Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

Chemotherapy with the use of next-generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as postremission treatment is recommended for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo-HSCT have yielded similar outcomes. This meta-analysis was performed to evaluate allo-HSCT in first complete remission (CR1) versus chemotherapy for adult Ph+ ALL in the TKI era. METHODS: Pooled assessment of the hematologic and molecular complete response rates was performed after 3-month TKI treatment. Hazard ratios (HRs) were determined for disease-free survival (DFS) and overall survival (OS) benefit with allo-HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. RESULTS: Thirty-nine retrospective and prospective single-arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64% versus 58% and 5-year DFS of 58% versus 51%, respectively. The use of next-generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. CONCLUSION: Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients. This study provides novel evidence for allo-HSCT indications for Ph+ ALL in CR1 in the TKI era.

Dasatinib plus prednisone as induction and consolidation for adults with Ph-positive acute lymphoblastic leukaemia: A single-arm, multicentre, phase 2 trial.

To reducing chemotherapy-related toxicity, the chemo-free regimens become a new trend of Ph + ALL treatment. Therefore, we conducted a phase 2 trial of dasatinib plus prednisone, as induction (Course I) and early consolidation (Courses II and III) treating newly diagnosed Ph + ALL. The trial was registered at www.chictr.org.cn, ChiCTR2000038053. Forty-one patients were enrolled from 15 hospitals. The complete remission (CR) was 95% (39/41), including two elderly induction deaths. By the end of Course III, 25.6% (10/39) of patients achieved a complete molecular response. With a median follow-up of 15.4 months, 2-year disease-free survival (DFS) were 100% and 33% for patients who receiving haematopoietic stem cell transplantation (HSCT) at CR1 and receiving chemotherapy alone respectively. When censored at time of HSCT, 2-year DFS were 51% and 45% for young and elderly patients (p = 0.987). 2-year overall survival were 45%, 86% and 100% for patients without HSCT, receiving HSCT after relapse and receiving HSCT at CR1 respectively. A total of 12 patients had marrow recurrences and one had CNS relapse, with 38% occurred early (between Courses I and III). IKZF1 gene deletion was shown to be associated with relapse (p = 0.019). This chemo-free induction and early consolidation regimen was efficacious and well-tolerated in de novo Ph + ALL. Allogeneic HSCT conferred definite survival advantage after chemo-free induction.

CAG (cytarabine, aclarubicin and granulocyte colony-stimulating factor) regimen for core binding factor acute myeloid leukaemia with measurable residual disease.

Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFß::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment less than or equal to 0.5. The molecular response rate and median decrease ratio of fusion transcripts at the molecular level of the CAG regimen were 52% and 0.53, respectively. The median fusion transcripts before CAG treatment was 0.25% whereas after CAG was 0.11%. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P = 0.028), respectively, and 6 of 15 patients achieved a molecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at 3 years among all patients was 72.7% ± 10.7%. The common grades 3-4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.

PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα.

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3 treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3 shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia.

PURPOSE: The purpose of this study was to identify the incidence, sites and main pathogens, and risk factors for infectious complications occurring in patients with adult acute myeloid leukemia (AML) during the first course of venetoclax combined with decitabine or azacitidine. METHODS: A retrospective cohort analysis was performed of 81 patients with AML older than 14 years who received the first cycle of venetoclax combined with a hypomethylating agent (HMA) between March 2018 and March 2021 at our institution. Infectious complications, if any, were documented. RESULTS: Among a total of 81 cases of AML, 59 (72.8%) patients occurred infections, including fever without an identifiable source (28.8%), clinically documented infections (40.7%), and microbiologically documented infections (30.5%). The most commonly isolated organism in culture was Candida albicans, followed by Klebsiella pneumonia, and Pseudomonas aeruginosa. The 4-week and 8-week mortality rates were 3.7% and 7.4%, respectively. In multivariate analysis, a high proportion of blasts in bone marrow, decreased hemoglobin level, and fever with or without a documented infection at baseline were significant independent risk factors for infectious complications. CONCLUSION: Compared with conventional chemotherapy, the incidence of infectious complications of venetoclax combined with decitabine or azacitidine significantly decreased. Pretreatment high leukemia burden and fever were independent risk factors for infections.

Distributed Acoustic Sensing for Monitoring Linear Infrastructures: Current Status and Trends.

Linear infrastructures, such as railways, tunnels, and pipelines, play essential roles in economic and social development worldwide. However, under the influence of geohazards, earthquakes, and human activities, linear infrastructures face the potential risk of damage and may not function properly. Current monitoring systems for linear infrastructures are mainly based on non-contact detection (InSAR, UAV, GNSS, etc.) and geotechnical instrumentation (extensometers, inclinometers, tiltmeters, piezometers, etc.) techniques. Regarding monitoring sensitivity, frequency, and coverage, most of these methods have some shortcomings, which make it difficult to perform the accurate, real-time, and comprehensive monitoring of linear infrastructures. Distributed acoustic sensing (DAS) is an emerging sensing technology that has rapidly developed in recent years. Due to its unique advantages in long-distance, high-density, and real-time monitoring, DAS arrays have shown broad application prospects in many fields, such as oil and gas exploration, seismic observation, and subsurface imaging. In the field of linear infrastructure monitoring, DAS has gradually attracted the attention of researchers and practitioners. In this paper, recent research and the development activities of applying DAS to monitor different types of linear infrastructures are critically reviewed. The sensing principles are briefly introduced, as well as the main features. This is followed by a summary of recent case studies and some critical problems associated with the implementation of DAS monitoring systems in the field. Finally, the challenges and future trends of this research area are presented.

Minimal residual disease level determined by flow cytometry provides reliable risk stratification in adults with T-cell acute lymphoblastic leukaemia.

Minimal residual disease (MRD) is an important independent prognostic factor for relapse and survival in acute lymphoblastic leukaemia (ALL). Compared with adult B-cell ALL, reports of adult T-cell ALL (T-ALL) MRD have been scarce and mostly based on molecular methods. We evaluated the prognostic value of multiparameter flow cytometry (FCM)-based MRD at the end of induction (EOI-MRD). The present retrospective study included 94 adult patients with T-ALL. MRD was detected by six- to eight-colour FCM. Patients who were EOI-MRD positive had a higher cumulative incidence of relapse (CIR) (87·6% vs. 38·8%, P = 0·0020), and a lower relapse-free survival (RFS) (5·4% vs. 61·0%, P = 0·0005) and overall survival (OS) (32·7% vs. 69·7%, P < 0·0001) than those who were EOI-MRD negative. Moreover, for patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) at their first remission, EOI-MRD positivity was predictive of post-transplant relapse (2-year CIR: 68·2% vs. 4·0%, P = 0·0003). Multivariate analysis showed that EOI-MRD was an independent prognostic factor for CIR [hazard ratio (HR) 2·139, P = 0·046], RFS (HR 2·125, P = 0·048) and OS (HR 2·987, P = 0·017). In conclusion, EOI-MRD based on FCM was an independent prognostic factor for relapse and survival in adult T-ALL. For patients who underwent HSCT, EOI-MRD could be used to identify patients with a high risk of relapse after allo-HSCT.

The simpler, the better: oral arsenic for acute promyelocytic leukemia.

Arsenic trioxide and all-trans retinoic acid have become the frontline treatments for patients with acute promyelocytic leukemia (APL). Despite the long wait for an oral arsenic drug, a commercially available agent, realgar-indigo naturalis formula (RIF), was not launched in China until 2009. Since then, over 5000 APL patients have been treated with oral RIF in China. Oral arsenic not only shows a clinical efficacy comparable to that of IV formulations but also displays a better safety profile, improved quality of life, and lower medical costs for patients. The promising results promote incorporating an outpatient postremission therapy model into clinical practice for both low-risk and high-risk APL patients in China. In this review, we discuss the evolution of oral arsenic RIF in the treatment of APL, with a special focus on how to address the related complications during induction therapy.

A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia.

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

CDKN2A deletions are associated with poor outcomes in 101 adults with T-cell acute lymphoblastic leukemia.

The identification of genetic risk subgroups of T-cell acute lymphoblastic leukemia (T-ALL) may provide evidence for risk stratification and individualized treatment. We investigated the characteristics and prognostic value of tumor suppressor gene CDKN2A deletions in 101 patients with T-ALL. The CDKN2A deletion was present in 23% (23/101) of T-ALL by fluorescence in situ hybridization (FISH). The most common type of CDKN2A deletion was homozygous deletion (70%, 16/23). A lower frequency of CDKN2A deletion was found in patients with early T-cell precursor (ETP) ALL than in patients with non-ETP-ALL (10.4% vs 34.0%; P = .008). Deletion of CDKN2A was significantly associated with younger age (P = .001), higher white blood cell (WBC) count (P < .001) and higher lactate dehydrogenase (LDH) level (P = .002). Patients with CDKN2A deletion had lower 2-year overall survival (OS) and event-free survival (EFS) rates than patients without CDKN2A deletion (2-year OS: 18.6% ± 8.9% vs 47.4% ± 6.2%, P = .032; EFS: 16.4 ± 8.3 vs 38.6 ± 5.9%, P = .022). In multivariable analysis, CDKN2A deletion was an independent adverse prognostic factor for OS (P = .016). In conclusion, adult T-ALL patients with CDKN2A deletion had a poor prognosis, and these patients might benefit from intensive chemotherapy or allogeneic hematopoietic stem-cell transplantation.

Biotransformation of arsenic trioxide by AS3MT favors eradication of acute promyelocytic leukemia: revealing the hidden facts.

Arsenic trioxide (ATO) is one of the most effective drugs for treatment of acute promyelocytic leukemia (APL). It could specifically target the PML/RARα fusion oncoprotein stability and induces APL cell differentiation as well as apoptosis. Although many studies have been conducted to document the anticancer effects and mechanism of ATO, there is little information about the association between biotransformation of ATO to active arsenic metabolites and APL therapy. Generally, ATO can be rapidly converted into trivalent methylated metabolites by arsenic (+3 oxidation state) methyltransferase (AS3MT) mostly in liver and redistributed to bloodstream of APL patients who receiving ATO treatment, thereby leading to a balance between cytotoxicity and differentiation, which is proposed to be the key event in successful treatment of APL. In this review, we comprehensively discussed possible roles of AS3MT and methylated arsenic metabolites in APL therapy, so as to reveal the association between individual differences of AS3MT expression and activity with the therapeutic efficacy of ATO in APL patients.

Balance between the toxicity and anticancer activity of arsenic trioxide in treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) has a long history and it is recognized as both poison and drug for more than two thousand years. Since the establishment of ATO as a frontline therapeutic agent for acute promyelocytic leukemia (APL), the survival of APL patients have been greatly improved and APL is turned from highly fatal to highly curable disease. Mechanistically, ATO can induce PML/RARα fusion protein degradation, causing APL cell differentiation and apoptosis. On the other hand, the side effects such as differentiation syndrome, cardiac conduction abnormalities and liver toxicity are often observed during the ATO treatment of APL in clinic. It is likely that the therapeutic and adverse effects of ATO is probably associated with its distinct pattern of metabolism and direct or indirect effects on different organs. In this review, we provided a comprehensive and in-depth elaboration of the cytotoxic mechanisms of ATO and its methylated metabolites based on in vivo or in vitro studies, trying to clarify the importance of achieving balance between the toxicity and anti-leukemic activity of ATO in APL treatment.

Identification of a point mutation PMLS214L-RARα that alters PML body organization, dynamics and SUMOylation.

Genetic mutations on PML-RARα in acute promyelocytic leukemia (APL) are reported to associate with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) resistance. Here we performed a retrospective analysis of APL patients and identified that the patient with S214L mutation on the PML moiety of PML-RARα showed resistance to both ATO and ATRA. Super-resolution microcopy was used to examine the structural response of PML bodies in wild-type or the S214L mutant cells upon drug treatment. Different protein density and fluidity were identified with the S214L mutant PML bodies by single particle quantification and FRAP analysis. We discovered that altered SUMOylation and ubiquitination might contribute to the drug resistance. Taken together, we have revealed that the S214L mutation on PML-RARα disrupted the organization of PML body and dynamics changes, perturbing structural responses to ATRA and subsequent oncoprotein degradation. Our findings shed new light on the structural alterations of PML bodies and mechanisms of APL drug resistance.

Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial.

BACKGROUND: Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 109 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. METHODS: We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. FINDINGS: Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27-36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3-4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3-4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). INTERPRETATION: Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. FUNDING: Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China.