Homoharringtonine-Based Induction Regimen Improved the Remission Rate and Survival Rate in Chinese Childhood AML: A Report From the CCLG-AML 2015 Protocol Study

Abstract

PURPOSE

Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML.

PATIENTS AND METHODS

This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years.

RESULTS

We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% v 73.9%, P = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm (P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm (P = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, P = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, P = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, P = .336).

CONCLUSION

HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

INTRODUCTION

AML is a heterogeneous group of diseases and accounts for 15% of childhood leukemia.¹ The overall survival (OS) rates have improved over the past several decades, with the 5-year OS ranging from 65% to 75%.^2-6 The standard induction regimen (DA) is the combination of daunorubicin (DNR) and cytarabine (Ara-C). The classical DNR+Ara-C+Etoposide (DAE) regimen composed of DA with etoposide (VP-16) is commonly applied in childhood AML.

CONTEXT

• Key Objective

• Etoposide has been reported to induce secondary hematologic malignancies, and all-trans retinoic acid (ATRA)–based therapy has been less confirmed among patients with non–acute promyelocytic leukemia AML. Previous studies have revealed the safety and effectiveness of the homoharringtonine (HHT)-based regimen in adult AML. To the best of our knowledge, our study is the first multicenter prospective observational clinical trial to compare the efficacy of a HHT-based induction regimen plus ATRA-based maintenance with a classic etoposide-based regimen (DAE) combined with cytarabine-based maintenance in childhood de novo AML.

• Knowledge Generated

• The HHT-based induction regimen increases the proportion of complete remission and improves 3-year overall survival (OS) and event-free survival (EFS) compared with the classical DAE induction regimen for patients with pediatric AML. ATRA-based maintenance has comparable effects with cytarabine-based maintenance in terms of OS and EFS.

• Relevance (C.F. Craddock)

• HHT-based induction regimens have the potential to improve outcomes in children with newly diagnosed AML and represent an important new therapeutic option in this clinical setting.*

• *Relevance section written by JCO Associate Editor Charles F. Craddock, MD.

Homoharringtonine (HHT), a Chinese medicine extracted from Cephalotaxus species, has been widely used to treat adult AML in China for more than 40 years.^7-9 Its antileukemic effects work primarily through the inhibition of protein synthesis to induce differentiation, inhibit proliferation, and promote apoptosis.^7,8,10,11 HHT has been verified to be efficacious when combined with DA (DAH) in several large trials.^12-14 Etoposide, a semisynthetic glycoside derivative of podophyllotoxin, has been reported to induce secondary hematologic malignancies.^15-17 Unlike adults, long-term quality of life and prevention for secondary tumors should be considered for children. Hence, an alternative selection for pediatric AML is imperative. We compared the application of HHT (the H arm) versus VP-16 (the E arm) combined with DA in this study.

Whether survival will benefit from maintenance therapy is still a matter of debate. Cytarabine-based maintenance has been tested in several trials and resulted in better survival in some of them.^18-24 All-trans retinoic acid (ATRA) has been confirmed to have a favorable effect in acute promyelocytic leukemia (APL). Some studies have shown that ATRA can induce maturation and apoptosis in AML blasts in vitro.^25-29 However, ATRA-based therapy has been less confirmed among patients with non-APL AML although some favorable results have been reported in some studies.^27,30-34 We design a second randomized location to Ara-C–based (the AC arm) or ATRA-based (the AT arm) maintenance.

We designed a randomized four-arm trial (H + AT arm, H + AC arm, E + AT arm, E + AC arm, Fig 1) in children with AML (except for APL) as recommended by experts in our clinical epidemiology and evidenced-based medicine center. Here, we report the 3-year outcomes in a large multicenter study of 1,253 children with AML treated by the Chinese Children's Leukemia Group (CCLG)-AML 2015 Protocol (online only) from 35 hospitals in China. This study was registered at the Chinese Clinical Trial Registry (ChiCTR-IPR-15006816).

FIG 1.

CONSORT diagram of patients with AML enrolled. ^aReasons for termination of the study were parents' selection. ^bNumbers of patients who had SCT. AC, cytarabine-based; AT, ATRA-based; BM, bone marrow; CCR, continuous CR; CR, complete remission; E, etoposide-based; H, HHT-based; SCT, stem-cell transplantation.

PATIENTS AND METHODS

Patients

Patients with newly diagnosed AML who were younger than 18 years and had not previously received any chemotherapy regimen were enrolled and treated according to the CCLG-AML 2015 protocol. Patients who were diagnosed with APL, juvenile myelomonocytic leukemia, or secondary AML (secondary to Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow [BM] failure syndromes) and who were unable to adhere to the trial protocol were excluded. Informed consent was obtained from all patients or legal guardians, and the study was conducted in accordance with the principles of the Declaration of Helsinki. This research has been approved by the ethics committee and clinical registration.

Study Design

Although this study was finally defined as a multicenter, prospective observational clinical trial, it was initially designed as a multicenter randomized controlled trial. Two main reasons were as follows. First, owing to a shortage of HHT that lasted for half a year, we had to assign patients to the E arm and randomly group them to maintenance regimens. Once supplies of HHT are replenished, the following patients were located to the H arm. Hospitals that reached balance between the two arms resumed random grouping thereafter. Second, in consideration of parents' selection and giving priority to patients' benefit, part of patients who were enrolled in the AT arm finally received cytarabine-based maintenance. We used block random assignment without stratification to minimize investigator and participant bias. Since the study was divided into four intervention groups, the block size was set to 8 and a random sequence was generated according to a random number table. Allocation was concealed with random envelopes.

CCLG-AML 2015 Protocol

All patients were stratified into three risk groups according to their cytogenetic risk profile, WBC count, central nervous system or testis involvement, remission status after induction therapy, and transformed AML (tAML) or myeloid sarcoma (MS) diagnosis (Appendix Table A1, online only).

Patients were randomly assigned to the H arm or the E arm. Induction I of DAE/DAHs consisted of VP-16 (100 mg/m² once daily) or HHT (3 mg/m² once daily) on days 1-5; DNR 40 mg/m² once daily on days 1, 3, and 5; and Ara-C 100 mg/m² once every 12 hours on days 1-7. Induction II (idarubicin+Ara-C+Etoposide [IAE]/IDA+Ara-C+HHT [IAH]) used idarubicin 10 mg/m² once daily on days 1, 3, and 5 as a substitute for DNR.

All patients uniformly received three courses of consolidation therapy (mitoxantrone+cytarabine arabinoside+Ara-C [MA]), (homoharringtonine+cytarabine arabinoside [HA]), and (cytarabine+L-asparaginase, [CLASP]). Patients in the high-risk group who were not candidates for hematopoietic stem-cell transplantation (HSCT) were administered another HA cycle (Appendix Table A2 and Fig A1, online only).

Patients intended to receive maintenance therapy were randomly assigned to the AT arm or AC arm for approximately 1 year. In the AT arm, one round of the ATRA-based regimen includes ATRA 20-30 mg/m² once daily one oral dose for the first 2 weeks and 6-mercaptopurine (6-mp) 50 mg/m² once daily one oral dose for the following 10 weeks. In the AC arm, Ara-C was administered as one intravenous dose of 40 mg/m² once daily on days 1-4 every 4 weeks, and 6-mp as one oral dose of 50 mg/m² once daily during the whole maintenance period (Appendix Fig A1).

Response Evaluation During and After Treatment

The primary end point is to compare the proportion of composite complete remission (CR) for de novo patients with AML who received two courses of induction therapy randomly assigned to the H arm (experimental) versus the E arm (control). Composite CR was defined as <5% blast cells in BM including CR with incomplete hematologic recovery (CRi). Other two primary end points were the 3-year event-free survival (EFS) of the intent-to-treat (ITT) population between the H arm and the E arm and the 3-year EFS of the per-protocol (PP) population among the four arms (H + AT arm, H + AC arm, E + AT arm, and E + AC arm). The secondary end points were the 3-year OS of the ITT or PP population between the two or four abovementioned arms. EFS was defined as the date from enrollment to the date of disease progression, treatment failure (failure to achieve CR, ie, <5% blast cells after at least two courses of induction treatment), confirmed relapse, or death, whichever occurred first. OS was defined as the date from enrollment to the date of death or last follow-up for surviving patients. The exploratory end points were to compare the CR rate between different subgroups according to risk stratification, genetic characteristics, risk factors (such as WBC counts at diagnosis), or the EFS and OS between different subgroups.

Statistical Analyses

We compared the experimental group (H arm) with the control group (E arm) for the ITT population. The sample size was chosen to detect an increase in 3-year EFS from 55% in the E arm to 60% in the H arm, with a hazard ratio (HR) of 0.70. With a type I error rate of 0.05% and 80% power, 215 patients were needed per arm. According to the actual condition and considering the second random assignment for maintenance therapy, we defined each arm with 200 patients and a total of 800 patients for four arms.

For analyses of CR rates, patients obtained CR after induction I were considered to have CR status even without assessment of induction II for any reason. Other missing data will be imputed as no CR. CR was compared using the χ² test or Fisher's exact test. The covariates for CR were analyzed by logistic regression. The 95% CIs of the RRs were calculated using the Koopman asymptotic score method (Prism 8.0). For survival analyses, missing data were imputed as censored. Dichotomous variables were compared using the χ² test. OS and EFS were estimated using the Kaplan-Meier method, and differences among the four arms were compared by the log-rank test with HRs estimated using the Cox model. The assessment of the effects of treatment in subgroups was post hoc. All tests were two-tailed with a significance threshold of 0.05. Bonferroni correction was used when multiple comparisons are needed. The adjusted alpha level is 0.05/n, where n is the total number of comparisons. Statistical analyses were performed using SPSS (IBM, version 23.0, Chicago, IL).

RESULTS

From August 2015 to October 2019, a total of 1,258 patients were enrolled from 35 centers. Five patients were ineligible because of incorrect diagnosis, and therefore, we included 1,253 patients in the ITT analyses. The median follow-up time was 29.4 months (IQR, 8.4-47.4). A total of 185 of 1,253 patients (14.8%) were lost to follow-up, of whom 70.0% were followed for over 12 months. Except for sex, baseline clinical characteristics did not differ significantly among the four arms (Table 1 and Appendix Table A3 [online only]). The median age was 75.0 months (IQR, 36.0-118.0). A total of 1,232 patients (98.3%) were assessed for cytogenetic characteristics, 742 patients (59.2%) had abnormal karyotypes or fusion genes, and 384 patients (30.6%) were t(8;21)/AML1-ETO–positive. A total of 659 patients were assigned to the E arm, and 594 were assigned to the H arm (Fig 1).

TABLE 1.

Patient Characteristics

A total of 961 patients achieved CR/CRi, and 474 (79.8%) in the H arm and 487 (73.9%) in the E arm obtained CR (risk ratio [RR], 1.08; 95% CI, 1.02 to 1.15; P = .014), particularly in patients with intermediate-risk stratification (80.1% v 72.0%; RR, 1.11; 95% CI, 1.001 to 1.24; P = .048) (Table 2 and Fig 2). Similar results were found for patients with normal karyotypes, those age between 1 and 10 years old, and those with WBC counts of ≥50 × 10⁹/L (Fig 2). After adjustment for age, sex, ethnicity, initial WBC count, the presence of tAML, the presence of MS, the presence of testicular involvement fusion genes, and cytogenetic risk, the odds ratio of CR for the H arm versus E arm was 1.49 (95% CI, 1.126 to 1.998; P = .006).

TABLE 2.

Treatment Response to Induction Therapy

FIG 2.

Risk ratios for remission rate by subgroup. CR, complete remission; CRi, incomplete hematologic recovery; E, etoposide-based; FAB, French-American-British; H, HHT-based; HHT, homoharringtonine; IR, intermediate risk; SR, standard risk; VP-16, etoposide.

In total, 888 (89.0%, 430 patients in the H arm and 458 patients in the E arm) of the 998 patients received consolidation treatment. Maintenance treatment was administered to 554 (62.4%) of these 888 patients, with similar proportions in each arm (Fig 1). Overall, 381 (29.4%) patients received HSCT, again showing that the distribution was well balanced across the four arms (Table 1).

According to the results of ITT analyses, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm (P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm (P = .022; Figs 3A and 3B). After adjustment for age, sex, ethnicity, initial WBC count, the presence of tAML, the presence of MS, the presence of testicular involvement, whether SCT was performed, fusion genes, and cytogenetic risk, the HR for death in the H arm versus the E arm was 0.75 (95% CI, 0.58 to 0.97; P = .031). The HR of events for the H arm versus the E arm was 0.77 (95% CI, 0.60 to 0.97; P = .028). The 3-year OS was 68.4% in the H + AT arm and 65.3% in the E + AC arm (P = .489). The 3-year EFS was 58.9% (95% CI, 52.6 to 64.7) in the H + AT arm and 54.6% (95% CI, 49.0 to 59.9) in the E + AC arm (P = .395, Figs 3C and 3D, Table 3).

FIG 3.

Kaplan-Meier survival of the intention-to-treat population. (A) OS and (B) EFS of all patients with different induction regimens. (C) OS and (D) EFS in the four arms. AC, cytarabine-based; AT, ATRA-based; E, etoposide-based; H, HHT-based; EFS, event-free survival; OS, overall survival.

TABLE 3.

Survival Results of Different Regimens by Subgroup

In subgroup analyses, it was observed that patients with AML1-ETO positivity in the H + AT arm had significantly better EFS (3-year EFS, 73.6% v 52.8%, P = .013) compared with those in the E + AC arm. Although the OS was also improved in the H + AT arm (82.4% v 66.4%, P = .043), this result did not reach statistical significance on the basis of the adjusted alpha level (Figs 4A and 4B, Table 3). In the analyses of patients with favorable and intermediate cytogenetics, the 3-year OS and EFS rates in the H + AT arm were 74.9% (95% CI, 67.6 to 80.8) and 66.6% (95% CI, 58.9 to 73.2), respectively, which did not significantly differ from those for the E + AC arm, with the 3-year OS of 70.9% (95% CI, 64.2 to 76.5; P = .452) and the 3-year EFS of 60.5% (95% CI, 53.6 to 66.7; P = .307), respectively (Appendix Fig A2 [online only] and Table 3). Patients in the low- and intermediate-risk groups who received the H + AT regimen (n = 89, PP population) achieved a 90.8% (95% CI, 82.5 to 95.3) 3-year OS and an 80.2% (95% CI, 70.0 to 87.2) 3-year EFS (Table 3).

FIG 4.

Survival of patients carrying AML1-ETO and the per-protocol population. (A) OS and (B) EFS of patients with AML with AML1-ETO positivity. (C) OS and (D) EFS of patients who were enrolled in maintenance (per-protocol analyses). AC, cytarabine-based; AT, ATRA-based; E, etoposide-based; EFS, event-free survival; H, HHT-based; OS, overall survival.

A total of 108 patients died during or after induction treatment, of whom 41 were in the H arm and 67 were in the E arm (6.9% v 9.6%, P = .077). Reasons for death were treatment abandonment (n = 59, 54.6%, 18 of whom were for parents' selection, 15 were for unresponsive to induction therapy), severe infection (n = 40, 37.0%), bleeding in vital organs (n = 8, 7.4%, two of whom were complicated with severe infections), disseminated intravascular coagulation (DIC) (n = 1, 0.9%), and multiple organ failure (n = 2, 1.8%).

Of the 554 patients who accepted maintenance treatment (PP population), 154 (27.8%) relapsed during or after maintenance treatment. Among patients of the H + AT arm, the 3-year OS and EFS were 86.1% and 70.7%, respectively, which did not differ from those in the other three arms (Figs 4C and 4D, Table 3). The 3-year OS and 3-year EFS for the PP population in the low- and intermediate-risk groups were 85.1% (95% CI, 81.2 to 88.2) and 75.5% (95% CI, 71.0 to 79.4), respectively. The PP population in the high-risk group achieved a 76.5% (95% CI, 67.4 to 83.4) (P = .022) 3-year OS and a 57.0% (95% CI, 47.5 to 65.5) 3-year EFS (P < .0001; Appendix Fig A3).

DISCUSSION

HHT-based induction regimens were mostly reported in patients with relapsed or refractory AML, chronic myeloid leukemia (CML), or myelodysplastic syndrome.^35-39 Only three studies^14,40,41 evaluated the efficacy of HHT-based chemotherapy in de novo patients, one of which was in patients with adult AML. In one study performed in de novo patients with pediatric AML,⁴⁰ a low-dose or standard-dose chemotherapy including HHT achieved a CR of 88.8% or 86.4%, respectively. In another study,⁴¹ 72.0% had a CR and the 5-year EFS was 88.0%. However, both of these studies were single-center studies. The only multicenter, randomized study reported by Jin et al¹⁴ concluded that 67% of patients in the DNR+Ara-C+HHT (DAH) group had CR, and the 3-year EFS was 32.7% (v DA, P = .08) in adult patients with AML.

To the best of our knowledge, this study is the first multicenter prospective observational clinical trial to compare the efficacy of a HHT-based induction regimen plus ATRA-based maintenance with a classic etoposide-based regimen (DAE) combined with cytarabine-based maintenance in childhood de novo AML. Although this study was originally designed as a randomized controlled trial, we had to yield real-world research because of the shortage of HHT and the priority given to ensuring patient benefit.

A significantly increased CR rate was observed with the replacement of HHT (79.8% v 73.9%), which was consistent with other studies of HHT combined with the DA regimen in de novo AML.^41,42 Several studies have shown that compared with the DA or DAE regimen, higher CR rates have been observed in adult AML treated with HHT-based regimens (67%-78.3%),^14,43-45 particularly for pediatric AML (81.6% and 82.97%).^42,46 Subgroup analyses revealed that more patients with intermediate cytogenetics or age from 1 to 10 years or a WBC of ≥ 50 × 10⁹/L in the H arm achieved CR compared with those in the E arm.

Patients in the H arm also had significantly improved OS and EFS than those in the E arm. Our results showed that the addition of HHT to induction treatment benefited patients with AML1-ETO positivity in obtaining a better survival than those in the E arm. Previous studies have shown similar results for both de novo and refractory/relapsed AML.^12,13,47,48 In vitro studies showed that HHT combined with aclarubicin and cytarabine (HAA) synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3–mediated cleavage of the AML1-ETO oncoprotein.⁴⁹ To our knowledge, our study is the first to confirm that the DAH regimen might also have this synergistic effect.

These results indicate that the HHT-based induction regimen could result in improved CR rates and survival compared with the classic DAE regimen.

Although the log-rank test for four arms showed no significance (the P value for OS was .0556; for EFS, it was .0872), we still wanted to explore difference between each two groups especially for the experimental group (H + AT arm) and the control group (E + AC arm). Hence, we conducted post hoc multiple comparisons (Table 3). Patients with favorable or intermediate cytogenetics who received the H + AT or the H + AC regimen achieved a 3-year OS of above 70% and a 3-year EFS of above 65%, which was similar to other studies.^41,42 Patients in the low- and intermediate-risk groups in the H arm who could receive maintenance had a 3-year OS of 85.1% and an OS of above 90% in the H + AT arm. Although our regimen recommended transplantation for patients in the high-risk group, some patients chose maintenance therapy over HSCT and achieved a 3-year OS of 76.5% and a 3-year EFS of 57.0%. These results show that patients in the low- and intermediate-risk groups can achieve a 3-year OS of 85% and a 3-year EFS of 75% once they can successfully enter the maintenance treatment. On the basis of the above findings, we still strongly recommend that high-risk patients receive transplantation. On the other hand, our results indicate that the risk stratification of the CCLG-AML 2015 protocol is useful in guiding the selection of treatment options and the prediction of prognosis.

Etoposide is widely used for many hematologic diseases. However, its potential risk of therapy-related secondary cancers has attracted attention,^15-17,50,51 especially for AML with MLL rearrangement.^52-55 Winick et al⁵⁰ reported that 10 of 205 patients with pediatric acute lymphoblastic leukemia developed secondary AML after treatment with etoposide. Mechanism depends on distinct biologic processes that etoposide involved, such as the induction of DNA double-strand breaks and the direct or indirect toxicity of etoposide metabolites. However, few studies have focused on VP-16–related secondary cancers that occur in AML because it is difficult to distinguish relapsed AML from secondary AML.

Among patients who accepted maintenance treatment in the H + AT arm, the 3-year OS and EFS rates were 86.1% and 70.7%, respectively, which did not differ from those in the other three arms. Although several studies in adult AML have not shown a significant advantage of ATRA for adult AML,^56-59 the study by Lazenby et al⁶⁰ indicated that further investigation is needed regarding the use of ATRA in the NPM1 mutation population. On the other hand, three additional studies have suggested that the addition of ATRA to induction or consolidation therapy may improve CR rate or survival.^32,61,62 However, no studies appear to have reported on the use of ATRA for maintenance therapy. ATRA has been reported to increase the sensitivity of AML cell lines to drugs such as Ara-C by downregulating the expression of B cell lymphoma-2, which is a proapoptotic protein.^63-65

Previous large, randomized clinical trials of maintenance had not shown significant improvement in OS. However, the CC-486 (oral azacitidine) has been approved for adult AML who achieved first CR/CRi after intensive induction and who are ineligible for HSCT on the basis of a randomized phase 3 clinical trial (QUAZAR AML-001).⁶⁶ Limited studies of methylation status in children and inadequate data regarding the efficacy of azacitidine in children AML have restricted its application.^67,68 Moreover, recruitment of patients for maintenance studies has always been difficult. A study by Burnett et al⁶⁹ showed that only 27% of older patients who were initially enrolled were randomly assigned for maintenance treatment.

One of the limitations of our study was that the median follow-up for the H arm was half a year shorter than that for the E arm, predominantly owing to the shortage of HHT during this period. The second limitation was that part of the patients allocated to the AT arm received cytarabine-based maintenance for they did not wish to pay for unknown risks. However, our trial was conducted at 35 centers nationwide with a large sample size, and selection bias was weakened to some extent. Our results are thus reflective of those that could be obtained from a real-world study.

In conclusion, our results indicate that the HHT-based induction regimen could result in higher CR and improved survival, which may be a better alternative for the treatment of de novo patients with childhood AML, particularly those with the AML1-ETO.

APPENDIX

FIG A1.

CCLG-AML 2015 protocol outline. The blue arrow represents one dose of Ara-C, yellow boxes represent 6-mp, and orange boxes represent ATRA. 6-mp, 6-mercaptopurine; A (Ara-C), cytarabine; AC, cytarabine-based; AT, ATRA-based; ATRA, all-trans retinoic acid; CCLG, Chinese Children's Leukemia Group; CLASP, cytarabine+L-asparaginase; D, daunorubicin; DAE, DNR+Ara-C+Etoposide; DAH, DNR+Ara-C+HHT; E, etoposide-based; H, HHT-based; HA, homoharringtonine+cytarabine arabinoside; HSCT, hematopoietic stem-cell transplantation; I, idarubicin; IAE, IDA+Ara-C+Etoposide; IAH, IDA+Ara-C+HHT; IR, intermediate risk; MA, mitoxantrone+cytarabine arabinoside; SR, standard risk.

FIG A2.

Survival of patients in standard- and intermediate-risk groups. (A) OS and (B) EFS of patients with favorable and intermediate cytogenetics. AC, cytarabine-based; AT, ATRA-based; E, etoposide-based; EFS, event-free survival; H, HHT-based; OS, overall survival.

FIG A3.

Survival of patients who received maintenance by risk group. (A) OS and (B) EFS of patients receiving maintenance for different risk stratifications. EFS, event-free survival; IR, intermediate risk; OS, overall survival; SR, standard risk.

TABLE A1.

CCLG-AML 2015 Risk Stratification

TABLE A2.

CCLG-AML 2015 Protocol

TABLE A3.

Distribution of FAB Types

AUTHOR CONTRIBUTIONS

Conception and design: Xiaoxia Peng, Tianyou Wang, Huyong Zheng

Financial support: Tianyou Wang, Huyong Zheng

Administrative support: Jing Li, Jing Wang, Tianyou Wang, Huyong Zheng

Provision of study materials or patients: Jing Li, Ju Gao, Ansheng Liu, Wei Liu, Hao Xiong, Changda Liang, Yongjun Fang, Yunpeng Dai, Jingbo Shao, Hui Yu, Lingzhen Wang, Li Wang, Liangchun Yang, Mei Yan, Xiaowen Zhai, Xiaodong Shi, Xin Tian, Xiuli Ju, Yan Chen, Jing Wang, Leping Zhang, Hui Liang, Sen Chen, Jingrong Zhang, Haixia Cao, Jiao Jin, Qun Hu, Junlan Wang, Yilin Wang, Min Zhou, Yueqin Han, Rong Zhang, Weihong Zhao, Xiaoli Wang, Limin Lin, Ruidong Zhang, Chao Gao, Liting Xu, Yuanyuan Zhang, Jia Fan, Ying Wu, Wei Lin, Jiaole Yu, Peijing Qi, Pengli Huang, Tianyou Wang, Huyong Zheng

Collection and assembly of data: Jing Li, Ju Gao, Ansheng Liu, Wei Liu, Hao Xiong, Changda Liang, Yongjun Fang, Yunpeng Dai, Jingbo Shao, Hui Yu, Lingzhen Wang, Li Wang, Liangchun Yang, Mei Yan, Xiaowen Zhai, Xiaodong Shi, Xin Tian, Xiuli Ju, Yan Chen, Jing Wang, Leping Zhang, Hui Liang, Sen Chen, Jingrong Zhang, Haixia Cao, Jiao Jin, Qun Hu, Junlan Wang, Yilin Wang, Min Zhou, Yueqin Han, Rong Zhang, Weihong Zhao, Xiaoli Wang, Limin Lin, Ruidong Zhang, Chao Gao, Liting Xu, Yuanyuan Zhang, Jia Fan, Ying Wu, Wei Lin, Jiaole Yu, Peijing Qi, Pengli Huang, Xiaoxia Peng, Huyong Zheng

Data analysis and interpretation: Jing Li, Chao Gao, Xiaoxia Peng, Yaguang Peng, Huyong Zheng

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Homoharringtonine-Based Induction Regimen Improved the Remission Rate and Survival Rate in Chinese Childhood AML: A Report From the CCLG-AML 2015 Protocol Study

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