Daratumumab for relapsed/refractory T-cell ALL or LL: Results from DELPHINUS study

Pediatric T-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) are aggressive, chemoresistant malignancies with poor prognosis and survival outcomes. Approximately 15–20% of pediatric patients with ALL or LL will be refractory or relapse after front-line treatment.¹ Preliminary studies suggested that daratumumab (DARA) combined with conventional chemotherapy would be effective against T-cell ALL/LL.

DARA, a human immunoglobulin G1_k monoclonal antibody that binds CD38, is approved for the treatment of multiple myeloma and has shown preclinical efficacy in ALL models. CD38 is a type II transmembrane glycoprotein that is highly expressed on myeloma cells and blasts in patients with T-cell ALL at diagnosis and relapse; therefore, it is a promising target for immunotherapy.^2,3 The phase II DELPHINUS study (NCT03384654) examined the safety and efficacy of DARA in addition to standard chemotherapy in pediatric/young adult patients with relapsed/refractory T-cell ALL and T-cell LL; results were presented by Laura E. Hogan at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.³ Below, we summarize the key findings.

Study design

This is an open-label, non-randomized phase II clinical trial evaluating the efficacy and safety of DARA in addition to vincristine, prednisone, L-asparaginase, and doxorubicin (VPLD) in pediatric and young adult patients (1–30 years of age) with T-cell ALL/LL who are refractory to one prior induction/consolidation regimen or in first relapse. Patients received age/risk-adjusted intrathecal therapy and response was measured by local bone marrow morphology at the end of each cycle.

Dosing schedule

DARA (16 mg/kg IV once a day on Days 1, 8, 15, and 22) was given in Cycles 1–2.

• Cycle 1: DARA in combination with VPLD (backbone)

• Vincristine: 1.5 mg/m² (maximum: 2.0 mg/m²) IV once a day on Days 1, 8, 15, and 22
• Prednisone: 40.0 mg/m² PO divided twice a day on Days 1–28
• PEG-asparaginase: 2,500 U/m² IM/IV once a day on Days 2 and 16
• Doxorubicin: 60.0 mg/m² IV once on Day 1

• Cycle 2: DARA in combination with  

• Methotrexate: 5.0 g/m² IV once on Day 2
• Cyclophosphamide: 1.0 g/m² IV once on Day 15
• Cytarabine: 75.0 mg/m² IV/SC once a day on Days 16–19 and Days 23–26
• 6-mercaptopurine: 60.0 mg/m² PO once a day on Days 15–28

Endpoints

• Primary endpoint was complete response (CR) rate in pediatric patients with T-cell ALL at the end of Cycle 1.
• Secondary endpoints included:

• Overall response rate: CR or CR with incomplete hematological recovery at any time before subsequent therapy or hematopoietic stem cell transplant
• Minimal residual disease negativity
• Event-free survival and overall survival
• Safety and tolerability
• Pharmacokinetics of DARA

Results

Patient baseline characteristics

A total of 22 pediatric and five young adult patients with T-cell ALL and ten patients with T-cell LL were enrolled in this clinical trial.

• T-cell ALL (pediatric): 22 patients completed Cycle 1, 18 completed Cycle 2, and six received DARA continuation.
• T-cell ALL (young adult): five patients completed Cycle 1, three completed Cycle 2, and one received DARA continuation
• T-cell LL: ten patients completed Cycle 1, six completed Cycle 2, and no patients received DARA continuation.
• All T-cell ALL patients expressed CD38 at baseline; further details on baseline characteristics are shown in Table 1.

Table 1. Baseline characteristics*

ALL, acute lymphoblastic leukemia; LL, lymphoblastic lymphoma. *Adapted from Hogan.3 †Criteria for enrollment included ≥5% blasts by morphology. ‡Time from the initial diagnosis to the first dose.
Characteristics	Pediatric T-cell ALL (n = 24)†	Young adult T-cell ALL (n = 5)†	T-cell LL (n = 10)
Median age (range), years	10.0 (2–17)	23.0 (18–25)	14.5 (5–22)
Sex, %
Female	41.7	0	10.0
Male	58.3	100.0	90.0
Median time‡ (range), years	2.5 (0.5–6.1)	0.6 (0.1–5.6)	0.8 (0.5–6.0)

Efficacy

• Overall, 41.7% of pediatric patients with T-cell ALL achieved CR at the end of Cycle 1.
• Overall response rate was 83.3%, 60%, and 40% in pediatric patients with T-cell ALL, young adult patients with T-cell ALL, and patients with T-cell LL, respectively (Figure 1).
• In total, 41.7% of pediatric patients with T-cell ALL and 20.0% of young adult patients with T-cell ALL achieved minimal residual disease negativity at any time during treatment.
• The median follow-up was 31.3 months, 25.4 months, and 16.4 months for pediatric patients with T-cell ALL, young adult patients with T-cell ALL, and patients with T-cell LL, respectively.
• Median event-free survival was 8.3 months, 8.0 months, and 2.9 months in pediatric patients with T-cell ALL, young adult patients with T-cell ALL, and patients with T-cell LL, respectively.
• Overall survival was 9.5 months in the pediatric patients with T-cell ALL, 13.6 months in the young adult patients with T-cell ALL, and 4.2 months in the patients with T-cell LL.

ALL, acute lymphoblastic leukemia; CR, complete response; Cri, CR with incomplete hematologic recovery; IV, intravenous; LL, lymphoblastic lymphoma; ORR, overall response rate; PR, partial response.
*Adapted from Hogan.³

Safety

• Adverse events (AEs) with DARA were consistent with those commonly seen with VPLD backbone therapy alone.
• The most common AEs included anemia, thrombocytopenia, neutropenia, and febrile neutropenia (Table 2).
• All pediatric patients with T-cell ALL had a Grade 3/4 treatment-emergent adverse event, 12 patients (50.0%) experienced a Grade 3/4 infection, and three patients (12.5%) experienced Grade 3/4 sepsis.
• No pediatric patients with T-cell ALL discontinued DARA due to AEs.
• One patient (4.2%) died of brain edema and hepatic failure attributed to study treatment (asparaginase allergy) but unrelated to DARA.

Table 2. TEAEs in pediatric patients with T-cell ALL*

AE, adverse event; TEAE, treatment-emergent adverse event. *Adapted from Hogan.3 †AEs were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or later.
Grade 3/4 TEAE† (≥20% of patients), %	Patients (n = 24)
Anemia	66.7
Thrombocytopenia	62.5
Neutropenia	50.0
Febrile neutropenia	45.8
Leukopenia	37.5
Increased alanine aminotransferase	25.0
Hypokalemia	25.0

Overall, 16 (66.7%) pediatric patients with T-cell ALL, four (80.0%) young adult patients with T-cell ALL, and eight (80.0%) patients with T-cell LL, experienced ≥1 infusion-related reaction of any grade. The most common infusion-related reactions in pediatric patients with T-cell ALL were abdominal pain, pyrexia, vomiting, and nausea (Table 3).

Table 3. Infusion-related reactions in pediatric/young adult patients with T-cell ALL*

Infusion-related reaction†, %	T-cell ALL, pediatric (n = 24)	T-cell ALL, young adult (n = 5)	T-cell LL (n = 10)
Any grade occurring in ≥10% of patients
Abdominal pain	25.0	0	10.0
Pyrexia	16.7	0	10.0
Vomiting	12.5	0	10.0
Nausea	12.5	0	0
Cough	12.5	0	40.0
Urticaria	12.5	0	0
Rash	4.2	20.0	0
Dyspnea	4.2	0	30.0
Pruritus	0	20.0	10.0
Rhinitis	0	20.0	0
Increased gamma glutamyl transferase	0	20.0	0
Musculoskeletal chest pain	0	20.0	0
Grade 3/4 occurring in any patients
Leukopenia	4.2	0	0
Abdominal pain	4.2	0	0
Thrombocytopenia	0	0	10.0
Bronchospasm	0	0	10.0
ALL, acute lymphoblastic leukemia; LL, lymphoblastic lymphoma. *Adapted from Hogan.3 †Infusion-related reactions were determined clinically by the treating physician and as guided by the protocol.

Pharmacokinetics

For pediatric patients with T-cell ALL, the mean serum concentration of DARA was 361 µg/mL on Day 22 of Cycle 2; this was higher than identified effective concentrations in adult patients with multiple myeloma,⁴ suggesting a DARA dose of 16 mg/kg IV once a day is sufficient.

Conclusion

In this phase II trial, DARA showed initial activity in combination with VPLD in pediatric and young adult patients with relapsed/refractory T-cell ALL or LL. The addition of DARA resulted in improved response rates, compared with VPLD backbone therapy alone, and had a manageable safety profile.