Guillain-Barre'-Like Syndrome After Nelarabine Treatment

台灣癌症醫誌 (J. Cancer Res. Pract.) 1(2), 124-127, 2014 DOI: 10.6323/JCRP.2014.1.2.04

journal homepage:www.cos.org.tw/web/index.asp Case Report

Guillain-Barre’-like Syndrome after Nelarabine Treatment

Ya-Ting Hsu, Tsai-Yun Chen*

Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Abstract. Although current treatment can improve the complete remission rate of T-cell acute lymphoblastic leukemia (T-ALL), approximately half of the patients relapse within the first 2 years and have poor prognosis. Nelarabine is a novel purine nucleoside analog, and has been proven efficacious against both refractory and relapsed T-ALL. However, its adverse neurological effects are also well recognized. We report a 37-year-old patient with relapsed T-ALL who developed weakness and paresthesia over the lower limbs bilaterally, with difficulty urinating, after three cycles of nelarabine were administered as bridging therapy to allogeneic stem cell transplantation. The patient’s symptoms were irreversible and progressed to complete paraple- gia in a week, and he expired due to disease progression after two months. Notwithstanding the proven efficacy of nelarabine, the drug’s potentially lethal neurological toxicity should always be carefully monitored during therapy.

Keywords : nelarabine, T-cell acute lymphoblastic leukemia, peripheral neuropathy

病例報告

Nelarabine 治療後產生多發性神經病變

許雅婷陳彩雲*

成功大學附設醫院內科部血液腫瘤科

中文摘要最近幾十年來，對於 T 細胞急性淋巴性白血病的治療已經有許多進步，大大改善了這類病人的完全緩解率。然而，其中仍有部分病人在兩年內疾病就重新復發，且對之後的化學治療反應不佳。Nelarabine，為新一代的嘌呤類似物，FDA 已經批准其用於至少 2 種化療方案治療無效或治療後復發的 T 細胞急性淋巴細胞性白血病，但是同時也有案例報告 nelarabine 導致的神經學毒性。我們報告的病例是一位 37 歲的男性，在 T 細胞急性淋巴性白血病復發時，接受了三個周期的 nelarabine，之後產生雙下肢無力，感覺異常及失禁的症狀。這些症狀逐漸加劇，病人在一周內變得無法行走站立至完全癱瘓，而且神經學症狀在停藥後並無改善。這位病人在兩個月後因為疾病惡化而過世。我們應了解 nelarabine 可能產生的毒性，並在使用 nelarabine 治療時，提高警覺，小心監測病人的神經學症狀。

關鍵字: 奈拉濱、T 細胞急性白血病、周圍神經病變

Open access under CC BY-NC-ND license. Y. T. Hsu et al./JCRP 1(2014) 124-127 125

INTRODUCTION (negative lumbar puncture finding), and received eight In the last 20 years, the treatment outcomes for pa- chemotherapy cycles of Hyper CVAD (cyclophos- tients with T-cell acute lymphoblastic leukemia phamide, vincristine, doxorubicin, and dexamethasone (T-ALL) have improved significantly. T-ALL patients alternative with methotrexate and cytarabine) (Octo- have achieved a complete remission rate of approxi- ber 2010 to May 2011) with complete remission. He mately 90%, with a 50% five-year overall survival then underwent maintenance therapy with POMP rate [1]. However, prognosis is still poor for patients (6-mercaptopurine, vincristine, methotrexate, and whose first line induction therapy failed, or suffered prednisone). Unfortunately, his disease relapsed in relapse. Thus, it is critical that an effective salvage June 2012. The patient subsequently underwent a therapy be developed to more successfully manage chemotherapy series consisting of Hyper CVAD, T-ALL, and further reduce patient mortality. ID-FLAG (idarubicin, fludarabine, cytarabine, and Nelarabine (Arranon®), a synthesized purine nu- G-CSF), without remission. Subsequently, one cycle cleoside analog and pro-drug of arabinosylguanine of nelarabine (1.5g/m2/day on day 1, 3, and 5) was nucleotide triphosphate (araGTP), results in the inhi- administered, and complete remission again was bition of DNA synthesis and cytotoxicity. The efficacy achieved. During the period of preparation for alloge- of nelarabine has been proven in several phase I and II neic stem cell transplantation, the patient received two trials [2-4], and it was approved by the FDA for additional cycles of nelarabine (650mg/m2/day for five T-ALL and T-cell lymphoblastic lymphoma for pa- days) in combination with cyclophosphamide and tients whose disease dose was unresponsive to or re- etoposide as a bridging therapy. lapse following treatment with at least two chemo- Two weeks after the last cycle of chemotherapy, therapy regimens since 2005. Although no incidents of the patient developed a gradual onset of weakness and hematological toxicity have surfaced, neurologically paresthesia over his bilateral legs and difficulty in adverse events accompanying nelarabine use have urination that requiring urethral catheterization. Upon been reported, such as peripheral neuropathy, seizure, further patient examination, the plantar response of and hallucination. We would like to report a patient both extensor tendons and the deep tendon reflexes of with T-ALL who received nelarabine who thereafter his lower extremities were absent. His neurological developed progressive ascending paralysis. symptoms progressively worsened to the point of complete numbness over the bilateral lower limbs CASE REPORT with an inability to stand, all manifesting over a peri- A 37-year-old man was diagnosed as having pre- od of one week. Cerebrospinal fluid analysis showed cursor T-cell lymphoblastic leukemia (initial WBC: no leukemia involvement or central nervous system 378 x 103/μL, blast cells: 93%, flow cytometry: CD2+, infection. Spinal magnetic resonance imaging (MRI) cCD3+, CD7+, MPO-, 46~47,XY,+10[9], +mar[3] revealed minimal scoliosis and only mild herniations [cp10] / 46,XY[10]). He had no CNS involvement of the L1-2 and L3-4 discs, which were not compatible with clinical presentations (Figure 1). A nerve conduction study (NCS) showed that the amplitude of *Corresponding author: Tsai-Yun Chen M.D. compound muscle action potentials (CMAPs) of the *通訊作者：陳彩雲醫師 bilateral common peroneal and tibial nerves were re- Tel: +886-6-2353535 ext.4260 duced, which was compatible with lower limb moder- Fax: +886-6-2752037 ate to severe sensorimotor polyneuropathy. A prelimi- E-mail: [email protected] nary diagnosis of nelarabine-related neuropathy was

126 Y. T. Hsu et al./JCRP 1(2014) 124-127

or in combination with other cytotoxic drugs. Alt- hough significant hematologic toxicity has not been observed, severe neurotoxicities, sometimes even fatal, have been reported. Kurtzberg et al. reported a phase I trial of nelarabine for refractory hematologic malignancies in which various doses (5, 10, 20, 40, 60, 75, and 90 mg/kg/d, for 5 consecutive days) of nelarabine were administered [2]. Neurologic events attributable to nelarabine were observed in 67 (72%) of 93 patients enrolled into the study. In 94% of patients, the onset of symptoms was typically within 12 days of the start of drug administration of the first treatment course. Transient somnolence, malaise, and fatigue beginning 6 to 8 days after the initiation of drug therapy were most frequently reported, particularly in adults. The data revealed the development of cumulative neurotoxicity in the form of hypoesthesias, paresthesias, or peripheral neuropathies in a total of 11 patients, all treated at the higher dose levels (1.2 g/m2; 30 and 60 mg/kg). Gokbuget et al. reported a single-arm phase II study conducted in adults with relapsed/refractory T-ALL or lymphoma (1.5 g/m2/d, on days 1, 3, and 5) [5]. In that study, 16% of all patients experienced neurotoxicities, and 7% of the patients reached grade III or IV. In one patient, treatment had to be stopped Figure 1. Mild herniations of L1-2, and L3-4 disc in because of a Guillain-Barre’-like syndrome presenting magnetic resonance imaging study with tetraparesis, hallucinations, and reduced vigi- lance, which developed at day 3 of the first cycle. The symptoms improved slowly after withdrawal. Recently, made, and we discontinued chemotherapy; additional- Hartz et al. had reported a T-ALL patient who devel- ly, a hold was applied to the patient’s stem cell trans- oped spinal cord necrosis following nelarabine treat- plantation due to his poor performance status. The ment with evolutional changes observed through spi- neurological defects progressed and were irreversible, nal MRI [6]. and the patient expired due to leukemia progression Several nucleoside analogs used as front-line after two months. therapy for patients with hematological malignancies induce dose-limiting adverse effects. The neurotoxici- DISCUSSION ties associated with nelarabine are similar to those Nelarabine is a novel purine analogue, and several observed with other purine analogs, such as cytarabine. phase I/II trials have identified the drug as a promising To date, the mechanism of purine analog-induced agent for patients with T-ALL either as a single agent neurotoxicity is still not fully understood. Kurtzberg et

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