NOPHO- DBH AML 2012 Protocol

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NOPHO- DBH AML 2012 Protocol Research study for treatment of children and adolescents with acute myeloid leukaemia 0-18 years Study Chair Sponsor Data Manager Jonas Abrahamsson Children s Cancer Centre
NOPHO- DBH AML 2012 Protocol Research study for treatment of children and adolescents with acute myeloid leukaemia 0-18 years Study Chair Sponsor Data Manager Jonas Abrahamsson Children s Cancer Centre Queen Silvias Childrens and Adolescents Hospital Gothenburg, Sweden E- mail Phone Fax Västra Götaland Regionen Regionens Hus Vänersborg Sweden Henrik Hasle Department of Pediatrics, Aarhus University Hospital Skejby 8200 Aarhus N, Denmark Tel Fax EUdract number Administration The study is a cooperative protocol including NOPHO, BSPHO, DCOG, Estonia and Hong Kong. Members of the NOPHO-DBH AML 2012 study committee Chairman Jonas Abrahamsson National coordinators Barbara de Belgium Moerloose Denmark Estonia Finland Hong Kong Iceland Norway Sweden The Netherlands Ghent University Hospital, Children s Hospital, Princess Elisabeth, Department of Pediatric Hematology- Oncology, 3K12D, De Pintelaan Gent, Belgium +32 (0) Fax +32 (0) Birgitte Lausen Dept of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Denmark Fax Kadri Saks Tallinn Children s Hospital, Dep. Hematology oncology, Tervise 28, Tallinn 13419, Estonia Fax Kirsi Jahnukainen Division of Hematology- Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Central Hospital, PL 281, Helsinki, Finland Fax Shau- Yin Ha Dept of Paediatrics & Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Fax Olafur G Jonsson Children s Hospital, Landspitali University Hospital, Hringbraut, 101 Reykjavik, Iceland Fax Bernward Zeller Pediatric Dept, Women and Children's Division, Oslo University Hospital Rikshospitalet, Mailbox 4950 Nydalen, N Oslo, Norway Fax Josefine Palle Dept of Woman s and Children s Health, Uppsala University, Uppsala, Sweden Fax Gertjan Kaspers Department of Pediatrics, VU University Medical Center Amsterdam De Boelelaan 1117, NL HV Amsterdam, The Netherlands Fax Data Manager Henrik Hasle Minimal residual disease flow cytometry Anne Tierens Cytogenetics Department of Pathology, Oslo University Hospital Radiumhospitalet, Mailbox 4950 Nydalen, N Oslo, Norway Fax Erik Forestier Barnkliniken NUS, Universitetssjukhuset, Umeå, Sweden /2113 Fax 2 1. LIST OF ABBREVIATIONS IMPORTANT NOTE PROTOCOL OUTLINE CHECKLIST AML SUMMARY OF PROTOCOL OBJECTIVES OF NOPHO-DBH AML BACKGROUND EARLY NOPHO AML PROTOCOLS (NOPHO-AML 84, 88 AND 93) NOPHO-AML THERAPY RESPONSE IN AML MINIMAL RESIDUAL DISEASE IN AML STEM CELL TRANSPLANTATION IN AML CYTOGENETICS IN AML GEMTUZUMAB OZOGAMICIN RANDOMISATION RELEVANT EXPERIENCES FROM OTHER STUDY GROUPS RECENT LARGE TREATMENT STUDIES INDUCTION THERAPY MINIMAL RESIDUAL DISEASE (MRD) CONSOLIDATION THERAPY STUDY POPULATION INCLUSION CRITERIA EXCLUSION CRITERIA WITHDRAWAL OF CONSENT RISK GROUPING HIGH-RISK GROUP STANDARD-RISK GROUP PATIENT AND DATA REGISTRATION MANDATORY DATA MANDATORY DATA BEFORE RANDOMISATION IN DNX STUDY ADDITIONAL MANDATORY DATA AT DIAGNOSIS MANDATORY DATA AT DAY 22 AFTER COURSE 1 (BEFORE FLADX RANDOMISATION) MANDATORY DATA BEFORE CONSOLIDATION (AT START OF HAM) REQUIRED EVALUATIONS, PROCEDURES AND DOCUMENTATION INITIAL EVALUATION EVALUATION AND PROCEDURES FOLLOWING INDUCTION COURSE 1 (MEC OR DXEC) TOXICITY BONE MARROW EVALUATION EVALUATION OF EXTRAMEDULLARY DISEASE RANDOMISATION IN THE FLADX STUDY CARDIAC EVALUATION EVALUATION AND PROCEDURES FOLLOWING INDUCTION COURSE TWO (ADXE OR FLADX) TOXICITY BONE MARROW EVALUATION EVALUATION OF EXTRAMEDULLARY DISEASE CARDIAC EVALUATION RISK STRATIFICATION EVALUATION AND PROCEDURES DURING CONSOLIDATION TOXICITY BONE MARROW EVALUATION EVALUATION OF CNS DISEASE EVALUATION AND PROCEDURES AFTER COMPLETION OF THERAPY EARLY DISEASE DETECTION LATE EFFECTS OF THERAPY EVALUATION OF PROTOCOL AND RANDOMISED STUDIES TREATMENT PLAN THERAPY OVERVIEW INITIATION OF THERAPY EVALUATION AFTER COURSE 1 (MEC OR DXEC) EVALUATION AFTER COURSE 2 (ADXE OR FLADX) CONSOLIDATION THERAPY OVERVIEW OF MRD FLOW SAMPLING DURING TREATMENT INDUCTION COURSE 1 MEC INDUCTION COURSE 1 DXEC INDUCTION COURSE 2 ADXE INDUCTION COURSE 2 FLADX CONSOLIDATION CONSOLIDATION COURSE 1 HAM LABORATORY REQUIREMENTS BEFORE START OF THE COURSE CONSOLIDATION COURSE 2 HA 3E LABORATORY REQUIREMENTS BEFORE START OF THE COURSE CONSOLIDATION COURSE 3 FLA LABORATORY REQUIREMENTS BEFORE START OF THE COURSE CNS THERAPY THERAPY OF ISOLATED EXTRAMEDULLARY DISEASE (NON-CNS) EVALUATION OF THERAPY RESPONSE STEM CELL TRANSPLANTATION SALVAGE THERAPY TREATMENT MODIFICATIONS DOSE REDUCTION IN CHILDREN 1 YEAR OR 10 KG OBESITY CARDIAC TOXICITY DAUNOXOME RANDOMISED STUDIES COMPARISON OF EFFICACY OF DAUNOXOME AND MITOXANTRONE IN COURSE 1 (DNX STUDY) SHORT RATIONAL PRIMARY OBJECTIVE SECONDARY OBJECTIVE PRIMARY ENDPOINT SECONDARY ENDPOINTS PATIENT NUMBERS AND POWER CALCULATION STUDY PROCEDURE COMPARISON OF THE EFFICACY OF ADXE AND FLADX AS THE SECOND INDUCTION COURSE (FLADX STUDY) SHORT RATIONAL PRIMARY OBJECTIVE SECONDARY OBJECTIVE PRIMARY ENDPOINT SECONDARY ENDPOINTS PATIENT NUMBERS AND POWER CALCULATION STUDY PROCEDURE QUALITY CONTROL AND TOXICITY REGISTRATION MONITORING OF AML GCP MONITORING SUPERVISION BY PROTOCOL COMMITTEE DATA SAFETY MONITORING COMMITTEE (DSMC) MONITORING OF ESSENTIAL LABORATORY INVESTIGATIONS TOXICITY REGISTRATION SUSPECTED UNEXPECTED SEVERE ADVERSE EVENTS (SUSARS) AND DEATHS SEVERE ADVERSE EVENTS (SAES) REPORTING OF SEVERE ADVERSE EVENTS AFTER INDUCTION AND CONSOLIDATION COURSES REPORTING OF LONG- TERM TOXICITY DEFINITIONS EVENT DEFINITION RELAPSE RESISTANT DISEASE EARLY DEATH DEATH IN CR SMN THERAPY RESPONSE DEFINITIONS POOR RESPONSE TO INDUCTION INTERMEDIATE RESPONSE TO INDUCTION GOOD RESPONSE TO INDUCTION POOR RESPONSE TO INDUCTION INTERMEDIATE RESPONSE TO INDUCTION GOOD RESPONSE TO INDUCTION COMPLETE REMISSION (CR) DIAGNOSTIC GUIDELINES THE DIAGNOSIS OF AML BONE MARROW MORPHOLOGY BLAST LINEAGE - IMMUNOPHENOTYPE GENETIC ABERRATIONS CNS DISEASE DIAGNOSTICS BIOBANK 16.4. MINIMAL RESIDUAL DISEASE FLOW CYTOMETRY FOR QUANTIFICATION OF CELLS WITH LAIP MRD FLOW GUIDELINES QPCR FOR FUSION GENE TRANSCRIPTS DRUG INFORMATION CUMULATIVE DOSES CYTARABINE ETOPOSIDE FLUDARABINE LIPOSOMAL DAUNORUBICIN (DAUNOXOME) METHOTREXATE MITOXANTRONE SUPPORTIVE CARE GENERAL RECOMMENDATIONS HYPERLEUKOCYTOSIS TUMOUR LYSIS SYNDROME (TLS) TREATMENT COAGULATION ABNORMALITIES AND BLEEDING INFECTION PREVENTION OF INFECTION NEUTROPENIC FEVER TRANSFUSION SUPPORT NUTRITION MUCOSITIS EMESIS ETHICAL CONSIDERATIONS POSSIBLE BENEFITS AND RISKS FOR PATIENTS INFORMED CONSENT FINANCIAL ISSUES PUBLICATION GUIDELINES LIST OF APPENDICIS REFERENCES 1. List of abbreviations AML ANC APL ARDS BFM BM BSA BSPHO BW CNS CR CRF CSF DCOG DS ECHO EFS EWOG- MDS FISH FLT3- ITD G- CSF GO GCP HEPA IT JMML LAIP LC MDS MLL MPAL MRC MRD NOPHO NPM1 OS PCR qpcr RD SAE SCT SUSAR TLS Acute myeloid leukaemia Absolute neutrophil count Acute promyelocytic leukaemia Adult respiratory distress syndrome Berlin Frankfurt Münster study group Bone marrow Body surface area Belgian Society of Paediatric Hematology Oncology Body weight Central nervous system Complete remission Case report form Cerebrospinal fluid Dutch Childhood Oncology Group Down syndrome Echocardiography Event- free survival European working group of MDS in childhood Fluorescence in situ hybridisation fms- like tyrosine kinase receptor- 3 internal tandem duplication Granulocyte colony stimulating factor Gemtuzumab ozogamicin Good Clinical practice High- efficiency particulate air intrathecal Juvenile myelomonocytic leukaemia Leukaemia aberrant immunophenotype Leukaemic cell(s) Myelodysplastic syndrome Mixed leukemia lineage gene Mixed phenotype acute leukaemia Medical Research Council Minimal residual disease Nordic society for paediatric haematology and oncology Nucleophosmin gene Overall survival Polymerase chain reaction Quantitative polymerase chain reaction Resistant disease Severe adverse event Stem cell transplantation Suspected unexpected severe adverse events Tumour lysis syndrome 7 UNL WBC Upper normal limit White blood cell count 2. Important note The NOPHO- DBH AML2012 protocol has the overall aim of increasing the cure rate of children with AML. It is a collaborative research protocol but also provides a standard treatment, which is considered as best available treatment. Although the protocol contains recommendations for standard therapy, it is not intended for use in unregistered patients. Treatment with this protocol is not recommended unless the AML protocol group has been consulted and the group will not take any responsibility, legal or otherwise for the use of the protocol in unregistered patients. The protocol includes two randomised studies, which will be conducted according to Good Clinical Practice (GCP) guidelines after approval from the national legal authorities. The study aims to improve therapy but also to increase the quality of diagnostic and response evaluation as well as data registration particularly regarding toxicity. This will increase the demands on the treating centres and physicians. To ensure that the intended high standards will be reached all participating centres must adhere to the following principles: All centres will sign a contract stating their commitment to perform the study and identifying the laboratories that will carry out diagnostic evaluation and minimal residual disease MRD monitoring for the centre (appendix 1). All patients should be registered in the NOPHO- AML registry within five days of commencing therapy. All deaths and Suspected Unexpected Severe Adverse Reactions (SUSARs) must be reported to the AML registry within 48 hours. Patients for whom mandatory data are lacking cannot enter the randomised studies. In all patients with an informative leukaemia aberrant immunophenotype (LAIP), MRD must be monitored with flow cytometry, standardised according to appendix 4. Significant treatment modifications, including dose reductions and delays should not be based only on personal views but on protocol recommendations and discussions with the study and/or national coordinator. The protocol has been prepared with great care but amendments may be necessary. These will be circulated to known participants in the trial, but institutions entering patients are in case of doubt advised to consult with the NOPHO website where the most current version of the protocol and all relevant appendices and other documents are available for NOPHO members and associated partners. Despite our best efforts, the possibility of errors within this document cannot be excluded. We remind investigators that the responsibility for any therapy given lies with the attending physician and that any adverse consequences arising from application of this treatment.should be regulated within the framework of regulations and insurance 8 policies in the individual countries and ICH- GCP guidelines. The content of the protocol is confidential and may not be distributed outside NOPHO treatment centres without the approval of the NOPHO- DBH AML 2012 Study Committee. For centres that for any reason do not participate in the randomised trials, treatment should be given according to the standard arms. This also applies to individual patients not taking part in the randomisations for other reasons (e g patient refusal). For each of the randomised studies a standard arm is depicted in the protocol. 9 3. Protocol outline Figure 1. Outline of NOPHO-DBH AML 2012 protocol. Note that HAM is omitted for standard risk patients with inv(16) * BM evaluation with MRD is done day 22. Patients with 5% leukaemic cells proceed immediately to course 2. Patients with 5% receive course 2 after recovery but weekly controls of BM with MRD should be performed. ** BM evaluation in patients who started course 2 early (i.e. had 5% LC after course 1) is performed on day 22 after course 2 whereas patients with 5% LC after course 1 are evaluated immediately before start of consolidation (HAM). Echocardiography should be performed prior to course 1, 2 and 3. 10 4. Checklist AML 5. Summary of protocol The outcome of paediatric acute myeloid leukaemia is still unsatisfactory with an overall survival around 70% and a relapse rate of 30-40% after primary treatment. The primary aim of the NOPHO- DBH AML 2012 study is to improve EFS and OS in children with AML. The protocol is a collaborative research study including the BSPHO, DCOG, Hong Kong and NOPHO paediatric AML groups. The patient group includes children and adolescents up to 19 years of age with de novo AML excluding patients with MDS- AML, myeloid leukaemia of Down syndrome and acute promyelocytic leukaemia. To improve outcome, an intensified induction regimen will be given and a response guided risk- group stratification using flow cytometric minimal residual disease measurements to evaluate therapy response will be used. Patients with a poor response to the two induction courses will be assigned to the high- risk group and receive consolidation therapy including stem cell transplantation whereas those with a good response will be given three chemotherapy courses as consolidation therapy. An exception are patients with good response and inv(16), who will not be given HAM and thus receive two consolidation courses only. The only other cytogenetic feature that will affect risk stratification is the presence of an FLT3- ITD mutation which, when not associated with concomitant nucleophosmin (NPM1) mutation, will stratify patients to the high- risk group. Effective induction therapy is crucial for outcome in AML and MRD levels following induction are highly predictive of outcome. AML 2012 includes two randomised studies that both address the efficacy of induction therapy. The first study is based on the induction course from the Japanese AML99 trial and compares the efficacy of mitoxantrone and DaunoXome in the first treatment course. The primary outcome measure is the MRD level on day 22 from start of the course. The second study compares ADxE (low- dose cytarabine, DaunoXome and etoposide) with FLADx (fludarabine, high- dose cytarabine and DaunoXome) as the second induction course. The primary endpoint is the MRD level at day 22 from start of the course. Secondary outcome measures in both studies include EFS, OS, remission rate and toxicity. AML 2012 is scheduled to run between five and six years and expected to recruit at least 300 patients. The study incorporates strict guidelines for cytogenetic characterisation of the disease and a standardised approach to flow cytometric MRD determination with central review of data files. Toxicity will be carefully monitored and the study will be conducted according to GCP guidelines. 12 6. Objectives of NOPHO- DBH AML 2012 The AML 2012 study is a treatment and research protocol with the overall aim of improving prognosis for children and adolescents with AML. This is to be achieved by better risk stratification based on MRD quantification and more intensive induction compared to previous NOPHO protocols. The protocol contains two randomised studies. The first compares the efficacy of mitoxantrone vs. liposomal daunorubicin in the first induction course (DNX study) and the second compares the efficacy of two courses, ADxE vs. FLADx, as the second induction course (FLADx study). Minimal residual disease measurement by flow cytometry will be employed for evaluation of early response to therapy and provide the main means for evaluation of the randomised studies and for treatment stratification. The protocol also includes studies addressing genetic and epigenetic aberrations in AML and the prognostic impact of minimal residual disease as determined by flow cytometry and/or PCR for specific genetic aberrations. The specific aims of the randomised studies are 1) To investigate if either DaunoXome or Mitoxantrone, when given in course 1, is more effective in reducing the MRD level to 0.1% as measured on day 22. 2) To investigate if either of the courses ADxE or FLADx is more effective in reducing the MRD level to 0.1% after the second induction course. The protocol will also compare the efficacy and toxicity of the treatment between the randomised arms and with previous NOPHO- AML protocols with the aims of 1) Improving both EFS and OS as compared to NOPHO- AML 93 and ) Improving EFS and OS for patients with intermediate response (5-14.9%) blasts after course 1 and patients with t(8;21). 3) Achieving improved anti- leukaemic effect with no increase or a decrease in early toxic deaths and deaths in CR. 4) Comparing outcome in subgroups of patients as defined by characteristics of both patients and disease such as age, FAB type and cytogenetics (e.g. t(8;21, inv(16) and MLL rearrangements). The protocol will also explore and when applicable compare the randomised treatment arms for 1) The incidence of severe infections and severe organ toxicity. 2) The feasibility of obtaining an informative leukemic immunophenotype in at least 80% of patients. 3) The correlation between MRD measurement by PCR and flow cytometry and the prognostic impact of MRD with either method after course 1 and 2 respectively. 13 7. Background 7.1. Early NOPHO AML protocols (NOPHO- AML 84, 88 and 93) Cure rates in paediatric AML were very low until the introduction of intensive chemotherapy in the late 1970s(1). In 1981, a pilot study in Oslo, introducing consolidation therapy with high- dose (HD) cytarabine in children, showed promising results and was used as the base for the first Nordic collaborative paediatric AML protocol(2). NOPHO- AML84 used an induction with three courses of doxorubicin, low- dose cytarabine and 6- thioguanine and consolidation with four courses of high- dose cytarabine and resulted in an EFS of 29%(3). Since the number of patients with resistant disease (15%) and relapse (46%) was high, the next protocol, NOPHO- AML88 was intensified. Etoposide, continuous infusion of cytarabine and mitoxantrone were added to induction and HD cytarabine was combined with etoposide or mitoxantrone in consolidation. Intensive timing was used for the first two induction courses. NOPHO- AML88 had a strong anti- leukaemic effect and the rate of resistant disease was reduced to 4% and relapse rate to 36%. However, although EFS increased to 41%, the treatment was very toxic and the frequency of early death and death in CR was unacceptably high at 9.3% each(3). NOPHO- AML93 used a response- AML 2004 Protocol N EFS 5 AML AML AML AML AML 93 AML 88 AML 84 Figure 2. Event-free survival in the four consecutive NOPHO AML studies. guided approach to retain the anti- leukemic effect while reducing toxicity. Thus, only patients who did not respond with 5% blast cells after the first course with doxorubicin, low- dose cytarabine, etoposide and 6- thioguanine (ATEDox), received the second course early after 14 days. This course was low- dose cytarabine and mitoxantrone (AM). In contrast, good responders repeated the first course but only after peripheral regeneration. NOPHO- AML93 was highly successful with an EFS of 51% and an OS of 65% at five years, results which at the time were world- leading(3). 14 7.2. NOPHO- AML 2004 AML 2004 used idarubicin instead of doxorubicin in the first induction course, since other studies suggested that idarubicin could be more effective than other anthracyclines(4, 5). The response- guided approach from the 1993 protocol was AML 2004 Protocol N OS 5 AML AML AML AML AML 93 AML 88 AML 84 Figure 3. Overall survival at 5 years in the four consecutive NOPHO AML studies. retained but all patients were given AM as the second induction course. Patients were allocated to the high- risk group if they had 15% blasts after the first course or did not achieve CR after the second course. Until 2009, patients with 11q23 abnormalities other than t(9;11) were also classified as HR. However, the majority of these patients are under 2 years and compliance to the SCT recommendation was poor. An
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