Pediatric Acute Promyelocytic Leukemia Research Articles

Clinical Features and Treatment Outcome of Pediatric Acute Promyelocytic Leukemia in Combined Military Hospital, Dhaka

Background: Acute promyelocytic leukemia (APML) is a relatively rare blood disease in children that is highly curable with current treatment strategies. It is a distinct type of AML characterized by chromosomal translocations involving the retinoid acid receptor (RAR-A) gene on chromosome 17. It accounts for 20-25% of all AML cases. The aim of this study was to describe the diagnostic features of pediatric APL and the result with ATRA and ATO based protocol. Methods: It was a descriptive type of cross-sectional study with purposively selected 10 newly diagnosed APML patients treated in the Pediatric Oncology unit of the Department of Pediatrics in CMH Dhaka during the period of 2018 to 2022. Diagnosis of all patients were done by aspirating bone marrow morphology and cytogenetic t(15:17) or t(11:17) transcript. Informed written consent was taken from parents. Data were collected by semi-structured questionnaire and analyzed by Statistical Package for Social Sciences (SPSS version 25). Results: Among 10 respondents median age was 4.2 years with female predominant (60%). Most common clinical presentations at diagnosis were fever (100%), bleeding manifestations (100%), Hepatomegaly (90%) bony tenderness (90%), splenomegaly (70%), and lymphadenopathy (70%). Almost all the patients had low Hb & low platelet count & WBC were variable. Cytogenetic analysis revealed 90% had PML/RARA positive & 30% had FLT3/ITD positive. All of these patients were treated with trans-retinoic acid (ATRA) based treatment, which led to 80% cases ATRA syndrome. Other common toxicities noticed febrile neutropenia (50%), severe headache (30%), hyperpigmented skin (10%), pseudotumor cerebri (10%) and others. There were 10% relapse cases, which later proceeded to relapse protocol and were in remission. The remaining 90% of patients were alive and in remission until the last day of follow-up. Conclusion: With ATRA-based treatment overall survival is good achieved remission and only 10% of patients developed relapse. Bangladesh Armed Forces Med J Vol 56 No (2) December 2023, pp 1-9

Pediatric acute promyelocytic leukemia and Fanconi anemia: Case report and literature review.

Acute promyelocytic leukemia (APL) represents 5%-10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the most common inherited bone marrow failure syndromes caused by biallelic pathogenic variants (PV) in specific DNA-repair genes. Biallelic PVs in FANCD1/BRCA2 (FA-D1) account for 3% of FA and are associated with early-onset leukemia and a high risk of solid tumors. We report a 4 year-old boy from non-consanguineous parents diagnosed with standard risk APL. This child had café-au-lait spots and an extra thumb remnant. Genomic sequencing revealed two PV in FANCD1/BRCA2 confirming a diagnosis of FA-D1. Chromosomal breakage studies were compatible with FA. Each parent carried one variant and had no personal history of cancer. Morphological then molecular remissions were achieved with all-trans retinoic acid and Arsenic trioxide. This patient underwent haploidentical stem cell transplant. In addition to our patient, a literature search revealed four additional patients with APL/FA, with a total of three patients with FA-D1. This raises the possibility of an association between such rare disorders. Practical management of APL in the setting of FA-D1 is discussed with an overview of current evidence and knowledge gaps.

Coagulopathy in pediatric acute promyelocytic leukemia in Bangladesh: A single-center, prospective study

BackgroundAcute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia in childhood. It usually presents with a characteristic coagulopathy. The study aims to determine the extent and outcome of this coagulation disorder. MethodsThis prospective observational study was conducted at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, and included PML:RAR-α (Promyelocytic Leukemia-Retinoic Acid Receptor-α) positive APL cases. At presentation, all patients were assessed with coagulation parameters and followed up clinically and hematologically while treated with ATRA (all-trans-retinoic acid)-based chemotherapy. The presence of disseminated intravascular coagulation (DIC) was determined using the DIC scoring system of the International Society on Thrombosis and Hemostasis (ISTH). ResultsAmong 20 APL cases, the mean DIC score was 5.75 ± 0.6, and DIC was detected in 90% (n = 18/20) of the patients. The incidence of fatal thrombo-hemorrhagic complications was 15% (n = 3/20). Though hemorrhagic complications are more common, thrombosis may also occur in pediatric APL.

Integrated Analysis Focusing on Genome-Wide DNA Methylation in Pediatric Acute Promyelocytic Leukemia: The Jccg Study, JPLSG AML-P05

Introduction: Pediatric acute promyelocytic leukemia (APL) represents approximately 5%-10% of all acute myeloid leukemia (AML). While the prognosis of APL patients has dramatically improved with the use of all-trans retinoic acid and arsenic trioxide, cases of relapse still exist. Moreover, the molecular biological basis of pediatric APL remains unknown. In adult and pediatric AML, to predict prognosis, DNA methylation patterns have been proposed as biomarkers. In this study, we aimed to investigate the molecular biological basis of pediatric APL and validate biomarkers associated with prognosis using an integrated analysis, including DNA methylation analysis, targeted deep sequencing, and RNA sequencing, in patients enrolled in the Japanese AML-P05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Methods: Pediatric de novo APL patients (n = 38) who participated in the JPLSG AML-P05 trial from 2006 to 2009 were analyzed. Genome-wide DNA methylation analysis (n = 34), targeted deep sequencing (n = 35), RNA sequencing (n = 34), and motif analysis (n = 34) were performed. In the DNA methylation analysis, the Infinium MethylationEPIC v2.0 Kit (Illumina) was used. Results: Based on the most variable 1,000 DNA methylation values between patients, unsupervised hierarchical clustering classified APL patients into four clusters (cluster 1, 2a, 2b, and 3). Clusters 1 and 2a (n = 15) demonstrated a significantly higher DNA methylation levels at 87 CpG sites out of 1,000 compared to clusters 2b and 3 (n = 19). A part of the 87 CpG sites locate on the genes, such as CPM, GRB10 and BAALC, which have been reported to be associated with APL prognosis. A significant DNA methylation difference was found between the “high” (cluster 1 and 2a) and “low” (cluster 2b and 3) methylation groups at 2,372 CpG sites (Figure). Patients in the high methylation group presented with significantly worse outcomes compared to those in the low methylation group (3-year overall survival: 80% vs. 100%, p = 0.043; 3-year event-free survival: 73.3% vs. 94.7%, p = 0.049). Additionally, among the 2,372 CpG sites, motif analysis was performed for 783 CpG sites with an average methylation difference of 0.3 or higher. The binding domain of EBF1 was enriched among them. EBF1 is a critical transcriptional factor for B-cell differentiation. In the high methylation group, an aberrant B-cell differentiation was considered as a characteristic of APL. Gene expression analysis between the high and low methylation groups revealed significant differences in expression of 600 genes with more than twofold changes. Gene ontology analysis of the 600 genes revealed that their genes were enriched in T-cell and B-cell linage differentiation. In the targeted deep sequencing analysis, a total of 41 mutations in 21 genes in 25 patients were identified. The most frequent mutation was NRAS. Interestingly, previously unreported mutations in EP300 and BRCA2 were identified in APL, with EP300 mutations detected only in the high methylation group. Conclusions: DNA methylation analysis suggests that DNA methylation levels at specific CpG sites are effective biomarkers for the prognosis of pediatric APL. The presence of the EBF1 binding motif in the vicinity of these CpG sites suggests the involvement of EBF1 in prognosis.

Outcomes of Paediatric Acute Promyelocytic Leukaemia in the UK

Acute Promyelocytic Leukaemia (APL) is characterized by unique genetic and molecular abnormalities, clinical features, and treatment strategies. It accounts for 5-10% of paediatric acute myeloid leukaemia (AML) cases. APL is defined by the t(15;17)(q24;q21) chromosomal translocation, leading to the formation of the PML-RARA fusion protein, which plays a crucial role in leukemogenesis. All-trans retinoic acid (ATRA) has revolutionized APL management by targeting the PML-RARA fusion protein and inducing complete remission in the majority of patients. Arsenic trioxide (ATO) has emerged as an effective therapeutic agent, particularly in cases with ATRA resistance or relapse. ATO is now widely recommended as part upfront treatment. However, access to ATO has been limited by funding sources in certain countries. This retrospective national study presents the treatment strategies, complications, and survival outcomes of 50 paediatric patients, aged 1 to 18 years, diagnosed with APL in the UK over an 8-year period, between 1 st November 2014 and 31 st October 2021. There were 21 (42%) high risk (HR) patience and 29 (58%) non-HR patients in the cohort. The majority of patients received a chemotherapy-free regimen comprising ATRA and ATO, with additional agents used selectively. Chemotherapy was usually given to patients in the event of lack of access to ATO or clinical urgency. Availability to ATO varied between countries within the UK. Event-free survival (EFS) and overall survival (OS) were evaluated, with a minimum 2 years follow up from diagnosis and median follow-up of 8 years. Overall, the cohort demonstrated a high OS of 94%, with no significant difference observed between HR and non-HR patients. However, HR patients experienced significantly lower EFS, with all relapses occurring in this group. Relapsed patients received varied treatment regimens, including ATRA, ATO, and chemotherapy, with favourable outcomes. This study contributes valuable insights into the management and outcomes of paediatric APL in the UK, emphasizing the importance of early diagnosis and risk stratification for optimal treatment decisions. Addressing disparities in ATO availability and promoting consistent funding across NHS Trusts will be crucial in further improving patient outcomes and reducing relapse rates in APL. Future research should focus on refining treatment protocols and exploring novel therapeutic strategies to enhance the long-term survival of paediatric APL patients. The study highlights the challenges associated with ATO availability across NHS Trusts, impacting treatment decisions and outcomes for APL patients.

Plasma cell-free DNA in patients with acute promyelocytic leukemia treated with arsenic trioxide.

Cell-free DNA (cfDNA) is free DNA found in circulating blood that originates from apoptosis or necrosis, and elevated cfDNA concentrations have been reported in cancers and other diseases. In this study, the concentrations and fragment distributions of plasma cfDNA were preliminary investigated in elderly (n = 1) and pediatric (n = 1) patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO). A slight increase in cfDNA concentrations was observed in the APL patients compared with healthy controls. The change in plasma cfDNA concentrations corresponded to the change in plasma arsenic concentrations during ATO treatment. The fragment distribution pattern did not differ before and during treatment. Three ladder fragments were observed in part of the cfDNA in the second consolidation therapy in an elderly APL patient and the first consolidation therapy of a pediatric APL patient, while two fragments were observed in all other treatment periods. Moreover, APL-related gene mutations were successfully genotyped from plasma cfDNA by using polymerase chain reaction-based methods and these results are consistent with those from leukocytes. This study is the first to report the concentrations and fragment patterns of cfDNA from APL patients treated with ATO. The results suggested that plasma cfDNA concentration in APL patients increased with ATO treatment and that cfDNA is released mainly via neutrophil extracellular traps (and/or necrosis) in addition to apoptosis. To confirm whether cfDNA concentrations and fragment patterns can be used as a biomarker for APL treated with ATO, further accumulative data are needed.

Treatment of Pediatric Acute Promyelocytic Leukemia with Retinoic Acid and Arsenic Trioxide along with Chemotherapy.

Outcomes of childhood acute promyelocytic leukemia (APL) have exceeded 90% in the era of differentiating agents. In resource-limited settings, early mortality secondary to coagulopathy remains a significant challenge. Differentiation syndrome is a unique complication of APL therapy that requires a high degree of suspicion for timely initiation of therapy. A retrospective study of children ≤15 y of age with APL diagnosed between January-2013 and June-2019 treated at a tertiary cancer centre was conducted. Patients with a total leukocyte count ≥10,000/µL were risk stratified as high-risk. Treatment included differentiating agents, all-trans retinoic acid and arsenic trioxide along with chemotherapy. Baseline demographics, clinical complications and outcomes were analysed. Out of 90 patients treated, 48 (53%) had high-risk APL and 25 (28%) presented with significant bleeding manifestations. Response to therapy was excellent with 96% of evaluable patients achieving molecular remission by the end of consolidation phase. Differentiation syndrome occurred in 23 (25%) patients of which two expired. Early mortality rate was 5.5% and was due to severe hemorrhage most often at the time of presentation. The 3-y overall survival of the entire cohort was 91% (95%CI: 85-97%). Two of 4 patients with relapse of disease could be salvaged with only differentiating agents followed by autologous transplantation. Long-term outcomes of Indian children with APL are excellent. Timely management of coagulopathy and prompt initiation of differentiating agents along with appropriate cytoreductive measures is critical. Efforts to build academic-community partnerships to ensure timely diagnosis and emergency care in order to reduce early mortality are needed.

Differentiation syndrome and coagulation disorder — comparison between treatment with oral and intravenous arsenics in pediatric acute promyelocytic leukemia

Realgar-Indigo naturalis formula (RIF), with A4S4 as a major ingredient, is an oral arsenic used in China to treat pediatric acute promyelocytic leukemia (APL). The efficacy of RIF is similar to that of arsenic trioxide (ATO). However, the effects of these two arsenicals on differentiation syndrome (DS) and coagulation disorders, the two main life-threatening events in children with APL, remain unclear. We retrospectively analyzed 68 consecutive children with APL from South China Children Leukemia Group-APL (SCCLG-APL) study. Patients received all-trans retinoic acid (ATRA) on day 1 of induction therapy. ATO 0.16 mg/kg day or RIF 135 mg/kg·day was administrated on day 5, while mitoxantrone was administered on day 3 (non-high-risk) or days 2–4 (high-risk). The incidences of DS were 3.0% and 5.7% in ATO (n = 33) and RIF (n = 35) arms (p = 0.590), and 10.3% and 0% in patients with and without differentiation-related hyperleukocytosis (p = 0.04), respectively. Moreover, in patients with differentiation-related hyperleukocytosis, the incidence of DS was not significantly different between ATO and RIF arms. The dynamic changes of leukocyte count between arms were not statistically different. However, patients with leukocyte count > 2.61 × 109/L or percentage of promyelocytes in peripheral blood > 26.5% tended to develop hyperleukocytosis. The improvement of coagulation indexes in ATO and RIF arms was similar, with fibrinogen and prothrombin time having the quickest recovery rate. This study showed that the incidence of DS and recovery of coagulopathy are similar when treating pediatric APL with RIF or ATO.

Safety and Efficacy of Arsenic Trioxide in the Treatment of Newly Diagnosed Pediatric Acute Promyelocytic Leukemia: Results from the JPLSG AML-P13 Study

Aims: Arsenic trioxide (ATO) has shown to be effective in patients with acute promyelocytic leukemia (APL), which has led to a dose reduction of cytotoxic agents in the treatment of APL. To investigate safety and efficacy of ATO in Japanese children with APL, we conducted a nationwide prospective study, JPLSG AML-P13 (jRCTs051180191). Patients & Methods: Between December 2014 and November 2018, children (0-18 years old) with newly diagnosed APL were enrolled in the AML-P13 study. All patients received two courses of induction therapy consisting of ATRA, cytarabine, and daunorubicin. Patients who achieved hematological complete remission (HCR) were allocated to the standard risk (SR) group and received three intensification cycles consisting of ATRA and ATO, followed by intermittent ATRA maintenance therapy. Patients who did not obtain HCR after induction courses were allocated to the high risk (HR) group and received intensified schedule of ATO, followed by gemtuzumab ozogamicin monotherapy and maintenance therapy consisting of 6-mercaptopurine and methotrexate. Results & Discussions: Among the 32 patients registered, 5 patients were excluded due to a lack of PML::RARA fusion or other reasons, and the remaining 27 patients received the protocol therapy (full analysis set). During induction courses, grade 3 disseminated intravascular coagulation was observed in 9 patients (33.3%). APL differentiation syndrome and induction death were not reported. Two patients were taken off protocol therapy due to a progressive disease (regarded as an event) and a safety issue, respectively. Among the 25 patients who completed induction therapy, 23 patients obtained HCR. During intensification cycles of ATO, grade 3 or higher non-hematological adverse events (AEs) were observed in 3 patients: prolonged QTc interval in 2 and dysesthesia in one. Regarding hematological AEs, 10 to 30% patients exhibited grade 4 neutropenia during each intensification cycles, but no patients experienced severe infectious complications. Two patients who did not obtain HCR received HR regimen without any apparent AEs. All 25 patients including 2 HR patients achieved molecular remission at the end of intensification and molecular remission rate was 100.0% [95% C.I. 86.3-100.0%]. No patients suffered from relapse, and 3-year EFS rate and 3-year OS rate in full analysis set were 96.3% [76.5-99.5%] (Figure) and 100.0% [87.2-100.0%], respectively. We previously reported an inferior outcome of younger children (less than 5 years old) treated with conventional ATRA and chemotherapy in the JPLSG AML-P05 study (Takahashi H. Br J Haematol 2016). However, 4 children under 5 years of age at diagnosis in the AML-P13 study remains in molecular remission, indicating efficacy of ATO in this age group of children. Interpretations: The AML-P13 study demonstrated an excellent outcome in children with APL and showed that ATO could be administered safely in children with APL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obesity in children with acute promyelocytic leukemia: What is its prevalence and prognostic significance?

To compare outcomes of obese and nonobese pediatric patients with acute promyelocytic leukemia (APL) from the Cancer and Leukemia Group B trial (CALGB) 9710 and the Children's Oncology Group trial AAML0631. Data including demographics, adverse events, overall and event-free survival (EFS) were analyzed. The prevalence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall and EFS in the obese population on multivariable analysis on AAML0631 but not on CALGB 9710. Eleven patients died during therapy or in follow-up. The prevalence of obesity is higher in pediatric patients with APL compared to the general population. The decreased EFS and OS in obese patients on AAML0631 suggest that the presence of obesity can influence outcomes using the most current treatment. These findings support the need for further research on the potential role of obesity in pediatric APL leukemogenesis.

Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO.

The ATRA/ATO combination treatment of acute promyelocytic leukemia (APL) represents a paradigm of successful targeted and chemotherapy-free treatment in oncology. This therapeutic strategy is aimed at sparing patients from chemotherapy toxicity, while maintaining an excellent survival with a low risk of relapse. Main induction treatment-related complications are differentiation syndrome (DS) and hyperleukocytosis, which is related to DS and its severity. In the period December 2019 – December 2020, 8 children with newly diagnosed APL underwent induction therapy with ATRA/ATO in our center. In patients with WBC≥10x109/L  two doses of Gemtuzumab Ozogamicin (GO) were  added. In case of severe DS or hyperleukocytosis the differentiating agents were discontinued, high dose dexamethasone (DXM) and/or hydroxyurea (HU) were recommended. Five patients presented WBC<10x109/L ; all  developed hyperleukocytosis and three also had DS and were initially treated with HU and DXM; due to unsatisfactory control of the symptoms GO was added in two of them.. One of the three patients with presenting WBC≥10x109/L, developed pseudotumor cerebri and another one DS. The supportive treatment was effective in all cases. Our experience shows that patients, treated with ATRA/ATO only, may develop marked hyperleukocytosis and severe DS, which may be unresponsive to discontinuation of differentiating agents and administration of HU and DXM and may benefit from the use of GO. Adequate intensive support therapy is crucial to rescue patients with severe DS.

Pediatric acute promyelocytic leukemia (APML): A single centre experience from South India with ATRA-ATO protocol

Pediatric acute promyelocytic leukemia (APML): A single centre experience from South India with ATRA-ATO protocol

PCR- Negative Atypical PML-RARA Rearrangement in Pediatric Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a special type of acute myeloid leukemia (AML), accounting for about 5% to 10% of children with AML. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARA gene fusion. Most patients can be diagnosed by traditional karyotype analysis, Fluorescence-In-Situ Hybridization (FISH), or Reverse Transcription-Polymerase Chain Reaction (RT-PCR). We report the case of a child with acute promyelocytic leukemia (APL) who had characteristic chromosome translocation t(15;17) and rare PML-RARA gene mutation. This patient had an excellent response to chemotherapy, suggesting that this mutation will not affect the treatment and prognosis of APL.

De-Escalating Therapy in Pediatric Acute Promyelocytic Leukemia

High cure rates are achieved in adults with acute promyelocytic leukemia (APML) using combined all-trans retinoic acid (ATRA) and arsenic trioxide,

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/μL) and high-risk APL (white blood cell count ≥10 000/μL) cohorts. All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. Event-free survival (EFS) at 2 years after diagnosis. Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. ClinicalTrials.gov Identifier: NCT02339740.

Outcome and complications of pediatric acute promyelocytic leukemia in Bangladesh

Pediatric acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia of childhood. But it may have many early complications, especially in developing countries. This study aims to describe the outcome and complications of pediatric APL patients in Bangladesh. This prospective observational study was conducted in the pediatric hematology and oncology department of Bangabandhu Sheikh Mujib Medical University, Dhaka from September 2017 to March 2019. In this study, PML:RAR-α (Promyelocytic leukemia-retinoic acid receptor-α) positive APL cases were included and observed while being treated with risk-directed ATRA (All-trans-retinoic acid) based chemotherapy. Among twenty PML:RAR-α positive APL cases, 13 children were in the high risk group and hemorrhagic manifestations were present in 95% of patients. Post-induction remission was achieved in 85% of the patients. 3-year overall survival was 70% (45-85% with 95% confidence interval). There was no refractory disease or relapses. Neutropenic sepsis was the most common complication and also the most common cause of mortality. In Bangladesh, the 3-year overall survival of pediatric APL is 70% (45-85% with 95% CI). Post-chemotherapy neutropenic sepsis is the most common complication and also the most common cause of mortality in this potentially curable malignancy in Bangladesh.

Recent Advances in the Management of Pediatric Acute Myeloid Leukemia-Report of the Hungarian Pediatric Oncology-Hematology Group.

Simple SummaryThe outcome of pediatric AML improved considerably worldwide during the past few decades. Hereby, we summarize the therapeutic results of pediatric AML patients registered between 2012 and 2019 in Hungary. As compared to our previous results, improvement was registered in event-free (EFS) and overall (OS) survival, which can be attributed to the application of contemporary diagnostic and therapeutic guidelines, advanced supportation, and higher efficacy of hematopoietic stem cell transplantation. Between 2016 and 2019, a statistically significant increment of 2-year EFS was confirmed over the period between 2012 and 2015. The most prominent progress was observed in acute promyelocytic leukemia (APL). Multidimensional flow cytometry made possible the prompt introduction of ATRA in two cases with M3v, who also represent the first pediatric APL patients in Hungary to be treated with arsenic-trioxide. Besides joining multinational pediatric AML treatment groups, our future aims include the introduction of centralized treatment centers and diagnostic facilities.Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012–2015 and 2016–2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups.

Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: A Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group.

PurposeAcute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea.Materials and MethodsSeventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively.ResultsOf 801 acute myeloid leukemia children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×109/L than in those with initial WBC ≥ 10×109/L (p=0.020).ConclusionThis study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.

Population Pharmacokinetics and Safety of Oral Tetra-Arsenic Tetra-Sulfide Formula in Pediatric Acute Promyelocytic Leukemia.

BackgroundAn oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.MethodsEleven newly diagnosed and one relapsed pediatric patient (4–14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.ResultsA total of 107 arsenic concentrations (0.1–75.0 µg L−1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63–82.18) L h−1 kg−1 and 230.37 (85.96–495.68) L kg−1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3–4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.ConclusionThe pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.

Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome.

Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among the geographic regions with relatively higher percentages in the Latin American population. We aimed to explore the population burden of pediatric APL, gathering information from the population-based cancer registry (PBCR) and the diagnosis of APL obtained through incident cases from a hospital-based cohort. The homozygous deletion in glutathione S-transferases (GSTs) leads to a loss of enzyme detoxification activity, possibly affecting the treatment response. Mutations in the RAS pathway genes are also considered to be a key component of the disease both in the pathogenesis and in the outcomes. We have assessed mutations in a RAS–MAP kinase pathway (FLT3, PTPN11, and K-/NRAS) and GST variant predisposition risk in the outcome. Out of the 805 children and adolescents with acute myeloid leukemia (AML) who are registered in the PBCR, 35 (4.3%) were APL cases. The age-adjusted incidence rate (AAIR) was 0.03 per 100,000 person-years. One-hundred and sixty-three patients with APL were studied out of 931 AML cases (17.5%) from a hospital-based cohort. Mutations in FLT3, KRAS, and NRAS accounted for 52.1% of the cases. Patients with APL presented a 5-year probability of the overall survival (OS) of 67.3 ± 5.8%. A GST-theta 1 (GSTT1) null genotype conferred adverse prognosis, with an estimated hazard ratio of 2.8, 95% confidence interval (CI) 1.2–6.9. We speculate that the GSTT1 polymorphism is associated with therapeutics and would allow better OS of patients with APL with a GSTT1 null genotype.