Treatment of Refractory T-Lympho- Blastic Leukaemia and Lymphoma with Nelarabine

Pharmacotherapy

Treatment of refractory T-lymphoblastic leukaemia and lymphoma with nelarabine

T. Bauters, H. Robays, Y. Benoit, B. De Moerloose

The guanine nucleoside congener nelarabine has been approved and reimbursed for use in patients with refractory or relapsed T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. Pharmacokinetic and pharmacodynamic investigations during clinical phase II trials have proven its value as single agent in achiev- ing good clinical responses. Nelarabine as single-agent induced an overall response rate (complete response with or without complete haematological recovery) of 23% in paediatric patients and 31% of adult patients. The median overall survival for adult patients was 20.6 weeks (95% confidential interval (CI): 13-36 weeks). The 1-year survival rate for adults was 28% (95% CI 15-43%). In paediatric patients, the median overall survival was 13.1 weeks [95% CI 8.7-17.4] and survival at one year was 14% [95% CI 3-26%]. Dose-limiting toxicity observed in Phase I and II trials included central and peripheral neurotoxicity. This article describes the mechanism of action and pharmacotherapeutic properties of nelarabine, its therapeutic efficacy, toxicity profile, dosage and administration regimens. (Belg J Hematol 2011;2:70-4)

Introduction are candidates for allogeneic SCT. T-cell haematological malignancies are uncommon The need for new chemotherapy regimens for the and progress rapidly in the absence of effective the- treatment of refractory leukaemia has led to the in- rapy. With the exception of T-cell acute lymphoblas- vestigation of nucleoside analogues.1,2 tic leukaemia (T-ALL), they are often associated with Nelarabine (Atriance®, GlaxoSmithKline, United a poor prognosis. The most effective strategy in re- Kingdom) is approved by the Food and Drug Admi- lapsed/refractory patients seems to be allogeneic nistration (FDA) in 2005 and by the European Me- stem cell transplantation (SCT) after induction of a dicines Agency (EMA) in 2007. It has been licensed second or third complete remission. The benefit ho- and reimbursed in Belgium for the treatment of pae- wever, has not been demonstrated in randomised diatric and adult patients with T-ALL and T-cell studies so far. In addition, age limitations, disease- lymphoblastic lymphoma (T-LBL) whose disease related co-morbidity, and the need for histocompa- has not responded to or has relapsed following tre- tible donors cause that only a fraction of the patients atment with at least two chemotherapy regimens.1,3-5

Authors: T. Bauters1, H. Robays1, Y. Benoit2, B. De Moerloose2, 1Department of Pharmacy, 2Department of Paediatric Haemato-Oncology, Ghent University Hospital, Ghent, Belgium. Please send all correspondence to: T. Bauters, PhD, PharmD, Ghent University Hospital, Department of Pharmacy, -1 K12, De Pintelaan 185, B-9000 Ghent, Belgium, tel: 0032 9 332 50 56, email: [email protected] Conflict of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. Key words: nelarabine, neurotoxicity, pharmacotherapy, T-cell acute lymphoblastic leukaemia and lymphoma

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Figure 1. Chemical structure of nelarabine; ARA-G and ARA-GTP conversion.

Mechanism of action more toxic to T-lymphoblasts than other blast cells Nelarabine is a water-soluble prodrug, which is O- due to enhanced accumulation of ARA-GTP in T- demethylated by adenosine deaminase to the deoxy- cells and increased elimination of ARA-GTP from B- guanosine analog, 9-β-D-arabinofuranosylguanine cells. This correlates with clinical response (ARA-G) (Figure 1).2,6-11 Nelarabine is 10 times more data.5,7,12,13 soluble than ARA-G.11 It acts as a cytotoxic agent and inhibits DNA synthesis. Nelarabine is a member of the purine nucleoside analogues, a class with Pharmacological profile high immunosuppressive and antineoplastic activi- For nelarabine, being administered as an infusion, ty. 2,6-11 Other members of this class are among others the maximum concentration was obtained at the fludarabine, clofarabine and cladribine.6,7,11 end of the infusion.5,7 The average maximum con- After administration, nelarabine is rapidly deme- centration and area under the curve for nelarabine thoxylated in blood by adenosine deaminase to are essentially proportional to the administered ARA-G, which is transported into cells by nucleosi- dose. As a result of rapid conversion to ARA-G, nela- de transporters.7,11 Once inside the cell, ARA-G is rabine is soon undetectable in the blood and there phosphorylated, and converted to the active 5’-tri- is a much greater exposure of tissues to ARA-G than phosphate, ARA-GTP. Accumulation of ARA-GTP in to nelarabine.2 A further effect of this rapid conver- leukaemic blasts causes incorporation into DNA. sion is that the plasma elimination half-life (t ½) of This leads to inhibition of DNA synthesis and indu- nelarabine is short compared with that of ARA-G ces apoptosis.5,12,13 Other mechanisms of action in- (30 minutes versus 3 hours, respectively). These fin- clude inhibition of RNA synthesis and ribonucleo- dings were demonstrated in patients with refractory tide reductase inhibition.5 ARA-G is thought to be leukaemia or lymphoma given a nelarabine dose of

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1,500 mg/m2 (adults) or a 650 mg/m2 (paediatrics). Off-label use of nelarabine Nelarabine and ARA-G are both widely distributed Occasionally, the off-label use of nelarabine has been throughout the body and are not substantially reported. In cutaneous and peripheral T-cell lymp- bound to human plasma proteins (less than 25%). homa, nelarabine monotherapy lacked efficacy and Nelarabine and ARA-G are partially eliminated by led to significant toxicity.16 the kidneys (urine: nelarabine 7%, ARA-G 27%) wit- Nelarabine has been combined with etoposide and hin 24 hours of infusion on day 1.2,5,12,13 cyclophosphamide as salvage therapy in 7 paediatric relapsed/refractory T-ALL and T-LBL cases. All patients had some response and 5 of 7 went into CR Therapeutic efficacy after one or 2 courses.17 Adults The AALL0434 study, that has recently been ope- The therapeutic efficacy of single-agent intravenous ned, will determine whether or not the incorporati- nelarabine in adult patients with refractory or re- on of nelarabine into a Children’s Oncology Group lapsed T-ALL or T-LBL was evaluated in a phase II, (COG) augmented Berlin-Frankfurt-Münster (BFM)- open-label, multicentre, clinical trial.2,14 based treatment improves outcome for children, A total of 26% of adult patients (n=10) achieved a adolescents and young adults with newly diagnosed complete response (CR) with full haematologic re- T-ALL.18 covery; and an additional 5% (n=2) achieved CR without complete haematologic recovery (CRi). Toxicities There were no differences in response rates between Toxicity data using nelarabine in adults revealed that T-ALL and T-LBL: 8 of 26 patients (31%) with T- the most frequent grade 3 or higher non-haematolo- ALL and 4 of 13 patients (31%) with T-LBL had a gic events were fatigue (18%) and muscle weakness CR/CRi. The median overall survival for all treated (11%).2,5,14 Other common toxicities reported are patients was 20 weeks (95% confidential interval gastrointestinal symptoms (nausea, vomiting, diarr- (CI) 13-36 weeks). The 1-year survival rate for all hoea, stomatitis) in 51%, but only one of these treated patients was 28% (95% CI 15-43%). events was severe (diarrhoea grade 3). Peripheral sensory neuropathy was reported in 37% of pa- Children and young adults tients, but all these events were grade 1 or 2. Perip- Nelarabine as single-agent induced an overall res- heral motor neuropathy accounted for 21% of pa- ponse rate (complete response with or without com- tients; most of them were grade 1 or 2 with only one plete haematological recovery) of 23% in paediatric grade 3 adverse event (AE). Only one grade 4 AE of patients.2 the nervous system (reversible depressed level of A phase II study with 121 paediatric patients was consciousness) was observed. performed by the Children’s Oncology Group.15 The safety data reported by the Cancer and Leuke- Four different patient strata were analysed. Stratum mia Group B (CALGB) study revealed that grade 3 1 consisted of patients in first relapse with greater or 4 haematologic toxicity was observed in approxi- than 25% bone marrow involvement; stratum 2 pa- mately 70% of patients, while grade 3 and 4 gas- tients were in second relapse with greater than 25% trointestinal disorders occurred in less than 1% of bone marrow involvement. The third stratum inclu- the treated patients. Overall, 72% of the patients ded patients with central nervous system (CNS) re- had neurologic events from which 10% were grade lapse, and the fourth patients with extramedullary 3 and 3% grade 4.19 (non-CNS) relapse. Complete plus partial response Similar neurotoxicity was seen in children and was rates at the final dose levels (650 mg/m² per day for reported for all subjects who were enrolled in the stratum 1 and 2; and 400 mg/m² per day for strata phase II study performed by the COG and received 3 and 4) were 55% (stratum 1); 27% (stratum 2); at least one drug dose.15 In 18% of the patients 33% (stratum 3); and 14% (stratum 4). In paediatric (n=27), there were 31 episodes of greater than gra- patients, the median overall survival was 13.1 weeks de 3 neurologic adverse events. [95% CI 8.7-17.4] and survival at one year was 14% It is important to mention that the scientific leaflet [95% CI 3-26%].3 specifically warns for severe neurotoxicity, including

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severe somnolence, seizure, and peripheral neurop- Conclusion athy ranging from numbness and paresthesias to mo- Nelarabine demonstrates clinically significant anti- tor weakness and paralysis. Adverse effects associated neoplastic activity in adult and paediatric patients with demyelination or similar to Guillain-Barré syn- with relapsed/refractory T-ALL/LBL. The main ad- drome (ascending peripheral neuropathies) have also verse events associated with its administration are been reported. Full recovery from these events did neurological, which can be severe. Further studies not always occur after cessation of nelarabine. are needed to determine whether the addition of The risk of neurotoxicity may increase in patients nelarabine to frontline regimens in sequence with with concurrent or previous intrathecal chemother- other standard chemotherapy agents will increase apy or a history of craniospinal irradiation. Close the cure rates of patients with T-ALL/LBL. monitoring for neurological events is strongly recommended, and nelarabine must be discontinued at the first sign of neurological events of grade 2 or References greater.5 1. Kline J, Larson RA. Nelarabine in the treatment of refractory T-cell Patients receiving nelarabine are recommended to malignant diseases. Expert Opin Pharmacother 2006;7:1791-9. receive intravenous hydration according to standard 2. DeAngelo DJ. Nelarabine for the treatment of patients with relapsed or medical practice for the management of hyperuri- refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. caemia in patients at risk of tumour lysis syndrome. Hematol Oncol Clin N Am 2009:1121-35. For patients at risk of hyperuricaemia, the use of al- 3. European Medicines Agency. Atriance: scientific discussion [online]. lopurinol should be considered. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_ library/EPAR_-_Product_Information/human/000752/WC500027918.pdf. Dosage and administration [accessed 2010 Nov 3]. The recommended dose of nelarabine for adults and 4. http://www.riziv.be [accessed 2010 Dec 2]. adolescents (aged 16 years and older) is 1,500 mg/ 5. E-Compendium. Scientific Leaflet Atriance (in Flemish). Available from m2 administered intravenously over two hours on URL: http:/www.ecompendium.be/. [Accessed on 4 October 2010]. days 1,3 and 5 and repeated every 21 days. 6. Robak T, Lech-Maranda E, Korycka A, Robak E. Purine nucleoside In children, dose recommendation of nelarabine is analogs as immunosuppressive and antineoplastic agents: mechanism of 650 mg/m2, administered intravenously over one action and clinical activity. Curr Med Chem 2006;13:3165-89. hour daily for 5 consecutive days, repeated every 21 7. Kisor DF. Nelarabine: a nucleoside analog with efficacy in T-cell and other days. In clinical studies, both the 650 mg/m2 and leukemias. Ann Pharmacother 2005;39:1056-63. 1,500 mg/m2 dose have been used in patients in the 8. Ravandi F, Gandhi V. Novel purine nucleoside analogues for T-cell- age range 16 to 21 years. Efficacy and safety were lineage acute lymphoblastic leukaemia and lymphoma.Expert Opin Investig similar for both regimens. The prescribing physician Drugs 2006;15:1601-13. should consider which of the two possible treat- 9. Apostolidou E, Swords R, Alvarado Y, Giles FJ. Treatment of acute ment regimens is appropriate. lymphoblastic leukaemia : a new era. Drugs 2007;67:2153-71. Limited clinical pharmacology data are available for 10. Gandhi V, Plunkett W. Clofarabine and nelarabine: two new purine patients below the age of 4.5 nucleoside analogs. Curr Opin Oncol 2006;18:584-90. 11. Buie LW, Epstein SS, Lindley CM. Nelarabine: a novel purine Renal impairment antimetabolite antineoplastic agent. Clin Ther 2007;29:1887-99. Nelarabine has not been studied in individuals with 12. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, renal impairment. As nelarabine and ARA-G are par- Inc.; 2010. URL: http://cp.gsm.com. Updated November 2010. tially renally excreted, patients with renal impair- 13. UpToDate, Inc. [database online]. Waltham, MA, 2010. URL https:// ment must be closely monitored for toxicities while www.uptodate.com/home/index.html. Updated November 2010. treated with nelarabine.5 14. DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, et al. Nelarabine induces complete remissions in adults with relapsed Hepatic impairment or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic Nelarabine has not been studied in patients with he- lymphoma: Cancer and Leukemia Group B study 19801. Blood patic impairment and caution in these patients is 2007;109:5136-42. warranted.5 15. Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M,

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Key messages for clinical practice

1. Nelarabine is a prodrug of ARA-G and inhibits DNA synthesis resulting in cell death.

2. Nelarabine is licensed and reimbursed in Belgium for the treatment of paediatric and adult patients with T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.

3. The median overall survival time was 13.1 and 20.6 weeks in paediatric and adult patients receiving nelarabine as single-agent, with corresponding 1-year survival rates of 14% and 28%.

4. Toxicity of nelarabine is generally acceptable, but serious treatment-limiting neurological adverse events may occur in some patients.

et al.Children’s Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. J Clin Oncol 2005;23:3376-82. 16. Czuczman MS, Porcu P, Johnson J, Niedzwiecki D, Kelly M, Hsi ED, et al.; for the Cancer and Leukemia Group B. Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901. Leukemia & Lymphoma 2007;48:97-103. 17. Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 2010;150:345-35. 18. Winter S, Devidas M, Wood B, Borowitz M, Loh M, AsselinB, et al. Nelarabine may be safely incorporated into a phase III study for newly diagnosed T-lineage acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2010;116:378 (#865, ASH 2010). 19. Cohen MH, Johnson JR, Massie T, Sridhara R, McGuinn WD Jr, Abraham S, et al. Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma. Clin Cancer Res 2006;12:5329-35.

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