Inotuzumab as Post-Trasplantation Therapy for Adult High-risk B-cell Precursor Acute Lymphoblastic Leukemia

This is a single arm study in which participants with high-risk B-cell precurdsor acute lymphoblastic leukemia (BCP ALL) enrollled in the immunochemotherapy schedule according to PETHEMA ALL-2025 protocol will receive Inotuzimab Ozogamicin as post-transplantation therapy to prevent relapse. The relapse rate of the participants will be compared to that of high-risk BCP ALL patients receiving transplantation within the PETHEMA ALL-2025 protocol. In addition, the presence of adverse events and severe adverse events will also be monitored in order to know if this treatment is as safe as or comparable to that of patients not receiving this drug. A safety analysis will be performed in the first 5 patients with special consideration of haematological and hepatic toxicity.

Three doses of 0,5mg/m2 of Inotuzumab Ozogamicin will be given to participants at day +70 post-transplantation and a minimum interval of 30 days between consecutive administrations. All patients will receive treatment until treatment is completed, unacceptable toxicity, disease progression, patient withdrawal, loss of follow-up, end of study, study completion, or death, whichever is first. This regimen is intended as post-allo-HSCT relapse prophylaxis/maintenance rather than treatment of active relapsed disease. Patients will be monitored upto 24 months after the last drug infusion (month 3, 6, 9, 12, 18, 24).

• Inotuzumab Ozogamicin (IO) (Drug): Three doses of 0,5mg/m2 of Inotuzumab Ozogamicin will be given to participants at day +70 post-transplantation and a minimum interval of 30 days between consecutive administrations. All patients will receive treatment until treatment is completed, unacceptable toxicity, disease progression, patient withdrawal, loss of follow-up, end of study, study completion, or death, whichever is first.

Primary outcomes

• Efficacy of Inotuzumab Ozogamicin (InO) in the prevention of relapse in terms of the relapse rate [24 months]: Evaluation of the efficacy of InO in terms of relapse rate, defined as percentage of patients who experience a relapse after achieving complete remission.
• Efficacy of InO in the prevention of relapse in terms of the cumulative incidence of relapse (CIR) [24 months]: Evaluation of the efficacy of InO in terms of CIR, defined as time interval between the date of complete remission and the date of relapse, considering any death not related to relapse as a competing event.
• Efficacy of InO in the prevention of relapse in terms of the disease-free survival (DFS). [24 months]: Evaluation of the efficacy of InO in terms of DFS, defines as time interval between the date of complete remission and relapse, death from any cause or last follow-up.

Secondary outcomes

• Safety profile of treatment with InO after allogeneic hematopoietic stem cell trasnplantation (allo-HSCT) in terms of side effects, adverse events (AEs) and serious AEs (SAEs) related to treatment [24 months]: The safety profile of the treatment will be assessed based on: * Incidence of AEs. * Percentage of patients discontinuing therapy due to AEs. * Percentage of patients requiring dose modifications due to AEs. * Incidence of SAEs. * Changes in laboratory analysis from the hematology and blood chemistry panel. * Incidence of deaths and primary cause of death. A safety analysis will be performed in the first five patients with special consideration of haematological and hepatic toxicity.
• Centralized study the minimal residual disease (MRD) in bone marrow (BM) [22 months]: MRD will be centrally analized in BM prior to drug administration, as well as at 3-, 6-, 9-, 12-, 18- and 22-months post allo-HSCT by Next Generation Flow Cytometry. Negative MRD will be considered when there is <0.01% of leukemic cells among all cell counts.
• Analysis of the immune reconstitution in peripheral blood [22 months]: Analysis of the immune reconstitution in peripheral blood prior to drug administration and at 3-, 6-, 9-, 12-, 18- and 22-months post allo-HSCT, evaluated by immunophenotypic study (NGF) of specific markers of B-cells, T-cells and myeloid cells, among others.
• Analyse the cumulative incidence of graft failure and acute and chronic graft-versus-host disease (GVHD). [24 months]: Analysis of the cumulative incidence of graft failure, defined as time interval from allo-HSCT to graft failure (failure to achieve sustained engraftment of donor cells). Cumulative incidence of acute GVHD (aGVHD), defined as time interval from allo-HSCT to aGVHD, staged and graded according to the MAGIC criteria previously published. Cumulative incidence of chronic GVHD (cGVHD) as time interval from allo-HSCT to cGVHD, based on the NIH criteria previously published.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patient is, in the investigator's opinion, willing and able to adhere/comply with visit schedule and other protocol requirements.
2. Patient must be able to understand the study procedures.
3. Patients aged ≥18 years at the time of signing the informed consent form.
4. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
5. Patient with CD22-positive high risk ALL according to any of the following criteria:

   i. Definition of high risk ALL according to the PETHEMA LAL 2019 protocol criteria including MRD stratification at the end of induction and during treatment and adverse cytogenetics at diagnosis (hypodiploid karyotype, KMT2A (MLL) alterations, homozygous TP53 deletions/mutations, and IKZF1 and CDKN2A/B deletions).

ii. Patients who are in first CR at the time of transplantation, irrespective of MRD status as assessed by immunophenotypic study.

iii. Allo-HSCT from an HLA-identical, mismatched or haploidentical sibling or unrelated donor, with myeloablative, reduced toxicity or non-myeloablative conditioning.

iv. Stable hematopoietic engraftment defined by neutrophils >1000/μL for at least 3 consecutive days and platelets >50000/μL for 7 days with transfusion independence and donor chimerism >90% assessed in peripheral blood.

Exclusion Criteria:

1. Prior exposure to inotuzumab ozogamicin or known hypersensitivity to inotuzumab ozogamicin or to any of its excipients.
2. Ph-positive lymphoblastic leukemia
3. Cord blood HSCT.
4. Creatinine clearance <30 ml/minute.
5. Bilirubin, GOT and GPT > 2 times the upper limit of the institution's reference values.
6. History of previous liver disease or hepatic veno-occlusive disease/sinusoid obstruction syndrome.
7. Active hepatitis B or C
8. Fungal infection or relevant uncontrolled infection.
9. Active grade 3-4 acute graft-versus-host disease or acute or chronic hepatic graft-versus- host disease grade ≥2
10. Graft-versus-host disease prophylaxis with sirolimus at enrolment that cannot be discontinued prior to initiation of trial treatment.
11. Absence of haematological recovery
12. Uncontrolled concomitant disease (cardiac, renal, pulmonary, psychiatric).
13. Uncontrolled non-hematological tumor
14. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
15. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study.
16. Women who are pregnant or breastfeeding, or who intend to become pregnant during participation in the study, or women of childbearing potential who are unwilling or unable to use a highly effective contraceptive method during treatment and for at least 8 months after the last dose; and male participants with female partners of childbearing potential who are unwilling or unable to use a highly effective contraceptive method during treatment and for at least 5 months after the last dose.

• Arancha Bermúdez, Study chair, Hospital Marqués de Valdecilla