Jurnal Internasional Semakin sederhana, semakin baik: arsenik oral untuk leukemia promyelocytic akut
Arsenic trioxide and all trans retinoic acid has become a frontline treatment for patients with acute promyelocytic leukemia (APL). Despite the long wait for oral arsenic drugs, a commercially available agent, the naturalist-indigo realgar-formula (RIF), was not launched in China until 2009. Since then, more than 5000 APL patients have been treated with oral RIF in China. Oral arsenic not only shows comparable clinical efficacy with IV formulation but also displays a better safety profile, improved quality of life, and lower medical costs for patients. Promising results promote the incorporation of post-outpatient therapy models into clinical practice for low-risk and high-risk APL patients in China. In this review, we discuss the evolution of oral arsenic RIF in APL treatment, with a special focus on how to overcome complications associated during induction therapy.
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Explain the efficacy of oral arsenic realgar -indigo naturalis formula (RIF) in the treatment of acute promyelocytic leukemia (APL)
Determine the toxicity of oral arsenic RIF in APL treatment and strategies for overcoming related complications during induction therapy
Identification of clinical implications regarding the use of oral arsenic RIF in APL treatment [APL] 19659019] Release date: August 15, 2019; Expiry date: August 15, 2020
Acute promyelocytic leukemia (APL) has become a very curable disease. 1 ⇓ ⇓ –  –  –  4 trans- trans retinoic acid (ATRA) and arsenic trioxide (ATO) ) is the backbone of modern treatments for APL and has caused total remission (CR) in 90% to 100% of patients in clinical trials and overall survival (OS) between 86% and 97%. 5 ⇓ ⇓ [1945 ⇓ ⇓  ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ] [1945 [1945 ⇓ – 15 Research that changed the APL0406 practice reported by Lo-Coco et al showed that APL patients were not at risk of high levels can be cured using chemotherapy-free ATRA and ATO-free regimens, 10 14 which provide evidence for the National Comprehensive Cancer Network guidelines. 16
However, patients who receive IV ATO must be hospitalized, which is not cost-effective and uncomfortable. Therefore, oral arsenic drugs have long been awaited. 17 ⇓ ⇓ – 20 The only commercially available agent, named realgar-indigo naturalist formula (RIF), was launched at China in 2009. RIF not only shows clinical efficacy but also displays a better safety profile, improved quality of life, and lower medical costs for patients. 21 [ ] – 23 Promising results led to the incorporation of RIF into Chinese APL management guidelines starting in 2014. 24 25 There is a need for strong for oral arsenic for APL patients both in China and in western countries. 17 ⇓ ⇓ – 20 25 ⇓ ⇓ 25 25 ⇓ ⇓ 25 ⇓ [1945 – 30 Although the use of oral ATO has been reviewed, 18 oral RIF, the only oral agent commercially available, has never been comprehensively reviewed. Therefore, in this review, we systematically discuss China's experience with oral RIF for the treatment of APL, with a particular focus on managing complications associated with RIF.
In China, there are 4 types of oral arsenic formulations: tetra-arsenic tetrasulfide (As 4 S 4 ), which was isolated from ore known as realgar; ATO (As 2 O 3 ); Qinghuang powder (realgar and indigo naturalist); and RIF (realgar, indigo naturalist, radix salviae miltiorrhizae, and radix pseudostellariae). Zhou et al first reported that 2 APL patients newly diagnosed reached CR and maintained CR continuously for 4 years using Qinghuang powder in 1986. 31 Lu et al reported long-term follow-up data in treated patients with Oral As 4 S 4 in 2002. 32 Kumana et al reported oral ATO solutions as treatment of APL patients in 2002 33 ; New ATO capsule formulations developed in Australia are being evaluated by the Phase 1 Australasian Group (ALLG) Leukemia and Lymphoma Study (APML5; ACTRN12616001022459). ORH-2014 is another oral ATO formulation. A phase 1 study to determine the recommended dose and evaluate the safety and tolerability of ORH-2014 in patients with advanced hematological disorders ( clinicaltrials.gov identifiers NCT03048344 ; led by F. Ravandi, MD Anderson Cancer Center, Houston, TX) was completed in February 2019. Based on promising results, ORH-2014 will enter phase 3 trials in the near future
However, RIF is currently the only commercially available agent. RIF was first developed by Huang et al in 1980, and the first RIF study for APL was reported in 1988. 34 Based on the results of systematic research by Huang et al and Qian et al, this drug was approved by the Supervisory Agency Chinese Medicine and Food (FDA) in 2009 for the treatment of APL. 34 35 One RIF pill is 270 mg and contains 30 mg realgar, 125 mg of indigo naturalis, 50 mg radix salvia miltiorrhizae, 45 mg radix pseudostellariae, and 20 mg garment film. Wang et al demonstrated the anti-APL activity of RIF in vitro and in vivo. 36 They found that indigo naturalis and radix salviae miltiorrhizae facilitate intracellular arsenic transport by increasing aquaglyceroporin regulation 9. A clear synergistic effect of component differences is shown in APL cell differentiation and apoptosis. 36 Furthermore, a series of clinical trials led by Zhu et al promoted the incorporation of RIF into the APL China management guidelines and their widespread use in China. 21 ⇓ – 23 28 ⇓ – 30 37 ⇓  ⇓ – 40
In China, RIF is commercially available in all regions except Hong Kong, Macau and Taiwan. More than 5000 APL patients, adults and children, have been treated with oral RIF. The high cost effectiveness of RIF is also an important factor for its wide use. The cost of RIF treatment is around $ 22.00 (US dollars; 150 yen) per day for patients weighing ∼60 kg. The median medical costs were $ 13 183.49 in the RIF group and $ 24 136.98 in the ATO IV group ( P <.0001 dalam="" protokol="" yang="" termasuk="" kemoterapi=""> 29 which included not only the price of medicines but also the price of blood products, laboratory tests, non-laboratory tests, bed / hospital care, and other medical costs Higher medical costs are mostly generated from costs associated with day care facilities for IV ATO infusion.
With post-outpatient therapy models outpatient treatment completely free of chemotherapy with oral ATRA and RIF, the median total medical costs were reduced to $ 4675.00 (range, $ 3174.00 to $ 12,698.00) in APL patients who were not at high risk 30 and $ 7540.00 ($ 5490.00 to $ 26 530.00) for high-risk patients. 36 In China, the majority of the costs (70%) ∼85%) of RIF are covered by Basic Insurance for Employees Urban, Basic Insurance for City Residents, and New Rural Cooperative Medical Schemes, yan g covers more than 95% of the population. 28 Therefore, the direct economic burden of patients with APL is significantly reduced, which makes RIF very attractive in China.
Oral RIF results in gradual intestinal absorption. When administered orally at 1 dose of 2.5 g (including 0.4 g As 4 S 4 ) in 10 healthy donors, the results showed a maximum serum concentration (Cmax) of 0, 1057 ± 0.0031 mg / L, half-life t1 / 2α at 3.207 ± 0.526 hours, t1 / 2β at 9.266 ± 1.344 hours, and the area under the curve (AUC) at 2.5508 ± 0.1528 mg × h / L. 41 When given IV, almost all ATO is bound to hemoglobin and quickly leaves circulation to the peripheral tissues. Arsenic accumulates mainly in the hair, nails, liver, lungs, heart, and kidneys. When given at 1 dose of 10 mg ATO in 8 APL patients, the results showed Cmax 6.85 μmol / L (5.54-7.30), t1 / 2α of 0.89 ± 0.29 hours, and t1 / 2β of 12.13 ± 3.31 hours. 42
When given orally at 60 mg / kg RIF per day and 25 mg / m 2 per day ATRA every day, sustained plasma arsenic concentration would be achieved after 7 days, which is less than that seen with ATO IV at 0.16 mg / kg per day (median, 24.4 μg / L [range, 11.5-64.0 μg / L] and 56.3 μg / L [range, 21.7-89.5 μg/L]; P =. 0048) 21 Both RIF and ATO are mostly excreted by the kidneys. We found that after completing 12 months of therapy with RIF or ATO, arsenic concentrations in hair, nails, plasma, and urine samples were all within the normal range described for healthy control. 21
Huang et al conducted a series of studies to confirm the efficacy of RIF for APL patients. 34 35 43  ⇓ – 45 In the earliest study, RIF alone (n = 44) reached a CR level of 100% in newly diagnosed APL patients. and relapse. 34 A CR level of 93.8% (15 of 16) was achieved when RIF plus chemotherapy was used as induction therapy. 34 In subsequent studies that included newly diagnosed (n = 161) and relapse (n = 43) APL patients at a single center between 1988 and 2005, a CR rate of 96.08% (196 of 204) was achieved with the 3-year and 5-year OS levels were 88.52% and 86.88%, respectively, when RIF worked together. combined with chemotherapy as a post-liberation therapy. 43 Randomized, double-blinded phase 2 multicenter trial designed to compare the efficacy and safety of RIF vs ATRA as induction therapy. 35 The CR rates were 96.7% (59 of 61) and 94.9% (56 of 59) for the RIF and ATRA groups, respectively. The time to reach CR is 49 days and 44 days, respectively. 35 This data promotes RIF approval by the Chinese FDA in 2009.
To assess the efficacy of combining RIF and ATRA as the first. line treatment, we started a randomized phase 3 trial of RIF vs ATO IV formulation in 242 patients newly diagnosed with APL. 21 All patients received ATRA combined with arsenic as an induction therapy and 3 cycles of consolidated chemotherapy with homoharringtonine, mitoxantrone, or daunorubicin plus cytarabine for the maintenance phase. RIF was confirmed not to be inferior to ATO IV in terms of 2-year disease-free survival (DFS; 98.1% vs 95.5%), CR levels, and OS. 21 Long-term follow-up data indicate that the estimated 7-year cumulative relapse (CIR) incidence, free survival (EFS), and OS levels are similar between the RIF and ATO groups (4.69% vs 5.25%, P = 98; 93.70% vs 89.37%, P = 0.37 and 95.37% vs 90.92%, P = 0.31, respectively). Estimates of 7 years of CIR, EFS, and OS were also similar between high-risk and non-high-risk groups (2.44% vs 5.04%, P = 0.55; 91.20% vs 91.49 %, P = 0.74, and 93.48% vs 92.96%, P = 0.82). 22 Based on the APL0406 study reported by Lo-Coco et al with chemotherapy-free regimens for APL, 10 we conducted a pilot study in which 20 patients with high non-risk APL were enrolled, and rates of CR 100% was achieved under treatment with RIF and ATRA without chemotherapy with a median of 29.5 days (range, 28-40 days). 30 All 20 patients were still alive on February 1, 2019 and were in CR with a median follow-up of 65 months (range, 59-71 months). Post-outpatient care significantly reduces the costs associated with health care. 26 30 Next, we began a randomized controlled trial to compare the efficacy and toxicity of RIF-ATRA with IV ATO-ATRA in patients with newly diagnosed non-high-risk APL. 23 In total, 109 patients were enrolled and assigned to the RIF-ATRA (n = 72) or the ATO-ATRA treatment group (n = 37). After a median of 32 months of follow-up, 2-year EFS was 97% of patients (67 of 69) in the RIF-ATRA group and 94% (34 of 36) in the ATO-ATRA group in modified intentions for the treating population. Noninferiority is confirmed in populations that intend to treat and per-protocol populations. During induction therapy, 2 patients in the ATO-ATRA group died due to bleeding. 23
APL patients at high risk are at the center of the final battle for healing for all APL patients. . 13 37 46 We conducted a single central cohort study of 20 high-risk APL patients to evaluate the efficacy and safety of RIF plus ATRA between April 2014 and September 2016. 37 RIF (60 mg / kg per day) plus ATRA (25 mg / m 2 per day) combined as induction therapy to CR. Hydroxyurea alone or in combination with cytarabine is used to control hyperleukocytosis during induction therapy. Consolidation therapy includes RIF in the 4-week regimen and 4 weeks for 4 cycles and ATRA in the 2-week and 2-week regimens for 7 cycles. All 20 patients reached CR with a median time of 30 days (range, 28-50 days). With a median follow-up of 33 months, there was no haematological recurrence. Only 2 patients experienced molecular recurrence at 12 and 15 months. Estimated 3-year OS and EFS levels are 100% and 89.4%, respectively. 33 This post-outpatient treatment has proven to be effective, comfortable, and cost-effective for high-risk APL.
For pediatric patients with APL, the outpatient model of oral chemotherapy is also attractive. We conducted a single central cohort study between April 2014 and October 2016. Nine patients (13-18 years) received the same protocol as in the previous report. 46 With a median of 15-month follow-up, all of 9 patients achieved CR hematology and complete molecular remission. The total stay time is 17 days (4-37 days). No haematological or molecular recurrence occurred at the last follow-up. Estimated level of EFS and OS 2 years is 100%. Of note, all patients completed post-treatment therapy in outpatients with good quality of life. 46 In China, a randomized trial was designed to compare between ATO IV and oral RIF in pediatric patients.  47 Eighty-two newly diagnosed APL child patients were randomly assigned to the ATO group (n = 42) or RIF (n = 40). Induction and consolidation treatments contain ATO or RIF, ATRA, and low intensity chemotherapy. They found that the estimated 5-year EFS level was 100% in both groups, and the side effects were mild. However, patients in the RIF group had significantly shorter hospital stays than patients in the ATO group. This interim analysis shows that RIF is as effective and safe as ATO IV for a child's APL, with the advantage of reducing hospital stay. A randomized multicenter controlled trial led by the Chinese Children's Leukemia Group of APL (CCLG-APL) was initiated to compare RIF plus ATRA and ATO plus ATRA in chemotherapy-free regimens and has been ongoing since July 2016 (ChiCTR-OIN-17011227). [19659162Table1 summarizes recent trials using RIF or IV ATO and ATRA as frontline treatments for newly diagnosed APL. There may be several reasons for the relatively low early mortality rate (% 1%) in the RIF group such as the bias in most clinical trials including low-risk patients, experienced doctors, timely hospitalization and availability of ATRA, and RIF. Prospective registration trials aimed at determining real world premature death rates using RIF and ATRA as induction are now underway in China and we await the results.
Leukocytosis, defined as a white blood cell count (WBC) of more than 10 × 10 9 / L, is the most common complication (> 50%) during induction therapy with RIF and ATRA in APL patients who are not at high risk. Recognizing the risk factors for leukocytosis and providing preventive treatment is important in clinical practice. We evaluated red blood cell kinetics during induction treatment with RIF and ATRA in 35 high-risk non-APL patients. 39 The initial and peak median number of WBC is 1.62 (0.61-9.89) × 10 9 / L and 13.93 (2.16-80.01) × 10 ] 9 / L, respectively. Leukocytosis shows a single peak wave in all patients, and the average time to reach the peak is 10 days (range, 2-20 days). We found a cutoff value of 5 days for doubling of red blood cells with specificity of 69.23% and sensitivity of 90.91% for predicting leukocytosis. In subsequent experiments, we performed preemptive treatments to reduce the level of leukocytosis. 23 If the WBC amount is (4-10) × 10 9 / L before treatment, hydroxyurea is added on the first day using a dose of 1.0 three times a day, by mouth, days 1 through 7. If the amount of WBC 9 / L before treatment, hydroxyurea (dose 1.0 three times daily, by mouth, days 1-7) is added when the WBC amount increases to> 4 × 10 9 / L. When WBC counts increase to more than 30 × 10 9 / L during induction treatment, ATRA or RIF must be stopped for 3 to 7 days, and anthracyclines or cytosine arabinoside can be used. Among the RIF-ATRA group, 46 of 69 patients (67%) received hydroxycarbamide, 15 (22%) received cytarabine, and 5 (7%) received anthracycline during induction therapy. Leukocytosis developed in 28 of 69 patients (41%) during induction therapy with RIF and ATRA, and no early deaths occurred due to leukocytosis during induction therapy. 23
For high-risk APL patients, management of leukocytosis is very urgent in clinical practice. In a cohort study involving 20 patients, we adopted minimal WBC-based chemotherapy to reduce the burden of leukemia. 37 For patients with WBC counts (10-20) × 10 9 ] / L before treatment, only hydroxyurea (3.0 g daily in oral divided doses) was used from the day first until the number of WBC 9 / L is reached. For patients with WBC counts> 20 × 10 9 / L before treatment, hydroxyurea (3.0 g daily) and cytarabine (200 mg daily) are used from the first day to reduce the burden of leukemia until there is a WBC amount 9 / L. With this strategy, all 20 patients safely attain CR and avoid exacerbation of disseminated intravascular coagulation and bone marrow suppression associated with regular standard dose chemotherapy.
Differentiation Syndrome (DS) is a relative complication associated with regular standard dose chemotherapy. general and severe. seen in APL patients treated with ATRA and / or ATO. 48 49 DS occurs in ∼10% to 25% of APL patients during induction therapy after the start of ATRA and / or ATO. 50 51 In cases of suspected DS, stopping administration of ATRA and / or ATO and dexamethasone at a dose of 10 mg every 12 hours for a minimum of 3 days It is recommended to use a diuretic. For severe DS, ATRA and / or ATO treatment must be stopped. 52 Several clinical trials use prophylactic steroids for all patients during induction therapy to reduce the incidence and severity of DS. 53
Among patients with a WBC number of 9 / L, DS developed in 22 of 114 patients (19%) in the RIF-ATRA group and 29 of 117 patients (24.8%) in the ATO-ATRA group without prophylactic steroids. 21 In our other randomized controlled trial which included only APL patients who were not at high risk, DS developed in 26% of patients (18 of 69) in the RIF-ATRA group and in 28% of patients (10 of 36) in the ATO-ATRA group. 23 The average time of DS occurrence was 8 days in the RIF-ATRA group and 6 days in the arsenic trioxide-ATRA group. Severe DS occurred in 2 of 69 patients (3%) in the RIF-ATRA group and 1 in 36 patients (3%) in the arsenic trioxide-ATRA group and was fatal in 1 patient assigned to the ATO-ATRA group.  23 When using prednisone prophylaxis to treat DS in the APL0406 study, DS levels are relatively low. 10 DS developed in 19% of the ATO-ATRA group and 16% of the ATRA-chemotherapy group. Severe DS rates were 6% in each group and were fatal in 2 patients in the ATRA chemotherapy group. To date, there have been no prospective randomized trials to answer whether prophylactic approaches reduce the incidence and mortality of DS. In patients with severe DS, temporary cessation of ATRA and / or ATO is recommended. 52 53 Both drugs can be restarted after the syndrome is resolved
Liver damage  Hepatotoxicity has often been reported in studies using arsenic with or without ATRA, especially in the case of increase in liver enzymes. This complication can occur in up to 60% of cases. 10 However, hepatotoxicity is generally reversible and can be managed successfully with a reduction or temporary cessation of arsenic and / or ATRA. No fatal liver failure has been reported in recent trials. 10 12
RIF, as first-line monotherapy in a single center study, reported hepatotoxicity in 16 of 204 patients (7.8%), including 161 newly diagnosed patients and 43 APL patients who recur. 43 In a multicenter RCT study, RIF induction monotherapy caused hepatotoxicity in 8 of 78 APL patients newly diagnosed (10%) 35
After combining RIF with ATRA, the rate of hepatotoxicity increases significantly compared to RIF or ATRA alone, although the level of poisoning from 3-4 levels is relatively low. In our RCT study which included APL patients with WBC 9 / L counts, hepatotoxicity occurred in 74 of 114 patients (64.9%) and 87 of 117 patients (74.5%) in the RIF-ATRA group and the ATO-ATRA group, each. 21 Grade 3-4 liver toxicity rates were 9.6% and 12.0%, respectively. The incidence of grade 1-2 liver toxicity was 62.5% and 55.3%. All patients were treated primarily with a reduction or interruption of the dose ( 23 grade 1-4 liver toxicity was 58% (40 of 69) in the RIF-ATRA group and 78% (28 of 36) in the ATO-ATRA group (Table 3 in Zhu et al 23 ) and liver poisoning rates of 3-4 are 9% vs 14%. Toxicity is overcome by temporary stopping of ATRA, arsenic, or both. Conversely, the level of hepatotoxicity is relatively low in our study. recently of 20 high-risk APL patients. 37 Nine out of 20 patients (45%) in the RIF-ATRA group had level 1-2 hepatotoxicity, and no grade 3-4 hepatotoxicity occurred.  Diarrhea
With the use of RIF as a first-line treatment of monotherapy in a single center study, diarrhea occurred in 31 of 204 patients (15%), including 161 new patients, diagnosed and 43 APL patients relapsed. 43 In multicenter RCT studies, RIF as monotherapy i nduction caused diarrhea in 6 of 78 recently diagnosed APL patients (7.7%). 35 After combining RIF with ATRA in APL patients who were not at high risk, 6 of 66 patients (9%) in the RIF-ATRA group and 2 of 36 patients (6%) in the ATO-ATRA group had diarrhea. 23
Extension of the QTc interval
The extension of the QTc interval on electrocardiography (ECG) is a common and well-documented side effect of ATO. The GIMEMA-SAL-AMLSG trial APL0406 reported a prolonged QTc interval in 15 patients in the ATRA-ATO group (16%). 10
Prolonged QTc interval is not a common side effect of RIF at a dose of 60 mg / kg per day. However, at a high dose of 7.5 g per day as a first-line treatment of monotherapy in a single center study, prolonged QTc intervals (40440 ms) occurred in 17 of 71 recently diagnosed APL patients (23.9%). 42 Additionally, clinically significant arrhythmias are very rare, and nothing has been reported in recent trials using RIF and ATRA as first-line therapy. 21 23 ] 30 Because open electrolyte depletion during RIF and ATRA induction therapy is rare, K + and Mg Replacement of 2+ is not recommended routinely during home based therapy. ECG monitoring for extended QTc is recommended at least once in each RIF cycle.
Conclusions and future directions
Arsenic, as an ancient drug, has recently been revised to cure newly diagnosed APL and recur, both as a single agent . and in combination with other agents. We and others have observed that oral RIF arsenic has the same activity and may be a better toxicity profile than ATO IV, with superior patient quality of life and lower costs. The combination of RIF and ATRA has become the first-line treatment of newly diagnosed APL patients in China. Other arsenic derivatives may also be active in clinical settings. Postmission-based, outpatient, chemotherapy-free, outpatient care has become a reality for both low-risk APL patients, with studies that show sufficient evidence, and for high-risk patients, with studies that show promising primary results. The results of ongoing trials, including one in South America recommended by the International Consortium on Acute Leukemia from the American Society of Hematology (ASH-ICAL; which seeks to confirm the success of oral RIF), is eagerly awaited. Di jalan untuk menyembuhkan APL, ringkasan terbaik adalah: semakin sederhana, semakin baik.
Ucapan Terima Kasih
Pekerjaan ini didukung oleh hibah dari National Science Science Foundation of China (81570128 dan 81820108004) dan Program R&D Kunci Nasional of China (2016YFE0202800).
Para penulis mendedikasikan artikel ini untuk Francesco Lo-Coco, sebagai pengakuan atas dukungan dermawan yang terus-menerus dari studi ini pada arsenik oral untuk APL.
Kontribusi: H.-HZ, JH, dan JJ menyusun naskah dan berkontribusi pada rancangan akhir; dan F.L.-C. memberikan saran dan komentar tentang naskah tersebut.
Pengungkapan konflik kepentingan: Penulis menyatakan tidak ada kepentingan finansial yang bersaing.
Francesco Lo-Coco meninggal pada 3 Maret 2019.