Targeting CD38 in relapsed /refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy.

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) represent aggressive hematologic malignancies arising from precursor T-lymphocytes, characterized by rapid progression and a high risk of treatment failure.Although initial therapeutic approaches for newly diagnosed disease are generally effective, 10% to 25% of patients become refractory to or relapse after frontline therapy. Once relapse or refractoriness occurs, outcomes decline sharply, establishing relapsed/refractory T-ALL/LBL (R/R T-ALL/LBL) as a population with a particularly poor prognosis and no standardized, consistently effective salvage regimen. 1 – 3 The challenges associated with R/R T-ALL/LBL are well documented. Multiple studies describe survival in this setting as unsatisfactory, with limited curative options and no consensus on optimal management. 4 , 5

CD38 has emerged as a biologically relevant and potentially targetable antigen in T-ALL. Its expression is described as nearly ubiquitous, with up to 98% of patients exhibiting CD38-positive blasts and nearly 90% showing expression levels above 80%. 5 – 7 Preclinical evidence from patient-derived xenograft models demonstrated that daratumumab effectively targets CD38-positive T-ALL blasts and can overcome chemotherapy resistance, providing the rationale for clinical investigation in this setting. 8 This stability and frequency position CD38 as an appealing therapeutic target and provides a biologic rationale for exploring CD38-directed strategies in R/R T-ALL and T-LBL.

Daratumumab is a human IgG1κ monoclonal antibody that targets CD38, a transmembrane glycoprotein highly expressed on plasma cells and variably expressed on leukemic blasts, including T-ALL. After binding to CD38, daratumumab induces tumor-cell killing through several immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct apoptosis. In addition, daratumumab may exert immunomodulatory effects by depleting CD38-positive immunosuppressive cells, thereby enhancing antitumor immune activity ( Figure 1 ). 9 Daratumumab has demonstrated potent activity in multiple myeloma and has generated interest for repurposing in T-ALL/LBL given the high prevalence of CD38 expression. However, clinical experience in T-ALL remains limited, consisting primarily of case reports and small case series. Furthermore, emerging phase 2 data from studies such as the DELPHINUS trial indicate that daratumumab combined with conventional chemotherapy can elicit encouraging response rates and allow effective bridging to HSCT in pediatric and young adult cohorts with R/R T-ALL/T-LBL. 3 As a result, the full therapeutic potential, safety profile, and durability of responses to daratumumab, either as monotherapy or in combination with other agents have not been comprehensively defined. Figure 1. Mechanisms of action of daratumumab. Daratumumab targets CD38-positive malignant cells through immune-mediated cytotoxicity, phagocytosis, apoptosis, and immunomodulatory effects (This figure was generated with AI assistance and reviewed and approved by the authors).

Given these gaps, a systematic synthesis of existing evidence is needed to clarify the antileukemic activity, safety, and translational relevance of daratumumab in R/R T-ALL/LBL. Such a review will guide clinical decision-making, inform future research directions, and support the development of rational CD38-targeted strategies for this high-risk population.

Methods

Protocol and reporting

An a priori protocol defining the eligibility criteria, outcomes of interest, data extraction process, risk-of-bias assessment, and analytic methods was developed before data collection. The protocol was not prospectively registered; however, it is provided as Supplemental Material to enhance methodological transparency. The review was conducted and reported in accordance with the PRISMA 2020 guidelines. 10

Study eligibility and scope

This review evaluated real-world evidence on daratumumab use in patients with R/R T-ALL/T-LBL. Pediatric, adolescent/young adult, and adult populations were eligible. Studies were included when disease-specific data were extractable. Reports exclusively addressing newly diagnosed disease or other T-cell malignancies were not considered.

Eligible interventions included daratumumab administered via any route (intravenous or subcutaneous), as monotherapy or in combination with chemotherapy or targeted agents. There were no restrictions on dosing, schedule, or treatment line, and supportive or adjunctive therapies were permitted. No comparator was required, and single-arm studies were eligible.

Studies were required to report at least one clinical efficacy, survival, or safety outcome. Outcomes of interest included remission status, MRD assessment, survival endpoints, transplantation outcomes, CD38 expression, and treatment-related adverse events.

Eligible study designs comprised observational cohorts, case series, and individual case reports. Conference abstracts were included if they have enough data. Interventional clinical trials, reviews, editorials, laboratory-only studies, animal studies, and reports without extractable individual-level clinical data were excluded. Only English-language publications were considered.

Literature search and study selection

A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science from database inception through December 1, 2025. The search strategy combined controlled vocabulary terms and keywords related to T-ALL, T-LBL, CD38, and daratumumab. Reference lists of eligible articles and relevant conference proceedings, including ASH, EHA, and ASCO, were also screened to identify additional studies. Two reviewers independently screened titles and abstracts, followed by full-text assessment of potentially eligible articles. Any discrepancies were resolved by consensus or consultation with a third reviewer.

Data extraction

Data were independently extracted by two reviewers using a standardized electronic form. Extracted variables included study characteristics; patient demographics and disease features; prior treatment history; daratumumab dosing, route, and combination regimens; CD38 expression; clinical and MRD responses; survival outcomes; transplantation data; and safety events, including infusion-related reactions, cytopenias, and infections.

Quality assessment

The methodological quality of included studies was assessed using tools appropriate for the specific study design. For case reports and case series, which comprised a significant portion of the dataset, we utilized the Murad tool 11 to evaluate domains such as selection, ascertainment, causality, and reporting. Retrospective Cohorts were assessed for risk of bias using Newcastle-Ottawa Scale. 12 Of note, because most included studies were uncontrolled case reports or small case series, the tool was used to assess reporting quality and internal methodological completeness rather than to infer high certainty of evidence.

Statistical analysis

Descriptive statistics were used to summarize clinical characteristics, treatment patterns, and outcomes. Continuous variables, including age, number of prior lines of therapy, and blast percentages, were reported as medians with ranges or interquartile ranges (IQR), where available. Categorical variables, including sex, cytogenetic abnormalities, response rates, MRD status, transplantation outcomes, and adverse events, were presented as frequencies and percentages.

Response rates, including complete remission (CR), partial remission (PR), and no response (NR), were calculated for the aggregate population and stratified by study type where appropriate. MRD negativity was defined according to the thresholds reported in individual studies. The proportion of patients successfully bridged to allogeneic HSCT after daratumumab was also summarized.

Survival data were extracted as reported in the original studies. Overall survival was defined as the time from daratumumab initiation to death from any cause or last follow-up, while progression-free survival was defined as the time from daratumumab initiation to documented progression, relapse, death, or last follow-up. Because the evidence consisted predominantly of case reports and small case series, survival endpoints were inconsistently reported; some studies provided OS, others provided PFS, and some reported only follow-up duration after daratumumab initiation. In selected cases, survival duration was manually estimated from published figures, timelines, or Kaplan–Meier plots when exact numerical values were not provided.

Given the heterogeneity of study designs, treatment regimens, outcome definitions, and survival reporting, formal meta-analysis and pooled OS or PFS analysis were not performed. Instead, available time-to-event values were summarized descriptively as reported survival duration after daratumumab initiation using median and range. Data analysis was performed using standard spreadsheet software.

Ethics and data availability

Because this study synthesized published data only, institutional review board approval was not required. Extraction forms, analytic code, and pooled summary tables are available on request, and detailed results are presented in the supplemental material .

Results

Search strategy

A comprehensive literature search was performed in PubMed, Scopus, and Web of Science. The search identified 128 records (PubMed, n = 29; Scopus, n = 67; Web of Science, n = 32), with an additional three records retrieved through citation searching. After removal of 55 duplicates, 73 unique records underwent title and abstract screening, of which 54 were excluded. Nineteen full-text articles were reviewed for eligibility; five were excluded due to incorrect population (n = 1), inappropriate study design (n = 2), duplicate data (n = 1), or lack of individual-level data (n = 1). Two additional eligible studies were identified through reference screening. In total, 16 studies were included in the final review ( Figure 2 ). Figure 2. PRISMA flow diagram of study selection. Flowchart illustrating the identification, screening, eligibility assessment, and inclusion of studies in accordance with PRISMA guidelines.

Quality assessment

All included reports, except one retrospective study assessed using the Newcastle–Ottawa Scale, fulfilled the key methodological quality domains for case reports and case series, including adequate clinical description, exposure ascertainment, and outcome reporting. However, the overall certainty of evidence remained low because most studies were uncontrolled case reports or small case series, with inherent risks of selection bias, publication bias, confounding, and absence of comparator groups. Detailed results of the quality assessment are provided in Supplemental Tables 1 and 2 .

Baseline characteristics

A total of 16 studies, comprising 34 patients with R/R T-ALL/T-LBL (T-ALL; bone marrow involvement ≥20% or T-LBL; bone marrow involvement <20%), were included. 5 , 7 , 13 – 26 All studies were observational, consisting primarily of single-institution case reports or small case series published between 2018 and 2025 across Europe, Asia, and North America.

Most patients were diagnosed with T-ALL (31/34, 91.2%), with three cases of T-LBL (3/34, 8.8%). The cohort consisted predominantly of adults, with one pediatric patient (1/34, 2.9%)—a 2-year-old described by Ruhayel et al. 24 Sex was reported for 30 patients: 16 males (53.3%) and 14 females (46.7%). Sex was not reported in four cases (11.8%), all from Vakrmanová et al. 25

Cytogenetic and molecular findings were heterogeneous. Cytogenetic abnormalities varied widely ( Table 1 ), and most studies did not identify recurrent molecular alterations. High-risk molecular features and unusual disease biology were reported in individual cases, including a refractory patient harboring WT1, TP53, and JAK3 mutations 16 and a patient initially diagnosed with leukemia of ambiguous lineage, later reclassified as T-ALL after relapse, who ultimately underwent two allogeneic transplants prior to daratumumab therapy. 14 The early T-precursor (ETP) phenotype was confirmed in six patients, although reporting was inconsistent across studies. Table 1. Baseline characteristics of patients treated with daratumumab for T-ALL/T-LBL. No. Study ID Patient ID within study Country Study design Total eligible cases in study Diagnosis Age Sex Cytogenetic/karyotype abnormality Indication for daratumumab ETP status Prior systemic therapy lines Prior systemic therapies Prior allo-HSCT 1 Prejzner, 2023 22 Patient 1 Poland Case series 2 T-ALL 20 F t (2; 14) (q21; q23) Refractory disease NR 1 Steroid pretreatment; cyclophosphamide; hyper-CVAD No 2 Prejzner, 2023 22 Patient 2 Poland Case series 2 T-ALL 24 F del (5) (q22q33), del (11) (q22q33) Relapse NR 4 hyper-CVAD/MA; methotrexate, vincristine, and doxorubicin; clofarabine and cytarabine; bortezomib with venetoclax; nelarabine Yes 3 Vakrmanová, 2022 25 Patient 1 Czech Republic Case series 4 T-ALL NR NR NR Relapse NR 1 NR Yes 4 Vakrmanová, 2022 25 Patient 2 Czech Republic Case series 4 T-ALL NR NR NR Relapse NR 1 NR No 5 Vakrmanová, 2022 25 Patient 3 Czech Republic Case series 4 T-ALL NR NR NR Relapse NR 1 NR No 6 Vakrmanová, 2022 25 Patient 4 Czech Republic Case series 4 T-ALL NR NR NR Relapse NR 1 NR Yes 7 Molle, 2022 19 Patient 1 Denmark Case series 2 T-LBL 39 M NR Relapse NR 1 NOPHO2008 high-risk protocol; FLAG-IDA No 8 Molle, 2022 19 Patient 2 Denmark Case series 2 T-ALL 25 F NR Relapse NR 2 NOPHO2008 high-risk protocol; allo-HSCT conditioning with etoposide and TBI Yes 9 Punatar, 2021 23 Patient 1 India Case report 1 T-ALL NR F NR Relapsed/refractory disease Yes 4 3+7 followed by HiDAC; salvage chemotherapy; ALL-like salvage chemotherapy; FLAG-IDA; dexamethasone, vincristine, pegylated L-asparaginase, and bortezomib Yes 10 Fulcher, 2021 17 Patient 1 Canada Case report 1 T-ALL 20 F 47,XX,+6,+7 in 9/19 metaphases Refractory disease Yes 2 Hyper-CVAD; FLAG-IDA No 11 Mirgh, 2019 18 Patient 1 India Case series 2 T-ALL 57 M Normal Refractory disease Yes 1 UKALL-XII protocol No 12 Mirgh, 2019 18 Patient 2 India Case series 2 T-ALL 26 M NR MRD positivity Yes 2 Children’s Oncology Group 0232 protocol; Hyper-CVAD Yes 13 Begna, 2024 13 Patient 1 USA Case report 1 T-ALL 45 F TRB rearrangement at 7q34 and trisomy 9 Refractory disease NR 4 Hyper-CVAD; liposomal vincristine and venetoclax; venetoclax with FLAG-IDA; nelarabine Yes 14 Ruhayel, 2021 24 Patient 1 NR Case report 1 T-ALL 2 M Normal Refractory disease NR 4 BFM 2009 protocols IA and IB; COG AALL1231 high-risk intensification blocks; nelarabine-containing chemotherapy No 15 Bonda, 2018 14 Patient 1 India Case report 1 T-ALL 36 F NR MRD positivity Yes 4 3+7; ALL-like induction; vincristine, etoposide, bortezomib, dexamethasone, adriamycin, and L-asparaginase; FLAG-IDA; pegylated L-asparaginase, dexamethasone, bortezomib, and vincristine Yes 16 Ofran, 2020 20 Patient 1 Israel Case series 2 T-LBL 26 M NR Relapse NR 3 ECOG 2993-based induction; HiDAC/mitoxantrone; nelarabine Yes 17 Ofran, 2020 20 Patient 2 Israel Case series 2 T-ALL 45 F Normal Relapse NR 3 ECOG 2993-based induction; mitoxantrone plus HiDAC; nelarabine Yes 18 Castellanos, 2024 15 Patient 1 Spain Case report 1 T-ALL 19 M Normal Relapse NR 1 Hyper-CVAD; cyclophosphamide and prednisone prephase; intrathecal methotrexate, cytarabine, and dexamethasone No 19 Maraglino, 2025 5 Patient 1 Italy Case report 1 T-LBL 50 M Normal Refractory disease NR 2 Hyper-CVAD plus autologous HSCT; nelarabine monotherapy for 2 cycles No 20 Kaya, 2025 26 Patient 1 Turkey Case report 1 T-ALL 21 M Normal Refractory disease Yes 3 HOELZER protocol; FLEND plus PEG-asparaginase; BFM 2000 No 21 Feng, 2025 7 Patient 1 China Case report 1 T-ALL 60 F NR MRD positivity NR 1 Vincristine, daunorubicin, L-asparaginase, and prednisone induction chemotherapy No 22 Dai, 2024 16 Patient 1 China Retrospective cohort 2 T-ALL 25 M Normal Refractory disease NR 2 NR No 23 Dai, 2024 16 Patient 2 China Retrospective cohort 2 T-ALL 52 M NR Relapse NR 2 NR No 24 Peng, 2025 21 Aggregate cohort China Retrospective cohort 11 T-ALL Median 26; range 15–44 6 M/5 F NR MRD positivity in 9; relapse in 2 NR NR Intensive multidrug chemotherapy No Abbreviations: T-ALL, T-cell acute lymphoblastic leukemia; T-LBL, T-cell lymphoblastic lymphoma; CD38, cluster of differentiation 38; del(X), deletion of chromosome X; NOTCH1, neurogenic locus notch homolog protein 1; t(X; Y), translocation between chromosomes X and Y; TRB, T-cell receptor beta; 47,XX, karyotype with 47 chromosomes (trisomy) and female sex chromosomes; +X, trisomy of chromosome X; q, long arm of a chromosome; NA, not available; allo-HSCT, allogeneic hematopoietic stem cell transplantation; auto-HSCT, autologous stem cell transplantation; BFM, Berlin–Frankfurt–Münster chemotherapy protocol; COG, Children’s Oncology Group protocol; ECOG, Eastern Cooperative Oncology Group; FLAG-IDA, fludarabine, cytarabine, G-CSF, and idarubicin; FLEND, fludarabine, etoposide, nelarabine, and dexamethasone; HiDAC, high-dose cytarabine; hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MRD, minimal residual disease; NOPHO, Nordic Society of Paediatric Haematology and Oncology; PEG-asparaginase, pegylated L-asparaginase; TBI, total body irradiation; UKALL, United Kingdom acute lymphoblastic leukemia trial. *Table note: Each row represents one individual patient unless otherwise specified. Multiple rows with the same Study ID indicate different patients from the same publication. The “Total eligible cases in study” column refers to the number of eligible patients contributed by that study. For Peng et al., individual baseline characteristics were not available; therefore, the row is presented as aggregate cohort-level data.

Patients were heavily pretreated prior to daratumumab. Among evaluable cases, patients had received a median of 1.5 prior systemic therapy lines (range, 1–4), including standard multi-agent ALL regimens, nelarabine-based therapies, venetoclax-containing combinations, targeted agents, and salvage chemotherapy. Several patients had undergone prior allo-HSCT; notably, one patient relapsed after two allogeneic transplants before receiving daratumumab, 23 and another relapsed with CD38-positive disease six months after a second transplant and subsequently died. 14

Indications for daratumumab were refractory disease in 8 patients (8/34, 23.5%), overt relapse in 14 (41.2%), and MRD positivity in 12 (35.3%). CD38 expression was assessed in a subset of patients, with nearly all evaluable cases demonstrating CD38-positive blasts, supporting the rationale for daratumumab therapy. In one report, persistent high CD38 expression was documented at MRD-positive relapse, suggesting CD38 stability as a therapeutic target. 7 For details refer to Table 1 .

Daratumumab dosing schedule and route of administration

Among 21 patients with documented dosing, intravenous daratumumab at 16 mg/kg was used in 20 patients (95.2%), while one patient (4.8%) received 1,800 mg subcutaneously. 22 Dosing schedules were frequently extrapolated from myeloma protocols,and in at least one case, combination therapy was discontinued early because of toxicity, with continuation as daratumumab monotherapy. 25

The number of doses administered was reported in 20 of 33 evaluable cases (60.6%). Patients received a median of 8 doses (IQR, 3–14; range, 2–21), indicating substantial variability in treatment duration.

Protocl data was available for 29 patients. Of these, 23 (79.2%) received daratumumab in combination with other anticancer agents, while 6 (20.8%) received daratumumab monotherapy. Venetoclax-containing regimens were used in 16 patients, including the DV-CAG regimen (daratumumab, venetoclax, cytarabine, aclarubicin, and G-CSF) described by Peng et al. 21 as a transplant-bridging strategy. Nelarabine-based combinations were used in four patients (16.7%). Other regimens included dara-bortezomib-dexamethasone as a bridge to to haploidentical transplantation 5 and prolonged daratumumab maintenance after MRD eradication with subsequent donor lymphocyte infusion. 20 This heterogeneity reflects the absence of a standardized daratumumab-based protocol in R/R T-ALL/T-LBL. For details refer to Table 2 . Table 2. Daratumumab treatment characteristics and combination regimens. No. Study ID Patient ID within study Daratumumab route and dose Number of daratumumab doses Combination therapy with daratumumab Nelarabine included Venetoclax included Details of anticancer agents given with daratumumab 1 Prejzner, 2023 22 Patient 1 IV, 16 mg/kg 3 Yes Yes Yes Nelarabine; venetoclax; bortezomib 2 Prejzner, 2023 22 Patient 2 SC, 1,800 mg 3 Yes NR Yes Bortezomib; venetoclax; PEG-asparaginase 3 Vakrmanová, 2022 25 Patient 1 IV, 16 mg/kg 9 Yes NR NR NR 4 Vakrmanová, 2022 25 Patient 2 IV, 16 mg/kg 21 Yes NR NR NR 5 Vakrmanová, 2022 25 Patient 3 IV, 16 mg/kg 9 Yes NR NR NR 6 Vakrmanová, 2022 25 Patient 4 IV, 16 mg/kg 3 No NR NR NR 7 Molle, 2022 19 Patient 1 IV, 16 mg/kg 13 Yes Yes NR Nelarabine; pegylated asparaginase; dexamethasone 8 Molle, 2022 19 Patient 2 IV, 16 mg/kg 17 Yes Yes NR Nelarabine; dexamethasone 9 Punatar, 2021 23 Patient 1 NR 21 Yes NR NR Intrathecal methotrexate; 6-mercaptopurine; oral methotrexate 10 Fulcher, 2021 17 Patient 1 IV, 16 mg/kg 7 No NR NR None reported 11 Mirgh, 2019 18 Patient 1 IV, 16 mg/kg 14 Yes NR NR High-dose methotrexate as CNS prophylaxis after dose 8 of daratumumab 12 Mirgh, 2019 18 Patient 2 IV, 16 mg/kg 2 No NR NR NR 13 Begna, 2024 13 Patient 1 IV, 16 mg/kg 14 Yes NR NR Brentuximab vedotin 14 Ruhayel, 2021 24 Patient 1 IV, 16 mg/kg 2 No NR NR NR 15 Bonda, 2018 14 Patient 1 IV, 16 mg/kg 12 Yes NR NR Intrathecal methotrexate; 6-mercaptopurine; oral methotrexate 16 Ofran, 2020 20 Patient 1 IV, 16 mg/kg 8 No NR NR NR 17 Ofran, 2020 20 Patient 2 IV, 16 mg/kg 4 Yes NR NR Donor lymphocyte infusion 18 Castellanos, 2024 15 Patient 1 NR NR Yes Yes NR Nelarabine; radiotherapy 19 Maraglino, 2025 5 Patient 1 IV, 16 mg/kg 3 Yes NR NR Bortezomib; dexamethasone 20 Kaya, 2025 26 Patient 1 IV, 16 mg/kg 2 Yes NR Yes Venetoclax; azacitidine; dexamethasone 21 Feng, 2025 7 Patient 1 NR NR Yes NR Yes Venetoclax; azacitidine; homoharringtonine; cytarabine; aclarubicin 22 Dai, 2024 16 Patient 9 IV, 16 mg/kg NR Yes NR Yes DAC plus venetoclax 23 Dai, 2024 16 Patient 10 IV, 16 mg/kg NR Yes NR NR Hyper-CVAD-B plus PEG-asparaginase 24 Peng, 2025 21 Aggregate cohort IV, 16 mg/kg 2–4 Yes NR Yes Venetoclax; cytarabine; aclarubicin; G-CSF (DV-CAG regimen) Abbreviations: mg/kg, milligram per kilogram; SC, subcutaneous; mg, milligram; PEG-asparaginase, pegylated asparaginase; CNS, central nervous system; G-CSF, granulocyte colony-stimulating factor; DV-CAG, daratumumab, venetoclax, cytarabine, aclarubicin, and G-CSF; DLI, donor lymphocyte infusion; DAC, decitabine or decitabine-like; VEN, venetoclax; hyper-CVAD-B+PEG-Asp, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (part A) plus methotrexate and cytarabine (part B) plus PEG-asparaginase; NA, not available.

Efficacy, survival, and transplantation outcomes

Efficacy outcomes were available for all 34 patients. Complete remission (CR) was achieved in 30/34 patients (88.2%), partial remission (PR) in 2/34 (5.9%), and no response (NR) in 2/34 (5.9%). The Peng et al. cohort contributed 11 CRs. 21 Notably, Fulcher et al. reported that daratumumab was initially ineffective in the setting of high leukemia burden but subsequently achieved eradication of low-volume residual disease after tumor debulking with a nelarabine-containing salvage regimen. 17

Among the 30 patients achieving CR, MRD status was reported for 29 patients. Of these, 24/29 (82.8%) achieved MRD negativity and 5/29 (17.2%) remained MRD positive. In the Peng et al. cohort, 9/11 patients (81.8%) achieved MRD negativity, while 2/11 (18.2%) remained MRD positive after daratumumab-based therapy. 21

The median PFS was 10 months (range, 0.4–45), and the median OS was 10 months (range, 1.5–45). In Peng et al., median OS was not reached after a median follow-up of 15.4 months (range, 1.5–22.4). 21 These survival estimates should be interpreted cautiously, as many OS and PFS values were derived from last reported follow-up rather than confirmed progression or death events. This likely explains the similarity between OS and PFS, since both endpoints were often represented by the same follow-up duration when separate progression or death dates were unavailable.

In an exploratory treatment-strategy analysis, 6 patients received daratumumab monotherapy and 23 received daratumumab in combination with other anticancer agents. Among patients treated with monotherapy, 1/6 had NR and 1/6 achieved PR; similarly, among those receiving combination therapy, 1/23 had NR and 1/23 achieved PR. No formal statistical comparison was performed because of small sample size, regimen heterogeneity, selection bias, and confounding by indication.

Overall, 18/34 patients (52.9%) proceeded to allogeneic HSCT after daratumumab, including 8/11 patients from the Peng et al. cohort, 21 while 16/34 (47.1%) did not. Daratumumab was frequently used as a bridge to transplant, including in patients with refractory disease or early post-transplant relapse. Complex transplant histories were observed, including two patients who had undergone two prior allo-HSCTs before daratumumab therapy. 14 , 23 Among transplanted patients, 13/18 (72.2%) were alive at last follow-up and 5/18 (27.8%) had died. The median post-HSCT survival/follow-up was 8.6 months (IQR, 4.25–14.5; range, 1–42), with a mean of 11.4 months. Among patients who did not proceed to HSCT, 11/16 (68.8%) were alive and 5/16 (31.2%) had died at last follow-up.

Among the 10 reported deaths in the overall cohort, causes included disease progression or relapse in 7/10 (70%), septic shock in 1/10 (10%), GVHD in 1/10 (10%), and ARDS in 1/10 (10%). These transplant-related findings suggest that daratumumab may facilitate bridging to HSCT in selected patients; however, they should not be interpreted as a direct comparison between post-daratumumab HSCT and non-HSCT strategies, as transplant receipt was likely influenced by response, clinical fitness, donor availability, disease control, and incomplete patient-level reporting. Detailed outcomes are provided in Tables 3 and 4 . Table 3. Response, survival, transplantation, and safety outcomes after daratumumab-based therapy. No. Study ID Patient ID within study Response MRD status after daratumumab OS/PFS after daratumumab start, months Proceeded to allo-HSCT after daratumumab Survival after allo-HSCT, months Outcome after HSCT Cause of death Infusion reaction Cytopenia Infection 1 Prejzner, 2023 22 Patient 1 CR Positive 11 Yes 10 Alive NR NR Yes NR 2 Prejzner, 2023 22 Patient 2 CR Positive NR Yes 10 Alive NR NR Yes NR 3 Vakrmanová, 2022 25 Patient 1 CR Negative 11 Yes 7 Died Disease relapse NR NR NR 4 Vakrmanová, 2022 25 Patient 2 CR Negative NR Yes 5 Died Disease relapse NR NR NR 5 Vakrmanová, 2022 25 Patient 3 CR Negative NR Yes 15 Alive NR NR NR NR 6 Vakrmanová, 2022 25 Patient 4 NR Positive 1.7 No NR NR Disease progression NR NR NR 7 Molle, 2022 19 Patient 1 CR NR 45 Yes 42 Alive NR NR Yes NR 8 Molle, 2022 19 Patient 2 CR Negative 11.5 No NR NR Disease progression NR Yes Yes 9 Punatar, 2021 23 Patient 1 CR Negative 42 No NR NR NR Yes, grade 3 NR Yes 10 Fulcher, 2021 17 Patient 1 CR Negative 5.2 Yes 4 Alive NR NR NR NR 11 Mirgh, 2019 18 Patient 1 CR Negative NR Yes 1 Died Septic shock NR NR NR 12 Mirgh, 2019 18 Patient 2 CR Negative 10.7 No NR NR NR NR NR NR 13 Peng, 2025 21 Aggregate cohort CR, 11/11 Negative, 9/11 Median OS not reached; median follow-up 15.4 months, range 1.5–22.4 Yes, 8/11 NR NR NR Yes, 7 patients, grade 1–2 Yes, 7 patients, grade 3–4 NR 14 Peng, 2025 21 Patient 1 CR Negative 22 Yes 20 Alive NR NR Yes Yes 15 Peng, 2025 21 Patient 2 CR Positive 16.5 Yes 3.5 Died Disease relapse NR NR NR 16 Peng, 2025 21 Patient 3 CR Negative 19 Yes 18 Alive NR NR NR Yes 17 Peng, 2025 21 Patient 4 CR Negative 15.5 Yes 12.5 Alive NR NR NR NR 18 Peng, 2025 21 Patient 5 CR Negative 15 Yes 13 Alive NR NR NR NR 19 Peng, 2025 21 Patient 6 CR Negative 7 Yes 5.5 Died Graft-versus-host disease NR NR NR 20 Peng, 2025 21 Patient 7 CR Negative 10 Yes 1 Alive NR Yes, grade 1 Yes Yes 21 Peng, 2025 21 Patient 8 CR Negative 4 Yes 1.5 Alive NR NR Yes Yes 22 Peng, 2025 21 Patient 9 CR Negative 4 No NR NR NR Yes, grade 1 Yes NR 23 Begna, 2024 13 Patient 1 CR Negative 8 No NR NR NR NR NR NR 24 Ruhayel, 2021 24 Patient 1 PR NR 1.4 No NR NR Disease progression NR NR NR 25 Bonda, 2018 14 Patient 1 CR Negative 5 No NR NR NR NR NR NR 26 Ofran, 2020 20 Patient 1 CR Negative 10 No NR NR NR NR NR NR 27 Ofran, 2020 20 Patient 2 CR Negative 10.5 No NR NR NR NR NR NR 28 Castellanos, 2024 15 Patient 1 PR NR 1.5 No NR NR Disease progression NR NR NR 29 Maraglino, 2025 5 Patient 1 CR Negative 31 Yes 29 Alive NR NR NR NR 30 Kaya, 2025 26 Patient 1 CR NR NR No NR NR ARDS NR NR NR 31 Feng, 2025 7 Patient 1 CR Negative 10 Yes 7.2 Alive NR NR NR NR 32 Dai, 2024 16 Patient 9 NR Positive NR No NR NR NR NR NR NR 33 Dai, 2024 16 Patient 10 CR Negative NR No NR NR NR NR NR NR Abbreviations: CR, complete response; PR, partial response; NR, no response/not reported; MRD, minimal residual disease; OS/PFS, overall survival/progression-free survival; Dara, daratumumab; HSCT, hematopoietic stem cell transplantation; ARDS, acute respiratory distress syndrome; NA, not available. *Table note: Each row represents one individual patient unless otherwise specified. Multiple rows with the same Study ID indicate different patients from the same publication. For Peng et al., both aggregated cohort-level data and available individual patient-level outcomes are shown because some outcomes were reported in aggregate and others were extractable at the patient level. Table 4. Summary of efficacy, survival, and transplantation outcomes following daratumumab-based therapy (N = 34). Outcome category Result Patients evaluated for efficacy 34 Best overall response Complete remission (CR) 30/34 (88.2%) Partial remission (PR) 2/34 (5.9%) No response (NR) 2/34 (5.9%) Complete responders with MRD assessment 29 MRD negative 24/29 (82.8%) MRD positive 5/29 (17.2%) Median PFS 10 months (range, 0.4–45) Median OS 10 months (range, 1.5–45) Patients proceeding to allo-HSCT 18/34 (52.9%) Patients not proceeding to allo-HSCT 16/34 (47.1%) Post-HSCT outcomes Alive at last follow-up 13/18 (72.2%) Deceased 5/18 (27.8%) Median post-HSCT survival/follow-up 8.6 months (range, 1–42) Abbreviations: OS, overall survival; PFS, progression-free survival; MRD, measurable residual disease; HSCT, hematopoietic stem cell transplantation.

Safety

Because most patients received daratumumab in combination with multi-agent chemotherapy, attribution of cytopenia and infectious complications specifically to daratumumab was challenging. Several reports suggested that adverse events were more likely to be related to concomitant regimens or cumulative toxicity from prior therapies. In contrast, infusion-related reactions were clearly attributable to daratumumab, occurring in 10 patients, the majority of which were grade 1–2 (9/10, 90%). A grade 3 infusion reaction was reported in one patient, 23 leading to treatment discontinuation in that case, and no grade 4 reactions were observed. For details refer to Table 3

Discussion

This systematic review synthesizes the currently available evidence on daratumumab-based therapy in R/R T-ALL/T-LBL. Across 16 publications and 34 patients, we observed a high overall response rate, with 88.2% achieving complete remission (CR), substantial clearance of measurable residual disease (MRD), meaningful post-transplant survival in a heavily pretreated population, and a safety profile dominated by low grade infusion reactions. These findings support CD38 targeting as a rational and clinically active strategy in R/R T ALL/T LBL, a setting in which outcomes with conventional salvage therapy remain dismal.

Adult patients with R/R T-ALL/T-LBL experience very poor outcomes, with historical complete remission (CR) rates to first salvage of approximately 40–46% and median overall survival of 6–9 months, even with intensive chemotherapy and allogeneic transplantation. 27 – 29 In the phase 2 Delphinus study evaluating daratumumab as part of combination therapy in pediatric and young adult patients with R/R T-ALL/T-LBL (pediatric T-ALL = 24; young adult T-ALL = 5; pediatric or young adult T-LBL = 10), the best overall response rate was 74%, with a CR rate of 49%. 3

In this context, the 88.2% CR rate and 5.9% partial remission rate observed in our pooled cohort compare favorably with established benchmarks, particularly given the heavy pretreatment history of most patients and the high proportion with prior allogeneic transplantation. Although these data derive from uncontrolled reports on a highly selected patient population, the magnitude of response suggests that daratumumab-based regimens can induce deep remissions in a population otherwise characterized by chemotherapy resistance.

The biological rationale for CD38 targeting T-ALL/T-LBL is strong. Leukemic blasts express high and relatively homogeneous levels of CD38, and expression persists following multi-agent chemotherapy. 8 CD38 expression on normal hematopoietic cells is comparatively low, creating a therapeutic window for antibody-based strategies. Daratumumab, a human IgG1κ monoclonal antibody, induces tumor cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct apoptotic signaling. 30 Preclinical models have demonstrated potent daratumumab activity against CD38-positive T-ALL/T-LBL samples in vitro and in xenograft systems.

MRD status is now recognized as one of the most powerful prognostic factors in both adult and pediatric acute lymphoblastic leukemia, with MRD negativity consistently associated with lower relapse risk and improved long-term survival. 31 In T-ALL specifically, MRD positivity at key treatment landmarks and at the time of transplantation correlates with substantially higher relapse rates and inferior event-free survival. 32 In the Delphinus trial, 12 of the 29 patients with T-cell acute lymphoblastic leukemia—representing 41% of the total population and 50% of responding patients—achieved MRD-negative status. 3

Against this background, the finding that 82.8% of evaluable patients in our cohort achieved MRD negativity following daratumumab-based therapy suggests that CD38 targeting may be particularly effective as a debulking or MRD-eradicating strategy before allogeneic transplantation. This aligns with broader transplant literature showing superior outcomes in MRD-negative compared with MRD-positive patients undergoing allogeneic transplantation for acute lymphoblastic leukemia. 33 Although our review cannot definitively link MRD conversion to survival because of heterogeneous reporting, the observed pattern of frequent MRD negativity, successful transition to transplantation, and favorable post-transplant status in several patients supports the potential role of daratumumab as a bridge to transplantation in appropriately selected cases.

Most patients in our review received daratumumab alongside other cytotoxic or targeted agents, reflecting contemporary practice in which single-agent antibody therapy is rarely used in R/R T-ALL/LBL. Venetoclax-based combinations were particularly frequent, including multi-agent regimens such as DV-CAG (daratumumab, venetoclax, cytarabine, aclarubicin, and G-CSF). This observation aligns with emerging evidence showing meaningful activity of venetoclax—especially when combined with azacitidine, cladribine-based regimens, or CHG-like backbones in R/R T-ALL/LBL. 34

In the Delphinus trial, daratumumab was administered in combination with multiple chemotherapy agents, reflecting an intensive multi-agent strategy. The phase 2 DELPHINUS study evaluated daratumumab plus vincristine/prednisone/pegylated-asparaginase/doxorubicin reinduction in childhood and young adult T-cell ALL/LL in first relapse. 3 This protocol illustrates the breadth of cytotoxic and antimetabolite partners used alongside daratumumab. Additional retrospective evidence also supports the feasibility of daratumumab in combination with chemotherapy. 35 Interestingly, several reports documented complete remissions with daratumumab monotherapy in patients who were otherwise refractory to prior chemotherapy. 17 , 18 , 20 These cases suggest that daratumumab may exert direct anti-leukemic activity independent of combination partners.

Given the multifactorial nature of these regimens, the relative contribution of daratumumab versus the chemotherapy backbone cannot be fully delineated. Nevertheless, the consistently high complete remission and MRD-negative rates across diverse daratumumab-containing combinations—together with preclinical evidence of CD38-directed cytotoxicity—support the hypothesis that daratumumab functions as an active therapeutic component rather than a passive adjunct. Prospective studies will be required to determine whether daratumumab provides additive or synergistic benefit beyond optimized venetoclax- or nelarabine-based regimens.

Despite the heavily pretreated nature of the cohort, the median PFS and OS were both 10 months, with wide ranges, suggesting that some patients experienced clinically meaningful disease control after daratumumab-based therapy. These findings compare favorably with historical outcomes in adult R/R T-ALL/T-LBL, where median overall survival after first salvage is approximately 6 months and long-term survival remains uncommon. However, these survival estimates should be interpreted cautiously because many values were derived from last reported follow-up rather than mature time-to-event data. In the DELPHINUS trial, median event-free survival was 8.9 months for childhood T-ALL, 10.3 months for young adult T-ALL, 9.5 months for the pooled population, and 2.9 months for T-LBL. By contrast, in a small retrospective study of 20 patients with R/R ALL, including 10 with R/R T-ALL, treated with daratumumab-based therapy, the median overall survival was only 4 weeks and the complete remission rate was 20%, underscoring the aggressive biology and heterogeneity of outcomes in this setting. 35

The safety profile observed in this review is broadly consistent with the established experience of daratumumab in multiple myeloma and other CD38-expressing hematologic malignancies. No new safety signals were identified. This pattern mirrors prior observations in myeloma, where most infusion reactions occur during the first infusion and are generally manageable with premedication and supportive care. 36

Strengths

This review has several strengths. To our knowledge, it represents one of the most comprehensive syntheses focused specifically on daratumumab-based regimens in R/R T-ALL and T-LBL, extending earlier reviews that included mixed T-lineage and non–T-lineage acute leukemias or pre-2023 data. We systematically characterized response rates, MRD outcomes, transplant utilization, post-HSCT outcomes, and toxicity, providing a multidimensional overview of the current clinical role of daratumumab in this setting. In addition, the review captures a broad spectrum of real-world practice across multiple regions and time periods, reflecting the diversity of salvage strategies used in routine care and early-phase clinical research.

Future directions

Our findings support further exploration of rational daratumumab-based combinations, particularly with venetoclax, nelarabine, and other agents with established activity in T-ALL/T-LBL, to enhance response depth and durability while minimizing overlapping toxicity. Prospective multicenter trials are needed to validate these observations, define optimal dosing and scheduling, and clarify the role of daratumumab relative to other emerging immunotherapeutic approaches. Notably, prospective evaluation in the MRD-positive setting is already underway. The T-ALL-2024 trial ( NCT06570915 ) is a prospective, single-arm, multicenter, open-label phase II study evaluating the efficacy and safety of daratumumab in adult patients with T-ALL who remain measurable residual disease-positive after standard chemotherapy. By specifically targeting patients with flow cytometry-detectable MRD, this trial may help determine whether daratumumab is best positioned as an MRD-directed strategy rather than solely as salvage therapy for overt relapsed or refractory disease. Future studies incorporating standardized MRD assessment, uniform response criteria, and predefined transplant strategies will be essential to determine whether daratumumab improves long-term, transplant-adjusted outcomes.

Limitations

Important limitations should temper the interpretation of these findings. All included reports were observational and consisted predominantly of single-patient case reports or very small case series, making the analysis highly vulnerable to selection and publication bias. In particular, the high rates of complete remission and MRD negativity should not be interpreted as definitive estimates of treatment efficacy, because the denominator reflects published cases rather than all patients treated with daratumumab in clinical practice. Favorable or unusual responses are more likely to be reported, whereas non-response, early progression, or treatment-related complications may be underrepresented. The small sample size, heterogeneous treatment regimens, variable response assessment methods, inconsistent survival reporting, and limited follow-up further preclude robust subgroup analyses or pooled survival estimates. Therefore, these findings should be viewed as hypothesis-generating and require validation in prospective, systematically enrolled cohorts.

Conclusion

Daratumumab-based regimens may induce deep remissions and MRD negativity in selected patients with CD38-positive relapsed or refractory T-ALL/T-LBL and may facilitate bridging to allogeneic HSCT in some cases. However, these findings should be interpreted cautiously given the small sample size, predominance of case reports, and risk of publication bias. Prospective studies are needed to validate the efficacy, safety, and optimal positioning of daratumumab within salvage treatment algorithms.

Supplemental material

Supplemental Material - Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy

Supplemental Material for Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy by Abdulrahman F. Al-Mashdali, Mujahid O. Abdelraof, Monia Ibrahim, Mohammed Abdulgayoom, Shehab F. Mohamed and Honar Cherif in Therapeutic Advances in Hematology.

Supplemental Material - Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy

Supplemental Material for Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy by Abdulrahman F. Al-Mashdali, Mujahid O. Abdelraof, Monia Ibrahim, Mohammed Abdulgayoom, Shehab F. Mohamed and Honar Cherif in Therapeutic Advances in Hematology.

Supplemental Material - Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy

Supplemental Material for Targeting CD38 in relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma: A systematic review of daratumumab-based therapy by Abdulrahman F. Al-Mashdali, Mujahid O. Abdelraof, Monia Ibrahim, Mohammed Abdulgayoom, Shehab F. Mohamed and Honar Cherif in Therapeutic Advances in Hematology.

Acknowledgements

No external individuals or organizations contributed to the preparation of this manuscript beyond those listed as authors. During the preparation of this work, the authors used ChatGPT Premium primarily for language refinement, including proofreading, phrasing suggestions, and improving clarity. All content generated was reviewed and edited by the authors, who take full responsibility for the final manuscript.

Author contributions: AFA conceptualized the study, conducted literature review, and designed the data collection sheet. AFA, MOA, and MI collected and interpreted the data, drafted the manuscript, and designed the tables. AFA performed the statistical analysis. AFA, MOA, MA, SM, and HC provided critical intellectual input and revised the manuscript. AFA and MOA supervised the study. All authors reviewed and approved the final version of the manuscript. AFA and MA contributed equally.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Open access publication fees for this article will be supported by Qatar National Library (QNL).

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material: Supplemental material for this article is available online.

ORCID iDs

Abdulrahman F. Al-Mashdali https://orcid.org/0000-0002-1393-5302

Mohammed Abdulgayoom https://orcid.org/0000-0003-0622-8455

Ethical considerations

This study did not involve direct patient recruitment, interventions, or access to identifiable individual-level patient data. As this was a systematic review of previously published studies, institutional ethics approval and consent to participate were not required.

Data Availability Statement

All data supporting the findings of this study are included within the article and its supplementary materials. Additional information is available from the corresponding author upon reasonable request. *

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