Influence of white blood cell count trajectories on the risk of differentiation syndrome during induction therapy with all-trans-retinoic acid and arsenic trioxide in pediatric acute promyelocytic leukemia

FLT3 Mutations in Pediatric Acute Promyelocytic Leukemia; A Report from the Children's Oncology Group AAML0631 Trial

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.

Objective To explore the treatment of acute promyelocytic leukemia (APL), and the management of retinoic acid syndrome (RAS) during treatment of APL. Methods On December 28, 2018, one case of APL patient with complex karyotype complicated by RAS who was admitted to the Hematological Disease Center of Lanzhou General Hospital, was selected as the subject. By retrospective analysis, the clinical data of this patient were collected, and the clinical manifestations, diagnosis and treatment process were analyzed. Induction chemotherapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) was used to treat APL: ATRA 20 mg/time, twice a day, oral, d1-28; ATO 10 mL/d, intravenous injection, d1-14. The RAS treatment regimen was to reduce or discontinue ATRA or ATO, and intravenous injected dexamethasone 10 mg/time, twice a day as soon as possible until hypoxemia is relieved. When patient′s white blood cell count (WBC)>10×109/L and continuously elevated, anthracycline or cytarabine was administrated as appropriate. The procedure followed in this study were in accordance with the requirements of the World Medical Association Declaration of Helsinki revised in 2013. And this patient signed the informed consents for clinical trials. Results On January 1, 2019, the patient was diagnosed as APL, with PML-RARα (Bcr1 type) positive, complex karyotype and intermediate risk group, based on complete results of relevant laboratory and auxiliary examination. This patient achieved good efficacy after treatment of ATRA+ ATO regimen. After treatment with ATRA, the patient presented fever, respiratory failure, pleural effusion, and increased WBC, etc.. Then RAS was considered. After treatment with dexamethasone, pirarubicin and symptomatic treatment, the patient′s clinical symptoms of RAS were significantly improved. As of February 2019, the patient was generally in good condition and was currently being followed up regularly. Conclusions ATRA+ ATO regimen has a good efficacy in treatment of APL. When RAS appears during the treatment, glucocorticoids and corresponding treatment should be actively used. Since only one patient was retrospectively analyzed in this study, the exact efficacy of APL and RAS needs further verification by expanding the study sample size. Key words: Leukemia, promyelocytic, acute; Tretinoin; Arsenicals; Acute promyelocytic leukemia; Retinoic acid syndrome; PML-RAR;ATRA; ATO; Dexamethasone; Retrospective studies

Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients - a 25-year Italian experience.

CPSF6-RARG-positive acute myeloid leukaemia resembles acute promyelocytic leukaemia but is insensitive to retinoic acid and arsenic trioxide

Acute promyelocytic leukaemia (APL) is characterized by the reciprocal translocation t(15;17). The classical treatment strategy for APL features chemotherapy (anthracyclines) combined with all-trans-retinoic acid (ATRA). A phase 3 study showed that treatment associating ATRA and arsenic trioxide (ATO) was at least equivalent to ATRA plus chemotherapy, in patients aged between 18 and 71 years with standard-risk APL (Burnett et al., 2015). Commencing in 2015, while awaiting a formal biomedical research protocol, the Société Française de Lutte contre les Cancers et les Leucémies de l'Enfant et de l'Adolescent (SFCE), in conjunction with a European consortium, recommended ATRA combined with ATO for children with standard-risk (SR) APL, but only few safety data for children or adolescents are available (Iland et al., 2015; Creutzig et al., 2017; Kutny et al., 2017; Kayser et al., 2018). First objective was to evaluate the tolerance and adverse events related to ATO/ATRA therapy in children with APL treated in SFCE centres. Secondary objectives were evaluation of molecular residual disease development in those receiving ATO/ATRA therapy, and the survival of children and adolescents with APL treated since 2015. In this retrospective descriptive study, we collected data from patients <18 years of age with new APL diagnoses treated in SFCE centres between January, 2015 and March, 2018. Patients were treated using national recommendations based on the Lo-Coco adult protocol (Burnett et al., 2015). For SR patients, during induction of therapy, ATO was administered intravenously (0·15 mg/kg daily) and ATRA was given orally (25 mg/m2 daily). For high-risk (HR) patients, idarubicin (12 mg/m2) was added at days 1 and 3. Side effects were retrospectively captured and evaluated using the Common Terminology Criteria for Adverse Events (CTCAE, ver. 4.03, June 14, 2010). Differentiation syndrome is a potentially life-threatening complication developing in 2·5–30% of patients with newly diagnosed APL receiving ATRA. The syndrome was treated by dexamethasone (10 mg/m2/12 h intravenously). Temporary cessation of ATRA and/or ATO is indicated for severe cases (Lo-Coco et al., 2013). Arsenic trioxide tolerance was considered evident if the drug was not stopped before the end of treatment. Adverse events associated with ATO were recorded. Molecular complete remission (MCR) was reflected by the absence of PML–RARα fusion transcripts in bone marrow. Overall survival (OS) was calculated from the first day of treatment to death, or censored at last visit. Relapse-free survival (RFS) was calculated from cytological remission to the date of relapse, death, or the censor date. We present descriptive statistics. OS and RFS were determined using the Kaplan–Meier method. Statistical analyses were performed using Prism software (GraphPad Software, San Diego, CA, USA). Twenty-one patients aged 1 to 16 years were treated with ATO/ATRA in seven French SFCE centres. All APL patients received ATO/ATRA on day 1 (SR and HR). Leukocyte counts increased in 11 patients (52·4%) during induction therapy (Table 1). All received hydroxycarbamide. Nine patients (42·9%) underwent differentiation syndrome prophylaxis (dexamethasone), and four (19%) developed true differentiation syndrome. ATRA was temporarily interrupted in three of these four patients. The rates of differentiation syndrome did not differ between patients with preventive corticosteroid therapy and those without (P = 0·33). Eleven patients (52·4%) complained of significant headaches (grade 2). Only three (14·3%) exhibited papillary oedema, suggestive of pseudotumor cerebri, linked to ATRA. Two patients (9·5%) showed grade 1 QTc prolongation during induction therapy. Five patients (23·8%) developed sensitive neuropathies: severe (grade 3; n = 4) and moderate (grade 2; n = 1), only during induction, reversible for a few days, without recurrence during consolidation. Others sides effects were hypokalaemia (n = 3) and hypomagnesaemia (n = 1). No hepatic toxicity, no Wernicke encephalopathy and no chronic arsenic toxicities were observed. In three of the 21 patients (14%), ATO was suspended for a median of five [3; 8] days because of significant grade 3 neuropathic pain (n = 1), febrile neutropenia (n = 1), and hyperleukocytosis (n = 1; white blood cell count of almost 100 × 109/l) developing after ATO commenced. All patients achieved cytological remission during induction therapy with a median of 34 [28;60] days and molecular remission with a median of 8 [4–26] weeks. The OS and RFS rates after a mean follow-up of 17 [7; 56] months were 100% (Fig 1). ATO and ATRA were used to induce remission and for post-remission therapy in children with newly diagnosed APL. In the study by Creutzig et al. (2017), as in our study, no patient failed to respond to ATO induction. Differentiation syndrome occurred in four patients, which was twice the incidence in our series. Only three of our 21 patients (14·3%) required ATO suspension for few days, like those in the Creutzig et al. (2017) study (18·2%). Minor toxicities were quickly resolved (in both studies) by treating the symptoms alone. In the Lo-Coco adult protocol, some toxicities, such as hepatic toxic effects (63%) and QTc interval prolongation (17%) were more common than in our study (Burnett et al., 2015). The combination of ATRA and intensive chemotherapy has been effective in children with APL (Ortega et al., 2005; Sanz et al., 2009). The leading Lo-Coco study (Burnett et al., 2015) showed that ATO/ATRA was not inferior to conventional chemotherapy/ATRA in adults, and the OS was better than that after treatment with ATO alone (Testi et al., 2005). We confirmed these excellent results with OS and RFS rates of 100%, as also reported by Creutzig et al. (2017). The prognosis of the three HR patients was also excellent, which correlated with data of Burnett et al. (2015), Iland et al. (2015) and from the COG-AAML0631 study (Kayser et al., 2018). LikeCreutzig et al. (2017) and Zhou et al. (2010), we found no severe toxicity (≥grade 4) or secondary malignancies during follow-up after ATO monotherapy. However, the median follow-up times were longer in the German and Chinese studies (29 and 53 months, respectively). Combined ATRA/ATO therapy for paediatric patients with SR APL was well tolerated without any severe short-term toxicity. Residual disease seems to evolve favourably with such treatment, and quality of life appears to be satisfactory. Longer follow-up is warranted to assess long-term adverse effects of ATO. Taken together, data suggest that frontline use of ATO/ATRA is very encouraging and could become the standard treatment for paediatric patients with APL, even HR APL, after short induction periods featuring low doses of anthracyclines, like the ongoing COG trial AAML1331 (NCT02339740) examining a regimen in patients aged 12 months to 21 years. No author has any conflict of interest. EGS, SD, BB and GL participated in the conception and design of the study and critically revised the report. EGS and SD participated in data collection, data analysis and drafting of the report. All authors included patients and approved the final report. The English in this document was checked by at least two professional editors, both native speakers of English.

A Multicenter Clinical Study of Cccg - APL-2017 in the Treatment of Children with Acute Promyelocytic Leukemia

Predictors of Early Death in Childhood Acute Promyelocytic Leukemia: Results of an International Retrospective Study

The history of acute promyelocytic leukaemia.

Improved Prevention and Treatment Strategy of Differentiation Syndrome Contribute to Reduce Early Death of Patients with Acute Promyelocytic Leukemia

Incidence, Clinical Features and Outcome of Patients with Differentiation Syndrome in Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid (ATRA) Alone Versus ATRA Plus Idarubicin Versus ATRA Plus Arsenic Trioxide.

Early detection of differentiation syndrome by chest ultrasound in acute promyelocytic leukaemia.

Changes in White Blood Cell Counts Early during Treatment of Acute Leukemia Using Differentiating Chemotherapies

FLT3 Mutations Are Prevalent and Are Significantly Associated with Induction Death In Pediatric Acute Promyelocytic Leukemia, a Report From the Children's Oncology Group

Treatment outcomes for acute promyelocytic leukemia (APL) have improved with all-trans-retinoic acid and arsenic trioxide, yet relapse remains a concern, especially in pediatric patients. The prognostic value of minimal residual disease (MRD) post-induction and the impact of arsenic levels during induction on MRD are not fully understood. To evaluate the relationship between post-induction MRD levels and relapse-free survival (RFS) in pediatric APL patients, and to investigate the correlation between blood arsenic concentration levels during induction therapy and MRD status. A retrospective analysis of pediatric APL patients enrolled in a clinical trial from September 2011 to July 2020. We assessed the relationship between RFS and post-induction MRD levels using the log-rank test. The optimal MRD cut-off was determined using the "surv_cutpoint" function in the survminer R package. Arsenic concentration levels were monitored in 16 patients on days 7 and 14 of induction therapy, and Spearman correlation was used to analyze the relationship between arsenic concentrations and MRD levels. Among 176 pediatric APL patients, with a median follow-up of 6 years, 4 relapsed. Patients with MRD >3.1% had significantly lower RFS compared to those with MRD ⩽3.1% (94.6% vs 100%, p = 0.023). In addition, a negative correlation was found between blood arsenic concentration levels and post-induction MRD levels. Lower arsenic concentrations were associated with higher MRD levels, with significant correlations observed for trough concentrations (R = -0.666, p = 0.005) and peak concentrations (R = -0.499, p = 0.049) on day 7. Our study highlights the prognostic significance of post-induction MRD assessment in pediatric APL. We also demonstrate a negative correlation between blood arsenic concentration levels and MRD, suggesting that lower arsenic concentrations during induction therapy may contribute to a higher MRD burden. These findings may inform strategies to optimize treatment and improve outcomes in pediatric APL.Trial registration: www.clinicaltrials.gov (NCT02200978).