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International Registry

Relapsed AML 2009

Registry of children and adolescents with relapsed or refractory acute myeloid leukemia (AML)

AML-BFM-Study Group

Coordination

Dirk Reinhardt, MD, PhD Ursula Creutzig, MD, PhD

Pediatric Hematology and Oncology Pediatric Hematology and Oncology

Hannover Medical School University Children’s Hospital Münster

Carl-Neuberg-Str. 1 Albert-Schweitzer-Str. 33

D-30625 Hannover D- 48129 Münster

Tel.: +49 (0)511 532 6720 Tel.: +49 (0)511 604 66 77 or +49 (0)511 532 9123

Fax: +49 (0)511 532 9029 Fax: +49 (0)511/604 64 04 or +49 (0)511 532 9029

E-mail: [email protected] E-mail: [email protected]

Gertjan J.L. Kaspers, MD, PhD

Department of Pediatric Hematology/Oncology

VU medical center

De Boelelaan 1117

NL-1081 HV Amsterdam

The Netherlands.

Phone: +31 (0)20 444 2420

Fax: +31 (0)20 444 2422

E-mail: [email protected]

Registry center Statistician

Ursula Bernsmann Martin Zimmermann, PhD


Hannover Medical School Hannover Medical School

Carl-Neuberg-Str. 1 Carl-Neuberg-Str. 1

D-30625 Hannover D-30625 Hannover

Tel.: +49 (0)511 532 9123 E-mail: [email protected]

Fax: +49 (0)511 532 9029


International Registry AML Relapse 2009 / -June ’09 - 2 -

Addresses

Dirk Reinhardt, MD, PhD

Hannover Medical School

Pediatric Hematology and Oncology

Carl-Neuberg-Str. 1

D-30625 Hannover

Tel.: +49 (0)511 532 6720

Fax: +49 (0)511 532 9029


Gertjan J.L. Kaspers, MD, PhD

Department of Pediatric Hematology/Oncology

VU medical center

De Boelelaan 1117

NL-1081 HV Amsterdam

The Netherlands.

Phone: +31 – 20 444 2420

Fax: +31 – 20 444 2422


Ursula Creutzig, MD, PhD


University Children’s Hospital Münster

Albert-Schweitzer-Strasse 33

D-48129 Münster

Germany

Phone: +49 (0)511 604 66 77 or +49 (0)511 532 9123

Fax: +49 (0)511/604 64 04 or +49 (0)511 532 9029


Central Data Office International Statistician

Ursula Bernsmann Martin Zimmermann, PhD


Hannover Medical School Hannover Medical School

Carl-Neuberg-Str. 1 Carl-Neuberg-Str. 1

D-30625 Hannover D-30625 Hannover

Tel.: +49 (0)51 1532 9123 E-mail: [email protected]

Fax: +49 (0)511 532 9029


Geschützte Internetregistrierung: https://aml.mh-hannover.de/amlreg09/


Table of Contents

Abbreviations ........................................................................................................................................ 5

Synopsis .................................................................................................................................... 6

Summary .................................................................................................................................... 7Reference List .......................................................................................................................................... 8

International Registry AML Relapse 2009 ............................................................................. 10Objectives .............................................................................................................................................. 10

Eligibility ................................................................................................................................................. 10

Requested data: ..................................................................................................................................... 10

Reference diagnostics ........................................................................................................................ 11

Material banking ................................................................................................................................. 11

Data management and registration........................................................................................................ 12

Data pooling ....................................................................................................................................... 12

Data Monitoring Committee (DMC)........................................................................................................ 12

Registration Procedure .......................................................................................................................... 12

Ethical considerations ............................................................................................................................ 13

Patient/parent information and informed consent .................................................................................. 14

Registration form .................................................................................................................................... 16

Datenweitergabe .................................................................................................................................... 17

Einwilligungserklärung zur Lagerung und Nutzung biologischen Materials........................................... 18

Recommendations for diagnostics and treatment .............................................................. 25Diagnostics............................................................................................................................................. 25

Clinical evaluation, laboratory tests and follow-up ............................................................................. 25

Criteria of response and other definitions .......................................................................................... 25

Therapy .................................................................................................................................................. 27

Schedule overview ............................................................................................................................. 27

Conditions to start treatment .................................................................................................................. 27

Contradiction for full-dose treatment .................................................................................................. 28

Background and introduction.............................................................................................................. 28

Stem cell transplantation (SCT) ............................................................................................................. 30

Conclusion .......................................................................................................................................... 31

Special measures for reinduction........................................................................................................... 32

REINDUCTION FLAG + DaunoXome® .................................................................................................. 33

2nd REINDUCTION FLAG ...................................................................................................................... 34

CONSOLIDATION - high intensity ......................................................................................................... 35

CONSOLIDATION - low intensity ....................................................................................................... 36

CNS PROPHYLAXIS AND TREATMENT ............................................................................................. 37

Prophylaxis: ........................................................................................................................................ 37

Treatment of CNS leukemia ............................................................................................................... 37

STEM CELL TRANSPLANTATION ....................................................................................................... 37

Overview drugs ...................................................................................................................................... 38

Cytarabine .......................................................................................................................................... 38

Fludarabine......................................................................................................................................... 38

Supportive Care ..................................................................................................................................... 40


General measures .............................................................................................................................. 40

Hyperleukocytosis and metabolic derangement ................................................................................ 40

Prevention and treatment of infections ............................................................................................... 41

G-CSF ................................................................................................................................................ 42

Transfusion support ............................................................................................................................ 42

Cardiotoxicity monitoring .................................................................................................................... 44

Comments:Performance scales ............................................................................................................. 48

Performance scales ............................................................................................................................... 49

Lansky score: 0-16 years ................................................................................................................... 49

Karnofsky score: 16 years and older .................................................................................................. 49


Abbreviations

AML acute myeloid leukemia

ara-CTP arabinosylcytosine 5’-triphosphate

CR complete remission

DNX DaunoXome®

FAB French-American-British classification

FLAG fludarabine, cytarabine and G-CSF

FS fractional shortening

HID haplo-identical donor

ITH intrathecally

IV intravenously

LP lumbar puncture

LV left ventricle

LVET left ventricular ejection time

MRD minimal residual disease

MSD matched sibling donor

MUD matched unrelated donor

NR non response

PR partial response

SC subcutaneously

SCT stem cell transplantation

SF see FS

UNL upper normal level

International Registry AML Relapse 2009 / -June '09

Wichtiger Hinweis!

Die im Register „International Registry Relapsed AML 2009“ beschriebene

Therapiemöglichkeit ist eine Empfehlung der internationalen AML-Rezidiv Studiengruppe

bzw. der AML-I-BFM Gruppe (Leiter Prof. Dr. G. J. Kaspers [Amsterdam] bzw. Dr. David

Webb [London]), basierend auf den Ergebnissen der vorherigen, abgeschlossenen Studien

zur Behandlung von Rezidiven der akuten myeloischen Leukämie (AML) bei Kindern und

Jugendlichen.

Die Durchführung dieser Therapie empfiehlt sich nur an erfahrenen kinderonkologischen

Zentren mit intensivmedizinischer Behandlungsmöglichkeit (Behandlungszentren mit >20

kinderonkologischen Neuerkrankungen pro Jahr, Erfahrungen mit Hyperleukozytose) und an

Zentren mit Erfahrung in der Behandlung von refraktärer und rezidivierter AML im Kindes-

und Jugendalter bzw. Knochenmarktransplantationszentren.

Gemäß der publizierten Ergebnisse und der eigenen Erfahrungen zum Einsatz von

liposomalem Daunorubicin, Fludarabin in Kombination mit Cytarabin und/oder Anthrazyklinen

besteht eine relevante Gefahr für akute, subakute und chronische opportunistische

Infektionen, was Erfahrung in der Diagnostik und Therapie dieser Komplikationen und eine

Langzeitnachbetreuung der Patienten an einem erfahrenen kinderonkologischen Zentrum

erfordert.

Die Erstellung der Therapieempfehlung erfolgte mit größter Sorgfalt, dennoch können

mögliche Fehler nicht vollständig ausgeschlossen werden. Fehler oder Unklarheiten zur

Protokolldurchführung bitten wir umgehend zu melden.

Hiermit wird darauf hingewiesen, dass die Leitung des Registers keine juristische

Verantwortung für mögliche, aus der Anwendung der Therapie resultierende Folgen

übernimmt und der jeweils behandelnde Arzt allein für die Therapie verantwortlich ist.


Synopsis

COORDINATOR Dr. med. Dirk Reinhardt, MD, PhD Pediatric Hematology and Oncology Hannover Medical School Carl-Neuberg-Str.1, 30625 Hannover +495115326720 / FAX +495115329029

Gertjan J.L. Kaspers, MD PhD Department of Pediatric Hematology/Oncology VU medical center De Boelelaan 1117 NL-1081 HV Amsterdam The Netherlands. Phone: +31 – 20 444 2420 Fax: +31 – 20 444 2422 E-mail: [email protected]

located Hannover Medical School, Germany

Registry International Registry Relapsed AML 2009

Registry of relapsed and refractory acute myeloid leukemia (AML) in children and adolescents

CONDITION Relapsed or refractory AML in children and adolescants

OBJECTIVE(S) To register all children and adolescents with relapsed or refractory acute

myeloid leukemia

- incidence and frequency of relapsed and refractory AML

- background for clinical advisement and recommendation

- Data for biological studies concerning

o Diagnosis

o Prognosis

INTERVENTION (S) none

ELIGIBILTY Children and adolescents (age<18 years at diagnosis) with refractory AML or

relapse of AML

OUTCOME(S) Not applicable

TYPE registry

STATISTICAL ANALYSIS Descriptive statistics:

- Incidence of AML relapses

- Biological characteristics

- Prognostics factors

Rational Refractory and relapse AML is rare. The registration of all children and

adolescents with relapsed or refractory AML will assure profound expect advice

concerning diagnostics, prognostic factors, therapy, treatment response and

complications. Central reference diagnostics will improve the quality of diagnosis.

Biological research could be supported with patient’s material and correlated to

clinical course of disease.

SAMPLE SIZE 100 patients per year

DURATION The registry will be closed if any Phase III clinical trial will be open for this patient

group.


Summary

Children and adolescents with relapsed or refractory AML still have an unfavorable prognosis.

Internationally several clinical trials confirmed the efficacy and feasibility of an combined chemotherapy

with anthracyclines and cytarabine (or derivates).

In postremission the need of an allogenic stem cell transplantation is generally accepted. Only in specific

cases (very late relapse and lack of matched donor, insufficient first line therapy) and autologous stem

cell transplantation or even chemotherapy only could be considered. Following prognostic factors of

relapsed AML have been identified:

Duration of first remission, cytogenetics and response to the first re-induction element (analyzed at day

28 by morphology).

In Germany, Austria and the Czech Republic since 1997 different combinations of anthracyclines and

cytarabine have been successfully studied. Both, liposomal daunorubicin and cytarabine (AML Rezidiv

97) and the idarubicin combined with fludarabine, cytarabine and G-SCF showed encouraging efficacy

and limited toxicity1-3. Comparable results have been reported by other groups in children and adults4-15.

The results were the basic for the international Relapsed AML 2001/01 trial. Although the preliminary

analysis of the randomised comparison of L-DNR-FLAG versus FLAG showed no significant advantage

of the overall survival, improved remission and less toxicity supported a benefit of L-DNR/FLAG16-20.

After finishing the international Relapsed AML 2001/01 trial, the patients should be registered to the

“International Registry Relapsed AML 2009”.

The aims are to evaluate the incidence and frequency of relapsed and refractory AML in children and

adolescents, assurance of substantial advisement for therapy, identification of biological and prognostic

factors and the support of associated research projects.

The expected number of patients will be between 25 and 35 (Germany, Austria and Czech Republic).

Zusammenfassung

Rezidivierte und refraktäre akute myeloische Leukämien (AML) bei Kindern und Jugendlichen sind

selten und haben eine ungünstige Prognose. In den letzten Jahren wurden verschiedene Kombinationen

von Chemotherapie in Therapieoptimierungsstudien getestet. Der Einsatz von Antracyclinen kombiniert

mit Cytarabin bzw. Cytarabinderivaten hat dabei in verschiedenen Studien bei Kindern und Jugendlichen

die besten Remissionsraten und Überlebenschancen ergeben. Allgemein akzeptiert ist die

Notwendigkeit der allogenen Stammzelltransplantation als Postremissiontherapie. Unter bestimmten

Umständen wie z.B. einem sehr späten Rezidiv und fehlendem gut passenden Spender kommen auch

autologe Stammzelltransplantation oder nur chemotherapeutischen Ansätze infrage.

Als prognostische Faktoren für ein Rezidiv der AML gelten: Dauer der 1. Remission; Zytogenetik und

insbesondere das Ansprechen auf die Reinduktionstherapie (Blasten % an Tag 28).

In Deutschland, Österreich und der Tschechischen Republik wurden seit 1997 verschiedene Ansätze

untersucht. Dieses waren einmal der Einsatz des liposomal formulierten Daunorubicin (DaunoXome, L-

DNR) in Kombination mit Cytarabin sowie Idarubicin mit Fludarabin, Cytarabin und G-CSF (FLAG) 1-3.

Ähnliche Ergebnisse wurden auch von anderen Gruppen bei Kindern und Erwachsenen berichtet 4-15.

Die ermutigenden Ergebnisse waren Grundlage der international AML Relapse 2001/01 Studie 16-20.


Hier konnte bei einer großen Anzahl von Patienten die Effizienz und vertretbare Toxizität der

Kombination von L-DNR und FLAG dokumentiert werden. Obwohl in bezug auf das Gesamtüberleben

bei den vorläufigen Ergebnissen bislang keine signifikanter Vorteil bewiesen werden konnte, weisen

eine bessere Remissionsrate bei gleicher oder verminderter Toxizität auf einen eventuellen Vorteil des

Zusatzes von L-DNR im Vergleich zur Therapie nur mit FLAG hin.

Nach Abschluss der internationalen Rezidivstudie wird deshalb diese Kombination zur Behandlung von

Rezidiven bei Kindern und Jugendlichen empfohlen.

Gleichzeitig werden alle Rezidive und refraktären AML in dem Register Relapsed AML 2009 erfasst.

Ziele des Registers sind die Erfassung der Häufigkeit und Inzidenz der Rezidive, Sicherstellung der

umfassenden und fundierten Therapieberatung, Identifikation prognostischer Faktoren, Entwicklung

diagnostischer Methodik und die Unterstützung biologischer und klinischer Forschungsprojekte.

Die erwartete Patientenaufnahme in das Register beträgt pro Jahr 25 bis 35 Patienten (Deutschland,

Österreich, Tschechische Republik).

Reference List

(1) Fleischhack G, Hasan C, Graf N, Mann G, Bode U. IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an

effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow

transplantation: experiences of a phase II trial. Br J Haematol. 1998;102:647-655.

(2) Fleischhack G, Graf N, Hasan C, Ackermann M, Breu H, Zernikow B, Bode U. [IDA-FLAG (idarubicin,

fludarabine, high dosage cytarabine and G-CSF)--an effective therapy regimen in treatment of recurrent acute myelocytic leukemia

in children and adolescents. Initial results of a pilot study]. Klin Padiatr. 1996;208:229-235.

(3) Reinhardt D, Hempel G, Fleischhack G, Schulz A, Boos J, Creutzig U. [Liposomal daunorubicine combined

with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children]. Klin Padiatr. 2002;214:188-194.

(4) Yavuz S, Paydas S, Disel U, Sahin B. IDA-FLAG regimen for the therapy of primary refractory and relapse

acute leukemia: a single-center experience. Am J Ther. 2006;13:389-393.

(5) Viniou NA, Vassilakopoulos TP, Giakoumi X, Mantzouranis M, Pangalis GA. Ida-FLAG plus imatinib mesylate-

induced molecular remission in a patient with chemoresistant Ph1+ acute myeloid leukemia. Eur J Haematol. 2004;72:58-60.

(6) de la RJ, Regadera A, Martin G, Cervera J, Sanz G, Martinez J, Jarque I, Garcia I, Andreu R, Moscardo F,

Jimenez C, Molla S, Benlloch L, Sanz M. FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of

patients with high-risk myeloid malignancies. Leuk Res. 2002;26:725-730.

(7) Luczynski W, Muszynska-Roslan K, Krawczuk-Rybak M, Kuzmicz M, Iwaszkiewicz-Pawlowska A, Kaliszewski

J. Results of IDA-FLAG programme in the treatment of recurrent acute myeloblastic leukaemia--preliminary report. Med Sci Monit.

2001;7:125-129.

(8) Steinmetz HT, Schulz A, Staib P, Scheid C, Glasmacher A, Neufang A, Franklin J, Tesch H, Diehl V, Dias WP.

Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and

secondary AML. Ann Hematol. 1999;78:418-425.

(9) Latagliata R, Breccia M, Fazi P, Iacobelli S, Martinelli G, Di Raimondo F, Sborgia M, Fabbiano F, Pirrotta MT,

Zaccaria A, Amadori S, Caramatti C, Falzetti F, Candoni A, Mattei D, Morselli M, Alimena G, Vignetti M, Baccarani M, Mandelli F.

Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in

patients older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008;143:681-689.

(10) Camera A, Rinaldi CR, Palmieri S, Cantore N, Mele G, Mettivier V, Miraglia E, Mastrullo L, Grimaldi F, Luciano

L, Guerriero A, Rotoli B, Ferrara F. Sequential continuous infusion of fludarabine and cytarabine associated with liposomal

daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients. Ann Hematol.

2009;88:151-158.

(11) Fassas A, Anagnostopoulos A. The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia.

Leuk Lymphoma. 2005;46:795-802.

(12) Clavio M, Venturino C, Pierri I, Garrone A, Miglino M, Canepa L, Balleari E, Balocco M, Michelis GL, Ballerini

F, Gobbi M. Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk

acute leukemia. Ann Hematol. 2004;83:696-703.


(13) Russo D, Piccaluga PP, Michieli M, Michelutti T, Visani G, Gugliotta L, Bonini A, Pierri I, Gobbi M, Tiribelli M,

Fanin R, Piccolrovazzi S, Baccarani M. Liposomal daunorubicin (DaunoXome) for treatment of poor-risk acute leukemia. Ann

Hematol. 2002;81:462-466.

(14) Piccaluga PP, Visani G, Martinelli G, Isidori A, Malagola M, Rondoni M, Baccarani M, Tura S. Liposomal

daunorubicin (DaunoXome) for treatment of relapsed meningeal acute myeloid leukemia. Leukemia. 2002;16:1880-1881.

(15) Muggia FM. Liposomal encapsulated anthracyclines: new therapeutic horizons. Curr Oncol Rep. 2001;3:156-

162.

(16) Kaspers GJ, Zimmermann M, Fleischhack G, Tamminga R, Gibson B, Armendariz H et al. Relapsed Acute

Myeloid Leukemia in Children and Adolescents: Interim Results of the International Randomised Phase III Study Relapsed AML

2001/01. 5th Bi-annual Symposium on Childhood Leukemia, Noordwijkerhout, The Netherlands: 2006.

(17) Kaspers GJ, Zimmerman M, Fleischhack G et al. Relapsed Acute Myeloid Leukemia in Children and

Adolescents: Interim Report of the International Randomised Phase III Study Relapsed AML 2001/01 [abstract]. Blood.

2006;108:570a.

(18) Kaspers GJ, Zimmermann M, Reinhardt D et al. Prognostic Significance of Early Treatment Response in

Pediatric Relapsed Acute Myeloid Leukemia: Results from the International Study Relapsed AML 2001/01 [abstract]. Blood.

2007;110:546a.

(19) Kaspers GJL, Zimmermann M, Reinhardt D et al. Clinical Relevance of Early Treatment Response in Pediatric

Relapsed Acute Myeloid Leukemia (AML): Study Relapsed AML 2001/01 [abstract]. Ann Hematol. 2008;87:S2.

(20) Kaspers GJL, Zimmermann M, Reinhardt D et al. Prognostic Significance of Time to Relapse in Pediatric AML:

Results from the International Randomised Phase III Study Relapsed AML 2001/01 [abstract]. Blood. 2008;112:1022-1023.


International Registry AML Relapse 2009

Newly diagnosed acute myeloid leukemia (AML) is a rare disease in children and adolescents. The

prognosis has improved using intensive chemotherapy with or without stem cell transplantation.

However, 5-10% of patients do not achieve first complete remission (CR) due to resistant disease

(primary refractory AML), and 30-50% of CR patients relapse. Primary refractory AML and relapsed AML

have a poor prognosis, with an overall survival of less than 25%. For first relapse disease, the prognosis

mainly depends on the time of relapse. If early (duration of 1st remission less than 1 year) the 2nd CR

rate is about 50%, and overall survival 10% or less. If late, the second CR rate is 80-90% and the overall

survival up to 40%. Multiple relapsed AML has an even worse prognosis. Several treatment schedules

have been studied recently, and progress seems feasible.

Within the German BFM group between 1997 and 2001 two clinical trials demonstrated the feasibility

and efficacy of combinations of anthracyclines (idarubicine / liposomal daunorubicin) and

cytarabine/fludarabine in childhood relapsed AML. The encouraging results were the fundament of the

International Relapsed AML 2001/01 Study, recruiting more than 500 patients (2001 to 2009).

As the Relapsed AML 2001/01 was finished in 3/2009, there is still a need to register all children and

adolescents with refractory or relapsed AML. This should allow evaluating the incidence, to identify new

diagnostic procedures and prognostics factors, improve diagnostic security by central reference

diagnostics, and assure qualified expert advice concerning prognosis, therapy, response and

complications. In addition, central material banking will supply selected research projects with patients’

material and enable correlating biological results with clinical data.

Objectives

To register all children and adolescents with relapsed or refractory acute myeloid leukemia

- incidence and frequency of relapsed and refractory AML

- basis for profound clinical advisement and recommendation

- Data for biological studies concerning

o Diagnosis

o Prognosis

Eligibility

All children and adolescents with relapsed or refractory AML younger than 18 years at diagnosis

Requested data:

Patient´s characteristics

Biological and Features of the AML

Registration form

Reference diagnostics

- central morphology

- central immunophenotyping

- cytogenetics / molecular genetics

Material banking

Material which is not required for diagnostics will be stored according to the following algorithm.

At diagnosis:

Basic Diagnostics

Morphology 6 unstained smears BM/PB

Immunophenotyping 11x 70µl heparinized BM / PB

Cytogenetic 4 ml heparinized BM / PB

Molecular genetics (Fusion genes, FLT3 ITD, NPM1) 5µg DNA

Mononuclear cells (ficoll) 1 to5*106cells (back up) ( ~2 5ml)

Research:

Isolation of leukemic blasts (sorting); purity > 95% X ml available

Non leukemic cells storage

Leukemic blasts 5*106cells per ( ~10ml)

DNA 10µg per ( ~ 1ml)

RNA 5µg per ( ~ 2ml)

Leukemic stem cells (if possible: sorting strategy pending) 0.01 0.3%

DNA

RNA

Follow up (time point 1 to 6):

Morphology unstained smears BM/PB

Immunophenotyping 5x 100µl heparinized BM / PB

Mononuclear cells (ficoll) 1 *106cells (back up) ( ~2ml)

DNA 5µg per ( ~ 1ml)

RNA 1 to5µg per ( ~ 2ml)

The material is available for research projects according the priority list of the registry committee.

The priority list is based on the reviews of the international reviewers and the feasibility to provide

adequate material.



Data management and registration

Each participating group will refer to their clinical contact person and to the usual network of clinical

centers, data center and experts (statistician, laboratories, etc) for the application of this registry. The

international coordinator will act as a co-ordination unit for the monitoring and exchange of information

and for the pooling of the data.

The set of data to be collected and pooled by the participants. Each group may:

Toxicity collection after each course should be done using the common form

Centralize the forms for quality checks in its own data center, according to the approach routinely

used in the group.

decide whether to input data in their own data base and send data as a file for pooling (at least every

6 months) or to send each checked and corrected forms to the operating center in Hannover

In summary, the major requirements that each group will have to ask to each of its clinical oncology

centers are:

1. To register at the data center each patient with relapsed or refractory AML. Registration should be

done as soon as possible after diagnosis; entry on this registry can only be done with informed

consent.

2. To send at least every 6 months the forms on diagnosis, response, treatment, toxicity and events as

soon as they can be completed, to the central data office (see addresses).

Data pooling

A common coding system and format has been made, for use by the data managers and/or

statisticians, in order to minimize mistakes in data exchange. This coding system is defined for the

purpose of data pooling only: it is required that a data set including each registered patient is prepared

with this format by the data managers and/or statisticians of each group. The data have to be sent every

6 months for pooling to the operating center, in a file structured according to a file that will be forwarded

separately to the data managers/statisticians, or on forms. The operating center, in collaboration with the

clinical contact person and the data manager/statistician of each group, pools the data and circulates a

report on these data.

Data Monitoring Committee (DMC)

Such a committee (two clinicians and one statistician) will be installed. Members of the DMC are

experienced researchers not involved in the trial who will be responsible for providing the principal

investigators with guidance on the trial conduction and, in case of problems, on whether the trial should

be stopped, modified or continued.

Registration Procedure

There will be a continuous possibility (7 days/week, 24 hours/day) of computerized registration. The

local/national representatives for data management will be instructed by the central data office (Martin

Zimmermann) about the procedure. After that, these local data managers will distribute login names and

passwords to all participating centers of their group. Then, each individual center will have the possibility


to register a new patient using the internet. Alternatively, the registration can be done centrally by the

local group/national data manager, or the central data office in Hannover.

There will be a back-up procedure if the internet system is not available. In these circumstances, please

consult your local representative for data management, or if not available the central data office for this

study in Hannover.

Publication and other policies

Authors on abstracts and manuscripts:

- Final main publications to be written by international coordinators

- Members of the writing committee will be included

- Clinical contact persons of each of the participating groups, if a total of at least 2 patients has been

included from that group in the International Registry Relapsed AML 2009, will be included

- International statistician

- Manuscripts concerning add-on studies only will include those who made a significant contribution to

that particular study, according to international guidelines for authorship

Other guidelines:

- Participating groups are obliged to send all required patient data every 6 months to the central data

office in Hannover. Groups who fail to do so will loose their status as collaborating group.

Ethical considerations

All patients with a refractory or relapsed AML should be registered. Due to the rareness of the disease,

sufficient data to analyse incidence and prognostic factors could only be generated in a collaborative

European registry. Diagnostics will be improved by a central reference diagnostics. In addition, all

patients will benefit from an expect advice based on the response data of the treated patients, potential

side effects or complications.

Coordinated add-on studies, using left material and correlated to the clinical course of disease will

generate new insights to leukemogenesis, new diagnostics or prognostic factors.

The treatment recommendation is based on several clinical trials in adults and children and could be

state as “best available option”.

International Registry AML Relapse 2009 / -June ’09 - 14a -

Patient/parent information and informed consent

Information Sheets

Dear Parent / Guardian,

We would like to invite your child to be registered to an International Registry Relapsed AML 2009.

Before you decide whether you would like your child to take part it is important for you to understand

why the registry is being done and what it will involve. Please take time to read the following information

carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or if you would

like more information. Take time to decide whether or not you wish your child to take part.

1. What is the purpose of the registry? AML relapses in children or adolescents are rare. To learn more about incidence, prognostics

factors or new diagnostic markers, an European collaboration is necessary. Central reference

diagnostics will improve the diagnostically security. The analysis of given treatment, response, side

effects and complication from all children and adolescents enables a profound expert advice in all

patients, especially in case or rare events.

2. Which kind of data will be transferred? The registry aimed to gather and analyze data on:

patients characteristics / symptoms

features of the leukemic blasts

treatment response

side effects

severe complications

3. Are there any risks? There are no risks expected

4. Are there any benefits? The individual patient will benefit from improved diagnostics and the opportunity of qualified advice

5. What will happen, if new knowledge is available? If a new clinical trial will be started, the patients are eligible.

6. Will taking part in this study be kept confidential? All data will be handled confidential

Thank you for reading this information

International Registry AML Relapse 2009 / June 2009 - 14b -

Patienteninformation

International Registry Relapsed AML 2009

Name, Vorname des Patienten:................................................................................Geb.-Datum:...............................................................................................................Sorgeberechtigter/Gesprächspartner:.........................................................................................................................................................................................................Ärztin/Arzt....................................................................................................................

Lieber Patient, liebe Eltern,bei Ihnen bzw. Ihrem Kind wurde ein Rückfall der akuten myeloischen Leukämie (AML) festgestellt. Auch wenn Sie bzw. Ihr Kind bereits in der vorangegangenen Therapie viele in der Behandlung der AML wirksame zytostatische Medikamente erhalten haben, gibt es auch beim Rückfall der Erkrankung (Rezidiv) erneut die Möglichkeit einer Behandlung. Die Erfahrungen in der Behandlung von Rückfällen der akuten myeloischen Leukämie (AML) im Kindes- und Jugendalter sind begrenzt. Es liegen jedoch Ergebnisse mehrerer Studien in Deutschland, Europa und den USA vor. In diesen Untersuchungen konnte bei mehr als 50% der behandelten Kinder eine erneute Remission, d.h. das erneute Verschwinden der Leukämiezellen erreicht werden. Danach sollte sich dann eine Knochenmarktransplantation anschließen, um ein langfristiges Überleben zu erreichen.

Durch diese Maßnahmen überlebten insgesamt etwa ein Drittel der Patienten die nächsten 5 Jahre, ohne dass es Hinweise für einen erneuten Rückfall gegeben hat. Allerdings sind die Chancen in Abhängigkeit von einer Reihe von Risikofaktoren unterschiedlich (Dauer zwischen der Ersterkrankung und dem Rückfall, genetische Eigenschaften der AML, Ansprechen auf die erneute Therapie).

Aufgrund der bisherigen Erfahrungen aus nationalen und internationalen Studien (Int. Relapsed AML 2001/01) wird eine intensive Chemotherapie mit der Kombination von liposomalem Daunorubicin (L-DNR), Fludarabin, Cytarabin und der Gabe des Wachstumsfaktors G-CSF empfohlen. Wenn eine erneute Remission erreicht wird, sollte eine Stammzelltransplantation angeschlossen werden, bevorzugt von einem guten passend Geschwisterkind oder einem Fremdspender.

Das liposomale Daunorubicin ist ein Anthracyclin, das mit einer „Hülle aus Fetten verpackt“ ist. Hierdurch sollen mögliche Schädigungen des Herzens, die bei der Behandlung mit hohen Dosierungen auftreten könnten, vermindert werden

Erläuterungen zur Therapie und den NebenwirkungenDas "L-DNR/FLAG“ oder „FLAG"-Schema sind Therapien, die über einen Zeitraum von 4 Tagen verabreicht werden und sich aus den drei Medikamenten (Zytostatika) Daunorubicin, Cytarabin und Fludarabin bzw. Cytarabin und Fludarabin zusammensetzen. Diese Medikamente greifen in unterschiedlicher Weise die sich teilenden Leukämiezellen an und bewirken so deren Vernichtung. Cytarabin ist Ihnen möglicherweise bereits bekannt, da Sie bzw. Ihr Kind es bereits in der Vorbehandlung der AML in anderer Kombination erhalten haben. Die Wirksamkeit ist in vielen nationalen und internationalen AML-Studien des Kindes- und Erwachsenenalters belegt. Das Medikament Fludarabin ist bisher nur in begrenztem Umfang bei Kindern, aber umfangreicher bei erwachsenen Patienten erfolgreich in der AML-Rezidivbehandlung eingesetzt worden. Zusätzlich zu diesen Medikamenten wird bereits vor Start der Therapie und ab Tag 15 täglich bis zur Blutbilderholung ein Wachstumsfaktor für weiße Zellen (Leukozyten) eingesetzt, der sogenannte „Granulozyten-Kolonien stimulierende Faktor“ (G-CSF). Dieser Faktor soll


einerseits zu Beginn der Therapie mehr Leukämiezellen aus der ruhenden Phase in die Teilungsphase bringen, um so die Wirksamkeit der Behandlung zu verbessern.

In der Erstbehandlung der AML haben Sie bzw. Ihr Kind bereits die sogenannten Anthrazykline erhalten. Diese Medikamente können bei einigen Patienten möglicherweise Schädigungen des Herzen verursachen. Das Risiko, dass eine solche Schädigung auftritt, hängt direkt mit der gegebenen Gesamtmenge dieser Medikamente zusammen. Andererseits sind die Anthrazykline gerade gegen Leukämiezellen der AML sehr wirksam. Seit einiger Zeit gibt es das Anthrazyklin „Daunorubicin“ in einer Fetthülle (so genannten Liposomen) verkapselt, das auch in dieser Form als so genanntes "liposomales Daunorubicin" (L-DNR) wirksam ist. Untersuchungen ergaben Hinweise, dass bei Verwendung des Medikaments in dieser Form die Schädigung des Herzens seltener ist.

Bei Ansprechen auf diese Therapie (Kontrollen erfolgen wie in der Ersttherapie durch Knochenmarkpunktionen und ggf. Liquorpunktionen) wird der behandelnder Arzt Sie über weitere Therapiemöglichkeiten informieren. Im Rahmen des Registers empfehlen wir, dass nach erreichen einer Remission (Verschwinden der sichtbaren Leukämiezellen) eine Knochenmarktransplantation/ Stammzelltransplantation durchgeführt wird. Ziel der Transplantation ist es, das mit dem "DNX-FLAG / FLAG"-Schema erreichte Ergebnis zu festigen und die Langzeitprognose zu verbessern. In Abhängigkeit vom zeitlichen Ablauf ist eine Behandlung mit Cytarabin und Thioguanin zur Überbrückung vorgesehen. Sollte eine Knochenmarktransplantation erst nach einem längeren Zeitraum möglich sein, so wird die intensivere Behandlung mit Cytarabin und Etoposid empfohlen. Bei der Knochenmarktransplantation kommt in erster Linie ein Familienangehöriger (Geschwister), infrage, der/die weitgehend übereinstimmende Gewebemerkmale aufweist (HLA-identisch). Sollte es in der Familie keinen Spender geben, wird ein fremder Spender gesucht, der gleiche Gewebemerkmale wie Ihr Kind aufweist (HLA identisch).

Nebenwirkungen: Wie Ihnen bereits aus den vorangegangenen Behandlungen bekannt ist, greifen die zytostatischen Medikamente leider auch alle gesunden, schnell wachsenden Zellen in unserem Organismus an. Kurzzeitige Nebenwirkungen neben Übelkeit, Erbrechen, Fieber und Kopfschmerzen können daher vorübergehender Haarausfall, Entzündungen der Darm- und Mundschleimhaut sowie Blutbildveränderungen sein. Die Blutbildveränderungen können dabei die bereits durch die Leukämie bedingten Veränderungen wie Verminderung der roten Blutzellen, der weißen Blutzellen und der Blutplättchen noch verstärken, wodurch eine hohe Blutungsgefahr und Infektionsgefahr besteht. Bluttransfusionen sind daher unvermeidbar. Bei Fieber sind intravenöse Antibiotika-Gaben erforderlich. Des Weiteren kann es durch diese Therapie oder durch infektiöse Komplikationen auch zu Organschäden, insbesondere zur Schädigung des Herzen, seltener der Lunge, Leber oder Niere, oder zu neurologischen Störungen kommen. Langfristig können das Wachstum und die Fortpflanzungsfähigkeit beeinträchtigt sein, und es besteht ein höheres Risiko für das spätere Entstehen einer zweiten bösartigen Erkrankung. Schwerwiegende Infektionen oder Organschädigungen können auch zum Tod führen.

Die Durchführung der Therapie ist nur unter stationären Bedingungen möglich. Da die zu erwartenden Blutbildveränderungen relativ lange anhalten und die damit verbundene Gefahr von Komplikationen durch Blutungen oder Infektionen hoch ist, ist in der Regel auch für die weitere Behandlung bis zur Blutbilderholung ein Krankenhausaufenthalt erforderlich.

Wissenschaftliche Begleituntersuchungen Parallel zur Durchführung dieser Therapie sind wissenschaftliche Begleituntersuchungen zur Untersuchung der Biologie und des Verhaltens der Leukämiezellen im Blut und Knochenmark (Untersuchungen zur Charakterisierung der Leukämiezellen / Untersuchungen zur minimalen Resterkrankung [(MRD]) wie in der Erstbehandlung der AML vorgesehen. Diese erfolgen parallel zu anderen Routineuntersuchungen und bedeuten keine zusätzlichen Blut- oder Knochenmarkentnahmen. Diese Untersuchungen können insbesondere bei Optimierungen der Therapie zukünftiger Patienten behilflich sein (siehe Einwilligung Materialübertragung).


Weitergabe von patientenbezogenen Daten Im Rahmen des Registers ist die Erfassung der patientenbezogenen Daten (Name, Vorname, Geb.-Datum, Diagnose, Befunde, Therapie, Verlauf) zur medizinischen Dokumentation vorgesehen. Dadurch wird einerseits eine Zusammenarbeit zwischen verschiedenen Kliniken möglich und andererseits ist es die Voraussetzung für die genauere Diagnosestellung und die Überwachung der Therapie.

Alle Personen, die Daten erfassen oder Einblick in die gespeicherten Daten haben, unterliegen der Schweigepflicht und sind zur Wahrung des Datengeheimnisses entsprechend dem §40 des Bundesdatenschutzgesetzes verpflichtet. Alle erhobenen oder gespeicherten personenbezogenen Daten werden ausschließlich zum Zwecke der wissenschaftlichen Forschung verarbeitet und genutzt und anonymisiert, sobald das in der Auswertung möglich ist. Die personenbezogenen Daten werden an folgende Zentren übermittelt bzw. dürfen eingesehen werden durch:

Registerleitung:

Prof. Dr. med. Dirk Reinhardt AML-BFM Studienleitung Medizinische Hochschule Hannover Pädiatrische Hämatologie und Onkologie Carl-Neuberg-Str. 1 30625 Hannover

(Form to be on Institution headed paper)

Addressogram:

PARENT/CHILD CONSENT FORM

(Version No., Date)

Title: International Relapsed AML 2009 Registry

Name of Local Researcher: Please initial boxes

1. I confirm that I have read and understood the information sheet(s),

and have had the opportunity to ask questions and had satisfactory

answers to them.

2. I understand that my child’s participation is voluntary and that I am free

to withdraw at any time, without giving any reason, without his/her medical care

or legal rights being affected.

3. I understand that information from my child’s medical notes may be looked at

and information passed on to responsible individuals from cancer research bodies,

where it is relevant to research, to the national registration bodies and to regulatory

authorities where it is relevant to my child’s participation in research.

Relevant information will be collected and held securely and kept confidential.

4. I agree for my child’s additional tissue to be collected, stored and used for

ethically-approved research.

5. I agree for my child to be registered in the

International Relapsed AML 2009 Registry

Name of patient

Name of parent/guardian Date Signature

Name of parent/guardian Date Signature

Researcher Date Signature


Registration form

ONLY TO BE USED IF THE INTERNET PROCEDURE IS NOT AVAILABLE

Whenever possible, please use the internet for registration:

https://aml.mh-hannover.de/amlreg09/

To: Local Data Office for the International Registry Relapsed AML 2009

FAX nr: E-mail:

or:

To Int. Registry Relapsed AML 2009



Carl-Neuberg-Str. 1

30625 Hannover, Germany

FAX +49 511 532 9029 Tel +49 511 532 9123

I declare that the patient I will include is eligible for the Registry Relapsed AML 2009 for relapsed or

refractory AML. I have obtained formal written informed consent, which I will forward soon.

Treating Pediatric Oncologist:

Name:

Center:

Phone: Fax:

E-mail:

Patient data: a) primary refractory disease

(please b) refractory to other reinduction protocol after relapse

encircle) b) first relapse 1) early 2) late

c) subsequent relapse

Initials:

Date of birth:

PLEASE CONTACT YOUR LOCAL OR THE INTERNATIONAL DATA OFFICE FOR

REGISTRATION IN CASE THE INTERNET PROCEDURE IS NOT AVAILABLE



Datenweitergabe

Einwilligungserklärung zur Weitergabe und Verarbeitung der Patientendaten

im Rahmen des Registers “AML Rezidiv 2009” / “Registry Relapsed AML 2009”

Ich erkläre mich damit einverstanden, dass personenbezogenen Daten (Name, Geburtsdatum, Wohnort,

Diagnose mit Befunderhebung, Verlauf usw.) die meines Sohnes/meiner Tochter

....................................................................................................................................................

Name, Vorname Geb.-Datum

verarbeitet werden (Speicherung, Übermittlung, Veränderung, Löschen). Das Verarbeiten der Daten

dient der medizinischen Dokumentation im Rahmen der Zusammenarbeit mehrerer Kliniken um eine

bessere Erarbeitung der Diagnosen und eine Überwachung der Therapie in den einzelnen Kliniken zu

gewährleisten. Diese Dokumentation ist für eine Bewertung des Behandlungserfolgs im Rahmen desRegisters unerlässlich. Die Daten werden an folgendes Zentrum übermittelt

Abteilung für Hämatologie und Onkologie der Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1,

30625 Hannover (= Prof. Dr. Reinhardt, Leitung des Int. Registers für AML-Rezidive 2009).

Alle Personen, die Einblick in die gespeicherten Daten haben, sind zur Wahrung des

Datengeheimnisses verpflichtet. Sie werden um Ihr Einverständnis zur Verarbeitung dieser Daten

gebeten.

Datum: -- / -- /----

_______________________________ _________________________________

Sorgeberechtigte/r Sorgeberechtigte/r

Gesprächsführende/r Ärztin/Arzt: ...............................................................................

Datum /Unterschrift

Zeugin/Zeuge: .............................................................................................................

Datum / Unterschrift


Material

Einwilligungserklärung zur Lagerung und Nutzung biologischen Materials

Bei den notwendigen Untersuchungen bei Diagnose und im Verlauf der Behandlung (Knochenmark/

Blutentnahmen) können von den entnommenen Material Restmengen übrig bleiben, die nicht mehr für

die Diagnosestellung oder Verlaufskontrolle erforderlich sind. Diese Leukämiezellen/Blutzellen meines

Kindes können zur Erforschung der akuten myeloischen Leukämie in ihren molekularen, genetischen,

immunologischen und anderen, mit der Krankheit direkt verbundenen Merkmalen, untersucht und

gegebenenfalls für die Entwicklung neuer Behandlungsverfahren eingesetzt werden.

Die Entnahme des Blutes/Knochenmarks ist nicht mit zusätzlichen Schmerzen oder

Risiken verbunden, sie erfolgt im Rahmen der notwendigen Blut- oder Knochenmarkentnahme bei

Diagnosestellung oder im Verlauf.

Auf diese Weise sollen die Diagnosestellung sicherer gemacht werden, das biologische Verständnis der

Erkrankung verbessert und neue therapeutische Ansätze gefunden werden.

Für Studien, die eine zusätzliche Probenentnahme (Anzahl/ Menge) erfordern, sind gesonderte

Einwilligungen erforderlich.

Die Verwendung des Materials kann nur nach Beschluss einer wissenschaftlichen Kommission(1)

erfolgen.

Eine kommerzielle Nutzung des Materials wird ausgeschlossen.

Die Lagerung des Materials erfolgt in den Referenzlaboren der AML-BFM Studiengruppe.

Medizinische Hochschule Hannover; Pädiatrische Hämatologie/Onkologie (Prof. Dr. Reinhardt)

Ich lehne die Weiterverwendung von gewonnenen Materialien für Forschungszwecke ab

Ich stimme der Verwendung in

(1) anonymisierter 5

(2) pseudonymisierter 1 oder (3) nicht anonymisierter Form für konkrete Studienfragen zu.

In den Fällen (2) und (3) wird die Verwendung

für alle Studienmöglichkeiten erlaubt für alle Studien erlaubt, die im Kontext der Fragestellung stehen, für die ursprünglich das

Material gespendet wurde.

eine Kontaktaufnahme für die Zustimmung zur Verwendung in weiteren Studien erlaubt. eine Kontaktaufnahme für die Zustimmung zur Verwendung in weiteren Studien nicht erlaubt.

1Bei der Pseudonymisierung werden die Angaben, die die Identifikation des Patienten ermöglichen (Name, Geburtsdatum,

Herkunft) durch einen Code ersetzt, der ausschließlich von der Studienleitung entschlüsselt werden kann. Dadurch haben zum

einen die beteiligten Forschungsgruppen keine Möglichkeit, einen Patienten zu identifizieren, in dringenden Fällen (z.B. wenn ein

Forschungsergebnis direkt dem individuellen Patienten nützen könnte) kann aber die Studienleitung den Patienten identifizieren.

Bei der Anonymisierung ist keine Rückverfolgung oder Identifikation des Patienten möglich.


Übereignung

Ich übereigne die meinem Kind entnommenen Blut- bzw. Gewebeproben hiermit an die oben genannte

Institution bzw. Person.

Unentgeltlichkeit

Ich bin mir bewusst, dass ich/mein Kind für die Spende der Blut- bzw. Gewebeprobe kein Entgelt

erhalte/erhält. Ich bin mir bewusst, keinerlei Ansprüche auf Vergütung, Tantieme oder sonstige

Beteiligung an finanziellen Vorteilen und Gewinnen zu haben, die möglicherweise auf der Basis der

Forschung mit der Blut- bzw. Gewebeprobe meines Kindes erlangt werden.

Widerruf der Zustimmung zur Probenverwendung

Ich weiß, dass ich meine Zustimmung zur Verwendung der Blut- bzw. Gewebeprobe meines Kindes

jederzeit und ohne Angabe von Gründen gegenüber der oben genannten Institution / Person widerrufen

kann und dass dies keinen Einfluss auf etwaige weitere ärztliche Behandlung meines Kindes hat.

Im Falle des Widerrufs bin ich damit einverstanden, dass die Blut- bzw. Gewebeprobe zu

Kontrollzwecken weiter aufbewahrt wird. Ich habe das Recht, deren Vernichtung zu verlangen, sofern

gesetzliche Bestimmungen der Vernichtung nicht entgegenstehen.

Ich bin mir bewußt, dass eine Vernichtung der Blut- bzw. Gewebeprobe auf meinen Wunsch nicht

möglich ist, wenn sie anonymisiert aufbewahrt wird.

Ort, Datum ................., ...............................

Unterschriften

...................................... .........................................

Sorgeberechtigte/Mutter Sorgeberechtigter/Vater

...................................... ..........................................

Patient/in zuständiger Arzt/Ärztin

(1) Kommission: Von dem Beratungsgremium des Registers Int. AML-Relapse 2009 werden 3-5

Wissenschaftler (z. Zt. Prof. Dr. Serve, Frankfurt, Prof. S. Izraeli, Tel Aviv, Prof. P. Vyas, Oxford) gewählt, die die

Qualität wissenschaftlicher Projekte und die Antragsteller prüfen und begutachten. Das

Beratungsgremium legt dann eine Prioritätenliste für die Weitergabe von Material fest.


Please fax or mail to the appropriate coordination office! Or

+49 511 532 9029

International Registry Relapsed AML 2009: Registration

Identification number : |___________________________________________|

Surname / Initials: |___________________________________________|

Date of Birth |__|__|__|__|__|__| Gender |__| male |__| female

dd/mm/yr

Enters registry: |__| no |__| yes Informed consent: |__| no |__| yes

Date of initial diagnosis: |__|__|__|__|__|__| Date of relapse: |__|__|__|__|__|__|

dd/mm/yy dd/mm/yy

Number of relapse: |__| first |__| second |__| third or more

Resistant disease: |__| at initial diagnosis |__| at 1st relapse |__| at 2nd relapse

FAB type at initial diagnosis: _____ Auer rods |__| no |__| yes M4 eo |__| no |__| yes

Cytogenetics at initial diagnosis:

|__| no result

|__| examined, no result

|__| not examined

|__| no data

|__| normal karyotype

|__| t(9;22), Philad.-Chrom.

|__| 11q23 ( t(4;11),t(9;11), etc)

|__| t(1;19)

|__| t(4;11)

|__| t(8;14) / der (8q24)

|__| 14q11-aberrations

|__| del (6q)

|__| der (9p)

|__| der (12p)

|__| >50 (hyperdiploid)

|__| t(8;21)

|__| t(15;17)

|__| inv(16)

|__| t(9;11)

|__| t(6;9)

|__| der(3q)

|__| +4

|__| +8

|__| +9

|__| -5/5q-

|__| -7/7q-

|__| missing X-

chromosome

|__| +12

|__| 17q

|__| t(1;22)

|__| other aberrations

Molecular aberration (specify):____ (e.g. AML1/ETO etc) Results neg |__|pos. |__|

Liver enlargement: |__| no |__| yes ______ cm below costal margin in MCL

Spleen enlargement: |__| no |__| yes ______ cm below costal margin in MCL

Leukocytes : |__| |__|__|__| |__|__|__| x 109/l Platelets |__| |__|__|__| |__|__|__| x 109/l

Blasts % peripheral blood: |__|__|__| Blasts % BM: |__|__|__| LDH (U/l): |__|__|__|__|__|

CNS disease at initial diagnosis

|__| no |__| yes, blasts in the spinal fluid Cells in the spinal fluid at day 0: |_|_|_|/mm³

|__| yes, with symptoms (white blood cells)

(cranial nerve dysfunction, CNS mass, retinal infiltration, etc.)

Artificial contamination of spinal fluid with blood: |__| no |__| yes


Pat. ID ____________________ International Registry Relapsed AML 2009

Data at Relapse - investigations

FAB type: __________ Auer rods |__| no |__| yes M4 Eo |__| no |__| yes

Cytogenetics at relapse:

|__| no result

|__| examined, no result

|__| not examined

|__| no data

|__| normal karyotype

|__| t(9;22), Philad.-Chrom.

|__| 11q23 ( t(4;11),t(9;11), etc)

|__| t(1;19)

|__| t(4;11)

|__| t(8;14) / der (8q24)

|__| 14q11-aberrations

|__| del (6q)

|__| der (9p)

|__| der (12p)

|__| >50 (hyperdiploid)

|__| t(8;21)

|__| t(15;17)

|__| inv(16)

|__| t(9;11)

|__| t(6;9)

|__| der(3q)

|__| +4

|__| +8

|__| +9

|__| -5/5q-

|__| -7/7q-

|__| missing X-chromosome

|__| +12

|__| 17q

|__| t(1;22)

|__| other aberrations

DATA AT RELAPSE, continued

Molecular aberration:________ (e.g. AML1/ETO, CBF/MYH11, MLL/AF9)

Results: |__| neg |__| pos

Bone marrow involv. |__| no |__| yes CNS involvement |__| no |__| yes

Gonadal involv. |__| no |__| yes Other localisations |__| no |__| yes

Liver enlargement: |__| no |__| yes ______ cm below costal margin in MCL

Spleen enlargement: |__| no |__| yes ______ cm below costal margin in MCL

Leukocytes : |__| |__|__|__| |__|__|__| x 109/l Platelets: |__| |__|__|__| |__|__|__| x 109/l

Blast % peripheral blood: |__|__|__| Blast % BM: |__|__|__| LDH (U/l): |__|__|__|__|__|__|

CNS disease at relapse:

|__| no |__| yes, blasts in the spinal fluid Cells in the spinal fluid at day 0: |_|_|_|/mm³

_| yes, with symptoms (white blood cells)

(cranial nerve dysfunction, CNS mass, retinal infiltration, etc)

Artificial contamination of spinal fluid with blood: |__| no |__| yes Weight [kg] |__|__| Height [cm] |__|__|__| Information submitted by:

Signature:_____________________________________ Date: __________________________

Tel/FAX no.: _____________________________


Acute events

To: International Data Office

FAX: +49 – 511 532 9029


And to: Local Data Office of the Own Group

FAX:

E-mail:

Date:

This is to inform you that we have observed a serious adverse event in a patient with relapsed or

refractory AML.

Identification number : _____________________|

Surname / Initials: ________________________|

Date of Birth |__|__|__|__|__|__| Gender |__| male |__| female

dd/mm/yr

Reporting pediatric oncologist/treating physician:

Name:

Center:

Phone:

Fax:

E-mail:

Please indicate:

- death Y/N

- life-threatening Y/N

- permanently disabling Y/N

Comments:

International Registry AML Relapse 2009 / June ’09

Prof. Dr. D. Reinhardt

Pediatric Hematological laboratory (K10)


Carl-Neuberg-Str. 1

Tel.: +49/ 511/ 532 9019 30625 Hannover

fax: +49/ 511/ 532 9029 Germany

requested

Morphology

Immunophenotyping

Cytogenetics1 / Molecular genetics

Hospital: Patient: (label)

Address: ........................................... Name: .....................................

……………........................................ Prename: ................................

……………........................................ date of birth: ......../........../...........

Telephone: (.................)....................

Diagnosis: ................................(FAB)..... Date:......./......../................

Relapse: � yes Refractory: � yes Secondary malignancy: � yes

Cytogenetics at de-novo AML: ______________

Immunological data: .........................................................(immunophenotype, if available)

Last treatment block: ......................

Start: ....../....../....... til ....../......../........

Peripheral blood Bone marrow

� smears (at least 6; unstained) � smears (at least 6; unstained)

� PB (2x10ml, heparinized) � Bone marrow (3x10ml, heparinized)

� Ficoll isolated nucleated cells � Ficoll isolated nucleated cells

BMA: .......................... (date)

hemoglobin: ........ g/dl WBC: ............x109/l platelets: ..............x109/l

BM-blasts: ............. %

Send to :1 Institut für Zell- und Molekularpathologie

Prof. Dr. D. Reinhardt Professorin Dr. B. SchlegelbergerHematological laboratory MHH (OE 5120) Pediatric Hematology/Oncology Carl-Neuberg-Str. 1Hannover Medical School D-30625 HannoverCarl-Neuberg-Str. 1 30625 Hannover

Germany



Group representatives for clinical and data management

Clinical Data management

AIEOP Carmelo Rizzari Roberto Rondelli

e-mail [email protected] [email protected]

phone +39 – 39 233 3513 +39 – 51 636 4667

fax +39 – 39 230 1646 +39 – 51 34 5759

AML-BFM-G Dirk Reinhardt J.E. Müller


phone +49 – 511 532 6720 +49 – 511 532 9123

fax +49 – 511 532 9029 +49 – 511 532 9029

BFM-A: Michael Dworzak Nora Muehlegger


phone +43 – 1 40170 480 +43 – 1 40170 4390

fax +43 – 1 40170 481 +43 – 1 40170 7430

CWPGH Petr Smisek Alena Vrzalova


phone +420 – 2 2443 2201/2251/2232 +420 – 2 2443 2243

fax +420 – 2 2443 2220 +420 – 2 2443 2220

DCOG Gertjan J.L. Kaspers Karin van der Pal-de Bruin


(new e-mail address)

phone +31 – 20 444 2420 +31 – 70 367 4545

fax +31 – 20 444 2422 +31 – 70 367 0868

EORTC-CLCG/FRALLE Noel Philippe Noel Philippe


phone +33 – 4 7238 5780 +33 – 4 7238 5780

fax +33 – 4 7238 5503 +33 – 4 7238 5503

GATLA Hortensia Armendariz Francisco J. Lastiri


phone +54 – 221 451 4641 +54 – 11 4806 8457

fax +54 – 221 457 5209 +54 – 11 4806 8457

Hong Kong S.Y. Ha S.Y. Ha


phone +852 - 2855 3453 +852 - 2855 3453

fax +852 - 3005 7808 +852 - 3005 7808


Hungary E. Magyarosy E. Magyarosy


phone +36 – 1 459 9108 +36 – 1 459 9108

fax +36 – 1 459 9154 +36 – 1 459 9154

Israel Batia Stark David Steinberg


phone +972 – 3 925 3669 +972 – 3 640 8035/8036

fax +972 – 3 925 3042 +972 – 3 640 9357

Moscow-Minsk Alexei Maschan Alexei Maschan


phone +7 – 095 936 9423/935 6656 +7 – 095 936 9423/935 6656

fax +7 – 095 935 5510 +7 – 095 935 5510

MRC Owen Smith Rachael Clack


phone +35 3 – 1 416 2014/2953 +44 – 1865 40 4861

fax +353 – 1 410 3475 +44 – 1865 40 4849

NOPHO Liisa Hovi Göran Gustafsson


phone +358 – 9 4717 2720 +46 – 8 5177 2484

fax +358 – 9 4717 4707 +46 – 8 5177 3184

PINDA J. Quintana J. Quintana


phone +56 – 2 210 4073 +56 – 2 210 4073

fax +56 – 2 210 4075 +56 – 2 210 4075

St. Jude Raul C. Ribeiro Annette Stone, R.H.I.A.


phone +1 – 901 495 3694 +1 – 901 495 3192

fax +1 – 901 495 3122 +1 – 901 495 2405

SHOP Amparo Verdeguer Dainora Jaloveckas


phone +34 - 96 398 7727 +34 - 93 458 3800

fax +34 - 96 398 7727 +34 - 93 459 0997

International Registry AML Relapse 2009 / June ’09 – Recommendations

- 25 -

Recommendations for diagnostics and treatment

Diagnostics

Clinical evaluation, laboratory tests and follow-up

Send unstained smears (BM and PB; 6 each) and heparinised BM (2x 10ml) to your reference

laboratory for central diagnosis, and if possible send material for research studies in order to be

able to address the additional objectives of the study.

Before the start of the treatment the following parameters need to be obtained:

- medical history and physical examination

- performance status (depending on age, either the Karnofsky or Lansky Performance scale)

- ophthalmologic finding (retinal infiltration)

- complete blood count (hemoglobin, platelets, white blood cell count and differentiation). This

should be determined within 2 days prior to the first reinduction course.

- serum chemistry: creatinine, sodium, potassium, calcium, phosphate, ALAT, bilirubin, uric

acid, LDH, CK, glucose, total protein, albumin; clotting (APTT, PT, fibrinogen).

- HLA typing (if not done previously)

- recent information on the viral serology (antibodies: EBV, HSV, CMV, PVB19, HAV, HBV,

HCV, HIV; PCR: CMV, HCV) and IgG and IgA levels should be available.

- bone marrow examination (marrow cellularity and percentage of blasts). Perform a biopsy in

case of a dry tap. This should be performed within 3 days prior to the first reinduction course.

Bone marrow should also be sent to the reference laboratory for confirmation of the

diagnosis, and should be studied for immunophenotype and cytogenetics. Please consider to

participate in research studies.

- lumbar puncture (quantification of cells and protein, pathological examination), also to be

done within 3 days from the start of reinduction chemotherapy.

- urine (protein, glucose, ery’s)

- Chest X-Ray

- Abdominal ultrasound

- MRI (=NMR) of the brain in case of (the suspicion on) localized symptomatic CNS disease

- Electrocardiogram

- Echocardiography (please refer to the more comprehensive guidelines below)

- Lung function test (optional)

Criteria of response and other definitions

CNS disease

5 white blood cells/mm3 (ie, 5/ l, or 15/3 l) and unequivocal evidence of blasts on

cytospin examination, and/or clinical (seizures, cranial nerve palsy and symptoms of

increased cranial pressure or other signs/symptoms not readily explained by another

disease) and/or radiological evidence of leukemic infiltration in the central nervous

system. In all of the symptomatic cases, a MRI should be made. CSF not evaluable in

case of >50/3 erythrocytes.

Complete remission


- 26 -

5% leukaemic blasts in the bone marrow with signs in the BM of normal haematopoiesis

and with clear signs of regeneration of normal blood cell production in the peripheral

blood (platelets > 50x109/l without transfusions, neutrophils >1.0x109/l), and no leukaemic

cells in the PB or anywhere else.

Death, early

Death during the first 2 months of treatment (ie, before the time that complete remission

could have been documented). The cause of death (disease, therapy or both) should be

recorded as well as the last known percentage of blasts in the BM.

Death, toxic

Death due to treatment-related complications, and not caused by the leukemia itself

Partial remission

No complete remission, BM blasts > 5 20% and/or no regeneration

Refractory disease = non-responder

More than 20% of blasts in the bone marrow after 1 or 2 complete blocks of

chemotherapy, and/or elsewhere documented leukemic cells after 2 complete blocks of

chemotherapy

Relapse

After a documented complete remission, the recurrence of 10% unequivocal leukemic

cells (occasionally, 10-20% blasts in the BM does not represent a relapse!) in a

representative bone marrow, and/or evidence of leukemic infiltration or recurrence at any

site. CSF with <5 cells/mm3 but with blasts on the cytospin examination should be

investigated repeatedly, as should the BM in case of >5<10% leukemic cells and in case

of doubt otherwise.

Relapse, early first

Relapse within 1 year from initial diagnosis

Relapse, late first

Relapse occurring 1 year or later from initial diagnosis

Serious adverse event

Death, life-threatening or permanently disabling event, or grade 3 or 4 cardiotoxicity.

Therapy

This registry aims to evaluate the incidence and frequency of AML relapses in children and

adolescents. Further, a central reference diagnostics for the participating hospitals is offered. The

coordination center of the registry will provide clinical advice concerning diagnostics, treatment,

prognosis and alternative therapies.

To assure an informed advisory service, the administered therapy, treatment response and side

effects should be documented.

Based on the previous studies and the preliminary results from the international Relapsed AML

2001/01 trial, the registry committee recommended the following schedule:

Schedule overview

Relapsed AML Registry I-BFM-SG

BMP

day 1 8 15 21-28 42-56 MRD MRD MRD MRD

FLAG

Relapsed AML2009 registry version 2

Dnx: liposomal daunorubicine; L-DNRFl: fludarabineA: ARA-C; CytarabineG: G-CSFSCT: stem cell transplantationI: IdarubicinRIC: reduced intensity conditioningTG: thioguanineMRD: Minimal residual diseaseBMP: bone marrow puncture

Dnx-FLAG

>20% blasts

eligible phase I/II studies

SCTallo MSDallo MUD, if not available

Early relapse RIC/Haplo SCT

Late relapse RIC/autoSCT

AEor

cytarabine/thioguanine

characterisationmorphologyimmunophenotypingcyto-/molecular genetics

No CR/CRp>20% blasts

Conditions to start treatment

1. Children and adolescents <18 years of age at start of chemotherapy

2. Primary refractory AML

3. First relapsed AML

4. Signed written informed consent according to local policies

Patients with a combined relapse, or an isolated extramedullary relapse, or a bone marrow

relapse (isolated or combined) with <20% blasts in the BM are eligible.


- 27 -


- 28 -

Contradiction for full-dose treatment

1. Symptomatic cardiac dysfunction (CTC grade 3 or 4) and/or a Fractional Shortening at

echocardiography below 29%

2. A Karnofsky performance status <40% (children >=16 years) or an Lanksy performance

status of <40% (children < 16 years) before start of chemotherapy

3. Any other organ dysfunction (CTC grade 4) that will interfere with the administration of the

therapy according to this protocol (e.g. transaminases >10 times the UNL)

4. Inability to potentially complete the treatment protocol for any other reason

5. FAB type M3 (please refer to your local group for one of the treatment alternatives)

Background and introduction

Newly diagnosed acute myeloid leukemia (AML) is a rare disease in children. The prognosis has

improved using intensive chemotherapy with or without stem cell transplantation. However, 5-10%

of patients do not achieve first complete remission (CR) due to resistant disease (primary

refractory AML), and 30-50% of CR patients relapse. Primary refractory AML and relapsed AML

have a poor prognosis, with an overall survival of less than 25%. For first relapse disease, the

prognosis mainly depends on the time of relapse. If early, defined as within 1-1.5 years from initial

diagnosis, the second CR rate is about 50%, and overall survival 10% or less. If late, defined as

after 1-1.5 years from diagnosis, the second CR rate is 80-90% and the overall survival up to

40%. Multiple relapsed AML has an even worse prognosis. Several treatment schedules have

been studied recently, and progress seems feasible using new drugs and new drug combinations.

The currently available alternatives are described below.

Liposomal daunorubicin (DaunoXome®)

Daunorubicin is a well-known anthracycline with proven efficacy in AML. Anthracyclines are

intensely used in first-line treatment, which limits its use in case of refractory or relapsed disease,

because of its cardiotoxicity. This cardiotoxicity is dose-related, and becomes an increasing

problem in case of higher cumulative doses (Lipshultz 1991). Such cumulative doses have

normally been given in first-line treatment. Another cumbersome side-effect of anthracyclines is

mucositis. DaunoXome® is a combination of daunorubicin and a unilamellar liposomal transport

system. Because of the chemical formula, the compound is relatively stable in the plasma.

Because of the preferential release of free daunorubicin intracellularly, the plasma level of free

daunorubicin is lower than in case of infusion with daunorubicin itself. In a mouse model,

liposomal doxorubicin had no cardiotoxicity like in saline-treated controls, but did have significant

antileukemic activity (Forssen 1981). In an isolated perfused rat model, DaunoXome® had no

cardiotoxicity in contrast to free daunorubicin (Pouna 1996). DaunoXome® had a relatively low

incorporation in heart muscle as compared to tumor cells (Forssen 1992). The above may explain

the absence of cardiotoxicity of DaunoXome® in 277 AIDS patients with Kaposi’s sarcoma, who

received cumulative doses of DaunoXome® of up to 1700 mg/m2, >600 mg/m2 in 53 patients at a

total group mean cumulative dose of 481 mg/m2 (Gill 1996). Out of 979 Kaposi’s sarcoma patients

treated with DaunoXome®, 1 patient developed cardiotoxicity with clinical symptoms (Summary of

Product Characteristics, Gilead Sciences, 5 June 2001). In general, liposomal anthracyclines

cause less cardiotoxicity at higher cumulative doses than conventional anthracyclines (Levitt

1999). Animal solid tumor studies showed that at equivalent daunorubicin dosages, DaunoXome®

had significantly increased antitumor activity and less toxicity as compared to free daunorubicin

(Corbett 1978, Forssen 1994). Significant penetration of DaunoXome® into the cerebrospinal fluid


- 29 -

and brain is unlikely, since liposomes cross the blood-brain barrier poorly, if at all (Tökés 1980).

This is also the case for free anthracyclines. However, the penetration may be different in e.g.

brain tumors (Zucchetti 1999). A clinical study of the AML-BFM group (Creutzig et al., unpublished

data) is in progress, in which DaunoXome® is given in combination with cytarabine in relapsed

AML patients. Initially, DaunoXome® at 60 mg/m2/day was given on days 1 and 5 of a course

including 4 days of continuously iv cytarabine (500 mg/m2/day for 4 days), which course was

repeated after 4-5 weeks. Because of limited toxicity, the current cohort of patients is being

treated with an extra infusion of DaunoXome® on day 3 of each of the 2 courses. No

cardiotoxicity has been seen sofar, but follow-up is short. Based on these data, it was decided to

include DaunoXome® in this treatment protocol.

FLAG +/- Idarubicin

The favorable effect of combining fludarabine and cytarabine, leading to an increased

arabinosylcytosine 5’-triphosphate (ara-CTP) accumulation as compared to that achieved by

cytarabine alone, was initially described by Gandhi et al. (1993). In addition, it has been reported

that G-CSF combined with cytarabine may render AML cells more sensitive to the latter drug

(Tafuri 1990), which may be explained by the increased ara-CTP accumulation - associated with

increased deoxycytidine kinase activity – in case of pre-exposure to G-CSF as reported by Braess

et al. (2000). Finally, Gandhi et al. (1995) reported that G-CSF significantly increased the

accumulation of the active metabolite of fludarabine. Thus, the combination of fludarabine,

cytarabine and G-CSF (FLAG) emerged, although the role of G-CSF has been questioned (Estey

1994). Several colleagues in the UK used FLAG for reinduction of relapsed AML. Retrospectively,

data on 40 patients were obtained using a questionnary (Gibson et al., unpublished data), with

subsequent CR in 21/30 (70%) relapse patients and CR in 3/7 primary refractory patients. One

patient died of pneumocystis carinii pneumonia. Grade 4 hematological toxicity was the rule.

Fleischhack et al. (1998) treated 38 (update: 44) relapsed AML patients with IDA-FLAG, ie,

idarubicin added to FLAG, followed by again IDA-FLAG or FLAG. Three patients received FLAG

only. Toxicity was marked. Numbers were small, but the time of myelosuppression was shorter

after FLAG than after IDA-FLAG. Except for grade 4 hematological toxicity, infections with often

pulmonary involvement was a relatively frequent complication, and were more often seen after

IDA-FLAG than after FLAG. CR rates were 56% and 75% in early and late relapses respectively

(updated but not published data: 58% and 78% respectively). This protocol applies the FLAG

schedule with G-CSF starting 1 day before and to be continued during chemotherapy, based on

the above summarised studies.

FLAG + DaunoXome®

Fleischhack et al. (Bonn, unpublished data) have piloted this regimen in 10 patients with relapsed

AML. Toxicity was tolerable and similar as with IDA-FLAG. Five patients had mild mucositis, eight

fever of unknown origin, one gram-positive bacteremia, and one a pneumonia. Five patients

achieved CR and proceeded to SCT, two patients were partial responders and three patients did

not respond and died. This pilot study shows that FLAG in combination with DaunoXome® is

feasible and has antileukemic activity. However, 2 consecutive courses of FLAG + DaunoXome®

(3 x 60 mg/m2/day) is anticipated to be too toxic.

Other reinduction chemotherapy regimens

Cytarabine or other agents have been studied in combination with well-known drugs such as

etoposide and amsacrine, with significant antileukemic activity (Miller 1991, Ozkaynak 1998,

Steuber 1996, Whitlock 1997, Baruchel unpublished). Data on the use of new agents such as


- 30 -

topotecan in children have not been reported yet. Cladribine® (2-chloro-deoxyadenosine) has

been studied in relapsed AML as well. The response rate in 17 children was 59%, including a CR

rate of 47% (Santana 1992). However, these investigators subsequently investigated this drug in

93 children with newly diagnosed AML or myelodysplastic syndrome (MDS), and found that at an

overall CR rate of 40% after 2 courses of cladribine®, patients with FAB type M5 responded

significantly better than non-M5 patients, with CR rates of 71% and 24% respectively. Therefore,

cladribine does not seem very active in non-FAB M5 type cases.

CNS prophylaxis and treatment

Overt CNS leukemia is relatively rare in AML. This protocol applies high-dose chemotherapy, with

an anticipated CNS prophylactic effect as well. This is also true for the conditioning regimen (see

later), that all children are supposed to get. There is virtually no literature available on CNS

prophylaxis and treatment in this patient-group to further refine or substantiate the

recommendations given in this protocol, which were therefore extensively discussed and agreed

upon.

Consolidation chemotherapy

To consolidate an achieved CR, and to have time to prepare a transplant if not available

immediately, further chemotherapy seems indicated. Whether this is really necessary and if so,

which drugs should be used, is essentially unknown. Yet, in these high-risk patients, further

intensive treatment seems justified. Therefore, a schedule of VP16 and cytarabine given by

continuous infusion has emerged. In case of a delayed SCT and a contra-indication for this high-

intensity consolidation regimen, a low-intensive combination of orally thioguanine and cytarabine

subcutaneously is proposed. Extensive experience with this regimen has been obtained within the

BFM-AML protocols.

Stem cell transplantation (SCT)

Allogeneic SCT is associated with major morbidity and mortality. Therefore, allogeneic SCT

should be considered in the context of the prognosis with chemotherapy only. In patients with

primary refractory and relapsed AML, this prognosis is very poor. Moreover, few long-term

survivors have been described after chemotherapy only for this particular disease, in contrast to

chemotherapy followed by SCT. Although not proven in properly designed randomised clinical

trials, allogeneic SCT may have a bigger impact on the prognosis than autologous SCT, because:

1) a graft-versus-leukemia effect may be present in the allogeneic, but not (or less) in the

autologous setting, and 2) the autologous transplant is likely to contain minimal residual leukemia

cells, which may cause a relapse. On the other hand, allogeneic SCT may be complicated by

graft-versus-host-disease. We do recommend allogeneic SCT for all patients who achieve CR,

preferably using a matched sibling donor (MSD), or if not available, a matched unrelated (MUD)

donor. Patients with refractory disease or early relapse and lack of a matched donor might be

eligible for an alternative or experimental allogeneic SCT. In late relapses without a matched

donor, autologous SCT may be used. There are several proposals for the conditioning regimen,

including a combination of busulfan, cyclophosphamide and melphalan. Experiences using this

regimen in children with myelodysplastic syndrome were good (Locatelli 1994). Depending on the

type of donor, additional immunosuppression may be required in conditioning. Patients who were

not irradiated previously and who will have a SCT for the 1st time should have for instance

TBI/cyclophosphamide (also depending on age) as conditioning instead of busulfan,

cyclophosphamide and melphalan.


- 31 -

Conclusion

The above summary shows that the DNX-FLAG regimen seems relatively effective with tolerable

toxicity. Another point of concern is the cardiotoxicity of anthracyclines, which is a major potential

problem in these patients because of their initial treatment leading to high cumulative doses of

these drugs already. However, anthracyclines are among the most effective drugs in AML.


- 32 -

Special measures for reinduction

High cell counts

Patients with high peripheral blast counts (>50-100x109/l) and significant organomegaly have

increased problems related to metabolic abnormalities, bleeding, and hyperviscosity. Platelets

should be transfused if < 15-30x109/l; in this phase, hemoglobin should not be raised above 6

mmol/l (= 9,6 g/dl); treatment of coagulation disorders is required. The use of leukopheresis,

exchange transfusion, or hemodialysis may be necessary. To prevent tumor lysis syndrome, the

patient should be well hydrated, alkalinized and get allopurinol before start of therapy:

Allopurinol: 200-300 mg/m2 p.o. divided q 8-12 hours; give at least 2 doses prior to

initiation of therapy (alternatively, uricozyme may be used)

Hydration: 2400-3000 ml/m2/day; be careful with potassium containing solutions;

electrolyte substitions only based on laboratory results; check fluid balance

NaHCO3: 4 g/m2/day (= 50 mEq/m2/day) to maintain urine pH 7-8

High dose ARA-C

During cytarabine and for 24-48 hours after completion, dexamethasone ophthalmic solution or

isotears (q 6 hours) should be used to prevent cytarabine induced conjunctivitis.

Because of the association of streptococcus viridans infection and high dose cytarabine, penicillin

prophylaxis is recommended from completion of cytarabine administration until neutrophil

recovery.

Nurses and doctors should be aware of the relatively high (up to 15%) incidence of neurotoxicity,

which may necessitate to interrupt or stop high-dose cytarabine administration.

Pyridoxine (300 mg/m2/day in 2 doses) might ameliorate cytarabine-induced mucositis.

Granulocyte colony stimulating factor

G-CSF will be used as part of the FLAG regimen (please refer to “background and introduction”).

After discontinuation at day 6 it is recommended to restart G-CSF at day 15 of each reinduction

course in order to shorten the period of neutropenia in these patients who all are at high risk for

severe infections, of which the occurrence is correlated with the duration of neutropenia. G-CSF

can be stopped again upon neutrophil recovery, as locally defined. The use of G-CSF for

prevention or treatment of chemotherapy induced fever and neutropenia before day 15 is

considered useless.

Irradiation of blood products

Mainly due to fludarabine and body irradiation, profound and long term lymphocytopenia can be

expected to occur. Therefore, cellular blood products should be irradiated with 25 Gy to prevent

transfusion related graft versus host disease, at least up to 6 months after the last fludarabine

administration. Of course, all blood products should be leukocyte-depleted as well. Similarly,

irradiation and leukocyte-depletion of the blood products is required at least up to 6 months after

SCT.

REINDUCTION FLAG + DaunoXome®

Perform BMA and LP first!

BMA after course 1 not earlier than 28 days after the start of course 1, but in case of delay, not

later than day 42 after the start of course 1.

Relapsed AML Registry I-BFM-SG

DNX-FLAGReinduction

L-DNR 80 mg/m²/d day 1,3,5120min infusion

Fludarabine 30 mg/m²/d day 1 to 5

30min infusion

Cytarabine 2000 mg/m² day 1 to 53hr infusion

G-CSF 200 g/m2/dosesubcut. or i.v. (for 6 days,given before fludarabine)

Cytarabine/Pred/Mtx i.th. day 1

day

LP

BMP BMP

0 1 2 3 4 5 6

Relapsed AML2009 registryversion 2


- 33 -

2nd REINDUCTION FLAG

Course 2 may start not earlier than 28 days after the start of course 1, and only in case of good

clinical condition, platelets > 50x109/l (without transfusions) and neutrophils > 1.0x109/l. An

exception are patients with partial remission after course 1, who retain too low neutrophils and/or

platelets, likely to be due to residual leukemia. These patients – if in good enough clinical

condition – may continue treatment irrespective of the blood counts, after BMA.

FLAGReinduction

G-CSF 200µg/m²/d SC/IV day 0 to 5

Fludarabine 30 mg/m²/d day 1 to 530 min IV infusion, after G-CSF

Cytarabine 2000 mg/m²/d day 1 to 53hr IV infusion, begin 4 h after start of Fludarabine

Cytarabine/Pred/MTX day 1

IT bolus injection, age related dosage

day

LP

BMP

0 1 2 3 4 5

In case of a body weight <12 kg, calculate dose according to weight as follows: [weight (kg) x dose (per m2)] /30.

10 mg8 mg6 mg4 mgPred

12 mg10 mg8 mg6 mgMTX

30 mg26 mg20 mg16 mgAraC

3 year2<3year1<2year<1 year


- 34 -

CONSOLIDATION - high intensity

Perform BMA + LP first! BMA after the 2nd reinduction course not earlier than 28 days after the

start of course 2, but in case of delay, not later than day 42 after that start.

If no CR after course 2: eligible for alternative options

To be started not earlier than 28 days after the start of course 2, and only in case of good clinical

condition, platelets > 50x109/l (without transfusion) and neutrophils > 1.0x109/l

To be given as consolidation to all patients, if a SCT is not available immediately.

Cytarabine 500 mg/m²/d day 1-496 hrs continous IV infusion

Etoposide 100 mg/m²/d day 1-5 3hr IV infusion

Cytarabine/Pred/MTX day 1

IT bolus injection, age related dosage

LP

BMP

1 2 3 4 5 6

10 mg8 mg6 mg4 mgPred




day



- 35 -

CONSOLIDATION - low intensity

Perform BMA and LP first! BMA after the 2nd reinduction course not earlier than 28 days after the

start of course 2, but in case of delay, not later than day 42 after that start. If no CR after course 2:

off study

To be started not earlier than 28 days after the start of course 2, and only in case of good clinical

condition, platelets > 50x109/l (without transfusion) and neutrophils > 1.0x109/l

To be given only if a SCT is not available immediately, to patients who will not tolerate the 3rd

course of high-intensity consolidation chemotherapy.

Consolidation

Thioguanine 100 mg/m2/d day 1 to 28PO once daily (evenings)

Cytarabine 75 mg/m2/d day 1 to 4SC bolus injectionday 15 to 18

Cytarabine/Pred/MTX day 1IT bolus injection, age adjusted dosage

LP

BMP

1 4 15 18 28 day10 mg8 mg6 mg4 mgPred





Criteria for reduction or discontinuation of consolidation therapy:

% Dose

6-Thioguanin Leukocytes > 3.0x109/l 150

Leukocytes > 2.0x109/l; < 3.0x109/l 100

Leukocytes > 1.0x109/l; < 2.0x109/l 50

Leukocytes < 1.0x109/l 0

Cytarabine Leukocytes > 2.0x109/l and

Platelets > 80x109/l 100

Below these counts discontinuation for 1 week


- 36 -


- 37 -

CNS PROPHYLAXIS AND TREATMENT

Prophylaxis:

There should be no evidence of CNS leukemia (see below).

Cytarabine/ methotrexate/ prednisolone should be administered three times, intrathecally at age-

adjusted doses (Table), via a lumbar puncture (LP). Give the first and second dose one day

before the start of reinduction course 1 and 2 respectively (not simultaneously with high dose

cytarabine). Give the third dose at the start of consolidation treatment. Cranial irradiation is not

recommended.

Table. Intrathecal medication (LP) in case of CNS prophylaxis

Age

mg/dose mg/dose

Cytarabine Methotrexate Prednisolone

mg/dose

<1 year 16 6 4

1<2 year 20 8 6

2<3 year 26 10 8

3 years 30 12 10

Treatment of CNS leukemia

CNS leukemia is defined on page 31. Triple intrathecal medication at age-adjusted doses (Table),

by LP. The first dose should be given immediately before the start of reinduction course 1. The

second and subsequent doses should be given every 7 days until 1 week after complete

clearance of the CSF of leukemic blasts. Then, 2 more doses must be given, one immediately

before the start of the second reinduction course, and the other at the start of consolidation

treatment.

Table. CNS leukemia: Intrathecal medication via lumbar puncture or reservoir; to be given every

week until 1 week after complete blast clearance of the CSF.

Age Cytarabine

mg/dose, every week

Methotrexate

mg/dose, every week

Prednisolone

mg/dose, every week

<1 year 16 6 4

1<2 year 20 8 6

2<3 year 26 10 8

3 years 30 12 10

Cranial irradiation is not recommended, but may be considered in those patients who do achieve

complete remission but who will not undergo SCT, and who did not receive cranial irradiation in

the past.

STEM CELL TRANSPLANTATION

All patients should be treated according to the AML-SCT synopsis (see attachment)


- 38 -

Overview drugs

Cytarabine

This nucleoside analogue (pyrimidine antagonist) is an antimetabolite that is mainly metabolised

in the liver. It may cause myelosuppression, hepatotoxicity, exanthema, malaise, and gastro-

intestinal toxicity such as nausea, vomiting, stomatitis, and ileus. At high doses, fever, severe

diarrhea, central nervous system disturbances such as somnolence, cerebellar ataxia and

nystagmus, keratitis, veno-occlusive disease, pneumonitis and adult respiratory distress

syndrome with streptococcus viridans infection are possible. Intrathecal administration has been

associated with headache, fever, vomiting, and pleiocytosis, rarely with aseptic meningitis or

central nervous system disturbances. To prevent keratitis, indifferent or corticoid eye drops every

4-6 hours are recommended during and until 12 hours after stopping cytarabine. Prolonged

corticoid eye drops have side-effects as well, such as infection. Conjunctivitis should be treated

with corticoid eye drops. To prevent streptococcal infection, penicilline prophylaxis may be

considered starting as soon as neutropenia develops after high-dose cytarabine until neutrophils

> 0.5x109/l. Patients who developed grade 3 or 4 neurotoxicity following high-dose cytarabine

should not receive further high-dose cytarabine, but are eligible for continuous lower-dose

cytarabine.

Fludarabine

This nucleoside analogue (purine antagonist) is an antimetabolite that is excreted mainly in the

urine. After phosphorylation, it is less susceptible to deamination than cytarabine. Main side-

effects are myelosuppression, fever, chills, malaise, nausea, and vomiting. More rare are auto-

immune phenomena (hemolytic anemia), pneumonitis, and CNS symptoms such as agitation.

Since it causes profound and long-term lymphocytopenia, irradiation of blood products to prevent

graft-versus-host disease and antifungal prophylaxis is strongly recommended, from the start of

treatment until 6 months after SCT or if SCT is not being perfomed until 6 months after the last

administration of fludarabine.

G-CSF

This is a drug produced in E. coli by recombinant DNA technology that stimulates the production

of neutrophils in the bone marrow. Side-effects occur occasionally, and concern beside local

irritation mainly bone pain, vasculitis and thrombocytopenia. G-GSF can be administered both

subcutaneously and i.v., but for the latter administration special attention has to be given to the

instructions for dilution and administration.

Liposomal daunorubicin (DaunoXome®)

This drug is the combination of an anthracycline with a unilamellar liposomal transport system.

Daunorubicin is released slowly, and then mainly excreted in the bile, less so in the urine.

Daunorubicin itself is metabolised to daunorubicinol, which is again mainly excreted in the urine

and in the bile. The drug should be soluted in dextrose 5% only, because of agglutination in other

solutions! Although not reported for DaunoXome®, the concomitant use of daunorubicin with

heparin or dexamethasone i.v. is complicated by precipitation. Therefore, these drugs should not

be used simultaneously i.v. with DaunoXome®. Because of its composition, care should be taken

when using DaunoXome® concomitantly with parenteral nutritional lipid solutions or other

liposmal products. Side-effects that have been described were nausea, vomiting, mucositis,

hepatotoxicity and the dose-limiting toxicity is myelosuppression. Cardiotoxicity is rare, but has


- 39 -

been documented both without (decreased left ventricular ejection fraction) and with clinical

symptoms (congestive heart failure).

In case of a fractional shortening at echocardiography below 29%, DaunoXome® should not be

given, at least not as part of this register. Another relative contra-indication is a previous serious

hypersensitivity reaction to DaunoXome® or any of its constituents.

In case of hepatic disturbances before the first administration of DaunoXome®, a reduction for all

three doses is recommended:

Transaminases >3-5 times upper normal limit (UNL): reduction of 25%.

Transaminases >5-10 times UNL: reduction of 50%

Transaminases >10 times UNL: not eligible

All three doses of DaunoXome® should be similar, in other words, no further reductions after the

first dose.

Thioguanine

This purine antagonist is an antimetabolite that is metabolised rapidly and then excreted renally. It

may cause myelosuppression, nausea, vomiting, anorexia, mucositis, diarrhea, hepatotoxicity,

and veno-occlusive disease.


- 40 -

Supportive Care

The treatment to be given is aggressive and immunosuppressive. Therefore, meticulous care is

required in the management of patients entering the study (Riley 1999).

General measures

* Venous access: placement of a double lumen central venous catheter for administration of

chemotherapy, nutrients, antibiotics and blood products is strongly advised.

* Tumor lysis prevention: to prevent tumor lysis syndrome, the patient should be well hydrated,

alkalinized and placed on allopurinol (or uricozyme) before initiation of therapy (see also page 14)

* Nutrition: the combination of chemotherapy induced vomiting, mucositis, infection, and

hemorrhage may result in significant weight loss. Progressive weight loss should be treated

aggressively with supplemental enteral or parenteral nutrition; enteral feedings are preferred to

parenteral; adjustment of the diet (p.e. no lactose or semi elementary) may be beneficial. Because

melphalan competes with phenylalanine for cellular uptake, amino acids as part of parenteral

nutrition should not be given one day before and two days following melphalan

* Nill-by-mouth: when enteral feedings must be withheld, protection of the gastric mucosa should

be initiated

* Antiemetics: prophylactic antiemetic therapy should be instituted to prevent chemotherapy

induced nausea and vomiting. Steroids should not be used in case of (suspected) fungal

infections.

* Mucositis: meticulous oral hygiene is required; tooth brushing, hydrogen peroxide, saline and

bicarbonate rinses; chlorhexidine solution; liberal use of pain medication for this condition is

encouraged. Stomatitis due to herpes virus may be confused with drug induced mucositis;

therefore, viral cultures should be obtained frequently. Anti-herpetic and anti-fungal therapy

should be given as indicated.

* Conjunctivitis prophylaxis: during cytarabine and for 24-48 hours after completion,

dexamethasone ophthalmic solution or isotears (q 6 hours) should be used to prevent cytarabine

induced conjunctivitis.

* Suppression of menstruation: menstruating females should receive depo-provera or another

suppressant during the entire course of the protocol until the platelet count is >40-50x109/l without

transfusion support.

* Vaccinations: these should be postponed till after completion of treatment

* Physical therapy: timely exercises for preventing and maintaining optimal motor skills are

recommended

* Psychosocioeconomic support: recommended

* Prevention and treatment of pain: according to local guidelines

Hyperleukocytosis and metabolic derangement

Patients with high peripheral blast counts (>50-100x109/l) and significant organomegaly have

increased problems related to metabolic abnormalities, bleeding, and hyperviscosity. Therefore,

special measures for reinduction are indicated and are described on page 14.


- 41 -

Prevention and treatment of infections

Prevention:

* mandatory hospitalization during and after treatment courses until the absolute neutrophil count

is rising (and depending on the clinical condition)

* barrier nursing

* HEPA air filtration in the nursing room if available

* oral hygiene (see above)

* treatment of infectious foci before initiating therapy: ENT, dental prior to initiating therapy;

multiple dental extractions may be necessary.

* surveillance cultures may be considered, according to local guidelines; routine culture of throat

to detect the presence of penicillin-resistant streptococcus

* test for toxoplasmosis, hepatitis viruses, CMV, varicella and HSV antibodies

* bowel decontamination may be considered, according to local guidelines (Guiot 1983)

* prophylactic antibiotics in case of bacteriaemia causing operations

* pneumocystis carinii prophylaxis with trimethoprim-sulfamethoxazole, e.g. 150/750 mg/m2/day

for 3 consecutive days every week (Hughes 1987); alternatives: dapsone or aerosolized

pentamidine

* because of the association of streptococcus viridans infection and high dose cytarabine,

penicillin prophylaxis is recommended from completion of cytarabine administration until

neutrophil recovery

* prophylactic treatment of fungal (including aspergillus) infections is recommended: e.g. with oral

itraconazole (liquid!, 5-10 mg/kg/day in 1-2 doses, maximum 600 mg/day)

* at the time of stem cell transplantation, prophylactic acyclovir for patients with positive HSV titers

* administration of zoster hyper immune globulin within 48 hours after a real varicella contact

* Restarting G-CSF at day 15 of each of both reinduction courses is recommended to reduce the

duration of neutropenia. G-CSF should be stopped again upon neutrophil recovery, as defined by

local guidelines.

Treatment in case of fever and neutropenia:

Because of the high risk of serious infectious complications, patients developing fever should be

treated for presumed sepsis with broad spectrum antibiotics. Because of the association of high

dose cytarabine with streptococcus viridans infection and because of the possibility of a

contaminated central venous line (staphylococci) the antibiotic regimen should include drugs

specific for the treatment of an infection with gram-positive bacteria (vancomycin, teicoplanin).

Antifungal therapy, such as amphotericin B should be administered when defervescence does not

occur within 3-5 days.

AML treatment is associated with a high risk of pulmonary aspergillus; however,

pulmonary infiltrates can also be caused by bacteria, virus (CMV), legionella and PCP; therefore,

agressive diagnostic measures including (repeated) high resolution CT scans, bronchoscopy with

biopsy or bronchoalveolar lavage, and open lung biopsy, should timely be contemplated.

G-CSF, if not given already, may be considered to reduce the duration of neutropenia, in

patients with life-threatening bacterial or fungal infections.

Treatment in case of a documented infection:

The empiric treatment may be adjusted when a specific cause for the infectious symptoms is

found, although broad-spectrum antibiotics remain (at least initially) indicated in case of

neutropenia.


- 42 -

G-CSF

Granulocyte colony stimulating factor (G-CSF) will be used as part of the FLAG regimen from the

day before starting fludarabine until the first day after fludarabine (for a total of 6 days). Adding G-

CSF to FLA has been decided because the pilot-studies were done with FLAG and because of

several papers describing favorable interactions of G-CSF with fludarabine and cytarabine

(Braess 2000, Gandhi 1995; see also “background and introduction”). After the discontinuation it

is recommended to restart G-CSF at day 15 of each reinduction course in order to shorten the

period of neutropenia in these patients at high risk for severe infections, of which the occurrence

is correlated with the duration of neutropenia. G-CSF appears safe in that it had no negative

impact on the prognosis of adult AML in 2 large randomised studies (Godwin 1998, Heil 1997),

and its use reduced duration of neutropenia, fever, hospitalisation, and use of antibiotics and

antifungals (Chen 1998, Godwin 1998, Heil 1997). G-CSF should be stopped again upon

neutrophil recovery, as locally defined. The use of G-CSF before day 15 of each course for

prevention or treatment of chemotherapy induced fever and neutropenia is considered useless,

although this has not been studied in this particular setting.

Transfusion support

* Bleeding due to thrombocytopenia should be treated promptly; during the induction period and

throughout admissions for fever and neutropenia, it is recommended that the platelet count be

maintained >15-30x109/l. Higher tresholds may be indicated, for instance in case of lumbar

punctures and surgery.

* Packed red blood cell transfusions should be used to correct hypovolemia from blood loss or

pre-existing anemia (Hb < 5 mmol/l = 8,0 g/dl). Higher threshold levels may be indicated in case

of pneumonitis or (imminent) bleeding or other causes of a compromised clinical condition.

* The blood products should be leukocyte-depleted to prevent HLA sensibilization; leukocyte-

depleted blood products can be considered CMV-safe.

* To prevent transfusion related graft versus host disease, cellular blood products should be

irradiated (25 Gy) during and at least till 6 months after fludarabine, in case of (imminent)

lymphopenia (< 500/ml), and from 2 weeks before till at least 6 months after stem cell

transplantation.

* In case of allo-immunization HLA-matched platelets may be required.

2. During initial treatment, i.e. the 1st course, to monitor the disease:

- At least twice weekly a complete hematological count and serum chemistry are needed as

described above

- a twice or more weekly physical examination is performed

- at day +15 after the start of reinduction treatment a bone marrow sample is obtained to

determine early clinical response, which may be different between both treatment arms and

which may have prognostic significance. Slides should also be send to the reference

laboratory for morphological (and flowcytometrical) examination, together with peripheral

blood slides.


- 43 -

1. Before the start of each treatment course the remission status and toxicity should be

determined.

- bone marrow and peripheral blood morphology (with central review by the reference

laboratories)

- lumbar punction (quantification of cells and protein, pathological examination of the CSF)

- physical examination

- complete blood count and blood chemistry (see above)

- echocardiography (see page 30)

- the patient should be followed for events (relapse/death), both after discontinuation of

treatment according to this protocol and after proceeding to bone marrow transplantation.

Toxicity data must be determined according to the NCI Common Toxicity Criteria after each

treatment course, with special attention for cardiac abnormalities. The Therapy Checklist must be

documented carefully.

Serious adverse events (defined on page 31) must be reported immediately to the central data

office in Hannover (as well as to the own data center).

Table 1. Investigations before, during and after initial treatment.

Before

start of

treatme

nt

Weekly Day 15 after

start of

course I

Weekly Day 28-42 after

start of course I

Medical history *

Physical examination * Twice or more * Twice or more *

Performace status * * *

Therapy checklist * * * * *

Hematology (see text) * Twice or more * Twice or more *

Chemistry (see text) * Twice or more * Twice or more *

Bone marrow

punction1

* * *

Send BM and PB to

reference laboratory

* * *

Send bone marrow to

Amsterdam for drug

resistance studies

(research)

*

BM and PB for MRD

(central laboratories;

research)

* * *

Lumbar puncture * *

Echocardiography * *

1In case of a dry tap, perform a biopsy


- 44 -

Cardiotoxicity monitoring

Why: to determine possible short- and long-term cardiotoxicity, and to detect any differences in

the incidence and severity of cardiotoxicity in patients who did or did not receive liposomal

daunorubicin.

When: Echocardiography should be performed within 1 week before start of reinduction

treatment, within 1 week prior to the second course (FLAG), within 1 week prior to the

conditioning regimen as part of SCT, and 6 months after SCT. In case of a normal FS of >28%,

then repeat echocardiography every 3 years (earlier if clinically indicated). In case of an abnormal

FS, then repeat echocardiography at least every year. Additional echocardiography (and other

monitoring) may be indicated in case of growth spurt, involvement in regular strenuous exercise,

growth hormone and/or sex hormone replacement therapy and in case of pregnancy.

How: M-mode echo measurements according to the American Heart Association guidelines.

Whenever possible, the patient should be afebrile and have a normal haemoglobin (>9 g/dl, >5.6

mmol/l). If an ECG is not recorded simultaneously with M-mode echo, greatest and least LV

dimensions should be used for diastolic and systolic measurements respectively. Please note the

date of each scan, along with the height, body weight, and three blood pressure measurements

(preferably obtained during the last part or immediately after the echo; ensure that the cuff is in

place before starting the echocardiography), as well as initials, gender, race, and identification

number.

Please save all the information of one patient on one (or more) tape (VHS/S-VHS) to allow central

review at a later stage. At least, save the recordings on tape, and note which type of echo-

machine was used.

What:

- Attach ECG

- Baseline echocardiogram: apical 4 chamber view

apical 5 chamber view (with aorta)

short axis left ventricle (papillary muscle level)

short axis left ventricule (aortic valve/pulmonary

artery level)

- Baseline colour Doppler: apical 4 chamber (mitral, tricuspid, aortic flows)

- Pulsed Doppler: aortic flow (measurement of LVET)

mitral valve (tips of mitral valve leaflets)

- M-mode: left ventricle – parasternal long axis

M-mode cursor perpendicular to interventricular septum in a plane where the mitral valve and

aorta (aortic valve) are visible

M-mode cursor immediately below tips of mitral valve

Confirm on tape that the M-mode cursor is positioned correctly

M-mode recording of aortic valve opening (for LVET) if aortic Doppler was not obtained (see

above)

Record a minimum of 10 good quality cardiac cycles

Record blood pressure (see above)

Fractional Shortening will be used as main measurement of cardiac function.


- 45 -

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- 48 -

Acute event form

To: International Data Office

FAX: +49 – 511 532 9029


And to: Local Data Office of the Own Group

FAX:

E-mail:

Date:

This is to inform you that we have observed a serious adverse event in a patient with relapsed or

refractory AML

Reporting pediatric oncologist/treating physician:

Name:

Center:

Phone:

Fax:

E-mail:

Please indicate:

- death Y/N

- life-threatening Y/N

- permanently disabling Y/N

Comments:


- 49 -

Performance scales

Lansky score: 0-16 years

Fully active 100

Minor restriction in normal physical activity 90

Active, but tires more quickly 80

Both greater restriction and less time spent in active play 70

Minimal active play, busy with quieter activities 60

Gets dressed, but no active play, able to participate in all quiet play

and activities

50

Mostly in bed, participates in quiet activities 40

In bed, needs assistance even for quiet play 30

Often sleeping, play limited to passive activity 20

No play, does not get out of bed 10

Unresponsive 0

Karnofsky score: 16 years and older

Normal, no complaints, no evidence of disease 100

Able to carry on normal activities 90

Normal activity with effort 80

Cares for self, unable to carry on normal activity or to do active

work

70

Requires occasional assistance, is able to care for most of own

needs

60

Requires considerable assistance, frequent medical care 50

Disabled, requires special care/assistance 40

Severely disabled, hospitalization 30

Hospitalization, very sick, active treatment 20

Moribund, fatal processes in progression 10

Dead 0


- 50 -

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cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of

childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II

trial. Br J Haematol. 1998;102:647-655.

2. Fleischhack G, Graf N, Hasan C, Ackermann M, Breu H, Zernikow B, Bode U. [IDA-FLAG

(idarubicin, fludarabine, high dosage cytarabine and G-CSF)--an effective therapy regimen in

treatment of recurrent acute myelocytic leukemia in children and adolescents. Initial results of a

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myeloid leukemia. Eur J Haematol. 2004;72:58-60.

6. de la RJ, Regadera A, Martin G, Cervera J, Sanz G, Martinez J, Jarque I, Garcia I, Andreu R,

Moscardo F, Jimenez C, Molla S, Benlloch L, Sanz M. FLAG-IDA regimen (fludarabine,

cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid

malignancies. Leuk Res. 2002;26:725-730.

7. Luczynski W, Muszynska-Roslan K, Krawczuk-Rybak M, Kuzmicz M, Iwaszkiewicz-Pawlowska

A, Kaliszewski J. Results of IDA-FLAG programme in the treatment of recurrent acute

myeloblastic leukaemia--preliminary report. Med Sci Monit. 2001;7:125-129.

8. Steinmetz HT, Schulz A, Staib P, Scheid C, Glasmacher A, Neufang A, Franklin J, Tesch H, Diehl

V, Dias WP. Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-

FLAG) for treatment of refractory, relapsed, and secondary AML. Ann Hematol. 1999;78:418-425.

9. Latagliata R, Breccia M, Fazi P, Iacobelli S, Martinelli G, Di Raimondo F, Sborgia M, Fabbiano F,

Pirrotta MT, Zaccaria A, Amadori S, Caramatti C, Falzetti F, Candoni A, Mattei D, Morselli M,

Alimena G, Vignetti M, Baccarani M, Mandelli F. Liposomal daunorubicin versus standard

daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients

older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008;143:681-689.

10. Camera A, Rinaldi CR, Palmieri S, Cantore N, Mele G, Mettivier V, Miraglia E, Mastrullo L,

Grimaldi F, Luciano L, Guerriero A, Rotoli B, Ferrara F. Sequential continuous infusion of

fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in

primary refractory or relapsed adult acute myeloid leukemia patients. Ann Hematol. 2009;88:151-

158.

11. Fassas A, Anagnostopoulos A. The use of liposomal daunorubicin (DaunoXome) in acute myeloid

leukemia. Leuk Lymphoma. 2005;46:795-802.

12. Clavio M, Venturino C, Pierri I, Garrone A, Miglino M, Canepa L, Balleari E, Balocco M,

Michelis GL, Ballerini F, Gobbi M. Combination of liposomal daunorubicin (DaunoXome),

fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia. Ann Hematol.

2004;83:696-703.

13. Russo D, Piccaluga PP, Michieli M, Michelutti T, Visani G, Gugliotta L, Bonini A, Pierri I, Gobbi

M, Tiribelli M, Fanin R, Piccolrovazzi S, Baccarani M. Liposomal daunorubicin (DaunoXome) for

treatment of poor-risk acute leukemia. Ann Hematol. 2002;81:462-466.

14. Piccaluga PP, Visani G, Martinelli G, Isidori A, Malagola M, Rondoni M, Baccarani M, Tura S.

Liposomal daunorubicin (DaunoXome) for treatment of relapsed meningeal acute myeloid

leukemia. Leukemia. 2002;16:1880-1881.

15. Muggia FM. Liposomal encapsulated anthracyclines: new therapeutic horizons. Curr Oncol Rep.

2001;3:156-162.

16. Kaspers GJ, Zimmermann M, Fleischhack G, Tamminga R, Gibson B, Armendariz H et al.

Relapsed Acute Myeloid Leukemia in Children and Adolescents: Interim Results of the

International Randomised Phase III Study Relapsed AML 2001/01. 5th Bi-annual Symposium on

Childhood Leukemia, Noordwijkerhout, The Netherlands: 2006.


- 51 -

17. Kaspers GJ, Zimmerman M, Fleischhack G et al. Relapsed Acute Myeloid Leukemia in Children

and Adolescents: Interim Report of the International Randomised Phase III Study Relapsed AML

2001/01 [abstract]. Blood. 2006;108:570a.

18. Kaspers GJ, Zimmermann M, Reinhardt D et al. Prognostic Significance of Early Treatment

Response in Pediatric Relapsed Acute Myeloid Leukemia: Results from the International Study

Relapsed AML 2001/01 [abstract]. Blood. 2007;110:546a.

19. Kaspers GJL, Zimmermann M, Reinhardt D et al. Clinical Relevance of Early Treatment Response

in Pediatric Relapsed Acute Myeloid Leukemia (AML): Study Relapsed AML 2001/01 [abstract].

Ann Hematol. 2008;87:S2.

20. Kaspers GJL, Zimmermann M, Reinhardt D et al. Prognostic Significance of Time to Relapse in

Pediatric AML: Results from the International Randomised Phase III Study Relapsed AML

2001/01 [abstract]. Blood. 2008;112:1022-1023.

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Appendix Common Toxicity Criteria Name/Initials:

Toxicity during therapy elements of the International Registry Relapsed AML 2009 Course: FLAG/DNX 1 FLAG 2 Consol. high int. Consol. low int. other ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Please check the appropriate field in each parameter(Classification according to NCI Common-Toxicity-Criteria, modified by SIOP, from: GPOH: Data Management Workgroup)

Grade 0 1 2 3 4 5 n.d

general condition normal

activity

mild impairment age-related activities

strongly decreased

bedridden, in need of

care

intensive care, very

sick

death n.d.

Toxicity: Hematology

Hemoglobin

(g/dl)

normal for age > 10.0 8.0 – 10.0 6.5 – 7.9 < 6.5 n.d.

WBC (109/l) > 4.0 3.0 - 3.9 2.0 - 2.9 1.0 - 1.9 < 1.0 n.d.

Granulo’s (109/l) > 2.0 1.5 - 1.9 1.0 - 1.4 0.5 - 0.9 < 0.5 n.d.

Platelets (109/l) > 100 75 - 100 50 - 74.9 10 - 49.9 < 10 n.d.

Infections

Infection none mild moderate, pathogen

not identified; I.V.

antibiotics

severe, pathogen

identified; I.V.

antibiotics

life threatening, with

hypotension

death n.d.

fever (°C) none 37.1 - 38 38.1 - 40 > 40 for < 24 h. > 40 for >= 24 h. n.d.

Toxicity: nausea n.d.

nausea none adequate food

intake

can eat, decreased

intake

almost no food intake TPN necessary n.d.

vomiting (No of

episodes in 24h)

0 1 2 - 5 6 - 10 >10 or TPN

necessary

n.d.

Mucous membrane toxicity

stomatitis none painless ulcer,

erythema

painful erythema or

ulceration, can still

eat

painful erythema or

ulceration, cannot eat

TPN required, due to

stomatitis

n.d.

diarrhea(stools/day)

none 2 -3 4-6 or nightly stool

or light cramps

7 - 9 or incontinence or

severe cramps >= 10 or bloody

diarrhea or TPN

n.d.

Skin toxicity n.d.

changes in the

skin

None erythema dry desquamation,

vasculitis, pruritus

moist desquamationen,

ulcerations

exfoliative

dermatitis, necroses

death n.d.

Kidney toxicity

creatinine normal for age < 1.5 x norm. 1.5. - 3.0 x n. 3.1 - 6.0 x n. > 6.0 x n n.d.

proteinuria (g/l) None < 3 3 - 10 > 10 nephrot. Syndrome n.d.

hematuria None microscopic macroscopic, no

clots

macroscopic, clots Transfusion required n.d.

creatinine-

clearence

>= 90 60 - 89 40 - 59 20 - 39 <= 19 n.d.

Liver toxicity

bilirubin normal for age < 1.5 x n. 1.5. - 3 x n. > 3 – 10 x n. > 10 x n n.d.

SGOT / SGPT normal for age <= 2.5 x n. 2.6 - 5.0 x n. 5.1 - 20.0 x n. > 20 x n. n.d.

Cardiac toxicity death n.d.

arrhythmia None Asympt., no

therapy

recurr./persist., no

therapy

therapy required hypotension, ventr.

arrhyth.,defibrillation

death n.d.

cardiac function Normal Asymptomat., EF

of <20% of

baseline

asymptomat., EF

of >20% of baseline

mild CHF,

therapeutically

compensated

severe / refractory

CHF

death n.d.

echocardio.: LV-

SF

> 30 % > 25% - <= 30 % > 20 % - <= 25 % > 15 % - <= 20 % <= 15 % n.d.

Neurological toxicity

Central

neurotoxicity

None mild somnolence,

or agitation;

drowsiness

somnolence < 50%

of the time,

moderate

disorientation

somnolence > 50% of

the time, severe

disorient.,

hallucinations

coma, seizures death n.d.

Peripheral

neurotoxicity

None paresthesias, mild

subjective weakness

severe paresthesias

and/or mild

weakness

unbearable

paresthesias, deficits in

motor funct.

paralysis death n.d.

Hemoglobin: g/dl x 0.62 = mmol/l; SGOT/SGPT = ASAT/ALAT; Other toxicity: _______________________

Date______________________ Signature: _______________________

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Inte

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AM

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DE

International Registry Relapsed AML 2009, Supplementary Form

Page 2/2

Appendix Common Toxicity Criteria Name/Initials:

Treatment of Children and Adolescents with Refractory or Relapsed AML FAB M 3 with Arsenic Trioxide (ATO)________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Please check the appropriate field in each parameter(Classification according to NCI Common-Toxicity-Criteria, modified by SIOP, from: GPOH: Data Management Workgroup)

Grade 0 1 2 3 4 5 n.d

general condition normal

activity

mild impairment age-related activities

strongly decreased

bedridden, in need of

care

intensive care, very

sick

death n.d.

Toxicity: Hematology

Hemoglobin

(g/dl)

normal for age > 10.0 8.0 – 10.0 6.5 – 7.9 < 6.5 n.d.

WBC (109/l) > 4.0 3.0 - 3.9 2.0 - 2.9 1.0 - 1.9 < 1.0 n.d.

Granulo’s (109/l) > 2.0 1.5 - 1.9 1.0 - 1.4 0.5 - 0.9 < 0.5 n.d.

Platelets (109/l) > 100 75 - 100 50 - 74.9 10 - 49.9 < 10 n.d.

Infections

Infection none mild moderate, pathogen

not identified; I.V.

antibiotics

severe, pathogen

identified; I.V.

antibiotics

life threatening, with

hypotension

death n.d.

fever (°C) none 37.1 - 38 38.1 - 40 > 40 for < 24 h. > 40 for >= 24 h. n.d.

Toxicity: nausea n.d.

nausea none adequate food

intake

can eat, decreased

intake

almost no food intake TPN necessary n.d.

vomiting (No of

episodes in 24h)

0 1 2 - 5 6 - 10 >10 or TPN

necessary

n.d.

Mucous membrane toxicity

stomatitis none painless ulcer,

erythema

painful erythema or

ulceration, can still

eat

painful erythema or

ulceration, cannot eat

TPN required, due to

stomatitis

n.d.

diarrhea(stools/day)

none 2 -3 4-6 or nightly stool

or light cramps

7 - 9 or incontinence or

severe cramps >= 10 or bloody

diarrhea or TPN

n.d.

Skin toxicity n.d.

changes in the

skin

None erythema dry desquamation,

vasculitis, pruritus

moist desquamationen,

ulcerations

exfoliative

dermatitis, necroses

n.d.

Kidney toxicity

creatinine normal for age < 1.5 x norm. 1.5. - 3.0 x n. 3.1 - 6.0 x n. > 6.0 x n n.d.

proteinuria (g/l) None < 3 3 - 10 > 10 nephrot. Syndrome n.d.

hematuria None microscopic macroscopic, no

clots

macroscopic, clots Transfusion required n.d.

creatinine-

clearence

>= 90 60 - 89 40 - 59 20 - 39 <= 19 n.d.

Liver toxicity

bilirubin normal for age < 1.5 x n. 1.5. - 3 x n. > 3 – 10 x n. > 10 x n n.d.

SGOT / SGPT normal for age <= 2.5 x n. 2.6 - 5.0 x n. 5.1 - 20.0 x n. > 20 x n. n.d.

Cardiac toxicity n.d.

arrhythmia None Asympt., no

therapy

recurr./persist., no

therapy

therapy required hypotension, ventr.

arrhyth.,defibrillation

death n.d.

cardiac function Normal Asymptomat., EF

of <20% of

baseline

asymptomat., EF

of >20% of baseline

mild CHF,

therapeutically

compensated

severe / refractory

CHF

death n.d.

echocardio.: LV-

SF

> 30 % > 25% - <= 30 % > 20 % - <= 25 % > 15 % - <= 20 % <= 15 % n.d.

Neurological toxicity

Central

neurotoxicity

None mild somnolence,

or agitation;

drowsiness

somnolence < 50%

of the time,

moderate

disorientation

somnolence > 50% of

the time, severe

disorient.,

hallucinations

coma, seizures death n.d.

Peripheral

neurotoxicity

None paresthesias, mild

subjective weakness

severe paresthesias

and/or mild

weakness

unbearable

paresthesias, deficits in

motor funct.

paralysis death n.d.

Hemoglobin: g/dl x 0.62 = mmol/l; SGOT/SGPT = ASAT/ALAT; Other toxicity: _______________________

Date______________________ Signature: _______________________

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