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Description: Abstract 4572 Background: RIC has been applied mainly for elderly patients and patients with comorbidity to expand opportunity for such adult patients to undergo HSCT. The burden of late effects after HSCT followed by myeloablative conditioning is not negligible in pediatric patients. RIC should be introduced to avoid not only treatment related morbidity (TRM) but also late effects for children even if they are not ineligible for myeloablative transplantation. However, enhanced graft-versus-leukemia (GVL) effect by choosing an alternative donor in the setting of RIC-HSCT for pediatric ALL hasn't been clarified, so far. Methods: We retrospectively analyzed 22 children with ALL who underwent RIC followed by HSCT from an alternative donor between 2001 and 2008 in our institute. Results: The median age of 22 patients at HSCT was 9 years (range one year - 19 years). 8 patients in CR1, two in CR2 and 12 beyond CR2 underwent HSCT from an alternative donor followed by Flu 180mg/m2 and LPAM 140 mg/m2 containing RIC. 8 patients who relapsed after myeloablative HSCT and 5 patients with Ph1-ALL were included. Unrelated bone marrow (BM) in 7 patients and unrelated cord blood in 4 were transplanted. 11 patients were transplanted from a haplo-identical parent (8, BM; 3, selected CD34 positive peripheral blood mononuclear cells). Engraftment was confirmed in 21 transplants out of 22 (95.4%). Death of TRM within 100 days after transplant was observed in 3/22 (13.6%). Acute graft-versus-host disease (GVHD) grade IV wasn't observed. Acute GVHD grade II and III occurred in 8/21 (38.1%) and 6/21 (28.6%), respectively. Chronic GVHD was seen in 8/16 (50%). 14 patients (63.6%) out of 22 are surviving after RIC-HSCT for median 36 months (range, 24 – 100 months). 9 patients (90%) out of 10 in CR1/CR2 and 5 (41.7%) out of 12 beyond CR2 are surviving. Conclusion: These results suggest RIC-HSCT from an alternative donor for pediatric ALL can be performed safely and similar outcome can be expected compared to myeloablative transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: [Background] We have been performing reduced-intensity stem cell transplantation (RIST) to avoid preconditioning-related complications. However, the effectiveness of RIST in pediatric patients with acute lymphoblastic leukemia (ALL) remains to be clarified. [Methods] We retrospectively reviewed 37 pediatric patients with ALL in second complete remission (CR2) who underwent first allogeneic hematopoietic stem cell transplantation (allo-SCT) between 1993 and 2012 in our institute. We compared the outcomes of RIST with those of myeloablative stem cell transplantation (MAST). [Results] The median age at allo-SCT was 9 years (range, 1 to 18 years). There were 33 B-lineage ALL, 3 T-lineage ALL, 1 lineage unknown ALL, and none of Philadelphia chromosome-positive ALL. Sixteen patients received HLA-matched bone marrow (7 related; 9 unrelated), 12 HLA-mismatched bone marrow (11 unrelated; 1 HLA haploidentical related), 4 cord blood, and 5 CD34 positive peripheral blood stem cells (HLA haploidentical related). In all patients, the 5-year overall survival (5y-OS) rate and the 5-year event free survival (5y-EFS) rate were 75.1% and 56.5%, respectively. Seven patients underwent RIST and 30 patients underwent MAST. The median follow-up durations of RIST and MAST groups were 3.3 years (range, 0.9 to 8.2 years) and 11.3 years (range, 0 to 21.2 years), respectively. The 5y-OS rates in RIST and MAST groups were 85.7% and 59.8%, and the 5y-EFS rates were 71.4% and 53.3%, respectively. The 5-year cumulative transplant-related mortality (TRM) rates in RIST and MAST groups were 0% and 31.0%, and the 5-year cumulative relapse rates were 28.6% and 24.3%, respectively. [Discussion] In our series, the cumulative relapse rate in RIST group was similar with that in MAST group, and the cumulative TRM rate in RIST group was lower than that of MAST group. Therefore, both of the 5y-OS and the 5y-EFS rates in RIST group seem to be better than those in MAST group. The outcomes of RIST in our series do not seem to be poorer. Although further studies are needed because of the small size of patients and short follow-up duration, RIST can be considered as the first transplantation for pediatric patients with ALL in CR2. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1161 Poster Board I-183 Introduction The number of cord blood transplantation (CBT) is rapidly increasing. In this setting, development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) appears to be at high risk. To clarify this issue, we retrospectively analyzed EBV serology and clinical course of 57 patients who received CBT during the past 12 years. Patients and methods We underwent 79 CBT until 2008. Fifty-seven patients were available for assessing EBV serology. The mean age of patients was 63 months (range, 6m-28y5m). The underlying disease was hematologic malignancy (n=27), hematologic non-malignancy (n=10), autoimmune disease (n=2), solid tumor (n=7), and EBV-associated T/NK-LPD (n=11). Results Forty-six (80.7%) of the 57 recipients were EBV seropositive before CBT (sero+/). Nineteen (41.3%) of 46 EBV seropositive recipients before CBT became EBV seronegative after CBT (sero+/sero-). Five patients (8.8%) developed EBV-associated post-transplantation LPD. Three of the 5 LPD patients arose from 27 patients of sero+/sero+ group, and the time of onset of LPD was 2-6 months after CBT. Two of them died of LPD. The remaining 2 patients arose from 19 patients of sero+/sero- group, and the time of onset of LPD was 6-9 months. These 2 patients were successfully treated. None of the 11 patients (6 in sero-/sero- group and 5 in sero-/sero+ group) developed LPD. Discussion Among EBV seropositive patients, about 60% of them remained seropositive (endogenous infection group), and 40% of them became seronegative after CBT. The latter group is likely to experience exogenous infection (secondary primary infection). In both instances, incidence of LPD seems to be quite high. Therefore regular monitoring of EBV serology and EBV-DNA load after CBT should be essentially required for all CBT patients. Disclosures No relevant conflicts of interest to declare.

Description: Background: The introduction of tyrosine kinase inhibitor (TKI) has reduced the indications for allogeneic hematopoietic stem cell transplants (HSCT) in patients with chronic myeloid leukemia (CML). In children and adolescents/young adults (AYA), however, the long-term side effects of TKI and financial burden could become a future issue. Thus, the role of HSCT with reduced intensity conditioning (RIC) as an alternative to TKI especially in the first chronic phase (CP1) should be defined for children and AYA with CML. However, less is well-known about the efficacy of RIC regimens on children and AYA with CML, in chronic phase (CP) as well as advanced phase. Aims: To describe the long-term outcomes of children and AYA with all phases of CML treated with a RIC HSCT and to define potential prognostic factors for outcome. Patients and Methods: We retrospectively analyzed 3796 patients with CML using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation and included children and AYA under 30 years old at HSCT who underwent allo-HSCT between 2001 and 2014 and received TKI before HSCT. The myeloablative conditioning regimen was defined as TBI ≥ 8 Gy, busulfan 〉 8mg/kg, or melphalan 〉 180 mg/m2. Result: The characteristics of patients are summarized in Table 1. RIC was selected preferentially in patients with better status. The median follow-up of survivors was 64 months (3 - 171 months). There was no significant difference in 5-year overall survival (OS) among CP (124 cases), accelerated phase (AP) (23 cases) and blastic phase (BP) (53 cases) at diagnosis, 83%, 71% and 73%, respectively. In CP at diagnosis, 5-year OS was significantly higher in CP1 (89 cases) at HSCT than in CP2≤/AP/BP (35 cases) (89% versus 66%, p = 0.0004), and in CP1 at HSCT, there was no difference in 5-year OS between myeloablative conditioning (MAC) (58 cases) and RIC (31 cases) (both 89%) (Figure 1). However, 5-year OS in RIC was significantly higher in children (0-14 years old, 23 cases) than in AYA (15-29 years old, 8 cases) (95% versus 75%, p = 0.0495). Two of eight AYA patients with CP1 died after RIC HSCT due to grade IV acute GVHD-related complications without disease relapse, suggesting that the indications for RIC in AYA with CP1 should be carefully judged. In AP/BP at diagnosis, 5-year OS was significantly higher in the second chronic phase (CP2) (48 cases) at HSCT than in the third chronic phase (CP3)≤/AP/BP (28 cases) (82% versus 56%, p = 0.0073). However, the rate of major cytogenetic response (MCyR) at HSCT was significantly higher in CP2 than in CP3≤/AP/BP, and when focusing only on MCyR at HSCT in AP/BP at diagnosis, there was no difference in 5-year OS between CP2 at HSCT (40 cases) and CP3≤/AP/BP (13 cases) (83% versus 78%). On condition of MCyR at HSCT in AP/BP at diagnosis, regardless of the phase at HSCT, there was no difference in 5-year OS between MAC (46 cases) and RIC (7 cases: 2 in children and 5 in AYA) (79% versus 100%) (Figure 2), suggesting that even in AP/BP at diagnosis, RIC could be indicated for the patients with good response to TKI. On multivariate analysis, disease phase at HSCT and time from diagnosis to HSCT were independent predictors of OS in CP at diagnosis (Table 2), and cytogenetic response at HSCT and stem cell source in AP/BP at diagnosis (Table 3). There was no significant difference of OS between MAC and RIC. Conclusion: In HSCT for CML after TKI administration, the indications for RIC in children under 15 years old with CP1 are appropriate. In RIC HSCT for AYA patients under 30 years old with CP1, caution should be exercised in transplant-related mortality rather than disease progression. Furthermore, even in AP/BP at diagnosis, RIC could be indicated for children and AYA patients with MCyR at HSCT. Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis.: Honoraria.

Description: Background. For the purpose of increasing survival rate and minimizing early and late toxicities, we conducted a clinical study of an individualized treatment of AML in children between Jun/2002 and September/2014. Minimal residual disease (MRD)-based stratification was employed in this study, and patients in the high-risk group underwent allogeneic hematopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning (RIC). This study was following our previous studies of a basic research on MRD in 1990s, and an early multi-center study between Feb/1999 and May/2002 [Miyamura T, et al. IJH 79: 243-249, 2004]. Methods. The main eligibility criteria were as follows: children with newly diagnosed de novo AML (excluding FAB M3), and with written informed consent obtained by the patients' guardians and the patients if aged 16 years or more. The main exclusion criteria were children with organ failure, and with uncontrolled infections. The treatment consisted of one induction chemotherapy and 5 courses of consolidation chemotherapy originating from the AML99 protocol [Tsukimoto I, et al. JCO 27: 4007-4013, 2009]. Patients with Down syndrome were treated with a dose-reduced protocol. WT1 mRNA in PB, WT1 mRNA in BM, and chimeric-gene mRNA in BM were measured as MRD markers by quantitative RT-PCR. MRD was assessed at every hematopoietic recovery after course of chemotherapy. Patients were categorized into 5 groups: (a) non-complete remission (non-CR; blast cells 〉= 5% in BM) after the induction therapy, (b) MRD positive after 1st consolidation therapy, (c, d) MRD negative after 1st consolidation, and (e) patients without any MRD markers available. The patients whose MRD became negative after the 1st consolidation were divided into two: (c) reemerging MRD after 2nd consolidation or later, and (d) continuously negative for MRD. Patients in categories (a), (b) and (c) underwent allogeneic RIC-HSCT (with one exception of myeloablative conditioning (MAC)). HLA-haploidentical HSCT was performed for the patients in (a). MRD monitoring was finished with a negative result for MRD after the last course of consolidation in the group of (d). Results. Enrolled patient number was 35. A median age at diagnosis was 2 years old (range; 2 months - 20 years old). Three patients were stratified in the group of (a), 12 in (b), 4 in (c), 10 in (d), and 6 in (e). Eighteen patients (51.4%) underwent allogeneic HSCT. Five-year EFS (5y-EFS) was 77.9+/-7.4%, and 5y-OS was 86.0+/-6.6%, with 7.0 years of an median observation period (range; 0.7-12.6 years). Among non-Down syndrome patients (n = 29), 5y-EFS was 77.7+/-8.1%, and 5y-OS was 87.5+/-6.9%. RIC seemed to work, as resulted in a 5y-EFS 75.4+/-12.6% (2 relapses and 1 non-relapse mortality) and a 5y-OS 77.9+/-14.1% in all patients who underwent HSCT (excluding group (a)). Discussion. It has already reported that the AML99 protocol, which did not employ MRD-based stratification, resulted in a 5y-EFS 61.6% and a 5y-OS 75.6%. Although direct comparison of our presenting strategy and the AML99 protocol cannot be carried out mainly because ours was conducted one decade later and time-event data was missing in the AML99 report for log-rank test, our strategy may contribute to shortening the treatment period and increasing the 1st continuous CR rate. In addition, RIC potentially contributes to reducing late complications [Shimizu M, et al. BMT 47: 141-142, 2012]. In the AML99 study 18.1% (41/227) received allogeneic MAC-HSCT in 1st CR, and 32.2% relapsed in total [2]. Therefore, RIC-HSCT in the present study seems to be comparable with those of MAC-HSCT. Conclusion. Our strategy of MRD-based stratification and RIC-HSCT for childhood AML may provide a promising platform for further study. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4501 Background: Recently, HSCT has been widely used as a curative therapy for refractory hematological/malignant diseases. However, late complications after HSCT such as endocrine disorders, infertility, short stature and secondary cancers have been recognized as serious problems in children. Late complications are assumed to be much more serious in younger children, especially in infants. Therefore, we retrospectively evaluated late complications among patients who underwent HSCT before one-year-old age in our institute to clarify this big issue. Methods and results: We performed HSCT in 530 children from 1993 to 2009. Among these 530 patients, 33 were infants (younger than 1- year - old) at HSCT. 23 infants with malignant disorders consisted of neuroblastoma 10, hepatoblastoma 2, rhabdomyosarcoma 1, retinoblastoma 1, acute lymphoblastic leukemia 5, myelodysplastic syndrome 2, acute myelogenous leukemia 2, and 10 infants with non-malignant disorders consisted of immunodeficiency 5, familial hemophagocytic lymphohistiocytosis/hemophagocytic syndrome 2, congenital metabolic disorder 1, severe aplastic anemia 1, pure red cell aplasia 1 were included. 9 infants underwent autologous HSCT and 24 underwent allogeneic HSCT. 22 infants received MAC and 11 received reduced-intensity conditioning (RIC). 26 out of 33 patients have been alive (MAC, 18/22 = 81.8 %; RIC, 8/11 = 72.7 %). Body height (BH) of 5 patients in RIC group who have been surviving longer than 5 years after HSCT is equal or taller than -2 standard deviation (SD) of BH. However, BH of 6 out of 13 evaluable patients in MAC group remains shorter than -2 SD (the shortest, -5.3 SD) of BH. All survivors in MAC group are suffering from one or more late complications such as growth hormone secretion insufficiency, premature puberty, hypothyroidism, gonadal failure and secondary cancers, therefore, they needs treatment and support for these late complications. Conclusions: The survival rate is similar (81.8 % versus 72.7 %) between MAC and RIC in infants, however, infants who underwent MAC-HSCT are suffering from late complications much more frequently and need treatment and support. These results suggest that less toxic conditioning should be adopted for infants who undergo HSCT to avoid serious late complications. Disclosures: No relevant conflicts of interest to declare.

Description: Background Previous studies showed an association between iron overload and hematopoietic transplant complications. Serum ferritin is widely used as an indicator for iron stores and an elevated pretransplantation level was strongly associated with inferior outcomes of transplantation in adults, though it has not been clarified well in pediatric patients. We studied prognostic impact of pretransplantation elevated ferritin levels on outcomes of allo-HSCT for pediatric hematological diseases. Patients and Methods We studied 93 consecutive pediatric patients (〈 18 years old) with hematologic disease who underwent allogeneic HSCT at Osaka Medical Center and Research Institute for Maternal and Child Health between 2003 and 2009 in whom pretransplantation serum ferritin levels were available. The patients were divided into two groups, pretransplantation serum ferritin level ≥ 1000 ng/mL (SF≥1000) and ferritin level 〈 1000 ng/mL (SF

Description: X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (γc) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G〉A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.