The efficacy and safety of nelarabine in relapsed or refractory T-cell acute lymphoblastic leukemia: a systematic review and meta-analysis

Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a subtype of acute lymphoblastic leukemia characterized by the proliferation of abnormal T-cell precursors. Nelarabine, a purine analog, has been approved as a targeted therapy for patients with refractory or relapsed T-ALL. This study aims to evaluate the efficacy and safety of Nelarabine, either as monotherapy or in combination with other therapies, in treating T-ALL. A systematic review and meta-analysis were conducted following PRISMA guidelines. We searched Cochrane CENTRAL, PubMed, and Google Scholar up to August 2024 for studies evaluating Nelarabine’s efficacy and safety in T-ALL patients. The primary outcome was complete response (CR), with secondary outcomes focusing on adverse events (AEs). Data were analyzed using a random effects model, with statistical significance set at p ≤ 0.05. Sixteen studies involving 1,865 patients were included, with 1,345 receiving Nelarabine. The pooled analysis revealed a CR rate of 37.9% (95% CI: 20.5–55.4%, p < 0.001) for Nelarabine monotherapy. Significant adverse events included neutropenia at 29.1% (95% CI: 9.1–49.1%, p < 0.001), thrombocytopenia at 32.4% (95% CI: 14.8–50.0%, p < 0.001), peripheral motor neuropathy at 17.1% (95% CI: 4.2–30.1%, p = 0.001), and peripheral sensory neuropathy at 15.3% (95% CI: 5.8–24.9%, p = 0.003). For combination therapy, infections occurred in 65.0% (95% CI: 27.1–103.0%, p < 0.001) of patients, febrile neutropenia in 48.7% (95% CI: -8.8–106.3%, p < 0.001), peripheral motor neuropathy in 10.5% (95% CI: 7.9–13.0%, p < 0.001), and peripheral sensory neuropathy in 23.1% (95% CI: 10.6–35.7%, p < 0.001). Nelarabine shows significant efficacy in treating refractory or relapsed T-ALL, with notable CR rates. However, its use, both as monotherapy and in combination therapy, is associated with considerable adverse events, particularly neurotoxicity and hematologic toxicities, necessitating careful monitoring. Further research is needed to optimize its application across diverse patient populations and to better manage its associated toxicities.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-024-06121-z.

Introduction

Acute Lymphoblastic Leukemia (ALL), a hematologic malignancy affecting the bone marrow and lymphoid organs, is characterized by the proliferation of early and abnormal B or T cell lymphoid precursors, ultimately replacing the normal hematopoietic cells [1]. T-ALL constitutes approximately 10% of childhood and 25% of adolescents and young adults diagnosed with acute lymphoblastic leukemia [2]. Like other forms of ALL, T-ALL exhibits a higher incidence in males than females [3]. The survival rate for pediatric patients of T-ALL stands at 90%, whereas adults tend to have less favorable outcomes, with survival rates ranging from 30 to 40%. Adult patients experience more relapses in 40–75% of cases, compared to 15–20% in the pediatric population [4].

T-cell Acute Lymphoblastic Leukemia (T-ALL), a specific subtype of ALL, further delineates itself as a neoplasm originating from early T-cell progenitors [5]. Genetic alterations frequently associated with T-ALL include NOTCH-1 present in more than 60% of cases, and the NK-L subclass of HOX transcription factor genes, namely TLX1, TLX2, NKX2-1, NKX2-2, and NKX2-5 with TLX-1 overexpression being the most prevalent in adults (30%) and TLX3 in of pediatric patients (20–25%) [6]. Highlighting T-ALL’s prevalence, a recent study reports an incidence of 0.13 cases per 100,000 population [7].

The conventional therapies for T-ALL are intensive chemotherapy regimens and allogeneic Hematopoietic stem cell transplants (HSCT) [8]. A recent study reports that HSCT, despite its potential benefits, continues to be associated with significant early and late treatment-related mortality (TRM) [9]. The primary contributors to the early mortality encompass infections, toxicity, and graft vs. host Disease (GVHD) [10]. These findings emphasize the need for targeted therapy among patients with relapsed T-ALL.

Nelarabine, a purine analog approved in 2005 by the FDA, is a targeted therapy for patients of T-ALL and T-cell Lymphoblastic Lymphoma(T-LBL) who have not responded to or have experienced relapse following two rounds of chemotherapy [11]. Nelarabine is a prodrug for Ara-G, a nucleoside analog, that ceases blast cell DNA synthesis, halting cell replication and leading to cell death. It is metabolically converted to Ara-G through methoxylation by adenosine deaminase and then phosphorylated to Ara-G triphosphate (Ara-GTP) by deoxycytidine kinase [12, 13]. A phase II trial by Children’s Oncology Group (COG) in pediatric patients with first and second relapses showed an increased complete response rate [14]. Nelarabine as a first-line combination therapy with hyper-CVAD that includes cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone, administered in Adults with T-ALL yielded an improved overall survival rate [15]. One-year overall survival was better in adults treated with Nelarabine and subsequent SCT with an acceptable safety profile [16]. Recent studies showed increased survival rates with Nelarabine administered in newly diagnosed children and adults [17, 18] without increased toxicity [18].

This study tends to discuss the efficacy and safety profile of Nelarabine as monotherapy or in combination with other therapeutic approaches for patients diagnosed with Refractory or relapsed T-ALL.

Methodology

This study was conducted adhering to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [19].

Data sources and search strategy

A comprehensive electronic search of Cochrane CENTRAL, PubMed and Google Scholar was conducted from inception to August 2024. Articles were searched using the keywords (Nelarabine) AND (T cell acute lymphoblastic leukemia OR Acute lymphoblastic lymphoma OR T-ALL OR ALL OR Refractory T-ALL OR Relapsed T-ALL) AND (efficacy OR potency OR safe* OR effect* OR feasibility). Furthermore, the references in retrieved articles were also manually reviewed for potentially relevant studies.

Study selection and eligibility criteria

All articles retrieved from the systematic search were imported into EndNote reference library, version X8.1 (Clarivate Analytics), where duplicates were subsequently removed. Two authors (AS and LS) independently reviewed and selected studies, with any disagreements resolved by a third author (UAB). Selected studies were retrieved for full-text review to confirm their relevance. The inclusion criteria for the studies were as follows:

1. Randomized trials as well as observational studies such as retrospective (case–control, cross-sectional) and prospective (cohort designs) were included in the study design.

2. Studies involving the use of Nelarabine as an intervention;

3. Studies where Nelarabine is used in combination with other medications or interventions like vincristine, high-dose methotrexate, etoposide, cytarabine and cyclophosphamide, if applicable.

The exclusion criteria were as follows:

1. studies published in languages other than English;

2. case reports, case series, editorials, commentaries, letters, meta-analyses, conference abstracts, opinion pieces, and other consensus reports, unavailable full-text articles, and studies lacking necessary information were disqualified.

Data extraction

Two researchers (LS and AS) independently extracted data and entered it into a standardized data extraction table in Excel. Any disagreement was solved through consensus or by a third researcher (NK). From the finalized articles we extracted information regarding authorship, publication year, study design, sample size, age, sex of the patients, and outcomes such as safety and efficacy parameters. The primary efficacy outcomes included complete response (CR) while safety outcomes include adverse events (AEs).

Data synthesis

Both narrative and quantitative approaches were employed to synthesize safety and efficacy measures, incorporating all eligible studies that met the inclusion criteria. Two authors (RR and AK) performed the data evaluation using the Review Manager Tool (Version 5.4.1, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and OpenMeta[Analyst] to assess the efficacy and safety of Nelarabine in patients with relapsed or refractory T-cell acute lymphoblastic leukemia. We utilized the Mantel-Haenszel (M-H) random effects model due to the variability in study methods and characteristics. Statistical significance was determined with a P-value of ≤ 0.05. For dichotomous variables, we calculated odds ratios (ORs) with 95% confidence intervals (CIs). For single-arm studies, we calculated the pooled proportions to estimate the overall prevalence of outcomes with corresponding 95% CIs. Statistical heterogeneity was assessed using the I² index, with values < 50%, 50–75%, and > 75% indicating low, moderate, and high heterogeneity, respectively. In cases where heterogeneity exceeded 90%, a sensitivity analysis was conducted using a leave-one-out approach to identify the study contributing to significant heterogeneity.

Quality assessment

Two authors (AS and LS) employed the US National Institutes of Health (NIH) Quality Assessment Tool, developed by the National Heart, Lung, and Blood Institute (NHLBI) from the National Institutes of Health, to evaluate the quality of observational studies [20]. The tool assessed potential flaws in study methods by considering factors such as bias (e.g., patient selection, performance, attrition, detection, and reporting), confounding, study power, and the strength of causality between interventions and outcomes. Reviewers could respond to each question on the tool with “yes,” “no,” or “cannot determine/not reported/not applicable.” The quality of RCTs) was assessed using the Cochrane Risk of Bias Tool (RoB 2.0) [21]. This tool evaluates the risk of bias in relation to patient selection, study performance, outcome detection, data attrition, reporting of study findings, and other potential biases. Judgments were categorized as ‘Low’ risk, ‘High’ risk of bias, or ‘Some concerns.’

Results

Literature search and baseline characteristics

A total of 804 publications were found after a thorough search using the keywords “Safety and Nelarabine, “Efficacy and Nelarabine,” and “Nelarabine and T-ALL.” After deleting duplicates, 459 records were screened based on title/abstract, and 104 articles were identified as potential publications for full-text screening. A total of 16 studies were included in this systematic review after applying the pre-defined inclusion and exclusion criteria [14–18, 22–32](Fig. 1).

Fig. 1.

PRISMA flow diagram of the number of studies screened and included in the systematic review

A total of 1,865 adult and pediatric patients were included in the study with 1,393 of them being male patients. In total 1345 patients received Nelarabine with 520 patients were in the non-Nelarabine group. The mean age of the Nelarabine group is 21.87 ± 16.28 years, while the mean age of the non-Nelarabine group is 24.20 ± 14.55 years. Table 1 lists the baseline characteristics of the studies included in our analysis.

Table 1.

Baseline characteristics of included studies

Author (year)	Country	Study design	Sample size (n)		Age (mean ± SD)			Male N (%)		Females N (%)		T-All (%)	Outcomes
			Nelarabine	Nonnelarabine	Nelarabine		Nonnelarabine	Nelarabine	Nonnelarabine	Nelarabine	Nonnelarabine		Safety parameters	Efficacy parameters
Shimony et al. 2022	Boston, MA	Retrospec -tive Cohort	Monotherapy-15	-	21 (3–62)		-	11 (73.3)	-	4 (26.7)	-	30 (68)	Anemia, Infections, Thrombocytopenia Neutropenia, Elevated Liver Enzymes	CR, PR
			Combination Therapy-29		19 (2–69)			22 (75.9)		7 (24.1)
Zwaan et al., 2017	Denmark, France, Russia, Spain, Italy, Netherlands, Poland, Germany	Phase IV Control trial	Monotherapy-28	-	11.5 ± 4.6		-	20 (71.4)	-	8 (28.6)	-	17 (60.7)	Thrombocytopenia Neutropenia, Anemia, AST, ALT, Pyrexia	CR
Cohen et al., 2006	USA	Phase II Control trial	Monotherapy (Pediatric)-84	-	11.6 ± 3.3		-	64 (76.1)	-	20 (23.8)	-	71	Peripheral neuropathy, Depressed consciousness, Tremor, Somnolence, Dizziness, Neuropathy, Headache	CR, PR
			Monotherapy (Adult)-103		37.2 ± 8.4			84 (81.6)		19 (18.4)		147
Commander et al., 2010	USA	Prospective Cohort	Combination Therapy- 7	-	12 ± 5.4		-	1(14.28)	-	6(85.71)	-	5	Hypoxia, Dyspnea, Motor neuropathy, Sensory neuropathy, Febrile neutropenia	NR
Czuczman et al., 2007	USA	Phase II Control trial	Monotherapy-19	-	52 ± 9.7		-	11 (57.8)	-	8(42.1)	-	19	Pyrexia, Infections, Fatigue, Bilirubin, Confusion, Depressed consciousness, Ataxia	CR, PR
Abaza et al., 2018	USA	Phase II Control trial	Combination Therapy-67	-	42.5 ± 12.7		-	51 (76.11)	-	16(23.89)	-	40	Infections, Peripheral neuropathy, Headache	CR, PR
Berg et al., 2005	USA	Phase II Control trial	Monotherapy-121	-	11.3 ± 4.1		-	111 (91.73)	-	10(8.27)	-	-	AST, ALT, Infections, Bilirubin, Vomiting, Hemorrhage	CR, PR
Candoni et al., 2020	Italy	Phase IV Control trial	Monotherapy-118	-	36.9 ± 13.4		-	86(72.8)	-	32(27.2)	-	77	Thrombocytopenia Neutropenia, Infections	CR, PR
Gokbudget et al., 2011	Germany	Phase II CT study	Monotherapy-126	-	33 (18–81)		-	93 (74)	-	33 (26)	-	107	Confusion, Dizziness, Memory impaired, Mood alteration, Neuropathy, Tremor, Fatigue, Insomnia, Somnolence, Guillain-Barre-like Syndrome	CR, PR
Kuhlen et al., 2017	Germany	Retrospect-ive cohort	Monotherapy-25	-	≤ 10 yrs: 12 > 10 yrs: 13		-	17 (68)	-	6 (24)	-	44 (84.6)	Seizure, Depressed level of consciousness, Peripheral motor neuropathy, Peripheral sensory neuropathy, Somnolence, Lethargy, Neuralgia	CR
			Combination therapy- 27		≤ 10 yrs: 10 > 10 yrs: 17			16 (59.3)		5(18.5)
Winter et al., 2015	Australia, Canada, New Zealand, Switzerland, USA	Phase III CT study	Combination therapy- 47	47	1–31 years			-	-	-	-	-	Sensory neuropathy, Motor neuropathy, Central neuropathy	NR
Sato et al., 2023	Japan	Phase II Control trial	Combination therapy High-risk-103	Standard-risk- 168	9 (6–13)	9 (6–13)		67 (65)	120 (71)	36 (35)	48 (29)	310	Infections, Blood disorders, Nervous system disorders, GIT disorders, Immune system disorders	-
			Combination therapy Very-high-risk-39		8 (6–15)			24 (62)		15 (38)
Dunsmore et al., 2012	USA	Pilot study	Combination Therapy-72	16	< 10 yrs: 34 ≥ 10 yrs: 38	< 10yrs: 9 ≥ 10yrs: 7		52 (72)	10 (62)	20 (27.7)	6 (37.5)	-	Central neurotoxicity, Neutropenia with infection, AST/ALT, Pancreatitis, Peripheral neuropathy	NR
Dunsmore et al., 2020	Australia, Canada, New Zealand, Switzerland, USA	Phase III CT study	Combination therapy-323	336	< 10 yrs: 151 10–15 yrs: 116 ≥ 16yrs: 56	< 10yrs: 178 10-15yrs: 104 ≥ 16yrs: 54		238 (73.7)	255 (75.9)	85 (26.3)	81 (24.1)	-	Peripheral sensory neuropathy, Peripheral motor neuropathy, Central neurotoxicity	NR
DeAngelo et al., 2007	USA	Phase II CT study	Monotherapy-39	-	37.5 ± 11.6	-		32	-	7	-	26	Thrombocytopenia, Neutropenia, Anemia, AST, ALT, Infections, Fatigue, Depressed consciousness	CR, PR
Yanagi et al., 2024	(Saitama, Japan)	Retrospective cohort	Combination therapy-8	-	7.85 ± 6.36	-		8	-	-	-	5	Infections, febrile neutropenia, peripheral sensory neuropathy	CR, PR

Quality assessment and publication bias

According to NIH quality assessment tool, all included observational studies, were of fair quality (Online Resource 1) [14–16, 22–29, 31, 32]. The three RCTs were assessed using the Cochrane Risk of Bias tool (Rob 2.0) [17, 18, 30]. Our overall judgment following the assessment was ‘Some concerns’, as illustrated in Figs. 2 and 3.

Fig. 2.

Publication bias - traffic light plot

Fig. 3.

Publication bias– weighted bar plot

Efficacy assessment of nelarabine

Complete response (CR) of nelarabine

Nine studies reported CR in 720 patients who received Nelarabine as monotherapy (Fig. 4) [14–16, 22–24, 26, 27, 31]. The pooled analysis revealed a CR proportion: 0.379 (95% CI: 0.205 to 0.554); p < 0.001, indicating a significant response rate among the treated patients. High heterogeneity was observed across the studies (I² = 97.1%). Studies that did not report CR or assessed patients after receiving Nelarabine in combination therapy were excluded from the analysis.

Fig. 4.

Forest plot (pooled prevalence of efficacy parameter CR with nelarabine monotherapy)

Additionally, two cohort studies reported CR rates in monotherapy versus combination therapy groups (Fig. 5) [22, 28]. The pooled analysis revealed no statistically significant difference in CR between the two groups [OR: 0.50 (95% CI: 0.21 to 1.17); p = 0.11]. The heterogeneity between the studies was zero (I² = 0%).

Fig. 5.

Forest plot (pooled prevalence of efficacy parameter CR reported in double-arm studies)

Relapse rate of nelarabine

A phase II clinical trial enrolled patients (< 25 years) with newly diagnosed T-ALL, stratified into standard-risk, high-risk and very-high-risk groups. Nelarabine was administered to those in the high-risk and very-high-risk groups. Relapse occurred in 37 out of 333 patients (11%), 13 out of 37 patients had received nelarabine. The 3-year cumulative relapse incidence was 7.8% (95% CI: 5.1–11.1), with bone marrow being the most common site of relapse [17]. In a phase III clinical trial involving children and young adults newly diagnosed with T-ALL, patients were treated with nelarabine alongside methotrexate (MTX) and high-dose methotrexate (HDMTX). Of the 323 patients receiving nelarabine, 39 experienced an event, with relapse being the most common (72.2%). The addition of nelarabine significantly reduced CNS relapse, with a 5-year cumulative incidence of 1.3% ± 0.63% compared to 6.9% ± 1.4% in those not receiving nelarabine (P = 0.0001) [18]. A phase II, single arm study evaluated relapse rate in patients after administrating nelarabine with Hyper-CVAD therapy. The study reported relapse in 21 patients (31%), including 13 T-ALL patients, with a median time to relapse of 7.3 months (range, 1.4 to 62 months) [15]. A pilot study on children diagnosed with T-ALL evaluated the relapse rate (RR) after adding nelarabine to a modified BFM 86 chemotherapy regimen. Among the 16 relapse events, three occurred during the consolidation phase, eleven during the maintenance phase (weeks 43–74), and two after therapy completion (at 4 months and 2.9 years, respectively) [29].

Overall survival (OS)

Nelarabine yielded favorable patient outcomes in terms of MRD, OS, DFS, and EFS. It was observed that 6/52 (11.53%) cases of MRD negative were recorded in patients who received chemotherapy alongside or in place of nelarabine [28]. In a phase III clinical study, patients with Refractory/Relapsed T-ALL had their OS evaluated. A notable distinction was noted in the 5-year OS rate of patients treated with nelarabine, with 90.3%±2.2% compared to 87.9%±2.3% for those who did not receive nelarabine. Additionally, patients who received nelarabine had a 5-year DFS of 92.3%±2.9% for MRD < 0.1% compared to 83.5%±3.9% for MRD ≥ 0.1% (p = 0.01) among patients who did not receive nelarabine [18].

In a study conducted in 2023, of the 333 patients, 35 (10%) had HSCT during the initial remission stage. The 3-year EFS was found to be 86.4%, and the 3-year overall survival was 91.3%, with a five-year median follow-up of 5.2 years. The 3-year event-free survival rates were 46·3%, 90·8%, 86·8%, and 92·0% for the standard risk, high-risk, very high-risk, and no-risk groups, correspondingly. Furthermore, the 3-year overall survival rates were 95·7% (95% CI 91·2–97·9%), 94·9% (88·1–97·8%), 86·8% (71·2–94·3%), and 64·1% (45·4–77·8%) for the standard risk, high-risk, very high-risk, and no-risk groups, respectively [17]. Additionally, a phase IV clinical trial established that patients who received SCT following nelarabine therapy had a favorably higher OS rate at one year (58% vs. 22%, p < 0.001), in contrast to those who did not receive nelarabine preceding the SCT. Post-SCT, the reported EFS was 35% at two and five years each [16].

Safety assessment of nelarabine

Nelarabine monotherapy

The common AEs observed in patients treated with Nelarabine monotherapy included neutropenia, thrombocytopenia, peripheral sensory and motor neuropathy, depressed consciousness and seizures. The pooled prevalence of these AEs is listed in Online Resource 2.

Neutropenia

Five studies reported the prevalence of neutropenia in 219 patients who received Nelarabine as monotherapy (Fig. 6) [16, 22, 23, 26, 31]. The pooled analysis revealed a neutropenia proportion: 0.291 (95% CI: 0.091 to 0.491); p < 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 92.87%).

Fig. 6.

Forest plot (pooled prevalence of neutropenia reported with nelarabine monotherapy)

Thrombocytopenia

Five studies reported the risk of thrombocytopenia in 219 patients who received Nelarabine monotherapy (Fig. 7) [16, 22, 23, 26, 31]. The pooled analysis revealed a thrombocytopenia proportion: 0.324% (95% CI: 0.148 to 0.50); p < 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 87.79%).

Fig. 7.

Forest plot (pooled prevalence of thrombocytopenia reported with nelarabine monotherapy)

Peripheral motor neuropathy

Four studies reported the prevalence of peripheral motor neuropathy in 270 patients who received Nelarabine monotherapy (Fig. 8) [24, 26, 28, 31]. The pooled analysis revealed a peripheral motor neuropathy proportion: 0.171% (95% CI: 0.042 to 0.301), p = 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 81.31%).

Fig. 8.

Forest plot (pooled prevalence of peripheral motor neuropathy reported with Nelarabine monotherapy)

Peripheral sensory neuropathy

Five studies reported the prevalence of peripheral sensory neuropathy in 285 patients who received Nelarabine monotherapy (Fig. 9) [22, 24, 26, 28, 31]. The pooled analysis revealed a peripheral sensory neuropathy proportion: 0.153% (95% CI: 0.058 to 0.249); p = 0.003, indicating a significant occurrence of this AE among the treated patients. Moderate heterogeneity was observed across the studies (I² = 74.81%).

Fig. 9.

Forest plot (pooled prevalence of peripheral sensory neuropathy reported with nelarabine monotherapy)

Depressed consciousness

Four studies reported the prevalence of depressed consciousness in 209 patients who received Nelarabine monotherapy (Fig. 10) [26–28, 31]. The pooled analysis revealed a seizure proportion: 0.035 (95% CI: -0.010 to 0.079); p = 0.197, indicating a non-significant occurrence of this AE among the treated patients. Moderate heterogeneity was observed across the studies (I² = 53%).

Fig. 10.

Forest plot (pooled prevalence of depressed consciousness reported with Nelarabine monotherapy)

Seizure

Four studies reported the prevalence of seizure in 266 patients who received Nelarabine monotherapy (Fig. 11) [22, 24, 28, 31]. The pooled analysis revealed a seizure proportion: 0.042 (95% CI: 0.004 to 0.080); p = 0.197, indicating a non-significant seizure occurrence among the treated patients. Low heterogeneity was observed across the studies (I² = 35.94%).

Fig. 11.

Forest plot (pooled prevalence of seizure reported with nelarabine monotherapy)

Nelarabine combination therapy

Commonly observed AEs in patients treated with Nelarabine combination therapy were infections, febrile neutropenia, peripheral motor and sensory neuropathy and seizures. The pooled prevalence of these adverse effects is listed in Online Resource 3.

Infection

Two studies reported the prevalence of infections in 96 patients who received Nelarabine as combination therapy (Fig. 12) [15, 22]. The pooled analysis revealed an infection proportion: 0.650 (95% CI: 0.271 to 1.030); p < 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 92.96%).

Fig. 12.

Forest plot (pooled prevalence of infection reported with combination therapy)

Febrile neutropenia

Four studies reported the prevalence of febrile neutropenia in 186 patients who received Nelarabine as combination therapy (Fig. 13) [17, 22, 25, 32]. The pooled analysis revealed a febrile neutropenia proportion: 0.487 (95% CI: -0.088 to 1.063); p < 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 98.94%).

Fig. 13.

Forest plot (pooled prevalence of febrile neutropenia reported with combination therapy)

Peripheral motor neuropathy

Four studies reported the prevalence of peripheral motor neuropathy in 519 patients who received Nelarabine as combination therapy (Fig. 14) [17, 18, 25, 30]. The pooled analysis revealed a peripheral motor neuropathy proportion: 0.105 (95% CI: 0.079 to 0.130); p < 0.001, indicating a significant occurrence of this AE among the treated patients. Zero heterogeneity was observed across the studies (I² = 0%).

Fig. 14.

Forest plot (pooled prevalence of peripheral motor neuropathy reported with combination therapy)

Peripheral sensory neuropathy

Six studies reported the prevalence of peripheral sensory neuropathy in 556 patients who received Nelarabine as combination therapy (Fig. 15) [17, 18, 22, 25, 30, 32]. The pooled analysis revealed a peripheral sensory neuropathy proportion: 0.231 (95% CI: 0.106 to 0.357), p < 0.001, indicating a significant occurrence of this AE among the treated patients. High heterogeneity was observed across the studies (I² = 90.28%).

Fig. 15.

Forest plot (pooled prevalence of peripheral sensory neuropathy reported with combination therapy)

Seizure

Three studies reported the prevalence of seizures in 243 patients who received Nelarabine as combination therapy (Fig. 16) [17, 22, 29]. The pooled analysis revealed a seizure proportion: 0.056 (95% CI: 0.027 to 0.084), p = 0.766, indicating a non-significant occurrence of this AE among the treated patients. Low heterogeneity was observed across the studies (I² = 0%).

Fig. 16.

Forest plot (pooled prevalence of seizure reported with combination therapy)

Discussion

The susceptibility of both adult and pediatric patients with T-ALL to increased rates of induction failure, early relapse, and central nervous system (CNS) relapse highlights a need for an effective treatment [33]. Nelarabine is a nucleoside prodrug metabolized into ara-G, which inhibits DNA synthesis in T-cells, showing a positive correlation with treatment response in T-ALL patients, particularly those refractory or relapsed after at least two chemotherapy regimens [34].

This systematic review and meta-analysis evaluate the efficacy and safety of Nelarabine in treating patients with T-ALL. The efficacy analysis revealed significant rates of CR among these patients. The safety profile was analyzed by categorizing AEs reported during Nelarabine monotherapy and combination therapy. In monotherapy, AEs included neutropenia, thrombocytopenia, peripheral sensory and motor neuropathy, depressed consciousness, and seizures. Among these, all were statistically significant except for depressed consciousness and seizures, with thrombocytopenia being the most prevalent. For patients receiving Nelarabine in combination therapy, commonly observed AEs were infections, febrile neutropenia, peripheral motor and sensory neuropathy, and seizures. All were significant except for seizures, with infections being the most frequently reported AE. These findings highlight Nelarabine’s potential as an effective therapeutic option for T-ALL patients.

The significant CR rates observed in the analysis align with the findings from prior study [35]. Achieving a CR rate where over a third of patients experienced total disease disappearance is remarkable, especially considering the aggressive nature of T-ALL and the scarcity of effective treatment options. Furthermore, several patients showed substantial tumor reduction, even if they did not reach complete remission, highlighting the treatment’s potential efficacy. Gokbudget’s study was included in the sensitivity analysis because it represents the largest cohort of adults with T-ALL treated with Nelarabine, focusing on a high-risk population with predominantly refractory disease [27]. Despite the challenging nature of the patient group, the study reported notable remission rates, particularly in specific subgroups like thymic T-ALL. The study also highlighted that while age did not influence the CR rate, it did impact overall survival, underscoring the importance of SCT in older patients and the independent tolerability of Nelarabine across age groups [27]. The findings underscore the variability in Nelarabine’s efficacy across different a patient population, which was reflected in the sensitivity analysis.

These responses are valuable considering the generally poor prognosis and few available treatments for T-ALL. The lack of response in some patients may be attributed to factors such as disease aggressiveness, prior treatments, biological variability, or individual differences in response to Nelarabine. An additional analysis comparing CR rates between monotherapy and combination therapy groups found no significant difference, suggesting that Nelarabine may have comparable efficacy in both approaches. This consistency allows clinicians to tailor therapy to individual patient needs without compromising the likelihood of a complete response. However, more research is needed in this area to explore factors influencing treatment outcomes and optimize its use in different contexts.

The findings from the safety analysis of Nelarabine as monotherapy are consistent with the previous study, reinforcing the known safety profile of the drug [35]. The frequently reported non-neurologic and non-hematologic toxicities, such as pain, fever, infections, dizziness, nausea, headaches, and rashes, indicates that these mild to moderate side effects are common and manageable, ensuring that patients can continue their therapy with minimal disruption. Additionally, neurotoxicities such as paresthesia, ataxia, tremor, neuropathy, amnesia, peripheral sensory and motor neuropathy are observed. The typical appearance of these symptoms around 12 days after the initiation of the regimen underscores the importance of close monitoring during this critical period [36]. Monitoring is crucial because early detection of neurotoxicity can allow for timely interventions, potentially preventing more severe outcomes. Musculoskeletal pain frequently occurred following administration of the drug, often necessitating the use of oral or intravenous narcotics for relief. Among the included study population, only one patient experienced a respiratory event with hypoxia and dyspnea attributed to infection, as reported by Commander et al. [25].Overall, the AEs associated with Nelarabine are a result of its potent anti-cancer effects, as it is a purine nucleoside analog that interferes with DNA synthesis. While this action is effective against T-ALL cells, it also impacts other rapidly dividing cells and sensitive tissues in the body [34].

Neutropenia was the most prevalent grade 3–4 hematologic toxicity observed in 80 patients in both mono- and combination therapy, followed by thrombocytopenia in 79 patients in our analysis (Online Resource 2 and 3). In the phase I trial conducted by Kurtzberg and colleagues, hematologic toxicities were observed, with mild to moderate neutropenia and thrombocytopenia occurring in both pediatric and adult patients. These toxicities were more commonly seen in pediatric patients compared to adults [36]. Among patients who attained a documented complete response or showed no documented bone marrow involvement, no grade 3 or 4 hematologic toxicities were noted. At the study’s conclusion, it was found that hematologic toxicities were not cumulative or dose-limiting.

Patients undergoing monotherapy are more susceptible to both peripheral sensory and motor neuropathy compared to those receiving combination therapy. This increased risk aligns with findings from Cohen et al., where potential risk factors such as central neurotoxicity, central neuropathy, motor neuropathy, and sensory neuropathy were identified in patients treated with Nelarabine [24]. The connection lies in Nelarabine’s metabolite, ara-G, which can accumulate in the nervous system, leading to neurotoxicity. Neurons in the central nervous system are particularly vulnerable to disruptions in nucleoside metabolism, resulting in these neuropathic symptoms [34]. Notably, these patients often had a history of prior treatment with other chemotherapeutic agents known to induce neurotoxicity, and many had relapsed or refractory hematologic malignancies before starting Nelarabine.

Dunsmore et al. reported that Grade 3 to 4 peripheral neuropathy was observed in 15% of patients, and 4% experienced non-seizure central neurotoxicity [29]. Significant neurotoxicity directly associated with Nelarabine (Guillain-Barré-like syndrome) was seen in only one out of 72 patients [29]. The lower incidence of toxicity was attributed to reduced exposure to other neurotoxic agents, such as vincristine, high-dose methotrexate, and cranial irradiation [29]. Nelarabine inclusion did not increase rates of myelosuppression or infection.

Hematopoietic stem cell transplantation (HSCT) remains the primary treatment for T-cell acute lymphoblastic leukemia (T-ALL) despite its complications, especially in young patients. There is an urgent need to develop therapies with comparable efficacy but fewer associated risks. Sato et al. reported that only 10% of patients underwent HSCT in the first complete remission due to poor initial response, compared to 18.5% in a previous study [17]. This suggests that Nelarabine is a viable and safe alternative, enhancing first-line treatment for relapsed or refractory T-ALL.

Nelarabine has shown effectiveness in treating T-ALL, but our study faced several limitations that may have influenced the results. The sample sizes were often inadequate and varied significantly in terms of age and demographics. Adverse events were assessed inconsistently across studies, leading to challenges in comparability. Furthermore, the combination of Nelarabine with different chemotherapeutic agents introduced variability in outcomes due to differences in dosage, administration schedules, and patients’ prior treatment histories. The variability in treatment protocols and the scarcity of follow-up data further complicated the analysis. Variability in randomization procedures, dosages, frequency, and sample sizes in the control and intervention posed a challenge when pooling the data together. Furthermore, we were unable to conduct an efficacy analysis on studies involving Nelarabine in combination therapy due to insufficient data. The limited data in specific subgroups also prevented us from comparing the efficacy outcomes between T-ALL and T-LBL patients. An aspect of our meta-analysis was the heterogeneity among the included studies evaluating AEs which can be attributed to the variation in study designs, population demographics, variability in data collection methods, or statistical analysis model therefore it is imperative to continue further research on the drug so as to resolve the possible ‘publication bias’. It is critical to broaden the focus of clinical studies to include a wider population to get more broadly applicable and meaningful results to the public. In addition, individuals with comorbid conditions—such as hypertension, obesity, cardiovascular diseases, neurological disorders, and renal dysfunctions—that are frequently present in the population must be included. Furthermore, it is indispensable to research diverse population groups to address heterogeneity that permeates most studies, accounting for genetic, environmental and baseline disparities. Furthermore, future studies should incorporate additional outcomes to provide a more comprehensive understanding. In particular, it is crucial for future research to explore and clarify the underlying reasons for the heterogeneity observed in our meta-analysis, to better understand the factors contributing to this variability.

Conclusion

Nelarabine has emerged as a promising treatment option for patients with T-cell acute lymphoblastic leukemia (T-ALL), particularly those who are refractory or have relapsed after previous therapies. Our systematic review and meta-analysis demonstrated significant efficacy, with noteworthy rates of complete and partial remission. The safety profile of Nelarabine, though characterized by certain adverse events such as neurotoxicity and hematologic toxicities, remains manageable with proper monitoring and care. However, the study faced limitations and therefore highlights the need for further research to refine the use of Nelarabine and optimize its effectiveness across diverse patient populations. Future studies should aim to include broader and more diverse demographic groups, consider patients with comorbidities, and explore additional outcomes to address the observed heterogeneity and potential publication bias. In conclusion, while Nelarabine offers a valuable therapeutic option for T-ALL, ongoing research is essential to fully understand its potential and to develop more tailored treatment strategies that maximize patient outcomes. Therefore, to close the significant gaps in our understanding of the condition, further longitudinal studies are the need of time.

Electronic supplementary material

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Abbreviations

ALL

Acute Lymphoblastic Leukemia

T-ALL

T-cell Acute Lymphoblastic Leukemia

HTLV-I

Human T-cell Leukemia Virus type I

TRM

Treatment-related mortality

HSCT

Hematopoietic stem cell transplants

GVHD

Graft vs. host Disease

T-LBL

T-cell Lymphoblastic Lymphoma

Ara-GTP

Ara-G triphosphate

COG

Children’s Oncology Group

CR

Complete response

PR

Partial response

RR

Response rate

CNS

Central nervous system

EFS

Event-free survival

OS

Overall survival

Author contributions

LS: Conceptualization, Project Administration, Methodology, Investigation, Writing - original draft preparation. NK: Conceptualization, Formal analysis and data curation, Writing - original draft preparation, Visualisation. AS: Conceptualization, Methodology, Writing - original draft preparation. AK: Formal analysis and data curation, Writing - original draft preparation. RR: Formal analysis and data curation, Writing - original draft preparation. UAB: Methodology, Writing - original draft preparationMTZ: Writing - review and editing, Project AdministrationAA: Writing - review and editing.

Funding

The authors did not receive support from any organization for the submitted work. No funding was received to assist with the preparation of this manuscript. No funding was received for conducting this study. No funds, grants, or other support was received.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

All authors read and approved the manuscript.

Financial support and sponsorship

None.

Presentation

None.

Competing interests

The authors declare no competing interests.

Conflict of interest

None.