Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab

Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab in Patients With Treatment-Resistant Mixed Chimerism or Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia After Allogeneic Stem Cell Transplantation

This phase 2 study is designed to evaluate the safety, tolerability and efficacy of allogeneic donor lymphocyte infusions (DLI) combined with the bispecific T cell engager blinatumomab in B-precursor ALL patients who have mixed chimerism (MC) or are MRD-positive after allogeneic SCT and are refractory to at least one MRD- or MC-targeted therapy (i.e. blinatumomab, DLI, tyrosine kinase inhibitors or other agents).

Inclusion Criteria:

1. Adult patients with CD19+ B-precursor ALL (as determined by immunophenotyping) in hCR (defined as having less than 5% blasts in bone marrow) after allogeneic SCT.

2. One, or a combination of the following documented after an interval of at least 2 weeks since cessation of the most recent leukemia-targeting therapy (i.e. chemotherapy, immunotherapy or cellular therapy, except for intrathecal prophylaxis):

   • Positivity for CD19+ MRD (molecular failure or molecular relapse), defined as presence of MRD at a level of ≥10^-4 according to an assay with a minimum sensitivity of 10^-4.
   • Donor chimerism <90%, as determined by analysis of host and donor STRs in bone marrow sample engraftment analysis.

3. At least one previous line of treatment for MRD-positivity and/or reduced donor chimerism (i.e. blinatumomab, DLI, TKI or other agents) after allogeneic SCT.

4. For those with BCR/ABL-positive B-precursor ALL only: persistence of MRD and/or MC following at least one ≥ second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerance to second generation TKI and intolerance to or persistence of MRD and/or MC following imatinib mesylate.

5. Availability of allogeneic donor lymphocytes from the subject's donor (at least 2 x 10^8 T cells/kg).

6. Subject has provided written informed consent prior to initiation of any study-specific activities/procedures.

7. Subject has provided informed consent to be followed up in the GMALL-Registry.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

9. Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min.

10. Hepatic function as follows:

    • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN)
    • Alkaline phosphatase (ALP) < 3.0 x ULN
    • Bilirubin ≤ 2.0 x ULN (unless considered due to Gilbert's syndrome or hemolysis)

11. For female subjects only: Women of child-bearing age have to use a reliable method of contraception.

Exclusion Criteria:

1. Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician.
2. Eligibility for standard chemotherapy, as considered by the treating physician.
3. Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) prior to baseline MRD and/or chimerism assessment.
4. Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment.
5. Any grade of GvHD currently requiring treatment.
6. Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy).
7. Evidence of current CNS involvement by ALL.