Academic Background and Problem

Acute lymphoblastic leukemia (ALL) is a malignant hematologic disease, particularly challenging to treat in older patients, with limited treatment options and poor outcomes. Traditional chemotherapy regimens yield long-term survival rates of only 20%-30% in elderly patients. Therefore, finding more effective and better-tolerated treatment strategies has become a focus of clinical research. Inotuzumab Ozogamicin (InO), an antibody-drug conjugate targeting the CD22 antigen, has shown significant efficacy in relapsed/refractory ALL. However, its application as a frontline treatment in elderly patients has not been fully validated.

This study aimed to evaluate the safety and efficacy of InO combined with low-intensity chemotherapy as a frontline treatment for elderly patients with newly diagnosed CD22-positive, Philadelphia chromosome-negative (Ph-) B-cell precursor ALL (BCP-ALL). The primary goal was to improve the 1-year overall survival (OS) rate and explore its long-term efficacy in this patient population.

Study Source

This study was conducted by Patrice Chevallier and colleagues from multiple research centers in France, Finland, and the Czech Republic, in collaboration with the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the French Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). The results were published on October 17, 2024, in the Journal of Clinical Oncology.

Study Design and Process

Study Design

The EWALL-InO study was an open-label, multicenter, prospective phase II clinical trial, registered under NCT03249870. The study enrolled patients aged 55 years and older with newly diagnosed CD22-positive, Ph- BCP-ALL. The treatment regimen included two induction phases, six cycles of consolidation chemotherapy, and 18 months of maintenance chemotherapy. Allogeneic hematopoietic stem cell transplantation (allo-SCT) was permitted after three consolidation cycles.

Treatment Protocol

1. Prephase: Patients received corticosteroid treatment.
2. First Induction: Patients received vincristine, dexamethasone, and three doses of InO (0.8 mg/m² on day 1, 0.5 mg/m² on days 8 and 15).
3. Second Induction: Patients received cyclophosphamide, dexamethasone, and two doses of InO (0.5 mg/m² on days 1 and 8).
4. Consolidation Therapy: Patients received up to six cycles of consolidation chemotherapy.
5. Maintenance Therapy: Patients received 18 months of maintenance chemotherapy.

Study Endpoints

The primary endpoint was 1-year overall survival (OS). Secondary endpoints included mortality during induction, hematologic recovery, response rates, minimal residual disease (MRD) status, event-free survival (EFS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR).

Study Results

Patient Characteristics

Between December 2017 and March 2022, 131 patients were enrolled, with a median age of 68 years. Among them, 47% were male, and 53% were female.

Treatment Feasibility

One patient died during the prephase, 130 patients received the first induction, and 120 patients received the second induction. After the second induction, 118 patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with 113 patients receiving at least one consolidation cycle and 76 patients initiating maintenance therapy.

Response Rates and MRD

After the first induction, 88.5% of patients achieved CR/CRp, with 71% having MRD1 <10^-3 and 56% having MRD1 <10^-4. After the second induction, 90% of patients achieved CR/CRp, with 86% having MRD2 <10^-3 and 80% having MRD2 <10^-4.

Survival Rates

The 1-year OS was 73.2%, and the 2-year OS was 55%. The 1-year RFS was 66%, and the 2-year RFS was 50%. The 1-year CIR was 25%, and the 2-year CIR was 38%. Among the 10 patients who underwent allo-SCT, the 2-year OS and RFS were both 90%, with no relapses.

Prognostic Factors

High-risk cytogenetics and CD22 expression <70% were associated with worse OS. High-risk cytogenetics and MRD2 ≥10^-4 were associated with lower RFS and higher CIR.

Safety

Three patients died during the first induction, two from multiple organ failure and one from hemorrhage. No deaths occurred during the second induction. The most common grade 3-4 adverse events were infections and hepatic dysfunction. Only one non-fatal sinusoidal obstructive syndrome (SOS) was reported.

Conclusion

This study demonstrates that InO combined with low-intensity chemotherapy is an effective and well-tolerated frontline treatment for elderly patients with CD22-positive, Ph- BCP-ALL. The 1-year OS rate of 73.2% and low treatment-related mortality support the use of InO as a first-line therapy in this patient population. These findings provide strong evidence for InO to become a new standard of care for elderly ALL patients.

Study Highlights

1. High Response Rates: 90% of patients achieved CR/CRp after induction, with 80% having MRD2 <10^-4.
2. Low Toxicity: Only three patients died during induction, and one non-fatal SOS occurred.
3. Long-Term Survival: The 1-year OS was 73.2%, and the 2-year OS was 55%. Allo-SCT patients had a 2-year OS and RFS of 90%.

Study Significance

This study offers a new, effective, and well-tolerated treatment option for elderly ALL patients, significantly improving survival rates and quality of life. The results support the use of InO as a frontline therapy in elderly ALL patients and lay the groundwork for future phase III prospective studies.