Oral Realgar-Indigo Naturalis Formula Research Articles

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes

PurposeThe synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar–indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML).MethodsIn this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events.ResultsThe median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups.ConclusionThe results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

Oral Realgar-Indigo Naturalis Formula Versus Intravenous Arsenic Trioxide for Non-High-Risk Patients with Acute Promyelocytic Leukemia: Interim Results of a Multicenter Randomized Controlled Trial APL16

Oral Realgar-Indigo Naturalis Formula Versus Intravenous Arsenic Trioxide for Non-High-Risk Patients with Acute Promyelocytic Leukemia: Interim Results of a Multicenter Randomized Controlled Trial APL16

Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.

Treatment paradigm of acute promyelocytic leukemia (APL) is by no mean the most remarkable story of cancer therapy. Recently, the advent of oral arsenic formulations (oral-arsenic trioxide and Realgar-Indigo Naturalis formula (RIF)) based regimens may provide a therapeutic advance by curing APL with two oral agents. Indeed, the oral RIF plus all-trans-retinoic acid (ATRA) without chemotherapy display highly efficacy in patients with APL. The safety profile of RIF plus ATRA make possible to treat APL patients in a home-based manner during postremission therapy. To our knowledge, RIF was the first commercially available oral arsenic agent approved in China. The RIF plus ATRA regimens are becoming a preferred frontline care for APL in China. In this review, we will discuss the history, current evidences and challengers of RIF-based strategies in APL. More and more APL patients may enjoy a cure with a normal quality-of-life after induction in the near future.

Treatment of non-high-risk acute promyelocytic leukemia with realgar-indigo naturalis formula (RIF) and all-trans retinoid acid (ATRA): study protocol for a randomized controlled trial

BackgroundAcute promyelocytic leukemia (APL) is a highly curable disease when treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO). The combination of ATO and ATRA has become the standard therapeutic protocol for induction therapy in non-high-risk APL. An oral arsenic realgar-indigo naturalis formula (RIF) has also showed high efficacy and it has a more convenient route of administration than the standard intravenous regimen. Unlike in previous trials, the arsenical agent was used simultaneously with ATRA during post-remission therapy in this trial.MethodsThis study was designed as a multicenter, randomized controlled trial. The trial has a non-inferiority design with superiority being explored if non-inferiority is identified. All patients receive ATRA-ATO during the induction therapy. After achieving hematologic complete remission (HCR), patients were randomly assigned (1:1) to receive treatment with ATRA-RIF (experimental group) or ATRA-ATO (control group) as the consolidation therapy. During the consolidation therapy, the two groups receive ATRA plus RIF or intravenous ATO 2 weeks on and 2 to ~ 4 weeks off until molecular complete remission (MCR), then ATRA and oral RIF 2 weeks on and 2 to ~ 4 weeks off giving a total of six courses.DiscussionThis trial aims to compare the efficacy of ATRA-ATO versus ATRA-RIF in non-high-risk patients with APL, to demonstrate that oral RIF application reduces the total hospitalization days and medical costs. The simple schedule was studied in this trial.Trial registrationClinicalTrials.gov, NCT02899169. Registered on 14 September 2016.

Efficacy and the Adverse Effects of Oral Versus Intravenous Arsenic for Acute Promyelocytic Leukemia: A Meta-Analysis of Randomized-Controlled Studies.

Acute promyelocytic leukemia, a subtype of acute myeloid leukemia, is highly curable. In subgroup of patients with non-high-risk acute promyelocytic leukemia, intravenous arsenic trioxide plus all-trans-retinoic acid is considered the preferred regimen for acute promyelocytic leukemia. Recently, there are interests in the use of the oral form of arsenic, named the Realgar-Indigo naturalis formula, but the data on its efficacy and safety are still relatively limited. The current study was conducted with the aims to identify and summarize the results of all available randomized-controlled studies. A systematic review was conducted in the 2 major databases, utilizing the terms for arsenic and acute promyelocytic leukemia. Eligible studies had to be randomized-controlled studies that compared efficacy and/or adverse effects of oral arsenic versus intravenous arsenic for treatment of patients with acute promyelocytic leukemia. The Mantel-Haenszel method was used to pool the effect estimates and 95% confidence intervals of the included studies together. A total of 4 randomized controlled studies with 482 patients with acute promyelocytic leukemia (258 in Realgar-Indigo naturalis formula group and 224 in intravenous arsenic trioxide group) were included in the meta-analysis. The chances of achieving complete remission were numerically higher in the Realgar-Indigo naturalis formula group but the difference was not statistically significant (pooled odds ratio: 4.59, 95% CI: 0.74-28.57, I 2 = 0%). Similarly, other efficacy outcomes, including 30-day mortality rate, overall survival, and event-free survival, also tended to favor the Realgar-Indigo naturalis formula group but the difference was not statistically significant. There was no significant difference in the chance of developing differentiation syndrome, cardiac complications, grades 3 to 4 liver toxicity, grades 3 to 4 renal toxicity, and infection between the 2 groups. The results may suggest that all-trans-retinoic acid plus oral Realgar-Indigo naturalis formula regimen is, at minimum, not a worse alternative to the standard all-trans-retinoic acid plus intravenous intravenous arsenic trioxide regimen for treatment of acute promyelocytic leukemia, especially for patients with low-to-intermediate risk.

Pilot Study on the Safety of Intravenous Arsenic Trioxide and Oral Realgar-Indigo Naturalis Formula Administrated in Children with Acute Promyelocytic Leukemia: A Single-Center Study

Objective Intravenous arsenic trioxide (ATO) and all-trans retinoic acid have become the front-line treatments for patients with acute promyelocytic leukemia (APL). Realgar-Indigo naturalis formula (RIF), an oral arsenic drug, not only shows a clinical efficacy comparable to ATO but also promotes incorporating an outpatient postremission therapy model into clinical practice for both low-risk and high-risk APL patients in China. However, the safety of ATO/RIF used in children with APL is unknown. To assess the safety of arsenic (ATO/RIF) administrated in children with APL, we designed the study. Methods Children with newly diagnosed APL treated with CCLG-APL2016 protocol (ChiCTR-OIN-17011227) in Beijing Children's Hospital from July 2016 to December 2018 were eligible for the study. The arsenic concentrations in different tissues, including plasma, urine, hair and nail, were measured at 10 time points: before ATO/RIF(D0), on the 7th, 14th and 28th day of ATO/RIF administration(D7, D14, D28), on the end of consolidation therapy (Con), during the 10 weeks of maintenance therapy (W10), on the cessation of therapy, after six months, one year and 1.5 years without arsenic administration. Adverse reactions were observed to evaluate the safety of arsenic received in children with APL. Results Nineteen patients with newly diagnosed APL were enrolled, including 9 boys and 7 girls with an onset average age of (10.9±3.7) years. There were 14 patients in low-risk group (white cell count <10,000/ul) and 5 patients in high-risk group (white cell count≥10,000/ul). All of them got hematologic complete remission (HCR) and molecular complete remission (MCR). The time to get HCR and MCR were 31 days (range, 27~74days) and (72.2±16.4) days, respectively. Besides, there were 13 patients getting ATO and 6 patients getting RIF in induction phase, and all patients receiving RIF as an outpatient postremission therapy. It showed that plasma and urine arsenic levels were significantly elevated after ATO/RIF administration. The median plasma arsenic ranged from 38.4 ng/ml to 76.10 ng/ml on D7, D14, D28, Con and W10 while the median urine arsenic retention ranged from 1562.80ng/ml to 3791.00ng/ml on D7, D14, D28, Con and W10. Plasma arsenic level rapidly decreased to 1.01 ng/ml after six months without RIF administration, which was slightly higher than D0 (1.01ng/ml vs 0.60ng/ml, P=0.043) and decreased to normal after 1 year without arsenic administration compared with D0 (0.55 ng/ml vs 0.60ng/ml, P=0.655). Urine arsenic level decreased to normal within 0~6 months off therapy (25.80ng/ml vs 13.74ng/ml, P=0.866). Hair arsenic (6480.95ng/g, range 2616.20-14683.70ng/g) and nail arsenic levels (17896.85ng/g, range 400.00-30334.00ng/g) peaked at the time of cessation of therapy. Hair arsenic level decreased to normal within half a year off arsenic (156.50 ng/g vs 103.45 ng/g, P=0.345) while nail arsenic retention decreased to normal after 1 year off arsenic (P=0.655). In addition, Spearman rank correlation analysis showed that plasma arsenic concentration was positively correlated with urine (r=0.825, P<0.001), hair (r=0.595, P<0.001) and nail (r=0.584, P<0.001) arsenic. Urine arsenic were also positively correlated with hair (r=0.624, P<0.001), and nail (r=0.575, P<0.001). And arsenic concentration in hair was positively correlated with nail (r=0.805, P<0.001), too. Conclusions Through the detection of arsenic concentration in different periods and different tissues, it was found that the plasma arsenic concentration could be maintained within the effective concentration range in each treatment stage, and the arsenic concentration in plasma and hair gradually decreased to normal after six months off arsenic. Urine and nail arsenic went down to normal after 1 year off arsenic. Up to now, with a longest follow-up period of 34.7 months and the mean follow-up time of 19.6 months, the short-term response of arsenic disappeared after symptomatic therapy or arsenic reduction, and no chronic side effects of arsenic were observed. Therefore, the use of ATO/RIF in children with APL is safe, but it still needs long-term follow-up. Disclosures No relevant conflicts of interest to declare.

Long-term follow-up of children with acute promyelocytic leukemia treated with Beijing Children’s Hospital APL 2005 protocol (BCH-APL 2005)

We studied the outcomes of children with APL treated by the Beijing Children’s Hospital’s (BCH) acute promyelocytic leukemia (APL) 2005 protocol (BCH-APL2005). The clinical data of 77 patients enrolled from January 2005 to June 2015 were analyzed retrospectively. The hematologic complete remission (CR) rate and overall survival (OS) rate were evaluated between standard-risk (SR) and high-risk (HR) groups. Prognostic factors and complications were investigated in these two groups. CR in the SR and HR groups was 96.4% (54/56) and 85.7% (18/21), respectively, while the 10-year OS was 94.6% (53/56) and 76.2% (16/21), respectively. The cumulative incidence of early death was 6.5% (5/77), and the SR and HR groups were 1.8% (1/56) and 19.0% (4/21), respectively. Only two patients relapsed, and the relapse rate was 2.6% (2/77). According to Kaplan–Meier analysis, the SR group had a significantly better long-term survival than HR counterparts (p= .016). Initial leukocyte count was the only prognostic factor (p= .016) by univariate analysis, while other factors, such as FLT3-ITD and platelet count, had no correlation with prognosis. In addition, early deaths were mainly due to intracranial hemorrhage. Although the combination of all-trans retinoic acid (ATRA) and chemotherapy can improve the outcome of APL patients, the early deaths and anthracycline-related cardiac toxicity were relatively higher in our study. Current efforts focus on reducing or even avoiding chemotherapy in APL children and rest on the frontline regimen of intravenous arsenic trioxide or oral realgar-indigo naturalis formula plus ATRA, which is the direction for APL treatment.

Efficacy and safety of early switching to an outpatient therapy model using oral arsenic plus retinoic acid based-regimen in newly diagnosed acute promyelocytic leukemia

Realgar-Indigo naturalis formula(RIF)is an oral form of arsenic developed for treatment of acute promyelocytic leukemia (APL). We retrospectively evaluated the efficacy and safety of a novel RIF combined with all-trans retinoic acid (ATRA) based chemotherapy-free approach in newly diagnosed APL patients. Patients received oral ATRA (25 mg/m2/day in 2 divided doses) plus intravenous arsenic trioxide (0.15 mg/kg/day) or oral RIF (60 mg/kg/day in 3 divided doses) as induction chemotherapy, followed by 2 consolidations with ATRA plus RIF and maintenance therapy with intermittent ATRA and RIF. From January 2015 to December 2017, 40 subjects were enrolled. Eighteen subjects were male. Median age was 42 years (range, 14–77 years) and 10 subjects were ≥ 60 years. All subjects achieved a complete morphologic remission after initial induction. Molecular complete remission achieved 100% after second RIF plus ATRA consolidation. Median follow-up of survivors was 27 months (range, 7–43 months). The 2-year event-free survival (EFS) and overall survival (OS) were both 100%. Adverse events were modest and all patients needed only outpatient care during postremission therapy. Compared to our historical RIF plus ATRA with chemotherapy regimen (the Chinese APL07 trial), the inpatient treatment duration was greatly reduced by the RIF plus ATRA regimen. Our data indicates that early switching to RIF plus ATRA based chemotherapy-free approach has yielded encouraging outcomes and might be considered a practicable option to treat patients with newly diagnosed APL.

Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study.

Intravenous arsenic trioxide (ATO) has been adopted as the first‐line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar‐Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As4S4, has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML‐RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all‐trans‐retinoic acid and low intensity chemotherapy. End points included event‐free survival (EFS), adverse events and hospital days. After a median 3‐year follow‐up, the estimated 5‐year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.

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

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. 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. 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). 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. 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.

Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials

ObjectiveIntravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients.MethodsWe conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months.The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%.ResultsComplete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p= 0.12).The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p >0.05).ConclusionsRIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054). DisclosuresNo relevant conflicts of interest to declare.

The kinetics of white blood cell and the predictive factors of leukocytosis under oral or intravenous arsenic as the first-line treatment for acute promyelocytic leukemia

ObjectiveWe aimed to compare the kinetics of white blood cell (WBC) and explore predictive factors of leukocytosis in non-high-risk acute promyelocytic leukemia (APL), with oral arsenic plus all-trans retinoic acid (ATRA) or intravenous arsenic trioxide (ATO) plus ATRA as a first-line treatment. MethodsThe absolute count, doubling time and peak time of WBC were analyzed in 64 newly diagnosed non-high-risk APL patients who were treated with different induction regimens containing either oral Realgar-indigo naturalis formula (RIF) (n=35) or ATO (n=29). The end points were the dynamic changes of the WBC counts during induction. The time points started at day 1 and were selected over 3-day intervals for 28days. ResultsAmong the 64 included patients, the median initial and peak WBC counts were 1.78×109/L (range 0.31–9.89) and 12.16×109/L (range 1.56–80.01), respectively. The incidence of differentiation syndrome was 9.38%. The dynamic changes in leukocytosis showed a single peak wave in all the patients, and the median time to peak was 10 (range 2–26) days. A higher WBC count was observed in the RIF group than in the ATO group after 10days of treatment (9.22×109/L vs. 4.10×109/L, p=0.015). Patients with the peak WBC count >10×109/L had a shorter WBC doubling time compared to patients with a lower peak WBC (RIF group 4days vs. 7days, p=0.001; ATO group 4.5days vs. 23days, p=0.002). Univariate and multivariable analyses showed that the doubling time of WBC is an independent factor for the peak WBC count. ConclusionDifferent kinetics of WBC proliferation were observed during induction with oral arsenic plus ATRA and ATO plus ATRA. The doubling time of WBC is an important independent factor for predicting the peak WBC count.

Oral Tetra-Arsenic Tetra-Sulfide Formula Versus Intravenous Arsenic Trioxide As First-Line Treatment of Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trial

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups. Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

Oral Realgar-Indigo Naturalis Formula Achieved Comparably High Rate of Remission and Survival to Intravenous Arsenic Trioxide As a Front-Line Treatment in Newly Diagnosed Acute Promyelocytic Leukemia: A Multi-Center Randomized Trial APL07

AbstractAbstract 140 BackgroundArsenic trioxide increases the rate of complete remission (CR) and prolongs long-term overall survival in patients with acute promyelocytic leukemia (APL). We demonstrated that an oral arsenic-containing Realgar-Indigo naturalis formula (RIF) could yield clear synergistic effects in an in vivo murine APL model as well as an in vitro APL cell lines. The efficacy and safety of this formula were confirmed by a CR rate of 96.7% and reasonable safety profile in a multicenter Phase II clinical trial in China. To find out whether oral RIF could achieve similar remission and survival with ATO, the Chinese APL Cooperative Group conducted a phase 3 randomized study (APL07) that compared oral RIF with ATO in both the induction and maintenance therapies. MethodsIn this phase 3 randomized trial, 242 newly diagnosed APL patients were randomly assigned to receive oral RIF (n=121, daily 60 mg per kg body weight) or ATO (n=121, daily 0.15 mg per kg body weight) as a part of induction therapy. All patients also received all-trans-retinoic acid (ATRA; daily 25 mg per square meter) as induction therapy, and were between the ages of 15 and 60 years. After achieving CR, all patients were given three courses of consolidation chemotherapy with anthracycline and cytosine arabinoside. The maintenance treatment included eight cycles of sequential use of ATRA and RIF or ATO for two years. The primary endpoint was disease-free survival (DFS). The secondary endpoints were the rate of CR and overall survival (OS) and safety. ResultsAt a median follow-up of 28 months, no significant differences were noted between RIF group and ATO group with respect to CR rate (99.1% vs.97.2%, P=0.62), DFS (98.9% vs.97.64%, P=0.6) (Figure 1A) and OS at 3 years (99.1% vs.96.6%, P=0.18) (Figure 1B). The rates of adverse events were similar in the two groups. The rate of treatment-related grade 3/4 liver toxic effects was 9.6% in the RIF group and 12.0% in the ATO group(p=0.67). When on the arsenic-containing treatment, the plasma arsenic content was higher in the ATO group than in the RIF group (56.3 vs. 23.6 μg/L, p=0.0002). The median levels of arsenics concentration of plasm, urine, hair and nail samples after completing therapy 12 months were below the lower limit of the normal control. ConclusionsOral Realgar-Indigo naturalis formula yielded a comparable high remission and long-term survival with arsenic trioxide as front-line treatment of newly diagnosed APL [Display omitted] . Disclosures:No relevant conflicts of interest to declare.