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DARZALEX® (daratumumab)

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Use of DARZALEX + DARZALEX FASPRO in Acute Lymphoblastic Leukemia or Acute Lymphoblastic Lymphoma

Last Updated: 02/20/2025

SUMMARY

DARZALEX for intravenous (IV) use + DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for use in patients with B-cell or T-cell acute lymphoblastic leukemia or acute lymphoblastic lymphoma. Janssen does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
DELPHINUS is a phase 2 study evaluating the safety and efficacy of DARZALEX in patients between the ages of ≥1 to ≤30 years with relapsed/refractory (R/R) precursor B-cell or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.¹
- Hogan et al (2022)² presented (at the 58th American Society of Clinical Oncology [ASCO] Annual Meeting) the initial results of this study evaluating the efficacy, safety, and pharmacokinetics (PK) of DARZALEX in pediatric (1 to 17 years old) or young adult (18-30 years old) patients with R/R T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. At the end of cycle 1, complete response (CR) was achieved in 10 of 24 (41.7%; 90% confidence interval [CI], 24.6-60.3) pediatric patients with T-cell acute lymphoblastic leukemia. The most common grade 3/4 treatment-emergent adverse event (TEAE) in pediatric T-cell acute lymphoblastic leukemia patients was anemia (66.7%). The most common grade 3/4 infusion-related reaction (IRR) in pediatric patients with T-cell acute lymphoblastic leukemia was leukopenia and abdominal pain (4.2% each). The most common grade 3/4 IRR in patients with T-cell lymphoblastic lymphoma was thrombocytopenia and bronchospasm (10% each).
- Bhatla et al (2024)³^,⁴ reported updated results of the phase 2 DELPHINUS study. The overall response rates (ORR) were 14.3% for pediatric patients with B-cell acute lymphoblastic leukemia, 83.3% for pediatric patients with T-cell acute lymphoblastic leukemia, 80% for young adult patients with T-cell acute lymphoblastic leukemia, and 50% for patients with T-cell lymphoblastic lymphoma. The CR, CR with incomplete hematologic recovery (CRi), partial response (PR), progressive disease (PD), and stable disease (SD) rates are summarized in Table: Efficacy Outcomes for B-Cell and T-Cell Cohorts. Minimal residual disease (MRD)-negativity at any time during treatment was achieved in 11 (45.8%) pediatric patients with T-cell acute lymphoblastic leukemia, 1 (20%) young adult patient with T-cell acute lymphoblastic leukemia, and 5 (50%) patients with T-cell lymphoblastic lymphoma. The median event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) rates are summarized in Table: Summary of EFS, RFS, and OS Rates. No new safety concerns were identified with DARZALEX. Any-grade and grade 3/4 TEAEs occurred in all patients (100%). The most common grade 3/4 TEAEs across the cohorts were hematologic events. Grade 3/4 infections occurred in 1 pediatric patient with B-cell acute lymphoblastic leukemia (grade 4 sepsis), 12 (50%) pediatric patients with T-cell acute lymphoblastic leukemia, 2 (40%) young adult patients with T-cell acute lymphoblastic leukemia, and 3 (30%) patients with T-cell lymphoblastic lymphoma. IRRs after the first DARZALEX infusion were reported in 4 (57.1%) pediatric patients with B-cell acute lymphoblastic leukemia, 16 (66.7%) pediatric patients with T-cell acute lymphoblastic leukemia, 4 (80%) young adult patients with T-cell acute lymphoblastic leukemia, and 8 (80%) patients with T-cell lymphoblastic lymphoma.
Cerrano et al (2022)⁵ conducted a retrospective, multicenter, observational cohort study that evaluated the efficacy and safety of DARZALEX in patients with R/R or minimal residual disease (MRD)-positive acute lymphoblastic leukemia or lymphoblastic lymphoma. The overall response rate (ORR) was 20%, and median overall survival (OS) was 4 weeks. There were no unexpected toxicities reported. One grade 2 IRR was reported in the entire cohort.
Muller et al (2022)⁶ published preclinical data of DARZALEX in combination with a modified cluster of differentiation 47 (CD47) antibody in patients with T-cell acute lymphoblastic leukemia.
Vogiatzi et al (2019)⁷ published preclinical data investigating the efficacy of DARZALEX in combination with chemotherapy and the correlation of CD38 expression levels in patients with T-cell acute lymphoblastic leukemia.
Bride et al (2018)⁸ assessed the preclinical efficacy of DARZALEX in T-cell acute lymphoblastic leukemia.
For information on ongoing clinical trials investigating the use of DARZALEX in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, please visit www.clinicaltrials.gov.
Other relevant literature on preclinical data and case reports have been referenced in addition to the data from clinical studies that are summarized below.⁹^-³¹

PRODUCT LABELING

DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf.
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

BACKGROUND

A potential target in T-cell acute lymphoblastic leukemia is CD38. CD38 is a type II-transmembrane glycoprotein, and one of its main roles is in the regulation of cytoplasmic calcium flux that regulates signal transduction in immune cells.⁸ T-cell acute lymphoblastic leukemia blasts often express high CD38 levels.¹³ Daratumumab is a monoclonal antibody that binds to a specific epitope of CD38.⁸

CLINICAL DATA

DELPHINUS (ALL2005; clinicaltrials.gov identifier: NCT03384654) is an ongoing, open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX in patients with R/R precursor B-cell or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.¹^,² Hogan et al (2022)² presented the initial results of the phase 2 DELPHINUS study evaluating the efficacy, safety, and PK of DARZALEX in pediatric (1 to 17 years old) or young adult (18-30 years old) patients with R/R T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Bhatla et al (2024)³^,⁴ reported updated results of the phase 2 DELPHINUS study that evaluated the efficacy and safety of DARZALEX in pediatric (1-17 years old) patients with B-cell or T-cell acute lymphoblastic leukemia (stage 1) and young adult (18-30 years old) patients with T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (stage 2).

Study Design/Methods

The study enrolled 47 patients and consists of 2 cohorts. The study design has been presented in the Figure: Study Design.

Study Design¹^,²

Graphical user interface, text

Description automatically generated

Abbreviations: 6-MP, 6-mercaptopurine; allo-HSCT, allogeneic hematopoietic stem cell transplant; BID, twice daily; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; CP, cyclophosphamide; CR, complete response; CrCl, creatinine clearance; CSF, cerebrospinal fluid; Dara, daratumumab; DXR, doxorubicin; EFS, event-free survival; GFR, glomerular filtration rate; GVHD, graft vs host disease; HSCT, hematopoietic stem cell transplant; IM, intramuscular; IV, intravenous; MRD, minimal residual disease; MTX, methotrexate; ORR, overall response rate; OS, overall survival; Ph+, Philadelphia chromosome positive; PO, orally; PRED, prednisone; PS, performance status; Q2W, twice a week; QD, once daily; QW, once weekly; RFS, relapse-free survival; SC, subcutaneously; ULN, upper limit of normal range; VCR, vincristine.
^aB-cell cohort for stage 1: patients aged 1 to <18 years with acute lymphoblastic leukemia in ≥2nd relapse or refractory to 2 prior induction treatments with ≥5% blasts in bone marrow; stage 2: patients aged 1-30 years with acute lymphoblastic leukemia in ≥2nd relapse or refractory to 2 prior induction treatments with ≥5% blasts in bone marrow, acute lymphoblastic lymphoma in ≥2nd relapse or refractory to 2 prior induction regimens with measurable disease.
^bT-cell cohort for stage 1: patients aged 1 to <18 years with acute lymphoblastic leukemia in 1st relapse or refractory to 1 prior induction/consolidation treatment with ≥5% blasts in the bone marrow; stage 2: patients aged 1-30 years with acute lymphoblastic leukemia in 1st relapse or refractory to 1 prior induction/consolidation treatment with ≥5% blasts in bone marrow, acute lymphoblastic lymphoma in 1st relapse or refractory to 1 prior induction/consolidation treatment with measurable disease, aged 1-30 years.
^cPatients received age/risk-adjusted intrathecal therapy, and those who achieved CR after cycles 1 or 2 could proceed to allo-HSCT off-study.
^dFor patients who achieved a CR and required a short interval of treatment prior to transplant, Dara 16 mg/kg IV could be given QW (total of 4 doses) after completion of cycle 1 or Q2W (total of 2 doses) after completion of cycles 2-6 or once after completion of cycles ≥7. There was a 2-week interval from the last dose of Dara and the start of conditioning therapy for the transplant. Other standard maintenance chemotherapy could also be given after the discontinuation of study treatment and prior to transplant.
^eMaximum 2 mg.
^fCycle 2 was optional to allow further treatment for those who did not achieve CR or to consolidate the response prior to HSCT.
^gDuration from the date of first treatment to the first documented treatment failure or date of relapse from CR or death.

Hogan et al (2022)² presented the initial results of the phase 2 DELPHINUS study evaluating the efficacy, safety, and PK of DARZALEX in pediatric (1 to 17 years old) or young adult (18-30 years old) patients with R/R T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.

Study Design/Methods

Primary endpoint: CR in pediatric T-cell acute lymphoblastic leukemia patients at the end of cycle 1 (null hypothesis [H₀], CR rate ≤30%; alternative hypothesis [H_a]: CR rate ≥60%)
Secondary endpoints: ORR, percentage of MRD-negative patients, patients receiving allogeneic hematopoietic stem cell transplant (allo-HSCT), maximum plasma concentration (C_max) and minimum plasma concentration (C_min) of daratumumab, anti-daratumumab antibodies, concentration of daratumumab in cerebrospinal fluid (CSF), event-free survival (EFS), OS, safety, tolerability, and PK of daratumumab

Results

Patient Characteristics

Overall, 39 patients were included in this analysis. The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.

Baseline Patient and Disease Characteristics²

Characteristic	T-cell acute lymphoblastic leukemia		T-cell lymphoblastic lymphoma (n=10)
Characteristic	Pediatric patients (n=24)	Young adult patients (n=5)	T-cell lymphoblastic lymphoma (n=10)
Median age (range), years	10 (2-17)	23 (18-25)	14.5 (5-22)
Sex, n (%)
Male	14 (58.3)	5 (100)	9 (90)
Female	10 (41.7)	0 (0)	1 (10)
Median time from initial diagnosis to first dose (range), years	2.5 (0.5-6.1)	0.6 (0.1-5.6)	0.8 (0.5-6)
Cycle of treatment received, n
Cycle 1	22	5	10
Cycle 2	18	3	6
DARZALEX continuation	6	1	0 (0)
CNS involvement at study entry, n (%)	4 (16.7)	2 (40)	2 (20)
Abbreviation: CNS, central nervous system.

Efficacy

The median (range) follow-up duration for the pediatric/young adult T-cell acute lymphoblastic leukemia, young adult T-cell acute lymphoblastic leukemia, and T-cell lymphoblastic lymphoma groups was 31.3 (0.8-40.1), 25.4 (2.6-25.4), and 16.4 (1.6-19) months, respectively.
At the end of cycle 1, CR was achieved in 10 of 24 (41.7%; 90% CI, 24.6-60.3) pediatric patients with T-cell acute lymphoblastic leukemia.
Efficacy outcomes are summarized in Table: Efficacy Outcomes.

Efficacy Outcomes²

Parameter	T-cell acute lymphoblastic leukemia		T-cell lymphoblastic lymphoma (n=10)
Parameter	Pediatric patients (n=24)	Young adult patients (n=5)	T-cell lymphoblastic lymphoma (n=10)
ORR^a,b, n (%)	20 (83.3)	3 (60)	5 (50)
90% CI	65.8-94.1	18.9-92.4	15-69.7
CR^a,c, n (%)	13 (54.2)	3 (60)	4 (40)
CRi^a, n (%)	7 (29.2)	-	-
PR^a, n (%)	-	-	1 (10)
MRD-negativity^a, n (%)	10 (41.7)	1 (20)	5 (50)
Median EFS^d, months (90% CI)	8.3 (5.3-20.5)	8 (2.6-NE)	2.9 (1.3-4.9)
Median OS^e, months (90% CI)	9.5 (7-NE)	13.6 (4.5-NE)	4.2 (1.7-5.6)
Abbreviations: CI, confidence interval; CR, complete response; CRi, complete response with incomplete hematologic recovery; EFS, event-free survival; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate; OS, overall survival; PR, partial response.^aAt any time during treatment.^bORR data after Cycle 2 will be available at end of study ^cCriteria for CR: bone marrow blasts, <5%; absolute neutrophil count, >1×10⁹/L; platelet count, >100×10⁹/L; No evidence of circulating blasts or extramedullary disease ^dEFS was defined as the time from the date of first treatment to the first documented treatment failure or date of relapse from CR or death due to any cause, whichever occurred first. ^eOS was measured from the date of first treatment to the date of death due to any cause.

Safety

Grade 3/4 TEAEs were reported in all pediatric patients with Tcell acute lymphoblastic leukemia. See Table: Grade 3/4 TEAEs (≥20%) in Pediatric Patients with T-cell Acute Lymphoblastic Leukemia.
Grade 3/4 infection was reported in 12 (50%) patients.
- Grade 3/4 sepsis and septic shock was reported in 3 patients.

Grade 3/4 TEAEs (≥20%) in Pediatric Patients with T-cell Acute Lymphoblastic Leukemia²

Event, n (%)	T-cell acute lymphoblastic leukemia
Event, n (%)	Pediatric Patients (n=24)
Hematologic
Anemia	16 (66.7)
Thrombocytopenia	15 (62.5)
Neutropenia	12 (50)
Febrile neutropenia	11 (45.8)
Leukopenia	9 (37.5)
Nonhematologic
Increased alanine aminotransferase	6 (25)
Hypokalemia	6 (25)
Abbreviation: TEAE, treatment-emergent adverse event.

Among pediatric patients with T-cell acute lymphoblastic leukemia, none discontinued DARZALEX due to adverse events (AEs), and 1 (4.2%) death reported due to TEAEs (brain edema and hepatic failure) related to the study treatment but unrelated to DARZALEX.
≥ IRRs of any grade were reported in 16 (66.7%) pediatric patients with T-cell acute lymphoblastic leukemia, 4 (80%) young adult patients with T-cell acute lymphoblastic leukemia, and 8 (80%) patients with T-cell lymphoblastic lymphoma. See Table: Infusion-Related Reactions.

Infusion-Related Reactions²

IRR, n (%)	T-cell acute lymphoblastic leukemia		T-cell lymphoblastic lymphoma (n=10)
IRR, n (%)	Pediatric patients (n=24)	Young adult patients (n=5)	T-cell lymphoblastic lymphoma (n=10)
Any grade occurring in >10% of patients
Abdominal pain	6 (25)	0	1 (10)
Pyrexia	4 (16.7)	0	1 (10)
Vomiting	3 (12.5)	0	1 (10)
Nausea	3 (12.5)	0	0
Cough	3 (12.5)	0	4 (40)
Urticaria	3 (12.5)	0	0
IRR	2 (8.3)	1 (20)	0
Rash	1 (4.2)	1 (20)	0
Dyspnea	1 (4.2)	0	3 (30)
Pruritus	0	1 (20)	1 (10)
Rhinitis	0	1 (20)	0
Increased gammaglutamyltransferase	0	1 (20)	0
Musculoskeletal chest pain	0	1 (2)	0
Grade 3/4 occurring in any patients
Leukopenia	1 (4.2)	0	0
Abdominal pain	1 (4.2)	0	0
Thrombocytopenia	0	0	1 (10)
Bronchospasm	0	0	1 (10)
Abbreviation: IRR, infusion-related reaction.

Pharmacokinetics

The mean serum trough concentration (C_trough)for daratumumab was 361 (standard deviation [SD], 106) μg/mL at cycle 2 day 22 in pediatric patients with T-cell acute lymphoblastic leukemia.
The mean CSF C_trough of daratumumab was 1.07 μg/mL at cycle 2 day 15.

Bhatla et al (2024)³^,⁴ reported updated results of the phase 2 DELPHINUS study that evaluated the efficacy and safety of DARZALEX in pediatric (1-17 years old) patients with B-cell or T-cell acute lymphoblastic leukemia (stage 1) and young adult (18-30 years old) patients with T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (stage 2).

Study Design/Methods

Primary endpoint: CR rate in patients with B-cell acute lymphoblastic leukemia within 2 cycles of therapy or CR rate in patients with T-cell acute lymphoblastic leukemia at the end of cycle 1 (defined as <5% bone marrow blasts, absence of circulating blasts or extramedullary disease, and full recovery of the absolute neutrophil count [>1×10⁹/L] and platelet count [>100×10⁹/L]).³
Secondary endpoints: ORR (CR + CRi at any time before the start of subsequent therapy or hematopoietic stem cell transplant [HSCT] for patients with acute lymphoblastic leukemia and CR + PR for patients with lymphoblastic lymphoma), percentage of MRD-negative patients, EFS, RFS, OS, safety, and PK of daratumumab.³

Results

Patient Characteristics

Overall, 7 and 39 patients were included in the B-cell and T-cell cohorts, respectively.³ Demographic and baseline characteristics are summarized in Table: Demographic and Baseline Characteristics For B-Cell and T-Cell Cohorts.

Demographic and Baseline Characteristics For B-Cell and T-Cell Cohorts³

Characteristic	B-Cell Acute Lymphoblastic Leukemia	T-Cell Acute Lymphoblastic Leukemia		T-Cell Lymphoblastic Lymphoma (n=10)
Characteristic	Pediatric Patients (n=7)	Pediatric Patients (n=24)	Young Adult Patients (n=5)	T-Cell Lymphoblastic Lymphoma (n=10)
Median age (range), years	5 (4-17)	10 (2-17)	23 (18-25)	14.5 (5-22)
Sex, n (%)
Male	3 (42.9)	14 (58.3)	5 (100)	9 (90)
Female	4 (57.1)	10 (41.7)	0 (0)	1 (10)
Race, n (%)
White	5 (71.4)	18 (75)	2 (40)	8 (80)
Asian	0 (0)	1 (4.2)	1 (20)	0 (0)
Black/African American	0 (0)	0 (0)	1 (20)	0 (0)
American Indian/Alaska Native	0 (0)	0 (0)	1 (20)	0 (0)
Not reported	2 (28.6)	5 (20.8)	0 (0)	2 (20)
Hispanic/Latino ethnicity, n (%)	1 (14.3)	4 (16.7)	2 (40)	1 (10)
Median time from initial diagnosis to first dose (range), years	2.7 (1.6-4.3)	2.5 (0.5-6.1)	0.6 (0.05-5.6)	0.8 (0.5-6)
Median lines of prior systemic therapy (range)	2 (1-10)^a	1 (1-1)	1 (1-1)	1 (1-1)
Median time from last progression of prior systemic therapy to first dose (range), days	15 (10-112)	8.5 (4-23)	7 (2-26)	11 (4-25)
Median blast count (range)^b, %	62 (20-99)	67 (6.7-98)	71 (32.4-96.2)	4 (0-65)
Extramedullary disease, n (%)	0 (0)	4 (16.7)	2 (40)	10 (100)
CNS negative at study entry, n (%)	7 (100)	20 (83.3)	3 (60)	8 (80)
Abbreviations: ALL, acute lymphoblastic leukemia; CNS, central nervous system; LL, lymphoblastic lymphoma. ^aTwo patients were listed in error as receiving only 1 prior systemic therapy. Both patients received >1 prior line of treatment; however, access to data entry was terminated after site closure and subsequent database lock, and the data could thus not be corrected. ^bTumorous leukemia/lymphoma cells (n [%]) present in the bone marrow as assessed by bone marrow aspirate/biopsy.

Efficacy

Overall efficacy outcomes are summarized in Table: Efficacy Outcomes for B-Cell and T-Cell Cohorts.
- B-cell cohort³:
  - All patients received cycle 1 treatment, and 4 patients continued treatment in cycle 2.
- All patients discontinued DARZALEX and chemotherapy; reasons for discontinuation were as follows: PD (n=5), death due to PD (n=1), and physician's decision (n=1).
  - No patients achieved CR within 2 treatment cycles.
  - One patient achieved CRi, 3 patients had refractory acute lymphoblastic leukemia, and 3 patients experienced PD as their best response.
  - This cohort was closed, and no additional efficacy endpoints were presented.
- T-cell cohorts³^,⁴:
  - All patients with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma were treated in cycle 1, and 18 (75%) pediatric patients with T-cell acute lymphoblastic leukemia, 4 (80%) young adult patients with T-cell acute lymphoblastic leukemia, and 6 (60%) patients with T-cell lymphoblastic lymphoma were treated in cycle 2.
  - Seven pediatric patients with T-cell acute lymphoblastic leukemia entered the DARZALEX continuation phase as a bridge to HSCT (1 patient after cycle 1 and 6 patients after cycle 2). One young adult with T-cell acute lymphoblastic leukemia also entered after cycle 1, whereas no patient with T-cell lymphoblastic lymphoma received DARZALEX continuation.
  - Discontinuation of DARZALEX and backbone chemotherapy was observed in 8 pediatric patients with T-cell acute lymphoblastic leukemia (physician decision [n=5], PD [n=2], and death due to an AE of worsened/altered health status [n=1]), 3 young adult patients with T-cell acute lymphoblastic leukemia (AE [n=2] and PD [N=1]), and 4 patients with T-cell lymphoblastic lymphoma (physician decision [n=2], AE [n=1], and PD [n=1]).
  - Among patients with baseline extramedullary involvement, the best overall responses (all disease areas) were CRi (n=4/4) for pediatric patients with T-cell acute lymphoblastic leukemia, CRi (n=1/2) and refractory (n=1/2) for young adult patients with T-cell acute lymphoblastic leukemia, and CR (n=2/4) and PD (n=2/4) for patients with T-cell lymphoblastic lymphoma.
  - MRD-negativity at any time during treatment was achieved in 11 (45.8%) pediatric patients with T-cell acute lymphoblastic leukemia, 1 (20%) young adult patient with T-cell acute lymphoblastic leukemia, and 5 (50%) patients with T-cell lymphoblastic lymphoma.
  - A total of 18 (75%) pediatric patients with T-cell acute lymphoblastic leukemia received allogeneic HSCT. Similarly, 3 young adult patients with T-cell acute lymphoblastic leukemia (60%) and 3 patients with T-cell lymphoblastic lymphoma (30%) received allogeneic HSCT.
  - The MRD-negativity rate and allogeneic HSCT details are summarized in Table: MRD-Negativity Rates and Summary of Allogeneic HSCT for T-Cell Cohorts.
  - The median and observed 24-month EFS, RFS, and OS rates are summarized in Table: Summary of EFS, RFS, and OS Rates.

Efficacy Outcomes for B-Cell and T-Cell Cohorts³

Parameter, n (%) (90% CI^a)	B-Cell Acute Lymphoblastic Leukemia	T-Cell Acute Lymphoblastic Leukemia		T-Cell Lymphoblastic Lymphoma (n=10)
Parameter, n (%) (90% CI^a)	Pediatric Patients (n=7)	Pediatric Patients (n=24)	Young Adult Patients (n=5)	T-Cell Lymphoblastic Lymphoma (n=10)
Median treatment duration, months (range)	1.2 (0.8-2.3)	2.2 (0.5-2.9)	1.4 (1-2.1)	2.1 (0.8-2.3)
Median follow-up, months (range)	3.2 (1-4.7)	37.5 (0.8-45.7)	31.7 (2.6-31.7)	23 (1.6-25.3)
End of cycle 1
CR	-	10 (41.7) (24.6-60.3)^b	3 (60) (18.9-92.4)	3 (30) (8.7-60.7)
CRi/PR^c	-	4 (16.7) (5.9-34.2)	1 (20) (1-65.7)	2 (20) (3.7-50.7)
SD^c	-	-	-	3 (30) (8.7-60.7)
Refractory ALL	-	8 (33.3) (17.8-52.1)	1 (20) (1-65.7)	-
PD	-	0 (0)	0 (0)	2 (20) (3.7-50.7)
NE	-	0 (0)	0 (0)	0 (0)
Assessment not performed	-	2 (8.3) (1.5-24)	0 (0)	0 (0)
Any time up to the end of cycle 2
ORR	1 (14.3) (0.7-52.1)	20 (83.3) (65.8-94.1)	4 (80) (34.3-99)	5 (50) (22.2-77.8)
CR	0 (0)	12 (50) (31.9-68.1)	3 (60) (18.9-92.4)	4 (40) (15-69.7)
CRi/PR^c	1 (14.3) (0.7-52.1)	8 (33.3) (17.8-52.1)	1 (20) (1-65.7)	1 (10) (0.5-39.4)
SD^c	-	-	-	3 (30) (8.7-60.7)
Refractory ALL	3 (42.9) (12.9-77.5)	2 (8.3) (1.5-24)	1 (20) (1-65.7)	-
PD	3 (42.9) (12.9-77.5)	0 (0)	0 (0)	2 (20) (3.7-50.7)
NE	0 (0)	0 (0)	0 (0)	0 (0)
Assessment not performed	0 (0)	2 (8.3) (1.5-24)	0 (0)	0 (0)
Abbreviations: ALL, acute lymphoblastic leukemia; CI, confidence interval; CR, complete response; CRi, complete response with incomplete hematologic recovery; LL, lymphoblastic lymphoma; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. ^a90% CIs were based on the Clopper-Pearson exact test. ^bP=0.153.^cPR and SD for patients with T-cell LL only.

MRD-Negativity Rates and Summary of Allogeneic HSCT for T-Cell Cohorts³

Parameter	T-Cell Acute Lymphoblastic Leukemia		T-Cell Lymphoblastic Lymphoma (n=10)^a
Parameter	Pediatric Patients (n=24)	Young Adult Patients (n=5)	T-Cell Lymphoblastic Lymphoma (n=10)^a
MRD-negativity rate^a, n (%) (90% CI^b)
End of cycle 1^c	7 (29.2) (14.6-47.9)	0 (0)	5 (50) (22.2-77.8)
End of cycle 2^c	2 (8.3) (1.5-24)	1 (20) (1-65.7)	0 (0)
After treatment^d	1 (4.2) (0.2-18.3)	0 (0)	0 (0)
At any time	11 (45.8) (28.2-64.2)^e	1 (20) (1-65.7)	5 (50) (22.2-77.8)
Allogeneic HSCT rate, n (%) (90% CI^b)	18 (75) (56.5-88.5)	3 (60) (18.9-92.4)	3 (30) (8.7-60.7)
Median number of CD34⁺ cells transplanted (range), 10⁶/kg	5.3 (0.5-264)	4.6 (1.2-10)	3.7 (3.2-7.3)
Source of CD34+ cells transplanted^f, n (%)
Cord blood	2 (11.1)	0 (0)	1 (33.3)
Peripheral blood	7 (38.9)	2 (66.7)	1 (33.3)
Bone marrow	9 (50)	1 (33.3)	1 (33.3)
Median time to engraftment (range), days	18 (10-34)	26 (21-31)	20 (11-23)
Abbreviations: ALL, acute lymphoblastic leukemia; CD, cluster of differentiation; CI, confidence interval; HSCT, hematopoietic stem cell transplant; LL, lymphoblastic lymphoma; MRD, minimal residual disease. ^aMRD-negativity rate was calculated with the number of patients who were MRD-negative as the numerator and the number of patients in the all-treated analysis set as the denominator. In the T-cell LL cohort, bone marrow evaluation was only required if bone marrow disease was present at study entry; of the 5 patients with bone marrow involvement (≥5% bone marrow blasts) at baseline, 3 patients achieved MRD-negativity during the study. ^b90% CIs were based on the Clopper-Pearson exact test. ^cRates in cycle 1 and cycle 2 are mutually exclusive. ^dAssessed before the initiation of subsequent treatment and/or HSCT. ^eOne patient with pediatric T-cell ALL underwent an unscheduled MRD assessment on day 1 of cycle 3. This patient was included in the count for “at any time” but was not included at the end of cycle 1, at the end of cycle 2, or in posttreatment counts. ^fPercentages were calculated with the number of patients who had CD34⁺ cells sourced from the indicated tissue type as the numerator and the number of patients who underwent allogeneic HSCT as the denominator.

Summary of EFS, RFS, and OS Rates³

Parameter	T-Cell Acute Lymphoblastic Leukemia		T-Cell Lymphoblastic Lymphoma (n=10)
Parameter	Pediatric Patients (n=24)	Young Adult Patients (n=5)	T-Cell Lymphoblastic Lymphoma (n=10)
EFS
Median, months	8.9	10.3	2.9
24-month observed rate, %	36.1	20	20
RFS^a
Median, months	19.4	9.4	NE
24-month observed rate, %	48.6	33.3	50
OS
Median, months (90% CI)	10.9 (6.7-NE)	12 (4.5-NE)	4.2 (1.7-5.6)
24-month observed rate, %	41.3	25	20
Abbreviations: ALL, acute lymphoblastic leukemia; CR, complete response; CI, confidence interval; EFS, event-free survival; LL, lymphoblastic lymphoma; NE, not estimable; OS, overall survival; RFS, relapse-free survival.^aPatients who achieved CR.

Safety

No new safety concerns were identified with DARZALEX.³ Any-grade and grade 3/4 TEAEs occurred in all patients (100%) and are summarized in Table: TEAEs in B-Cell and T-Cell Cohorts.
- The most common grade 3/4 TEAEs across cohorts were hematologic events.
- Grade 3/4 infections occurred in 1 pediatric patient with B-cell acute lymphoblastic leukemia (grade 4 sepsis), 12 (50%) pediatric patients with T-cell acute lymphoblastic leukemia, 2 (40%) young adult patients with T-cell acute lymphoblastic leukemia, and 3 (30%) patients with T-cell lymphoblastic lymphoma.
- No specific infections occurred in >2 patients across the T-cell cohorts.
- Serious TEAEs occurred in 3 (42.9%) pediatric patients with B-cell acute lymphoblastic leukemia (febrile neutropenia, multiple organ dysfunction syndrome, and respiratory distress [n=1]; febrile neutropenia [n=1]; and febrile neutropenia, sepsis, and death [n=1]), 16 (66.7%) pediatric patients with T-cell acute lymphoblastic leukemia, 4 (80%) young adult patients with T-cell acute lymphoblastic leukemia, and 7 (70%) patients with T-cell lymphoblastic lymphoma. Events in ≥2 patients in the T-cell cohorts included pyrexia, febrile neutropenia, septic shock, hyperbilirubinemia, neutropenia, diarrhea, stomatitis, and cellulitis.
- DARZALEX discontinuation due to TEAEs occurred in 1 pediatric patient with T-cell acute lymphoblastic leukemia (brain edema/hepatic failure), 2 young adult patients with T-cell acute lymphoblastic leukemia (hyperbilirubinemia, neutropenia, septic shock, and thrombocytopenia [n=1]; psychotic disorder [n=1]), and 1 patient with T-cell lymphoblastic lymphoma (seizure). None of the events were attributed to DARZALEX.
- Death due to TEAEs was reported in 2 pediatric patients with B-cell acute lymphoblastic leukemia (multiorgan dysfunction syndrome [n=1]; unknown cause [n=1]), 2 pediatric patients with T-cell acute lymphoblastic leukemia (brain edema/hepatic failure due to backbone chemotherapy [n=1]; worsened or altered general health status [n=1]), and 1 patient with T-cell lymphoblastic lymphoma (pleural effusion). None of the deaths were attributed to DARZALEX.
- IRRs after the first DARZALEX infusion were reported in 4 (57.1%) pediatric patients with B-cell acute lymphoblastic leukemia, 16 (66.7%) pediatric patients with T-cell acute lymphoblastic leukemia, 4 (80%) young adult patients with T-cell acute lymphoblastic leukemia, and 8 (80%) patients with T-cell lymphoblastic lymphoma.
  - The most common IRRs were cough (42.9%) in pediatric patients with B-cell acute lymphoblastic leukemia; abdominal pain (20.7%), vomiting (13.8%), and pyrexia (13.8%) in patients with T-cell acute lymphoblastic leukemia; and cough (40%) and dyspnea (30%) in patients with T-cell lymphoblastic lymphoma.
- Throughout the study, none of the 36 evaluable patients tested positive for anti-DARZALEX antibodies.

TEAEs in B-Cell and T-Cell Cohorts³

TEAE, n (%)	B-Cell Acute Lymphoblastic Leukemia	T-Cell Acute Lymphoblastic Leukemia		T-Cell Lymphoblastic Lymphoma (n=10)
TEAE, n (%)	Pediatric Patients (n=7)	Pediatric Patients (n=24)	Young Adult Patients (n=5)	T-Cell Lymphoblastic Lymphoma (n=10)
Any-grade TEAE	7 (100)	24 (100)	5 (100)	10 (100)
Any-grade TEAEs in >50% of patients in any cohort
Febrile neutropenia	5 (71.4)	12 (50)	3 (60)	6 (60)
Anemia	4 (57.1)	16 (66.7)	2 (40)	10 (100)
Thrombocytopenia	2 (28.6)	18 (75)	3 (60)	9 (90)
Neutropenia	2 (28.6)	15 (62.5)	2 (40)	6 (60)
Leukopenia	3 (42.9)	9 (37.5)	1 (20)	5 (50)
Vomiting	2 (28.6)	15 (62.5)	2 (40)	5 (50)
Abdominal pain	2 (28.6)	12 (50)	3 (60)	4 (40)
Stomatitis	0 (0)	11 (45.8)	3 (60)	7 (70)
Constipation	2 (28.6)	6 (25)	4 (80)	2 (20)
Pyrexia	4 (57.1)	17 (70.8)	3 (60)	8 (80)
Fatigue	0 (0)	3 (12.5)	3 (60)	1 (10)
Hyperbilirubinemia	0 (0)	8 (33.3)	4 (80)	4 (40)
ALT increased	3 (42.9)	10 (41.7)	3 (60)	5 (50)
AST increased	2 (28.6)	5 (20.8)	3 (60)	5 (50)
Blood AP increased	0 (0)	0 (0)	4 (80)	0 (0)
Hypoalbuminemia	0 (0)	12 (50)	3 (60)	5 (50)
Hyponatremia	0 (0)	6 (25)	4 (80)	2 (20)
Cough	3 (42.9)	7 (29.2)	0 (0)	5 (50)
Hypoxia	2 (28.6)	4 (16.7)	3 (60)	0 (0)
Grade 3/4 TEAE	7 (100)	24 (100)	5 (100)	10 (100)
Grade 3/4 TEAEs in >40% of patients in any cohort
Febrile neutropenia	5 (71.4)	12 (50)	3 (60)	5 (50)
Anemia	3 (42.9)	16 (66.7)	1 (20)	10 (100)
Leukopenia	3 (42.9)	9 (37.5)	1 (20)	5 (50)
Neutropenia	2 (28.6)	15 (62.5)	2 (40)	6 (60)
Thrombocytopenia	1 (14.3)	15 (62.5)	3 (60)	9 (90)
Serious TEAE	3 (42.9)	16 (66.7)	4 (80)	7 (70)
TEAE leading to DARZALEX discontinuation	0 (0)	1 (4.2)	2 (40)	1 (10)
Death due to TEAEs	2 (28.6)	2 (8.3)	0 (0)	1 (10)
IRRs
Grade 1/2	4 (57.1)	15 (62.5)	4 (80)	7 (70)
Grade 3	0 (0)	1 (4.2)	0 (0)	1 (10)
Abbreviations: ALL, acute lymphoblastic leukemia; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; IRR, infusion-related reaction; LL, lymphoblastic lymphoma; TEAE, treatment-emergent adverse event.

Pharmacokinetics

B-cell cohort⁴:
- The mean peak serum concentration for daratumumab showed an increase of approximately 1.64-fold from 302 μg/mL (SD, 83.1) on day 1 of cycle 1 at end of infusion (EOI) to 494 μg/mL (SD, 184) on day 1 of cycle 2 at EOI, indicating accumulation after weekly daratumumab administration.
- The mean serum daratumumab concentration at the end of treatment was 58.9 μg/mL (SD, 50.7), which decreased to 11.5 μg/mL (SD, 6.06) by post-treatment week 8.
- Overall, the serum daratumumab concentrations observed in the B-cell acute lymphoblastic leukemia cohort were comparable to those seen in adult patients with multiple myeloma.
- After weekly administration of daratumumab, the mean cerebrospinal fluid concentration was 0.573 μg/mL (SD, 0.545) on day 1 of cycle 2 prior to dosing, significantly lower than the corresponding serum concentration, indicating no drug accumulation in the cerebrospinal fluid.
T-cell cohorts³:
- In pediatric patients with T-cell acute lymphoblastic leukemia, the mean peak serum concentration for daratumumab showed an increase of approximately 2.9-fold from 263 μg/mL (SD, 8.18) on day 1 of cycle 1 at EOI to 763 μg/mL (SD, 185) on day 22 of cycle 2 at EOI, indicating accumulation after weekly daratumumab administration.
  - The mean C_trough prior to dosing in pediatric patients with T-cell acute lymphoblastic leukemia was 324 μg/mL (SD, 184) and 369 μg/mL (SD, 105) on days 1 and 22 of cycle 2, respectively.
  - Comparable results were obtained in the young adult T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma cohorts.
- All but 1 pediatric patient with T-cell acute lymphoblastic leukemia provided a postbaseline CSF PK sample, resulting in a CSF PK-evaluable population of 38 patients.
- The daratumumab CSF concentration was similar in both the pediatric T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma cohorts.
- Among young adults with T-cell acute lymphoblastic leukemia, a lower daratumumab CSF concentration was observed over time.
- The mean CSF concentration in pediatric patients with T-cell acute lymphoblastic leukemia was 0.907 μg/mL (SD, 1.96) on day 15 of cycle 1 before dosing and 0.934 μg/mL (SD, 0.549) on day 15 of cycle 2 before dose.

Multicenter, Retrospective, Observational Study

Cerrano et al (2022)⁵ conducted a retrospective, multicenter, observational cohort study evaluating the efficacy and safety of DARZALEX in patients with R/R or MRD-positive T-cell or B-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.

Study Design/Methods

Patients received DARZALEX (16 mg/kg IV weekly for first the 8 doses; then once every 2 weeks for 8 doses; then once monthly until PD) alone or in combination with chemotherapy.
Inclusion criteria: Adult and pediatric patients with R/R or MRD-positive T- or B-lineage acute lymphoblastic leukemia or acute lymphoblastic lymphoma who received ≥1 dose of DARZALEX were included.
Co-primary endpoints: ORR (defined as the proportion of patients achieving CR or PR or proportion of patients who were MRD-positive at baseline achieving MRD-negativity) and OS.
- CR was defined as bone marrow blasts count <5% without evidence of extramedullary manifestations and PR was defined as bone marrow blasts count ≥5% and <25% with a reduction in leukemic involvement by ≥50%.
Additional endpoints: safety and bridge to allo-HSCT.

Results

Patient Characteristics

A total of 20 patients were included in this study (T-cell acute lymphoblastic leukemia, n=13; B-cell acute lymphoblastic leukemia, n=4; acute lymphoblastic lymphoma, n=2 [B-cell, n=1; T-cell, n=1]). Baseline patient and disease characteristics are summarized in Table: Baseline Characteristics.

Baseline Characteristics⁵

Characteristic	N=20
Male, n (%)	17 (85)
Age at initiation of DARZALEX, median (range), years	35 (8-73)
<18 years, n (%)	3 (15)
Patients with acute lymphoblastic leukemia, n (%)	18 (80)
T-cell	13 (65)
Early T precursor	4 (20)
B-cell	4 (20)
Mixed phenotype acute leukemia	1 (5)
Patients with acute lymphoblastic lymphoma, n (%)	2 (10)
T-cell	1 (5)
B-cell	1 (5)
Prior lines of treatment, median (range)	3 (1-4)
Prior allo-HSCT, n (%)	9 (45)
Disease status at initiation of DARZALEX, n (%)
Isolated bone marrow relapse	8 (40)
Bone marrow relapse with extramedullary involvement	8 (40)
Extramedullary disease with MRD positivity	2 (10)
Extramedullary disease only	1 (5)
MRD-positive CR	1 (5)
ECOG status at initiation of DARZALEX, median (range)	2 (0-4)
Concomitant chemotherapy, n (%)	9 (45)
Time from diagnosis to initiation of DARZALEX, median (range), months	13 (7-28)
Abbreviations: allo-HSCT, allogeneic hematopoietic cell transplant; CR, complete response; ECOG, Eastern Cooperative Oncology Group; MRD, minimal residual disease.

DARZALEX was administered as monotherapy in 11 patients (including 1 patient who received DARZALEX after a short dexamethasone pre-phase) and in combination with chemotherapy in 9 patients.

Efficacy

The ORR was 20% (MRD-negative CR, n=2; MRD-positive CR, n=1; PR, n=1). Efficacy outcomes are summarized in Table: Efficacy Outcomes.

Efficacy Outcomes⁵

Parameter	N=20
Response to DARZALEX
Responders, n (%)	4 (20)
MRD-negative CR	2 (10)
MRD-positive CR	1 (5)
PR	1 (5)
Non-responders, n (%)	16 (80)
SD	2 (10)
PD	12 (60)
NE	2 (10)
Post-DARZALEX allo-HSCT, n (%)	4 (20)
In patients with CR/PR	2 (10)
Duration of treatment, median (range), weeks	2 (2-120)
Discontinued treatment, n (%)	19 (95)
Abbreviations: allo-HSCT, allogeneic hematopoietic cell transplant; CR, complete response; MRD, minimal residual disease; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.

Median time to response was 4 weeks (after 2-6 infusions of DARZALEX).
Of the 4 patients who responded, 3 had T-lineage acute lymphoblastic leukemia and received DARZALEX monotherapy. Factors affecting response to DARZALEX are summarized in Table: Factors Affecting Response to DARZALEX.

Factors Affecting Response to DARZALEX⁵

Parameter^a	Responders (n=4)	Non-responders (n=16)	P value
Sex, n (%)	-	-	1
Male	4 (23.5)	13 (76.5)	-
Female	0 (0)	3 (100)	-
Age, years, median (range)	34 (25-45)	35.5 (8-73)	0.92
T-lineage, n (%)	3 (21.4)	11 (78.6)	1
B-lineage, n (%)	1 (20)	4 (80)	1
Lymphoblastic lymphoma, n (%)	1 (50)	1 (50)	0.37
Extramedullary disease, n (%)	2 (18.2)	9 (81.8)	1
Bone marrow MRD^b, n (%)	2 (66.7)	1 (33.7)	0.088
Bone marrow relapse, n (%)	1 (6.2)	15 (93.8)	0.013
Previous allo-HSCT, n (%)	2 (22.2)	7 (77.8)	1
Previous lines of treatment, n (%)	-	-	0.022
1	2 (100)	0 (0)	-
2	1 (25)	3 (75)	-
3	1 (9.1)	10 (90.9)	-
4	0 (0)	3 (100)	-
White blood cells, median (range), ×10⁹/L	3.36 (3-4.3)	4.66 (0.1-39.4)	0.91
Hemoglobin, median (range), g/dL	10 (10-11)	9.5 (8-13)	0.25
Platelets, median (range), ×10⁹/L	151 (70-233)	27 (1-199)	0.019
Peripheral blood blasts, median (range), %	0 (0-0)	24 (0-98)	0.034
Bone marrow blasts, median (range), %	2 (0-78)	50 (1-100)	0.099
ECOG score, n (%)	-	-	0.019
0	2 (100)	0 (0)	-
1	2 (40)	3 (60)	-
2	0 (0)	4 (100)	-
3	0 (0)	7 (100)	-
4	0 (0)	1 (100)	-
Abbreviation: allo-HSCT, allogeneic hematopoietic stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; MRD, minimal residual disease. ^aDisease status and patient characteristics were evaluated at initiation of DARZALEX therapy. ^bIncludes patients in complete remission with isolated measurable residual disease positivity and those with extramedullary relapse and measurable residual disease positivity in the bone marrow.

No significant association between CD38 expression on lymphoblasts at baseline and response was observed.
In the entire cohort, median OS was 4 weeks, and 3-month OS rate was 25%.⁵

Safety

There were no unexpected toxicities observed and 1 grade 2 infusion-related reaction was reported with DARZALEX.
At the final follow-up, 2 patients (both with T-cell acute lymphoblastic leukemia) were alive and in CR and 2 patients died due to relapse and treatment-related complications after allo-HSCT, respectively.⁵

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on
10 February 2025.

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