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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 G1k 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.
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.
DARA (16 mg/kg IV once a day on Days 1, 8, 15, and 22) was given in Cycles 1–2.
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.
Table 1. Baseline characteristics*
Characteristics |
Pediatric T-cell ALL |
Young adult T-cell ALL |
T-cell LL |
---|---|---|---|
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), |
2.5 (0.5–6.1) |
0.6 (0.1–5.6) |
0.8 (0.5–6.0) |
ALL, acute lymphoblastic leukemia; LL, lymphoblastic lymphoma. ‡Time from the initial diagnosis to the first dose. |
Figure 1. ORR in patients who received 16 mg/kg IV DARA once a day*
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
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 |
AE, adverse event; TEAE, treatment-emergent adverse event. |
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 |
T-cell ALL, young |
T-cell LL |
---|---|---|---|
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 |
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. |
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.
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.
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