Key PointsQuestion
Is treatment with arsenic trioxide and all-trans retinoic acid (ATRA) without maintenance chemotherapy safe and noninferior to a historically used chemotherapy regimen in maintaining event-free survival among pediatric patients with newly diagnosed acute promyelocytic leukemia (APL)?
Findings
In this nonrandomized, noninferiority trial of 154 pediatric patients with APL who received ATRA and arsenic trioxide therapy, 2-year event-free survival rates among those with standard-risk and high-risk APL were 98% and 96%, respectively, which were noninferior to the rates observed in the historical control group.
Meaning
This trial suggests that pediatric patients with APL could be safely treated with ATRA and arsenic trioxide while either eliminating or substantially reducing the use of cytotoxic chemotherapy among those with standard-risk or high-risk APL, respectively.
Importance
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.
Objective
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.
Design, Setting, and Participants
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.
Interventions
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.
Main Outcomes and Measures
Event-free survival (EFS) at 2 years after diagnosis.
Results
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).
Conclusions and Relevance
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.
Trial Registration
ClinicalTrials.gov Identifier: NCT02339740
The use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATRA/arsenic trioxide) for the treatment of acute promyelocytic leukemia (APL) has been associated with substantial improvements in outcomes, and APL is now the most curable subtype of acute myeloid leukemia. Children in the first North American Intergroup randomized clinical trial (INT0129) who received ATRA during induction therapy and/or maintenance therapy experienced significantly improved disease-free survival compared with those who received conventional chemotherapy only.1 Intensification of anthracycline and cytarabine chemotherapy in combination with ATRA further improved survival, as observed among children who received ATRA and idarubicin (AIDA) in the AIDA0493 study conducted by the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)–Italian Pediatric Hematology and Oncology Group (AIEOP).2 Patients receiving these intensive treatment regimens, which include high cumulative doses of anthracycline chemotherapy, have a high risk of chronic cardiac toxic effects.3,4
The Children’s Oncology Group (COG) AAML0631,5 a historically controlled prospective study of pediatric patients with newly diagnosed APL, included consolidation therapy with two 5-week cycles of arsenic trioxide combined with an anthracycline dose that was cumulatively decreased by approximately 40% compared with the AIDA0493 regimen. Study results revealed that arsenic trioxide was beneficial, with an excellent 2-year event-free survival (EFS) rate among patients with both standard-risk APL (97%) and high-risk APL (83%) and a low risk of relapse (4%). The APL0406 study,6-8 conducted by GIMEMA, Study Alliance Leukemia, and the German-Austrian Acute Myeloid Leukemia Study Group, included adult patients with standard-risk APL who were randomized to receive the AIDA2000 chemotherapy regimen or ATRA/arsenic trioxide therapy alone. Patients in the ATRA/arsenic trioxide arm had an excellent 2-year EFS rate of 97%. The regimen used in the Australasian APML4 study9 included idarubicin and ATRA/arsenic trioxide induction therapy, 2 ATRA/arsenic trioxide consolidation cycles, and 8 maintenance chemotherapy cycles. The 2-year EFS rate was 83% among 23 patients with high-risk APL.
The present COG study (AAML1331) evaluated a chemotherapy-free regimen similar to that used in the APL0406 study among pediatric patients with standard-risk APL. Patients with high-risk APL were enrolled in a separate arm of the study and received a distinct regimen that had not been previously used for the treatment of APL; this regimen included minimal anthracycline (idarubicin) exposure during induction therapy only, ATRA/arsenic trioxide therapy, and no maintenance therapy. The study objective was to examine whether 2-year EFS among pediatric patients with standard-risk and high-risk APL was noninferior compared with the 2-year EFS of patients in the AAML0631 study, which was used as the historical control.
The study began enrollment on June 29, 2015, and closed enrollment when the accrual goals were met for patients with standard-risk APL (June 19, 2018) and high-risk APL (May 7, 2019). Data were collected until October 31, 2020. Patients received treatment at 85 pediatric oncology centers (COG member sites) in Australia, Canada, and the US, with data submitted to a central COG database. The study protocol was approved by the institutional review boards of the participating pediatric oncology centers, and all participants (or their parents or guardians) provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline, with the exception of checklist items for randomization.
Patients eligible for the AAML1331 study were ages 1 to 21 years with newly diagnosed APL determined by morphologic features and cytogenetic testing and confirmed by real-time quantitative polymerase chain reaction (qPCR) testing for the presence of promyelocytic leukemia–retinoic acid receptor α (PML-RARα). Full eligibility criteria are available in the trial protocol in Supplement 1 and the eMethods in Supplement 2. Self-declared race and ethnicity data were collected by each treating institution and reported to the Children’s Oncology Group for study participants in compliance with the requirements of the National Institutes of Health. A total of 158 patients were stratified into risk groups based on their presenting white blood cell (WBC) count (<10 000/μL for the standard-risk APL cohort and ≥10 000/μL for the high-risk APL cohort).
Initiation of treatment with ATRA was encouraged at the first suspicion of APL. Induction therapy included twice daily oral ATRA, 12.5 mg/m2 per dose, and daily intravenous arsenic trioxide, 0.15 mg/kg; both treatments were initiated on day 1 and continued for at least 28 days until confirmation of hematologic complete remission or hematologic complete remission with incomplete hematologic recovery (maximum 70 days allowed). Patients with high-risk APL also received 4 doses of idarubicin, 12.0 mg/m2 per dose (patients with body surface area <0.6 m2 received 0.4 mg/kg per dose) on days 1, 3, 5, and 7 as well as empirical therapy for differentiation syndrome (definition in eMethods in Supplement 2) with twice daily dexamethasone, 2.5 mg/m2, on days 1 to 14. All patients received 4 cycles (3 cycles of 8 weeks’ duration and 1 cycle of 4 weeks’ duration) of ATRA/arsenic trioxide consolidation therapy and no maintenance therapy (eTable 1 in Supplement 2). Molecular remission was assessed at the end of consolidation cycle 2 and at the end of all therapies using qPCR testing for the presence of PML-RARα performed by certified laboratories. Evaluation for central nervous system (CNS) disease via lumbar puncture at initial diagnosis was recommended only for patients with neurologic symptoms. Only patients with evidence of leukemia promyeloblasts in atraumatic cerebrospinal fluid or with CNS hemorrhage received intrathecal triple therapy (eMethods in Supplement 2). The protocol included detailed guidelines for managing coagulopathy, leukocytosis, and differentiation syndrome (Supplement 1).
Primary aims included separate noninferiority comparisons for standard-risk vs high-risk APL to evaluate the 2-year EFS of patients in the present study (AAML1331) vs the AAML0631 study. The present study was initially designed for comparison with the AIDA0493 study but included a specified plan to amend the protocol to change the comparator group, which allowed comparison with the AAML0631 study when results were available. The EFS rate for patients with standard-risk APL in the present study was compared with a fixed EFS rate of 97% at 24 months (which was observed among patients with standard-risk APL in the AAML0631 study) using a noninferiority margin of 10%. The EFS rate for patients with high-risk APL in the present study was compared with a fixed EFS rate of 83% at 24 months (which was observed among patients with high-risk APL in the AAML0631 study) using a noninferiority margin of 14.5%. This noninferiority margin was based on the observed precision (measured by CI) of the EFS estimate for high-risk patients in the AAML0631 study. The Kaplan-Meier method was used to estimate 2-year EFS along with log-minus-log–transformed 90% CIs, which were separately calculated for patients with standard-risk and high-risk APL.
The Kaplan-Meier method was used to estimate overall survival (time from study entry until death) and EFS (time from study entry until failure to achieve hematologic complete remission or hematologic complete remission with incomplete hematologic recovery by day 70 of induction therapy; time from study entry until failure to achieve molecular remission after consolidation cycle 2, including consolidation therapy, if needed, for those with molecular residual disease; or time from study entry until relapse or death).10 Cumulative incidence was used to calculate relapse rate, which was defined as the time from the end of induction therapy (for patients in hematologic complete remission or hematologic complete remission with incomplete hematologic recovery) to relapse or death, in which deaths without relapse were considered competing events.11 Disease relapse was defined as the reappearance of promyeloblasts or abnormal promyelocytes (>5%) or 2 consecutive positive results for the presence of PML-RARα on qPCR tests of the bone marrow. Further details about the statistical design, including power calculations, are available in the redacted trial protocol in Supplement 1 and eMethods in Supplement 2.
Data were analyzed using SAS software, version 9.4 (SAS Institute). The significance threshold was 1-sided P < .05 for primary aims (with comparison for noninferiority and no separate equivalence analysis). Further details about the statistical analysis are available in the redacted trial protocol in Supplement 1 and the eMethods in Supplement 2.
Among 158 patients enrolled, 4 patients (3 with standard-risk APL and 1 with high-risk APL) were not evaluable because their APL diagnosis could not be confirmed by qPCR testing for the presence of PML-RARα. Thus, the final analyses included 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male [52.6%] and 73 female [47.4%]); of those, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. Only 8 patients (5.2%) withdrew from the study before completing therapy (Figure 1). Central review of cytogenetics was available for 144 patients. Among 144 patients, 101 (70.1%) had chromosomal translocation t(15;17) only, whereas 43 (29.9%) had additional genetic abnormalities that did not differ significantly between the standard-risk APL cohort (33 of 95 patients [34.7%]) vs the high-risk APL cohort (10 of 49 patients [20.4%]; P = .09). Clinical characteristics of patients in the AAML0631 study were similar (eg, 62 of 98 patients [63.3%] had chromosomal translocation t[15;17] only, and 36 of 98 [36.7%] had additional genetic abnormalities) (Table 1).
Patients with CNS disease or CNS hemorrhage received intrathecal triple therapy. Central nervous system hemorrhage occurred in 7 of 98 patients (7.1%) with standard-risk APL and 6 of 56 patients (10.7%) with high-risk APL, and 2 of those patients also met the criteria for CNS disease. An additional 5 patients had CNS disease without CNS hemorrhage.
Disease Complications and Treatment Toxic Effects
One patient with standard-risk APL died of sepsis on day 31 of induction therapy after experiencing complications of leukocytosis, coagulopathy, differentiation syndrome, and kidney failure requiring dialysis. Death rates during induction therapy in the AAML1331 vs AAML0631 studies were 0.6% vs 4.0% (P = .08) for all patients, 1.0% vs 0% (P = .16) for patients with standard-risk APL, and 0% vs 11.4% (P = .02) for patients with high-risk APL. Most patients (125 of 154 [81.2%]) in the AAML1331 study received ATRA before beginning protocol therapy, as recommended when APL was first suspected.
The differentiating effect of ATRA/arsenic trioxide therapy can produce an increase in WBC counts. Among patients with high-risk APL, cytoreduction was achieved with 4 doses of idarubicin therapy, but patients with standard-risk APL required initiation of hydroxyurea therapy if hyperleukocytosis developed. The median maximum WBC counts during induction therapy among patients with standard-risk APL were 13 985/μL (range, 5000/μL-82 600/μL). In total, 32 patients with standard-risk APL developed WBC counts greater than 10 000/μL, and 7 patients developed WBC counts greater than 50 000/μL. Symptoms consistent with differentiation syndrome during induction therapy were reported in 24 of 98 patients (24.5%) with standard-risk APL and 17 of 56 patients (30.4%) with high-risk APL. Among the 41 patients with differentiation syndrome, the most common symptoms were respiratory distress (28 patients [68.3%]) and fever (26 patients [63.4%]). Some patients had more severe complications of acute kidney failure (n = 2) or hypotension (n = 6), but no cases of congestive heart failure occurred (eTable 2 in Supplement 2). The median duration of treatment with dexamethasone therapy among patients with differentiation syndrome was 8 days (range, 0-28 days). Three patients received less dosing than the protocol-recommended minimum of 3 days.
Clinically significant bleeding or thrombosis events occurred in 20 of 154 patients (13.0%) during induction therapy. The most common types of bleeding were nasal, gingival, and vaginal. No deaths owing to coagulopathy occurred.
Overall, therapy was well tolerated, and rates of febrile neutropenia and infection were low. The number of days hospitalized was lower among patients in the AAML1331 study compared with the AAML0631 study (eg, median during consolidation cycle 4, 0 days [range, 0-21 days] vs 13 days [range, 0-34 days], respectively; P < .001) (eTable 3 in Supplement 2). Reporting of cardiac adverse events revealed low rates of organ dysfunction (eTable 4 in Supplement 2). The incidence of pseudotumor cerebri, an adverse effect of ATRA, was 12 of 154 patients (7.8%) during induction therapy and ranged from 0 of 145 patients (0%) during consolidation cycle 4 to 7 of 151 patients (4.6%) during consolidation cycle 1.
All patients achieved hematologic complete remission or hematologic complete remission with incomplete hematologic recovery before day 70 of induction therapy. The median duration of induction therapy was 47 days (range, 14-75 days), which included a 14-day treatment-free period between the end of induction therapy and the initiation of consolidation therapy. All patients who received qPCR testing for the presence of PML-RARα at the end of consolidation cycle 2 were in molecular remission (Figure 1; eResults in Supplement 2).
The 2-year overall survival rates in the AAML1331 study were 99.0% (90% CI, 94.8%-99.8%) among patients with standard-risk APL and 100% (90% CI, 93.0%-100%) among patients with high-risk APL. The 2-year EFS rates were 98.0% (90% CI, 93.4%-99.3%) among patients with standard-risk APL and 96.4% (90% CI, 88.2%-98.8%) among patients with high-risk APL (eFigure in Supplement 2). These rates met the prespecified statistical plan criteria, revealing that the EFS rates for both standard-risk and high-risk APL cohorts were noninferior to EFS rates in the AAML0631 study (Figure 2; Table 2). 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. No secondary cancers were reported.
Three patients had APL relapse, with a cumulative incidence of relapse at 2 years of 2.1% (1.1% for those with standard-risk APL and 3.9% for those with high-risk APL). Molecular relapse was counted as an event based on the study protocol and included patients who had normal marrow promyeloblast counts (<5%) but positive results for the presence of PML-RARα on 2 consecutive qPCR tests of the bone marrow. One patient with standard-risk APL experienced molecular bone marrow relapse (along with CNS 2a status [promyeloblasts present but cerebrospinal fluid WBC count <5/μL]) 4 months after therapy, received chemotherapy and autologous stem cell transplant, and was alive at last follow-up more than 3.5 years after diagnosis. One patient with high-risk APL experienced molecular relapse at 4 months after therapy and was alive at 3.5 years after diagnosis (relapse treatment was not reported). Another patient with high-risk APL experienced relapse in the bone marrow at 9 months after therapy, received chemotherapy and allogeneic stem cell transplant, and was alive at approximately 3 years after diagnosis.
This noninferiority trial found excellent patient survival rates, suggesting that ATRA/arsenic trioxide therapy was beneficial for the treatment of pediatric patients with standard-risk and high-risk APL. The study results confirmed that pediatric patients with standard-risk APL could be safely treated with ATRA/arsenic trioxide therapy and could achieve results similar to those in adult patients, for which this treatment has become the preferred regimen. We also found the best outcomes to date among a large group of patients with high-risk APL. The novel treatment regimen for those with high-risk APL, which included limited use of anthracycline (during induction therapy only) without other cytotoxic chemotherapy and shortened treatment duration without the use of maintenance therapy, set a new standard for the treatment of childhood APL.
Similar to adults with APL, presenting WBC count has also historically been associated with outcomes among pediatric patients with APL. In the Italian GIMEMA-AIEOP AIDA0493 study, patients with high-risk APL (WBC count at diagnosis ≥10 000/μL) had a 10-year EFS rate of 59% compared with 83% among patients with standard-risk APL.2 Both the International Consortium for Childhood APL study (ICC APL-01) and the AAML0631 study included risk-adapted therapy, with a reduction in anthracycline dose compared with the AIDA0493 study.5,12 The AAML0631 study included two 5-week arsenic trioxide cycles during consolidation therapy based on the favorable results reported in the North American Intergroup C9710 randomized clinical trial of patients with APL.13,14 Notably, in the AAML0631 study, the relapse rate was low (4%) and was similar among patients with both standard-risk and high-risk APL.5 Arsenic trioxide consolidation therapy successfully eliminated the increased relapse risk that is traditionally associated with high-risk APL, albeit in the context of a regimen with multiple intensive cytotoxic chemotherapy cycles and prolonged maintenance therapy. Patients with high-risk APL still had a higher rate of early death during induction therapy compared with patients with standard-risk APL (11.4% vs 0%), which accounted for most of the difference in EFS between groups.
The AAML1331 study design tested the benefit of repeated cycles of ATRA/arsenic trioxide therapy without maintenance therapy, but the study included important differences in induction therapy between the standard-risk and high-risk APL treatment arms. Treatment in the standard-risk APL arm was based on the ATRA/arsenic trioxide chemotherapy-free regimen developed by investigators at the MD Anderson Cancer Center.15,16 Further evaluation of this regimen in the APL0406 study found that almost all adult patients with standard-risk APL could be cured with ATRA/arsenic trioxide therapy without chemotherapy.6,7 However, the AAML1331 study used a lower pediatric dose of ATRA (25 mg/m2 per day) to minimize pseudotumor cerebri, which are adverse effects more commonly observed among children than adults receiving ATRA. The results of the AAML1331 study confirmed that the ATRA/arsenic trioxide regimen was safe and beneficial (2-year EFS rate of 98%) for the treatment of pediatric patients with standard-risk APL.
The design of the high-risk APL arm included 4 doses of idarubicin in the induction cycle along with continuous dosing of ATRA/arsenic trioxide based on the induction regimen used in the Australasian APML4 study.17 The APML4 regimen had favorable results among 23 patients with high-risk APL and is included as a preferred regimen in the National Comprehensive Cancer Network guidelines for the treatment of adults with high-risk APL.18 In contrast to the APML4 study, the AAML1331 study initiated arsenic trioxide on day 1 of induction therapy to rapidly reverse APL coagulopathy and included 14 days of dexamethasone therapy to prevent differentiation syndrome. An MD Anderson Cancer Center study,15 the SWOG 0535 study,19 and the UK MRC17 study20 all used ATRA/arsenic trioxide–based therapy for adult patients with high-risk APL, but induction therapy included treatment with gemtuzumab ozogamicin rather than an anthracycline. Specific to the AAML1331 study, the consolidation therapy used for the treatment of high-risk APL was the same as that used for standard-risk APL. In contrast to the regimen used in the APML4 study and the AIDA0493 and AAML0631 studies of pediatric APL, no maintenance therapy was administered in the AAML1331 study. This lack of maintenance therapy substantially shortened the duration of therapy, from greater than 2 years to approximately 9 months, while achieving high survival rates (2-year EFS of 96.4%) among patients with high-risk APL. It will be important to evaluate long-term outcomes for this novel regimen.
The differentiating effect of both arsenic trioxide and ATRA can result in hyperleukocytosis. Patients with high-risk APL received 4 doses of idarubicin therapy, which produced rapid reductions in WBC counts. Patients with standard-risk APL who developed hyperleukocytosis (WBC >10 000/μL) required hydroxyurea therapy. Clinical signs and symptoms of differentiation syndrome were successfully managed with ATRA/arsenic trioxide dose-holding plus dexamethasone therapy, and only 8 patients experienced more severe complications associated with differentiation syndrome, including hypotension and kidney dysfunction.
The rates of CNS disease and relapse among patients with pediatric APL are generally low.21 Arsenic trioxide can penetrate the CNS and achieve cerebrospinal fluid levels at approximately 50% of serum levels.22 Central nervous system disease at relapse was observed in 2 of 3 APL relapses among patients in the AAML0631 study, which included treatment with prophylactic intrathecal cytarabine for all patients (3 doses for those with standard-risk APL and 4 doses for those with high-risk APL) but only 2 cycles of arsenic trioxide in consolidation.5 In the AAML1331 study, intrathecal triple chemotherapy was administered only to patients with documented CNS disease or CNS hemorrhage. The latter group received this treatment because studies conducted by the PETHEMA (Programa Para el Estudio de la Terapéutica en Hemopatías Malignas) group identified CNS hemorrhage as a risk factor associated with relapse.23-25 Only 1 case of CNS 2 disease (ie, promyeloblasts present but cerebrospinal fluid WBC count <5/μL) was observed in the few patients who experienced relapse in the AAML1331 study, revealing that most patients with pediatric APL who received arsenic trioxide did not require intrathecal treatment. However, among patients with CNS disease or CNS hemorrhage, intrathecal triple therapy was beneficial. Because many pediatric patients require sedation when undergoing lumbar puncture, limited use of intrathecal therapy in the AAML1331 study represented a substantial advancement in the treatment of pediatric patients with APL; this limited use can decrease the risk of sedation complications and the neurological or neurocognitive adverse effects of intrathecal therapy.
The low early death rate in the present study, particularly among patients with high-risk APL, may be associated with several features of the treatment regimen that differed from the AAML0631 study. Patients were encouraged to start pretreatment with ATRA when APL was first suspected, and this approach has been associated with fewer early deaths.26-28 Early introduction of arsenic trioxide on day 1 of therapy (even concurrently with idarubicin doses in patients with high-risk APL) has been associated with rapid degradation of PML-RARα and promyeloblast apoptosis and may help stabilize coagulopathy.29 Dexamethasone rather than prednisone therapy (as used in the APML4 and APL0406 studies) was administered as prophylaxis against differentiation syndrome based on the low rates of complications associated with differentiation syndrome that were observed in the PETHEMA LPA2005 study, which used dexamethasone therapy.30 The protocol included detailed recommendations for monitoring differentiation syndrome and coagulopathy and provided aggressive supportive care guidelines. As patients enrolled in the study, the treating site was contacted by email to highlight the risk of early death, reference supportive care, and offer advice from expert study committee members. The early death rate among pediatric patients with APL is approximately 5%, and a high initial WBC count (ie, high-risk APL) is a clear risk factor associated with early death.26 The early death rate was approximately 10% in the high-risk APL cohorts of both the AIDA0493 and AAML0631 studies.2,5 The supportive care used in the AAML1331 study was associated with no deaths among the 56 patients with high-risk APL.
This study has limitations. These limitations included its design as a historical comparison study and its sample of fewer than 200 patients; however, the study is considered large for an assessment of APL because of the rarity of the disease. The results are generalizable because of broad multi-institutional involvement through a large cooperative group. Disease events beyond 2 years after diagnosis rarely occur among pediatric patients with APL, but it will be important to assess long-term outcomes from this study. Although the treatment regimen used in the AAML1331 study was beneficial, numerous doses of intravenous arsenic trioxide (typically requiring administration in a health care facility) are a major stressor for patients and families. Thus, the next steps in optimizing APL therapy will be to minimize the burden of care by evaluating emerging oral forms of arsenic and to ensure that these oral treatments can safely and successfully replace intravenous arsenic trioxide.31
This nonrandomized, noninferiority trial found that pediatric patients with standard-risk APL could be successfully and safely treated with ATRA/arsenic trioxide therapy, similar to adult patients with standard-risk APL. Among pediatric patients with high-risk APL, the administration of ATRA/arsenic trioxide therapy, with idarubicin added only during induction and no maintenance therapy, was associated with excellent event-free and overall survival rates. These outcomes met noninferiority criteria, with the additional advantages of the regimen including shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days in the hospital.
Accepted for Publication: August 2, 2021.
Published Online: November 11, 2021. doi:10.1001/jamaoncol.2021.5206
Corresponding Author: Matthew A. Kutny, MD, Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 Seventh Ave S, Lowder 512, Birmingham, AL 35233 (mkutny@peds.uab.edu).
Author Contributions: Dr Kutny had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Feusner and Gregory contributed equally as co-last authors.
Concept and design: Kutny, Alonzo, Abla, Rajpurkar, S. Hardy, Gamis, Kolb, Feusner, Gregory.
Acquisition, analysis, or interpretation of data: Kutny, Alonzo, Abla, Rajpurkar, Gerbing, Wang, Hirsch, Raimondi, Kahwash, K. Hardy, Meshinchi, Gamis, Kolb, Gregory.
Drafting of the manuscript: Kutny, Alonzo, Gerbing, Hirsch, Raimondi, Meshinchi, Gamis, Kolb, Gregory.
Critical revision of the manuscript for important intellectual content: Kutny, Alonzo, Abla, Rajpurkar, Wang, Hirsch, Kahwash, K. Hardy, S. Hardy, Gamis, Kolb, Feusner, Gregory.
Statistical analysis: Kutny, Alonzo, Gerbing, Wang.
Obtained funding: Kutny.
Administrative, technical, or material support: Abla, Rajpurkar, Wang, Raimondi, Kahwash, K. Hardy, S. Hardy, Gregory.
Supervision: Kutny, Abla, Kolb, Gregory.
Conflict of Interest Disclosures: Drs Kutny and Hirsch reported receiving grants from the Children’s Oncology Group during the conduct of the study. Dr Rajpurkar reported receiving personal fees from Novo Nordisk outside the submitted work. No other disclosures were reported.
Funding/Support: This work was supported by grants U10CA180886 and U10CA180899 from the National Institutes of Health (Children’s Oncology Group) and grant U24CA196173 from the St. Baldrick’s Foundation (Children’s Oncology Group).
Role of the Funder/Sponsor: The Children’s Oncology Group investigators designed the trial. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program reviewed the trial, made recommendations for changes, and approved the final trial design. All amendments were reviewed and approved by the NCI. The Children’s Oncology Group investigators conducted the trial and performed the collection, management, analysis, and interpretation of the data. The authors prepared, reviewed, and approved the manuscript. The decision to submit the manuscript for publication was made by the authors.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Additional Contributions: Teni Karimian, MS, of Children’s Oncology Group (COG), and Jeannette Cassar, BA, of COG, served as protocol coordinators; Wendy Lee, LVN, of COG, was the research coordinator (all received salary support from COG for assisting with the conduct of this study). Vicky Poss, CCRP, of the University of Alabama at Birmingham, was the study clinical research associate; Kathleen Adlard, RN, MN, CPON, of Children’s Hospital of Orange County, was the study nurse; and Sean Green, PharmD, BCOP, of Lucile Packard Children’s Hospital, Stanford University, was the study pharmacist. Vani Shanker, PhD, of Saint Jude Children’s Research Hospital, provided scientific editing of the manuscript. We thank the COG institutions and investigators who cared for children enrolled in this study. We also thank the patients and their families for their willingness to participate in the study.
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