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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 vs. matched donor (MSD or MUD), the pooled odds ratio (OR) was 0.94 (95% CI, 0.79–1.12; I2, 22%); while for haplo vs. 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 chronic 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 Micro-Abstract This systematic review and meta-analysis compared the outcomes of stem cell transplantations (SCT) using haplo and other stem cell sources. The overall survival was comparable between haplo-SCT and other stem-cell sources-SCT. Compared to matched-sibling donor SCT, the cumulative relapse incidence was significantly lower in haplo-SCT but acute and chronic graft-versus-host disease were significantly higher in haplo-SCT.

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.

Thanks to its ability to inhibit deoxyribonucleic acid synthesis, 6-mercaptopurine (6-MP), is one of the indispensable medications for acute lymphoblastic leukemia (ALL) patients. Nevertheless, some patients may succumb to myelotoxicity, leading to treatment disruption or even life-threatening events. Owing to the advances in pharmacogenomics, the genetic polymorphism of genes regulating purine synthesis has been identified and physicians can adjust the dose of 6-MP according to each polymorphism. Such polymorphisms genetically vary among ethnicities. In this article, 2 genetic polymorphisms, namely thiopurine methyltransferase and Nudix (nucleoside diphosphate linked moiety X) type motif 15, are clinically discussed, with a special focus on the clinical studies in Thai children with ALL.

Objective: To determine the clinical features and treatment outcomes of pediatric extracranial germ cell tumor (EGCT) in Thailand.Materials and methods: A retrospective chart review of children under 15 years old with newly diagnosed EGCT who were treated at Faculty of Medicine Siriraj Hospital from January, 2004 to December, 2013 was conducted.Results: Forty-four patients were included in the study. The median age at diagnosis was 1.74 years (1 day-14.7 years) with the median follow up time of 6.9 years (14 days-15.2 years). Twenty-eight patients (64%) had extragonadal tumor. The most common primary tumor location was the sacrococcygeal area. Majority of the patients (61%) had malignant EGCT; yolk sac tumor was the most common diagnosis. Six patients (14%) had stage IV disease. Forty patients (91%) underwent surgery; 27 patients (61%) received chemotherapy. Thirty-eight patients (86%) achieved remission; 3 patients (7%) subsequently relapsed at a median time of 1 year. Eight patients (18%) died, mostly from tumor progression. The 5-year event-free survival (EFS) and overall survival (OS) rate were 78.3% and 81.1%, respectively. Patients achieving total tumor removal had significantly better 5-year EFS and OS. Cox regression analysis revealed that the adequacy of surgery was the only prognostic factor for survival. Conclusion: The survival rate of pediatric EGCT in our study was relatively favorable, but still inferior to that of developed countries. Novel therapy may be warranted for those patients who are unresponsive to the current treatment.

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 vincr...

Chayamon Takpradit,1 Chonthida Wangkittikal,2 Supattra Rungmaitree,3 Jassada Buaboonnam,1 Nattee Narkbunnam,1 Kamon Phuakpet,1 Nassawee Vathana,1 Kleebsabai Sanpakit,1 Bunchoo Pongtanakul1 1Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 2Division of Hematology and Oncology, Department of Pediatrics, Chonburi Hospital, Chonburi, Thailand; 3Division of Pediatric Infectious Diseases, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Bunchoo PongtanakulDivision of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok Noi, Bangkok, 10700, ThailandTel +66 2-419-5971Fax +66 2-866-3021Email pongtanakul@yahoo.comBackground: 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.Keywords: antifungal prophylaxis, children, fluconazole, hematopoietic stem cell transplantation, posaconazole

Highlights • This is the first report on targeted T cell therapy against retinoblastoma (RB). • A novel GD2-specific CAR T with safety switch effectively killed RB. • Repetitive antigen exposure, the tumor cells gradually lost GD2 expression and increased PD-L1 expression. • The first report on RB tumor evolvement after targeted T cell therapy., 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.

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.

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.

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.

Background: Patients with transfusion-dependent thalassemia (TDT) risk iron overload and require iron chelation therapy. Salvage 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) for > 24 months, after failing to respond to once-daily deferasirox (OD-DFX). Results: We enrolled 22 patients (14 males and 8 females; median age, 9.2 [3–15.5] years). The median erythron 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 6.5 (3.2–19) mg/g dry wt. There were 18 responders (81.8%) and 4 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 end-of-study 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 7 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 inadequate responders are warranted to better determine the efficacy and safety profile of TDD-DFX.

Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P 0.001).The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

Although the outcome of childhood leukemia and severe aplastic anemia (SAA) has improved, infectious complications are still the major concern, particularly invasive fungal infection (IFI), which is one of the most common causes of infectious related death in such patients with prolonged neutropenia. A retrospective study of IFI in pediatric patients with newly diagnosed and relapsed acute leukemia and SAA in Siriraj Hospital, Mahidol University, Thailand, was conducted. There were 241 patients (150 patients with ALL, 35 patients with AML, 31 patients with relapsed leukemia and 25 patients with SAA) with the median age of 5.4 years (rage, 0.3-16.0 years). The overall prevalence of IFI was 23.2%, and the breakdown prevalence in ALL, AML, relapsed leukemia and SAA were 12.7%, 37.1%, 45.2% and 40.0% respectively. Candida tropicalis was the most common identifiable organism. Pulmonary IFI caused by invasive aspergillosis was the most common site of infection. The overall case-fatality rate was 50.0% with the highest rate in relapsed leukemia of 92.9%. In multivariable analysis, the age > 4 years, AML, relapsed leukemia and SAA were found to be independent risk factors of IFI with adjusted odds ratio of 2.3, 4.1, 5.1 and 3.7 respectively. In SAA group, only very severe aplastic anemia (ANC < 200 mm3) was found to be associated with development of IFI with odds ratio of 32.7. IFI in Thai children with hematologic diseases appeared to be prevalent with high fatality. Anti-fungal prophylaxis should be considered in patients with SAA to prevent IFI.

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. 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. 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. 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.

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.

Background The efficacy of combination chemotherapy with methotrexate (MTX) and asparaginase is not well known in relapsed and refractory acute leukemia after contemporary therapy. Procedure A retrospective study of pediatric patients with relapsed or refractory acute myeloid leukemia (AML) who received MTX and asparaginase as a salvage therapy at St. Jude Children Research Hospital was performed. MTX was given intravenously followed by a dose of asparaginase intramuscularly or intravenously 24 hours later. The chemotherapy cycle was repeated every 7–10 days. Response, survival, and toxicities were evaluated. Results Fifteen patients, median age 10.5 years (range, 1.1–18.5 years), were treated. Median number of previous therapeutic regimens was three (range, 1–4). Six patients responded to treatment (three had morphologic complete remission with incomplete blood count recovery, two had partial remission, and one had stable disease for 16 months), and four are still alive. Three of six responders had monoblastic leukemia, and also developed tumor lysis syndrome. The 1- and 2-year overall survival rates are 35.6% and 17.8%, respectively. The most common adverse event was transient elevation of transaminases (nine patients). Two patients developed pancreatitis. Episodes of febrile neutropenia were rare (two patients), and most courses (75 out of 93 total courses) were given in an outpatient setting. Conclusions Combination chemotherapy with MTX and asparaginase appears to be an effective salvage therapy and well tolerated in patients with relapsed or refractory childhood AML, even in those heavily pretreated with contemporary frontline or salvage therapy. Pediatr Blood Cancer 2013; 60: 1161–1164. © 2013 Wiley Periodicals, Inc.

Introduced in 1988 by Kaneko and colleagues, selective ophthalmic arterial infusion of chemotherapeutic drug has recently gained more interest among retinoblastoma experts worldwide. The report showed that the procedure could be repeated up to 12 treatments without serious side effects. We report a 4-year-old girl with bilateral retinoblastoma. The left eye was enucleated for the group E disease. The right eye started with 3 retinal tumors (group C) was treated with systemic chemotherapy plus local therapy. Seven months after the last cycle of chemotherapy, the tumor recurred close to the fovea. Systemic chemotherapy was reinitiated without success. To avoid aggressive cryotherapy and external-beam radiotherapy, selective ophthalmic arterial infusion of chemotherapeutic drugs was performed for 15 sessions. The tumor responded partially without evidence of drug-induced retinal toxicity by the electroretinogram. Minor irregularities of the inner wall of supraclinoid portion of the internal carotid artery were observed only at the sixth session. Narrowing of the vascular lumen occurred on the last 2 sessions. We demonstrate that this technique when performed repeatedly could result in the anatomic changes of the small blood vessel. Careful follow-up is necessary for early detection of any serious consequences.

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.

Purpose: To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myelogenous leukemia (AML) and monitor the emergence of secondary FLT3 tyrosine kinase domain (TKD) mutations during treatment. Experimental Design: Six children with relapsed/refractory AML were treated with sorafenib in combination with clofarabine and cytarabine, followed by single-agent sorafenib if not a candidate for transplantation. Sunitinib was initiated after sorafenib relapse. Bone marrow samples were obtained for assessment of FLT3 TKD mutations by deep amplicon sequencing. The phase of secondary mutations with ITD alleles was assessed by cloning and sequencing of FLT3 exons 14 through 20. Identified mutations were modeled in Ba/F3 cells, and the effect of kinase inhibitors on FLT3 signaling and cell viability was assessed. Results: Four patients achieved complete remission, but 3 receiving maintenance therapy with sorafenib relapsed after 14 to 37 weeks. Sunitinib reduced circulating blasts in two patients and marrow blasts in one. Two patients did not respond to sorafenib combination therapy or sunitinib. FLT3 mutations at residues D835 and F691 were observed in sorafenib resistance samples on both ITD-positive and -negative alleles. Deep sequencing revealed low-level mutations and their evolution during sorafenib treatment. Sunitinib suppressed leukemic clones with D835H and F691L mutations, but not D835Y. Cells expressing sorafenib-resistant FLT3 mutations were sensitive to sunitinib in vitro. Conclusions: Sunitinib has activity in patients that are resistant to sorafenib and harbor secondary FLT3 TKD mutations. The use of sensitive methods to monitor FLT3 mutations during therapy may allow individualized treatment with the currently available kinase inhibitors. Clin Cancer Res; 19(20); 5758–68. ©2013 AACR.

Introduction: Although routine tissue iron monitoring using magnetic resonance imaging (MRI) has become a standard clinical management of both transfusion dependent and non-transfusion dependent thalassemias (TDT & NTDT) in several developed countries since this module can provide a better organ-directed iron measurement and related to clinical outcome including morbidity and mortality secondary to iron overload (IOL). However, accessibility of this monitoring remains limited in several developing countries including Thailand, where thalassemia and hemoglobinopathies are highly prevalent. Earlier in 2016, we have demonstrated that although not so perfectly crafted, a cross-sectional measurement of serum ferritin (SF) can be used for determination of IOL as a predictive marker; in NTDT, MRI for liver iron concentration (LIC) should be performed in those with SF >300 ug/L and for TDT, the SF cut off of >2,500 and >3,500 ug/L are useful to predict patients with severe LIC (>15 mgFe/g dw) and cardiac siderosis (T2*< 20 ms) (Ekwattanakit S. et.al., EHA 2016). In this study, we performed a further analysis to evaluate whether a serial measurement of SF and its trend can provide a better prediction. Objectives: To evaluate the clinical utility of serial SF trend compared with a cross-sectional SF cut-off for early detection of IOL in a real-life practice in thalassemic patients in order to select the most vulnerable patients for further MRI evaluation in a resource limited setting. Methods: In this prospective study, total 968 standard MRI for LIC and cardiac T2*were performed at Siriraj hospital during 2009-2014 and paired clinical data including serial SF measurements were collected from 301 thalassemia patients; NTDT (N=76; 109 LIC and 95 cardiac T2* results) and TDT (N=155; 478 LIC and 474 cardiac T2*). In addition, 71 patients were NTDT with regular blood transfusion later on in their life, mainly Hb E/β thalassemia (218 LIC and 210 cardiac T2*). These patients were evaluated for IOL using SF every 4-12 weeks during their follow up. Median follow up time was 96 months. Receiver operating characteristic (ROC) analysis was performed using different SF cut-off levels (1000, 1500 and 2000ug/L) and percentage of serial SF measurements that above each these cut-off levels (50 and 75%) during different durations before MRI (1, 2, or 3 years priori) for predicting liver IOL (LIC >5 in NTDT and severe liver siderosis; LIC > 15 mgFe/g dw) and cardiac IOL (T2* Results: Baseline characteristics were shown in Table1. In NTDT, using ROC analysis, SF >1000 ug/L over 75% of serial measurements in 1-year period prior to MRI can predict LIC > 5 mgFe/g dw with the AUC of 0.59 with PPV 86.7% and NPV 51.1% and serial SF >1500 ug/l over 50% of measurement in a year prior predict LIC >15 mgFe/g dw (AUC of 0.72, PPV 75% and NPV 89.7%). Only 1 NTDT had cardiac IO. These newly identified criteria do not provide a more sensitive predictor of LIC results than our previous SF cut-off. In TDT population, the majority of patients were HbE/β thal (78%) and cardiac iron overload was detected mainly in patients older than 15 yrs (81/83; 97.6%). The best predictor for LIC>15 mgFe/g dw was SF >2000 ug/L over 75% of serial measurement durations in 3-year period (AUC 0.778, PPV 50.8%, NPV 95.5%). However this cut-off during 1 year priori also provided a similar prediction (AUC 0.769, PPV 51%, NPV 93.6%). This cut-off value also provided the best prediction for cardiac T2* < 20 ms in all age group (AUC 0.754, PPV 31.5%, NPV 97.4%) and a higher sensitivity and specificity when it was applied in patients >15 yrs of age (AUC 0.764, PPV 41.9%, NPV 96.3%). In NTDT with regular transfusion, all cardiac IOL (N=19) occurred after 15 years of age and again the same criteria was the good predictive cut-off for cardiac IO (AUC 0.788, PPV 19%, NPV 100%) and severe LIC >15 mgFe/g dw (AUC 0.728, PPV 52.8%, NPV 87.3%). Conclusions: In a resource limited setting for MRI evaluation, a serial measurement of SF and its values in thalassemic patients who received regular blood transfusion above the cut-off of 2000 ug/L over 75% of measurement in one year priori could be used as a predictive marker for selecting the most vulnerable TDT for MRI evaluation since this criteria is strongly associated with severe liver (LIC > 15 mgFe/g dw) and cardiac siderosis (T2* Disclosures Siritanaratkul: Novartis: Research Funding; Jansen-Cilag: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Wood:Celgene: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; World Care Clinical: Consultancy; AMAG: Consultancy; Celgene: Consultancy. Viprakasit:Agios: Consultancy; Mersanger: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Faculty of Medicine, Siriraj Hospital, Mahidol University: Employment; Shire: Research Funding.

BACKGROUND: The effect of body mass index (BMI) on the treatment outcomes of children with acute myeloid leukemia (AML) is unclear and needs further evaluation. METHODS: Children with AML (n = 314) who were enrolled in 4 consecutive St. Jude protocols were grouped according to BMI (underweight