Study of Inotuzumab Ozogamicin Combined to Chemotherapy in Older Patients With Philadelphia Chromosome-negative CD22+ B-cell Precursor ALL

INO schedule of administration will be as described in the refractory/relapsed INO-VATE study for the first cycle, with sequential day 1/8/15 doses of 0.8, 0.5 and 0.5 mg/m2, respectively. Reduced dose of INO will be used for the second and last cycle (0.5 mg/m2 on day 1/8). This was retained in order:

1. to minimize potential toxicities, including liver disorders and prolonged thrombocytopenia; and
2. to allow delivery of subsequent chemotherapy consolidations cycles.

• Inotuzumab ozogamicin (INO) (Drug): INO schedule of administration is as follows: * First induction course: 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 * Second induction course: 0.5 mg/m² on day 1, and 0.5 mg/m² on day 8

Primary outcomes

• Assessment of overall survival (OS) [one year]: The primary objective of the trial is to assess overall survival (OS) observed at 1 year after administration of INO and chemotherapy in older Ph-negative BCP-ALL patients.

Secondary outcomes

• Assessment of adverse events (AEs) [3 months]: Type, duration and frequency of AEs up to 3 months of induction course 1 or 2
• Rate of complete remission (CR / CRp) [35 days]: CR/CRp response rate after INO-based induction course 1 and 2
• Assessment of Minimal residual disease (MRD) [35 days]: Flow cytometry and Ig-TCR MRD levels, after INO-based induction course 1 and 2 and impact on outcomes
• Rate of early death [100 days]: Early death (ED) rate at 30, 60 and 100 day from treatment initiation
• Composite measure for Duration of response (DOR), Disease-free survival (DFS) and cumulative incidence of relapse (CIR) [one year]: Duration of response (DOR), Disease-free survival (DFS) and cumulative incidence of relapse (CIR)

Sex: All, ages: 55 Years to any

Inclusion Criteria:

* Patients aged more than 55 years old,
* With confirmed diagnosis of BCP-ALL according to World Health Organisation (WHO) criteria expressing the CD22 antigen by flow cytometry (20% or more positive blast cells),
* Without central nervous system (CNS) involvement,
* Without BCR-ABL fusion by standard cytogenetics, Fluorescence In Situ Hybridization (FISH) analysis and/or RT-PCR,
* Previously untreated,
* Eligible to intensive chemotherapy, due to general health status,
* ECOG performance status ≤ 2,
* Patients must have the following laboratory values unless considered due to leukemia: AST and ALT ≤ 2.5 x upper the limit of normal (ULN); estimated GFR ≥ 50 mL/min using the MDRD equation; total and direct serum bilirubin ≤ 1.5 x ULN; electrolyte panel within normal ranges for the institution unless attributed to the underlying disease.
* Written informed consent obtained prior to any screening procedures.
* Eligible for National Health Insurance in France.

Exclusion Criteria:

* Concurrent therapy with any other investigational agent or cytotoxic drug,
* Prior documented chronic liver disease,
* Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) or positive HIV serology,
* Female patients who are pregnant or breast feeding or patients of childbearing potential not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of maintenance.
* Male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months following the last dose of maintenance.
* Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study.

• Results publication: Chevallier P, Leguay T, Delord M, Salek C, Kim R, Huguet F, Hicheri Y, Wartiovaara-Kautto U, Raffoux E, Cluzeau T, Balsat M, Roth-Guepin G, Tavernier E, Lepretre S, Bilger K, Bergugnat H, Berceanu A, Alexis M, Doubek M, Brissot E, Hunault-Berger M, Lebon D, Turlure P, Chantepie S, Belhabri A, Wickenhauser S, Bastie JN, Cacheux V, Himberlin C, Banos A, Gardin C, Bonnet S, Plantier I, Pica GM, Escoffre-Barbe M, Boissel N, Dombret H, Clappier E, Rousselot P; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) and the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL); European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL). Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia. J Clin Oncol. 2024 Dec 20;42(36):4327-4341. doi: 10.1200/JCO.24.00490. Epub 2024 Oct 17. PMID 39418626

• Patrice CHEVALLIER, MD, Principal investigator, Nantes University Hospital

NIH grants: 2016