Research

JAMA Oncology | Original Investigation

Assessment of Arsenic Trioxide and All-trans Retinoic Acid

for the Treatment of Pediatric Acute Promyelocytic Leukemia
A Report From the Children’s Oncology Group AAML1331 Trial
Matthew A. Kutny, MD; Todd A. Alonzo, PhD; Oussama Abla, MD; Madhvi Rajpurkar, MD; Robert B. Gerbing, MA; Yi-Cheng Wang, MS;
Betsy A. Hirsch, PhD; Susana Raimondi, PhD; Samir Kahwash, MD; Kristina K. Hardy, PhD; Steven Hardy, PhD; Soheil Meshinchi, MD, PhD;
Alan S. Gamis, MD, MPH; Edward A. Kolb, MD; James H. Feusner, MD; John Gregory Jr, MD

Supplemental content
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 ⱖ10 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. Author Affiliations: Author
The 2-year EFS estimates were noninferior to the historical comparator group, and affiliations are listed at the end of this
advantages of the regimen included shorter treatment duration, lower exposure to article.
anthracycline and intrathecal chemotherapy, and fewer days hospitalized. Corresponding Author: Matthew A.
Kutny, MD, Division of Hematology/
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02339740 Oncology, Department of Pediatrics,
University of Alabama at
Birmingham, 1600 Seventh Ave S,
JAMA Oncol. 2022;8(1):79-87. doi:10.1001/jamaoncol.2021.5206 Lowder 512, Birmingham, AL 35233
Published online November 11, 2021. (mkutny@peds.uab.edu).

(Reprinted) 79
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 Research Original Investigation Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia

T
he use of all-trans retinoic acid (ATRA) and arsenic tri-
oxide (ATRA/arsenic trioxide) for the treatment of acute Key Points
promyelocytic leukemia (APL) has been associated with
Question Is treatment with arsenic trioxide and all-trans retinoic
substantial improvements in outcomes, and APL is now the most acid (ATRA) without maintenance chemotherapy safe and
curable subtype of acute myeloid leukemia. Children in the first noninferior to a historically used chemotherapy regimen in
North American Intergroup randomized clinical trial (INT0129) maintaining event-free survival among pediatric patients with
who received ATRA during induction therapy and/or mainte- newly diagnosed acute promyelocytic leukemia (APL)?
nance therapy experienced significantly improved disease- Findings In this nonrandomized, noninferiority trial of 154
free survival compared with those who received conventional pediatric patients with APL who received ATRA and arsenic
chemotherapy only.1 Intensification of anthracycline and cy- trioxide therapy, 2-year event-free survival rates among those with
tarabine chemotherapy in combination with ATRA further im- standard-risk and high-risk APL were 98% and 96%, respectively,
proved survival, as observed among children who received ATRA which were noninferior to the rates observed in the historical
control group.
and idarubicin (AIDA) in the AIDA0493 study conducted by the
Gruppo Italiano per le Malattie Ematologiche dell'Adulto Meaning This trial suggests that pediatric patients with APL could
(GIMEMA)–Italian Pediatric Hematology and Oncology Group be safely treated with ATRA and arsenic trioxide while either
(AIEOP).2 Patients receiving these intensive treatment regi- eliminating or substantially reducing the use of cytotoxic
chemotherapy among those with standard-risk or high-risk APL,
mens, which include high cumulative doses of anthracycline
respectively.
chemotherapy, have a high risk of chronic cardiac toxic effects.3,4
The Children’s Oncology Group (COG) AAML0631,5 a his-
torically controlled prospective study of pediatric patients with standard-risk APL (June 19, 2018) and high-risk APL (May 7,
newly diagnosed APL, included consolidation therapy with two 2019). Data were collected until October 31, 2020. Patients re-
5-week cycles of arsenic trioxide combined with an anthracy- ceived treatment at 85 pediatric oncology centers (COG mem-
cline dose that was cumulatively decreased by approxi- ber sites) in Australia, Canada, and the US, with data submit-
mately 40% compared with the AIDA0493 regimen. Study re- ted to a central COG database. The study protocol was approved
sults revealed that arsenic trioxide was beneficial, with an by the institutional review boards of the participating pediat-
excellent 2-year event-free survival (EFS) rate among pa- ric oncology centers, and all participants (or their parents or
tients with both standard-risk APL (97%) and high-risk APL guardians) provided written informed consent. This study
(83%) and a low risk of relapse (4%). The APL0406 study,6-8 followed the Consolidated Standards of Reporting Trials
conducted by GIMEMA, Study Alliance Leukemia, and the (CONSORT) reporting guideline, with the exception of checklist
German-Austrian Acute Myeloid Leukemia Study Group, in- items for randomization.
cluded adult patients with standard-risk APL who were ran-
domized to receive the AIDA2000 chemotherapy regimen or Patients
ATRA/arsenic trioxide therapy alone. Patients in the ATRA/ Patients eligible for the AAML1331 study were ages 1 to 21 years
arsenic trioxide arm had an excellent 2-year EFS rate of 97%. with newly diagnosed APL determined by morphologic fea-
The regimen used in the Australasian APML4 study 9 in- tures and cytogenetic testing and confirmed by real-time quan-
cluded idarubicin and ATRA/arsenic trioxide induction therapy, titative polymerase chain reaction (qPCR) testing for the
2 ATRA/arsenic trioxide consolidation cycles, and 8 mainte- presence of promyelocytic leukemia–retinoic acid receptor α
nance chemotherapy cycles. The 2-year EFS rate was 83% (PML-RARα). Full eligibility criteria are available in the trial pro-
among 23 patients with high-risk APL. tocol in Supplement 1 and the eMethods in Supplement 2. Self-
The present COG study (A AML1331) evaluated a declared race and ethnicity data were collected by each treat-
chemotherapy-free regimen similar to that used in the ing institution and reported to the Children’s Oncology Group
APL0406 study among pediatric patients with standard-risk for study participants in compliance with the requirements of
APL. Patients with high-risk APL were enrolled in a separate the National Institutes of Health. A total of 158 patients were
arm of the study and received a distinct regimen that had stratified into risk groups based on their presenting white blood
not been previously used for the treatment of APL; this regi- cell (WBC) count (<10 000/μL for the standard-risk APL co-
men included minimal anthracycline (idarubicin) exposure hort and ≥10 000/μL for the high-risk APL cohort).
during induction therapy only, ATRA/arsenic trioxide
therapy, and no maintenance therapy. The study objective Treatment
was to examine whether 2-year EFS among pediatric Initiation of treatment with ATRA was encouraged at the first
patients with standard-risk and high-risk APL was noninfe- suspicion of APL. Induction therapy included twice daily oral
rior compared with the 2-year EFS of patients in the ATRA, 12.5 mg/m2 per dose, and daily intravenous arsenic tri-
AAML0631 study, which was used as the historical control. oxide, 0.15 mg/kg; both treatments were initiated on day 1 and
continued for at least 28 days until confirmation of hemato-
logic complete remission or hematologic complete remission
with incomplete hematologic recovery (maximum 70 days al-
Methods lowed). Patients with high-risk APL also received 4 doses of
The study began enrollment on June 29, 2015, and closed en- idarubicin, 12.0 mg/m2 per dose (patients with body surface
rollment when the accrual goals were met for patients with area <0.6 m2 received 0.4 mg/kg per dose) on days 1, 3, 5, and

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 Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia Original Investigation Research

7 as well as empirical therapy for differentiation syndrome statistical design, including power calculations, are available
(definition in eMethods in Supplement 2) with twice daily dexa- in the redacted trial protocol in Supplement 1 and eMethods
methasone, 2.5 mg/m2, on days 1 to 14. All patients received 4 in Supplement 2.
cycles (3 cycles of 8 weeks’ duration and 1 cycle of 4 weeks’ Data were analyzed using SAS software, version 9.4 (SAS
duration) of ATRA/arsenic trioxide consolidation therapy and Institute). The significance threshold was 1-sided P < .05 for
no maintenance therapy (eTable 1 in Supplement 2). Molecu- primary aims (with comparison for noninferiority and no sepa-
lar remission was assessed at the end of consolidation cycle 2 rate equivalence analysis). Further details about the statisti-
and at the end of all therapies using qPCR testing for the pres- cal analysis are available in the redacted trial protocol in
ence of PML-RARα performed by certified laboratories. Evalu- Supplement 1 and the eMethods in Supplement 2.
ation for central nervous system (CNS) disease via lumbar punc-
ture at initial diagnosis was recommended only for patients
with neurologic symptoms. Only patients with evidence of leu-
kemia promyeloblasts in atraumatic cerebrospinal fluid or with
Results
CNS hemorrhage received intrathecal triple therapy (eMethods Patient Characteristics
in Supplement 2). The protocol included detailed guidelines Among 158 patients enrolled, 4 patients (3 with standard-risk
for managing coagulopathy, leukocytosis, and differentia- APL and 1 with high-risk APL) were not evaluable because their
tion syndrome (Supplement 1). APL diagnosis could not be confirmed by qPCR testing for the
presence of PML-RARα. Thus, the final analyses included 154
Statistical Analysis patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male
Primary aims included separate noninferiority comparisons for [52.6%] and 73 female [47.4%]); of those, 98 patients (63.6%)
standard-risk vs high-risk APL to evaluate the 2-year EFS of pa- had standard-risk APL, and 56 patients (36.4%) had high-risk
tients in the present study (AAML1331) vs the AAML0631 study. APL. Only 8 patients (5.2%) withdrew from the study before
The present study was initially designed for comparison with completing therapy (Figure 1). Central review of cytogenetics
the AIDA0493 study but included a specified plan to amend was available for 144 patients. Among 144 patients, 101 (70.1%)
the protocol to change the comparator group, which allowed had chromosomal translocation t(15;17) only, whereas 43
comparison with the AAML0631 study when results were avail- (29.9%) had additional genetic abnormalities that did not dif-
able. The EFS rate for patients with standard-risk APL in the fer significantly between the standard-risk APL cohort (33 of
present study was compared with a fixed EFS rate of 97% at 95 patients [34.7%]) vs the high-risk APL cohort (10 of 49 pa-
24 months (which was observed among patients with standard- tients [20.4%]; P = .09). Clinical characteristics of patients in
risk APL in the AAML0631 study) using a noninferiority mar- the AAML0631 study were similar (eg, 62 of 98 patients [63.3%]
gin of 10%. The EFS rate for patients with high-risk APL in the had chromosomal translocation t[15;17] only, and 36 of 98
present study was compared with a fixed EFS rate of 83% at [36.7%] had additional genetic abnormalities) (Table 1).
24 months (which was observed among patients with high- Patients with CNS disease or CNS hemorrhage received in-
risk APL in the AAML0631 study) using a noninferiority mar- trathecal triple therapy. Central nervous system hemorrhage
gin of 14.5%. This noninferiority margin was based on the ob- occurred in 7 of 98 patients (7.1%) with standard-risk APL and
served precision (measured by CI) of the EFS estimate for high- 6 of 56 patients (10.7%) with high-risk APL, and 2 of those pa-
risk patients in the AAML0631 study. The Kaplan-Meier method tients also met the criteria for CNS disease. An additional 5
was used to estimate 2-year EFS along with log-minus-log– patients had CNS disease without CNS hemorrhage.
transformed 90% CIs, which were separately calculated for
patients with standard-risk and high-risk APL. Disease Complications and Treatment Toxic Effects
The Kaplan-Meier method was used to estimate overall sur- One patient with standard-risk APL died of sepsis on day 31 of
vival (time from study entry until death) and EFS (time from induction therapy after experiencing complications of leuko-
study entry until failure to achieve hematologic complete re- cytosis, coagulopathy, differentiation syndrome, and kidney
mission or hematologic complete remission with incomplete failure requiring dialysis. Death rates during induction therapy
hematologic recovery by day 70 of induction therapy; time in the AAML1331 vs AAML0631 studies were 0.6% vs 4.0%
from study entry until failure to achieve molecular remission (P = .08) for all patients, 1.0% vs 0% (P = .16) for patients with
after consolidation cycle 2, including consolidation therapy, standard-risk APL, and 0% vs 11.4% (P = .02) for patients with
if needed, for those with molecular residual disease; or time high-risk APL. Most patients (125 of 154 [81.2%]) in the
from study entry until relapse or death).10 Cumulative inci- AAML1331 study received ATRA before beginning protocol
dence was used to calculate relapse rate, which was defined therapy, as recommended when APL was first suspected.
as the time from the end of induction therapy (for patients in The differentiating effect of ATRA/arsenic trioxide therapy
hematologic complete remission or hematologic complete re- can produce an increase in WBC counts. Among patients with
mission with incomplete hematologic recovery) to relapse or high-risk APL, cytoreduction was achieved with 4 doses of ida-
death, in which deaths without relapse were considered com- rubicin therapy, but patients with standard-risk APL required
peting events.11 Disease relapse was defined as the reappear- initiation of hydroxyurea therapy if hyperleukocytosis devel-
ance of promyeloblasts or abnormal promyelocytes (>5%) or oped. The median maximum WBC counts during induction
2 consecutive positive results for the presence of PML-RARα therapy among patients with standard-risk APL were 13 985/μL
on qPCR tests of the bone marrow. Further details about the (range, 5000/μL-82 600/μL). In total, 32 patients with

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 Research Original Investigation Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia

acute kidney failure (n = 2) or hypotension (n = 6), but no cases

Figure 1. Participant Enrollment, Treatment, and Follow-up
of congestive heart failure occurred (eTable 2 in Supple-
158 Pediatric patients with APL enrolled
ment 2). The median duration of treatment with dexametha-
sone therapy among patients with differentiation syndrome
4 Excluded was 8 days (range, 0-28 days). Three patients received less dos-
3 Had negative results for ing than the protocol-recommended minimum of 3 days.
PML-RARα on RT-qPCR test
1 Did not have results from Clinically significant bleeding or thrombosis events oc-
RT-qPCR test for PML-RARα curred in 20 of 154 patients (13.0%) during induction therapy.
before initiating protocol
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 neu-
98 With standard-risk APL 56 With high-risk APL received tropenia and infection were low. The number of days hospi-
received induction therapya induction therapyb
talized was lower among patients in the AAML1331 study com-
pared with the A AML0631 study (eg, median during
1 Died during induction therapy 1 Withdrew
1 Withdrew 1 Physician determined consolidation cycle 4, 0 days [range, 0-21 days] vs 13 days
1 Declined further receipt further receipt of protocol [range, 0-34 days], respectively; P < .001) (eTable 3 in Supple-
of protocol therapy therapy was not in
patient’s best interest ment 2). Reporting of cardiac adverse events revealed low rates
of organ dysfunction (eTable 4 in Supplement 2). The inci-
96 Received cycle 1 of
consolidation therapy 55 Received cycle 1 of dence of pseudotumor cerebri, an adverse effect of ATRA, was
consolidation therapy 12 of 154 patients (7.8%) during induction therapy and ranged
from 0 of 145 patients (0%) during consolidation cycle 4 to 7
3 Withdrew
55 Received cycle 2 of of 151 patients (4.6%) during consolidation cycle 1.
2 Declined further receipt of
consolidation therapy
protocol therapy
1 Did not consent to further
data submission Response Data
1 Withdrew
1 Declined further receipt All patients achieved hematologic complete remission or he-
93 Received cycle 2 of of protocol therapy matologic complete remission with incomplete hematologic
consolidation therapy recovery before day 70 of induction therapy. The median du-
54 Had 100% molecular ration of induction therapy was 47 days (range, 14-75 days),
remission rate
1 Withdrew which included a 14-day treatment-free period between the end
1 Did not consent to further
data submission of induction therapy and the initiation of consolidation therapy.
54 Received cycle 3 of
consolidation therapy All patients who received qPCR testing for the presence of
92 Had 100% molecular
PML-RARα at the end of consolidation cycle 2 were in molecu-
remission rate lar remission (Figure 1; eResults in Supplement 2).
1 Withdrew
1 Physician determined The 2-year overall survival rates in the AAML1331 study
further receipt of protocol
92 Received cycle 3 of therapy was not in were 99.0% (90% CI, 94.8%-99.8%) among patients with stan-
consolidation therapy patient’s best interest dard-risk APL and 100% (90% CI, 93.0%-100%) among pa-
tients with high-risk APL. The 2-year EFS rates were 98.0%
92 Received cycle 4 of 53 Received cycle 4 of (90% CI, 93.4%-99.3%) among patients with standard-risk APL
consolidation therapy consolidation therapy
and 96.4% (90% CI, 88.2%-98.8%) among patients with high-
risk APL (eFigure in Supplement 2). These rates met the pre-
1 Experienced APL relapse 2 Experienced APL relapse
specified statistical plan criteria, revealing that the EFS rates
for both standard-risk and high-risk APL cohorts were nonin-
APL indicates acute promyelocytic leukemia; PML-RARα, promyelocytic ferior to EFS rates in the AAML0631 study (Figure 2; Table 2).
leukemia–retinoic acid receptor α; and RT-qPCR, real-time quantitative
polymerase chain reaction. The median follow-up duration was 24.7 months (range, 0-49.5
a
Standard-risk APL was defined as a white blood cell count of less than months) for patients with standard-risk APL and 22.8 months
10 000/μL. (range, 0-47.7 months) for patients with high-risk APL. No sec-
b
High-risk APL was defined as a white blood cell count of 10 000/μL or greater. ondary cancers were reported.
Three patients had APL relapse, with a cumulative inci-
dence of relapse at 2 years of 2.1% (1.1% for those with standard-
standard-risk APL developed WBC counts greater than risk APL and 3.9% for those with high-risk APL). Molecular re-
10 000/μL, and 7 patients developed WBC counts greater than lapse was counted as an event based on the study protocol and
50 000/μL. Symptoms consistent with differentiation syn- included patients who had normal marrow promyeloblast
drome during induction therapy were reported in 24 of 98 pa- counts (<5%) but positive results for the presence of PML-
tients (24.5%) with standard-risk APL and 17 of 56 patients RARα on 2 consecutive qPCR tests of the bone marrow. One
(30.4%) with high-risk APL. Among the 41 patients with dif- patient with standard-risk APL experienced molecular bone
ferentiation syndrome, the most common symptoms were re- marrow relapse (along with CNS 2a status [promyeloblasts pre-
spiratory distress (28 patients [68.3%]) and fever (26 patients sent but cerebrospinal fluid WBC count <5/μL]) 4 months af-
[63.4%]). Some patients had more severe complications of ter therapy, received chemotherapy and autologous stem cell

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 Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia Original Investigation Research

Table 1. Characteristics of Patients Enrolled in the Children’s Oncology Group AAML0631 and AAML1331 Studies

Standard-risk APL cohort, No./total No. (%)a High-risk APL cohort, No./total No. (%)b
Characteristic AAML0631 (n = 66) AAML1331 (n = 98) P value AAML0631 (n = 35) AAML1331 (n = 56) P value
Sex
Female 35/66 (53.0) 48/98 (49.0) 22/35 (62.9) 25/56 (44.6)
.61 .09
Male 31/66 (47.0) 50/98 (51.0) 13/35 (37.1) 31/56 (55.4)
Age, median (range), y 14.8 (2.4-21.3) 15.4 (2.3-21.7) .62 15.2 (2.0-19.0) 12.6 (1.1-20.8) .22
Racec
American Native 2/63 (3.2) 3/82 (3.7) >.99 0 0 NA
Asian 0 3/82 (3.7) .26 3/35 (8.6) 3/49 (6.1) .69
Black 7/63 (11.1) 13/82 (15.9) .41 3/35 (8.6) 13/49 (26.5) .04
White 51/63 (81.0) 59/82 (72.0) .21 27/35 (77.1) 33/49 (67.3) .33
Otherd 3/63 (4.8) 4/82 (4.9) >.99 2/35 (5.7) 0 .17
Ethnicitye
Hispanic 14/64 (21.9) 32/86 (37.2) 5/34 (14.7) 14/50 (28.0)
.04 .15
Non-Hispanic 50/64 (78.1) 54/86 (62.8) 29/34 (85.3) 36/50 (72.0)
M3v 6/66 (9.1) 16/98 (16.3) .18 14/35 (40.0) 24/56 (42.9) .79
Cytogenetic complexityf
Chromosomal 38/66 (57.6) 62/95 (65.3) 24/32 (75.0) 39/49 (80.0)
translocation t(15;17)
only .32 .63
Additional abnormalities 28/66 (42.4) 33/95 (34.7) 8/32 (25.0) 10/49 (20.4)
ECOG scoreg
0 39/64 (60.9) 62/98 (63.3) .70 9/33 (27.3) 27/56 (48.2) .04
1 14/64 (21.9) 22/98 (22.4) .91 11/33 (33.3) 17/56 (30.4) .86
2 6/64 (9.4) 6/98 (6.1) .54 8/33 (24.2) 5/56 (8.9) .07
3 1/64 (1.6) 5/98 (5.1) .40 2/33 (6.1) 2/56 (3.6) .63
4 4/64 (6.3) 2/98 (2.0) .22 3/33 (9.1) 3/56 (5.4) .67
WBCs, median (range), 1.8 (0.4-9.5) 2.4 (0.2-8.9) .21 25.2 (11.2-173.8) 41.1 (10.2-255.1) .17
×1000/μL
Platelets, median (range), 19.0 (3.0-198.0) 21.0 (2.0-650.0) .65 24.0 (5.0-107.0) 18.5 (5.0-99.0) .42
×1000/μL
Abbreviations: APL, acute promyelocytic leukemia; ECOG, Eastern Cooperative standard-risk cohort and 1 patient in the high-risk cohort. In the AAML1331
Oncology Group; M3v, microgranular variant; NA, not applicable; WBC, white study, ethnicity was unknown for 12 patients in the standard-risk cohort and 6
blood cell. patients in the high-risk cohort.
a f
Standard-risk APL was defined as a WBC count of less than 10 000/μL. In the AAML0631 study, data were missing for 3 patients in the high-risk
b
High-risk APL was defined as a WBC count of 10 000/μL or greater. cohort. In the AAML1331 study, data were missing for 3 patients in the
c
standard-risk cohort and 7 patients in the high-risk cohort.
In the AAML0631 study, race was unknown for 3 patients in the standard-risk
g
cohort. In the AAML1331 study, race was unknown for 16 patients in the In the AAML0631 study, 2 patients in the standard-risk cohort and 2 patients in
standard-risk and 7 patients in the high-risk cohort. the high-risk cohort were not evaluated. In the AAML1331 study, 1 patient in
d
the standard-risk cohort and 2 patients in the high-risk cohort were not
Races in this category included Native Hawaiian, other Pacific Islander, and
evaluated.
multiple races (not specified).
e
In the AAML0631 study, ethnicity was unknown for 2 patients in the

transplant, and was alive at last follow-up more than 3.5 years standard-risk APL could be safely treated with ATRA/arsenic tri-
after diagnosis. One patient with high-risk APL experienced oxide therapy and could achieve results similar to those in adult
molecular relapse at 4 months after therapy and was alive at patients, for which this treatment has become the preferred regi-
3.5 years after diagnosis (relapse treatment was not re- men. We also found the best outcomes to date among a large
ported). Another patient with high-risk APL experienced re- group of patients with high-risk APL. The novel treatment regi-
lapse in the bone marrow at 9 months after therapy, received men for those with high-risk APL, which included limited use
chemotherapy and allogeneic stem cell transplant, and was of anthracycline (during induction therapy only) without other
alive at approximately 3 years after diagnosis. 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 his-
Discussion torically been associated with outcomes among pediatric patients
This noninferiority trial found excellent patient survival rates, with APL. In the Italian GIMEMA-AIEOP AIDA0493 study, patients
suggesting that ATRA/arsenic trioxide therapy was beneficial for with high-risk APL (WBC count at diagnosis ≥10 000/μL) had a
the treatment of pediatric patients with standard-risk and high- 10-year EFS rate of 59% compared with 83% among patients with
risk APL. The study results confirmed that pediatric patients with standard-risk APL.2 Both the International Consortium for

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 Research Original Investigation Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia

Figure 2. Overall and Event-Free Survival Among Patients in the Children’s Oncology Group AAML1331
and AAML0631 Studies by Risk Group

A Event-free survival for standard-risk APL B Event-free survival for high-risk APL
1.0 1.0
Event-free survival

Event-free survival
0.8 0.8
0.6 0.6 AAML 1331
0.4 0.4 AAML 0631
0.2 0.2
P = .71 for 2-year EFS P = .05 for 2-year EFS
0 0

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Years from study entry Years from study entry
No. at risk No. at risk
AAML0631 66 63 62 51 25 6 0 0 AAML0631 35 30 29 26 14 1 0 0
AAML1331 98 91 86 39 8 0 0 0 AAML1331 56 54 39 15 4 0 0 0

C Overall survival for standard-risk APL D Overall survival for high-risk APL

1.0 1.0
0.8 0.8
Overall survival

0.6 Overall survival 0.6

0.4 0.4
The AAML0631 study included 66
0.2 0.2
P = .78 for 2-year OS P = .02 for 2-year OS patients with standard-risk APL and
0 0 35 patients with high-risk APL. The
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 AAML1331 study included 98 patients
Years from study entry Years from study entry
with standard-risk APL and 56
No. at risk No. at risk patients with high-risk APL.
AAML0631 66 64 63 52 26 7 0 0 AAML0631 35 30 30 26 14 1 0 0 APL indicates acute promyelocytic
AAML1331 98 92 87 40 8 0 0 0 AAML1331 56 54 41 16 4 0 0 0 leukemia; EFS, event-free survival;
and OS, overall survival.

Table 2. Patient Survival in the Children’s Oncology Group AAML0631 and AAML1331 Studies
AAML0631 participants, AAML1331 participants,
Variable No./total No. (%) No./total No. (%) [90% CI] P value
Total patients, No. 101 154 NA
Standard-risk APL 66/101 (65.3) 98/154 (63.6) [NA] NA
High-risk APL 35/101 (34.7) 56/154 (36.4) [NA] NA
Early death
Standard-risk APL 0 1/98 (1.0) [NA] .16
Abbreviations: APL, acute
High-risk APL 4/35 (11.4) 0 .02 promyelocytic leukemia;
2-year EFS rate EFS, event-free survival; NA, not
applicable; OS, overall survival.
Standard-risk APL 64/66 (97.0) 96/98 (98.0) [93.4-99.3] .71a
a
The 2-year EFS in the AAML1331
High-risk APL 29/35 (82.9) 54/56 (96.4) [88.2-98.8] .05a
study met protocol-prespecified
2-year OS rate noninferiority assessments
Standard-risk APL 65/66 (98.5) 97/98 (99.0) [94.8-99.8] .78 compared with the AAML0631
study for both the standard-risk and
High-risk APL 30/35 (85.7) 56/56 (100) [93.0-100] .02
high-risk APL cohorts.

Childhood APL study (ICC APL-01) and the AAML0631 study in- pared with patients with standard-risk APL (11.4% vs 0%), which
cluded risk-adapted therapy, with a reduction in anthracycline accounted for most of the difference in EFS between groups.
dose compared with the AIDA0493 study.5,12 The AAML0631 The AAML1331 study design tested the benefit of re-
study included two 5-week arsenic trioxide cycles during consoli- peated cycles of ATRA/arsenic trioxide therapy without main-
dationtherapybasedonthefavorableresultsreportedintheNorth tenance therapy, but the study included important differ-
American Intergroup C9710 randomized clinical trial of patients ences in induction therapy between the standard-risk and
with APL.13,14 Notably, in the AAML0631 study, the relapse rate high-risk APL treatment arms. Treatment in the standard-
was low (4%) and was similar among patients with both standard- risk APL arm was based on the ATRA/arsenic trioxide chemo-
risk and high-risk APL.5 Arsenic trioxide consolidation therapy therapy-free regimen developed by investigators at the MD
successfully eliminated the increased relapse risk that is tradition- Anderson Cancer Center.15,16 Further evaluation of this regi-
ally associated with high-risk APL, albeit in the context of a regi- men in the APL0406 study found that almost all adult pa-
men with multiple intensive cytotoxic chemotherapy cycles and tients with standard-risk APL could be cured with ATRA/
prolonged maintenance therapy. Patients with high-risk APL still arsenic trioxide therapy without chemotherapy.6,7 However,
had a higher rate of early death during induction therapy com- the AAML1331 study used a lower pediatric dose of ATRA (25

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 Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia Original Investigation Research

mg/m2 per day) to minimize pseudotumor cerebri, which are disease (ie, promyeloblasts present but cerebrospinal fluid WBC
adverse effects more commonly observed among children than count <5/μL) was observed in the few patients who experi-
adults receiving ATRA. The results of the AAML1331 study con- enced relapse in the AAML1331 study, revealing that most pa-
firmed that the ATRA/arsenic trioxide regimen was safe and tients with pediatric APL who received arsenic trioxide did not
beneficial (2-year EFS rate of 98%) for the treatment of pedi- require intrathecal treatment. However, among patients with
atric patients with standard-risk APL. CNS disease or CNS hemorrhage, intrathecal triple therapy was
The design of the high-risk APL arm included 4 doses of ida- beneficial. Because many pediatric patients require sedation
rubicin in the induction cycle along with continuous dosing of when undergoing lumbar puncture, limited use of intrathe-
ATRA/arsenic trioxide based on the induction regimen used in the cal therapy in the AAML1331 study represented a substantial
Australasian APML4 study.17 The APML4 regimen had favorable advancement in the treatment of pediatric patients with APL;
results among 23 patients with high-risk APL and is included as this limited use can decrease the risk of sedation complica-
a preferred regimen in the National Comprehensive Cancer Net- tions and the neurological or neurocognitive adverse effects
work guidelines for the treatment of adults with high-risk APL.18 of intrathecal therapy.
In contrast to the APML4 study, the AAML1331 study initiated ar- The low early death rate in the present study, particularly
senic trioxide on day 1 of induction therapy to rapidly reverse APL among patients with high-risk APL, may be associated with sev-
coagulopathy and included 14 days of dexamethasone therapy eral features of the treatment regimen that differed from the
to prevent differentiation syndrome. An MD Anderson Cancer AAML0631 study. Patients were encouraged to start pretreat-
Center study,15 the SWOG 0535 study,19 and the UK MRC17 study20 ment with ATRA when APL was first suspected, and this ap-
all used ATRA/arsenic trioxide–based therapy for adult patients proach has been associated with fewer early deaths.26-28 Early
withhigh-riskAPL,butinductiontherapyincludedtreatmentwith introduction of arsenic trioxide on day 1 of therapy (even con-
gemtuzumab ozogamicin rather than an anthracycline. Specific currently with idarubicin doses in patients with high-risk APL)
to the AAML1331 study, the consolidation therapy used for the has been associated with rapid degradation of PML-RARα
treatment of high-risk APL was the same as that used for standard- and promyeloblast apoptosis and may help stabilize
risk APL. In contrast to the regimen used in the APML4 study and coagulopathy. 29 Dexamethasone rather than prednisone
the AIDA0493 and AAML0631 studies of pediatric APL, no main- therapy (as used in the APML4 and APL0406 studies) was ad-
tenance therapy was administered in the AAML1331 study. This ministered as prophylaxis against differentiation syndrome
lack of maintenance therapy substantially shortened the dura- based on the low rates of complications associated with dif-
tion of therapy, from greater than 2 years to approximately 9 ferentiation syndrome that were observed in the PETHEMA
months, while achieving high survival rates (2-year EFS of 96.4%) LPA2005 study, which used dexamethasone therapy.30 The
among patients with high-risk APL. It will be important to evalu- protocol included detailed recommendations for monitoring
ate long-term outcomes for this novel regimen. differentiation syndrome and coagulopathy and provided ag-
The differentiating effect of both arsenic trioxide and ATRA gressive supportive care guidelines. As patients enrolled in the
can result in hyperleukocytosis. Patients with high-risk APL study, the treating site was contacted by email to highlight the
received 4 doses of idarubicin therapy, which produced rapid risk of early death, reference supportive care, and offer ad-
reductions in WBC counts. Patients with standard-risk APL who vice from expert study committee members. The early death
developed hyperleukocytosis (WBC >10 000/μL) required hy- rate among pediatric patients with APL is approximately 5%,
droxyurea therapy. Clinical signs and symptoms of differen- and a high initial WBC count (ie, high-risk APL) is a clear risk
tiation syndrome were successfully managed with ATRA/ factor associated with early death.26 The early death rate was
arsenic trioxide dose-holding plus dexamethasone therapy, and approximately 10% in the high-risk APL cohorts of both the
only 8 patients experienced more severe complications asso- AIDA0493 and AAML0631 studies.2,5 The supportive care used
ciated with differentiation syndrome, including hypotension in the AAML1331 study was associated with no deaths among
and kidney dysfunction. the 56 patients with high-risk APL.
The rates of CNS disease and relapse among patients with
pediatric APL are generally low.21 Arsenic trioxide can pen- Limitations
etrate the CNS and achieve cerebrospinal fluid levels at ap- This study has limitations. These limitations included its design
proximately 50% of serum levels.22 Central nervous system dis- as a historical comparison study and its sample of fewer than 200
ease at relapse was observed in 2 of 3 APL relapses among patients; however, the study is considered large for an assessment
patients in the AAML0631 study, which included treatment of APL because of the rarity of the disease. The results are gen-
with prophylactic intrathecal cytarabine for all patients (3 doses eralizable because of broad multi-institutional involvement
for those with standard-risk APL and 4 doses for those with through a large cooperative group. Disease events beyond 2 years
high-risk APL) but only 2 cycles of arsenic trioxide in after diagnosis rarely occur among pediatric patients with APL,
consolidation.5 In the AAML1331 study, intrathecal triple che- but it will be important to assess long-term outcomes from this
motherapy was administered only to patients with docu- study. Although the treatment regimen used in the AAML1331
mented CNS disease or CNS hemorrhage. The latter group re- study was beneficial, numerous doses of intravenous arsenic tri-
ceived this treatment because studies conducted by the oxide (typically requiring administration in a health care facil-
PETHEMA (Programa Para el Estudio de la Terapéutica en ity) are a major stressor for patients and families. Thus, the next
Hemopatías Malignas) group identified CNS hemorrhage as a steps in optimizing APL therapy will be to minimize the burden
risk factor associated with relapse.23-25 Only 1 case of CNS 2 of care by evaluating emerging oral forms of arsenic and to

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 Research Original Investigation Arsenic Trioxide and All-trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia

ensure that these oral treatments can safely and successfully lar to adult patients with standard-risk APL. Among pediat-
replace intravenous arsenic trioxide.31 ric 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 out-
Conclusions comes met noninferiority criteria, with the additional
This nonrandomized, noninferiority trial found that pediat- advantages of the regimen including shorter treatment
ric patients with standard-risk APL could be successfully duration, lower exposure to anthracycline and intrathecal
and safely treated with ATRA/arsenic trioxide therapy, simi- chemotherapy, and fewer days in the hospital.

ARTICLE INFORMATION Supervision: Kutny, Abla, Kolb, Gregory. newly diagnosed acute promyelocytic leukemia
Accepted for Publication: August 2, 2021. Conflict of Interest Disclosures: Drs Kutny and (APL) in children. Blood. 2005;106(2):447-453.
Hirsch reported receiving grants from the Children’s doi:10.1182/blood-2004-05-1971
Published Online: November 11, 2021.
doi:10.1001/jamaoncol.2021.5206 Oncology Group during the conduct of the study. 3. Thomas X, Le QH, Fiere D. Anthracycline-related
Dr Rajpurkar reported receiving personal fees from toxicity requiring cardiac transplantation in
Author Affiliations: Division of Hematology/ Novo Nordisk outside the submitted work. No long-term disease-free survivors with acute
Oncology, Department of Pediatrics, University of other disclosures were reported. promyelocytic leukemia. Ann Hematol. 2002;81(9):
Alabama at Birmingham, Birmingham (Kutny); 504-507. doi:10.1007/s00277-002-0534-8
Department of Preventive Medicine, Keck School of Funding/Support: This work was supported by
Medicine, University of Southern California, Los grants U10CA180886 and U10CA180899 from the 4. Shankar SM, Marina N, Hudson MM, et al;
Angeles (Alonzo); Division of Hematology/ National Institutes of Health (Children’s Oncology Cardiovascular Disease Task Force of the Children’s
Oncology, Hospital for Sick Children, Toronto, Group) and grant U24CA196173 from the Oncology Group. Monitoring for cardiovascular
Ontario, Canada (Abla); Pediatric Hematology/ St. Baldrick’s Foundation (Children’s Oncology disease in survivors of childhood cancer: report
Oncology, Wayne State University, Detroit, Group). from the Cardiovascular Disease Task Force of the
Michigan (Rajpurkar); Children’s Oncology Group, Role of the Funder/Sponsor: The Children’s Children’s Oncology Group. Pediatrics. 2008;121(2):
Monrovia, California (Gerbing, Wang); Division of Oncology Group investigators designed the trial. e387-e396. doi:10.1542/peds.2007-0575
Laboratory Medicine, University of Minnesota The National Cancer Institute (NCI) Cancer Therapy 5. Kutny MA, Alonzo TA, Gerbing RB, et al. Arsenic
Medical Center–Fairview, Minneapolis (Hirsch); Evaluation Program reviewed the trial, made trioxide consolidation allows anthracycline dose
Department of Pathology, St Jude Children’s recommendations for changes, and approved the reduction for pediatric patients with acute
Research Hospital, Memphis, Tennessee final trial design. All amendments were reviewed promyelocytic leukemia: report from the Children’s
(Raimondi); Department of Pathology and and approved by the NCI. The Children’s Oncology Oncology Group phase III historically controlled trial
Laboratory Medicine, Nationwide Children’s Group investigators conducted the trial and AAML0631. J Clin Oncol. 2017;35(26):3021-3029.
Hospital, Columbus, Ohio (Kahwash); Division of performed the collection, management, analysis, doi:10.1200/JCO.2016.71.6183
Behavioral Medicine/Neuropsychology, Children’s and interpretation of the data. The authors 6. Lo-Coco F, Avvisati G, Vignetti M, et al; Gruppo
National Medical Center, Washington, District of prepared, reviewed, and approved the manuscript. Italiano Malattie Ematologiche dell’Adulto;
Columbia (K. K. Hardy, S. Hardy); Clinical Research The decision to submit the manuscript for German-Austrian Acute Myeloid Leukemia Study
Division, Fred Hutchinson Cancer Research Center, publication was made by the authors. Group; Study Alliance Leukemia. Retinoic acid and
Seattle, Washington (Meshinchi); Division of Disclaimer: The content is solely the responsibility arsenic trioxide for acute promyelocytic leukemia.
Hematology/Oncology, Children’s Mercy Hospital of the authors and does not necessarily represent N Engl J Med. 2013;369(2):111-121. doi:10.1056/
and Clinics, Kansas City, Missouri (Gamis); Division the official views of the National Institutes of NEJMoa1300874
of Pediatric Hematology/Oncology, Nemours/Alfred Health.
I. DuPont Hospital for Children, Wilmington, 7. Platzbecker U, Avvisati G, Cicconi L, et al.
Delaware (Kolb); Division of Hematology/Oncology, Additional Contributions: Teni Karimian, MS, of Improved outcomes with retinoic acid and arsenic
Benioff Children’s Hospital Oakland, Oakland, Children’s Oncology Group (COG), and Jeannette trioxide compared with retinoic acid and
California (Feusner); Division of Pediatric Cassar, BA, of COG, served as protocol chemotherapy in non–high-risk acute
Hematology/Oncology, Atlantic Health System, coordinators; Wendy Lee, LVN, of COG, was the promyelocytic leukemia: final results of the
Goryeb Children’s Hospital, Morristown, New research coordinator (all received salary support randomized Italian-German APL0406 trial. J Clin
Jersey (Gregory). from COG for assisting with the conduct of this Oncol. 2017;35(6):605-612. doi:10.1200/JCO.2016.
study). Vicky Poss, CCRP, of the University of 67.1982
Author Contributions: Dr Kutny had full access to Alabama at Birmingham, was the study clinical
all of the data in the study and takes responsibility 8. Cicconi L, Platzbecker U, Avvisati G, et al.
research associate; Kathleen Adlard, RN, MN, Long-term results of all-trans retinoic acid and
for the integrity of the data and the accuracy of the CPON, of Children’s Hospital of Orange County, was
data analysis. Drs Feusner and Gregory contributed arsenic trioxide in non–high-risk acute
the study nurse; and Sean Green, PharmD, BCOP, of promyelocytic leukemia: update of the APL0406
equally as co-last authors. Lucile Packard Children’s Hospital, Stanford
Concept and design: Kutny, Alonzo, Abla, Rajpurkar, Italian-German randomized trial. Leukemia. 2020;
University, was the study pharmacist. Vani Shanker, 34(3):914-918. doi:10.1038/s41375-019-0589-3
S. Hardy, Gamis, Kolb, Feusner, Gregory. PhD, of Saint Jude Children’s Research Hospital,
Acquisition, analysis, or interpretation of data: provided scientific editing of the manuscript. We 9. Iland HJ, Collins M, Bradstock K, et al;
Kutny, Alonzo, Abla, Rajpurkar, Gerbing, Wang, thank the COG institutions and investigators who Australasian Leukaemia and Lymphoma Group. Use
Hirsch, Raimondi, Kahwash, K. Hardy, Meshinchi, cared for children enrolled in this study. We also of arsenic trioxide in remission induction and
Gamis, Kolb, Gregory. thank the patients and their families for their consolidation therapy for acute promyelocytic
Drafting of the manuscript: Kutny, Alonzo, Gerbing, willingness to participate in the study. leukaemia in the Australasian Leukaemia and
Hirsch, Raimondi, Meshinchi, Gamis, Kolb, Gregory. Lymphoma Group (ALLG) APML4 study:
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