Hemoglobin H Disease and Growth: A Comparative Study of DHbH and NDHbH Patients.

Background: Hemoglobin H disease (HbH), a hemoglobinopathy resulting from abnormal alpha globin genes, is classified into two categories: deletional HbH (DHbH) and non-deletional HbH (NDHbH). The alpha-mutation genotypes exhibit a range of clinical anemias, which differentially impact patient growth. Objectives: This retrospective study assessed the growth of HbH patients at Siriraj Hospital, Mahidol University. Methods: Patients diagnosed with HbH between January 2005 and April 2021 were analyzed using growth standard scores of the Thai Society for Pediatric Endocrinology (2022 version) and BMI-for-age Z scores of the World Health Organization. Growth failure was defined as a patient's height for age exceeding two standard deviations below the mean. Results: Of the 145 HbH patients, 75 (51.7%) had NDHbH, with --SEA/αCSα being the most common genotype (70 patients; 93.3%). The mean baseline hemoglobin level was significantly lower in NDHbH patients than in DHbH patients (8.16 ± 0.93 g/dL vs. 9.51 ± 0.68 g/dL; P < 0.001). Splenomegaly and growth failure prevalences were higher in NDHbH patients (37.3% vs. 0%, with P < 0.001, and 22.7% vs. 8.6%, with P = 0.020, respectively). Multivariable analysis revealed splenomegaly > 3 cm was associated with growth failure (OR = 4.28; 95% CI, 1.19-15.39; P = 0.026). Conclusions: NDHbH patients exhibited lower hemoglobin levels and more pronounced splenomegaly than DHbH patients. Growth failure can occur in both HbH types but appears more prevalent in NDHbH. Close monitoring of growth velocity is essential, and early treatment interventions may be required to prevent growth failure.

ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia.

Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016). Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.

Outcomes of Overt and Non-overt Disseminated Intravascular Coagulation Using the ISTH DIC Scoring System in Children: A Single-Center Study.

Background: Several disseminated intravascular coagulation (DIC) scoring systems are used for prognosticating the clinical outcomes of patients with DIC. However, research on children is scarce. Therefore, this study compared the clinical outcomes of overt and non-overt DIC using the International Society on Thrombosis and Hemostasis (ISTH) DIC scoring system. Methods: This retrospective study reviewed data on children aged one month to 15 years diagnosed with DIC between 2003 and 2014. Results: Of 244 patients, 179 (73.4%) had overt DIC, and 65 (26.6%) had non-overt DIC. The most common causes were infection (84.8%), tissue injury (7%), and malignancies (2.9%). The 28-day case fatality rate was significantly higher for overt than non-overt DIC (76% vs. 15.6%; P < 0.001). DIC scores were significantly associated with mortality (R2 = 0.89). Each clinical parameter (platelet count, prothrombin time, and fibrin degradation products) was associated with mortality (P = 0.01). On multivariable analysis, the factors associated with death were platelet counts ≤ 50 000 cells/mm3 (OR, 2.42; 95% CI, 1.08-5.42; P = 0.031); overt DIC score (OR, 7.62; 95% CI, 2.94-19.75; P < 0.001); renal dysfunction (OR, 2.92; 95% CI, 1.34-6.37; P = 0.007); shock (OR, 39.62; 95% CI, 4.99-314.84; P = 0.001); and acute respiratory distress syndrome (OR, 25.90; 95% CI, 3.12-214.80; P = 0.003). Conclusions: The 28-day case-fatality rate was significantly higher for patients with overt than non-overt DIC and concordant with ISTH scores. ISTH DIC scores can be used as a clinical predictor for DIC in children.

Ototoxicity and long-term hearing outcome in pediatric patients receiving cisplatin.

BACKGROUND: Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment. METHODS: A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss. RESULTS: In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > . CONCLUSIONS: The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.

A Comparison of the Clinical Outcomes of Haploidentical Transplantation and Other Graft Sources in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Most likely due to the availability of potential stem cell sources, there appears to be a growing usage of haploidentical (haplo) donors for cases of acute lymphoblastic leukemia involving high-risk features or relapse. PATIENTS AND METHODS: This study compared the outcomes of stem cell transplantations (SCTs) using haplo and other stem cell sources, namely, matched sibling donors (MSDs), matched unrelated donors (MUDs), and cord blood transplantations (CBTs). Literature searches were conducted of the MEDLINE and Embase databases from inception to December 2020. RESULTS: Twenty-eight studies were examined (17 retrospective and 11 prospective). There were no significant differences in the overall survival of haplo and those of the other stem-cell sources. For haplo versus matched donor (MSD or MUD), the pooled odds ratio (OR) was 0.94 (95% CI, 0.79-1.12; I2, 22%); while for haplo versus CBT, the OR was 1.24 (95% CI, 0.78-1.96; I2, 28%). The cumulative relapse incidence was significantly higher for MSD than haplo (OR, 0.69; 95% CI, 0.48-0.99; I2, 48%). Both grade II-IV acute and long-term graft-versus-host disease (GVHD) were significantly higher for haplo than MSD (OR, 1.78; 95% CI, 1.15-2.74; I2, 28%; and OR, 1.33; 95% CI, 1.00-1.77; I2, 14%, respectively). The other clinical outcomes did not demonstrate any statistical differences. CONCLUSION: The outcomes of patients treated with haplo-SCT appear comparable with those of the SCTs using other sources. The higher probability of developing GVHD supports the need for a novel method to harness T-cell alloreactivity.

Long-Term Effectiveness, Safety, and Tolerability of Twice-Daily Dosing with Deferasirox in Children with Transfusion-Dependent Thalassemias Unresponsive to Standard Once-Daily Dosing.

BACKGROUND: Patients with transfusion-dependent thalassemia (TDT) risk iron overload and require iron chelation therapy. Second-line therapy is warranted for patients demonstrating poor chelation responses. PATIENTS AND METHODS: We retrospectively studied the serum-ferritin (SF), and liver-iron-concentration (LIC) outcomes of patients with TDT treated with twice-daily dosing of deferasirox (TDD-DFX) > 24 months, after failing to respond to once-daily deferasirox (OD-DFX). RESULTS: We enrolled 22 OD-DFX nonresponders (14 males and eight females; median age, 9.2 [3-15.5] years). The median blood transfusion was 216 (206-277) ml/kg/year. The median TDD-DFX treatment period was 30 (24-35) months. Before initiating TDD-DFX, the median SF level was 2,486 (1,562-8,183) ng/ml, while the median LIC was 6.6 (3.2-19) mg/g dry wt. There were 18 TDD-DFX responders (81.8%) and 4 TDD-DFX nonresponders. The median SF-level change was -724 (-4,916 to 1,490) ng/mL. The median LIC change was -2.14 (-13.7 to 6.8) mg/g dry wt. The 1-year and 2-year SF levels and LICs were statistically significant (SF, P = 0.006/0.005; and LIC, 0.006/0.005, respectively). There were no treatment interruptions secondary to adverse events. In the follow-up of the TDD-DFX responder group, 11 of the 18 had a reduced dose, whereas the remaining seven continued with the same dose. CONCLUSIONS: TDD-DFX appears to be an alternative treatment approach for patients refractory to OD-DFX, with a favorable long-term safety profile. Further studies with larger groups and pharmacogenetic analyses of OD-DFX responders are warranted to determine the efficacy and safety profile of TDD-DFX.

Antifungal Prophylaxis with Posaconazole versus Fluconazole in Children with Neutropenia Following Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Experience.

BACKGROUND: Invasive fungal diseases (IFDs) are common and contribute to mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). The relative efficacies of posaconazole (POS) and fluconazole (FLU) as primary antifungal prophylaxes are uncertain. METHODS: A retrospective study was performed on children treated with allogeneic HSCT who received POS or FLU during the early neutropenic period. The efficacies, safety, and tolerabilities of the prophylaxes were compared. RESULTS: Data on 78 HSCT recipients were analyzed. Most had thalassemia (58%). Pre-engraftment, POS and FLU were administered to 41 and 37 cases, respectively. There were no proven cases of IFD. However, 2 POS cases and 1 FLU case had probable IFDs. The IFD incidences of the POS (5%) and FLU (3%) groups demonstrated no statistical difference (p = 0.620). Of the 75 surviving cases receiving FLU post-engraftment (including 39 cases previously given POS), 3 had proven IFDs whereas 3 had probable IFDs (total, 6 [8%]) within 1 year post-HSCT. No cases discontinued the prophylaxes due to drug intolerance. The common adverse events with POS and FLU were not significantly different. Only 19% of the patients achieved the therapeutic POS level, with a starting dose of 4 mg/kg thrice daily. CONCLUSION: POS and FLU demonstrate comparable levels of effectiveness, safety, and tolerability as IFD prophylaxes for neutropenic children treated with allogeneic HSCT. Determination of the optimum POS dose and duration requires larger studies.

Invasive Fungal Diseases in Children with Acute Leukemia and Severe Aplastic Anemia.

Although the outcomes of childhood leukemia and severe aplastic anemia (SAA) have improved, infectious complications are still the major concern. Particularly worrisome are invasive fungal diseases (IFDs), one of the most common causes of infectious-related deaths in patients with prolonged neutropenia. A retrospective study was conducted of IFDs in pediatric patients with newly diagnosed or relapsed acute leukemia, or with SAA, at Siriraj Hospital, Mahidol University, Thailand. There were 241 patients: 150 with acute lymphoblastic leukemia (ALL), 35 with acute myeloid leukemia (AML), 31 with relapsed leukemia, and 25 with SAA. Their median age was 5.4 years (range, 0.3-16.0 years). The overall IFD prevalence was 10.7%, with a breakdown in the ALL, AML, relapsed leukemia, and SAA patients of 8%, 11.4%, 19.3%, and 16%, respectively. Pulmonary IFD caused by invasive aspergillosis was the most common, accounting for 38.5% of all infection sites. Candidemia was present in 34.6% of the IFD patients; Candida tropicalis was the most common organism. The overall case-fatality rate was 38.5%, with the highest rate found in relapsed leukemia (75%). The incidences of IFDs in patients with relapsed leukemia and SAA who received fungal prophylaxis were significantly lower than in those who did not (P = N/A and 0.04, respectively). IFDs in Thai children with hematological diseases appeared to be prevalent, with a high fatality rate. The usage of antifungal prophylaxes should be considered for patients with SAA to prevent IFDs.

Using of deferasirox and deferoxamine in refractory iron overload thalassemia.

BACKGROUND: Iron overload is a major complication of transfusion-dependent thalassemia (TDT) and requires iron chelation (IC) therapy. However, a combination therapy may be required for patients responding poorly to monotherapy. METHODS: Nine TDT patients previously treated with IC were enrolled; five patients were previously treated with deferasirox (DFX) twice daily. The dose of DFX was 20-40 mg/kg/day, while the dose of deferoxamine (DFO) was 18-40 mg/kg/day for 3-6 days/week. RESULTS: At the 6- and 12-month time points, six and eight patients demonstrated decreased serum ferritin levels, with median reductions of 707 ng/mL (range, 1,653-5,444 ng/mL) and 1,129 ng/mL (range, 1,781-7,725 ng/mL) compared to the baseline, respectively. Eight patients also had a reduced liver iron concentration (LIC), with a median reduction of 3.9 mg/g dry wt (range, 8.3-11.1 mg/g dry wt). Of the five patients treated with DFX twice daily, four responded to combination therapy. All responsive patients could finally stop DFO after the decline in LIC. Moreover, there were no treatment-related complications. CONCLUSION: The combination of DFX and DFO proved to be effective and without significant toxicities for TDT patients who had been unresponsive to standard IC therapy. Further studies with a larger cohort size and long-term follow-up are warranted to elucidate the efficacy of the combination.

Clinical outcomes and prognosis of Thai retinoblastoma patients.

BACKGROUND: Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe-saving outcomes. METHODS: The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. RESULTS: In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high-risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5-year overall survival rate was 90.3%, an improvement compared to the previous study. The 5-year enucleation-free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3 months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high-risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). CONCLUSIONS: Survival rates and globe-saving rates appear to have improved; however, advanced-stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow-up are warranted.

GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma - assessing tumor and T cell interaction.

A novel disialoganglioside 2 (GD2)-specific chimeric antigen receptor (CAR)-modified T cell therapy against retinoblastoma (RB) were generated. GD2-CAR consists of a single-chain variable fragment (scFv) derived from a monoclonal antibody, hu3F8, that is linked with the cytoplasmic signaling domains of CD28, 41BB, a CD3ζ, and an inducible caspase 9 death fusion partner. GD2 antigen is highly expressed in Y79RB cell line and in several surgical RB tumor specimens. In vitro co-culture experiments revealed the effective killing of Y79RB cells by GD2-CAR T cells, but not by control CD19-CAR T cells. The killing activities of GD2-CAR T cells were diminished when repeatedly exposed to the tumor, due to an attenuated expression of GD2 antigen on tumor cells and upregulation of inhibitory molecules of the PD1 and PD-L1 axis in the CAR T cells and RB tumor cells respectively. This is the first report to describe the potential of GD2-CAR T cells as a promising therapeutic strategy for RB with the indication of potential benefit of combination therapy with immune checkpoint inhibitors.

Impact of splenectomy on outcomes of hematopoietic stem cell transplantation in pediatric patients with transfusion-dependent thalassemia.

BACKGROUND: The role of splenectomy prior to hematopoietic stem cell transplantation (HSCT) is controversial. Only few studies compared the outcomes of splenectomized and nonsplenectomized children with transfusion-dependent thalassemia (TDT) undergoing allogeneic HSCTs. METHODS: A retrospective analysis was undertaken on a transplantation cohort of TDT patients; August 1987-December 2014 to compare transplant outcomes between splenectomized and nonsplenectomized groups. RESULTS: Ninety-six transplants in 86 TDT patients were analyzed. Sixteen patients were splenectomized before HSCTs. The splenectomized patients were significantly older (8.0 ± 1.9 vs 4.7 ± 0.6 years; P = 0.001), had larger livers and spleens (P = 0.001), and had a significantly shorter neutrophil engraftment time (absolute neutrophil count > 500/mm3 ; 15.0 ± 2.3 vs 19.2 ± 1.3 days; P = 0.004). Graft rejection occurred in 13.8% of the nonsplenectomized group, but not among the splenectomized patients. Though the splenectomized group's mortality rate was higher (25.0% vs 8.8%), this was not statistically significant (P = 0.491). The main causes of death in both groups were severe infections. The five-year overall survival (OS) rate was better for the nonsplenectomized group (91.78% vs 75.00%; P = 0.06). CONCLUSIONS: Although splenectomies prior to HSCT for the TDT patients in our cohort were associated with faster neutrophil engraftments and lower rejection rates, they did not produce significantly better OS or affect the mortality. As the splenectomies did not provide any distinct advantages, this procedure should not be routinely performed as a pre-HSCT regimen for TDT patients with splenomegaly. Better pre-HSCT preparation for TDT patients, including early and adequate blood transfusions to avoid splenomegaly, is recommended.

Prevalence and Clinical Outcome of Philadelphia-Like Acute Lymphoblastic Leukemia: Systematic Review and Meta-analysis.

BACKGROUND: The presence of Philadelphia (Ph)-like ALL among patients with acute lymphoblastic leukemia (ALL) may indicate a poor prognosis similar to Ph+ ALL, although the data are still inconclusive and the prevalence of Ph-like ALL varied considerably across studies. PATIENTS AND METHODS: We performed a systematic review and meta-analysis in order to identify all cohort studies of patients with ALL that reported the prevalence of Ph-like ALL and to summarize their results together. The pooled prevalence and rate were calculated by the DerSimonian-Laird random-effect model with double arcsine transformation. RESULTS: Across the 15 included studies describing 11,040 ALL patients, the peak prevalence of the presence of Ph-like ALL among patients with ALL was between ages 11 and 40 years, where the pooled prevalence was 25.8% to 26.2%. The pooled 5-year overall survival rate of Ph-like ALL was 42.8% (95% confidence interval, 23.9-64.1; I2 93%). Comparative analysis with B-other ALL patients was conducted by the Mantel-Haenszel method; it found that Ph-like ALL patients had a significantly lower chance of being alive at 5 years (pooled odds ratio, 0.35; 95% confidence interval, 0.25-0.50; P < .00001, I2 = 40%). The chance of Ph-like ALL patients surviving at 5 years was similar to Ph-positive ALL patients (pooled odds ratio, 0.72; 95% confidence interval, 0.26-2.02; P = .53, I2 = 77%). CONCLUSION: Ph-like ALL is not uncommon among ALL patients, and its presence is associated with an unfavorable outcome. More investigations are needed for better therapeutic options.

Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia.

BACKGROUND: 6-Mercaptopurine (6-MP) is considered the backbone of therapy in the maintenance phase of acute lymphoblastic leukemia (ALL). Gene polymorphisms involved in thiopurine degradation are predictors of toxicity in patients treated with 6-MP. We investigated the effects of nucleoside diphosphate linked moiety X (nudix) type motif 15 (NUDT15) polymorphism NUDT15c.415C>T on neutropenia incidence, dose adjustment for 6-MP, and survival rates in Thai children with ALL. METHODS: Children diagnosed with ALL who received 6-MP in the maintenance phase of treatment, in 2005-2016, were retrospectively enrolled. RESULTS: The subjects consisted of 102 patients (median age, 5.2 years; 58 boys). On genetic testing 78, 22, and two patients were normal (CC), heterozygous (CT), and homozygous (TT), respectively. The incidence of neutropenia at 3 months was significantly higher in the CT/TT than CC polymorphism groups (OR, 12; 95%CI: 3.781-38.085, P < 0.001). The mean dose of 6-MP at 3, 6, and 12 months was significantly lower in the CT/TT versus the CC group (P < 0.001). The 5 year overall survival (OS) rate for CC was 80.4%, and for CT/TT, 95.5% (P = 0.34). The 5 year event-free survival (EFS) for CC and CT/TT was 75.1% and 85.7%, respectively (P = 0.17). After adjusted risk classification, no significant differences were observed for OS or EFS between the CC and CT/TT groups. CONCLUSION: Patients harboring the CT/TT polymorphism of NUDT15 had a significantly higher incidence of neutropenia during the first 3 months of maintenance, resulting in significantly lower doses of 6-MP.

Outcomes of pediatric retinoblastoma treated with ICEV regimen: A single-center study.

Retinoblastoma is the most common intraocular malignancy in children. The aim of this study was to investigate the efficacy and toxicity of combination ifosfamide, carboplatin, etoposide, and vincristine (ICEV) in advanced-stage pediatric retinoblastoma [International Classification of Retinoblastoma (ICRB) group D or E], and in ICRB group C in the second eye in simultaneously treated bilateral retinoblastoma. The medical records of retinoblastoma patients treated with concurrent ICEV regimen and focal therapy were retrospectively reviewed. The ICEV treatment protocol was, as follows: ifosfamide 1800 mg/m2 on Days 1-3; MESNA 600 mg/m2 on Days 1-3; carboplatin 560 mg/m2 on Day 1; etoposide 150 mg/m2 on Days 1-3; and vincristine 1.5 mg/m2 on Day 1. Of 16 retinoblastoma patients, 13 had bilateral disease. Seven first eyes in bilateral disease that were enucleated prior to ICEV therapy were excluded. Twenty-two eyes were finally included (six group C, six group D, and ten group E). Median follow-up was 3.4 years, and the median number of ICEV courses was 7. Fifteen globes could be salvaged, 12 responded to ICEV (six group C, five group D, and one group E), and three unresponsive eyes could be salvaged with external beam radiation therapy (EBRT). Enucleation-free and relapse-free survival was 68.2 and 54.5%, respectively. The results of this study suggest ICEV as an alternative therapeutic approach for globe salvage in pediatric retinoblastoma, especially in ICRB groups C and D with manageable acute toxicity. Further study in larger cohort is needed to confirm the effectiveness of treatment.

Hematologic Malignancies Associated With Mediastinal Germ Cell Tumors: 10 Years' Experience at Thailand's National Pediatric Tertiary Referral Center.

Mediastinal germ cell tumor (MGCT), which accounts for 1% to 3% of extragonadal germ cell tumors, has unique manifestations; it is associated with several types of hematologic malignancy, particularly myeloid neoplasm. The aim of this study was to report the 10-year incidence, clinical characteristics, and outcomes of MGCT at Thailand's national pediatric tertiary referral center. This retrospective study included patients diagnosed with MGCT at the Department of Pediatrics, Siriraj Hospital during 2005 to 2014. Eight patients (all male) were diagnosed with MGCT. Five of 8 patients were found to have hematologic abnormalities. Three patients were diagnosed with acute myeloid leukemia (AML) (one patient with M1, another having M7, and the other with M0). Another patient had mixed MGCT with mediastinal myeloid sarcoma (MMS). The other patient had malignancy-associated hemophagocytic lymphohistiocytosis syndrome (M-HLH). Isochromosome 12p was detected in 3 patients (AML [2], mixed MGCT/MMS [1]). Four of 5 patients with hematologic abnormalities died of hematologic abnormalities or treatment complication (AML [3], M-HLH [1]). One patient with mixed MGCT/MMS survived with chemotherapy. All patients with AML and MMS were nonseminomatous MGCT and the onset of myeloid malignancies were within 1 year after the diagnosis of MGCT. Associated hematologic malignancies should be suspected in MGCT with abnormal blood count or hematologic symptoms. Isochromosome 12p was the most common cytogenetic finding in MGCT-associated myeloid malignancies patients. Those with nonseminomatous MGCT should have their blood count carefully monitored especially during the first year after the diagnosis of MGCT. Better treatment alternatives for MGCT with associated hematologic malignancies are warranted to ameliorate adverse outcomes.

Evaluation of artemisinins for the treatment of acute myeloid leukemia.

PURPOSE: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models. METHODS: Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models. RESULTS: ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo. CONCLUSIONS: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML.

Bisphosphonate Therapy for Refractory Langerhans Cell Histiocytosis: A Case Report.

Although patients diagnosed as Langerhans cell histiocytosis (LCH) with bone lesion initially respond well to treatment, some may experience relapse or refractory disease. Pamidronate, a potent N-bisphosphonate, has been used in several primary bone diseases, benign bone tumors, and metastatic bone cancers. The mechanism includes an inhibitory effect on osteoclast activity by decreasing development and recruitment of osteoclast progenitors and promoting osteoclast apoptosis. Herein, we introduce a seven-month-old Thai girl who was diagnosed as multiple-relapse LCH with refractory bone lesions and was treated with standard and salvage steroid-based therapies. After receiving two courses of intravenous pamidronate, she had marked clinical and radiographical improvement without any adverse events. She has been in remission for two years after receiving six courses of therapy. This report supports the efficacy ofpamidronate in LCH-related bone lesions, but further studies in large cohort are warranted.

Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia.

FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD-positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML.