ALBERT

Description: Introduction: Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells that harbor somatic GATA1 gene mutation. Although most patients show spontaneously resolution without therapeutic interventions, approximately 20% of TAM cases result in early deaths within 9 months and 20% of survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. Although the risk factors associated with early deaths are known, the definite clinical predictive indicators of AMKL onset in patients with TAM remain unclear. Therefore, we analyzed 167 TAM patients with DS enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) to determine the clinical characteristics of TAM and predictive factors of leukemia development. Patients and Methods: Between May 2011 and February 2014, 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study. Somatic GATA1 gene mutations were confirmed in 163 (98%) patients using Sanger and/or next-generation sequencing. Minimal residual disease using flow cytometry (FCM-MRD; cut-off level, ≥0.1%) was monitored at 1 (n = 133) and 3 months (n = 104). Results: Median (range) gestational age, birth body weight, white blood cell (WBC) count, and percentage of blasts at diagnosis were 37 (29-40) weeks, 2,612 (1,066-3714) g, 38.3 (2.4-478.7) × 109 cells/L, and 37% (0.5%-95.5%), respectively. Systemic edema and organ hemorrhage was observed in 31/167 (19%) and 14/167 (8%) patients, respectively; 68/167 (41%) patients received some therapeutic interventions, including low-dose cytarabine (LDCA; n = 52), exchange blood transfusion (n = 20), and systemic steroid therapy (n = 31). Early death (

Description: In the diagnosis of childhood bone marrow failures (BMFs), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, few studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMFs. To determine the clinical differences among AA, RCC, and RCMD, we compared clinical outcomes for patients with AA, RCC, and RCMD in Japan. From February 2009 to December 2013, 252 patients were registered to the central morphology review system of the Japanese Society of Hematology and Oncology and were diagnosed with BMFs. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. RCC is defined as persistent cytopenia with 10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with 2 cell lineages. Patients with inherited BMFs were excluded by family history and physical examination. Further, Fanconi anemia was excluded by chromosome fragility test　and Dyskeratosis congenita was screened by measuring the telomere length of the peripheral lymphocytes by flowcytometry. Out of 252 patients, 63 were classified as AA, 131 as RCC, and 58 as RCMD. Median ages in AA, RCC, and RCMD groups were 10, 8, and 7 years, respectively (p=0.07). The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p

Description: In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria of refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, no studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMF. The Japanese Society of Pediatric Hematology and Oncology has established a central review system of morphology. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry. RCC is defined as persistent cytopenia with 10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with 2 cell lineages. We classified childhood BMF into AA, RCC, and RCMD in our central review. From February 2009 to February 2015, 1,300 cases were prospectively reviewed. Of the 1,300 cases, 582 were classified as BMF. Among them, 99 were classified as AA, 230 as RCC, 128 as RCMD, 50 as hepatitis-related BMF, 4 as PNH, and 71 as inherited BMF. Of the 71 cases with inherited BMF, 35 were diagnosed as Fanconi anemia, 14 as Shwachman-Diamond syndrome, and 12 as dyskeratosis congenita. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical findings for 457 patients classified with AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 10, 9, and 7 years, respectively (p

Description: Introduction: Transient abnormal myelopoiesis (TAM) occurs in approximately 10% of infants with Down syndrome (DS). Although most patients achieve spontaneous remission, some develop severe organ failure and die in their infancy. Previous studies have identified several risk factors associated with early death in such cases, including a high white blood cell (WBC) count, early gestational age, and ascites (Massey GV, 2006; Muramatsu H, 2008; Klusmann JH, 2008). Although chemotherapy with low-dose cytosine arabinoside (LDCA) has been applied for severe cases, its side effect profile has not been fully demonstrated in an adequate number of patients. Here we prospectively analyzed 168 infants with DS who were diagnosed with TAM, including 52 patients treated with LDCA. We assessed the efficacy and safety of LDCA therapy in these cases. Patient and Methods: Between May 2011 and February 2014, 168 infants (90 boys and 78 girls) were diagnosed with TAM and prospectively registered in the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) TAM-10 study. GATA1 gene mutations were identified in all except 7 patients who had a very low blast percentage. The median (range) of WBC count was 38.6 (2.4-478.7) × 109 cells/L, and the median (range) of gestational age was 37 (29-40) weeks. Thirty one (18%) patients developed anasarca at diagnosis, and 23 (14%) patients developed acute megakaryocytic leukemia. Results: The overall survival (OS) rate and the event-free survival (EFS) rate at 1 year from diagnosis [95% confidential interval (CI)] were 86.3% (80.1-90.7), and 80.2% (73.2-85.5), respectively. Univariate analysis identified the following covariates as risk factors associated with early death (

Description: In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. In addition, inherited BMF (IBMF) should be excluded from acquired BMF. The 2008 WHO classification has proposed a provisional entitiy, “refractory cytopenia of childhood (RCC)”. The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) in adults. Currently, it is recommended that children who meet the criteria for RCMD should be considered as RCC in the WHO classification until the number of lineages involved have been fully evaluated with regard to their relative importance as prognostic factors in childhood MDS. To enable diagnosis based on the WHO classification, the Japanese Society of Pediatric Hematology and Oncology in February 2009 established a central review system of BM morphology, including peripheral blood (PB) and BM smears and specimens from trephine biopsies in childhood BMF. PB and BM smears were reviewed by two pediatric hematologists, and the specimens from BM trephine biopsies were reviewed by a pathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry for patients with BMF. RCC is defined as persistent cytopenia with 10% within one cell lineage. On the other hand, the criteria of RCMD in adult MDS is defined as persistent cytopenia with 2 cell lineages. We introduced the RCMD criteria in this central review. From February 2009 to October 2013, 1,000 cases including 536 males and 464 females were prospectively reviewed. The median age was six years (range, 0–39 years). Of the 1,000 cases, 575 were classified as BMF, and of them, 137 were classified as AA, 236 as RCC, 103 as RCMD, 38 as hepatitis-related BMF, 3 as PNH and 58 as IBMF. Of the 58 cases with IBMF, 21 were diagnosed as Fanconi anemia, 12 as Shwachman–Diamond syndrome, and 8 as dyskeratosis congenita. Seventeen patients suspected of IBMF were undiagnosed. In 97 advanced cases of MDS, 24 were classified as refractory anemia with excess blasts (RAEB), 6 as secondary MDS, and 21 as therapy-related MDS. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical data for 476 patients classified as AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 9, 8, and 7 years, respectively (p = 0.007). The male/female ratio in AA, RCC, and RCMD groups was 1.1, 1.2, and 3.6, respectively (p = 0.034). When patients were classified according to the disease severity criteria for AA, 78% of the patients with AA had very severe or severe disease, whereas only 38% of the patients with RCC and 28% of the patients with RCMD had very severe or severe disease (p 〈 0.001). Chromosomal abnormalities were detected in two patients (1%) with AA (trisomy 8), 10 patients (4%) with RCC (monosomy 7, n = 2; trisomy 8, n = 6; other, n = 2), and 12 patients (12%) with RCMD (monosomy 7, n = 5; trisomy 8, n = 2; other, n = 5) (p = 0.001). Out of the 476 patients, 67 (AA, n = 32; RCC, n = 32; RCMD, n = 3) were administered IST with rabbit antithymocyte globulin (ATG) and cyclosporine. After 6 months, the response rate to IST was not significantly different among the three groups; AA, 41%; RCC, 47%; RCMD, 100% (p = 0.142). In conclusion, the entity of RCMD should be applied to childhood MDS because patients with RCMD exhibited a significantly high frequency of chromosomal abnormalities at the time of diagnosis. To definitively determine whether these three diseases are different entities, it would be necessary to prospectively compare the clinical outcomes and biological findings in a larger number of patients with AA, RCC, and RCMD. Disclosures No relevant conflicts of interest to declare.

Description: Purpose It is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute leukemia including acute lymphoblastic leukemia (ALL). Even after refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study showed that age younger than 10 years was a factor of good prognosis; however, the details in children are unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory ALL. Patients and Methods The data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. In total, 325 patients with ALL younger than 21 years old when HSCT was performed between January 2001 and December 2015 and who harbored blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative regimens and reduced-intensity conditioning regimens were analyzed. Patients were classified as having poor-risk cytogenetics with either t(4;11), t(9;22), t(8;14), hypodiploidy or near triploidy, or more than 5 cytogenetic abnormalities. Other ALL cytogenetic findings were classified as other abnormalities or normal. Myeloablative conditioning was defined as total body irradiation (TBI) of 〉8 Gy and the administration of 8 mg/kg of busulfan (BU), 〉140 mg/m2 of melphalan, or 〉10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented. Results The median follow-up time of survivors was 1145 days (range 110-3710). The median age was 11 years. Thirty-five percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS of ≥90. The rate of pre-HSCT fungal infection was 14%. Fifty-nine patients had more than 25% marrow blasts when HSCT was performed. When HSCT was performed, 10%, 60%, and 30% of patients exhibited primary induction failure, first relapse, and second or later relapse, respectively. Ninety-one percent of patients had neutrophils and 67% exhibited platelet recovery by day 100. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) on day 100 was 43%. The cumulative incidence of chronic GVHD (cGVHD) at 3 years after HSCT was 19%. Two hundred and forty-seven patients died. The causes of death were leukemia progression (57%), followed by graft failure (11%), GVHD (10%), hemorrhage (6%), and infection (5%). The 3-year OS rate in all the patients was 22% (95% confidence interval (CI), 18-27). Age, white blood cell count at diagnosis, prior history of central nervous disease, disease status, conditioning regimens, donor-recipient human leukocyte antigen match, graft type, or year in which HSCT was performed did not affect the OS. Grade ≥2 aGVHD did not affect OS. Whereas Patients with chronic GVHD had better 3-year OS (49%, 95% CI 35-61%) compared to that in patients without chronic GVHD (22%, 95% CI 16-29%) (p = 0.001) (Figure 1). Multivariate analysis showed that other than cGVHD, low PS (relative risk (RR): 2.53), blasts in bone marrow greater than 25% (RR: 1.43), T cell phenotype (RR: 1.86), high-risk or normal cytogenetics (RR: 1.42), and a history of HSCT (RR: 1.90) were significant adverse pre-HSCT variables (Table 1). Patients who had 0 or 1 (n = 113), 2 (n = 113), and 3-5 pre-HSCT variables (n = 99) had 42% (95% CI, 32-51), 17% (95% CI, 10-25), and 6% (95% CI, 2-13) 3-year OS, respectively (Figure 2). Conclusion Some patients with refractory pediatric ALL achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. Disclosures No relevant conflicts of interest to declare.

Description: Background: Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) characterized by bone marrow failure and pancreatic insufficiency. Patients with SDS have propensity to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although it is the third most common IBMFS following Fanconi anemia and Diamond-Blackfan anemia in western countries, the incidence of SDS has been considered to be much lower in Japan. Patients and methods:In addition to the cases of SDS diagnosed by SBDSgene mutation analysis at Kyoto University, we captured those from the central review system of the Japanese Society of Pediatric Hematology and Oncology and the targeted sequencing system for IBMFS at Nagoya University as well as the previous Japanese nationwide survey for SDS that was conducted in 2010. Results:A total of 47 cases from 43 families with biallelic SBDSgene mutation were captured. After the previous nationwide survey, 21 cases were accumulated in the past 8 years: 2.6 cases per year in average. Median age at presentation is 0 year, and median age at diagnosis is two years. Male-female ratio of the patients was 2.1:1. Birth weight was less than 2500g in approximately half of the patients. Most common mutation was 183-184TA〉CT/258+2T〉C (73%) followed by 258+2T〉C/258+2T〉C (6.6%). Notably, a patient with heterozygous 258+2T〉C mutation was shown to have exon 3 deletion in the SBDS gene by whole exome sequencing. Clinical features at initial visit were various kinds of cytopenia, failure to thrive, steatorrhea, liver dysfunction, short stature, and skeletal abnormalities. Pancreatic insufficiency and/or pancreatic abnormality in imaging studies were found in almost all patients. Neutropenia was documented in one-third of the cases at initial visit; however, eventually 89% of the patients had neutropenia. Other hematological abnormalities were anemia (64%), thrombocytopenia (69%), and pancytopenia (40%). Bone marrow examination revealed hypoplasia (60%), dysplasia (36%), and chromosome abnormalities (23%) including del(20q), i(7q), and complex chromosome abnormalities. Four male patients (8.5%) of the cohort were documented to develop AML. Age at onset of AML was more than 18 years in three patients. Three patients complicated with AML and two patients with severe bone marrow failure underwent hematopoietic stem cell transplantation (HSCT). Interestingly, one patient with AML harboring normal karyotype is alive without relapse 20 years after HSCT. Three patients (6%) died; the cause of death was AML in two and complication of HSCT in one. Conclusion: Along with growing recognition of the disease among physicians and establishment of mutation analysis system, newly diagnosed cases of SDS were accumulated constantly. SDS may be more common than previously thought in our country. Clinical characteristics are similar to those that were reported in previous studies. As shown in a recent study on a large MDS cohort from an international registry of HSCT, patients with SDS may develop AML in adulthood and have very poor prognosis. The SDS cohort in Japan may provide a platform to investigate clinical and genetic factors associated with severity and phenotypes of the disease under a relatively uniform ethnic background. Disclosures No relevant conflicts of interest to declare.