Glivec in pediatric CML patients with sustained complete molecular response (STOPIMAPED)

An international collaborative study to discontinue Imatinib/Glivec® in pediatric CML patients with sustained complete molecular response (STOPIMAPED) A collaborative IBFM study of the CML study group

Version December 6, 2011

PROTOCOL SYNOPSIS

Title

Indication

Objectives

Endpoints

An international collaborative study to discontinue Imatinib/Glivec® in pediatric CML patients with complete molecular response. Philadelphia chromosome positive patients treated with Imatinib and with complete molecular response To estimate the percentage of quantitative RT-PCR negative pediatric CML patients in which Imatinib discontinuation result in sustained complete molecular remission To determine whether restarting of Imatinib or another tyrosine kinase inhibitor in case of molecular relapse results in a molecular remission again. Primary endpoints: Molecular relapse free survival at 6 and 24 months. Duration of complete molecular remission after stopping Imatinib. Secondary endpoints: Prognostic studies. Overall survival and survival without progression. Efficacy of restarting Imatinib in a period of 6 months after molecular relapse.

Number of patients

60 patients

Outline and timing

4 yrs international protocol of the IBFM CML study group. Enrollment duration: 24 months, Follow-up: minimum 24 months for all patients

Inclusion criteria

Pediatric CML patients treated with Imatinib having achieved and maintained complete molecular remission for at least 2 years. Informed consent needs to be signed.

Exclusion criteria

Non-CML patients, or CML patients with complete cytogenetic reponse but with a moderate molecular response.

Study plan

Investigate rates of relapses, and duration of complete molecular response after discontinuation of Imatinib, survival and progression and efficacy of restarting Imatinib after molecular relapse.

Study medication

none

Checklist for Inclusion:

Patient characteristics and histology on CML disease until inclusion Prove of 2 year complete molecular response with results of lab tests of the country’s reference laboratory over the last two years (see appendix 4) measured at least 6 times during the last 2 years. CMolR is defined as undetectable mRNA transcripts by RT quantitation and nested PCR with a sensitivity of at least 10-4 or as the ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale Material (frozen cells, unstained microscopic slides) stored for isolation for identification of BCR-ABL genomic breakpoints

Summary and Background Chronic myeloid leukemia is a rare disease in children; SEER databases record an incidence of 2% of all leukemias in children < 15 years (accounting for 1 case/million/year) increasing up to 9% in children aged 15-19 years (2.2 cases/million/year). Presently treatment consists of BCR/ABL kinase inhibitors as first choice drugs, in both adults and children. Only approximately 60% of the treated children have a sibling donor or a good matched non-related donor for stem cell transplantation. All others remain on BCR/ABL kinase inhibitor such as imatinib and/or newer generations of BCR/ABL targeting kinase inhibitors. Recently, several adverse long-term effects have been described in adult series and scarce case reports in children treated with BCR/ABL kinase inhibitors, such as imatinib. For instance, decreased growth development, aberrant bone composition and incomplete pubertal development are reported as a result of long-term treatment with tyrosine kinase inhibitors such as Imatinib. Due to the rareness of the disease in children, collaborating international pediatric studies are lacking. Besides opening an international CML registry to investigate the long-term (side-) effects, the possibility of imatinib discontinuation needs to be explored as a possible final solution for the disease and long-term side effects. Many adolescents already discontinue Imatinib themselves. In the meantime, promising results are described in the “STIM”study (small serie of adult CML patients) in which imatinib is stopped; 40% remained in a complete molecular response. Most patients (>90%) with molecular relapse experienced this relapse early (<7 months) after stopping Imatinib. All relapsed patients achieved a second molecular remission after restarting Imatinib. So, the international CML treating physicians of the IBFM are confronted with drug discontinuation of several patients themselves, or with reasons such as impaired growth development and/or complications or toxicity. Therefore, this international collaborative study will determine the efficacy of discontinuation of Imatinib on sustained complete molecular response in Philadelphia chromosome positive CML pediatric patients treated with imatinib. At this moment there is no consensus in the adult community of CML treating physicians about the exact definition of the cut-off value for the BCR-ABL/ABL level. The abovementioned “STIM” study used as cut-off undetectable transcripts of BCR/ABL with a sensitivity of 10-5. Whereas the latest upcoming European study concerning the discontinuation of tyrosine kinase inhibitors will use a cut-off of 10-4 transcripts of BCR/ABL with a sensitivity of at least 10 -4. In this study we decided to use a sensitivity of at least 10-4. The international reference laboratories used for this analysis are board certified and good standardized methods exist internationally to follow the patients during time. In conclusion, patients may enter no earlier than 2 years after sustained complete molecular remission (CMolR) is achieved. CMolR is defined as undetectable mRNA transcripts by RT quantitation and nested PCR with a sensitivity of >10-4 or the ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale. The international pediatric CML committee recommends not to discontinue outside clinical trials. Moreover, the IBFMSG CML advises that all patients in major complete response who discontinue treatment despite this recommendations are reported to the

international database at the DCOG. These observational observations will give insights concerning the reasons of discontinuation, the molecular status of the patient at the time of discontinuation and his outcome. This study is an IBFM international study from the CML working group. The aim of the IBFM CML working group is to offer the best standard of care to children and adolescents with CML, relying on the improved knowledge of the disease and updated research.

Principal Investigator:

Prof. Dr. Eveline de Bont Pediatric oncologist/hematologist, Head pediatric oncology/hematology Beatrix Children’s Hospital, University Medical Center Groningen (UMCG), Groningen, The Netherlands Tel: +31 50 3614213 Fax: +31 50 3614235 Email: [email protected]

Coinvestigators of the IBFM steering committee: Dr. Frederic Millot, Unité d'hémato-oncologie pédiatrique CHU de Poitiers 86 000 Poitiers France Tel: 00 33 (0)5 49 44 30 78 Fax: 00 33( 0)5 49 44 33 03 Email : [email protected] Prof. Dr. Meinolf Suttorp Div. Pediatric Hematology and Oncology Dpt. of Pediatrics Univ. Hospital Carl Gustav Carus Fetscherstr. 74 D-01307 Dresden, Germany Tel.: +49 351 458 3522 FAX: +49 351 458 5864 e-mail: [email protected] Prof. Dr. Andrea Biondi, Professor of Pediatrics University of Milano-Bicocca Director, Department of Pediatrics Hospital S.Gerardo/Fondazione MBBM Via Pergolesi, 33 20052 Monza (IT) phone: +39-039-2333513 FAX: +39-039-2301646 Email: [email protected]

Prof. Dr. Andre Baruchel, Chef de Service Hématologie-Immunologie Pédiatrique Hôpital Robert Debré (AP-HP) 48 Bd Sérurier 75935 PARIS Cedex 19 Université Paris Diderot et EA 35-18 Institut Universitaire d'Hématologie Paris Tel: +33 1 40 03 53 88 Fax: +33 1 40 03 47 40 Email: [email protected]

Trial Office Dutch childhood Oncology group (DCOG), Leyweg 299, 2545 CJ Den Haag The Netherlands Tel +31 70 3674545 Fax: +31 70 3598718 Email: [email protected]

Statistics: Joelle Guilhot, PhD Biostatistician Clinical Investigation Center, CIC 802 INSERM University Hospital 86021 - Poitiers - FRANCE Phone (33) 5.49.44.49.14 Fax (33) 5 49.44.46.91 e-mail [email protected] [email protected]

Regional coordinators: The Netherlands: Eveline de Bont Pediatric oncologist/hematologist Beatrix Children’s Hospital, University Medical Center Groningen (UMCG), Groningen, The Netherlands Tel: +31 50 3614213 Fax: +31 50 3614235 Email: [email protected]

Germany: Meinolf Suttorp Div. Pediatric Hematology and Oncology Dpt. of Pediatrics Univ. Hospital Carl Gustav Carus Fetscherstr. 74 D-01307 Dresden, Germany Tel.: +49 351 458 3522 FAX: +49 351 458 5864 e-mail: meinolf.suttorp@uniklinikum-

dresden.de France: Frederic Millot Unité d'hémato-oncologie pédiatrique CHU de Poitiers 86 000 Poitiers France Tel: 00 33 (0)5 49 44 30 78 Fax: 00 33( 0)5 49 44 33 03 Email : [email protected]

Italy: Andrea Biondi Professor of Pediatrics University of Milano-Bicocca Director, Department of Pediatrics Hospital S.Gerardo/Fondazione MBBM Via Pergolesi, 33 20052 Monza (IT) phone: +39-039-2333513 FAX: +39-039-2301646 Email: [email protected]

France : Andre Baruchel, Chef de Service Hématologie-Immunologie Pédiatrique Hôpital Robert Debré (AP-HP) 48 Bd Sérurier 75935 PARIS Cedex 19 Université Paris Diderot et EA 35-18 Institut Universitaire d'Hématologie Paris Tel: +33 1 40 03 53 88 Fax: +33 1 40 03 47 40 Email: [email protected]

Data Security Monitoring Board: Prof Dr Francois Guilhot, Clinical Investigation Center, CIC 802 INSERM University Hospital 86021 - Poitiers - FRANCE Phone (33) 5.49.44.49.14 Fax (33) 5 49.44.46.91 [email protected] Prof Dr Andreas Hochhaus, Dir. Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Klinik für Innere Medizin II, Erlanger Allee 101, 07747 Jena Tel.:+49 (0) 3641-9 32 42 01 Fax: +49 (0) 3641-9 32 42 02 Mailto: [email protected] Dr Martin Zimmermann, Medizinische Hochschule Hannover, Kinderklinik IV, Paediatrische Oncologie Ceuberg-Strasse 1 D-30625 Hannover Tel: +49 (511) 532 3764 Fax: +49 (511) 532 9029 Mailto: [email protected]

Sponsor:

Dutch Childhood Oncology Group (DCOG), Leyweg 299, 2545 CJ Den Haag The Netherlands Tel +31 70 3674545 Fax: +31 70 3670868 Email: [email protected]

LIST OF ABBREVIATIONS AIEOP ALL AML AML-BFM ANC AP APL BC BM BSPHO CCG CCR CMolR CNS COG CP CR CSF DCOG DFS EFS FAB FISH GO IBFM-SG ICC (APL) JMML MDS MRC MRD MSD MUD NOPHO NR OS POG PR SCT VOD WBC WHO

Associazione Italiana Ematologia ed Oncologia Pediatrica Acute lymphoblastic leukemia Acute myeloid leukemia AML Berlin-Frankfurt-Münster group Absolute neutrophil count Accelerated Phase Acute promyelocytic leukemia Blast crisis Bone marrow Belgian Society of Paediatric Haematology-Oncology Children's Cancer Group (USA) Continued complete remission Complete Molecular remission Central nervous system Children’s Oncology Group (USA) Chronic Phase Complete remission Cerebrospinal fluid Dutch Childhood Oncology Group Disease-free survival Event-free survival French American British Fluorescent in situ hybridization Gemtuzumab ozogamicin International Berlin-Frankfurt-Münster Study Group International Consortium on Childhood (APL) Juvenile myelomonocytic leukemia Myelodysplastic syndrome Medical research council (UK) Minimal residual disease HLA-matched sibling donor HLA-matched unrelated donor Nordic Society for Paediatric Haematology and Oncology No response Overall survival Pediatric Oncology Group (USA) Partial response Stem cell transplantation Veno-occlusive disease White blood cell count World Health Organization

Table of Contents Page

Inhoud 1 2

OBJECTIVES ....................................................................................................................... 12 BACKGROUND AND RATIONALE ....................................................................................... 13 2.1 Chronic Myeloid Leukemia (CML) in children ........................................................... 13 2.2 Treatment protocols before the introduction of Imatinib: ....................................... 13 2.3 Introduction of imatinib in pediatric CML ................................................................ 14 2.4 First results of withholding imatinib in CML patients ............................................... 15 3 PATIENT ELIGIBILITY CRITERIA .......................................................................................... 18 4.1 Therapy overview: ..................................................................................................... 19 4.2 Definitions.................................................................................................................. 20 5 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS................................................... 22 5.1 Required observations at start of Imatinib discontinuation ..................................... 22 5.2 Examination during the restart of imatinib treatment at a molecular relapse ........ 22 5.3 Laboratory tests to evaluate BCR-ABL status ............................................................ 23 6 STATISTICAL CONSIDERATIONS......................................................................................... 24 6.1 Objectives and methods : .......................................................................................... 24 6.2 Number of analyses: .................................................................................................. 24 6.3 Samples size:.............................................................................................................. 25 6.4 Stopping rules: ........................................................................................................... 25 6.5 Data Security Monitoring Board ................................................................................ 25 7 OPERATIONAL ASPECTS AND DATA MANAGEMENT ........................................................ 26 8 PATIENT INFORMATION, INFORMED CONSENT, INSURANCE .......................................... 28 9 PATIENT SAFETY AND EVENT REPORTING ........................................................................ 29 References ................................................................................................................................ 32 Appendix: ................................................................................................................................. 36 1. (Serious) adverse Event report form; will follow at the onset of the trial. ................... 36 2. Patient information form; the Dutch version ............................................................... 37 3. Data monitoring form; will follow at the onset of the trial .......................................... 46 4. List of reference laboratories from the Muller et al Leukemia 2009, 23: 1957-1963. . 47 5. Dutch laboratory appendix specific for the Netherlands.............................................. 48

1

OBJECTIVES

Primary Objectives: To determine the percentage of Philadelphia chromosome positive pediatric CML patients (initially presented in chronic phase or accelerated phase) in which Imatinib discontinuation results in sustained complete molecular remission Secondary objective: To determine whether restarting of Imatinib in case of (molecular) relapse results in a second molecular response or remission.

Endpoints: Primary endpoints: Molecular relapse free survival at 6 and 24 months Duration of complete molecular remission after stopping Imatinib Secondary endpoints: Prognostic studies Overall survival and survival without progression Efficacy of restarting Imatinib in a period of 6 months after molecular relapse

2

BACKGROUND AND RATIONALE

2.1

Chronic Myeloid Leukemia (CML) in children

Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by the BCR-ABL tyrosine kinase protein; the product of the BCR-ABL fusion gene. In over 90% of cases a reciprocal translocation of chromosome 9 and chromosome 22, t(9;22) is found, the so called Philadelphia chromosome. The BCR-ABL protein has a constitutive tyrosine kinase activity, resulting in an abnormal cell cycle, inhibition of apoptosis and increasing cell proliferation. CML is a rare disease in children and is diagnosed in approximately 2% of children with leukemia. The diagnosis is made by cytomorphological, cytochemical, immunological, cytogenetic and molecular techniques on bone marrow aspirate and peripheral blood. The BCR-ABL fusion gene detected by cytogenetic and/or molecular techniques is found in over 90% of all CML cases. In less than 10% of CML patients the classical fusion gene cannot be found; however other translocations of 22q11 to different regions than 9q34 (3%) or multiple translocations involving 3 or more chromosomes (3%) can be found. In these cases molecular techniques are essential to show rearrangements of ABL and BCR genes to establish the diagnosis (Goldman et al, NEJM 2003). It is important to realize that the BCR-ABL fusion gene is not exclusively found in CML patients; this fusion gene can be detected in 3-10% of childhood leukemia’s. On the molecular level the classical BCR-ABL protein (210 kD) can be distinguished by molecular weight from the BCR-ABL fusion protein (190 kD) in ALL and AML. The different proteins are the results of other breakpoints. BCR-ABL (190 kD) positive acute leukemia’s ought to be treated in line with ALL or AML protocols. The disease typically follows two or three phases: (i) a chronic phase (CP); without treatment this progresses within 3 to 6 years into (ii) a somewhat ill-defined accelerated phase (AP), which, in turn will culminate in (iii) blast crisis (BC) within 3 to 6 months without treatment. Blast crisis exhibits all features of acute leukemia with either myeloid or lymphoid morphology.

2.2

Treatment protocols before the introduction of Imatinib:

Until the introduction of Imatinib allogenic hematopoietic stem cell transplantation has been recommended as first-line treatment in CML since it is considered to be the only treatment modality with curative potential. (Silver et al review Blood 1999)There is no doubt that allogenic hematopoietic stem cell transplantation (HSCT) can result in cure of CML. However, also after alloSCT very late relapses occur (Goldman JCO 2010). In the pediatric setting cure should be the goal of treatment, rather than delay of disease progression. (Ref: Lange T et al, Leukemia 2005, Cwynarski K et al, BLOOD 2003; Suttorp M et al 2009). Besides the anti-leukemic effect of myeloablative chemo- and radio-therapeutic conditioning regimens, transplantation outcomes also depend on the alloreactive graft-versus-leukemia effect. Overall survival rates were 60-80% for CML patients transplanted in chronic phase

(Pulsipher et al 2004 Kolb et al 1990) However, the procedure has a significant transplantrelated morbidity and mortality (i.e. infection, bleeding, rejection, graft-versus host disease, veno-occlusive disease, sterility).

2.3

Introduction of imatinib in pediatric CML

In the 1980’s Interferon α (IFN-α) was introduced as a treatment option for patients without a suitable donor. Often IFN-α was combined with cytarabine. This treatment resulted in an increased survival time of 1 to 2 years. Even major cytogenetic responses could be achieved. The introduction of Imatinib (Glivec®) dramatically changed results for patients without a suitable donor. Imatinib (Glivec®) is a BCR-ABL tyrosine kinase inhibitor, fitting to the BCR-ABL fusion protein resulting in apoptosis and proliferation block. The results of studies with Imatinib are promising (Kantarjian et al, Blood 2003). Patients treated in accelerated phase or blast crises with Imatinib can still respond, albeit for a shorter time (Talpaz et al, Blood 2002, Kantarjian et al, Blood 2002 and Sawyers et al, Blood 2002).

Table 3: Responses of defined subpopulations of CML patients with Imatinib after initial treatment failure Imatinib Chronic phase Complete hematological response

95%

Major Cytogenetic response

60%

Accelerated phase Complete hematological response

82%

Major cytogenetic response

24%

Blast crisis Complete hematological response

52%

Major cytogenetic response

16%

The first randomized trials with Imatinib compared to IFN-α/Ara-C showed not only hematological responses but also a great amount of major or complete cytogenetic responses in the Imatinib treatment group (Hughes et al, 2003). Moreover, in the light of very late relapses, the study of Hehlmann et al clearly showed that allogenic stem cell transplantation cannot be recommended anymore for front-line therapy in newly diagnosed CML patients. This study proposes that initial treatment can consist of a trial with modern drug treatment of tyrosine kinase inhibitors (Helhmann et al, 2007). In those who fail to respond and/or develop intolerance transplantation remains an effective therapeutic solution (Pavlu et al, 2011)

Ongoing studies with Imatinib demonstrated that not only complete hematological and cytogenetic repsonses (Hughes et al, 2003) can be achieved but that in 74% of patients a complete molecular response is achieved. (Baccarani et al, 2004). It still remains unknown whether eventual cure can be reached in CML patients treated with monotherapy Imatinib monotherapy. Drug resistance of CML clones is thought to result from mutations in the kinase domain of the BCR-ABL gene resulting in resistance to imatinib inhibition and subsequent selection advantage of such clones. An average of 2% incidence of progression to accelerated phase or blast crisis in the first years and less than 1% thereafter over the years for patients who start with imatinib monotherapy in chronic phase has been demonstrated in adults (Druker et al 2006). Unresponsiveness to the drug has been observed more frequently in patients with less than 3 logs of reduction in BCR-ABL transcripts after 12 months of therapy. However, minimal residual disease is reported to continue to decrease over years. Therefore we are confident that achieving a 3 log reduction is an important endpoint, but failure to do so does not necessary indicate failure of therapy. Some of the patients with failure can be rescued by increasing imatinib dose or with other cytoreductive strategies (Kantarjian et al, 2003, Talpaz et al, 2002). Progression free survival is best when major cytogenetic responses are attained within 3 months of the commencement of imatinib. Moreover, patients who remained in complete cytogenetic response for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse (Marin et al, 2005). Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg/day for adults) may induce higher rates of complete molecular responses. For example, less than 4% of patients achieved complete molecular response in the IRIS study (Glivec at the standard dose of 400 mg/day), while a rate of 28% was reported in a phase II trial of newly diagnosed CML patients treated with 800 mg/day imatinib daily (Guilhot F for the IRIS study group, 2004, Kantarjian HM, 2004). Moreover, the total %-age of cytogenetic responders as well as major molecular responders is increased. Recent update of concepts and management recommendations are summarize by the European Leukemianet (Baccarani et al 2009)

2.4

First results of withholding imatinib in CML patients

Imatinib has greatly improved survival rates in CML. However, side effects are described. Three published case reports in children with CML treated with Imatinib describe growth deceleration. After discontinuation of Imatinib (because of SCT) one patient successfully achieved accelerated growth again (Kimoto et al, 2009), while another patient at the onset of puberty experienced catch-up growth (Mariani S, et al 2008). The third pt is still prepubertal and shows ongoing growths deceleration under Imatinib. (Schmid et al 2009) In adult series it was demonstrated that long term side effects of imatinib are aberrant bone composition, such as demonstrated in Berman et al and Grey et al (2006). A paper of Fitter et al, (2008) demonstrated an increased trabecular bone formation and a decrease in serum calcium and phosphate related to Imatinib treatment in adult CML patients. This study demonstrated that Imatinib significantly modulates bone turnover in vivo. In children case reports also suggest aberrant bone composition along with decreased growth development (Kimoto et al 2009). Preliminary data of the French pediatric CML group by Millot et al demonstrated that in 22 patients with sufficient data a significant decrease of height

standard deviation scores (SDS) was observed (median: -0.37, p<0.0001) between start of the imatinib treatment and after 12 months Imatinib treatment (Millot et al 2009). Especially in children these (possible) long-term side-effects are of great importance for the development of the children into adults as healthy as possible. A pilot study of the first patients (n=12) who discontinued imatinib therapy has been reported (Rousselot et al. 2007; Update ASH 2009 abstract # 859). This study describes for the first time that discontinuation of Imatinib, resulted in a sustained complete molecular response in 50% of the patients with a median follow-up of 42 (37-49) months after discontinuation. All patients were pre-treated with interferon-alpha (IFN), and most had responded to IFN before imatinib treatment. Koskenvasa et al (ASH abstract # 2008) suggested that previous interferon use was essential to have a sustained molecular response after Imatinib discontinuation in a small group of adult CML patients. Two other case reports underscored the possibility of imatinib withdrawal (Verma et al, 2008 and Guastafierra et al, 2009) A new, multicenter study the « Stop Imatinib » (STIM) study was started in July 2007 and results were presented at recent ASH meetings (Mahon et al, 2008, 2009) and recently published in the Lancet Oncology 2010 by Mahon et al. The aim of this study was to evaluate the persistence of complete molecular remission (CMolR) after stopping imatinib in a larger cohort. The criteria for inclusion were imatinib treatment for at least 3 years and sustained CMolR. Sustained CMolR was defined as BCR-ABL/ABL levels below a detection threshold corresponding to a 5-log reduction (undetectable signal using RQ-PCR) for at least 2 years. Molecular relapse, defined as RQ-PCR positivity, was taken into account if confirmed in two successive assessments. This prospective, multicenter, non-randomised study included 100 patients with a median age of 63 years (range 29–80 years). Median follow-up was 17 months and 69 patients had at least 12 months follow-up. Forty-two (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7 and one at month 19). At 12 months, the probability of persistent CMolR for these 69 patients was 41% (95% CI 29-52). At the time of analysis, all patients who relapsed responded to reintroduction of imatinib: 16 of these 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMolR that was sustained after Imatinib rechallenge. So, this study concludes that imatinib can be safely discontinued in patients with a CMolR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibtors. (Mahon et al 2010) In conclusion, long-term imatinib use has been correlated with growth disadvantages in children as one of the major side effects. Moreover, bone composition is changed due to imatinib. This concern prompted us to study the possibilities of stopping imatinib in pediatric CML patients. Studies in adult CML patients confirm that complete molecular remission can be sustained after discontinuation of imatinib. Relapses occur almost always within 6 months after discontinuation. All relapsed patients could be rescued again with imatinib and showed a good second response upon imatinib.

Both results prompted us to design a new international study for pediatric CML patients treated with Imatinib and who achieved CMolR to discontinue Imatinib treatment. Due to the low patient numbers in each country this study needs to be an international multicenter study. The measurement of the BCR-ABL levels is extremely important to monitor the molecular status of the individual patients in all the countries. We will use the BCR-ABL reference laboratories in the various countries to obtain reliable and comparable BCR-ABL analysis. (Further information is given in paragraph 4 and 5.)

3

PATIENT ELIGIBILITY CRITERIA

Inclusion Criteria Philadelphia positive CML in chronic or accelerated phase at diagnosis as defined by the diagnostic criteria Age 18 years at time of study entry Written informed consent obtained according to national and institutional regulations Treated with ongoing Imatinib/Glivec at any dose for at least 3 years Sustained complete molecular response for at least 2 years measured at least 6 times during the last 2 years. CMolR is defined as: undetectable mRNA transpcripts by RT quantitation and nested PCR with a sensitivity of >10-4 or the ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale Previous treatment with autologous transplantation or interferon alpha or busulfan or hydroxyurea and previous or present treatment with Imatinib in combination with interferon alpha, pegylated interferon alpha, or cytarabine are allowed.

Exclusion Criteria o Philadelphia chromosome negative CML o Philadelphia chromosome positive CML in blast phase o Juvenile myelomonocytic leukemia (JMML) o Myelodysplastic syndrome (MDS) o Fanconi anemia o Positive pregnancy test o Patients with previous allogenic stem cell transplantation

Recommendation: we recommend to reanalyse all previous available samples in the national reference laboratory before inclusion in the study.

4

TREATMENT PLAN

4.1

Therapy overview:

CML, Imatinib (>=3 years) Complete Molecular Response (CMolR) sustained > 2 yrs

Discontinue Imatinib CMolR continued

prolongate discontinuation

CMolR lost

Restart Imatinib following local policy/guidelines at a dose/m2 identical to the initial dose

Before the start of the protocol (discontinuation of Imatinib) evaluation needs to be done. Patient characteristic file has to be reported and appropriate evaluations supporting 3 years of Imatinib and 2 years of complete molecular response needs to be fulfilled. For this protocol the definition is of CMolR is defined as undetectable mRNA transpcripts by RT quantitation and nested PCR with a sensitivity of >10-4 or the ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale. Intensive follow up will last 24 months after discontinuation of Imatinib. Blood samples for BCR/ABL PCR have to be evaluated at least every 4 weeks or more frequently within the local institution and/or centrally depending on the regulations for each country. Restmaterial will be stored. When the BCR/ABL shows ongoing complete molecular remission the patient will continue without Imatinib. However, when a loss of Complete Molecular Response is encountered a new blood sample has to be drawn within 2 weeks and the finding of BCR/ABL positive PCR has to be confirmed in the institution as well as in the referral laboratory for the country following the guidelines for each collaborating country. In case of molecular relapse, patients should be restarted and resume the identical dose per m2 of Imatinib or another tyrosine kinase inhibitor immediately following a complete

diagnostic work-up according to local policy. In the bone marrow aspirate cytogenetic and molecular analysis for BCR/ABL needs to be performed. Response on restarting treatment will be measured by molecular analysis of peripheral blood/bone marrow aspirates. The results need to be reported for the study at 1, 3, and 6 months.

4.2

Definitions

In the latest European Leukemianet update the definition for CMolR is defined as undetectable BCR-ABL mRNA transcripts by real time quantitative and/or nested PCR in two consecutive blood samples of adequate quality (sensitivity > 10-4) (Baccarani et al JCO 2009). Definition is given in Table 1. Table 1: definitions Molecular** Complete (CMolR)

Major (MMR)

Undetectable BCR-ABL mRNA transcripts by real time quantitative and nested PCR in two consecutive blood samples of adequate quality (sensitivity > 10-4) or ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale. Ratio of BCR-ABL to ABL ( or other housekeeping genes) < or = 0.1% on the international scale

**For a standardized assessment of the MolR, the conversion of each laboratory data of the international scale is mandatory to correct for the variability of the assays in different laboratories. To allow for intralaboratory variations, a fluctuation of less than one log requires confirmation. For this purpose we will use the national reference or regional laboratories collaborating in the harmonization of molecular monitoring of CML therapy in Europe (Muller MC et al, Leukemia 2009). See also Appendix 4. Due to low patient numbers in each country, this study needs to be an international collaborating study to demonstrate the effects for children with CML and is therefore an initiative of the I-BFM-SG CML committee. In the study of Mahon et al (The “STIM” study, Lancet Oncology 2010) the results are presented of adult CML patients who stopped Imatinib after two years of complete molecular response. It worked out to remain without Imatinib treatment in 40% of the patients. Importantly, it needs to be stressed that patients with loss of complete molecular response restarted Imatinib at the identical dose as before and responded again to Imatinib. At this moment there is no consensus in the adult community of CML treating physicians about the exact definition of the cut-off value for the BCR-ABL/ABL level. The abovementioned “STIM” study used as cut-off undetectable transcripts of BCR/ABL with a sensitivity of 10-5. Whereas the upcoming European study concerning the discontinuation of tyrosine kinase inhibitors will use a cut-off of 10-4 transcripts of BCR/ABL with a sensitivity of at least 10-4. In this study we decided to use a sensitivity of at least 10 -4. The international

reference laboratories used for this analysis are board certified and good standardized methods exist internationally to follow the patients during time. To be able to strictly monitor the discontinuation of Imatinib with frequent BCR/ABL measure-ments,all the participating countries need to be able to do this BCR/ABL analysis. In 2009 a harmonization of the BCR-ABL measurements has been initiated as described extensively in the paper of Muller et al, Leukemia 2009. The harmonization resulted in an established BCR/ABL measurements expressed as percentage on the International Scale beside the possibility of a negative nested PCR as definition for CMolR. Nearly all countries are included in the list of national reference laboratories for BCR/ABL measurements. In this study we propose that each collaborating country uses their national reference or regional laboratory as mentioned in Muller et al, Leukemia 2009 (appendix 4). When countries are not aware of such a laboratory in their neighbourhood they can contact the principal investigator and discuss possibilities of collaboration with other countries. So, at least the assays must give the following results to be able to include patients in this trial: 1. that the patient has undetectable mRNA transpcripts by RT quantitation and nested PCR with a sensitivity of >10-4 (see definition CMolR). 2. or that the patient has a ratio of BCR-ABL to ABL (or other housekeeping genes) < or = 0.01% on the international scale. In this study we will investigate whether a DNA-based monitoring of minimal residual disease on genomic DNA analysis for BCR-ABL gene fusion detection is superior in following molecular responses in these children compared to the RT-PCR assays (Karl et al, 2010). For this reason it is essential to store material from diagnosis and to store 5-10 ml EDTA restmaterial. All the materials can be sent to the study center for centrally performed BCRABL tests on DNA to correlate the study outcome to the various laboratory methods for BCRABL determinations. Definition of Molecular relapse: that the patient has a ratio of BCR-ABL to ABL (or other housekeeping genes) > or = 0.01% on the international scale on two successive measurements. The two measurements have an interval of 2 weeks.

5

REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS

First of all, it needs to be stated that it is essential to stick to the strict monitoring of the BCR/ABL status in the included patients every 4 weeks. In case molecular relapse is suspected upon the BCR/ABL measurement, the BCR/ABL analysis needs to be repeated in 2 weeks.

5.1

Required observations at start of Imatinib discontinuation Physical examination including weight, height and pubertal development, medical history, and assessment of performance status. History of the various responses during treatment with Imatinib (dates of hematological response, cytogenetic response and molecular response) for at least 2.5 years (information needed: dosages per square meter, reductions and interruptions of Imatinib) Laboratory evaluation concerning status of BCR-ABL is mandatory to state that the patient has obtained a complete molecular response at the start of the study (for definition see chapter 4). Hemoglobin, WBC with differential count, platelet count. Store of left over/rest material, at least store DNA of 5 ml EDTA blood sample to be used for DNA-based monitoring of minimal residual disease in addition to some material of diagnosis, such as a bone marrow cytology slide..

Evaluation during study period First year: every month physical examination including weight, height and pubertal development, blood count and BCR/ABL status. Second year: every 2 months physical examination including weight, height and pubertal development, blood count and BCR/ABL status. Third year: every 3 months physical examination including weight, height and pubertal development, blood count and BCR/ABL status. Fourth and fifth years: every 6 months physical examination including weight, height and pubertal development, blood count and BCR/ABL status. Thereafter the Guidelines of each country will be followed.

5.2 Examination during the restart of imatinib treatment at a molecular relapse The patient will restart imatinib as recommended in this protocol or another tyrosine kinase inhibitor following the guidelines and good clinical practice in each country. We recommend to consult the principal investigator of the country to discuss the possibility of a stem cell transplantation after reinduction. However, the trial needs information about the response of the restarting treatment (dosage per square meter) by reports about molecular responses at 1, 3, and 6 months.

5.3

Laboratory tests to evaluate BCR-ABL status

Each collaborating country will perform their molecular assays. Certified laboratories as listed in appendix 4 or who recently, met these criteria after publication are allowed to perform these tests for this study. The Co-PI of a country is responsible for the adequate BCR-ABL molecular measurement in the country following the guidelines defined in Muller et al Leukemia 2009. The following results for the molecular assays are taken as Complete molecular remission (CMolR) 1. that the patient has undetectable mRNA transcripts by RT-PCR and nested PCR with a sensitivity of >10-4 (see definition CMolR). 2. Or that the treating center can give the following result: the ratio of BCR-ABL to ABL ( or other housekeeping genes) < or = 0.01% on the international scale. Both test results are sufficient to be able to include patients for the trial. However, it is essential to store restmaterial to perform the various tests centrally as well as for the DNA-based monitoring of minimal residual disease. The following results for the molecular assays are taken as molecular relapse: Detectable mRNA transcripts by RT quantitation and nested PCR with a sensitivity of >10-4 or the ratio of BCR-ABL to ABL (or other housekeeping genes) >0.01% on the international scale. The BCR-ABL measurement need to be determined by laboratories on the list as a laboratory that is harmonising their BCR-ABL assays internationally, and confirmed by a second analysis point, indicating the increase in relation to the first analysis point at two successive assessments with an interval of two weeks.

6

STATISTICAL CONSIDERATIONS

6.1

Objectives and methods :

The primary analysis will be the evaluation of the molecular relapse free survival ( MolRFS). Time to molecular relapse will be measured from the date of imatinib discontinuation to the date of molecular relapse or the date of last molecular examination for patients who did not relapse. The MolRFS will be estimated by the non parametric Kaplan-Meier method. The major endpoints will be the estimated rate of patients without molecular relapse at 6 and 24 months. Estimates will be provided with 95% confidence intervals.

The secondary analyses will include: Prognostic studies : Prognostic factors potentially associated with persistence of CMolR are mainly age, sex, adjusted Sokal score (risk group), time from diagnosis to the onset of Imatinib, Imatinib treatment duration (overall and until the first CMolR was recorded), duration of CMolR until TKI discontinuation. Relevant parameters will be investigated by univariate analysis, using non parametric tests (Mann-Whitney U test, Fisher’s exact test, Spearman’s rank correlation coefficient and scatter plots, or log rank-test as appropriate). Candidate prognostic factors will then be analysed using multivariate analysis. After check for adequacy, regression models will be fitted. The planned models are mainly a logistic regression after 6 months of follow-up for all patients and additional Cox models taking into account longer and heterogeneous periods of follow-up. Efficacy of restarting treatment for patients who relapse Overall survival and Progression free survival analyses, progression being defined as accelerated phase, blast crisis and/or death whichever come first. Estimates will be provided using the Kaplan-Meier method. Analyses will be performed using SAS V.9 (SAS, Cary NC) and R with an overall type I error of 0.05 for final analyses

6.2

Number of analyses:

Two analyses are planned, one interim and one final analysis. The interim analysis is planned after the enrolment of 20 patients for futility and security considerations.

The analysis will be performed when all of these 20 patients will have 6 months of follow-up and the following key parameters will be checked : . the enrolment of the patients . the rate of molecular relapse . the outcome after resuming treatment of the patients who had molecular relapse The results will be transferred to the DSMB; if no amendment is decided, the study will continue up to the planned enrolment of 60 patients. The final analyses will be performed within 6 months when all included patients have 24 months of follow up.

6.3

Samples size:

The number of pediatric CML patients treated with Imatinib and for at least 2 year in complete molecular remission, being low, the sample size was based on the potential recruitment only. Based on this number of 60 patients, the rates of molecular relapse (without censored follow-up) will be estimated using 95% confidence interval with a maximum range of 26% (rate +/- 13%). Morever, and assuming that the molecular relapse rate will be around 50% within one year, as for adult patients, the expected number of molecular relapse will be around 30. This number of event will allow some prognostic studies.

6.4

Stopping rules:

In addition to potential amendments which could be derived from the recommendations of the DSMB, during the trial any progression to accelerated or blastic phase while Imatinib is stopped according to the trial recommendations, will lead to discontinuation of the study.

6.5

Data Security Monitoring Board

A Data Security/Safety Monitoring Board (DSMB) is established to perform ongoing safety surveillance and to perform interim analyses on the safety data and efficacy of treatment. The independent DSMB committee is formed by two clinicians and one statistician who gives recommendations about continuation of the trial as planned. The purpose of this paragraph is to describe the roles and responsibilities of the independent DSMB for this trial. The aim of the DSMB is to protect and serve trial patients and to assist and advise Principal Investigators so as to protect the safety and monitor the overall conduct of the trial. The conduct of the trial will be assessed by the DMSB in relation to the safety monitoring stopping guidelines (paragraph 9.1). The DMSB will meet at least yearly, or more frequent when necessary according to the safety guidelines. The DMSB will be informed about the conduct of the trial, and interim analysis and suspected (unexpected or expected) serious adverse events with annual reports before their meeting or more frequent when necessary. The DMSB will report each year after their meeting to the Steering committee their conclusions and advices.

7

OPERATIONAL ASPECTS AND DATA MANAGEMENT

Each participating group will refer to the contact person of the group and to the usual network of the clinical centres, data centre and experts for the application of this protocol, the monitoring of the data collection and data quality. The coordinating Investigator, the regional coordinators and the Trial Office DCOG will act as a Coordination Unit for the monitoring and exchange of information and for pooling of the data. More specifications will follow by the head of the DCOG Trial Office, such as that each group will use the data collection forms designed for this protocol, centralize the forms in its own group data centre for quality checks and input, collect and keep it its own data in the common study database. Each group is required to register each new patient with CML, report immediately each event to its own group data centre and to the regional coordinator and to the Trial Office at the DCOG. Case Report Forms (CRFs) about diagnosis, different treatment phases, toxicity and followup should be filled in. Each participating center in the specific countries submits CRFs to the national Trial Office. After visual checks, the CRFs are sent to the DCOG from there on. At the DCOG Trial Office, the CRFs are entered in a secure database. The data is checked visually for consistency and completeness when entered in the database. Thereafter, validation checks will be performed. The following rules for completing paper CRFs have to be observed: CRFs are to be filled in with a blue/black ballpoint pen in clear handwriting. Mistakes are to be cancelled by a simple horizontal line and correction is to be written above or next to it. The correction has to be signed and dated. Data fields which cannot be completed due to missing information have to be marked and commented. Every first page of the CRF starts with the patient unique registration number and date of birth. Every last page of the CRF ends with the date of completion and signature of the local data manager. All requested data fields should be answered completely; even if there is no major change from a previous examination. At all times the local investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered.

Time points for submitting CRFs CRF: 1 month after inclusion into this trial, CRF at 3 monthly intervals, until 24 months, CRF at molecular relapse and restart of treatment, CRFs concerning a SAE, immediately after occurrence of SAE. See Chapter 12 Patient safety and event reporting.

CRF’s have to be send to: DCOG Trial Office POBox 43515 2504 AM The Hague The Netherlands

The archiving of all study relevant documents at the local/national centers and at the DCOG will be handled according to national law. Each patient receives an unique patient number (UPN). All study relevant data will be stored electronically and handled confidentially. The investigators and all members of a trial centre or other persons involved in the trial are obliged to keep study data and information confidential and to grant access only to individuals who are involved in the study. The database will be send to Clinical Investigation Center, Inserm, Poitiers, for statistical analyses as described before. Annual reports are made for the Study Committee and for the Data Safety Monitoring Board. NB. There are plans to use the ProMISe Remote Data Entry System for collecting the necessary information for this protocol. Information will follow at the onset of the trial.

8 PATIENT INFORMATION, INFORMED CONSENT, INSURANCE Before signing the informed consent form the patient and/or his/her parents/legal representatives must be informed about the disease, about discontinuation of treatment according to the clinical trial including estimated duration, possible effects of the discontinuation of treatment, and the assessment required for the start of discontinuation and about alternative treatment options. The patients and/or their parents/legal representatives must have sufficient time to decide about trial participation and must have the opportunity to ask all questions they may have concerning the trial before signing the consent form. Informed consent should be obtained according to national and institutional regulations. The informed consent should ask for permission to send data about the clinical characteristics and outcome to the DCOG and for storing biological material for (future) leukemia-specific studies. The signature of the legal representative is required for children and adolescents below 18 years. Consent can be withdrawn at any time. Insurance Each country will organize their own insurance for patients following the regulations in each country. For the participating institutes in the Netherlands regulations and procedures will be followed as mentioned below. For the Netherlands (in dutch): Ingevolge art. 7 van de Wet medisch wetenschappelijk onderzoek met mensen (Stbl. 1998, 161) is voor de deelnemende proefpersonen een verzekering afgesloten die de door het onderzoek veroorzaakte schade door dood of letsel van de deelnemende proefpersonen dekt. Deze verzekering voldoet aan de bepalingen van het Besluit verplichte verzekering bij medisch-wetenschappelijk onderzoek met mensen (Stbl. 2003, 266). Aan het onderzoek deelnemende proefpersonen zullen schriftelijk worden ingelicht over deze verzekering. Elke aan het onderzoek participerende instelling draagt zorg voor de verzekering van de in de eigen instelling te includeren proefpersonen.

9

PATIENT SAFETY AND EVENT REPORTING

Feasibility and adherence to the discontinuation of Imatinib will be reported for all trial subjects. Each CML patient must be carefully monitored during the course of the protocol. Necessary assessments will include physical examinations, vital signs (systolic/diastolic blood pressure, pulse rate, and body temperature), clinical laboratory tests (hematology, BCR/ABL measurements), and reported or observed adverse events. CRF reporting after discontinuation of Imatinib Every 3 month a CRF has to be filled out for the time period until 24 month after discontinuation of Imatinib. For this special trial “discontinuation of Imatinib”, a molecular relapse is a situation which need urgent reporting in 72 hours after this event occurred. So, a molecular relapse requires expeditious handling and reporting (within 72 hours after occurrence) to DCOG Trial Office to comply with trial requirements. SAE reporting by FAX: . please use the fax: 0031 - 70 - 359 8718 (DCOG Trial Office) and to the investigator in your own country Collection of complete information concerning molecular relapses is extremely important.

Toxicity Reporting in case Imatinib is restarted For every time point (1, 3, 6 months) there is a CRF which has to be filled out together with a toxicity form. In the toxicity forms known side effects of the applied drugs are listed and ranked according to severity from 1, mild severity to 5, death (adapted from NCI Common Toxicity Criteria). In addition, an event that meets the criteria of serious adverse event should also be reported on a SAE form within 48 hours at the DCOG Trial Office (for events in the Netherlands) or the trial office in the various countries (appendix 1). Adverse events in case Imatinib is restarted Adverse events (AEs) are defined as any untoward medical occurrence in a patient or a clinical investigation subject administered a pharmaceutical product, and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related. Pre-existing conditions which worsen during a study are to be reported as AEs. AEs will be assessed continuously and graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (a copy can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html). Frequency and severity, and outcomes of AEs will be determined.

The causality relationship of the drug to the AEs will be assessed by the coordinating investigator as either: 1. Certain: There is a reasonable causal relationship between the drug treatment and the AE. The event responds to withdrawal of study treatment (dechallenge), and recurs with rechallenge when clinically feasible. 2. Probable: There is a reasonable causal relationship between the treatment and the AE. The event responds to dechallenge. Rechallenge is not required. 3. Possible: There is reasonable causal relationship between the treatment and the AE. Dechallenge information is lacking or unclear. 4. Not likely: There is a temporal relationship to treatment administration, but there is not a reasonable causal relationship between the treatment and the AE. 5. Not related: There is not a temporal relationship to treatment administration (too early, or late, or study drug not taken), or there is a reasonable causal relationship between another drug, concurrent disease, or circumstance and the AE. AEs should be followed to resolution or stabilization, and reported as SAEs as they become serious. Serious Adverse Event The definition of a Serious Adverse Event (SAE) is an adverse event occurring at any dose and resulting in one of the following outcomes: (a) death, (b) is life threatening, (c) an unexpected admission to hospital or unexpected prolongation of existing hospitalization, (d) a persistent or significant disability or incapacity to conduct normal life’s functions, (e) a congenital anomaly or birth defect in the offspring. Every SAE can be classified as expected or unexpected. Expected SAEs are toxic reactions described in the drug information. An unexpected SAE is all toxicity that does not meet the description for expected SAE or the nature/ severity of the event is not consistent with the applicable drug information. A SAE report should be completed for any event where doubt exists regarding its status of seriousness. Adverse Event Monitoring and Reporting The principal investigator is responsible for monitoring the safety of patients who enroll in the study. All AEs occurring after any administration of the drug will be followed until resolution. The descriptions and grading scales found in the revised NCI CTCAE version 3.0 will be used for adverse event reporting. A copy of the CTCAE version 3.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html). Adverse events need to be reported until 60 days after the end of the trial, or until another treatment regimen is started, whichever occurs first. However, in the case of AEs occurring later than this deadline but which are considered related to the study by the investigator, such AEs still need to be reported. Reporting Serious Adverse Events All SAEs occurring during the study or within 30 days after the end of the trial must be reported to the principal investigator within 24 hours of occurrence. Adverse events classified as "serious" must be recorded on the SERIOUS AE (SAE) page of the CRF and

require expeditious handling and reporting (within 48 hours after occurrence) to DCOG Trial Office to comply with regulatory requirements. SAE reporting by FAX: . In case of initial SAE-reporting, please use the fax: 0031 - 70 - 359 8718 (DCOG Trial Office) and to the investigator in your own country Collection of complete information concerning SAEs is extremely important. If only limited information is initially available, follow-up reports are required. Thus, follow-up information which becomes available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge summaries and autopsy reports), should be collected subsequently, if not available at the time of the initial report, and immediately sent using the same procedure as the initial SAE report. For ongoing SAEs a follow-up report should be sent at least oncemonthly. The investigator is responsible for submitting these follow-up reports for all SAEs, until the SAE has resolved or until the patient’s condition stabilizes (in the case of persistent impairment), or the patient dies. The principal investigators are responsible for reporting SAEs/SUSARS to the IRB or other applicable regulatory authority. In accordance with local regulations, the DCOG Trial Office will notify Investigators of all AEs that are serious, unexpected, and certainly, probably, or possibly related to the trial. This notification will be in the form of a SUSAR report. Upon receiving such notices, the Investigator must review and retain the SUSAR reports with the Investigator Brochure. Where required by local regulations or when there is a central Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study, the Sponsor will submit the SUSAR report to the appropriate IRB/IEC. The sponsor, together with the principal investigators, will determine if the informed consent requires revision. Forms are available in Appendix

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Marin D, Kaeda J, Szydlo R et al. Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse. Leukemia. 2005;19:507-512. Merx K, Muller MC, Kreil S et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia. 2002;16:1579-1583. Millot F, Guilhot J, Nelken B et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia. 2006;20:187-192. Millot F et al, Imatinib Is Efficient but Has a Negative Impact On Growth in Children with Previously Untreated chronic Myelogenous Leukaemia (CML) in Early Chronic Phase (CP): Results of the French National Phase IV Trial.ASH abstract 2009; 114: 863. Morley, Alexander A., Bartley, Paul, Ross, David M, Latham, Sue, Martin-Harris, Henry, Budgen, Brad, Wilczek, Vicki, Branford, Susan, Hughes, Timothy: DNA-Based Monitoring of Minimal Residual Disease(MRD) in Chronic Myeloid Leukemia(CML). ASH Abstracts 2008 112: 1111 Müller MC, Cross NC, Erben P, Schenk T, Hanfstein B, Ernst T, Hehlmann R, Branford S, Saglio G, Hochhaus A. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009 Nov;23(11):1957-63. O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New England Journal of Medicine. 2003;348:994-1004. Olavarria E, Craddock C, Dazzi F et al. Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation. Blood. 2002;99:3861-3862. Pavlu J, Szydlo R, Goldman J, Apperley J. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117: 755-763. Pulsipher MA. Treatment of CML in pediatric patients: Should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy? Pediatric Blood & Cancer. 2004;43:523-533. Ross, Davi D M, Grigg, Andrew, Schwarer, Anthony, Arthur, Christopher, Loftus, Kerryn, Mills, Anthony K, Filshie, Robin, Columbus, Ruth, Reynolds, John, Seymour, John F, Branford, Susan, Hughes, Timothy: The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early. ASH Abstracts 2008 112: 1102

Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, Blanchet O, Marit G, Gluckman E, Reiffers J, Gardembas M, Mahon FX. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007 Jan 1;109(1):58-60. Russo, Domenico, Rosti, et al: Phase II Multicentric Explorative Study of Intermittent Imatinib (IM) Treatment (INTERIM) in Elderly Patients with Ph+ Chronic Myeloid Leukemia (CML) Who Achieved a Stable Complete Cytogenetic Response (CCgR) with Standard IM Therapy. ASH Abstracts 2009 114: 860 Sawyers CL, Hochhaus A, Feldman E et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530-3539. Shah NP, Tran C, Lee FY et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401. Schmid H, Jaeger BA, Lohse J, Suttorp M: Longitudinal growth retardation in a prepupertal girl with chronic myeloid leukemia on long-term imatinib treatment. (Letter to the editor). Haematologica; 94: 1177-1179 (2009) Suttorp M, Claviez A, Bader P, Peters C, Gadner H, Ebell W, Dilloo D, Kremens B, Kabisch H, Führer M, Zintl F, Göbel U, Klingebiel T: Allogeneic stem cell transplantation for treatment of chronic myeloid leukemia in pediatric and adolescent patients: results of the prospective trial CML-paed I. Klin Padiatr 221:351-357 (2009) Suttorp M, Yaniv I, Schultz K: Controversies in the treatrnent of CML in children and adolescents: TKI versus BMT? Biol Blood Marrow Transplant 17:S115-S122 (2011) Suttorp M, Millot F: Treatment of Pediatric Chronic Myeloid Leukemia in the year 2010: Use of Tyrosine Kinase Inhibitors and Stem Cell Transplantation. Hematology - ASH Educational Program 2010; p368-376 Talpaz M, Silver RT, Druker BJ et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928-1937. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-2302. Verma D, Kantarjian H, Jain N, Cortes J. Sustained complete molecular response after imatinib discontinuation in a patient with chronic myeloid leukemia not previously exposed to interferon alpha. Leuk Lymphoma. 2008 Jul;49(7):1399-402.

Appendix 1. (Serious) adverse Event report form; will follow at the onset of the trial. 2. Patient information form; included the Dutch version; English translation version will follow at the onset of the trial. 3. Data monitoring form; will follow at the onset of the trial 4. List of reference laboratories from the Muller et al Leukemia 2009, 23: 1957-1963. 5. Dutch laboratory appendix specific for the Netherlands

2.

Patient information form; the Dutch version Patiënteninformatiebrief International STOPIMAPED studie

Officiele titel: “An international collaborative study to discontinue Imatinib/Glivec® in pediatric CML patients with sustained complete molecular response” Geachte mevrouw, heer, Inleiding Bij uw kind is eerder een (Philadelphia chromosoom positieve) Chronische myeloide leukemie (CML) vastgesteld. Uw kind wordt behandeld met Imatinib (merknaam Glivec). Waarom deze studie? CML is een zeldzame ziekte bij kinderen: 2% van alle leukemieën bij kinderen jonger dan 15 jaar en 9% bij kinderen van tussen 15 en 19 jaar is CML. De tegenwoordige behandeling bestaat uit een remmer zoals het medicijn Imatinib, zowel bij volwassenen als kinderen. Recent zijn er verschillende lange termijn effecten beschreven in studies bij volwassenen en in enkele studies bij kinderen die behandeld worden met Imatinib. Deze effecten zijn vooral verminderde groei ontwikkeling, afwijkende bot samenstelling en incomplete puberale ontwikkeling. Deze complicaties op de lange termijn worden bij een minderheid van de patiënten waar genomen. Op dit moment is een internationale registratie geopend om dit voor kinderen met een CML te registreren. Door de bijwerkingen op de lange termijn is het raadzaam te onderzoeken of uiteindelijk de behandeling met Imatinib kan worden gestaakt. In de huidige studie waar uw medewerking voor wordt gevraagd is het voorstel om onder goed gecontroleerde omstandigheden de Imatinib te staken. Door de zeldzaamheid van de ziekte bij kinderen, is dit een internationale studie waar vele landen over de wereld in samenwerken. Veel volwassenen beëindigen zelf de Imatinib met soms goed resultaat. Intussen zijn er veelbelovende resultaten beschreven in kleine aantallen volwassenen, die de Imatinib hebben beëindigd. Namelijk bij 40% van de volwassenen is de ziekte niet terug gekomen. Dat betekent dat de kans dan erg groot is dat de ziekte ook op de lange termijn wegblijft en medicijnen niet meer nodig zijn. De patiënten die de ziekte na het staken van het gebruik van Imatinib toch terugkrijgen krijgen dat meestal binnen 6 a 7 maanden na het beëindigden van de Imatinib. Alle patiënten met een terugval werden opnieuw behandeld met Imatinib of een soortgelijk middel en kwamen weer goed onder controle.

Deze internationale studie zal vaststellen wat het effect is van het beëindigen van het medicijn Imatinib bij (Philadelphia chromosoom positieve) CML patiënten. Wat houdt deze behandeling in? Het stoppen van de behandeling met Imatinib onder zorgvuldige controle met behulp van bloed en/of beenmerg bepalingen. Als er sprake is van voortdurende complete moleculaire remissie (ziekte vrij) dan zullen de controles steeds minder frequent in de tijd worden. Imatinib zal dan niet herstart worden. Bij de groep die wel een terugval krijgt zal de Imatinib of een soortgelijk medicijn naar keuze van de behandelende dokter herstart moeten worden. Uit eerder gegevens bij volwassenen blijkt dat na de herstart van een dergelijk medicijn de CML weer goed reageert. Wat zijn de voor- en nadelen van deelname aan het onderzoek?

Voordelen: - de kinderen worden minder blootgesteld aan extra bloed en/of beenmerg puncties als ze uiteindelijk ook geen behandeling meer behoeven na de studie; - Minder lange termijn effecten. Nadelen: - kans op terugval van de ziekte tijdens de onderzoeksperiode maar deze is weer behandelbaar zoals eerdere studie van de volwassen groep patiënten liet zien. Vrijwillige deelname en toestemming Deelname aan het onderzoek horend bij het STOPIMAPED studie is vrijwillig. Voordat we met het stoppen van de Imatinib beginnen vragen we u een toestemmingsformulier te ondertekenen waarin staat dat u weet wat behandeling volgens het STOPIMAPED protocol inhoudt en wat de mogelijke voor- en nadelen zijn. Als u besluit dat uw kind niet meedoet aan het onderzoek dan heeft dit geen invloed op de zorg en aandacht die uw kind in het kader van zijn behandeling krijgt. De behandeling gaat dan verder volgens de huidige standaardbehandeling. Ook vragen wij uw toestemming om de gegevens over het verloop van de behandeling en het opgeslagen restmateriaal te mogen gebruiken voor wetenschappelijk onderzoek. U krijgt voldoende tijd om hierover na te denken (minimaal 7 dagen) en u kunt te allen tijde om extra informatie vragen of op eenmaal genomen beslissingen terugkomen. Wanneer uw kind meedoet, kunt u op ieder moment stoppen, zonder opgaaf van redenen. De onderzoeker kan het onderzoek beëindigen als het in het belang van de gezondheid van uw kind is. Na ondertekening zal u een kopie van het ondertekende toestemmingsformulier worden meegegeven.

Verzekering Er is een verzekering afgesloten voor onverwachte schade die u lijdt door uw deelname aan dit wetenschappelijk onderzoek. Het betreft de schade door letsel of overlijden die zich openbaart gedurende de deelname aan dit onderzoek en de schade die zich openbaart binnen vier jaar na beëindiging van deelname aan dit onderzoek. Het bedrag waarvoor de verzekering is afgesloten is maximaal € 5.000.000,- voor de totale schade die zich per verzekeringsjaar bij proefpersonen heeft geopenbaard bij alle onderzoek dat door het Universitair Medisch Centrum Groningen en Rijksuniversiteit Groningen wordt verricht, maximaal € 3.500.000,- voor de totale schade bij dit onderzoek en maximaal € 450.000,- per proefpersoon. Bepaalde soorten van schade kennen wettelijk gelimiteerde vergoedingen. Van de dekking door de verzekering is uitgesloten: schade van te verwachten risico's zoals beschreven in de schriftelijke informatie voor proefpersonen, tenzij deze ernstiger zijn dan beschreven; bij deelname door patiënten: schade door verslechtering van de gezondheid of het uitblijven van de verbetering van de gezondheid; schade waarvan (nagenoeg) zeker is dat deze zich bij de proefpersoon zal voordoen; schade door aantasting van de gezondheid van de proefpersoon die zich ook geopenbaard zou hebben wanneer de proefpersoon niet aan dit onderzoek had deelgenomen; schade die zich bij nakomelingen openbaart als gevolg van een nadelige inwerking van het onderzoek op het genetisch materiaal van de proefpersoon; De verzekering is afgesloten bij de Onderlinge Waarborgmaatschappij Centramed, Postbus 191, 2270 AD Voorburg onder polisnummer 624.529.102. Indien u schade heeft geleden of het vermoeden daarvan heeft, dient u zich direct met Prof. dr. E.J.S.M. de Bont (lid van het onderzoeksteam) telefoonnummer 050-3614213 in verbinding te stellen en zijn aanwijzingen op te volgen. Ook kunt u in zo’n geval contact op te nemen met de juridisch stafmedewerker van het UMCG bereikbaar via telefoonnummer 050-3614929 of 050-3614304. Verantwoording en vertrouwelijkheid Voor het onderzoek verzamelen wij algemene patiëntgegevens. Alle gegevens van uw kind zullen zorgvuldig en vertrouwelijk worden behandeld. Inzage in de oorspronkelijke medische dossiers is slechts voorbehouden aan daartoe geautoriseerde en gekwalificeerde medewerkers van het trialbureau van SKION. Ook is het mogelijk dat medewerkers van de Inspectie voor de Gezondheidszorg of bevoegde inspecteurs van een buitenlandse overheid en leden van de Medisch Ethische Toetsings Commissie inzage krijgen. Dit kan nodig zijn om de betrouwbaarheid en kwaliteit van het onderzoek na te gaan. Onderzoeksgegevens zullen worden gehanteerd met inachtneming van de Wet Bescherming Persoonsgegevens en het privacyreglement van SKION. Alle medische gegevens en lichaamsmaterialen die worden verzameld zullen van een codenummer worden voorzien.

Persoonsgegevens (zoals naam en adres) zullen niet gebruikt worden in studiedocumentatie, in rapporten of publicaties over onderzoek. De uiteindelijke resultaten van onderzoek worden gerapporteerd in medisch-wetenschappelijke literatuur en/of op medische congressen. Voor dit onderzoek is goedkeuring verkregen van een erkende Medisch Ethische Toetsing Commissie en van de Raad van Bestuur van het ziekenhuis waar de behandeling plaatsvindt. De voor dit onderzoek geldende internationale richtlijnen zullen nauwkeurig in acht worden genomen. Ook uw huisarts wordt van de behandeling op de hoogte gebracht. Wanneer dat voor u een probleem is kunt u dat ter sprake brengen met uw behandelend kinderarts-oncoloog.

Vragen, klachten Bij vragen of opmerkingen kunt u contact opnemen met uw behandelend kinderartsoncoloog of met Prof. Dr. E.S.J.M de Bont Afdelingshoofd Kinderoncologie/-hematologie Beatrixkinderkliniek UMCG, telefonisch bereikbaar via 050-3614213. Als u, los van de onderzoeker, nadere informatie wenst over het onderzoek, kunt u een onafhankelijk arts raadplegen die niet zelf betrokken is bij dit onderzoek maar wel deskundig op dit gebied is. U kunt hiervoor contact opnemen met mevrouw Prof. Dr. J.C. Kluin, hematoloog, tel. 050-3611644 Na ondertekening van het toestemmingsformulier behorend bij deze patiënteninformatie ontvangt u hiervan een kopie. Wanneer uw kind tussen de 12 en 18 jaar is, moet hij of zij zelf ook toestemming geven voor deelname aan dit onderzoek.

Toestemmingsformulier STOPIMAPED studie Door dit toestemmingsformulier te tekenen verklaar ik het volgende: Ik ben goed geïnformeerd, zowel mondeling als schriftelijk. Ik heb de gelegenheid gehad vragen te stellen en heb de informatie goed begrepen. Ik heb begrepen dat ik door de onderzoeker op tijd op de hoogte wordt gesteld als er nieuwe informatie beschikbaar komt die van belang is. Ik heb begrepen dat deelname aan het onderzoek geheel vrijwillig is en dat ik te allen tijde verdere deelname kan weigeren, zonder dat dit gevolgen heeft voor de verdere behandeling van mijn kind of de relatie met de behandelend arts. Ik begrijp dat bevoegde personen, tijdens of na het onderzoek inzage kunnen hebben in het medisch dossier van mijn kind. Mij is meegedeeld dat mijn kind voor onvoorziene schade voortvloeiend uit deelname aan dit onderzoek verzekerd is volgens Nederlands recht. Ik ben ervan op de hoogte dat mijn huisarts wordt geïnformeerd over de behandeling. Ik heb kennisgenomen van de folder ‘SKION en medisch-wetenschappelijk onderzoek’. Eventuele aanvullende vragen zijn voldoende beantwoord. 1.

Ik geef wel / geen * toestemming voor behandeling volgens dit onderzoek.

2.

Ik geef wel / geen * toestemming dat gegevens van mij/mijn kind worden opgeslagen en verwerkt ten behoeve van controle op de kwaliteit van behandeling, wetenschappelijk onderzoek of statistiek, onder de voorwaarden zoals beschreven in de folder.

3.

Ik geef wel / geen * toestemming dat het diagnostisch materiaal dat bij SKION is opgeslagen kan worden gebruikt ten behoeve van wetenschappelijk onderzoek, onder de voorwaarden zoals beschreven in de folder.

4.

Ik geef wel / geen * toestemming dat ten behoeve van wetenschappelijk onderzoek de databestanden van SKION te combineren met gegevens die elders bekend zijn, zoals de doodsoorzakenstatistiek bij het CBS of de Nederlandse Kankerregistratie, onder de voorwaarden zoals beschreven in de folder.

Naam patiënt:

……………………………………

Geboortedatum:

………………………

Naam ouder/voogd

Handtekening

……………………………..

………..……………..….

Naam ouder/voogd (indien van toepassing)

Handtekening

……………………………..

………..……………..….

Datum ………..…………….. Datum ………..……………..

Als behandelend arts verklaar ik dat ik bovengenoemde deelnemer heb uitgelegd wat het onderzoek inhoudt en dat ik borg sta voor de vertrouwelijke omgang met zijn / haar gegevens. Naam arts

Handtekening

……………………………..

………..……………..…

Datum .……………………..

Na ondertekening zal u een kopie van het ondertekende toestemmingsformulier worden meegegeven. * doorhalen wat niet van toepassing is.

Patiënteninformatiebrief International STOPIMAPED studie Officiele titel: “An international collaborative study to discontinue Imatinib/Glivec® in pediatric CML patients with sustained complete molecular response” Informatie voor kinderen en jong volwassenen vanaf 12 jaar Beste ___________, Inleiding Je bent bij de afdeling kinderoncologie onder behandeling voor CML (Chronische myeloide leukemie).

Waarom deze studie? CML komt zeer weinig voor bij kinderen. De huidige behandeling bestaat uit een medicijn dat Imatinib heet. Uit studies met volwassenen en kinderen is gebleken dat Imatinib een aantal lange termijn effecten kan hebben bijvoorbeeld bij de groei en bij ontwikkelingen in de puberteit. Dat willen we daar waar mogelijk voorkomen. In dit onderzoek willen we onderzoeken of Imatinib te stoppen is en de ziekte dan niet terugkomt . Doordat de ziekte heel weinig voorkomt bij kinderen is het noodzakelijk om dit soort studies te doen in aan samenwerkende internationale studies. Dit betekent dat ook kinderziekenhuizen uit andere Europese landen mee werken aan dit onderzoek. Het voorstel van deze studie is om na langdurig gebruik te stoppen met het medicijn Imatinib onder goede begeleiding. We hebben bij volwassenen gezien dat de ziekte na het stoppen van het medicijn Imatinib bij een grote groep niet meer terug komt. Dat betekent dat de kans dan erg groot is dat de ziekte ook op de lange termijn wegblijft en medicijnen niet meer nodig zijn. De kinderen die de ziekte toch terugkrijgen na het stoppen van de Imatinib zullen opnieuw behandeld worden met Imatinib of een soortgelijk middel. We verwachten dan dat de ziekte weer onder controle zal komen. Deze internationale studie zal vaststellen wat het effect is van het stoppen van het gebruik van het medicijn Imatinib bij kinderen.

Wat houdt deze behandeling in?

Het stoppen van de behandeling met Imatinib onder controle van bepalingen in bloed en/of beenmerg. Als er sprake is van voortdurend en compleet wegblijven van de ziekte, dan zullen de controles steeds minder worden. Gebruik van het medicijn Imatinib zal dan niet herstart worden. Bij die kinderen die de ziekte weer terug krijgen, zal het medicijn Imatinib (of een soortgelijk medicijn naar keuze van de behandelende dokter) herstart worden. Uit eerdere gegevens bij volwassenen blijkt dat na de herstart de ziekte CML weer goed reageert op het medicijn. Wat zijn de voor- en nadelen van deelname aan het onderzoek?

Voordelen: - je zult minder extra bloed en/of beenmerg puncties moeten doen als de ziekte na de studie periode weg blijft; - je hebt geen last van eventuele bijwerkingen op de lange termijn. Nadelen: - er is kans dat de ziekte terug komt, maar deze is weer goed te behandelen. Vrijwillige deelname en toestemming Toestemming voor STOPIMAPED studie is vrijwillig. Als je niet aan de STOPIMAPED wilt deelnemen dan hoef je daar geen reden voor te geven. Als je ouder bent dan 12 jaar moeten jij en je ouders/verzorgers samen beslissen of je toestemming geeft voor deelname de studie. Zowel jij als je ouders/verzorgers moeten een handtekening zetten onder het toestemmingsformulier. In dit formulier staat dat je weet wat deze studie inhoudt. Je krijgt voldoende tijd om hierover na te denken (minimaal 7 dagen) en je kunt nog altijd om extra informatie vragen. Het toestemmingsformulier is toegevoegd aan de informatiebrief die je ouders gekregen hebben. Wanneer je niet dezelfde mening hebt als je ouders/verzorgers kun je dit bespreken met je behandelend arts. Verzekering Er is een verzekering afgesloten voor het geval er iets gebeurt dat we niet verwachten en waarvan je schade ondervindt. Voor verdere informatie over de verzekering, zie het informatieformulier voor je ouders/verzorgers.

Verantwoording en vertrouwelijkheid Een aantal personen mogen jouw medische gegevens en de gegevens van het onderzoek zien. Deze personen mogen de gegevens gebruiken voor dit onderzoek, maar zij mogen de

gegevens alleen bekend maken zonder jou naam of andere zaken die herkenning mogelijk maken. Hiervoor hebben we aparte formulieren waarop alleen een nummer staat. Als we over het onderzoek schrijven, komt er nooit een naam in het stuk voor. Het kan nodig zijn dat gecontroleerd wordt of alles goed wordt genoteerd. Dan worden de ingevulde formulieren door anderen dan dokters vergeleken met de gegevens in je ziekenhuispapieren. Dat gebeurt ook vertrouwelijk zodat anderen niets van je te weten komen. Normaal gesproken mag alleen jou behandelend arts en zijn/haar team jou gegevens inzien. Als je meedoet met dit onderzoek gaan meer mensen jouw medische gegevens en onderzoeksgegevens bekijken. De personen die jou medische en onderzoeksgegevens kunnen gaan bekijken zijn: de medewerkers van het onderzoeksteam de mensen van de toetsingscommissie die de studie heeft goedgekeurd, de bevoegde medewerkers van de Inspectie voor de Gezondheidszorg, bevoegde inspecteurs van een buitenlandse overheid. De onderzoeksgegevens worden, als jij en je ouders/verzorgers daar toestemming voor geven, 20 jaar bewaard. Dit is om alles goed te kunnen onderzoeken. De onderzoeksresultaten worden opgeschreven in medisch-wetenschappelijke teksten en/of op medische bijeenkomsten.

Vragen, klachten Bij vragen of opmerkingen kun je contact opnemen met de behandelend kinderartsoncoloog of met Prof. dr. E.S.J.M de Bont Afdelingshoofd Kinderoncologie/-hematologie Beatrixkinderkliniek UMCG, telefonisch bereikbaar via 050-3614213. Als je, los van de onderzoeker, meer informatie wenst over het onderzoek, kun je een onafhankelijk arts raadplegen die niet zelf betrokken is bij dit onderzoek maar wel deskundig op dit gebied is. U kunt hiervoor contact opnemen met mevrouw Prof.dr. J.C. Kluin, hematoloog, telefonisch bereikbaar via het algemene UMCG nummer 050-3616161. Neem de tijd om deze informatie door te spreken en aarzel niet om je vragen te stellen. Als je besluit om met het onderzoek mee te doen dan krijgen jij en je ouders een kopie van dit document, nadat jij, je ouders en de behandelend arts het formulier allen getekend hebben.

Toestemmingsformulier STOPIMAPED studie Door dit toestemmingsformulier te tekenen verklaar ik het volgende: Ik ben goed geïnformeerd, zowel mondeling als schriftelijk. Ik heb de gelegenheid gehad vragen te stellen en heb de informatie goed begrepen. Ik heb begrepen dat ik door de onderzoeker op tijd op de hoogte wordt gesteld als er nieuwe informatie beschikbaar komt die van belang is. Ik heb begrepen dat deelname aan het onderzoek geheel vrijwillig is en dat ik te allen tijde verdere deelname kan weigeren, zonder dat dit gevolgen heeft voor mijn verdere behandeling of de relatie met mijn behandelend arts. Ik begrijp dat bevoegde personen, tijdens of na het onderzoek inzage kunnen hebben in mijn medisch dossier. Mij is meegedeeld dat onvoorziene schade voortvloeiend uit deelname aan dit onderzoek verzekerd is volgens Nederlands recht. Ik ben ervan op de hoogte dat mijn huisarts wordt geïnformeerd over de behandeling. 1.

Ik geef wel / geen * toestemming voor behandeling volgens dit protocol.

2.

Ik geef wel / geen * toestemming dat mijn gegevens worden opgeslagen en verwerkt ten behoeve van wetenschappelijk onderzoek, onder de voorwaarden zoals beschreven in de patiënteninformatiebrief.

3.

Ik geef wel / geen * toestemming dat het diagnostisch materiaal dat bij SKION is opgeslagen kan worden gebruikt ten behoeve van wetenschappelijk onderzoek, onder de voorwaarden zoals beschreven in de patiënteninformatiebrief.

4.

Ik geef wel / geen * toestemming om ten behoeve van wetenschappelijk onderzoek de databestanden van SKION te combineren met gegevens die elders bekend zijn, bijvoorbeeld bij het Centraal Bureau voor de Statistiek, onder de voorwaarden zoals beschreven in de patiënteninformatiebrief.

Naam patiënt:

……………………………………

Geboortedatum: ………………………

Handtekening

Datum

………..……………..….

………..……………..

Als behandelend arts verklaar ik dat ik bovengenoemde deelnemer heb uitgelegd wat het onderzoek inhoudt en dat ik borg sta voor de vertrouwelijke omgang met zijn / haar gegevens. Naam arts

Handtekening

Datum

……………………………………

………..……………..….

………..……………..

Na ondertekening zal u een kopie van het ondertekende toestemmingsformulier worden meegegeven. * doorhalen wat niet van toepassing is.

45 IBFM CML studygroup protocol called STOPIMAPED study December 6, 2011

3.

Data monitoring form; will follow at the onset of the trial

46 IBFM CML studygroup protocol called STOPIMAPED study December 6, 2011

4. List of reference laboratories from the Muller et al Leukemia 2009, 23: 1957-1963. Table 3 List of participating laboratories: Country City Name Institution National reference laboratory Austria Vienna Gerlinde Mitterbauer-Hohendanner Ehemalige I. Medizinische Universitae tsklinik x Austria Vienna Thomas Lion Forschungsinstitut fuer krebskranke Kinder Belgium Brussels Hakim El Housni Erasme Hospital x Belgium Leuven Nancy Boeckx University Hospital Gasthuisberg x Croatia Zagreb Renata Zadro Clinical Hospital Center Zagreb x Czech Republic Brno Jiri Mayer University Hospital Brno Czech Republic Olomouc Peter Rohon Dept. of Hemato-oncology x (covers Slovakia) Czech Republic Prague Jana Rulcova UHKT x Denmark Aarhus Lykke Grubach Immunhaematologisk lab. x Denmark Odense Niels Pallisgaard Odense University Hospital Finland Turku Veli Kairisto Turku University Hospital Laboratories x France Bordeaux Francois-Xavier Mahon Universite´ Victor Segalen France Lille Claude Preudhomme Laboratoire d’Hematologie A France Lyon Sandrine Hayette Centre hospitalier Lyon sud France Marseille Jean Gabert Faculte´ de Medecine Nord France Paris Jean-Michel Cayuela Hopital Saint-Louis x Germany Dresden Christian Thiede Universitaetsklinikum Carl Gustav Carus Germany Duesseldorf Frank Neumann Universitaetsklinikum Duesseldorf Germany Frankfurt Heike Pfeifer Universitaetsklinikum Frankfurt Germany Greifswald Frank Schueler Universitaet Greifswald Germany Hamburg Philippe Schafhausen Universitaetsklinikum Hamburg-Eppendorf Germany Hannover Nils von Neuhoff Medizinische Hochschule Germany Jena Thomas Flohr Oncoscreen Germany Kiel Christiane Pott Universitaetsklinik Schleswig-Holstein, Campus Kiel Germany Leipzig Thoralf Lange Universitaetsklinikum Leipzig Germany Mainz Georg He Johannes Gutenberg-Universitaet Mainz Germany Mannheim Martin Muller/Andreas Hochhaus Universitaet Heidelberg, Universitaetsmedizin Mannheim x Germany Muenchen Susanne Schnittger Muenchner Leukaemie Labor Germany Muenster Utz Krug Universita¨ tsklinikum Mu¨ nster Germany Ulm Frank Stegelmann Universitaetsklinikum Ulm Greece Athens Katerina Zoi Foundation for Biomedical Research x Hungary Budapest Hajnalka Andrikovics National Center of Blood Transfusion Services x Israel Tel-Hashomer Tali Tohami Chaim Sheba Medical Center x Italy Bologna Giovanni Martinelli University of Bologna Italy Naples Fabrizio Pane CEINGE Italy Turin Giuseppe Saglio Ospedale Universita‘ di Torino x Lithuania Vilnius Mindaugas Stoskus Vilnius University Hospital Santariskiu Clinics Netherlands Amsterdam Jeroen Janssen VU medisch centrum, Afdeling Hematologie Netherlands Rotterdam Peter Valk Erasmus MC, Molecular Diagnostics x Netherlands Rotterdam Vincent van der Velden Erasmus MC, Department of Immunology Norway Tromso/Oslo Dag Andre Nymoen SINTEF x Poland Krakow Tomasz Sacha Katedra i Klinika Hematologii CMUJ x Portugal Lissabon Joana Diamond Instituto Portugues de Oncologia de Lisboa x Romania Bucharest Rodica Talmaci Fundeni Clinical Institute x Russia Moscow Andrey Misyurin Research Center for Hematology x Russia St. Petersburg Michael V. Dubina St. Petersburg State Pavlov Medical University Slovenia Ljubljana Tadej Pajic University Medical Centre Ljubljana x Spain Barcelona Dolors Colomer Unitat d’Hematopatologia, Hospital Clinic x Spain Barcelona Josep Nomdedeu Hospital de la Santa Creu i Sant Pau Sweden Stockholm Gisela Barbany University Hospital Sweden Uppsala Hans Ehrencrona Uppsala University Hospital x Switzerland Bern Elisabeth Oppliger-Leibundgut Inselspital x Turkey Istanbul Ugur O¨ zbek I.U., DETAE x UK Liverpool Richard E. Clark Royal Liverpool University Hospital UK London Letizia Foroni Hammersmith Hospital UK Salisbury Nick Cross Salisbury District Hospital x UK Glasgow Nicola Broster Glasgow Royal Infirmary USA Portland Rick Press Oregon Health & Science Universitys

47 IBFM CML studygroup protocol called STOPIMAPED study December 6, 2011

5.

Dutch laboratory appendix specific for the Netherlands

LABORATORIUMONDERZOEK STOPIMAPED, Nederlandse bijlage Moleculaire diagnostiek Perifeer Bloed Bij aanvang van de studie dient de moleculaire remissie bevestigd te zijn. De nationale principal investigator is verantwoordelijk voor het verzamelen van deze uitslag. Voor moleculaire bepaling van BCR-ABL tijdens de studie dient op onderstaande tijdstippen perifeer bloed naar het SKION laboratorium te worden verzonden. Het SKION draagt zorg voor bewerking en verzending van het materiaal ten behoeve van het nationale gecertificeerde MRDlaboratorium. Benodigd materiaal heparine bloed: 5 ml en EDTA bloed: 5 ml? (DNA bepaling) Tijdstippen afname: Eerste jaar: 4-wekelijkse bepaling van BCR- ABL Tweede jaar: 2-maandelijkse bepaling van BCR-ABL Derde jaar: 3-maandelijkse bepaling van BCR- ABL Vierde en Vijfde jaar: 2-jaarlijkse bepaling van BCR-ABL Bij recidief en herstart imatinib-therapie: Bepaling moleculaire respons 1 – 3 – 6 maanden na herstart therapie Uitslag De uitslag wordt schriftelijk aan de behandelend arts meegedeeld. Instructies voor verzenden Patient telefonisch aanmelden bij de SKION (070-3674545). Hierbij worden naam, geboortedatum en indien van toepassing de (voorlopige) diagnose gemeld, alsmede gegevens over het afgenomen materiaal. Hemoblok: Bloed kan in een, door de SKION verstrekt hemoblok worden verstuurd. Gelieve op het verzendformulier duidelijk aan te geven welk afnamepunt het materiaal betreft. Instructies voor verzending per Fiege (BLS koerier) naar het SKION laboratorium: zie SKION website onder www.SKION.nl/verzenden materiaal

48 IBFM CML studygroup protocol called STOPIMAPED study December 6, 2011