18. A mean age was 56 ranging from 19 to 79 years old. The number of high risk and standard status patients were 243 and 44, respectively. High risk disease status is defined as residual uncontrolable tumor cells despite of chemotherapy such as primary refractory and beyond CR1 and standard risk is as in remission in a meaning of tumor control. MDS and SAA patients who need frequent transfusions and intensive care for infection are defined as standard risk. Preparative regimen mainly composed of fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. Some patients were contiditioned with iv-busulfan without TBI. Graft-versus- host disease prophylaxis was composed of cyclosporine or tacrolimus alone.Results: We analyzed the association of various factors on engraftment in possible 158 patients. Eighty eight % (95% CI, 83%–93%) of patients were engrafted on a median days of 20 (range, 11–55 days) after transplant. Multivariate analysis revealed 5 to 6 antigen match in GVH direction was a significant independent factor for engraftment as well as CD34 dose, while HLA in HVG direction did not significantly influence on engraftment. Three-year estimated overall survival (OS) in total 287 cases was 39.6% (95% CI: 33.5–45.8%). Standard risk patients (n=44) showed 3-year OS of 53.8% (95% CI: 38.3–69.2%) and high risk (n=243) was 26.3% (95% CI:20.2–32.5%). Tacrolimus GVHD prophylaxis group (n=159) had superior 3y-OS of 33.8%(95% CI: 25.9–41.8) to cyclosporine alone with 3yOS of 22.4 % (95% CI: 14.2–30.7). We previously reported pre-engraftment immune reaction characterized by high-grade fever and weight gain and developed on a median of day 9. More intensive immune suppression after RI-CBT using tacrolimus decreased the incidence and severity of PIR and increased OS.Conclusion: RI-CBT is a feasible approach even for relatively aged patient population (Mean age=56) with advanced hematological malignancies.