Brief Summary:
The understanding of acute lymphoblastic leukemia (ALL) in childhood and adolescence has
largely changed due to extensive genetic research in recent years: ALL is now considered to be a
very heterogeneous disease group. The leukemia cells present themselves with quite differently
activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate
methods of assessing therapy response ("minimal residual disease [MRD] tests") has provided
new insights into very different mechanisms of action, including factors influenced by host
factors; this has had practical clinical consequences for the use of more individualized therapy.
Multimodal therapies have enabled a cure level of over 80% for ALL in this age group. However,
the own and international study data show that the therapy toxicity of the contemporary
chemotherapy concepts has become unacceptably high, in particular with respect to those
intensified therapies used for the treatment of patients at high risk of ALL relapse.
The AIEOP-BFM ALL 2017 study therefore aims for an innovative integrated approach that will not
only adapt the risk stratification to new prognostic markers using more comprehensive
diagnostics, but above all, qualitatively reorient the therapy. The most important consequence
will be that this study is testing immunotherapy with the bispecific antibody blinatumomab as an
alternative to particularly intensive and toxic chemotherapy elements in precursor B-cell ALL (pB-
ALL) patients with detectable chemotherapy resistance and at high risk of relapse. With the aim to
complement the effects of the conventional chemotherapy, Blinatumomab is in addition tested in
the large group of pB-ALL patients at intermediate relapse risk with seemingly unremarkable
leukemia, but who account for a large proportion of all relapses. Targeted therapy is also used in
the form of the proteasome inhibitor bortezomib for patients with pB-ALL and slow response to
the drugs of the induction chemotherapy with the aim to overcome intrinsic chemotherapy
resistance of the ALL cells. In patients with T-lineage ALL, who have particularly poor chances for
cure after relapse, the established consolidation chemotherapy has proved to be particularly
effective. This chemotherapy phase is therefore tested in a longer and more intensive form in
such T-ALL patients with intermediate or slow early treatment response with the aim to reduce
the relapses rate in this subgroup.
Condition or disease Int
Acute Lymphoblastic Drug: BlinatumomabDrug: BortezomibDrug: CyclophosphamideDrug: CytarabineDrug: Dau
Leukemia, Pediatric PhosphateDrug: IfosfamideDrug: 6-MercaptopurineDrug: MethotrexateDrug: Pegaspargase
Show detailed description
Study Design
Go to
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 5000 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: pB-ALL/MR: 2 parallel groups (R-MR) or 2x2 factorial
pB-ALL/HR: 2 parallel groups (R-HR) or 2x2 factorial
T-ALL/early non-SR: 2 parallel groups (R-T).
pB-ALL/SR: Single group.
T-ALL/early SR: Single group.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: International Collaborative Treatment Protocol for
Actual Study Start Date : July 15, 2018
Estimated Primary Completion Date : July 14, 2028
Estimated Study Completion Date : July 14, 2028
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia
Genetic and Rare Diseases Information
Center resources: Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Childhood Acute Ly
mphoblastic Leukemia Acute Graft Versus Host Disease Lymphosarcoma
U.S. FDA Resources
Arms and Interventions
Go to
Arm
Active Comparator: pB: early (non-)HR-standard/MR-standard
Induction (5 wks): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT methotrexate (M
Consolidation (6 w/4 w): "Consolidation extended" (control arm of randomization R-eHR) with cyclophosphamid
pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabin
Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX
Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclopho
Maintenance (until 2 years after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of r
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Experimental: pB: early HR-exp./MR-standard
Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX
Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophos
bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59)
Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX
Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclopho
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of ran
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Experimental: pB: early (non)HR-standard/MR-exp.
Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX
Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamid
"Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-mercaptopu
Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX
Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosp
Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomizati
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Experimental: pB: early HR-exp./MR-exp.
Arm
Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX
Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophos
bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59)
Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX,IT MTX
Reinduction (6 weeks): "Protocol II" with dexamethasone, vincristine, doxorubicin, PEG-L-asparaginase, IT MTX,
Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomizati
Maintenance phase (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Active Comparator: pB: early (non-)HR-standard/HR-standard
Induction (5 w): as in other pB arms
Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamid
"Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX
Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) w
cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide
Reinduction (3x4 w): "Protocol III" given 3 times with dexamethasone, vincristine, doxorubicin, pegaspargase, IT
Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX
Erwinase is given in case pegaspargase allergy. Pts with poor response to intensified consolidation receive Myoc
Arm
Arm
Arm
Experimental: pB: early HR-exp./HR-standard
Induction (5 w): as in other pB arms
Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophos
bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59)
Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) w
cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide
Reinduction (3x4 w): as in arm "pB: early (non-)HR-standard/HR-standard"
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive
Arm
Arm
Arm
Experimental: pB: early (non-)HR-standard/HR-exp.
Induction (5 w): as in other pB arms
Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamid
"Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX
Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cyta
15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR)
Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard"
Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX
Erwinase is given in case of pegaspargase allergy. Pts with poor response to intensified consolidation receive My
Arm
Arm
Experimental: pB: early HR-exp./HR-exp.
Arm
Induction (5 w): as in other pB arms
Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophos
bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59)
Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cyta
15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR)
Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after init
Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive
Arm
Arm
pB: early non-HR/SR
Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX
Consolidation (4 w): "Consolidation short" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX
Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX
Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosp
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Active Comparator: T: early non-SR-standard/(non-)HR
Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase
additional CPM
Consolidation (4 w): "Protocol IB regular" (control arm in randomization. R-T) with cyclophosphamide, cytarabin
non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR"
HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard"
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive
Arm
Arm
Arm
Experimental: T: early non-SR-exp/(non-)HR
Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase
additional CPM
Consolidation (6 w): "Protocol IB long" (experimental arm in randomization R-T) with cyclophosphamide, cytara
non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR"
HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard"
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive
Arm
Arm
Arm
T: early SR/non-HR
Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase
Consolidation (4 w): "Protocol IB regular" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX
Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX
Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosp
Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX
Erwinase is given in case of allergy to pegaspargase.
Arm
Arm
Outcome Measures
Go to
Primary Outcome Measures :
1. Event-free survival [ Time Frame: Assessed up to 120 months from start of study ]
Randomization R-eHR, R-HR and R-T: Time from randomization until the first event
defined as follow: cytomorphological or molecular non-response (resistance to protocol
treatment, considered as event at day zero), relapse, second malignancy or death from
any cause. This will be called EFS time.
2. Disease-free survival [ Time Frame: Assessed up to 120 months from start of study ]
Randomization R-MR: Time from randomization until the first event defined as follow:
Relapse, second malignancy or death from any cause. This will be called DFS time.
Secondary Outcome Measures :
1. Survival [ Time Frame: Assessed up to 120 months from start of study ]
All patients/randomizations: Time until death from any cause, starting at the same time
point as the EFS/DFS.
2. Treatment-related mortality [ Time Frame: Assessed up to 120 months from start of
study ]
Frequency and incidence of treatment-related mortality in induction or continuous
complete remission
3. Adverse Events of interest/Serious Adverse Events [ Time Frame: Assessed up to 120
months from start of study ]
Frequency and incidence of adverse events of interest and serious adverse events in
specific protocol phases, randomized arms and overall during follow-up
4. MRD response [ Time Frame: Measurements of MRD response at end of randomized
treatments (intended time frame 13 weeks in R-eHR/R-T, 26 weeks in R-HR, 34 weeks in R-
MR). ]
MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) as well as
after the first/second cycle of Blinatumomab or after the HR 2'/HR 3' block (R-HR)
5. Proportion of patients with Blina Poor-Response [ Time Frame: Measurements of MRD
response intended after 30 weeks from individual start of treatment, assessment of
proportion at 120 months from start of study ]
Proportion of patients with poor MRD response to the first Blinatumomab cycle
("Blinatumomab Poor-Response") (R-HR)
Eligibility Criteria
Go to
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and
family members or friends about deciding to join a study. To learn more about this study, you or
your doctor may contact the study research staff using the contacts provided below. For general
information, Learn About Clinical Studies.
Ages Eligible for Study: up to 17 Years (Child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
newly diagnosed acute lymphoblastic leukemia or
newly diagnosed 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 A
subsequent removal from the study is only allowed if the inclusion criteria turn out not to
be fulfilled or in the case of pregnancy of the patient.
Exclusion Criteria:
Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
bilineal leukemia with a 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 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 (e.g. severe
congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangiectasia…)
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
