AIEOP-BFM ALL 2017

Author:  Julia Dobke, Janina Heilmann, erstellt am 2018/09/05, Last modification:  2021/08/25

AIEOP-BFM International collaborative treatment protocol for children and

ALL 2017 adolescents with acute lymphoblastic leukemia

Disease Aacute lymphoblastic leukemia

Type International inter-group multi-center open-label randomized clinical trial

(Phase III)

Problem /
Objectives
Primary study questions
Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by
genetics and/or inadequate treatment response over the course of induction:
Can the pEFS from time of randomization be improved by additional therapy
with the proteasome inhibitor Bortezomib during an extended consolidation
treatment phase compared with standard extended consolidation?
Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or
inadequate treatment response by the end of consolidation: Can the pEFS
from time of
randomization be improved by a treatment concept including two cycles of
postconsolidation immunotherapy with Blinatumomab (15 μg/m²/d for 28 days
per cycle)
plus 4 doses intrathecal Methotrexate replacing two conventional highly
intensive chemotherapy courses?
Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics
and intermediate MRD response: Can the probability of disease-free survival
(pDFS) from time of randomization be improved by additional therapy with
one cycle of postreintensification immunotherapy with Blinatomomab (15
μg/m²/d for 28 days)?
Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients
defined by treatment response over the course of induction: Can the pEFS
from time of
randomization be improved by the extension of the standard of care
consolidation phase by 14 days with an increase of the consolidation
cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by
50%?
Therapy / Study
arms
pB-ALL (or unknown Immunophenotype)
Trial participants with a pB-ALL will be stratisfied at two timepoints. At
timepoint 1 (end of induction therapy) stratification will be done in early HR or
in early non-HR. At timepoint 2 (end of consolidation threapy) the stratification
in one of the following final risk group takes place, depending on
clinical/biological factors and MRD:
 
Timepoint 1
early High Risk (early HR) oder
early non-High Risk (early non-HR)
 
Timepoint 2:
Standard Risk (SR),
Medium Risk (MR) oder
High Risk (HR)

Therapy before timepoint 1

All participants are treated with the same therapy.

Therapy after timepoint 1

early HR: Participants fulfilling the criteria for the study-arm early HR, will be
randomized after induction and will be treated or with the extended
consolidation (standard arm) or the extended consolidation plus Bortezomib
(experimental arm).

Early non-HR: Participants fulfilling the criteria for the study-arm early non-
HR, are not randomized an will be treated with the standard consolidation.

Therapy after timepoint 2

SR: all participants are treated with chemotherapy without a special
intensivation therapy (induction, consolidation, reinduction) followed by
maintenance therapy. SR-patients have no primary indication for allogene
stem cell transplantation.

MR: all paticipants are treated with an intensive chemotherapy (induction,

consolidation, reinduction), followed by maintenance therapy. Before the start
of the maintenance therapy a randomization takes place: the randomized
participants will be treated or with 1 cycle of Blinatumomab followed by
mainetenance therapy or by maintenance therapy only (controll-arm). MR-
patients have no primary indication for allogene stem cell transplantation.

HR: All participants are randomized after the first course of chemotherapy: or
they are treated with further courses of HR-chemotherapy or they are treated
with 1 to 2 cycles with the immunotherapy Blinatumomab (the number
depends on the MRD-results). Thereafter for all participants will be decided
depending on the MRD-result, if the participants will go on directly with an
allogenehematopoetic stem cell transplantation or another reinduction therapy
is needed.
Depending on the risk-criteria of every participant the donor of the stem cells
may be a matched family donor (MSD or MD) or also a matched unrelated
donor (MMD).

T-ALL
Participants with a T-ALL will be stratisfied at 2 timepoints: at timepoint 1 (end
of induction therapy) participants will be treated in arm early SR or in early
non-SR. At timepoint 2 (end of consolidation therapy) the stratification takes
place in one of the folowing risk-groups

timepoint 1:
early Standard Risk (SR) or into
early non-Standard Risk (early non-SR)

timepoint 2:
non-High Risk (non-HR) or
High Risk (HR)

Therapy before timepoint 1:

Participants with a T-ALL are devided after the prephase with prednisone in
two groups: participants with prednisolone good response, PGR, are treated
with an induction therapy with dexamethasone; participants with predinsone
poor response, PPR, will be treated with an intensified induction therapy with
prednisolone and cyclophosphamide.

Therapy after timepoint 1

Early SR: allparticiiopants are treated with the standard-consolidation

Early non-SR: all participants will be randomized after the induction therapy
and will be treated or with the standard-consolidation or witht an extended
consolidation (experimantal arm).

Therapy after timepoint 2

non-HR: the participants will be treated with a mulimodal chemotherapy
followe by a maintenance therapy. The have no primary indication for a
allogen hematopoetic stem cell transplantation (HSCT).

HR: all participants are treated with 3 intensive chemotherapy courses.

Depending of the MRD-result at timepoint 3 it will be decided, if the
participants will go on directly to HSCT or if more chemotherapy before HSCT
is needed.
Inclusion  newly diagnosed acute lymphoblastic leukemia or newly diagnosed
Criteria mixed phenotype acute leukemia (MPAL) meeting one of the following
criteria: biphenotypic with a dominant T or B lineage assignment,
bilineal either with a dominant lymphoblastic population or if another
reasonable rationale exists to treat the patient with an ALL-based
therapy regimen
 newly diagnosed acute undifferentiated leukemia
 age < 18 years (up to 17 years and 365 days) at the day of diagnosis
 patient enrolled in a participating center
 written informed consent to trial participation and transfer and
processing of data

Exclusion  Ph+ (BCR-ABL1 or t(9;22)-positive) ALL2 - bilineal leukemia with a

Criteria lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells)
blast subset
 pre-treatment with cytostatic drugs
 glucocorticoid pre-treatment with ≥ 1 mg/kg/d Prednisolone equivalent
for more than two weeks during the last month before diagnosis
 treatment started according to another protocol
 underlying disease that does not allow treatment according to the
protocol
 other condition (either pre-existing or related to leukemia biology as
present at diagnosis) or circumstances that significantly conflict with
the treatment according to the protocol
 ALL diagnosed as second malignancy and preceding chemotherapy
and/or radiotherapy
 evidence of pregnancy or lactation period
 Sexually active adolescents not willing to use highly effective
contraceptive method (pearl index <1) until 12 months after end of
anti-leukemic therapy
 participation in another clinical trial except for add-on trials within the
scope of supportive care approved by the sponsor
 live vaccine immunization within 2 weeks before start of protocol
treatment

Status Start: 15.07.2018, End 14.07.2028

EudraCT AIEOP-BFM 2017 2016-001935-12

Entry Study
Register
Principal Prof. Dr. med. Martin Schrappe
Investigator

E-Mail all-bfm-studie@pediatrics.uni-kiel.de

Contact
Coordinating principal investigator
Prof. Dr. med. Martin SchrappeUniv.-Klinikum Schleswig-Holstein, Campus
KielKlinik für Kinder- und Jugendmedizin IArnold-Heller-Str.
324105 KielTelefon +49 (431) 500 20102Fax +49 (431) 500 20104

Trial coordination
Dr. med. Anja MörickeUniv.-Klinikum Schleswig-Holstein, Campus KielKlinik
für Kinder- und Jugendmedizin I, AIEOP-BFM ALL StudienzentraleArnold-
Heller-Straße 324105 KielTelefon +49 (431) 500 20150Fax +49 (431) 500
20144a.moericke@pediatrics.uni-kiel.de
Dr. med. Julia AltenUniv.-Klinikum Schleswig-Holstein, Campus KielKlinik für
Kinder- und Jugendmedizin I, AIEOP-BFM ALL StudienzentraleArnold-Heller-
Straße 324105 KielTelefon +49 (431) 500 20139Fax +49 (431) 500
20144julia.alten@uksh.de
Dr. med. Janina HeilmannUniversitätsklinikum Schleswig-HolsteinCampus
Kiel, Klinik für Kinder- und Jugendmedizin 1Arnold-Heller-Straße
324105 KielTelefon +490431 500 20139Fax +49431 500
20144janina.heilmann@ukse.de
Dr. med. Swantje BuchmannTelefon +49 - 431 - 500
20139swantje.buchmann@uksh.de

Trial documantation
Melanie Gerzmehle
Katja Schulte
Lisa Schmied
Susanne Timm
Christine Claviez
Tanja Schindelmeiser

Participants AIEOP (Italien) BFM-A (Österreich) BFM-G (Deutschland) BFM-CH (Schweiz)

ANZCHOG (Australien) CPH (Tschechische Republik) INS (Israel) SPHOS
(Slowakei)

Sponsoring Sponsor: Universitätsklinikum Schleswig-Holstein, Campus Kiel