Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease.

The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone:

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 probability of event-free survival (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 post-consolidation 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 post-reintensification immunotherapy with blinatumomab (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%?

Secondary study questions:

All randomizations: Can the overall survival be improved by the treatment in the experimental arm?

All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm?

Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib?

Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab?

Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm?

Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy?

Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase?

Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009?

A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase.

Patients with T-ALL and hyperleukocytosis (>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

• Blinatumomab (Drug): Experimental therapy in randomizations R-HR and R-MR
• Bortezomib (Drug): Experimental therapy in randomization R-eHR
• Cyclophosphamide (Drug): Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
• Cytarabine (Drug): Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block Myocet-FLA for patients with very high relapse risk
• Daunorubicin (Drug): Part of standard chemotherapy
• Myocet (Drug): Part of intensification block Myocet-FLA for patients with very high relapse risk
• Dexamethasone (Drug): Part of standard chemotherapy
• Doxorubicin (Drug): Part of standard chemotherapy
• Etoposide (Drug): Part of standard chemotherapy
• Fludarabine Phosphate (Drug): Part of intensification block Myocet-FLA for patients with very high relapse risk
• Ifosfamide (Drug): Part of standard chemotherapy
• 6-Mercaptopurine (Drug): Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
• Methotrexate (Drug): Part of standard chemotherapy
• Pegaspargase (Drug): Part of standard chemotherapy
• Prednisolone (Drug), also known as Prednisone: Part of standard chemotherapy
• Tioguanin (Drug): Part of standard chemotherapy
• Vincristine (Drug): Part of standard chemotherapy
• Vindesine (Drug): Part of standard chemotherapy
• Erwinase (Drug): Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

Primary outcomes

• Event-free survival [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.
• Disease-free survival [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 outcomes

• Survival [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.
• Treatment-related mortality [Assessed up to 120 months from start of study]: Frequency and incidence of treatment-related mortality in induction or continuous complete remission
• Adverse Events of interest/Serious Adverse Events [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
• MRD response [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)
• Proportion of patients with Blina Poor-Response [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)

Sex: All, ages: any to 17 Years

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

15 more sites not listed.

• Results publication: Schrappe M, Locatelli F, Valsecchi MG, Zugmaier G, Vossen-Gajcy M, Stary J, Attarbaschi A, Moricke A, Bourquin JP, Barbaric D, Elitzur S, Silvestri D, Kolenova A, Dalla-Pozza L, Bodmer N, Stanulla M, Alten J, Zaman F, Bergmann A, Cazzaniga G, Bruggemann M, Buldini B, Kohler R, Fazio G, Rossig C, Sramkova L, Parasole R, Hundsdorfer P, Putti MC, Borkhardt A, Fagioli F, Bettini LR, Poyer F, von Stackelberg A, Vinti L, Conter V, Zimmermann M, Rizzari C, Cario G, Biondi A; AIEOP-BFM ALL 2017 Consortium. Blinatumomab for Replacing Chemotherapy in Pediatric Acute Lymphoblastic Leukemia. N Engl J Med. 2026 Sep 17;395(11):1075-1089. doi: 10.1056/NEJMoa2604166. PMID 42748428
• Results publication: Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067. PMID 41671463
• Results publication: Domka K, Dabkowska A, Janowska M, Urbanska Z, Pastorczak A, Winiarska M, Fidyt K, Lachota M, Patkowska E, Sedek L, Perkowski B, Hunia J, Jakubowska J, Krzymieniewska B, Lech-Maranda E, Mlynarski W, Szczepanski T, Firczuk M. Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models. Haematologica. 2024 Nov 1;109(11):3520-3532. doi: 10.3324/haematol.2023.284853. PMID 38841802
• Results publication: Tufekci O, Evim MS, Gunes AM, Celkan T, Karapinar DY, Kaya Z, Baysal B, Baytan B, Kocak U, Yilmaz S, Cinar S, Oren H. Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey. J Pediatr Hematol Oncol. 2022 Mar 1;44(2):e396-e402. doi: 10.1097/MPH.0000000000002419. PMID 35129146

• Martin Schrappe, MD, Principal investigator, Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel