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THE NAZLI GAD-EL-MAWLA

AWARD

Recipient:Federico Sackmann-Muriel

29th May, 2003Brussels - Belgium

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“Historical development of pediatric clinical

trials in ALL in Argentina and other

Latin American countries”.

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Buenos Aires(24° 37’ S. Lat.58° 4’ W. Long)

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Acute Childhood Leukemia:A Ten-Year Study

The authors point at the prognostic importance of the level of the initial leukocyte count and also the rising

importance of leukemic infiltration of the CNS. For those who are called upon to counsel parents of leukemia patients

this report is fertile reading.Zuelzer W. et al: Amer J. Dis Children 100, 886-907, 1960

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INCTR2003D. Pinkel: St. Jude´s Children Research Hospital

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The Berlin Childhood Acute Lymphoblastic Leukemia

Therapy Study, 1970-1976

Hansjörg Riehm, MD Hans-Joachim LangermannHelmut Gadner, MD Edelgard OdenwaldGünter Henze, MD

The American Journal of Pediatric Hematology/Oncology Vol 2: 4, 1980

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Hospital de NiñosRicardo Gutierrez

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GATLA’S EVOLUTION1967-1990

3 Institutions Members in 1967.32 Institutions Members in 1990.There is a Member Institution or a Satellite of GATLA in most cities of the country with a metropolitan area over 100,000 inhabitants.GLATHEM was created in 1973: since then, Chile Costa Rica, Cuba, Brasil and Uruguay have participated with Argentina in some studies. The main office is in Buenos Aires.

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ARGENTINA

BRASIL

URUGUAYCHILE

COSTA RICACUBA

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Induction and maintenance of remission in acute leukemia

Effectiveness of Combination Therapy in 227 Patients

Santiago Pavlovsky, Jorge Peñalver, Mariana Eppinger-Helft, Federico Sackmann-Muriel,

Luis Bergna, Argimiro Suarez, Guillermo Vilaseca, Alberto Andino Pavlovsky and

Alfredo Pavlovsky.

Cancer: 31(2), 273-279, 1973

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Evaluation of induction of remission, intensification and

central nervous system prophylactic treatment in

acute lymphoblastic leukemiaFederico Sackmann-Muriel, Santiago Pavlovsky,

Jorge Peñalver, Guillermo Hidalgo, Angela Cebrián Bonesana, Mariana Eppinger-Helft,

Graciela H. de Macchi and Alfredo PavlovskyCancer: Vol 34,118-126, 1974

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Long Term Survival in Acute Leukemia in Argentina“A study of 78 cases”

Santiago Pavlovsky andFederico Sackmann-Muriel

Cancer: Vol 40(4), 1402-1409, 1977

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A.L.L. Protocols

ALL - 67ALL - 70ALL - 72ALL - 76ALL - 79ALL - 82ALL - 84ALL - 87ALL - 90

# of Events # of Patients35 37

101 117288 349259 336437 601105 213366 702221 59844 278

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Event free survival in ALLin children according to protocol

GATLA / GLATHEM

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SUMMARY GATLA/GLATHEM:Pediatric ALL studies 1967/1994

involving 3576 patients (*)Period 1: 1967/1972 155 patients2 or 3 induction drugs (R) No intensifications50% pts. received cranial radiotherapy (R)

Period 2: 1972/1982 1287 patients2 or 3 induction drugs (R) Short term consolidation (R)Reinforcement pulses (R)All received CNS prophylaxis. (R) RANDOMIZED (*) IJPH/O 5:177, 1998

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SUMMARY GATLA/GLATHEM:Pediatric ALL studies 1967/1994

involving 3576 patientsPeriod 3: 1982/1987 914 patientsProtocol I and Protocol IIBFM protocolMaintenance (R)

Period 4: 1987/1994 1220 patientsProtocol I - Protocol M (Methotrexate 1 or 2 g/m2)and Protocol II(BFM Protocol)

(R) RANDOMIZED

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SUMMARY GATLA/GLATHEM:Pediatric ALL studies 1967/1994

involving 3576 patients

Int J Pediat Hematol/Oncol 5: 177, 1998

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH AML ACCORDING TO PROTOCOL

Protocol # Pts # CR % PR UN DE OI11-AML-67 35 15 43 8 6 611-AML-70 44 25 57 1 3 1512-AML-73 56 29 52 11 7 9

3-AML-76 71 30 42 6 5 307-AML-80 66 44 67 5 15 2

3-AML- 83 175 126 72 5 12 324-AML-90 50 40 80 1 3 6T O T A L 497 309 62 37 51 100

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH AML ACCORDING

TO YEAR OF TREATMENT

Year # Pts # CR % PR UN DE OI

67-80 272 143 52 31 36 6283-90 225 166 74 6 15 38Total 497 309 62 37 51 100

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH NHL ACCORDING

TO PROTOCOL

Protocol # Pts # CR % PR UN DE OI

6-NHL-73 49 22 45 14 8 51-NHL-76 75 65 87 4 6 -1-NHL-81 59 42 71 3 4 10 1-NHL-84 145 117 80 7 5 169-NHL-88 95 85 89 4 1 5

T O T A L 423 331 78 32 24 36GATLA / GLATHEM

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH NHL ACCORDING

TO YEAR OF TREATMENT

Year # Pts # CR % PR UN DE OI

73-81 183 129 70 21 18 1584-88 240 202 84 11 6 21Total 423 331 78 32 24 36

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH HD ACCORDING TO PROTOCOL

Protocol # Pts # CR % PR UN DE OI1-HD-68 2 1 50 1 - -2-HD-72 72 51 71 16 5 -9-HD-77 161 149 92 6 5 11-HD-79 26 18 69 7 - 1

11-HD-84 12 8 67 3 1 -11-HD-86 100 95 95 3 2 -

7-HD-87 19 17 89 1 - 1T O T A L 392 339 86 37 13 3

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PERCENTAGE OF COMPLETE REMISSION IN CHILDREN WITH HD ACCORDING

TO YEAR OF TREATMENT

Year # Pts # CR % PR UN DE OI

68-84 273 227 83 33 11 286-87 119 112 94 4 2 1Total 497 339 86 37 13 3

GATLA / GLATHEM

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H o s p i t a l G a r r a h a nBuenos Aires - Argentina

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GARRAHAN HOSPITAL: ALL STUDIES

1- 1987/89 (Total/Evaluables): 99/ 92 pts (Similar ALL-BFM’86)

2- 1990/95 (Total/Evaluables): 403/374 pts (Similar ALL-BFM’90)

3- 1996/2002 (Total/Evaluables):478/430 pts (Similar ALL-BFM’96)

HPG, March, 2003

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7-ALL87: GENERAL OUTLINE

I

I M

M

II

LOW-RISK

HIGH-RISKA

BROTATIONAL

6MP+MTX

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04 8 12 16 20 24 28 32 48 52 56 102 104

CONTINUATION

STANDARD RISK (ER)

A BM III

A B M II

A

HR1 HR2 HR3 HR1 HR2 HR3 HR1 HR2 HR3

I

I

WEEKS

CONTINUATION

CONTINUATION

RDT

III

INTERMEDIUM RISK (IR)

HIGH RISK (HR)

1-ALL 90: GENERAL OUTLINE

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0

( * ) WBC > 100,000/mm3 and “T”ALL RECEIVE RDT 12 GY

4 8 12 16 20 24 28 32

1-ALL 96- BFM/HPG GENERAL OUTLINE

48 52 56 102 104

STANDARD-RISK

INTERMEDIUM RISK

HIGH-RISK

A BM II

A B M II (*)

ARM BA II

HR1 HR2 HR3 HR1 HR2 HR3

I'

I

WEEKS

RDT

ARM A

ARM B

ARM B

ARM C

R

R

II

II

TMO

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75867044

65746637

6472

52

OUTCOME%EFS (60 months)-SR-IR-HR

5814 (3.3)

3

8116 (4.5)

2

255 (5.7)

1

EVENTS-Relapses-Deaths in CR (%)-2nd Malignancies

416 (96.7)8 (1.9)6 (1.4)

353 (94.5)11 (2.9)10 (2.6)

88 (93.6)2 (2.2)4 (4.4)

RESPONSE -CR (%)-DEATHS IN INDUCTION (%)

-Non Response (%)

487 /430403 / 37499 / 92N/ evaluable

ALL96ALL90ALL87COMPARATIVE RESULTS

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EFS PROBABILITY FOR 3 SUCCESIVEPROTOCOLS

Time in months

EFS

Prob

abili

ty

0 15 30 45 60 75 90 1050.0

0.2

0.4

0.6

0.8

1.0

ALL90: 374 / 120 :65 (5)%ALL96: 430 / 89 :75 (0)%

ALL 87: 92 / 37 :64 (5)%Total/Events:EFS (SE)

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Countries participating in the ALLIC - BFM 2002

- Argentina - Chile- Croatia - Cuba- Czech Republic - Hong Kong- Hungary - Israel- Poland - Turkey- Ukraine - Uruguay - Yugoslavia

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0

mM##

10 12

R

RA1'

RA2'

RA3'

BM sample

12Gy*

II

HR:PRED-PRRI, M3 d15t(9;22)t(4;11)NR d33

BFM

BMT#

III

12 Gy* only for T-ALL

III III III

III

II

II18Gy*

IIAIEOP

I/I‘ **

d15

52

10 semanas de mantenimiento intermedio con 6-MP / MTX

RA1'

RA2'

RA3'

R

6-MP/MTX4 semanss.

6-MP/MTX4 semansas.

d33

SR

IR

R

IT MTX (IN CONTINUATION PHASE.)** Prot. I‘ (DNR 30mg/m2 x2 solo para RE con B-pc LLA)

dx

§

§

w12

II

## for B-pc ALL: MTX 2g/m2/ 24h x4, para T-ALL: MTX 5g/m2/24h x4

12 Gy* only for T-ALL

ALLIC-BFM 2002: GENERAL OUTLINE

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SUMMARY OFGATLA / GLATHEM TRIALS

In spite of economical problems in Latin America:

High quality clinical trials were able to be carried out.

Following the guidelines of GATLA/GLATHEM other countries (i.e. Brazil, Chile) have organized similar national studies in pediatric acute leukemia.

Quality improvement of pediatric medical care in community hospitals - not officially involved in trials, throughout meetings, rotations / training and exchange of information, are important further benefits of GATLA/GLATHEM activities.

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