Acute Promyelocytic Leukemia

Transcription

1 Acute Promyelocytic Leukemia Outline of Management Suleimman AlSweedan,MD,MS,FAAP Consultant Pediatric Hematology/oncology

2 TABLE OF CONTENTS Background 3 Pediatric APL Trials 4 Adult APL Trials 4 Diagnostic Workup 5 Treatment 6 Supportive Care Before Treatment 6 Monitoring and correction of coagulopathy 6 Pre-Induction 7 Induction Phase 8 Consolidation Phase 9 Maintenance 11 General Guidelines 11 Supportive Care 13 Retinoid Acid Syndrome 13 Disseminated Intravascular Coagulopathy 14 Pneumocytis Jerovecii (Carini) Pneumonia Prophylaxis 15 References 15 Roadmaps 16

3 MAINTENANCE (2years) 6 MP MTX ATRA REFRACTORY/ RELAPSE PROTOCOL STANDARD RISK WBC < 10 X 109/L Induction IDA (d 2,4,6,8) ATRA CONSOLIDATION I ATRA IDA ARAC IVB IT Cytarabine CONSOLIDATION II ATRA IT Cytarabine MITOX IVB MRD ve MRD -ve MRD +ve BM and PB for diagnostic PCR BM and PB for diagnostic PCR BM and PB for diagnostic PCR MRD +ve BM and PB for diagnostic PCR HIGH RISK WBC =/> 10 X 109/L Induction IDA (d 2,4,6,8) ATRA CONSOLIDATION I ATRA IDA ARAC IVB IT Cytarabine CONSOLIDATION II ATRA IT Cytarabine MITOX IVB CONSOLIDATION III ATRA IV Cytarabine IT Cytarabine IDA Figure 1: Treatment for PML RARα+ and all other retinoid sensitive subtypes of APL in children and adolescents NB: Patients with morphological APL may initially be treated according to this guideline, but patients who are subsequently found to lack a retinoid sensitive gene fusion should thereafter be treated on a standard AML protocol. ATRA All Trans Retinoic Acid (Tretinoin) IDA Idarubicin IT Cytarabine Intrathecal Cytarabine IV Cytarabine Intravenous Cytarabine MTX Methotrexate MITOX Mitoxantrone 6 MP 6 Mercaptopurine BM Bone Marrow PB Peripheral Blood

4 Background Acute Promyelocytic Leukemia (APML) is an AML in which abnormal promyelocytes predominate. Morphologically it exists as a hypergranular or typical APML and a microgranular (hypogranular) or variant type. APML constitutes 5-8% of all AML; however the incidence in children is much lower than in adults. This leukemia is characterized by the t(15;17)(q22;q12) translocation which involves the PML and RARA genes. The latest WHO classification has determined the diagnosis of APML to be synonymous with the translocation and it is also called AML with t(15;17)(q22;q12). On rare occasions the classical translocation may not be evident and these patients usually harbor a variant complex translocation with involvement of both chromosomes 15 and 17 along with at least one other chromosome. Additionally submicroscopic insertion of RARA into PML may also occur. These cryptic or masked translocations also behave similarly to the classic translocation and can be detected via FISH or PCR-based examinations. This guideline may be used for all patients with a diagnosis of acute promyelocytic leukemia who are PCR positive for the PML RARα transcript or rarer retinoid sensitive subtypes (e.g. NPM RARα, NuMA RARα) and who are less than 21 years of age. The treatment of APML was revolutionized by the introduction of All Trans Retinoic Acid (ATRA). ATRA acts on the aberrant retinoic acid receptor alpha (RARA) resulting in differentiation of the promyelocyte and subsequent apoptosis. This therapy resulted in significant reduction in the severe disseminated intravascular coagulopathy (DIC) and toxic mortality that was seen in patients treated with standard AML-based cytotoxic therapy. However, ATRA alone is incapable of resulting in curative outcomes and standard chemotherapeutic agents are used in conjunction to achieve a cure. Single agent cytotoxic agents, particularly anthracyclines, have been incorporated into APML protocols and have resulted in disease free survival rates in excess of 70%. All trans retinoic acid (ATRA) is included in all phases of therapy and intermediate dose Cytarabine is given during consolidation treatment. Following one induction course of treatment, standard risk patients will receive 2 consolidation blocks of treatment, whilst high risk patients will receive 3 consolidation blocks of treatment. Until such time as the results of these studies are available, these protocols will necessarily be used for the treatment of pediatric patients with APML. The PML RARα transcript should be monitored throughout and standard risk patients with detectable minimal residual disease (MRD) by real time quantitative reverse transcriptase polymerase chain reaction (RT qpcr) at the end of the second consolidation block should APML Protocol; updated 27/5/2013 Page 3

5 receive a third consolidation block identical to that delivered to high risk patients. Patients who are RT qpcr+ for PML RARα after completion of the third block of consolidation therapy are candidates for refractory/relapse treatment. Arsenic trioxide would be considered first line therapy in refractory/ relapsed disease. Refractory/relapsed patients who remain RT qpcr+ for PML RARα are candidates for allogeneic bone marrow transplantation (allo BMT), whilst those who achieve molecular remission may have individualized treatment with ongoing MRD monitoring. Patients with a white blood cell count 10,000/μL will be defined as standard risk and patients with a white blood cell count at diagnosis > 10,000/μL will be defined as high risk. Pediatric APL Trials Pediatric APL trials have been reported in the age of concurrent chemotherapy and ATRA induction. The largest and most impressive series to date has been published from Italy (the AIDA 0493 trial). There were 107 patients described in this report with a CR rate of 96%, a 10 year event free survival (EFS) of 76% and a 10 year overall survival (OS) of 89%.2 The PETHEMA pediatric results from two consecutive trials were recently published showing a CR rate of 92%, a 5 year EFS of 77% and a 5 year OS of 87%.This was achieved with anthracyclines and ATRA for induction and consolidation without other agents. A smaller French study showed comparable overall results using daunorubicin, cytarabine, and ATRA. Only limited pediatric data from the last North American intergroup trial C9710 have been released at this point. The CR rate, 3 year EFS and 3 year OS for the 57 eligible patients < age 15 years on this trial were 89%, 62% and 86% respectively. Only two of these 57 children were treated on the arsenic arm of the trial. There were no statistically significant differences in these figures compared to the adults who were randomized to the standard therapy arm without arsenic. Adult APL Trials The best published results to date in primarily adult APL patients have originated from Italy, Spain and France. These regimens have used concurrent chemotherapy and ATRA inductions. The consolidation regimens have been anthracycline based with or without the addition of other agents such as cytarabine, etoposide and 6-thioguanine. A maintenance phase of 2 years duration has been delivered. These regimens have resulted in event free survivals of greater than 70% and overall survivals of up to 89%. APML Protocol; updated 27/5/2013 Page 4

6 Diagnostic Workup The diagnosis and initiation of therapy for APML should be considered a medical emergency. In patients referred as or suspected to have APML the diagnosis should be confirmed as rapidly as possible, including the identification of the PML-RAR genetic lesion by FISH. Detailed history and physical examination Complete Blood count (CBC) with differential Renal Profile Bone Profile Hepatic Profile PT, PTT, INR, D-dimers Fibrinogen level Peripheral blood for FISH for PML- Peripheral blood sample for RQ-PCR for PML- Hepatitis screen, varicella zoster IgG antibody titer. Quantitative G6PD Bone Marrow Aspiration and Trephine biopsy o Routine Morphology o Flowcytometry o Cytogenetics o FISH for PMLo Bone marrow sample for RQ-PCR for PML- Echocardiogram HLA typing. CSF examination should not be done for these patients as the risk for intracranial hemorrhage is high. NOTE: A lumbar puncture is not required to be enrolled on study. If the diagnosis of APL is known or suspected, extreme caution must be exercised in performing a lumbar puncture during active coagulopathy. In addition a CT or MRI should be considered to rule out the possibility of an associated chloroma if CNS disease is suspected or proven. If CNS disease is documented, patients are still eligible Diagnosis A morphological diagnosis of APML is not sufficient. Genetic confirmation with either karyotype, FISH or PCR positivity for the t(15;17)- PML- translocation is mandatory. However, a presumptive diagnosis can be made from morphology, immunophenotype and the presence of coagulopathy. In all such cases, where APML is suspected, ATRA should be APML Protocol; updated 27/5/2013 Page 5

7 commenced immediately (without waiting for the genetic confirmation) and continued until the diagnosis is confirmed at genetic level. Genetic confirmation is mandatory. Treatment Supportive Care Before Treatment Monitoring and correction of coagulopathy While all patients with APML are at risk for hemorrhage, particularly intracranial and pulmonary, and thrombosis the following factors have been shown to incur a higher risk of developing a fatal hemorrhage: Patient with active bleeding Hypofibrinoginemia (<150 mg/dl) Increased levels of D-dimers combined with prolonged PT or PTT High WBC counts (>10 x 10 9 /L) Elevated serum creatnine Patients should have their coagulation factors (PT/PTT/D-dimer), platelet count and fibrinogen checked at least on a daily basis prior to and during the first week of therapy or until the coagulation parameters have normalized. More frequent testing may be required for some patients depending on the clinical condition and degree of coagulopathy. Patients with abnormalities in their results should receive fresh-frozen plasma, fibrinogen/cryoprecipitate and platelet transfusions liberally. The following guidelines should help with administration of these but the patient s clinical condition may warrant more stringent transfusion parameters: Fibrinogen level should be maintained >150 mg/dl. Platelets should be maintained >30 x 10 9 /L for patients with no active bleeding (including mucosal bleeding) and >50 x 10 9 /L for those with any bleeding. Consider using rfviia in cases of severe bleeding. Such replacement therapy should continue during induction therapy until disappearance of all clinical and laboratory signs of coagulopathy. Central venous catheterization, lumbar puncture and other invasive procedures should be avoided before and during remission induction due to high risk of heamorrhagic complications. APML Protocol; updated 27/5/2013 Page 6

8 Pre-Induction: Management as a medical emergency with the following simultaneous and rapid action 1 : 1. Start therapy with ATRA after initial suspicious of APL. 2. Supportive measures: Liberal Transfusion of FFP, fibrinogen, and platelets to maintain levels of: Fibrinogen > 150 mg/l Platelets > x 10 9 /L 3. Confirm genetic diagnosis by: Cytogenetics/FISH RT-PCR Anti-PML immune-staining 4- Hydration and prevention of tumor lysis syndrome.patients should be adequately hydrated with at least l/m2 /24 hrs given parenteral for a minimum of hours. 5- Allopurinol 100mg/m2 orally three times daily should start 24hours before chemotherapy and continue for 5 7 days. Since chemotherapy should not be delayed, rasburicase may be substituted in patients with a high tumor burden, as per local policy. Risk Classification: Risk of relapse was established at diagnosis according to a predictive model on the basis of patient leukocyte and platelet counts at diagnosis, as reported by a joint study of the PETHEMA and GIMEMA cooperative groups. Low-risk High-risk WBC 10 x 10 9 /L and WBC > 10 x 10 9 /L APML Protocol; updated 27/5/2013 Page 7

9 Induction Phase This guideline is only for children and adolescents with ATRA sensitive APL (including those with PML RARα, NPM RARα, NuMA RARα fusion transcript), since patients with APL FAB M3 but lacking one of the ATRA sensitive rearrangements could be undertreated by this guideline. Because APL is a hematological emergency, ATRA should be commenced as soon as the diagnosis is suspected. Treatment should not wait until the diagnosis of APL has been confirmed molecularly or cytogenetically. Patients subsequently found to lack an ATRA sensitive molecular lesion by RT PCR should be removed from this guideline and treated according to a standard AML protocol. Although the cytogenetic/molecular confirmation of APML (PML- translocation) is mandatory, in patients with high WBC counts (>10 x 10 9 /L) ATRA therapy can be initiated preemptively following a morphologic/immunophenotypic diagnosis of APML (AML M3). 1. Idarubicin 12mg/m 2 /day (0.4 mg/kg if < 0.6 m2), IVPB over 15 minutes on day 2, 4, 6, and 8 (4 doses). (If Idarubicin is given through a peripheral vein should be diluted with NS or D5W). Note dose modifications which may be required for idarubicin. In the case of hepatic dysfunction and bilirubin micromol/l ( mg/dl) reduce idarubicin dose by 50%. If bilirubin > 34 micromol/l (1.7 mg/dl) idarubicin is contraindicated. 2. In the case of renal impairment and serum creatinine micromol/L ( mg/dl) reduce idarubicin dose by 50%. A clinical decision is required on whether to give idarubicin if the serum creatinine exceeds 175 micromol/l (1.9 mg/dl). 3. Tretinoin (ATRA) 25mg/m 2 /day in divided doses BID orally until achievement of Complete Hematological Remission (CHR). ATRA may be used for a maximum of 90 days or until hematological CR, whichever is reached first. Bone marrow examination should be conducted on Day 30 of induction and if CHR is not achieved this should be repeated every 14 days until CHR. Special considerations: 1. Do not modify treatment based on additional cytogenetic abnormalities, CD56, BCR3 isoform, etc. 2. Temporary discontinuation of ATRA is only indicated in case of severe Retinoic Acid Syndrome (RAS) or pseudotumor cerebri. 3. Initiate dexamethasone immediately at the very earliest suspicion of RAS. Response assessment: 1. Delayed maturation or persistence of atypical promyelocytes is occasionally detectable several weeks after the start of treatment (up to days). APML Protocol; updated 27/5/2013 Page 8

10 2. Continue ATRA until terminal differentiation of blasts, which invariably occurs in virtually all patients. 3. Molecular and cytogenetic evaluation at the end of induction has no prognostic value in APL. Clinicians should refrain from making therapeutic decisions on the basis of these results. DEFINITIONS: All responses may be hematological, cytogenetic or molecular. Complete Remission : Hematological Remission the bone marrow is regenerating normal hematopoietic cells and contains <5% blast cells by morphology. The absolute neutrophil count in the peripheral blood should be >1.0x109/l and the platelet count > 100x109/l Cytogenetic Remission: Disappearance of the diagnostic clonal abnormality Molecular Remission (CRm) absence of leukemic fusion gene transcripts in bone marrow by RT qpcr, with an assay sensitivity of at least 10 4 Refractory Disease (RD) / Relapse: Resistant/Refractory Disease (RD) persistent detection of morphological, cytogenetic and/ or molecular evidence of APL after consolidation therapy Hematological Relapse: Reappearance of promyeloblasts/abnormal promyelocytes (>5%) in the bone marrow. Cytogenetic Relapse : Reappearance of the diagnostic cytogenetic abnormality after repeated negative cytogenetic analysis as determined by karyotype and/or FISH. Molecular Relapse Reappearance of PML RARα (or other APL fusion) transcript in two successive samples in patients previously in molecular remission. Consolidation Phases All patients who achieve complete hematological remission will proceed on to receive three (2-3) courses of consolidation therapy administered once every 4 weeks. Prior to each consolidation phase patients must have the following: Absolute Neutrophil Count (ANC) > X 1000 Platelet count > Echocardiogram with a normal ejection fraction (EF) and cardiac function. If the EF is within the normal range, but has decreased >10% from the baseline value, a nuclear APML Protocol; updated 27/5/2013 Page 9

11 medicine evaluation of cardiac function (RNA test) must be done to confirm this reduction. If confirmed, further therapy must be discussed within the Leukemia Team prior to proceeding forward. Quantitative PCR for PML-RARA should be done prior to each Consolidation cycle. Consolidation Course-I 1. Idarubicin 5mg/m 2 IVPB over 15 minutes IV for 4 days on day Cytarabine 200 mg/m 2 as 24 hours infusion on days ATRA 25mg/m 2 /day in divided doses BID orally for 15 days. 4. Intrathecal cytarabine (ARA-C) dosed according to age on Day 1 a. <2 years old: ARA-C 30mg b. 2-<3 years old: ARA-C 50mg c. 3 years or older ARA-C 70mg Consolidation Course-II 1. Mitoxantrone 10mg/m 2 /day IVPB over 15 minutes for 5 days on day ATRA 25mg/m 2 /day in divided doses BID orally for 15 days. 3. Intrathecal cytarabine (ARA-C) dosed according to age on Day 1 a. <2 years old: ARA-C 30mg b. 2-<3 years old: ARA-C 50mg c. 3 years or older ARA-C 70mg Consolidation Course-III (For high risk patients and Low risk patients with +ve MRD) 1. Idarubicin 12mg/m 2 IVPB for 2 consecutive days for intermediate and high risk patients). 2. Cytarabine 1000 mg/m 2 every 12 hours on days ATRA 25mg/m 2 /day in divided doses BID orally for 15 days. 4. Intrathecal cytarabine (ARA-C) dosed according to age on Day 1 will be administered only to patients with an initial WBC count >10 x 10 9 /L. Patients with WBC count below this level will not receive any CNS directed therapy. a. <2 years old: ARA-C 30mg b. 2-<3 years old: ARA-C 50mg c. 3 years or older ARA-C 70mg APML Protocol; updated 27/5/2013 Page 10

12 Maintenance Patients who achieve a Complete Cytogenetic Remission will be eligible to proceed on to maintenance therapy. CCR would be determined by a normal karyotype without t(15;17) detection and a negative result for FISH testing for PML-RARA. For patients who are PCR positive for PML-RARA at this time point should undergo bone marrow examination for morphology and cytogenetics to determine Cytogenetic Remission status. Patients who have achieved PCR negativity do not require bone marrow examination at this time point. Patients who have not achieved CCR should be discussed within the Leukemia Team prior to further therapy. In addition to the above, prior to starting the maintenance phase patients must have the following: Absolute Neutrophil Count (ANC) >1000 X 10 6 /L Platelet count > x 10 9 /L 1. Mercaptopurine (6-MP) 50mg/m 2 /day orally to be taken at bedtime daily 2 hours after meals. 2. Methotrexate 20mg/m 2 /day orally weekly 2 hours after meals. 3. ATRA 25mg/m 2 /day in divided doses BID orally for 15 days every 3 months. Administration with meals improves the bioavailability of ATRA. Maintenance therapy should continue for 2 years Quantitative PCR for PML-RARA should be done on a peripheral blood sample at least once every 6 months during maintenance therapy. General Guidelines: 1- Consolidation phase will start upon complete hematological recovery (ANC >1000 and platelets > 100,000) and bone marrow exam consistent with complete remission. 2- Maintenance will start after hematological recovery (ANC> 1000 and platelets >100,000) following consolidation course #3. APML Protocol; updated 27/5/2013 Page 11

13 3- Each Consolidation course will start when ANC>1000 and platelets>100, MP and MTX will be interrupted during maintenance if ANC drops below 500 or when platelets drop below 50,000. Both medications will be restarted at 50% of the previous dose when counts recover. Dose of 6-MP and MTX should be adjusted to maintain ANC between If ANC falls between 500 and 750 or platelets between 50,000 and 100,000 during maintenance, 6-MP and MTX doses will be reduced by 50% till counts recovery, at which time the dose will be increased to 75% of the original dose. 6- If ANC is <1000 or Platelets < 100,000 after 2 weeks off therapy, perform a bone marrow aspirate. Bone marrow may be postponed for one more week (3 rd week), if monocytes are increasing or if viral myelosupression is clinically suspected. 7- Treatment will be interrupted for serious infections. 8- Herpes Zoster infections: Both 6-MP and MTX will be held till lesions are crusted. 9- Hepatotoxicity: For increase in AST or ALT to greater than 200 U/L, obtain total bilirubin. Monitor hepatic enzymes and bilirubin biweekly during consolidation and monthly during maintenance as long as enzyme levels are more than 200. For persistent elevation (>200) for more than 1 month, exclude infectious hepatitis. Hold MTX and 6-MP if bilirubin is > 2mg/dl or if AST or ALT > 1000 U/L on 2 determinations one week apart. Resume at full dose when enzyme level is less than 200 U/L. 10- Severe diarrhea or persistent vomiting: Hold MTX. Resume at 50% of previous dose when symptoms are absent for a week and escalate as tolerated. 11- Mucositis: For grade 3 toxicity, reduce the dose of MTX and 6-MP by 50%. For grade 4 toxicity, hold MTX and 6-MP until resolution, then resume at 50 % of the previous dose and escalate as tolerated. 12- Neurotoxicity: Hold MTX until toxicity resolves. 13- Management of ATRA syndrome: Hold ATRA, give dexamethasone 10 mg IV BID with or without furosemide to reduce body weight and blood pressure. 14- A bone marrow sample is sent for conventional cytogenetics/fish at diagnosis to look for t (15;17) as well as PCR for PML-RARα mutation. APML Protocol; updated 27/5/2013 Page 12

14 A bone marrow sample will be sent for PCR to look for PML-RARα mutation at the end of consolidation, at the end of the first year of maintenance and at the end of therapy Dose modifications during Maintenance The dose of 6-MP should be titrated for each individual patient to maintain the ANC between 750 and 1250 X 10 6 /L and platelet count of >75 X 10 9 /L. 6-MP should be held for ANC <500 X 10 6 /L. Methotrexate (MTX) should be maintained at full dose except if ANC is <500 X 10 6 /L at which point it should be held. MTX should be restarted at full dose once the ANC has recovered to >1000 X 10 6 /L. There is no dose adjustment for ATRA and this should be administered at full dose. Supportive Care Retinoic Acid Syndrome About 25% of all patients being treated for APML with ATRA may develop the Retinoic Acid Syndrome (RAS). This starts between 2 days and several weeks after initiation of ATRA therapy. The overall mortality from RAS is between 5-13%. Manifestations include unexplained fever, respiratory distress, weight gain, fluid retention, pleural and pericardial effusions, hypotension, headache/pseudotumor cerebri and renal failure. The syndrome only occurs during induction therapy and is unique to patients with APML. Management Hold ATRA administration. Dexamethasone 10mg/m 2 /day IV divided q12 should be administered at the first sign of suspected RAS for a minimum of 3 days. If symptoms resolve Dexamethasone can be tapered down and discontinued. General supportive measures including diuresis and oxygen supplementation. On occasion patients may require PICU care with dialysis. After resolution of the symptoms, ATRA should be resumed at 75% of the initial dose. If there is no recurrence of symptoms, the dose of ATRA should be increased to full dose after 3-5 days. Care should be taken to ensure that no other agents which interact with ATRA metabolism are being used concomitantly (See Table). APML Protocol; updated 27/5/2013 Page 13

15 Drug Severity Documentations Summary Tranexamic acid Major Good Together may increase risk of thrombosis Aminocaproic acid Major Good Together may increase risk of thrombosis Tetracycline Major Fair May result in an increase risk of pseudotumor cerebri (benign intracranial hypertension) Fluconazole Moderate Good Increase risk of ATRA toxicities including Retinoic Acid syndrome Voriconazole Moderate Good Increase risk of ATRA toxicities including Retinoic Acid syndrome and increased risk of hypercalcemia Vitamin A Moderate Fair Increase risk of vitamin A toxicities Glucocorticoids Moderate Fair Decrease efficacy of ATRA Methotrexate Moderate Fair Increase risk of hepatoxicity Table: Drug interactions with ATRA Disseminated Intravascular Coagulopathy (DIC) Patients with APML can present with DIC or can develop this during the initial days of induction therapy. Full supportive measures including Fresh Frozen Plasma (FFP)/cryoprecipitate and cellular blood product transfusions should be initiated immediately. ATRA therapy should be started and continued in spite of DIC as this would result in leukemic blast differentiation and apoptosis. In patients with DIC and in particular those with high WBC counts Idarubicin can be delayed for up to 3 days while the patient continues on ATRA and is stabilized. Details of this management are provided above. APML Protocol; updated 27/5/2013 Page 14

16 Pneumocystis jerovecii (carinii) pneumonia prophylaxis All patients should be started on PJP prophylaxis following induction chemotherapy. First choice of prophylactic therapy is Trimethoprim-Sulfamethoxazone administered according to BSA on a BID schedule given on 2 consecutive days per week. Patients who are allergic to sulfa products or TMP-SMX or who develop neutropenia/cytopenias related to TMP-SMX should be treated with Pentamidine 300mg by nebulizer Or Pentamidine 4 mg/kg IV administered once every 4-6 weeks. PJP prophylaxis should continue beyond the end of maintenance therapy for 4-6 months after completion of therapy. References: 1. Treatment of Acute Promyelocytic Leukemia: ASH Educational Book Sanz MA et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96: , Treatment with All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children with Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group. JCO vol 23 (30): , APML Protocol; updated 27/5/2013 Page 15

17 Acute Promyelocytic Leukemia Induction Phase Standard Risk/ High Risk Chemotherapy Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 IDA X X X X ATRA X * 25/m 2 /day BID P.O x 90 days OR until CHR IDA (Idarubicin): 12mg/m 2 /day OR (0.4mg/hg/day if BSA <0.6m 2 ) x 4 doses, to be given over 15 minutes on day 2,4,6, and 8. * ATRA: All- Trans-Retinoic Acid (Tretinoin): 25/m 2 /day in two divided doses (BID) orally for a maximum of 90 days OR until achievement of Complete Hematological Remission (CHR) whichever is reached first. Bone Marrow examination should be repeated on day 30 of induction. If CHR is not achieved BM should be repeated every 14 days until CHR. APML Protocol Page 16

18 Acute Promyelocytic Leukemia Consolidation I Lab value parameters: Chemotherapy to be given on Day 0 if Absolute Neutrophil Count is greater than 1000 x 10 6 /L and platelets greater than Normal ejection fraction and cardiac function. Chemotherapy Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 IDA X X X X Cytarabine X X X X X X X IT Cytarabine ATAR X 25/m 2 /day BID P.O x 15 days IDA (Idarubicin): 5mg/m 2 IVPB over 15 minutes for 4 days on day 1-4. Cytarabine: 200mg/m 2 as 24 hours infusion on day 1-7. ATRA: 25mg/m 2 /day in divided doses BID orally x 15 days. Intrathecal Cytarabine: dosed according to age: a. < 2 years old: ARA-C 30mg. b. 2-<3 years old: ARA-C 50mg. c. 3 years or older: ARA-C 70mg. APML Protocol Page 17

19 Acute Promyelocytic Leukemia Consolidation II Lab value parameters: Chemotherapy to be given on Day 0 if Absolute Neutrophil Count is greater than 750 x 10 6 /L and platelets greater than Normal ejection fraction and cardiac function. Chemotherapy Day 1 Day 2 Day 3 Day 4 Day 5 Mitoxantrone X X X X X IT Cytarabine ATAR X 25/m 2 /day BID P.O x 15 days Mitoxantrone: 10mg/m 2 /day IVPB over 15 minutes for 5 days on day 1-5. ATRA: 25mg/m 2 /day in divided doses BID orally x 15 days. Intrathecal Cytarabine: dosed according to age: a. < 2 years old: ARA-C 30mg. b. 2-<3 years old: ARA-C 50mg. c. 3 years or older: ARA-C 70mg. APML Protocol Page 18

20 Acute Promyelocytic Leukemia Consolidation III For High risk patients and Low risk patients with +ve MRD Lab value parameters: Chemotherapy to be given on Day 0 if Absolute Neutrophil Count is greater than 750 x 10 6 /L and platelets greater than Normal ejection fraction and cardiac function. Chemotherapy Day 1 Day 2 Day 3 Day 4 IDA X X Cytarabine X X X X IT Cytarabine ATAR X 25/m 2 /day BID P.O x 15 days IDA (Idarubicin): 12mg/m 2 IVPB for 2 days. Cytarabine: 1000mg/m 2 every 12 hours on day 1-4. ATRA: 25mg/m 2 /day in divided doses BID orally x 15 days. Intrathecal Cytarabine: dosed according to age: a. < 2 years old: ARA-C 30mg. b. 2-<3 years old: ARA-C 50mg. c. 3 years or older: ARA-C 70mg. APML Protocol Page 19