Fixed-dose inotuzumab ozogamicin combined with vincristine and prednisone regimen as induction therapy for newly diagnosed B-cell acute lymphocytic leukemia Free

Background: Adult acute B-cell lymphocytic leukemia (B-ALL) exhibits significant prognostic heterogeneity. The complete remission (CR) rate of traditional induction chemotherapy is 70%-90%. Achieving measurable residual disease (MRD) negativity is a particularly important factor influencing long-term survival outcomes. Nevertheless, treatment-related toxicities are associated with conventional chemotherapy limit the advance in efficacy. Inotuzumab ozogamicin (INO), as an anti-CD22 antibody-drug conjugate, demonstrates potent efficacy and results in less myelosuppression used by dose escalation.

Objective: To further explore and optimize the induction strategies, we designed fixed-dose INO combines with vincristine and prednisone (VP) as a new regimen for newly diagnosed B-ALL.

Methods: In this multi-center, single-arm, prospective study, patients with newly diagnosed philadelphia chromosome positive (Ph+) or negative (Ph-) B-ALL were enrolled since May 2023. The study had registered in the Chinese Clinical Trial Register (ChiCTR), number ChiCTR2500104832 (Ph+) / ChiCTR2500105597 (Ph-).

Both groups (Ph- or Ph+) received INO combined with VP as induction therapy. INO was administered at a fixed-dose of 1 mg on days 1, 8, and 15, capped at a maximum cumulative dose of 2.7 mg/m². Vincristine was given at 1.4 mg/m² (up to a maximum of 4 mg) on days 1, 8, 15, and 22. Prednisone was administered orally in two patterns: 1 mg/kg daily from days 1 to 14, then 0.5 mg/kg daily from days 15 to 28, or 1 mg/kg on the first 4-days of each week for consecutive four weeks. For Ph+ patients, TKIs were added orally. Patients with peripheral blood leukocyte counts ≥ 25×10⁹/L were eligible for the preparative regimen. Patients received consolidation and maintenance therapy after CR.

The primary endpoint was overall response rate (ORR) which includes CR and CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), MRD negativity rate and safety as the secondary endpoint.

Result: By mid-June 2025, a total of twenty-two newly diagnosed B-ALL patients were recruited, included thirteen Ph- B-ALL and nine Ph+ B-ALL, with an ORR of 95.45% (21/22, 95% CI, 87%-100%), and flow MRD negativity of 86.36% (19/22, 95% CI, 72%-100%). All patients acquired remission both estimated CR, the MRD negativity rate was 90.48% (19/21, 95% CI, 78%-100%) among those achieved CR. Baseline characteristics and treatment response are detailed in the subgroups.

In the group of Ph- B-ALL, the median age was 56 (17-75) years old, the average peripheral blood leukocyte counts at diagnosed was 15.14 (2.08-33.14) × 10⁹/L, and median bone marrow blast was 85% (38%-96%). The CR rate of this group was 92.31% (12/13, 95%CI, 78%-100%), all these patients achieved CR both showed MRD negativity. Only one patient with IKZF1 mutation was evaluated as non-remission (NR), the NR rate was 7.69% (1/13, 95%CI, 0-22%).

In the group of Ph+ B-ALL, the median age was 45 (17-74) years old, average peripheral blood leukocyte counts was 61.32 (1.9-313.79) ×10⁹/L at diagnosed, median bone marrow blast was 87.5% (79%-96%). Six patients carried the BCR-ABL (p190) fusion gene, while three had BCR-ABL (p210). All of them accepted TKIs, four with imatinib, one with dasatinib and four with flumatinib. All the nine patients achieved CR, with a CR rate of 100% (9/9). Seven achieved MRD negativity by flow cytometry, the MRD negative rate was 77.78% (7/9, 95%CI, 50%-100%). Complex karyotype and NRAS mutations may be associated with a higher risk of MRD positivity.

During the follow-up treatment, Grade 3-4 hematological toxicity rarely occurred. The median duration of granulocytopenia was 0 (0-7) day and 11 (0-12) days, respectively for Ph- and Ph+ B-ALL. Only 7.69% (1/13) of Ph- B-ALL patients and 22.22% (2/9) of Ph+ B-ALL patients required platelet transfusion. Sinusoidal obstruction syndrome/venoocclusive disease (SOS/VOD) was observed in just one patient. No deaths due to pulmonary infections.

Conclusions: The fixed-dose INO combined with VP regimen can be regarded as a highly effective and low-toxicity induction therapy for newly diagnosed patients for both Ph- B-ALL and Ph+ B-ALL.