Gemtuzumab Ozogamicin (MylotargⓇ) as a Single Consolidation Therapy in Relapsed Pediatric Acute Myeloid Leukemia Patient: a Patient Who Refused Transfusion and Stem Cell Transplantation for Religious Belief

Despite improvement of long-term survival rate in pediatric acute myeloid leukemia (AML) during the last two decades, relapse/refractory disease remains a major obstacle to further improvement of prognosis. Moreover, there are only few therapeutic options which stimulate investigations for targeted, less toxic therapy. Gemtuzumab ozogamicin (GO, MylotargⓇ) is an anti-CD33 monoclonal antibody and there are ongoing studies evaluating safety and efficacy of this drug in relapsed/refractory AML patients. Still, the response rate is only 30% and the response does not last more than a year. We present a case of pediatric central nervous system relapsed AML who was treated with GO as a single consolidation therapy without stem cell transplantation because of religious belief and maintained CR status for more than 3 years.ope

Clinical Outcome of Relapsed or Refractory Burkitt Lymphoma and Mature B-Cell Lymphoblastic Leukemia in Children and Adolescents

PURPOSE: Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients. MATERIALS AND METHODS: RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed. RESULTS: Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05). CONCLUSION: Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.ope

Reproductive, Obstetric and Neonatal Outcomes in Women with Congenital Uterine Anomalies: A Systematic Review and Meta-Analysis

Congenital uterine anomalies (CUA) may influence reproductive performance, resulting in adverse pregnancy associated complications. This study aimed to assess the association of CUA subtypes with reproductive, obstetric, and perinatal outcomes. We performed a systematic search of the MEDLINE, EMBASE, and Cochrane libraries for studies comparing pregnancy outcomes between women with CUA and those with a normal uterus. The random effects model was used to estimate the odds ratios (ORs) with a 95% confidence interval (CI). Women with CUA had a lower rate of live births (OR 0.47; 95% CI 0.33-0.69), and a higher rate of first trimester miscarriage (OR, 1.79; 95% CI 1.34-2.4), second trimester miscarriage (OR 2.92; 95% CI 1.35-6.32), preterm birth (OR 2.98; 95% CI 2.43-3.65), malpresentation (OR 9.1; 95% CI 5.88-14.08), cesarean section (OR 2.87; 95% CI 1.56-5.26), and placental abruption (OR 3.12; 95% CI 1.58-6.18). Women with canalization defects appear to have the poorest reproductive performance during early pregnancy. However, unification defects were associated with obstetric and neonatal outcomes throughout the course of pregnancy. It may be beneficial for clinicians to advise on potential complications that may be increased depending on the type and severity of CUA.ope

Pneumococcal Sepsis 8 Years after Splenectomy for Chronic Immune Thrombocytopenia: A Case of Vaccinated 12-year-old Patient

Splenectomy is a safe and effective procedure in the refractory or chronic immune thrombocytopenia (ITP) patients. Overwhelming post-splenectomy infection (OPSI) is rare but fatal. The lifetime risk of post-splenectomy patients to develop an OPSI with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae or Neisseria meningitidis) is about 1-5% and the mortality is reported more than 50% in 48 hours. Though vaccination against encapsulated bacteria cannot prevent all infection, vaccination is essential for the patients. We report a case of OPSI in a 12-year-old post-splenectomy boy who was vaccinated pneumococcal polysaccharide 7-valent against pneumococcus (Streptococcus pneumoniae) 2 months before splenectomy.ope

Lower Diagnostic Value of Bone Marrow Biopsy in Children with Fever of an Unknown Origin

Background: Diagnostic value of Bone marrow (BM) biopsies for fever of unknown origin (FUO) remain controversial and BM biopsies are difficult to perform in young patients. Our study aimed to elucidate the diagnostic yield of BM biopsies in FUO patients of all age, particularly for diagnosing hematological malignant diseases. Methods: The medical records of 150 patients, hospitalized between January 1, 2008 and June 30, 2013, who underwent BM biopsies were evaluated to determine the cause of FUO. FUO was defined as fever (38.3℃, 101℉) either on several occasions during the 3 hospital days without a clear cause, after 1 week of invasive investigation, or after 3 outpatient visits. BM-specific diagnoses included those determined by BM biopsies (i.e., leukemia, lymphoma, myeloproliferative disease, myelodysplastic syndrome, aplastic anemia, and hemophagocytic lymphohistiocytosis). Results: The final diagnoses of 24 patients (16%) were determined by BM biopsies; the majority included hematologic diseases and malignant neoplasms. Low hemoglobin levels, thrombocytopenia, bicytopenia, increased Lactate dehydrogenase (LDH) and ferritin levels, and ultrasonographic/computed tomographic abnormalities were significant risk factors (P＜0.05). The young patient group (＜18 years old) was safer from the tendency of BM biopsy diagnosis compared to adult patient group (＞40 years old). Conclusion: Some laboratory abnormalities were related to the BM biopsy diagnostic yield. Furthermore, pediatric age was an important factor for deciding to do not perform excessive BM biopsies in FUO cases.ope

Prevalence and Clinical Implication of Partial Tandem Duplication of the Mixed Lineage Leukemia Gene in Pediatric Acute Leukemia

Background: The mixed lineage leukemia (MLL) gene may induce hematopoiesis and leukemia. Partial tandem duplication of MLL (MLL-PTD) is associated with poor prog-nosis in acute myeloid leukemia (AML); however, the significance of MLL-PTD in acute lymphoblastic leukemia (ALL) has not been thoroughly studied. We evaluated the in-cidence, relationship with other cytogenetic abnormalities, and the prognostic role of MLL-PTD in ALL.Methods: We reviewed medical records from pediatric patients diagnosed with ALL in Severance Hospital, Yonsei University Health System, South Korea from 2002 to 2008. MLL-PTD was detected by nested reverse transcriptase polymerase chain reaction.Results: In ALL patients, 50.0% (42/84) were positive for MLL-PTD. There was no sig-nificant difference in the 10-year overall survival (10Y OS) and event-free survival (EFS) between MLL-PTD-positive (+) and MLL-PTD-negative (–) groups (69.4% vs. 76.2%, P=0.609, and 62.6% vs. 66.7%, P=0.818, respectively). The combination of high level of lactate dehydrogenase (＞1,100 IU/L) and MLL-PTD(+) [MLL-PTD(+)/High LDH] was a statistically significant negative prognostic factor for 10Y OS and EFS (P=0.0226 and P=0.0230, respectively). In multivariate analysis, National Cancer Institute risk strat-ification and very high risk features were independent significant prognostic factors but MLL-PTD (+)/High LDH was not.Conclusion: MLL-PTD was observed frequently in pediatric ALL patients. MLL-PTD was not an independent prognostic factor. MLL-PTD (+)/High LDH should be evaluated fur-ther for its prognostic potential in ALL.ope

Role of Cyclosporine A in Pediatric Patients with Refractory Chronic Idiopathic Thrombocytopenic Purpura

Purpose: Since the treatment of chronic idiopathic thrombocytopenic purpura (ITP) remains unsatisfactory in patients refractory to standard therapy, alternative therapies such as splenectomy, danazol, rituximab and cyclosporine A (CsA) are being considered as recently. The efficacy and safety of CsA has already been proved to adult patients with chronic ITP, however, there was no previous study in pediatric patients. The purpose of this study was to evaluate the efficacy and side effect of CsA in pediatric chronic ITP patients. Methods: We reviewed medical records of nine steroid refractory chronic ITP patients diagnosed as chronic ITP who were treated with CsA during 2007 and 2009 retrospectively. Results: All nine patients received standard treatment of intravenous immunoglobulin G and steroid before receiving CsA. Average time duration to start CsA from diagnosis was 52 months. Three children (33%) showed more than partial response maintaining platelet count over 50×109/L, the other six patients did not show any effect. There were no remarkable toxicities other than mild chest discomfort and headache in two patients. Conclusion: CsA therapy is considered as a safe and effective treatment option in adult chronic ITP patients recently, however, there is nearly no study in pediatric patients only with few case reports. In this study only small portion of patients showed response to CsA. Since it was a small sized study with short term follow up, long term follow up with larger patient number is required to make conclusionope

t(12;17)(p13;q12)/TAF15-ZNF384 Rearrangement in Acute Lymphoblastic Leukemia

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Increasing and Worsening Late Effects in Childhood Cancer Survivors during Follow-up

Recent advances in childhood cancer treatment have increased survival rates to 80%. Two out of three survivors experience late effects (LEs). From a group of 241 survivors previously described, 193 were followed at the long-term follow-up clinic (LTFC) of Severance Hospital in Korea; the presence of LEs was confirmed by oncologists. We reported the change in LEs during 3 yr of follow-up. The median follow-up from diagnosis was 10.4 yr (5.1-26.2 yr). Among 193 survivors, the percentage of patients with at least one LE increased from 63.2% at the initial visit to 75.1% at the most recent visit (P = 0.011). The proportion of patients having multiple LEs and grade 2 or higher LEs increased from the initial visit (P = 0.001 respectively). Forty-eight non-responders to the LTFC were older and had less frequent and severe LEs than responders at initial visit (all P < 0.05). In multivariate analysis, younger age at diagnosis, older age at initial visit, a diagnosis of a brain tumor or lymphoma, and use of radiotherapy were significant risk factors for LEs (all P < 0.05). Adverse changes in LEs were seen among the survivors, regardless of most clinical risk factors. They need to receive comprehensive, long-term follow up.ope

Aberrant DNA Methylation of CDH1, p16 and DAPK in Childhood Acute Lymphoblastic Leukemia

Background: Hypermethylation of tumor suppressor gene has been reported in various types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. Methods: To evaluate the methylation status at initial diagnosis and morphologic complete remission (CR) period in childhood acute lymphoblastic leukemia (ALL), we analyzed the methylation status of three key genes (CDH1, p16 and DAPK) in 43 childhood ALL patients and 7 healthy bone marrow (BM) donors. Results: CDH1 was methylated in 26 (60.4%) patients, p16 in two (4.6%) patients and DAPK in six (13.9%) patients at the time of diagnosis. Twenty nine (67.4%) patients had methylation of at least one gene. None of the healthy BM donors showed methylation of the above genes. Age was the only factor which showed significant association with the presence of DNA methylation (P=0.03). None of the other clinicopathological factors showed association with initial methylation status. At the time of morphologic CR, all patients who had aberrant DNA methylation at the time of diagnosis had no detectable residual methylation. Conclusion: Since hypermethylation was found in around two thirds of pretreatment ALL patients and none in healthy BM donor, we suggest hypermethylation of some important genes is a biologic marker of childhood ALL. We recommend that further studies with a large number of patients should be conducted.ope