AIEOP-BFM ALL 2017

Aacute lymphoblastic leukemia

International inter-group multi-center open-label randomized clinical trial (Phase III)

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%?

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.

• 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

• Ph+ (BCR-ABL1 or t(9;22)-positive) ALL2 - 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 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