Arsenic Trioxide for Acute Promyelocytic Leukemia

Practice Guideline: Systemic Therapy Summary Arsenic Trioxide for Acute Promyelocytic Leukemia (LEUK Arsenic Trioxide) Leukemia Disease Site Group Effective: June 2014 Required Update: September 2016 Annual Review: September 2015

Systemic Therapy Summary 2 CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 2

Systemic Therapy Summary 3 ACKNOWLEDGEMENT AND SPONSORSHIP DISCLAIMERS There are no relevant conflicts of interest to disclose. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 3

Systemic Therapy Summary 4 Preface This document has been prepared by the Winnipeg Regional Health Authority/CancerCare Manitoba (WRHA/CCMB) Oncology Pharmacotherapeutic (P&T) Subcommittee s Systemic Therapy Summaries Working Group, as a means of disseminating drug information and formulary decisions made by the Subcommittee. The CCMB Provincial Pharmacy Program, Provincial Oncology Drug Program (PODP) and Clinical Practice Guidelines Initiative (CPGI) have contributed to the development of this summary. Systemic Therapy Summaries (STS) are being developed for drugs/or indications where the P&T Subcommittee, based on scientific data, has accepted clinical benefit. The P&T Subcommittee Chair and the CPGI Medical Director/Advisory Panel Chair approve all STS documents. The content of this STS was in large part adapted from the Formulary Addition Request submitted to the P&T Subcommittee by the CCMB Leukemia Disease Site Group (DSG), June 2014. This document will be reviewed, and updated as necessary, once in every twelve-month period; unless emerging evidence from scientific research dictates otherwise. Purpose This document is intended as a guide to facilitate the safe and effective clinical use of arsenic trioxide in the treatment of acute promyelocytic leukemia. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, nurses, and pharmacists at CancerCare Manitoba, Community Cancer Programs Network (CCPN) sites and WRHA Community Oncology Program sites. Disclaimer Use of this document should not preclude the practitioner s independent clinical judgment, nor should it replace consultation with the oncologist. It is the responsibility of the practitioner to develop an individualized treatment plan for each patient under his/her care, and ideally this should take place within the context of a multidisciplinary team. The unique needs and preferences of the patient and the family should always be reflected in the plan of care. This document is not a comprehensive drug monograph. Practitioners must refer to other sources for complete drug information. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 4

Systemic Therapy Summary 5 Arsenic Trioxide for Acute Promyelocytic Leukemia Protocol Code: LEUK Arsenic Trioxide Developed by: Leukemia Disease Site Group Date of Presentation to P&T Subcommittee: June 17, 2014 Treatment Recommendation The Leukemia Disease Site Group (DSG) recommends treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) in patients who meet the inclusion criteria (see below). Treatment Intent Curative Decrease regimen toxicity Rationale APL is a unique subtype of acute myeloid leukemia. APL is a rare disease with an average of 2.5 new cases in Manitoba per year in the last 10 years. With the introduction of all-trans retinoic acid-based therapy, the prognosis of APL tends to be quite good with a high cure rate. APL is associated with coagulopathy at the time of presentation which can be life-threatening therefore; APL should be managed as a medical emergency due to the high mortality risk caused by the bleeding diathesis. In Manitoba, all cases of APL should be initially managed at the Health Sciences Centre, under the care of the Leukemia/Bone Marrow Transplant service. APL is characterized by a translocation between chromosomes 15 and 17, which fuses promyelocyte (PML) and retinoic acid receptor (RAR-α) genes, creating a new fusion gene protein (PML-RAR-α). This protein has a number of actions, but one of the hallmarks is the loss of differentiation of promyelocytes into more mature myeloid cells. Initial studies using ATO have shown promising results in patients with relapsed or refractory disease, with rates of complete remission as high as 80%. The promising activity in the relapsed setting, combined with the low toxicity profile of ATO, resulted in interest in using ATO as a component of first-line therapy. Arsenic binds the PML component of the fusion gene product which deactivates the protein and leads to differentiation of promyelocytes. ATO has demonstrated synergy with all-trans retinoic acid (tretinoin or ATRA), which binds the RAR-α component of the fusion gene product. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 5

Systemic Therapy Summary 6 Clinical Benefit 1,2 (Level Ib Evidence see Appendix I) A phase III randomized trial was conducted comparing the LPA2005 regimen with a combination of ATRA and ATO in induction and consolidation phases in patients with low and intermediate risk APL. A total of 156 patients ranging in age from 18 to 71 years were enrolled and randomized to ATRA plus ATO or ATRA plus chemotherapy. All of the patients (100%) in the ATRA plus ATO group achieved complete remission compared to 95% of patients in the ATRA plus chemotherapy group (p = 0.12). There was greater early toxicity in the ATRA plus chemotherapy group, with four toxic deaths, as compared to none in the ATRA plus ATO group. Two patients in the ATRA plus ATO group terminated therapy due to toxicity. Differentiation syndrome occurred in 19% and 16% of the ATRA plus ATO arm and the ATRA plus chemotherapy arm, respectively. There was superior event free survival (EFS) and superior overall survival (OS) in patients randomized to ATRA plus ATO at 24 months compared to the ATRA plus chemotherapy group (p = 0.02). In addition, ATRA plus ATO was found to be reasonably well tolerated. The incidence of febrile neutropenia events (FNE) was markedly lower in the ATRA plus ATO group and there were no patients that developed grade 3 or 4 mucositis, compared to 19% in the ATO plus chemotherapy group. There was a significant increase in grade 3 or 4 hepatotoxicity in patients randomized to ATRA plus ATO, but in all cases this was resolved with a temporary cessation of ATO. Patients with high risk disease (white blood cell (WBC) > 10 x 10 9 /L) were included in a different randomized trial conducted by the Cancer and Leukemia Group B (CALGB) and the National Cancer Institute of Canada (NCIC). This study randomized 481 patients with APL to induction chemotherapy (ATRA, cytarabine and daunorubicin) followed by consolidation chemotherapy (daunorubicin plus ATRA) with or without two cycles of ATO as part of consolidation. This trial included patients with low, intermediate and high risk APL. In all patients, there was improved EFS and disease free survival, and a trend towards improved OS (p = 0.059) in patients who received ATO as part of consolidation. On the basis of improved EFS and trend towards improved OS seen in this randomized trial, there is a strong rationale to include ATO in consolidation for patients with APL. Patient Population and Selection Criteria Inclusion criteria Low risk or intermediate risk APL (WBC 10 x 10 9 /L) as part of induction and consolidation with an Eastern Cooperative Oncology Group (ECOG) performance status of 2; OR High risk APL (WBC > 10 x 10 9 /L) as part of consolidation; OR Salvage therapy for patients with relapsed or refractory APL, without previous treatment with ATO Exclusion criteria Significant arrhythmia or electrocardiogram (ECG) abnormality (includes congenital long QT syndrome, history of previous ventricular tachycardia, QTc > 450 msec on ECG, or significant bundle branch block) An ECOG performance status of 3 or 4 CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 6

Systemic Therapy Summary 7 CCMB Formulary Status 1. Formulary definition Arsenic trioxide: Formulary Restricted to prescribers of the bone marrow transplant (BMT)/Leukemia DSG All-trans retinoic acid: Reviewed by Pharmacare Home Cancer Drug (HCD) Program eligible 2. Adjudication process (All-Trans Retinoic Acid) Complete the HCD Program Registration Form (J:\Forms\Pharmacy\Home Cancer Drug Program) Send completed form to CancerCare Manitoba Pharmacy for processing 3. Restrictions NOTE: Patients that receive drug coverage through federal drug plans (e.g., First Nations and Inuit Health Benefits, Department of National Defence, Royal Canadian Mounted Police, Veterans Affairs, etc.) or provincial drug plans other than Pharmacare (e.g., Family Services, Palliative Care) do not require registration with the HCD Program Approved for administration at CCP sites Implementation and Safety Considerations The risk of hypersensitivity reactions is low to arsenic and therefore, no specific pre-medications are required. Prednisone (0.5 mg/kg/day) is given from day 1 until the end of induction to reduce the risk of differentiation syndrome for induction therapy only. Induction therapy is to be initiated in hospital, on GD6 at Health Sciences Centre. Most serious complications (differentiation syndrome, disseminated intravascular coagulation) occur during induction chemotherapy. PATIENT SAFETY ALERT: Look-alike, Sound-alike Medications To prevent medication error, prescribe All-Trans Retinoic Acid (Tretoin) using drug brand name Vesanoid to distinguish from Isotretinoin (Accutain ). CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 7

Systemic Therapy Summary 8 Treatment Regimen All-Trans Retinoic Acid and Arsenic Trioxide Low and Intermediate Risk 1 cycle = 28 days Drug Dose CCMB Administrative Guideline All-Trans Retinoic Acid (Tretinoin) Vesanoid Induction: 22.5 mg/m 2 BID (total daily dose = 45 mg/m 2 /day) From Day 1 until documented hematologic complete remission, or for a maximum of 60 days PO For Low/Intermediate Risk Patients Only: Consolidation: 22.5 mg/m 2 BID (total daily dose = 45 mg/m 2 / day) on Weeks 1 to 2, Weeks 5 to 6, Weeks 9 to 10, Weeks 13 to 14, Weeks 17 to 18, Weeks 21 to 22 and Weeks 25 to 26 (treatment is given for two weeks on and two weeks off, for a total of 7 cycles) PO Arsenic Trioxide Induction: 0.15 mg/kg once daily From Day 1 until documented hematologic complete remission, or for a maximum of 60 days IV in 100 ml normal saline (NS) over 2 hours For Low/Intermediate Risk Patients Only: Consolidation: 0.15 mg/kg once daily for 5 consecutive days per week on Weeks 1 to 4, Weeks 9 to 12, Weeks 17 to 20 and Weeks 25 to 28 (treatment is given for four weeks on and four weeks off, for a total of four cycles) IV in 100 ml NS over 2 hours CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 8

Systemic Therapy Summary 9 Treatment Regimen Consolidation High Risk Patients There is insufficient data to make a strong recommendation on a preferred consolidation strategy. One randomized trial showed that the addition of two cycles of ATO resulted in improved outcomes, compared to no ATO. Thus, the preferred strategy should incorporate ATO. One strategy might be to proceed with two cycles of ATO (with or without ATRA), followed by two cycles of anthracycline-based chemotherapy. In the absence of a specific recommendation, the treating team should consider patient and disease characteristics and make an individualized recommendation for each specific patient. This will be revised on a regular basis as more data becomes available. Central Nervous System Treatment Central nervous system (CNS) prophylaxis is not necessary in most patients with low and intermediate risk disease. In patients with intracranial haemorrhage or patients with high risk disease (WBC > 10 x 10 9 /L at diagnois), CNS prophylaxis can be considered. Due to the risk of bleeding complications, CNS prophylaxis should be held until consolidation. Maintenance Therapy High Risk Patients Only After completion of consolidation, all patients who test negative for PML-RAR-α should be started on: Mercaptopurine (50 mg/m 2 /day) orally; AND Methotrexate (15 mg/m 2 /week) orally; AND Vesanoid (45 mg/m 2 /day) orally in divided doses for 15 days every 3 months Maintenance therapy duration is 2 years. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 9

Systemic Therapy Summary 10 Clinical Monitoring and Follow-Up Recommendations Low and Intermediate Risk APL Vital signs to be reviewed immediately pre- and post-ato infusion. No post-infusion observation period is required during consolidation therapy. Hematology, chemistry and required tests prior to treatment Induction Platelet concentrate transfusion to maintain platelets > 30 x 10 9 /L during the first 10 days After 10 days, platelet concentrates will be transfused when platelet count is < 20 x 10 9 /L or in presence of hemorrhagic symptoms Packed red cell concentrates must be transfused to maintain hemoglobin (Hb) levels > 80 g/l Potassium level > 4 µmol/l (preferably in the high normal range) Magnesium level > 0.74 µmol/l (preferably in the high normal range) Baseline QTc < 450 msec Creatinine Clearance (CrCl) estimated > 30 ml/min Total bilirubin < 51 µmol/l Consolidation Absolute neutrophil count (ANC) > 1.5 x 10 9 /L and platelets > 100 x 10 9 /L pre-commencement of consolidation Potassium level > 4 µmol/l (preferably in the high normal range) Magnesium level > 0.74 µmol/l (preferably in the high normal range) Baseline QTc pre consolidation < 450 msec CrCl estimated > 30 ml/min Total bilirubin < 51 µmol/l CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 10

Systemic Therapy Summary 11 Hematology, chemistry and required tests during treatment Induction Baseline: o Complete blood count (CBC) and differential, platelets, electrolytes, calcium, magnesium, phosphate, urea, serum creatinine, alkaline phosphate, AST, ALT, bilirubin, lactate dehydrogenase (LDH), albumin, uric acid, cholesterol, triglycerides, international normalized ratio (INR), partial thromboplastin time (PTT), fibrinogen, herpes simplex virus (HSV), hepatitis B surface antigen (HBsAB), hepatitis B core antibody (HBcAb) At least 2-3 times a week: o CBC and differential, platelets, electrolytes, magnesium, urea, serum creatinine, alkaline phosphate, AST, ALT, bilirubin, LDH, calcium, phosphate At least weekly and as clinically indicated: o Uric acid, INR, PTT, fibrinogen Baseline ECG, then weekly and as clinically indicated Consolidation Baseline: o CBC and differential, platelets, electrolytes, calcium, magnesium, phosphate, urea, serum creatinine, alkaline phosphate, AST, ALT, bilirubin, LDH, albumin, uric acid, cholesterol, triglycerides, INR, PTT, fibrinogen At least 2-3 times a week: o CBC and differential, platelets, electrolytes, magnesium, urea, serum creatinine At least once weekly: o Alkaline phosphate, AST, ALT, bilirubin, LDH, calcium, phosphate At least weekly and as clinically indicated: o Uric acid Prior to each 4 week consolidation course: o INR, PTT, fibrinogen Baseline ECG, then weekly and as clinically indicated Clinical toxicity assessment CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 11

Systemic Therapy Summary 12 Patients should be instructed to monitor for and report any treatment related side effects. These may include edema, abdominal pain, diarrhea, nausea, vomiting, dizziness, headache or cough. Patient should be instructed to report shortness of breath or signs/symptoms of arrhythmias (dizziness, palpitations or fainting) Assessment of treatment response Complete remission (CR) defined as, bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; ANC > 1.0 x 10 9 /L; platelet count > 100 x 10 9 /L; independence of red cell transfusions (appropriate time for bone marrow assessment is at about 40-50 days post-initiation of induction) Molecular remission defined as absence of detection of minimal residual disease (MRD) by real time-polymerase chain reaction (RT-PCR), or a level of detection of < 1 in 10-4 ; testing should be performed in a bone marrow sample, initially taken at the completion of consolidation Molecular persistence is defined as PCR positivity in 2 consecutive bone marrow samples collected at the end of consolidation therapy For low and intermediate risk APL patients who are MRD negative at completion of consolidation therapy, MRD monitoring is not required. For high risk APL patients, MRD monitoring can be considered Any PCR-positivity (a change from the PCR-negativity) should be reported promptly by hematopathologist, by phone, to the attending haematologist/oncologist For the frequency and duration of follow-up after completion of therapy, please see the Leukemia Bone Marrow Transplant (L/BMT) Long-Term Follow-Up Guidelines CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 12

Systemic Therapy Summary 13 Common or Clinically Important Adverse Events* 3 (Refer to individual drug monographs for full details of adverse events) Hyperleukocytosis 10-50% of patients (severe 3%) Usually declines or normalizes spontaneously by end of induction cycle Thrombocytopenia 18% of patients (severe 13%) Tachycardia 55% of patients Diarrhea 63% of patients Vomiting 58% of patients Chills 38% of patients Fatigue 68% of patients (severe 5%) Pyrexia 63% of patients (severe 5%) QT prolongation 33-68% of patients (severe 3%) Develops gradually over a period of 6 to 24 days. QT changes do not continue to increase with continued exposure to arsenic and are transient, reversing gradually once therapy is completed QT changes more prominent in patients with hypokalemia or hypomagnesemia Can lead to torsades de pointes (TdP) which may be asymptomatic. Use arsenic cautiously in patients with known risk factors for TdP Arsenic can be initiated in patients with QTc values of < 430 msec (males) or < 450 msec (females) Consider treatment interruption in patients who reach an absolute QT/QTc interval value > 500 msec during treatment Hyperglycemia 45% of patients (severe 13%) CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 13

Systemic Therapy Summary 14 Headache 63% of patients (severe 3%) Paresthesia 33% of patients (severe 5%) Insomnia 43% of patients (severe 3%) APL differentiation syndrome (DS) 23-30% of patients Most commonly observed during induction treatment and likely to develop in patients who develop hyperleukocytosis Arsenic should be temporarily interrupted and high dose steroids initiated at the first signs of symptoms suggestive of this syndrome Consider hydroxyurea in situations of marked hyperleukocytosis (WBC > 10 x 10 9 /L) Cough 65% of patients; sometimes productive Dyspnea 15-40% of patients (severe 10%) Dermatitis 45% of patients * See Appendix III CTCAE v.4.0 CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 14

Systemic Therapy Summary 15 Precautions 3,4 Neutropenia Fever or other evidence of infection must be assessed promptly and treated aggressively. Renal dysfunction Patients with CrCl < 30 ml/min may require dose reduction. Acute arsenic toxicity Presents with convulsion, muscle weakness, confusion and ECG abnormalities. APL differentiation syndrome (DS) Defined as unexplained fever, dyspnea, pleural and/or pericardial effusion, pulmonary infiltrates, renal failure, hypotension and unexplained weight gain greater than 5 kg. Severe DS is defined as > 4 of these signs or symptoms and moderate DS is defined as > 2 signs or symptoms. Dexamethasone 10 mg IV BID should be initiated. Leukocytosis May develop after treatment initiation. Patients can be treated with hydroxyurea 500 mg QID for WBC between 10-50 x 10 9 /L, or 1000 mg QID for WBC > 50 x 10 9 /L. Discontinue hydroxyurea when WBC < 10 x 10 9 /L. Transient, mild headache May occur several hours after tretinoin ingestion. Hypervitaminosis A syndrome Has been observed with tretinoin, including xerodema, lip and mouth dryness, cheilitis, rash edema, nausea and vomiting and bone pain. Benign or idiopathic intracranial hypertension Pseudotumour cerebri may occur with an onset of about 3-17 days of tretinoin therapy. Venous and arterial thrombosis A risk during the first month of tretinoin treatment. Hepatitis B reactivation All patients should be tested for HBsAg and HBcAb. If either test is positive, patients should be treated with lamivudine 100 mg/day orally for the entire duration of the chemotherapy and for six months afterwards. The patients should also be monitored with frequent liver function tests and hepatitis B virus DNA at least every two months. If the hepatitis B virus DNA level rises during this monitoring, management should be reviewed with an appropriate specialist with experience managing hepatitis. Consider discontinuation of chemotherapy. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 15

Systemic Therapy Summary 16 Dose Modifications Hematological toxicities (except hepatotoxicity and QTc prolongation) Start Dose Level 0: 0.15 mg/kg ATO and 45 mg/m 2 /day Vesanoid Dose Level -1: 0.11 mg/kg ATO and 37.5 mg/m 2 /day Vesanoid Dose Level -2: 0.10 mg/kg ATO and 25 mg/m 2 /day Vesanoid Dose Level -3: 0.075 mg/kg ATO and 20 mg/m 2 /day Vesanoid Hematological ANC < 1 x 10 9 /L or platelets < 50 x 10 9 /L and more than 4 weeks in, reduce both drugs by one dose level ANC < 1 x 10 9 /L or platelets < 50 x 10 9 /L and more than 49 days or occurs on 2 consecutive courses, send bone marrow aspirate for RT-PCR analysis of PML/RAR-α. If persisting molecular CR, resume at one dose level lower than the previous dose for both drugs Liver dysfunction If hepatotoxicity is Grade 3-4 and LFTs > 5 x upper limit of normal (ULN): Hold dose until bilirubin and/or AST/ALP and/or alkaline phosphatase/gammaglutamyl transpeptidase (GGT) < 4 x ULN Resume at 50% of previous dose during the first week Increase to full dose if no further worsening If hepatotoxicity reappears, discontinue both drugs QT prolongation If QTc interval is > 450 msec: Hold ATO dose until QTc < 450 msec Resume as below if no prolongation after each escalation Week 1: 0.075 mg/kg arsenic trioxide Week 2 and thereafter: 0.15 mg/kg arsenic trioxide Other non-hematological toxicities Grade 2: reduce ATO and Vesanoid by one dose level Grade 3-4: hold both drugs until < grade 2, then resume at two dose level reduction CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 16

Systemic Therapy Summary 17 Drug Interactions 4 Drug-drug interactions QT/QTc interval prolongation or torsades de pointes avoid concomitant use due to the risk of potentially fatal arrhythmias. CYP 3A4 and CYP 2A and possibly CYP 2B1/2 arsenic acts as an inducer and may reduce the systemic concentration of substrates and/or efficacy of these isoenzymes. Strong P-glycoprotein or Multidrug Resistance-Associated Protein (MRP) inhibitors increase arsenic exposure and/or toxicity. Previous anthracycline use increase risk of QT prolongation. Drugs that disrupt electrolyte levels (i.e., laxatives, high dose corticosteroids) increase risk of arrhythmias. Avoid use. Clinical Considerations No central line is required for the infusion of ATO. If acute vasomotor reactions develop to ATO, the infusion is to be given over four hours. Dosing of ATO is based on total body weight. In obese patients, this may result in higher than expected plasma and tissue concentrations. Monitor all obese patients closely for signs of acute arsenic toxicity. ATO ampoule is single-use and does not contain any preservatives. After dilution in intravenous solutions, ATO is chemically and physically stable for 24 hours at 15-30 C and 48 hours at refrigerated temperatures (2-8 C). CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 17

Systemic Therapy Summary 18 References 1. Powell BL, Moser B, Stock W, et al. Arsenic Trioxide improves event-free and overall survival for adults with actue promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19): 3751-7. 2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for actue promyelocytic leukemia. N Engl J Med 2013;369(2):111-21. 3. British Columbia Cancer Agency. Cancer Drug Manual, Arsenic Trioxide Monograph. Updated June 2014 http://www.bccancer.bc.ca [Accessed 19 September 2014]. 4. CancerCare Ontario. Chemotherapy Regimen Arsenic Trioxide. Updated September 2014 http://www.cancercare.on.ca [Accessed 19 September 2014]. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 18

Systemic Therapy Summary 19 CCMB Contributors Dr. Walter Watral, BSc (Pharm), Pharm. D. Mrs. Kristi Hofer, BSc (Pharm), Senior Pharmacist, Operations Contact Physician Dr. Kristjan Paulson, Haematologist, Leukemia Disease Site Group Chair Approved By Dr. Ralph PW Wong, Medical Oncologist Chair, WRHA/CCMB Oncology Pharmacotherapeutic Subcommittee Dr. Vallerie Gordon, Medical Oncologist Medical Director and Advisory Panel Chair, CCMB Clinical Practice Guidelines Initiative We gratefully acknowledge the support of CancerCare Manitoba, the CancerCare Manitoba Foundation and the Provincial Oncology Clinical Practice Guidelines Initiative. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 19

Systemic Therapy Summary 20 Appendix I Levels of Evidence Ia Evidence obtained from meta-analysis of randomised controlled trials Ib Evidence obtained from at least one randomised controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomisation IIb Evidence obtained from at least one other type of well-designed, quasi- experimental study III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities British Committee for Standards in Haematology 2007 http://www.bcshguidelines.com CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 20

Systemic Therapy Summary 21 Appendix II ECOG Performance Status Scale 0 Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90-10) 1 Restricted in physical strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework or office work (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about greater than or equal to 50% of waking hours (Karnofsky 50-60) 3 Capable of only limited self-care, confined to bed or chair greater than or equal to 50% of waking hours (Karnofsky 30-40) 4 Completely disabled, cannot carry on any self-care, totally confined to bed or chair (Karnofsky 10-20) Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. Eastern Cooperative Oncology Group Robert Comis M.D., Group Chair CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 21

Systemic Therapy Summary 22 Appendix III Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Publish Date: 18 May 2009 Grades Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. A semi-colon indicates or within the description of the grade. A single dash (-) indicates a grade is not available. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for grade selection. Grade 5: Grade 5 (Death) is not appropriate for some AEs and therefore is not an option Activities of Daily Living (ADL): * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. CTCAE document available at: http://ctep.cancer.gov Accessed 10 September 2010 CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 22

Systemic Therapy Summary 23 CancerCare Manitoba 675 McDermot Avenue Winnipeg, Manitoba, Canada R3E 0V9 www.cancercare.mb.ca CCMB STS: LEUK Arsenic Trioxide June 2014 Effective: June 2014 Approved: September 2015 CancerCare Manitoba, June 2014. All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organization, or for commercial purposes is allowed without written permission of CancerCare Manitoba. CCMB, STS: Arsenic Trioxide for Acute Promyelocytic Leukemia p. 23