Daratumumab in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: The DELPHINUS Study

Academic Background

Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) are among the most common malignancies in children. Although the cure rate for newly diagnosed ALL and LL patients is relatively high, 10% to 25% of patients relapse or become refractory after initial treatment, particularly those with T-cell ALL/LL, who have a poor prognosis. Treatment options for relapsed/refractory ALL/LL are limited, and existing therapies often come with high toxicity and low efficacy. In recent years, significant progress has been made in immunotherapy for B-cell ALL (e.g., Blinatumomab, Inotuzumab Ozogamicin, and CAR-T cell therapy), but the treatment of T-cell ALL/LL remains challenging, primarily due to the lack of effective immune targets and low response rates to standard reinduction regimens.

CD38 is an antigen highly expressed in T-cell ALL/LL, providing a rationale for the use of daratumumab (Daratumumab), a monoclonal antibody targeting CD38, which has shown good efficacy in multiple myeloma and systemic light chain amyloidosis. This study aimed to evaluate the safety and efficacy of daratumumab combined with chemotherapy in children and young adults with relapsed/refractory T-cell ALL/LL.

Source of the Paper

This study was conducted by Teena Bhatla, Laura E. Hogan, and other co-authors from several internationally renowned medical institutions, including the Children’s Hospital of New Jersey, Stony Brook Children’s, and the Children’s Hospital of Philadelphia. The paper was published in the journal Blood on November 21, 2024, with the study identifier NCT03384654.

Study Design and Methods

Study Process

The DELPHINUS study was an open-label, multicenter, phase II clinical trial divided into two stages. The first stage evaluated the preliminary safety and efficacy of daratumumab in children with B-cell and T-cell ALL, while the second stage expanded to include young adults with T-cell ALL/LL. The primary endpoint was the complete response (CR) rate in B-cell ALL patients after two treatment cycles and in T-cell ALL patients after one treatment cycle.

Study Subjects

The study enrolled patients aged 1 to 30 years, divided into a B-cell ALL group (n=7) and a T-cell ALL/LL group (n=39). The B-cell ALL group consisted of relapsed/refractory cases, while the T-cell ALL/LL group included patients with first relapse or refractory disease. All patients received daratumumab combined with chemotherapy.

Treatment Regimen

Patients in the B-cell ALL group received daratumumab (16 mg/kg, weekly intravenous infusion) combined with vincristine, prednisone, and intrathecal methotrexate. Patients in the T-cell ALL/LL group received daratumumab combined with doxorubicin, vincristine, prednisone, pegylated asparaginase, and intrathecal methotrexate. The treatment cycle lasted 1 to 2 cycles, and patients could proceed to allogeneic hematopoietic stem cell transplantation (HSCT) based on disease progression.

Data Analysis

The primary endpoint was the CR rate, and secondary endpoints included overall response rate (ORR), event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), and minimal residual disease (MRD) negativity rate. Data analysis was performed using the Kaplan-Meier method, with a statistical significance level of 5%.

Study Results

B-cell ALL Group

Among the 7 B-cell ALL patients, none achieved CR, 1 patient achieved incomplete remission (CRi), 3 patients had refractory ALL, and 3 patients experienced disease progression. Due to poor efficacy, this group was terminated early.

T-cell ALL/LL Group

Among the 39 T-cell ALL/LL patients, the CR rate was 41.7% in the childhood T-cell ALL group, 60.0% in the young adult T-cell ALL group, and 30.0% in the T-cell LL group. The overall response rates (ORR) were 83.3%, 80.0%, and 50.0%, respectively. The MRD negativity rates were 45.8%, 20.0%, and 50.0%, respectively. The 24-month event-free survival (EFS) rates were 36.1%, 20.0%, and 20.0%, and the overall survival (OS) rates were 41.3%, 25.0%, and 20.0%, respectively. HSCT was successfully performed in 75.0% of childhood T-cell ALL patients, 60.0% of young adult T-cell ALL patients, and 30.0% of T-cell LL patients.

Safety

Daratumumab demonstrated a favorable safety profile, with no new safety concerns identified. The most common grade ³⁄₄ adverse events were hematologic events, such as febrile neutropenia, anemia, and thrombocytopenia. Infusion-related reactions (IRRs) were mostly grade ¹⁄₂ and did not lead to treatment discontinuation.

Conclusion

Daratumumab combined with chemotherapy demonstrated good safety and efficacy in children and young adults with relapsed/refractory T-cell ALL/LL, effectively bridging patients to HSCT. Although the efficacy in the B-cell ALL group was poor, the CR and ORR rates in the T-cell ALL/LL group were significantly better than historical controls, with a high HSCT success rate. The serum concentration of daratumumab reached the expected target, with limited distribution in the cerebrospinal fluid.

Study Highlights

1. Innovative Treatment Regimen: Daratumumab combined with chemotherapy provides a new treatment option for relapsed/refractory T-cell ALL/LL patients.
2. Significant Efficacy: The CR and ORR rates in the T-cell ALL/LL group were significantly better than historical controls, with a CR rate of 41.7% in the childhood T-cell ALL group.
3. Favorable Safety Profile: Daratumumab demonstrated a good safety profile, with no new safety concerns, and infusion-related reactions were mostly low-grade.

Study Significance

This study provides a new treatment option for relapsed/refractory T-cell ALL/LL patients, significantly improving CR rates and HSCT success rates. The combination therapy of daratumumab offers important insights for future clinical research, particularly in newly diagnosed or first-relapse T-cell ALL/LL patients, warranting further exploration.