ORIGINAL ARTICLE Age and High-Dose Methotrexate

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Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

MN Dufourg1, J Landman-Parker1, MF Auclerc2, C Schmitt3, Y Perel4, G Michel5, P Levy6, G Couillault7, V Gandemer8, MD Tabone1, F Demeocq9, JP Vannier10, T Leblanc2, G Leverger1 and A Baruchel2

1Service d’he´matologie et d’oncologie pe´diatrique Hoˆpital d’Enfant Armand Trousseau, AP-HP, Paris, France; 2Service d’he´matologie pe´diatrique Hoˆpital St Louis, AP-HP, Paris, France; 3Service de pe´diatrie II hospital d’Enfant Vandoeuvre les Nancy, Paris, France; 4De´partement de pe´diatrie CHU Pellerin Bordeaux, Paris, France; 5Service d’he´matologie pe´diatrique CHU La Timone, Marseille, Paris, France; 6De´partement d’informatique me´dicale Hoˆpital Tenon, AP-HP, Paris, France; 7Service de pe´diatrie CHR de Limoges; 8Service de pe´diatrie CHR Rennes; 9Service d’he´matologie CHR Clermont Ferrand and 10De´partement de pe´diatrie CHR Rouen, for the French cooperative group FRALLE

The objective of the study was to assess acute neurotoxicity Neurotoxicity during treatment have been reported since 7 associated with triple intrathecal therapy (TIT) high-dose 1970. The principal drugs incriminated are vincristine, metho- methotrexate (HD MTX) in children with acute lymphoblastic 2,10,11 leukemia (ALL). 1395 children were enrolled on FRALLE 93 trexate (MTX), Cyt and asparaginase. Vincristine mainly protocol from 1993 to 1999. Lower-risk group (LR, n ¼ 182) were causes peripheral neuropathies, ranging from abolition of the randomized to weekly low-dose MTX at 25 mg/m2/week (LD Achille’s reflex and paresthesias of the extremities to distal MTX, n ¼ 81) or HD MTX at 1.5 g/m2/2 weeks Â 6(n ¼ 77). motor impairment. These neuropathies are dose-dependent and Intermediate-risk group (IR, n ¼ 672) were randomized to LD usually reversible. High-dose intravenous and intrathecal (i.t.) 2 MTX (n ¼ 290) or HD MTX at 8 g/m /2 weeks Â 4(n ¼ 316). Higher- Cyt can cause syndrome combining seizures, encephalopathy, risk group (HR, n ¼ 541) prednisone-responder patients re- 12–14 ceived LD MTX and cranial radiotherapy. HR group steroid cerebella involvement and myelitis. Intrathecal (i.t.) MTX resistant cases were grafted (autologous or allogenic). TIT and high-dose methotrexate (HD MTX) can induce seizures, (MTX, cytarabine and methylprednisolone) was given every 2 polyradiculoneuritis, myelitis, transient neurological deficits and weeks during 16–18 weeks and every 3 months during multifocal encephalopathy. Asparaginase can contribute to this maintenance therapy in LR and IR patients. 52 patients (3.7%) neurotoxicity by modifying hemostasis, with an increased risk of developed neurotoxicity. Isolated seizures: n ¼ 15 (1.1%), cerebral thrombosis during treatment.14,15 peripheral and spinal neuropathy: n ¼ 17 (1.2%) and encephalo- The exact incidence of these complications is difficult to pathy: n ¼ 20 (1.4%). Age 410 years was significantly asso- 15–20 ciated with neurotoxicity (P ¼ 0.01) and use of HD MTX is determine, as most data come from isolated case reports. associated with encephalopathy (P ¼ 0.03). Sequels are re- Similarly, the outcome of children with acute neurotoxicity is ported respectively in 60 and 33% of spinal neuropathy and poorly documented. Yet improvements in outcome in recent encephalopathy cases. Current strategies tailoring risk of years have placed the accent on prevention of treatment neurological sequels has to be defined. sequels. We therefore analyzed acute neurotoxicity occurring Leukemia (2007) 21, 238–247. doi:10.1038/sj.leu.2404495; published online 14 December 2006 during the multicenter trial FRALLE 93, conducted between Keywords: neurotoxicity; acute lymphoblastic leukemia; pediatric 1993 and 1999, in order to determine their frequency and type, to identify possible risk factors and to determine the impact of this toxicity on overall outcome.

Introduction Patients and methods

Prevention of meningeal relapse is crucial for all children with Between 1993 and 1999, 1395 children with ALL (778 boys, acute lymphoblastic leukemia (ALL), as the central nervous 617 girls) were enrolled in the FRALLE 93 study. Informed system (CNS) is a known sanctuary for lymphoblasts. Initial CNS consent was obtained from all patients’ parents in accordance involvement is found in 3–5% of patients.1–4 However, majority 5 with national ethic rules. Median age was 5.2 years (1,5–15). of ALL patients have occult CNS involvement and the prognosis ALL was of the B lineage in 1195 cases (86%) and T cell in 200 of CNS relapses is still unsatisfactory, although recent improve- 6–8 cases (14%). The low-, intermediate- and high-risk (LR, IR and ment has been reported with event free survival up to 70%. HR) groups comprised respectively 182 (13%), 672 (48%) and CNS prophylaxis is currently based on intrathecal chemotherapy 541 (39%) children. Main clinical characteristics are resumed 7 (IT) with MTX steroid and cytarabine (Cyt) and prophylactic on Table 1. cerebral irradiation indicated for children with ALL with a HR of Acute neurological events were initially reported to the CNS relapse. The incidence of CNS relapse is currently between 9 coordinating investigators of the FRALLE 93 study. Following 1.5 and 5% depending on the study. the creation of a neurotoxicity task force, a standard ques- tionnaire was subsequently addressed to each participating Correspondence: Professor J Landman-Parker, Service d’he´matologie center and completed by the physician responsible for the child ´ ˆ et d’oncologie pediatrique, AP-HP hopital Armand Trousseau, 26 at the time of the event. avenue Arnold Netter, 75012 Paris, France. E-mail: [email protected] The following information concerning each event was Received 11 September 2006; revised 16 October 2006; accepted 20 recorded: clinical manifestations, treatment group, treatment October 2006; published online 14 December 2006 phase, number of IT and HD MTX courses received, MTX Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 239 Table 1 Clinical characteristics of the patients in the FRALLE 93 30 mg/MP 20 mg; 3–10 years: MTX 12 mg/Cyt 40 mg/MP 20 mg; study (n ¼ 1395) and with grade 3–4 acute neurotoxicity 410 years: MTX 15 mg/Cyt 40 mg/MP 20 mg. LR and IR patients received a total of 16 and 18 TIT FRALLE 93 Neurotoxicity respectively. HR (C1) children over 4 years received 12 TIT before CNS radiotherapy, whereas younger children received 18 Total number of patients 1395 52 TIT, without radiotherapy. TIT were delivered every 2 weeks Boys 778 (56%) 29 (56%) Girls 617 (44%) 23 (44%) during first 18 weeks and then every 3 months. Me´ dian age 5.2 (0.1–19.7) 7.1 (1.9–15) White cell count (G/l) 12 (0.3–1350) 11.1 (0.5–522) Methotrexate treatment. LR and IR patients were rando- B-cell 1195 (86%) 48 (92%) mized to either HD MTX or LD MTX during consolidation T-cell 200 (14%) 4 (8%) 2 2 CNS leukemia at presentation 42 (3%) 3 (6%) phase: respectively 25 mg/m vs HD MTX 1.5 g/m (6 courses 2 2 LR 182 (13%) 3 (6%) every 2 weeks) and 25 mg/m vs 8 g/m (4 courses every 2 IR 672 (48%) 32 (61%) weeks). In HD MTX groups, MTX was administered over 24 h. HR 541 (39%) 17 (33%) TIT was given Day 1 (D1) after the beginning of MTX infusion. LD MTX LR 81 0 Rescue by folinic acid was started at hour 36 (H36) 12 mg/m2 HD MTX LR 77 3 À7 every 6 h until MTX level reached 2.10 M. LD MTX IR 290 (48%) 17 (53%) o HD MTX IR 316 (52%) 15 (47%) Relapse 300 (18%) 11 (21%) Radiation therapy. C1 group children over 4 years of age Median follow-up (months) 66 88 received prophylactic CNS irradiation (18 Gy) up to the second 7 7 Overall 5-year survival rate 83 3% 86 9% cervical vertebra. Abbreviations: HD MTX, High-dose methotrexate; HR, high-risk; IR, intermediate-risk; LD MTX, Low-dose methotrexate; LR, low-risk. Statistical analysis Distribution of qualitative variables was compared with the two- sided Fisher’s exact test and w2 test. Considering the number of elimination, time since last IT, CSF abnormalities, radiological neurological events in each group, multivariate analysis was not and neurophysiologic findings, protocol modifications, sequel performed. The Kaplan–Meier method was used to evaluate and final status (up to July 2005). Neurotoxicity was defined disease-free survival probabilities and relapse risks. Compar- according to the criteria of the World Health Organization isons of two Kaplan–Meier curves were made using the log-rank (WHO) classification. Only grade 3–4 events are reported. test. In all analyses, the limit of significance was assigned as Peripheral neuropathies unequivocally owing to vincristine Pp0.05. (isolated sensory toxicity or moderate gait disorders) were not included in the study. Results

Treatment Fifty-two children (3.7%) had grade 3–4 acute neurotoxicity. The FRALLE 93 study population was stratified into three groups Their main characteristics are shown in Table 2 and Figure 3. (LR, IR and HR) based on the following risk factors: age, white Three types of neurological symptoms were observed, cell count at diagnosis, hemoglobin level, immunophenotype, peripheral and spinal neuropathy n ¼ 17 (33%), isolated seizures karyotype and steroid response. Low-risk group was defined by: n ¼ 15 (29%) and encephalopathy n ¼ 20 (38%). Eleven (21%) 9 age o7 and over 1 year, white cell count o10.10 /l, B lineage of the 52 children relapsed and seven (13.5%) died. Overall c-ALL CD 10 positive and no adverse cytogenetics findings. HR survival of the 52 patients is 86%79 with a median follow-up of group was defined by at least one major criteria : age 415 years 102 months. or below 1 year, white cell 4100.109/l, t(9;22) or t(4,11) or hypoploid or tetraploid caryotype, T-cell lineage or at least 2 minor criteria: age 410 years, tumor syndrome, Hb410 G/l, Seizures (n ¼ 15) white cell count 450.109/l, two myeloid antigens expression Fifteen patients had seizures; focal signs were seen in four cases such as CD13, CD33 or CD14. Intermediate group was defined (Table 3). Three patients presented subsequent seizures after by exclusion of two others groups. Treatment design is resumed 48 h. Ten out of 15 had clinical signs of acute arachnoiditis. In in Figures 1 and 2. HR patients received one of the following four cases, imaging studies at the end of treatment showed signal three treatment groups: group C1, steroid good responders: abnormalities of the white matter, compatible with MTX chemotherapy with two intensifications; group C2, very HR toxicity. patients steroid-resistant on D8 or M2 or M3 bone marrow at Six cases occurred during induction, four during consolida- day 21: intensification with six cycles of chemotherapy, tion, one during the interphase, two during intensification and followed by autografting; group C3, allogenic bone marrow two during maintenance therapy. The patients had received a transplantation (BMT) in case of HLA-matched sibling donor. median of three TIT (2–17), and the seizures occurred a median Allogenic BMT was indicated for all patients with t (9;22) or t of 8 days after the last injection. (4;11) or hypoploid caryotype. CT showed abnormalities in 4/14 documented cases. Two patients presented thrombosis after the sixth Asparaginase injection during induction. Both presented further risk factors CNS prophylaxis for thrombosis: oral contraception and partial protein S IT chemotherapy. Triple intrathecal therapy (TIT) was based deficiency in one case and oral contraception and familial on methylprednisolone (MP), MTX and Cyt. Dose regimen was hypertriglyceridemia in the other case. Two patients (patients 15 adapted to age: 0–1 year: MTX 6 mg/Cyt 15 mg/MP 20 mg;1–2 and 9) had imaging signs of ischemic stroke. In patient 15, the years: MTX 8 mg/Cyt 20 mg/MP 20 mg; 2–3 years: MTX 10 mg/Cyt seizures occurred during the maintenance phase with LD MTX,

Leukemia Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 240 INDUCTION LR INDUCTION IR VCR1,5mg/m2/d IV D8, D15, D22, D29 VCR1,5mg/m2/d IV D8, D15, D22, D29 PRED 60mg/m2/d D1-D7, 40mg/m2/d D8-D21, PRED 60mg/m2/d D1-D7, 40mg/m2/j D8-D21, L-Aspa 100000UI/m2/d IM x 6 D22-D35 L-Aspa 100000UI/m2/d IM x 6 D22-D35 TIT D1-D15 DNR 40mg/m2/d D8-D15 (-D22) TIT D1-D15

CONSOLIDATION 1 LR CONSOLIDATION 1 IR PRED 40mg/m2/d PO D1-D28 VP16 150mg/m2/d IV D1, D8, D15 VCR1,5mg/m2/d IV D1 Cyt 30mg/m2 x 2/d D1, D2, D8, D9, D15, D16 MTX : HD1500mg/m2/d or LD 25mg/m2/d PO D1, D15 Thioguanine 60mg/m2/d PO D1-D21 MTX 25mg/m2/d PO D8, D22 TIT D1, D15 6-MP 50mg/m2/d PO D1-D28 CONSOLIDATION 2 IR TIT D1, D15 (MTX LD) / D2, D16 (MTX HD) PRED 40mg/m2/d PO D29-D36, D57-D64 CONSOLIDATION 2 LR VCR 1,5mg/m2/d IV D29, D57 PRED 40mg/m2/d PO D29-D36, D57-D64 6-MP 50mg/m2/d PO D29-D77 VCR 1,5mg/m2/d IV D29, D57 MTX:HD 8000mg/m2/d or LD 25mg/m2/d PO D29, D43, 6-MP 50mg/m2/d PO D29-D77 D57, D71 MTX: HD 1500mg/m2/d or LD 25mg/m2/d PO D29, D43, MTX 25mg/m2/d PO D36, D50, D64, D78 D57, D71 TIT D29, D43, D57, D71 (LD MTX) MTX 25mg/m2/d PO D36, D50, D64 TIT D30, D44, D58, D72 (HD MTX) TIT D29, D43, D57, D71 (LD MTX) TIT D30, D44, D58, D72 (HD MTX)

INTENSIFICATION 1 (LR + IR) DEX 10mg/m2/d PO/IV D1-D14, degressive D15-D22 VDS 3mg/m2/d IV D1, D8, D15 ADRIA 25mg/m2/d IV D1, D8, D15 L-Aspa 6000UI/m2/d IV/IM D1, D3, D5, D8, D10, D12 TIT D1 (LR+IR), D15 (IR)

INTENSIFICATION 2 LR INTENSIFICATION 2 IR Cyt 30mg/m2 x 2/d D29, D30, D36, D37, D43, D44 VP16 150mg/m2/d IV D29, D36, D43 Thioguanine 60mg/m2/d PO D29-D49 Cyt 30mg/m2 x 2/d D29, D30, D36, D37, D43, D44 TIT D29 Thioguanine 60mg/m2/d PO D29-D49 TIT D29, D43

MAINTENANCE 20 months (girls) 32 months (boys) 2 2 12 pulses (1/ 4 weeks) VCR 1,5mg/m /d IV D 1 /PRED 40mg/m /d PO D1-D7 and 6-MP 75mg/m2/d ¾ weeks / MTX 25mg/m2/d PO ¾ weeks TIT n=6

Figure 1 LR and IR patients treatment design. ADRIA: adriamycine; VCR: vincristine; VDS: vindesine; PRED: prednisolone; L-Aspa Asparaginase; DNR: daunorubicine; Cyt: cytarabine; HD MTX: high-dose methotrexate; LD MTX: low-dose methotrexate; DEX: dexamethasone; 6-MP: 6 mercaptopurine; TIT: triple intrathecal therapy.

3 months after TIT. CT was normal but magnetic resonance but cognitive evaluation was not performed. To summarize, out imaging (MRI) showed a focal white matter hyposignal. In of 15 seizures, two were asparaginase-related, six methotrexate- patient 9, seizures occurred 8 days after the first intensive related, one link to CNS leukemia and the other six possibly to consolidation cycle with HD MTX COPADM (T-cell ALL with vincristine, IT or individual suceptibility but without optimal CNS involvement), CT after the seizures showed bilateral imaging investigations. parietal hypodensities; MRI showed CSF infiltration. Seven children had CT, three had both normal CT and MRI but angiographic-MRI was not performed in any cases. In only Peripheral and spinal neuropathy (n ¼ 17) one case (patient 12), the child was febrile at seizure onset and Clinical manifestations were of three principal types: (Table 4). blood culture yielded Staphylococci epidermidis. Most children had no treatment modifications. Fourteen children (14/15) Spinal involvement (seven patients, 16–22): Two patients had received the entire course of CNS prophylaxis; TIT were delayed flaccid quadriplegia with sensory and sphincter disorders. in one case and one child received IT without Cyt. Six children The other five patients had solely motor involvement; received antiepileptic therapy. None have functional sequels paraplegia was accompanied in three cases by pyramidal

Leukemia Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 241 INDUCTION HR INDUCTION VHR VCR1,5mg/m2/d IV D8, D15, D22, D29 VCR1,5mg/m2/d IV D8, D15, D22, D29 2 2 2 2 PRED 60mg/m /d D1-D7, 40mg/m /j D8-D21 PRED 60mg/m /d D1-D7, 40mg/m /j D8-D21 L-Aspa 100000UI/m2/d IM x 6 D22-D35 L-Aspa 100000UI/m2/d IM x 8 D20-D35 DNR 40mg/m2/d D8-D15-D22 DNR 40mg/m2/d D8-D9-D10-D15 TIT between D1 and D4-D8-D15 TIT between D1 and D4-D8-D15

CONSOLIDATION 1 HR (D1-D28) VP16 150mg/m2/d IV D1, D8, D15 Cyt 30mg/m2 x 2/d D1, D2, D8, D9, D15, D16 2 Thioguanine 60mg/m /d PO D1-D21 TIT D1, D15 CONSOLIDATION 2 HR (D29-D57) PRED 40mg/m2/d PO D29-D36 VCR 1,5mg/m2/d IV D29, D57 6-MP 50mg/m2/d PO D29-D50 LD MTX 25mg/m2/d PO D29, D36, D43 Or HD MTX 8000mg/m2/d D29, D43 (children < 4 years) TIT D29, D43 (LD MTX) or D30, D44 (HD MTX)

INTENSIFICATION n°1 HR idem intensification (1 + 2) IR

INTERPHASE HR PRED 40mg/m2/d PO D1-D8, D29-D36 VCR 1,5mg/m2/d IV D1, D29 6-MP 50mg/m2/d PO D1-D49 LD MTX 25mg/m2/d PO D1, D8, D15, D22, D29, D36 Or HD MTX 8000mg/m2/d D1, D15 (children < 4 years) Prophylactic CNS irradiation of 18 Gy between D40 and D55 (children > 4 years) TIT D1

INTENSIFICATION n°2.1 HR (D1-D28) INTENSIFICATION n°2.2 HR (D29-D57) PRED 40mg/m2/d PO D1-D14, VP16 150mg/m2/d IV D29-D43 VDS 3mg/m2/d IV D1, D8, D15 Cyt 30mg/m2 x 2/d D29, D30, D43, D44 L-Aspa 6000UI/m2/d IV/IM D1, D3, D5, D8, D10, D12 Thioguanine 60mg/m2/d PO D29-D49 DNR 30mg/m2/d D1-D8-D15 TIT D29 (children < 4 years) TIT D1 (children < 4 years)

MAINTENANCE (18 months) 6 pulse (4 weeks) VCR 1,5mg/m2/d IV D1 /PRED 40mg/m2/d PO D1-D7 And 6 6-MP 75mg/m2/d ¾ weeks / MTX 25mg/m2/d PO ¾ weeks TIT n=3

Figure 2 HR patients treatment design. VCR: vincristine – VDS: vindesine – PRED: prednisolone – L-Aspa: Asparaginase – DNR: daunorubicine – Cyt: cytarabine; HD MTX: high-dose methotrexate thioguanine; LD MTX: low-dose methotrexate; 6-MP: 6 mercapto-purine; TIT: triple intrathecal therapy.

signs (Babinski sign, brisk osteo-tendinous reflexes). Spinal case occurred during induction, two during consolidation, MRI was abnormal in 4/7 children, with peri-spinal contrast seven during intensification and five during maintenance enhancement in three cases and epidural enhancement in therapy. The median TIT number was 10 (2–18), and onset two cases (both abnormalities in one patient); occurred a median of 13 days after the last injection. Anterior horn involvement (three patients, 23–25): rapidly progressive purely motor neuropathy (flaccid paraplegia) with Six of the 15 children fully recovered but nine have chronic lesions of the anterior horn on nerve conduction study (NCS) sequels and recovered very slowly. Spinal involvement had the and electromyography (EMG). MRI was normal in every case; worst functional prognosis. After an average follow-up of two Peripheral involvement (five patients, 26–30): Sensory-motor years, physical examination of eight of these nine children radiculoneuritis and elevated proteinorachia (2/5); one child showed: persistent paraplegia and need for urinary drainage had CSF hypercellularity; EMG and NCS showed axonal (n ¼ 1, patient 16); walking possible with canes þ plastered lesions. MRI was always normal. Data were missing for two splints, urination by abdominal pushing (n ¼ 1, patient 20); of these 17 children because they were lost of follow-up. One walking with corrective splints for varus equinus (n ¼ 2);

Leukemia Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 242 Table 2 Clinical characteristics of the patients with acute toxicity according to neurological symptoms (n ¼ 52)

Seizure Encephalopathy Spinal and peripheral neuropathy

Total number of patients 15 20 17 Boys 8 (53%) 13 (65%) 8 (47%) Girls 7 (47%) 7 (35%) 9 (53%) Median age 9.6 (2–15) 7.7 (2.4–14.7) 4.8 (1.9–13.2) White cell count (g/l) 12.7 (0.5–430) 12.4 (2.2–522) 7.3 (1.5–119) B-cell 13 (87%) 19 (95%) 16 (94%) T-cell 2 (13%) 1 (5%) 1 (6%) CNS leukemia at presentation 2 1 0 LR 0 2 (10%) 1 (6%) IR 8 (53%) 12 (60%) 12 (71%) HR 7 (47%) 6 (30%) 4 (23%) LD MTX LR 0 0 0 MD MTX LR 0 2 1 LD MTX IR 6 (75%) 2 (17%) 9 (75%) HD MTX IR 2 (25%) 10 (83%) 3 (25%) Relapse 2 (13%) 6 (30%) 3 (18%) Bone marrow relapse 1 2 1 Testis relapse 1 1 Bone marrow and testis relapse 1 CNS relapse 1 1 Bone marrow and CNS relapse 1 1 Abbreviations: CNS, central nervous system; HD MTX, high dose methotrexate; HR, high-risk; IR, intermediate-risk; LD MTX, low dose methotrexate; LR, low-risk.

25 impaired gait without canes (n ¼ 2); walking unaided (n ¼ 2). Spinal 20 ALL treatment was modiﬁed in 11/15 cases: TIT were stopped in 15 Encephalopathies LD nine cases and replaced by CNS irradiation in two cases and by 10 MTX HD MTX in one case. Cyt was stopped in one case and 5 Encephalopathies HD vincristine in 8/15 cases. For three children, vincristine toxicity 0 MTX is difﬁcult to rule out because of the transient and moderate Seizures nature of the disorders.

Induction Interphase ConsolidationIntensification Maintenance Encephalopathy (n ¼ 20) Encephalopathy occurred in 20 children (six girls, 14 boys and Figure 3 Neurologic toxicity according to treatment phase and median age 7.9 years, range 2.4–14.7 years) (Table 5a, b). Two methotrexate dose. LD MTX: low-dose methotrexate; HD MTX: high- LR patients (2/2) and 10/12 IR patients were randomized to dose methotrexate. receive HD MTX. The manifestations were polymorphous, with

Table 3 Seizures (n ¼ 15)

Patient Phase HD MTX IT (n) Delay IT (dy) P (g/l) CSF (n/mm3) CT MRI

1 Consolidation IR À 3 0 1.24 3 Normal NP 2 Induction HR À 3 0 0.16 15 Normal NP 3 Induction IR + 2 0 0.23 2 Normal Normal then ischemic le´ sions 4 Induction HR À 3 2 0.1 1 Thrombosis Thrombosis 5 Maintenance IR À 17 4 0.98 0 Normal NP 6 Induction HR À 3 6 0.2 0 Normal NP 7 Interphase HR + 5 7 0.2 1 Normal NP 8 Consolidation IR À 5 8 0.09 1 Normal Normal 9 Intensification HR + 5 8 1.52 3 Normal then ischemic lesions Leukemic infiltration C1–C2 10 Intensification IR + 11 8 0.54 1 Normal NP 11 Consolidation IR À 3 10 0.12 2 Normal Normal then leukoencephalopathy 12 Consolidation IR À 4 14 0.61 1 Normal NP 13 Induction HR À 3 14 0.15 4 NP NP 14 Induction HR À 3 20 0.23 0 Thrombosis Thrombosis 15 Maintenance IR À 17 90 ND ND Normal Leukoencephalopathy Abbreviations: CNS, central nervous system, CSF, cerebrospinal fluid; CSF (n/mm3), cerebrospinal fluid leucocytes/mm3; CT, computed tomography; delay IT (dy), day number between last IT and seizure; HD MTX, high-dose methotrexate; HR, high risk; IR, intermediate risk; IT, intrathecal chemotherapy; IT nb, IT number before seizure; LR, low risk; MRI, magnetic resonance imaging; ND, no data; NP, not performed; P (g/l), proteinorachia in g/l.

Leukemia Table 4 Clinical characteristics of peripheral and spinal neuropathy (n ¼ 17)

Patient Phase HD MTX Initial symptoms Clinical status IT nb Delay IT (dy) P (g/l) CSF (n/mm3) NCV/EMG CT MRI Sequel

16 Intensification IR À Dysuria , pain, Quadriplegia 10 11 1.14 1 Motor neuropathy medullar NP Myelitis paraplegia flaccid paraplegia involvement urinary drainage 17 Maintenance IR + Painful Flaccid paraplegia 14 0 1.64 5 Lumbar sacral anterior horn NP Myelitis impaired gait Sensory disorder involvement 18 Intensification IR À Painful Para paresis 10 1 0.42 1 Nd NP Myelitis F Sensory disorder 19 Consolidation HR À Gait disorder Flaccid paraplegia 6 1 0.29 7 Motor axonal lesion NP Normal impaired gait 20 Maintenance IR À left foot painful Quadriplegia 15 15 0.24 4 Denervation NP Myelitis walking with canes Sensory disorder 21 Maintenance HR À Gait disorder and Para paresis 11 16 1.8 1 Axonal lesions (4 limbs) Normal Normal walking unaided painful 22 Maintenance IR À Gait disorder Flaccid paraplegia 14 15 0.2l 0 Purely motor neuropathy NP Normal walking unaided (anterior horn or medullar involvement) 23 Consolidation 2 IR À Progressive Flaccid paraplegia 4 14 0.41 1 Diffuse neurogenic NP Normal impaired gait involvement, anterior horn involvement 24 Maintenance IR À Gait disorder Flaccid paraplegia 18 13 1.3 3 Motor axonal deficit Normal Normal walking with corrective splints 25 Intensification IR À Progressive Flaccid paraplegia 10 14 0.2 0 Purely motor neuropathy NP Normal F (anterior horn or medullar involvement)

26 Induction IR À Dorsal painful Flaccid paraplegia 2 0 0.95 3.6 Sensory-motor involvement, Normal Normal walking with leukemia Dufourg lymphoblastic MN acute in neurotoxicity Acute and sensitive proximal motor axonal deﬁcit corrective splints disorder 27 Intensiﬁcation LR + Gait disorder Motor performance 9 ND 0.2 2 Axonal lesions NP NP F

decreased, OTR al et abolition 28 Intensification VHR À Harm painful 4 limbs deficit 4 0 0.1 0 Diffuse axonal neuropathy, NP Normal F reduced nerve conduction velocities (sciatic nerve), left radial nerve atrophy 29 Maintenance IR + Gait disorder Left sciatalgy 16 75 0.2 1 reduced nerve conduction NP Normal F velocities (inferior limbs) 30 Intensification IR À Walk refused Gait and sensitive 8 13 3.94 17 Polyneuropathy, major sensory NP Normal F disorder involvement 31 ND IR group + Gait disorder Flaccid paraplegia ND ND ND ND ND ND 32 ND HR group À Gait disorder Gait disorder ND ND ND ND ND ND Abbreviations: CNS, central nervous system, CSF, cerebrospinal fluid; CSF (n/mm3), cerebrospinal fluid leucocytes/mm3; CT, computed tomography; delay IT (dy), day number between last IT and seizure; EMG, electromyography; HD MTX, high-dose methotrexate; HR, high risk; IR, intermediate risk; IT, intrathecal chemotherapy; IT nb, IT number before seizure; LR, low risk; MRI, magnetic resonance imaging; NCV, nerve conduction velocity HD MTX; ND, no data; NP, not performed; P (g/l), proteinorachia in g/l. Leukemia 243 Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 244 Table 5a Encephalopathy, durationo48 h (n ¼ 12)

Patient Phase HD Clinical IT nb delay IT P (g/l) CSF CT MRI Sequel MTX manifestations (dy) (n/mm3)

33 Consolidation 2 IR + Left facial palsy, left 6 7 0.1 F NP Normal F inferior limb monoplegia, left arm paresis 34 Consolidation 2 IR + Left facial palsy, left 8 10 0.2 2 Normal Right parietal ischemia F hemiplegia 35 Maintenance IR + Right facial palsy, left 13 13 0.65 4 Normal Left ischemia F hemiplegia 36 Consolidation 1 HR À Headache, aphasia, 4 2 1.51 1 NP NP F depression 37 Intensification 1 HR À Cerebellar dysfuction 8 1 0.68 0 Normal NP Ataxia 38 Consolidation 1 IR + Slurr speach, ataxia 3 9 0.2 1 NP NP F (left inferior limb) 39 Consolidation 2 IR + Left hemiplegia 8 6 0.1 F Normal Normal F 40 Consolidation 2 IR À Aphasia, monoplegia 5 9 0.81 4100 Normal Normal F 41 Consolidation 2 IR + monoplegia 6 10 1.04 6 Normal Leukoencephalopathy F 42 Intensification 1 HR À Slurr speach, Right 6 9 0.31 1 NP Asymetric lateral F facial palsy, right ventricular enlargement monoplegia Leukoencephalopathy 43 Consolidation 2 IR + Abnormal 6 12 ND ND NP Leukoencephalopathy F movements 44 Consolidation 2 LR + Left then right 6 9 ND ND NP NP F hemiplegia Abbreviations: CNS, central nervous system, CSF, cerebrospinal fluid; CT, computed tomography; delay IT (dy), day number between last IT and seizure; EMG, electromyography; HD MTX, high-dose methotrexate; HR, high risk; IR, intermediate risk; IT, intrathecal chemotherapy; IT nb, IT number before seizure; LR, low risk; MRI, magnetic resonance imaging; NCV, nerve conduction velocity HD MTX; ND, no data; NP, not performed; P (g/l), proteinorachia in g/l.

Table 5b Encephalopathy, duration 448 h (n ¼ 8)

Patient Phase MTX Clinical IT nb delay IT P (g/l) CSF CT MRI Sequel HD manifestations (dy) (n/mm3)

45 Consolidation 2 IR + Change of mental 6 9 ND ND NP Leukoencephalopathy Left arm status hemiparesia deficit 46 Consolidation 2 HR À Aphasia, left facial 7 10 NP NP Normal Leukoencephalopathy Right palsy right Inferior hemiplegia limb deficit, 47 Consolidation 2 HR À Aphasia, diplegia, 7 8 0.23 2 Normal Leukoencephalopathy Right arm spasmodic laughing deficit and crying, right arm deficit 48 Consolidation 1 IR À Spasmodic laughing 3 15 0.3 0 Normal Leucoence´ phalopathie Right and crying, right hemiplegia hemiparesis, 49 Consolidation 2 LR + Choreoathetoid 6 7 0.2 0 NP Leukoencephalopathy F movements Haemorrhage 50 Consolidation 2 IR À Mental status 7 10 0.22 1 Normal Normal F change 51 Intensification 2 IR + Lethargy, confusion 14 7 0.43 22 NP Leukoencephalopathy Motor performance decreased 52 Consolidation 2 HR + Ataxia, slurr speach, 6 9 0.87 2 Normal Leukoencephalopathy Ataxia right inferior limb Haemorrhage paresis, right arm deficit Abbreviations: CNS, central nervous system, CSF, cerebrospinal fluid; CT, computed tomography; delay IT (dy), day number between last IT and seizure; EMG, electromyography; HD MTX, high-dose methotrexate; HR, high risk; IR, intermediate risk; IT, intrathecal chemotherapy; IT nb, IT number before seizure; LR, low risk; MRI, magnetic resonance imaging; NCV, nerve conduction velocity HD MTX; ND, no data; NP, not performed; P (g/l), proteinorachia in g/l.

Leukemia Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 245 Table 6 Risk factor analysis for neurotoxicity in patients treated in Table 7 Risk factor analysis for seizures FRALLE 93 protocol Group without Group with P-value Group without Group with P-value neurotoxicity seizures neurotoxicity neurotoxicity (n ¼ 1343) (n ¼ 15) (n ¼ 1343) (n ¼ 52) Male 749 8 0.85 Male 749 29 1.00 Age410 years 307 7 0.03 Age410 years 307 19 0.01 Initial meningeal 39 2 0.07 B-cell 1147 48 0.16 involvement CNS involvement 39 3 0.23 HD MTX LR group 77 0 LR group 179 3 0.11 HD MTX IR group 301 2 0.13 IR group 640 32 0.05 Relapse 289 2 0.44 HR group 524 17 0.36 Menigeal relapse 33 0 0.61 HD MTX LR 77 3 0.08 group Abbreviations: HD MTX, high-dose methotrexate; IR, intermediate risk; HD MTX IR group 301 15 0.55 LR, low risk. Relapse 289 11 0.24 CNS relapse 33 2 0.49 Abbreviations: CNS, central nervous system; HD MTX, high-dose methotrexate; IR, intermediate risk; HR, high risk; LR, low risk. Table 8 Risk factor analysis for spinal toxicity

Group without Group with P-value neurotoxicity spinal toxicity aphasia, hemiplegia, VI, VII, III paralysis, spasmodic laughing (n ¼ 1343) (n ¼ 17) and crying, ataxia and coma. The symptoms resolved within Male 749 8 0.47 48 h in 12/20 children (1/2–48 h). Sixteen cases occurred during Age410 years 307 3 0.61 consolidation, three during intensification and one during Initial meningeal 39 0 0.48 maintenance therapy with median TIT number of 6 (3–14) and involvement median of 9 days after the last IT injection (1–15). Imaging HD MTX LR group 77 1 0.31 HD MTX IR group 301 3 0.06 studies were abnormal in 12/17 documented cases, showing Relapse 289 3 0.69 mainly signs of leukoencephalopathy (10 cases) associated with CNS relapse 33 1 0.24 ischemia features in three cases, hemorrhage in two cases and thrombosis in one case. Four had both normal CT and MRI, one Abbreviations: CNS, central nervous system; HD MTX, high-dose methotrexate; IR, intermediate risk; LR, low risk. had normal CT but no MRI performed and three had no imaging studies. A clotting disorder (factor V Leiden heterozygote) was found in patient 35. Finally, interferon was detected in the CSF of 1/1 patient (patient 39). Seven/out of 20 children (33%) have Table 9 Risk factor analysis for encephalopathy a neurological deficit and require rehabilitation. We found no predictors of neurological recovery except initial duration Group without Group with P-value symptoms (oor 448 h). neurotoxicity encephalopathy Treatment was modified in 12/20 cases: cessation of TIT (n ¼ 1343) (n ¼ 20) (n ¼ 4), IT without MTX (n ¼ 2), IT without Cyt (n ¼ 1), HD MTX Male 749 13 0.41 or asparaginase withdrawal (n ¼ 4) and vincristine dose reduc- Age410 years 307 9 0.02 tion (n ¼ 1). HD MTX and TIT were replaced by 18 Gy CNS Initial meningeal 39 1 0.58 radiotherapy (n ¼ 1). involvement HD MTX LR group 77 2 0.15 HD MTX IR group 301 10 0.03 Relapse 289 6 0.36 Statistical analysis CNS relapse 33 2 0.10 Analysis of risk factors for neurological complications during treatment are summarized in Tables 6–9. Abbreviations: CNS, central nervous system; HD MTX, high-dose Comparing the neurological complications group to the methotrexate; IR, intermediate risk; LR, low risk. whole population of patients, age 410 years is associated with higher risk of neurotoxicity (P ¼ 0.01). When comparing each subgroup to the whole population of patients without neuro- Discussion toxicity, age 410 years is either associated with higher risk of neurotoxicity in encephalopathy (P ¼ 0.02) and seizures The global incidence of neurological complications of leukemia (P ¼ 0.03) subgroups but not in the spinal subgroup (P ¼ 0.61). therapy in children is difficult to appreciate owing to the small We found no association with leukemia type or initial CNS number of published series and their heterogeneity.21–30 More- leukemia (P ¼ 0.07), although a very small number of patients over, under description owing to insufficient means for presented seizure and CNS leukemia. monitoring is possible. When limited to grade 3–4 episodes, When-focusing on methotrexate in subsequent neurotoxicity, the neurological complications incidence in our series is 3.7%. HD MTX is highly significantly correlated to encephalopathy In the largest series reported to date, Mahoney et al.27 found (P ¼ 0.03). an overall incidence of 7.8% (95/1218) in low-risk ALL, seizures Event-free survival (EFS) and overall survival (OS) in representing 78/95 events. The authors attributed this acute subgroups with or without neurological complications are toxicity to HD MTX combined with IT MTX with non adapted without any significance (P ¼ 0.15 and P ¼ 0.36 respectively). folinic acid rescue (25 vs 69 mg/m2 in previous studies).

Leukemia Acute neurotoxicity in acute lymphoblastic leukemia MN Dufourg et al 246 Lo Nigro reported an incidence of 10/122 (8.2%) in inter- children with ALL.45 The frequency of this complication is mediate-risk ALL, with seizures (6/10), encephalopathy with probably underestimated as brain CT can initially be normal and coma (1/10), ataxia (1/10) and flaccid paraplegia (2/10) in vascular MRI not always performed.46,47 As vascular MRI allows children treated with HD MTX (2 or 5 g/m2) plus TIT.30 The better definition of cerebral tissues such exam has to be highest incidence (19% of 138 patients) was reported by Winick recommended. Thrombosis are currently under review in the et al.,23 with seizures (17/25), followed by transient hemiparesis FRALLE protocols. (6/25) and episodes of disorientation and irritability (2/25). Most In conclusion, we found a significant link between encepha- incidents occurred 10 days after concurrent systemic and lopathy and HD MTX in the FRALLE 93 protocol. Although intrathecal Cyt administration. IT Cyt was subsequently evaluation has been retrospective and therefore lead to some removed, but the incidence of neurotoxicity only fell when interpretation bias, this raises the question of how to identify rescue therapy was introduced. The authors concluded that patients at risk of such neurotoxicity. The only prognostic factor folinic acid probably modulated MTX toxicity and interactions identified here was age which was significantly higher in with other drugs such as Cyt. patients with neurological complications. Further studies are In our study, HD MTX administration was associated with a necessary to evaluate the predictive value of biological assays significant risk of encephalopathy (P ¼ 0,03). Pathogenesis of for neurological events linked to MTX. neurotoxicity related to methotrexate remains unclear.31–33 It Rare but severe peripheral and spinal neuropathies apparently has been suggested that MTX induces hyperhomocysteinemia, a related to intrathecal injections raise the question of TIT risk factor for vascular disease and thrombosis. Focal deficit, indications. microangiopathy and white matter lesions observed with MTX Isolated seizures are not accompanied by particular sequel argue for vascular pathogenesis. Moreover, CSF and plasma and do not justify long-term anticonvulsant therapy. They can, homocysteine concentration were found significantly greater in however, reveal cerebral thrombosis. And finally, the onset of patients with neurotoxicity after HD MTX treatment.34 But no severe neurological toxicity during treatment of childhood ALL significant differences in plasma or CSF homocysteine levels did not significantly compromise OS or EFS in our study. were found based on the five, 10-methylenetetrahydrofolate Detailed monitoring and report of neurological toxicity in reductase genotypes.35 In the Rubnitz et al.28 study, 8/259 further trials is essential. patients experienced methotrexate-induced transient encephalopathy (o3 days) with normal MRI in 7/8 cases and leukoencephalopathy in 1/8 case. Interestingly, age greater than Acknowledgements equal to 10 years at diagnosis was associated with the development of transient encephalopathy. We acknowledge David Young for editing. Preliminary report There is no consensus on the management of neurotoxicity in of the study has been reported at the annual meeting of the this setting. If symptoms persist, it seems unreasonable to American Society of Hematology (ASH) in 1999 (Blood 1999, continue HD MTX. In contrast, transient acute encephalopathy 94(10) (Suppl 1) 1285). does not seem to contraindicate MTX resumption.28,36 The incidence of spinal and peripheral neurotoxicity in our study was 1.2%, a figure compatible with the literature. In this References group the number median of IT injections was 10, compared to six in patients with encephalopathy and three in patients with 1 Balsom WR, Bleyer WA, Robison LL, Heyn RM, Meadows AT, seizures, pointing to the possible role of cumulative toxicity. The Sitarz A et al. Intellectual function in long-term survivors of prognosis was poor, 66% have severe functional sequels. The childhood acute lymphoblastic leukemia: protective effect of pre- gravity of the initial paresis and a lack of recovery during first irradiation methotrexate? A Childrens Cancer Study Group study. three months have previously been linked to a bad prognosis.37 Med Pediatr Oncol 1991; 19: 486–492. The mortality rate was lower than in the literature.38 Five 2 Bleyer WA. Central nervous system leukemia. Pediatr Clin North children had symptoms of polyradiculoneuritis. The mechanism Am 1988; 35: 789–814. 3 Pui CH. Acute leukemia in children. Curr Opin Hematol 1996; 3: is probably different, and the prognosis is better. Cyt is possibly 249–258. involved in spinal toxicity, although few relevant complications 4 Lauer SJ, Kirchner PA, Camitta BM. Identification of leukemic cells have been reported. In 1992, Resar14 report a case of in the cerebrospinal fluid from children with acute lymphoblastic myelopathy and a case of encephalopathy after IT Cyt (50 mg/m2 leukemia: advances and dilemmas. Am J Pediatr Hematol Oncol on three consecutive days). Furthermore, the review of 12 1989; 11: 64–73. other cases of the literature does not allow firm conclusions 5 Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. (Children’s Cancer concerning cumulative compared with a dose-toxic threshold Study Group A). Cancer 1970; 26: 404–409. 39 40 with Cyt. In the study by Watterson et al., on 23 patients 6 George SL, Ochs JJ, Mauer AM, Simone JV. The importance of an with hematologic malignancies (n ¼ 17), or solid tumors (n ¼ 6) isolated central nervous system relapse in children with acute receiving an intensive CNS prophylactic (13 had CNS involve- lymphoblastic leukemia. J Clin Oncol 1985; 3: 776–781. ment), three received only Cyt IT before developing myelopathy. 7 Unal S, Yetgin S, Cetin M, Gumruk F, Arslan D, Ozyurek E et al. 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A pilot study of intermediate-dose methotrexate 43,44 administration of Asparaginase. In the literature, sinovenous and cytosine arabinoside, ‘spread-out’ or ‘up-front, ‘ in continua- thrombosis prevalence of 0, 47% was found in a group of 2318 tion therapy for childhood non-T, non-B acute lymphoblastic

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