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Background Langerhans cell histiocytosis (LCH) is a rare disease characterized by the various systems involved and clinical manifestations with a wide range of symptoms. Objectives To describe clinical characteristics, imaging, treatment, and outcomes of pediatric LCH at Phramongkutklao Hospital, Bangkok, Thailand. Methods We conducted a 20-year retrospective review of the medical records of patients diagnosed with LCH from birth to 21 years old from January 1, 1997, to December 31, 2016. Results In all, 14 patients with median age of 2.5 years were studied. Six (43%) patients had single-system (SS) LCH. Five patients (63%) with multisystem (MS) LCH (n = 8. 57%) had risk-organ involvement (RO+). All patients had plain X-ray imaging of their skull with 11 (79%) showing abnormal findings. Tc-99m bone imaging and fluorodeoxyglucose F18 (FDG) positron emission tomography (PET)-computed tomography (CT) demonstrated abnormal findings in 8 (89%) and 4 (29%) patients, respectively. The 5-year event-free survival (EFS) for patients with RO+ MS-LCH was less than that for those without risk-organ involvement (RO−) MS-LCH and SS-LCH (20% vs. 100%, P = 0.005). Hematological dysfunction, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH. Conclusion FDG-PET-CT might have a greater accuracy to detect LCH disease than conventional plain X-ray and Tc-99m bone imaging. RO+ MS-LCH has been encountered with relapse and poor outcomes. Hematopoietic involvement, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH.

Boonchai Boonyawat,1 Chalinee Monsereenusorn,2 Apichat Photia,2 Nawachai Lertvivatpong,2 Varissara Kaewchaivijit,3 Punyanuch Jindatanmanusan,2 Piya Rujkijyanont2 1Division of Medical Genetics, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand; 2Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand; 3Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, ThailandCorrespondence: Piya RujkijyanontDepartment of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, 315 Ratchawithi Road, Ratchathewi, Bangkok, 10400, ThailandTel/Fax +66 2 644 4130Email piya_rujk@yahoo.comBackground: Mercaptopurine is a key agent in childhood leukemia treatment. Genetic polymorphism in the genes involving thiopurine metabolisms is related to 6-MP related toxicity.Objective: This study aimed to determine the prevalence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms among Thai children diagnosed with leukemia and their association with mercaptopurine-related myelotoxicity.Methods: Patients and survivors with a diagnosis of leukemia treated with mercaptopurine-containing chemotherapy regimens were enrolled. Clinical data and laboratory parameters during treatment as well as ITPA:c.94C>A and NUDT15:c.415C>T genotypes were analyzed.Results: In all, 99 patients with acute leukemia or survivors were enrolled in the study. The prevalences of ITPA:c.94C>A, NUDT15:c.415C>T, and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms were 34, 17, and 4%, respectively. Numbers of absolute neutrophil count (ANC) and platelet count significantly decreased among patients carrying NUDT15:c.415C>T compared with NUDT15 wild type patients with p-values< 0.001 and 0.019, respectively. The differences were not observed among patients carrying ITPA:c.94C>A compared with ITPA wild type patients. According to multivariate GEE, NUDT15:c.415C>T and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T had a significant negative effect on ANC during treatment (coefficient: − 463.81; CI: − 778.53, − 149.09; p-value=0.004 and coefficient: − 527.56; CI: − 1045.65, − 9.48; p-value=0.046). No significant effect of ITPA:c.94C>A on ANC during treatment was observed.Conclusion: ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms are common among Thai children with leukemia. A strong association with mercaptopurine-related myelotoxicity was observed among patients carrying either NUDT15:c.415C>T alone or combined with ITPA:c.94C>A.Keywords: NUDT15, ITPA, 6-MP, myelotoxicity, pediatric oncology

Chalinee Monsereenusorn,1 Thitiyaporn Sricharoen,2 Piya Rujkijyanont,1 Detchvijitr Suwanpakdee,3 Apichat Photia,1 Nawachai Lertvivatpong,1 Chanchai Traivaree1 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, Thailand; 2Buayai Hospital, Nakhon Ratchasima, Thailand; 3Division of Infectious Disease, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, ThailandCorrespondence: Chalinee MonsereenusornDivision of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, 315 Ratchawithi Road, Ratchathewi, Bangkok, 10400, ThailandEmail chalinee_monsereenusorn@pedpmk.orgBackground: The most common complication among pediatric oncology patients is febrile neutropenia (FN). Invasive fungal disease (IFD) is suspected when fever persists > 4– 7 days after empirical antibiotics. Its clinical characteristics and predictive factors associated with IFD among pediatric oncology patients with FN were thus explored.Methods: Pediatric oncology patients with FN between January 1, 2012 and December 31, 2016 were enrolled in this study. Clinical characteristics, including laboratory investigations, treatment modalities, and final outcomes of IFD were retrospectively reviewed and analyzed.Results: In all, 73 patients with 180 episodes of confirmed diagnosis of FN were studied. Median age at diagnosis was 6.2 years, with equal sex distribution. The most common diagnosis was acute lymphoblastic leukemia (n=91, 51%), followed by acute myeloid leukemia (n=47, 26%), Burkitt’s lymphoma (n=7, 4%) and neuroblastoma (n=7, 4%). Median absolute neutrophil count at FN diagnosis was 0 (0– 806) cells/mm3. IFD was diagnosed for 25 (14%) episodes. Mortality rates for FN and IFD were 4% and 20%, respectively. Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results, and prolonged broad-spectrum antibiotic administration were factors associated with IFD (P< 0.05). Prolonged duration between initiation of fever and antifungal administration for nearly 10 days was an independent factor in prediction of IFD occurrence (P= 0.014).Conclusion: Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results and prolonged broad-spectrum antibiotic administration were factors associated with IFD. Duration between initiation of fever and antifungal administration of nearly 10 days were considered a risk factors of IFD among patients with FN.IRB Reference Number: IRBRTA 825/2560.Keywords: febrile neutropenia, invasive fungal disease, pediatric oncology, risk factors, mortality

Few epidemiological studies of pediatric central nervous system (CNS) tumors have been performed using data from Southeast Asian national registries. Therefore, we aimed to examine data on CNS tumors from the first national childhood CNS tumor registry in Thailand. Newly diagnosed children with benign and malignant primary CNS tumors from 20 nationwide hospitals were included. Two eras in the Thai registry were studied to compare national protocol effectiveness, including 2003–2005 (before establishment of a pediatric CNS tumor protocol) and 2011–2012 (post-establishment). The first study period had 300 patients with an incidence of 7.5/1,000,000 person-years and the second had 168 patients with an incidence of 13.24/1,000,000 person-years. The three most common tumors were gliomas, medulloblastoma/primitive neuroectodermal tumor (PNET), and germ cell tumors. The most common tumor site was the cerebellum, followed by the brainstem and pineal region. Five- and 10-year overall survival (OS) rates were 46.62% (95% confidence interval [CI] 40.85–52.18) and 41.78% (95% CI 36.11–47.34), respectively, for the first period. The second period had a 5-year OS of 64.75% (95% CI 56.70–71.68). OS rates for gliomas, germ cell tumors, medulloblastoma/PNET, and ependymomas were better in the second period than in the first period. The incidence of primary childhood CNS tumors in our study is lower compared with other reports. Improvement of OS in the second study period might be because of establishment of the Thai Pediatric Oncology Group, and national protocols for childhood CNS tumors.

Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.

BACKGROUND Although congenital infantile fibrosarcoma (cIFS) is a rare soft tissue sarcoma among children, it constitutes one of the most common soft tissue sarcomas during the first year of life. Congenital mesoblastic nephroma (CMN) is the most common benign renal tumor usually developing during the first 3 months of life. cIFS and cellular type CMN (cCMN) share not only similar histopathologic features but identical molecular genetic abnormality including the ETV6/NTRK3 fusion gene. Here, we report an unusual case of cIFS occurring with cCMN. CASE PRESENTATION An 18-month-old girl presented with a 1-month history of abdominal distension and a few days' history of a palpable abdominal mass. A large heterogenous mass sized 9.0×11.2×11.6 cm on the right side of the abdomen and an isolated heterogenous lesion sized 4×4.5 cm within the right kidney were noted from the imaging study. Pathologic findings were consistent with cIFS and cCMN of the right kidney. In addition, both pathologic specimens contained the ETV6/NTRK3 fusion gene. CONCLUSION Although cIFS and cCMN share similar histopathologic features and molecular genetic abnormality, simultaneous occurrence of these 2 types of tumor is exceedingly rare. To our knowledge, this is the first unusual case report of concurrent cIFS and cCMN.

Hepatitis B is a major global health concern and can be prevented in the era of vaccination. Impaired immunological memory to primary immunization is a common chemotherapy-related complication among cancer survivors. The study aimed to determine protective immunity against hepatitis B virus (HBV) and anamnestic response to booster vaccination. In all, 107 pediatric cancer survivors previously immunized with primary hepatitis B vaccination were enrolled. A hepatitis B booster dose was administered to those with suboptimal seroprotection (anti-HBs

Early recognition and management are the key elements to prevent febrile neutropenia associated mortality. The prospective observational study aimed to investigate prognostic accuracy of serum lactate to predict septic shock within 48 hours among hemodynamically stable children with febrile neutropenia. In all, 99 pediatric oncology patients who developed febrile neutropenia were enrolled in the study. Clinical information during 48 hours and serum lactate at the time of enrollment were analyzed. Among 99 participating patients, 10 developed septic shock and 4 of those expired. No significant difference was found of patients’ baseline characteristics and basic laboratory parameters between patients with and without septic shock. Serum lactate was significantly elevated among patients developing septic shock ( P-value

Background Chemotherapy-induced nausea and vomiting (CINV) is a common complication in cancer treatment. Ondansetron is an effective antiemetic drug widely used to prevent CINV; however, the effective administrative dosing strategies among pediatrics remain unclear. The study aimed to investigate clinical effectiveness of single daily dosing versus divided dosing ondansetron. Methods In all, 194 children undergoing chemotherapy were randomized to receive either single daily dosing (0.3 mg/kg/dose) or divided dosing (0.15 mg/kg/dose every 8 hours) intravenous ondansetron for 24 hours. Clinical parameters including number of emesis episodes, nausea scores, appetite levels, parent's satisfaction, and adverse effects within 24 hours were analyzed. Results No significant differences were found between the two dosing strategies concerning number of emesis episodes and parent's satisfaction. However, nonleukemic hematologic malignancies and concurrent administration of intrathecal methotrexate-hydrocortisone-cytarabine (IT-MHA) were associated with increased risk of acute-phase vomiting. Interestingly, none of the patients aged under 7 years, receiving divided dosing ondansetron, presented nausea symptoms compared with those receiving single daily dosing (p-value .034). No significant differences regarding headache were observed between the two dosing strategies and none of the patients experienced QTc prolongation. Conclusion Ondansetron administered as divided dosing should be considered among children aged under 7 years to prevent chemotherapy-induced nausea and among patients receiving low emetogenic chemotherapy to maintain their appetite. Both administrative dosing strategies were well tolerated with no significant adverse effects.

Chanchai Traivaree,1 Napakjira Likasitthananon,2 Chalinee Monsereenusorn,1 Piya Rujkijyanont1 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand; 2Department of Pediatrics, Lat Krabang Hospital, Bangkok, Thailand Background: High-dose methotrexate (HD-MTX) is widely used as a standard chemotherapeutic agent in pediatric cancers. Most research studies have confirmed the therapeutic efficacy of HD-MTX; however, strategies to prevent side effects vary among institutions, especially in developing countries, with limited monitoring of plasma methotrexate level.Objective: To evaluate the effect of intravenous hydration during HD-MTX administration on plasma methotrexate clearance in pediatric oncology patients.Materials and methods: This study retrospectively reviewed 165 courses of HD-MTX administered to children with acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), or osteosarcoma. Demographic data of patients were collected. Adverse complications related to HD-MTX and 72-hour plasma methotrexate level were analyzed between patients receiving intravenous hydration ≥3,000 mL/m2/day and those receiving hydration

Background Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients. Methods Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients. Results In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function. Conclusion The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.

Background. Thalassemia is a common congenital hemolytic disorder. In severe cases, regular blood transfusion is essentially required. The role of premedications to prevent transfusion reactions is varied among institutions with no standard guideline.Objective. To prospectively compare the risk of transfusion reactions in thalassemia patients premedicated with acetaminophen and chlorpheniramine maleate (CPM) versus placebo prior to blood transfusion.Material and Method. A randomized, double-blinded, placebo-controlled transfusion reaction study of 147 eligible patients was analyzed. All administered red blood cell (RBC) products were leukoreduced blood products. Patients were monitored and followed for the development of transfusion reactions for 24 hours after RBC transfusion.Results. A total of 73 patients randomized to receive active drugs consisting of acetaminophen and CPM were compared to 74 patients receiving placebo. The overall incidences of febrile reaction and urticarial rash were 6.9% and 22% in the patients randomized to receive active drugs comparing with 9.5% and 35.2% in the patients receiving placebo with no significant differences between two groups. However, delayed development of urticarial rash at 4-24 hours after RBC transfusion was significantly higher in female and patients receiving placebo.Conclusion. Administration of premedications in thalassemia patients receiving RBC transfusion without a history of transfusion reactions does not decrease the overall risk of transfusion reactions. However, the use of CPM might be beneficial to prevent delayed urticarial rash in those patients especially in females (Thai Clinical Trial Registry (TCTR) study ID:20140526001).

Chanchai Traivaree,1 Chalinee Monsereenusorn,1 Piya Rujkijyanont,1 Warakorn Prasertsin,2 Boonchai Boonyawat3 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand; 2Department of Pediatrics, Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand; 3Division of Genetics, Department of Pediatrics, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand Introduction: Beta-thalassemia is a group of inherited hemolytic anemias and one of the most common genetic disorders in Thailand. The clinical spectrum of beta-thalassemia disease ranges from mild to severe clinical symptoms including mild beta-thalassemia intermedia (TI) and severe beta-thalassemia major (TM). Objective: This study aimed to determine the correlation between beta-globin gene (HBB) mutations and their phenotypic manifestations by evaluating patients’ clinical characteristics, transfusion requirements, growth and hematologic parameters, and hemoglobin typing among pediatric patients treated at Phramongkutklao Hospital. Materials and methods: Seventy beta-thalassemia patients, including 63 with beta-thalassemia/hemoglobin E (HbE) and 7 with either homozygous or compound heterozygous beta-thalassemia, were enrolled in this study. Their clinical presentation, growth parameters and laboratory findings were reviewed and analyzed. The mean follow-up time was 10.52±5.62 years. Mutation analysis in each individual was performed using multiplex amplification refractory mutation system (M-ARMS), direct DNA sequencing of beta-globin gene and gap PCR for 3.4 kb deletion detection. Results: All 7 homozygous and compound heterozygous beta-thalassemia patients were classified in TM. Among 63 patients with beta-thalassemia/HbE, 58 were classified in TM and 4 were classified in TI. Mean age at diagnosis was 0.8±0.49 years for homozygous or compound heterozygous beta-thalassemia and 3.43±3.5 years for beta-thalassemia/HbE. The most common HBB mutation was HBB:c.126_129delCTTT [codon 41/42 (-TCTT)] found in 34 alleles (48.6%). The height for age was also lower in homozygous beta-thalassemia patients (

Chanchai Traivaree,1,* Boonchai Boonyawat,2,* Chalinee Monsereenusorn,1 Piya Rujkijyanont,1 Apichat Photia1 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand; 2Division of Genetics, Department of Pediatrics, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand *These authors contributed equally to this work Background: α-Thalassemia, one of the major thalassemia types in Thailand, is caused by either deletion or non-deletional mutation of one or both α-globin genes. Inactivation of three α-globin genes causes hemoglobin H (Hb H) disease, and the combination of Hb H disease with heterozygous hemoglobin E (Hb E) results in AE Bart’s disease. Objective: This study aimed to characterize the clinical and hematological manifestations of 76 pediatric patients with Hb H and AE Bart’s diseases treated at Phramongkutklao Hospital, a tertiary care center for thalassemia patients in central Thailand.Patients and methods: Seventy-six unrelated pediatric patients, 58 patients with Hb H disease and 18 patients with AE Bart’s disease, were enrolled in this study. Their clinical presentations, transfusion requirement, laboratory findings, and mutation analysis were retrospectively reviewed and analyzed.Results: A total of 76 pediatric patients with Hb H and AE Bart’s diseases who mainly lived in central Thailand were included in this study. The clinical severities of patients with non-deletional mutations were more severe than those with deletional mutations. Eighty-six percent of patients with non-deletional AE Bart’s disease required more blood transfusion compared to 12.5% of patients with deletional AE Bart’s disease. Non-deletional AE Bart’s disease also had a history of urgent blood transfusion with the average of 6±0.9 times compared to 1±0.3 times in patients with deletional Hb H disease. The difference was statistically significant.Conclusion: This study revealed the differences in clinical spectrum between patients with Hb H disease and those with AE Bart’s disease in central Thailand. The differentiation of α-thalassemia is essential for appropriate management of patients. The molecular diagnosis is useful for diagnostic confirmation and genotype–phenotype correlation. Keywords: genotype, phenotype, Hb H disease, AE Bart’s disease, Thai children

Thalassemia free survival after allogeneic stem cell transplantation (SCT) is about 80–90% with either matched related or unrelated donors. However, the probability of finding a HLA-compatible donor is less than 50%. We explored the use of a mismatched related (“Haplo-”) donor. All patients received two courses of pre-transplant immunosuppression therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm) to facilitate engraftment. After two courses of PTIS, a reduced-toxicity conditioning regimen of rabbit anti-thymocyte globulin (ATG), Flu, and IV Busulfan (Bu) was given followed by T-cell replete peripheral blood progenitor cells (PBPC). GVHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (Post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was ten years (range, 2 to 20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two of three patients with high titers of donor-specific anti-HLA antibodies suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11 to 18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GVHD grade II, that quickly responded to steroid therapy. Only five patients developed limited chronic GVHD. Projected overall and event-free survival rates at two years are 95% and 94%, respectively. The median follow up time is 12 months (range; 7 to 33 months). This haplo-SCT protocol may yield excellent outcomes for thalassemia patients, and provide a treatment option for patients lacking a HLA-matched donor.

Cholangiocarcinoma is extremely rare in childhood and has been reported in association with other underlying diseases. The survival and prognosis are dismal especially in patients with unresectable or advanced stage cholangiocarcinoma. Overall survival in patients with metastatic cholangiocarcinoma could be increased by using combination chemotherapy with cisplatin and gemcitabine. A case of childhood cholangiocarcinoma was hereby reported.

Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high–risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.

Purpose Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. Patients and Methods All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. Results Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R245) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C245). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R245–positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C245 homozygous graft. Conclusion Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.

Patients with class 3 thalassemia with high-risk features for adverse events after high-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) are difficult to treat, tending to either suffer serious toxicity or fail to establish stable graft function. We performed HSCT in 18 such patients age ≥7 years and hepatomegaly using a novel approach with pretransplant immunosuppression followed by a myeloablative reduced-toxicity conditioning regimen (fludarabine and i.v. busulfan [Flu-IV Bu]) and then HSCT. The median patient age was 14 years (range, 10 to 18 years). Before the Flu-IV Bu + antithymocyte globulin conditioning regimen, all patients received 1 to 2 cycles of pretransplant immunosuppression with fludarabine and dexamethasone. Thirteen patients received a related donor graft, and 5 received an unrelated donor graft. An initial prompt engraftment of donor cells with full donor chimerism was observed in all 18 patients, but 2 patients developed secondary mixed chimerism that necessitated withdrawal of immunosuppression to achieve full donor chimerism. Two patients (11%) had acute grade III-IV graft-versus-host disease, and 5 patients had limited chronic graft-versus-host disease. The only treatment-related mortality was from infection, and with a median follow-up of 42 months (range, 4 to 75), the 5-year overall survival and thalassemia-free survival were 89%. We conclude that this novel sequential immunoablative pretransplantation conditioning program is safe and effective for patients with high-risk class 3 thalassemia exhibiting additional comorbidities.

Background aims Peripheral blood stem cells (PBSC) are increasingly used as an alternative to bone marrow in autologous transplantations. In adult patients, the peripheral blood CD34 + cell count is a good predictor of CD34 + cell yield in apheresis. However, the determinants of stem cell yield in the pediatric population have not been well established. Methods We retrospectively studied 396 apheresis procedures in 301 pediatric patients. Receiver operating characteristic (ROC) curves based on pre-apheresis peripheral blood CD34 + cell counts were generated to facilitate prediction of the optimal timing of PBSC collection. The associations between CD34 + cell yield and age and mobilization regimen were analyzed. Results Significant differences in CD34 + cell yield among different age groups were observed. Furthermore, higher CD34 + cell yields were obtained in patients receiving chemotherapy as part of the mobilization regimen than those without chemotherapy. A correlation was noted between the CD34 + cell yield and blood surrogate markers, including white blood cell count, absolute neutrophil count and pre-apheresis peripheral blood CD34 + cell count. Cut-off values of >35 CD34 + cells/μL in patients 45 CD34 + cells/μL in patients ≥15 years old were strong predictors of an adequate PBSC collection in one apheresis session. For clinical use, ROC curves and tables were generated to assist advance planning for PBSC collection. Conclusions The pre-apheresis peripheral blood CD34 + cell count is most useful in predicting PBSC yield. Our new cut-off values have better operating characteristics for children than the conventional value of 20 CD34 + cells/μL used for adults.

Bone marrow angiogenesis is increased in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but has not been studied in inherited or acquired marrow failure syndromes. Shwachman-Diamond syndrome (SDS) carries a high risk of MDS/AML and is characterised by marrow stromal dysfunction. Compared with controls, SDS patients without MDS/AML had higher marrow microvessel density. Stromal VEGF gene expression, stromal vascular endothelial growth factor (VEGF) secretion and VEGF levels in serum and marrow mononuclear cells were normal. Future studies should investigate the mechanism for increased angiogenesis in SDS, and whether SDS marrow, with its increased angiogenesis, promotes progression of malignant clones.