Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia

Study Overview
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Brief Summary
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This study is a treatment protocol with blinatumomab for infants under 1 year old who are diagnosed with acute lymphoblastic leukemia with a specific unfavorable genetic alteration. The purpose of the study is to improve the outcome of this disease in infants.

Detailed Description
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All infants that are eligible for this study and for whom the parents/legal representatives give informed consent will be enrolled in this study. All patients will receive one cycle of blinatumomab on top of the standard treatment backbone after induction therapy. Medium risk patients, that respond well to the 1st cycle will be treated with a 2nd cycle of blinatumomab replacing one chemo course after consolidation therapy. If they do not respond well enough they will be treated according to the current treatment standard. Minimal residual disease will be used to determine the response to blinatumomab. High risk patients will be eligible for allogeneic stem cell transplantation after the first blinatumomab cycle if they are Minimal Residual Disease (MRD) negative (defined as < 0.01%). Also medium risk patients with insufficient MRD response after induction or after the 1st cycle of blinatumomab will be allocated to high risk treatment and will be eligible for allogeneic stem cell transplantation.

Official Title
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Interfant-21 International Collaborative Treatment Protocol for Infants Under One Year With KMT2A-rearranged Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia.

Conditions
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Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia

Intervention / Treatment
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* Drug: Blinatumomab
* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed B- precursor acute lymphoblastic leukemia (ALL) or B- cell mixed phenotype acute leukemia (MPAL) according to the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017, with KMT2A-rearrangement. ≤365 days of age at time of diagnosis of ALL Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations. Exclusion Criteria: KMT2A-germline patients T-ALL Age > 365 days at the time of diagnosis Relapsed ALL Treatment with systemic corticosteroids (equivalent prednisone >10 mg/m2/day) for more than one week and/or any chemotherapeutic agent in the 4-week interval prior to diagnosis. Patients who received corticosteroids by aerosol are eligible for the study. Additional exclusion criteria for blinatumomab: CD19 negative B-precursor ALL at diagnosis CNS involvement (CNS2/CNS3 status) at the EOI. Patients with CNS disease at the time of diagnosis are eligible if CNS1 status is achieved prior to the start of the first blinatumomab cycle (lumbar puncture at  day 33 of induction). Proven hypersensitivity to the active substance or any of the excipients in blinatumomab. Patients who have received a live vaccine 28 days prior to blinatumomab administration or plan to receive a live vaccine prior to B-cell recovery after the last dose of blinatumomab. If exclusion criteria for blinatumomab are met, the patient should be treated according to the protocol but without blinatumomab.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 365 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Definition: Provide details about the Interventional Study Model. Limit: 1000 characters.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Medium Risk (MR)<br>Subject is defined as MR if > 6months of age at diagnosis, OR < 6 months of age with White Blood cell Count (WBC) < 300 at diagnosis and good prednisone response. Subject gets 1st cycle of blinatumomab. If MRD is >0.01%, after 1st cycle of blinatumomab, subject will be allocated to HR treatment from that phase, and will be eligible for HSCT. If MRD is undetectable or < 0.01% after the 1st cycle of blinatumomab (TP2) patient will be eligible for replacement of MARMA by 2nd cycle of blinatumomab after receipt of lymphoid style consolidation (Protocol IB) or of myeloid style consolidation (ADE/MAE). | Drug: Blinatumomab<br>* 1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4.<br>* Other names: Cycle 1;Drug: Blinatumomab<br>* 2nd cycle: 15 μg/m2/day as a 4 week continuous iv infusion<br>* Other names: Cycle 2;|
| Other: High risk (HR)<br>Subject is defined as HR if < 6 months of age with WBC > 300 at diagnosis OR poor prednisone response. Also MR patients with end of induction MRD ≥ 1%, or MRD > 0.01% after the 1st cycle of blinatumomab, will be allocated to HR treatment. Subject gets 1 cycle of blinatumomab. Thereafter patient is eligible for hematopoietic stem cell transplantation (HSCT) with or without experimental therapy in an investigational window. | Drug: Blinatumomab<br>* 1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4.<br>* Other names: Cycle 1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS). | The primary endpoint is EFS, defined as the time from diagnosis to resistance to induction, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy. | 8 years | 
| Endpoints by risk group | The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy. | 8 years | 
| Outcome for the entire study cohort and according to risk group | Outcome for the entire study cohort and according to risk group will be evaluated in terms of the protocol specific definition of EFS follows: the time from diagnosis to, resistance to proto-col, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up for patients without events. Cumulative incidence (or percentage) of resistance, CIR, death in CR and second malignancy will also be estimated. | 8 years | 
| Minimal Residual Disease | MRD response as defined in the protocol and frequencies of MRD levels | 8 years | 
| CD19 (cluster of differentiation antigen 19) negative relapse | Proportion of CD19 negative relapses in the entire study cohort and according to risk group | 8 years | 
| Myeloid lineage switches | Proportion of myeloid lineage switches in the entire study cohort and according to risk group | 8 years | 
| Grade ≥3 adverse event | Proportion of grade ≥3 adverse event (AEs) during the blinatumomab course(s). Proportion of adverse events of special interest (AESIs) and serious adverse events (SAEs) in all protocol phases. | 8 years | 
| Grade ≥2 cardiac disorders | Proportion of grade ≥2 cardiac disorders at 2 and 5 years after diagnosis | 5 years | 
| Overall survival after 1st relapse | Overall survival (OS) after first relapse, defined as the time from first relapse to death from any cause, in the entire study cohort and according to risk group | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infant under one year, KMT2A-rearranged