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2022-07-04T08:36:34.000Z

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

Jul 4, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in ALL

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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.

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*

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)

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.

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.

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

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*

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.
*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.

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.

  1. Michaux K, Bergeron C, Gandemer V, et al. Relapsed or refractory lymphoblastic lymphoma in children: results and analysis of 23 patients in the EORTC 58951 and the LMT96 protocols. Pediatr Blood Cancer. 2016;63(7):1214-1221. DOI: 1002/pbc.25990
  2. Bride KL, Vincent TL, Im SY, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131(9):995-999. DOI: 1182/blood-2017-07-794214
  3. Hogan LE. Oral abstract #10001. Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): Results from the phase 2 DELPHINUS study. American Society of Clinical Oncology Annual Meeting; Jun 6, 2022; Chicago, US.
  4. Xu XS, Yan X, Puchalski T, et al. Clinical implications of complex pharmacokinetics for daratumumab dose regimen in patients with relapsed/refractory multiple myeloma. Clin Pharmacol Ther. 2017;101(6):721-724. DOI: 1002/cpt.577

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