Authors: Akari Utsumi, Yuri Goto, Takaaki Suzuki...

BACKGROUND

Nelarabine is an antineoplastic purine analog used for the treatment of refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL). The most prominent side effect of nelarabine are neurotoxicity and hematologic disorder, which are considered dose-limiting factors. Although clinical studies have reported myopathy due to nelarabine, actual detailed outcomes were not well-known initial approval. The incidence of nelarabine induced rhabdomyolysis has been reported at 2% in study in children. Cases of rhabdomyolysis have been reported in adults from medical facilities in the United Sates with renal dysfunction or severe muscle symptoms after administration of multiple courses of nelarabine. In this report, we discuss a case of rhabdomyolysis diagnosed after a single course of nelarabine. In this case, creatine kinase (CK) level was elevated in grade 4, without renal dysfunction and severe muscle symptoms.

CASE PRESENTATION

A 46-year-old man from Japan was diagnosed with T-ALL and received a hematopoietic stem cell transplantation in first remission. However, the disease relapsed 6 months after transplantation. Nelarabine was selected as the next-line chemotherapeutic agent. The patient received 1500 mg/m of nelarabine on day 1 followed by a dose on days 3 and 5. CK levels, which were baseline before treatment, increased to grade 4 (18,620 IU/L) on the 8th day of treatment. He was diagnosed as rhabdomyolysis due to nelarabine with little possibility of other factors. He complained only of mild pain in his upper extremities and no other symptoms were noticed. The patient was managed with hydration. The pain lasted approximately 7 days, but there were no sequelae secondary to the rhabdomyolysis. Because of the elevation of CK in grade 4, we avoided re-administration.

CONCLUSION

In the patient administrated nelarabine, CK level was elevated in grade 4, without other symptoms of rhabdomyolysis. The results suggest that CK may be elevated at the onset of rhabdomyolysis caused by nelarabine, even in the absence of other symptoms. Therefore, it was suggested that monitoring CK during nelarabine administration is important for detecting rhabdomyolysis before it becomes severe. We consider that CK should be monitored even in absence of symptoms.

PubMed: 35690835
DOI: 10.1186/s40780-022-00247-w

Randomized Controlled Trial

Authors: Kimberly P Dunsmore, Stuart S Winter, Meenakshi Devidas...

PURPOSE

Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease.

PATIENTS AND METHODS

From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation.

RESULTS

The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( = .029). Differences between DFS in a four-arm comparison were significant ( = .01), with no interactions between the MTX and nelarabine randomizations ( = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% 6.9% ± 1.4%, respectively; = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.

CONCLUSION

The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Child; Cohort Studies; Disease-Free Survival; Female; Humans; Leucovorin; Male; Methotrexate; Polyethylene Glycols; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome

PubMed: 32813610
DOI: 10.1200/JCO.20.00256

Observational Study

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study.

Authors: Anna Candoni, Davide Lazzarotto, Felicetto Ferrara...

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.

Topics: Adolescent; Adult; Allografts; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Nalbuphine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Survival Rate

PubMed: 32777149
DOI: 10.1002/ajh.25957

Authors: Yasmin Abaza, Hagop M Kantarjian, Stefan Faderl...

Nelarabine, a water soluble prodrug of 9-β-D-arabinofuranosylguanine (ara-G), is a T-cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T-ALL) and T lymphoblastic lymphoma (T-LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper-CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty-seven patients, including 40 with T-ALL and 26 with T-LBL, were enrolled. Complete response rates in both T-ALL and T-LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow-up was 42.5 months. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper-CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper-CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T-ALL/LBL patients.

Topics: Adolescent; Adult; Aged; Arabinonucleosides; Female; Humans; Immunophenotyping; Male; Middle Aged; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Young Adult

PubMed: 29047158
DOI: 10.1002/ajh.24947

Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina...

BACKGROUND

Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine.

METHODS

The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings.

RESULTS

Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples.

CONCLUSIONS

These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arabinonucleosides; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Drug Synergism; Humans; Phosphoinositide-3 Kinase Inhibitors; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides; TOR Serine-Threonine Kinases; Triazines; Tumor Cells, Cultured

PubMed: 27776559
DOI: 10.1186/s13045-016-0344-4

Authors: Tamara Rothenburger, Katie-May McLaughlin, Tobias Herold...

The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.

Topics: Antineoplastic Agents; Arabinonucleosides; Biomarkers, Tumor; Cell Line, Tumor; DNA Methylation; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; SAM Domain and HD Domain-Containing Protein 1

PubMed: 32581304
DOI: 10.1038/s42003-020-1052-8

Randomized Controlled Trial

Authors: Stuart S Winter, Kimberly P Dunsmore, Meenakshi Devidas...

BACKGROUND

Nelarabine has shown impressive single agent clinical activity in T-cell acute lymphoblastic leukemia (T-ALL), but has been associated with significant neurotoxicities in heavily pre-treated patients. We showed previously that it was safe to add nelarabine to a BFM-86 chemotherapy backbone (AALL00P2). Children's Oncology Group (COG) AALL0434 is a Phase III study designed to test the safety and efficacy of nelarabine when incorporated into a COG augmented BFM-based regimen, which increases exposure to agents with potential neurotoxicity compared to the historical AALL00P2 regimen.

PROCEDURE

AALL0434 included a safety phase to assess nelarabine toxicity. Patients with high-risk (HR) T-ALL were randomized to receive Capizzi-style escalating methotrexate (MTX) plus pegaspargase or high dose (HD) MTX with/without six five-days courses of nelarabine. We report results from 94 patients who participated in the initial safety phase of the study.

RESULTS

There were no differences in the incidence of peripheral motor neuropathies, sensory neuropathies or central neurotoxicities among those randomized to the nelarabine (n = 47) and non-nelarabine arms (n = 47).

CONCLUSIONS

The addition of nelarabine to COG-augmented BFM chemotherapy regimen is safe and feasible. The ongoing AALL0434 Efficacy Phase will determine whether the addition of nelarabine treatment improves outcome for patients with T-ALL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Methotrexate; Neoplasm Staging; Polyethylene Glycols; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Young Adult

PubMed: 25755211
DOI: 10.1002/pbc.25470

Review

Authors: Tapan M Kadia, Varsha Gandhi

INTRODUCTION

T-cell acute lymphoblastic leukemia (ALL) and lymphoma (LBL) are aggressive hematologic neoplasms that are treated with combination chemotherapy in the frontline, but have limited options in the relapsed or refractory setting. Based on observations in patients with purine nucleoside phosphorylase (PNP) deficiency, a guanosine nucleoside analogue, arabinosylguanine (ara-G) was developed that provided T-cell specificity. Nelarabine was developed as the water-soluble, clinically useful-prodrug of ara-G and based on its activity was approved for the treatment of relapsed or refractory T-ALL/LBL. Areas covered: In this narrative review, we will summarize the preclinical studies, early dose-finding studies, and efficacy studies that led to approval of nelarabine. The review will succinctly cover response rates and safety signals reported during clinical development. We will also cover more recent work with nelarabine, including combination studies, modified dosing schedules, and frontline treatment approaches. Expert commentary: Based on evidence from the literature review and our own experience with nelarabine, we conclude that it is an effective agent in the treatment of T-cell malignancies. Understanding the factors that modulate the risk of dose-limiting neurotoxicity, how to mitigate this toxicity, and how to safely combine it with other active agents will continue to broaden its use.

Topics: Adult; Age Factors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

PubMed: 27869523
DOI: 10.1080/17474086.2017.1262757

Comparative Study

Authors: Kiyomi Morita, Nitin Jain, Hagop Kantarjian...

Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is characterized by a distinct immunophenotype (CD1a-negative, CD8-negative, CD5-negative or weak-positive <75%, myeloid/stem-cell markers positive) and poor clinical outcomes. Near-ETP ALL is transcriptionally similar to ETP-ALL but CD5 expression level is not low enough to meet the criteria of ETP immunophenotype. Outcomes of near-ETP ALL are not well characterized. We reviewed 171 patients with newly-diagnosed T-ALL/LBL. Patients were categorized into three groups; ETP (N = 27), near-ETP (N = 24), and non-ETP ALL/LBL (N = 120). ETP-ALL/LBL was associated with a significantly worse survival compared with non-ETP ALL/LBL: 5-year overall survival (OS) rates 32% versus 63% (p < .001). Outcome was similar between near-ETP and non-ETP ALL/LBL: 5-year OS rates 56% versus 63% (p = .543). Landmark analysis showed that allogeneic stem cell transplant (allo-SCT) in first remission was beneficial in ETP-ALL/LBL (5-year event-free survival rates 36% versus 18%, p = .030) but not in near-ETP or non-ETP ALL/LBL. Multivariate analysis selected the following as significant independent prognostic factors for OS: age ≥ 60 years (HR 3.11; p = .003); elevated WBC ≥100 × 10 /L (HR 2.60; p = .005); and ETP immunophenotype (HR 2.29; p = .010). A survival advantage with adding nelarabine to hyper-CVAD was observed in non-ETP ALL (5-year OS rates 83% versus 38% with hyper-CVAD plus neralabine versus hyper-CVAD, p = .003). In conclusion, outcome of ETP-ALL/LBL was poor and improved with allo-SCT; outcome of near-ETP ALL/LBL was similar to non-ETP ALL/LBL; the addition of nelarabine to hyper-CVAD improved the survival in non-ETP ALL only.

Topics: Adolescent; Adult; Aged; Allografts; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Bone Marrow; Cell Lineage; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Middle Aged; Mutation; Neoplasm Proteins; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prodrugs; Progression-Free Survival; Proportional Hazards Models; Retrospective Studies; Survival Rate; Vincristine; Young Adult

PubMed: 33639000
DOI: 10.1002/ajh.26144

Authors: Kimberly P Dunsmore, Meenakshi Devidas, Stephen B Linda...

PURPOSE

Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86-based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).

PATIENTS AND METHODS

In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m(2) once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m(2) once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m(2) once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]).

RESULTS

The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16).

CONCLUSION

Addition of nelarabine to a BFM 86-based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Peripheral Nervous System Diseases; Pilot Projects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

PubMed: 22734022
DOI: 10.1200/JCO.2011.40.8724