Letters to the Editor 2256 REFERENCES 7 Helbig G, Moskwa A, Hus M, Piszcz J, Swiderska A, Urbanowicz A et al. Durable 1 Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ et al. remission after treatment with very low doses of imatinib for FIP1L1-PDGFRalpha- Response to imatinib mesylate in patients with chronic myeloproliferative positive chronic eosinophilic leukaemia. Cancer Chemother Pharmacol 2011; 67: diseases with rearrangements of the platelet-derived growth factor beta. 967–969. N Engl J Med 2002; 347: 481–487. 8 Metzgeroth G, Walz C, Erben P, Popp H, Schmitt-Graeff A, Haferlach C et al. Safety 2 Bain BJ. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic PDGFRA, PDGFRB or FGFR1. Haematologica 2010; 95: 696–698. syndrome: a phase-II study. Br J Haematol 2008; 143: 707–715. 3 Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. A tyrosine 9 Pardanani A, D’Souza A, Knudson RA, Hanson CA, Ketterling RP, Tefferi A. Long- kinase created by fusion of the PDGFRA and FIP1L1 as a therapeutic target term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348: and clinical outcome. 2012; 26: 2439–2441. 1201–1214. 10 Erben P, Gosenca D, Mu¨ller MC, Reinhard J, Score J, Del Valle F et al. Screening for 4 Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S et al. The efficacy diverse PDGFRA or PDGFRB fusion genes is facilitated by generic quantitative of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hyper- reverse transcriptase polymerase chain reaction analysis. Haematologica 2010; 95: eosinophilic syndrome. Results of a multicenter prospective study. Haematologica 738–744. 2007; 92: 1173–1179. 11 Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C et al. 5 David M, Cross NC, Burgstaller S, Chase A, Curtis C, Dang R et al. Durable Recurrent finding of the FIP1L1-PDGFRA fusion in eosinophilia-associated responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL- and lymphoblastic T-cell lymphoma. Leukemia 2007; 21: negative chronic myeloproliferative disorders. Blood 2007; 109: 61–64. 1183–1188. 6 Gotlib J, Cools J. Five years since the discovery of FIP1L1-PDGFRA: what we have 12 Cross NC, Reiter A. Fibroblast growth factor receptor and platelet-derived growth learned about the fusion and other molecularly defined eosinophilias. Leukemia factor receptor abnormalities in eosinophilic myeloproliferative disorders. 2008; 22: 1999–2010. Acta Haematol 2008; 119: 199–206.

Long-term follow-up of ETV6–RUNX1 ALL reveals that NCI risk, rather than secondary genetic abnormalities, is the key risk factor

Leukemia (2013) 27, 2256–2259; doi:10.1038/leu.2013.136 two delayed intensification blocks and continuing therapy for a total of 2 (girls) or 3 (boys) years. ETV6–RUNX1 was determined by fluorescent in situ hybridization (FISH) using the TEL-AML1 ES probe (Abbott Diagnostics, Maiden- 9 The ETV6–RUNX1 fusion gene is present in 25% of children head, UK) or by reverse -PCR. Secondary abnormalities diagnosed with B-cell precursor acute lymphoblastic leukaemia affecting ETV6 or RUNX1 were determined in a representative cohort (BCP-ALL) and is associated with an excellent outcome.1 of 247 (67%) patients (Table 1) by FISH using two dual-colour break- Although ETV6–RUNX1-positive patients have a low relapse apart probes: ETV6 (Dako Ltd, Ely, UK) and home-grown RUNX1 9 rate and good outcome after relapse,2 averting relapse in (RP11-272A03/RP11-396G11, Sanger Institute, UK). Deletions of this prevalent subgroup warrants investigation. Previous IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1 and RB1 and the P2RY8– studies investigating risk factors in this subgroup have produced CRLF2 fusion were determined by multiplex ligation-dependent inconsistent results and have been hampered by small probe amplification (MLPA) in a representative cohort of 114 (31%) patient cohorts and/or treatment heterogeneity.3–6 ETV6–RUNX1 patients (Table 1) using the SALSA P335 kit (MRC Holland, alone is insufficient to cause overt leukaemia and numerous Amsterdam, The Netherlands).9 Event-free survival (EFS) and cooperating have been described.7 Therefore, we overall survival (OS) were calculated from the start of treatment to sought to assess the prognostic relevance of secondary relapse/death and death, respectively. Patients without an event of abnormalities targeting the ETV6 and RUNX1 genes as well as interest were censored at the date of last contact. Survival estimates other abnormalities (for example, IKZF1 ) in a large cohort were calculated using the Kaplan–Meier method and compared of patients. using Cox proportional hazard regression models, which conformed A total of 368 children with ETV6–RUNX1 BCP-ALL were treated to the proportional hazards assumption. on MRC ALL97/99.8 Both phases, ALL97 and ALL99, included a The clinical features and outcome of ETV6–RUNX1 patients by steroid and thiopurine randomization in induction and age group, WCC group, phase of trial, NCI risk group and key maintenance. In ALL97, patients received a 3-drug induction, 2/3 secondary abnormalities are detailed in Table 1. The majority of intensification blocks, central nervous system-directed treatment ETV6–RUNX1 patients were NCI-SR and the proportion did not and continuing therapy for a total of 2 years. High-risk patients, vary between ALL97 and ALL99: 135/175 (77%) versus 148/193 identified by the Oxford Hazard Score or cytogenetics, were (77%), respectively. After a median follow-up time of 9.2 years, transferred to a more intensive protocol. In ALL99, children were 47 (13%) relapses, 54 (15%) events and 20 (5%) deaths had been stratified according to National Cancer Institute (NCI) risk to recorded (Table 1). Only two patients failed to achieve a regimen A (standard risk (SR); o10 years and white cell count complete remission (CR), both of whom died within a month. (WCC) o50 Â 109 /L) or regimen B (high risk (HR); others). Patients Among the ALL99 cohort, nine (5%) patients were SER; two died received a 3/4-drug induction (regimen A/B) and were deemed to in remission, two relapsed and five achieved sustained CR. be slow early responders (SERs) if the day 15/8 marrow contained In agreement with previous observations,10–12 the temporal X25% blasts. Patients who were SERs or had high-risk pattern of relapses was later than observed for other subtypes of cytogenetics were transferred to regimen C. After induction, ALL and 490% occurred after the end of treatment (EOT): 3 (6%) patients received consolidation, two interim maintenance blocks, very early (o18 months after diagnosis), 4 (9%) early (418 months

Accepted article preview online 2 May 2013; advance online publication, 21 May 2013

Leukemia (2013) 2242 – 2267 & 2013 Macmillan Publishers Limited Letters to the Editor 2257 Table 1. Frequency and outcome of children with ETV6–RUNX1 B-cell precursor acute lymphoblastic leukaemia by NCI risk status and the presence of selected secondary genetic abnormalities

No. of Median Median WCC, No. of EFS at 8 Hazard ratio (95% CI) No. of OS at 8 Hazard ratio patients, age, years  109 /L events, years, % deaths years, % (95% CI) n (%) (range) (range) n (%) (95% CI) (%) (95% CI)

Total 368 4.2 (1.2–15.5) 10.7 (0.8–355.0) 54 (15) 85 (81–88) — 20 (5) 95 (92–96)

Age 1–9 years 350 (95) 4.0 (1.2–9.9) 11.5 (0.8–355.0) 49 (14) 85 (81–88) 2.39 (0.95–6.01) P ¼ 0.06 17 (5) 95 (92–96) 3.86 (1.13–13.19) P ¼ 0.03 10–18 years 18 (5) 11.3 (10.1–15.5) 4.5 (1.9–39.7) 5 (28) 72 (45–87) 3 (17) 83 (56–94)

White cell count o50 Â 109 /L 301 (82) 4.4 (1.5–15.5) 8.4 (0.8–49.4) 38(13) 86 (82–90) 2.11 (1.18–3.80) P ¼ 0.01 11(4) 96 (93–97) 3.89 (1.61–9.39) Po0.01 450 Â 109 /L 67 (18) 3.4 (1.3–9.6) 94 (50.4–355) 16(24) 76 (64–84) 9(13) 86 (75–92)

Phase of trial ALL97 175 (48) 4.3 (1.3–12.3) 10.7 (0.9–197.1) 33 (19) 81 (74–86) 0.58 (0.33–1.00) P ¼ 0.053 10 (6) 94 (90–97) 0.92 (0.38–2.20) P ¼ 0.843 ALL99 193 (52) 4.0 (1.5–15.5) 10.7 (0.9–355.0) 21 (11) 89 (83–93) [0.58 (0.33–1.00) P ¼ 0.05] 10 (5) 95 (90–97) [0.91 (0.38–2.19) P ¼ 0.84]

NCI risk group Standard 283 (77) 4.2 (1.5–9.9) 8.6 (0.8–49.4) 33 (12) 88 (83–91) 2.45 (1.41–4.22) Po0.01 8 (3) 97 (94–99) 5.40 (2.21–13.22) Po0.01 High 85 (23) 3.9 (1.3–15.5) 82.3 (1.9–355.0) 21 (25) 75 (65–83) [2.44 (1.41–4.23) Po0.01]3 12 (14) 86 (76–92) [5.40 (2.21–13.22) Po0.01]3

Secondary abnormalities FISH tested1 247 4.0 (1.3–15.5) 11.8 (1.7–203.0) 42 (17) 82 (77–87) 16 (6) 94 (90–96) ETV6 deletion 164 (67) 3.9 (1.5–15.5) 11.6 (2.0–200.0) 30 (18) 81 (74–87) 1.24 (0.64–2.43) P ¼ 0.52 10 (6) 94 (89–97) 0.82 (0.30–2.25) P ¼ 0.70 þ der(21) 38 (16) 4.4 (1.9–15.5) 8.3 (2.8–104.0) 9 (24) 75 (57–86) 1.47 (0.70–3.07) P ¼ 0.31 2 (5) 95 (80–99) 0.76 (0.17–3.38) P ¼ 0.73 t(12;21) þ 21 57 (23) 4.4 (1.3–15.5) 7.6 (2.2–184.0) 8 (14) 85 (73–92) 0.74 (0.34–1.61) P ¼ 0.45 3 (5) 95 (85–98) 0.76 (0.22–2.67) P ¼ 0.67

MLPA tested2 114 4.5 (1.3–11.7) 13.3 (0.8–197.1) 19 (17) 83 (75–89) 6 (5) 95 (89–98) CDKN2A/B 26 (23) 5.1 (2.5–10.7) 12.3 (0.8–173.0) 7 (27) 73 (52–86) 2.14 (0.84–5.43) P ¼ 0.11 1 (4) 96 (76–99) 0.65 (0.08–5.63) P ¼ 0.70 deletion PAX5 deletion 31 (27) 4.2 (1.8–10.7) 12.0 (2.4–197.1) 3 (10) 90 (73–96) 0.47 (0.14–1.61) P ¼ 0.23 1 (3) 97 (79–99) 0.53 (0.06–4.52) P ¼ 0.56 BTG1 deletion 24 (21) 4.1 (2.6–9.2) 15.4 (2.4–197.1) 3 (12) 88 (66–96) 0.68 (0.20–2.36) P ¼ 0.55 0 (0) 100 (–) NA Abbreviations: CI, confidence interval; EFS, event-free survival; FISH, fluorescent in situ hybridization; MLPA, multiplex ligation-dependent probe amplification; NA,notapplicable;NCI,NationalCancerInstitute;OS,overallsurvival;WCC, white cell count. Notes: (1) A total of 247/368 (67%) patients were screened by FISH for secondary abnormalities affecting ETV6 and RUNX1. The tested cohort was representative with respect to sex, age and survival. However, tested patients were more likely to have a WCC 450 Â 109/l (22 vs 10%, Po0.01) and a greater portion of ALL99 patients were tested compared with ALL97 patients (70 vs 53%, Po0.01). A total of five FISH tests failed: ETV6 (n ¼ 2) and RUNX1 (n ¼ 3) probe; (2) A total of 114/368 (31%) patients were screened for gene micro-deletions by MLPA. The tested cohort was representative with respect to sex, age, WCC, phase of trial and survival. The copy number for PAX5 and BTG1 could not be called one case each; (3) hazard ratio from a multivariate model that included two variables, one for phase of trial and one for NCI risk group.

from diagnosis and o6 months after EOT) and 40 (85%) late not directly comparable with our cohort who were treated relapses (46 months after EOT). However, in contrast to the between 1997 and 2001. Nordic Society of Paediatric Hematology and Oncology study,10 FISH and MLPA analyses of ETV6–RUNX1 patients revealed which had a higher overall relapse rate, we observed a plateau significant genetic heterogeneity, with 480% patients harbouring at 8 years with no relapses among 229 patients followed up for X1 of the tested abnormalities. Deletion of the non-rearranged 48 years. ETV6 allele was the most prevalent secondary abnormality and NCI-HR patients had significantly greater risk of suffering an was detected with equal frequency by FISH (164/245 (67%)) and event and death compared to NCI-SR patients. Patients treated on MLPA (68/105 (65%)). Gain of the normal or derived ALL99 suffered fewer relapses compared with ALL97, which 21 [der(21)t(12;21)] and deletions of CDKN2A/B, PAX5 and BTG1 resulted in a borderline improved EFS but not OS. NCI-SR patients were detected in 16–27% cases. Deletions of RB1, IKZF1 and EBF1 showed a significant improvement in EFS at 8 years in ALL99 were rarer occurring in nine (8%), six (5%) and five (4%) patients, compared with ALL97: 92% (95% confidence interval (CI) 86–96) respectively. Only a single case harboured a P2RY8–CRLF2 fusion. versus 84% (76–89), hazard ratio 0.46 (95% CI 0.22–0.94), None of the secondary abnormalities were associated with a P ¼ 0.033. However, the benefit for the much smaller group of distinctive patient profile with respect to sex, age, WCC or NCI risk NCI-HR patients was more marginal: 78% (62–87) versus 73% group. Moreover, there was no evidence of outcome hetero- (56–84), 0.81 (0.34–0.1.9), P ¼ 0.625. The difference in OS between geneity according to the presence of any of the secondary NCI-HR and NCI-SR was similar in both the ALL97 and ALL99 abnormalities investigated whether comparing patients with and phases: 85% (69–92) versus 97% (92–98), 5.45 (1.53–19.33), without the abnormality in question or using the size of the Po0.01 and 86% (72–93) versus 97% (92–98), 5.31 (1.50–18.85), subclone to investigate a trend effect (Table 1). Although our P ¼ 0.01, respectively. Multivariate analysis confirmed that the results contradict several studies that have reported an associa- adverse effect of NCI high-risk status was independent of trial tion,3–5 it is consistent with the largest and most recent study from phase and the adjusted HRs were not different (Table 1, Figure 1). Nordic Society of Paediatric Hematology and Oncology.6 Therefore, Our results demonstrate the importance of NCI status in ETV6– while these abnormalities may have had genuine prognostic RUNX1 patients. The observation that NCI and ETV6–RUNX1 status relevance on older protocols, there is no evidence that they need were independent risk factors is in agreement with other clinical to be considered on future protocols. We are not aware of any study groups,11,13 although in contrast with St Jude Children’s studies that have examined the prognostic effect of IKZF1, CDKN2A/ Research Hospital (SJCRH) who observed no effect of NCI risk B, PAX5, EBF1, BTG1 and RB1 deletions, specifically within an group among 168 ETV6–RUNX1 patients.12 However, as 450% of ETV6–RUNX1-positive cohort. Even though B25% patients their patients were treated on Total XV, which had significantly harboured a deletion of CDKN2A/B, PAX5 or BTG1, none impacted superior results and ran between 2000 and 2007, their results are significantly on outcome. The EFS for CDKN2A/B-deleted patients

& 2013 Macmillan Publishers Limited Leukemia (2013) 2242 – 2267 Letters to the Editor 2258 1.00 CONFLICT OF INTEREST The authors declare no conflict of interest.

0.75 ACKNOWLEDGEMENTS

ALL97 NCI-SR (n=135) We thank (1) Leukaemia and Lymphoma Research (formerly Leukaemia Research, UK) ALL97 NCI-HR (n=40) for financial support; (2) member laboratories of the UK Cancer Cytogenetic Group for 0.50 ALL99 NCI-SR (n=148) providing cytogenetic data and material; (3) past and present members of the ALL99 NCI HR (n=45) Leukaemia Research Cytogenetics Group for their contribution in establishing this data set; in particular, Halima Al-Shehhi, Kerry E Barber, Lucy Chilton, Amy Erhorn, Lisa Event Free Survival 0.25 Jones, Heather Morrison and Sarah Wright. Primary childhood leukaemia samples used in this study were provided by the Leukaemia and Lymphoma Research Childhood Leukaemia Cell Bank working with the laboratory teams in the Bristol Genetics Laboratory, Southmead Hospital, Bristol; Molecular Biology Laboratory, 0.00 Royal Hospital for Sick Children, Glasgow; Molecular Haematology Laboratory, Royal London Hospital, London; and Molecular Genetics Service and Sheffield Children’s 0 1 2 3 4 5 6 7 8 9 10 Hospital, Sheffield. Years from diagnosis

1,7 1,7 1,7,8 2 1.00 A Enshaei , CJ Schwab , ZJ Konn , CD Mitchell , SE Kinsey3,4, R Wade5, A Vora6, CJ Harrison1 and AV Moorman1 1Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK; 0.75 2Department of Paediatric Oncology, John Radcliffe Hospital, Oxford, UK; ALL97 NCI-SR (n=135) 3Department of Paediatric Haematology and ALL97 NCI-HR (n=40) 0.50 ALL99 NCI-SR (n=148) Oncology, Leeds General Infirmary, Leeds, UK; 4 ALL99 NCI HR (n=45) Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK; 5

Overall Survival Clinical Trial Service Unit, University of Oxford, Oxford, UK and 6 0.25 Department of Haematology, Sheffield Children’s Hospital, Sheffield, UK E-mail: [email protected] 7These authors contributed equally to this work. 0.00 8Former group member. 0 1 2 3 4 5 6 7 8 9 10 Years from diagnosis Figure 1. Kaplan–Meier plots showing the effect of National Cancer REFERENCES Institute (NCI) risk status (standard risk (SR) and high risk (HR)) on the 1 Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE et al. event-free (a) and overall (b) survival of children with ETV6–RUNX1- Prognostic effect of chromosomal abnormalities in childhood B-cell precursor positive acute lymphoblastic leukaemia treated on the MRC ALL97/ acute lymphoblastic leukaemia: results from the UK Medical Research Council 99 trial. ALL97/99 randomised trial. Lancet Oncol 2010; 11: 429–438. 2 Krentz S, Hof J, Mendioroz A, Vaggopoulou R, Dorge P, Lottaz C et al. Prognostic value of genetic alterations in children with first bone marrow relapse of was low, but it should be noted that the result was based on only childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 2012; 27: seven events and did not translate to an inferior OS. As expected, 295–304. the incidence of IKZF1 deletions among ETV6–RUNX1 patients was 3 Stams WA, Beverloo HB, den Boer ML, de Menezes RX, Stigter RL, van DE et al. lower than among childhood ALL generally. Given the strong Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and association reported between IKZF1 deletions and poor prognosis, it COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome. Leukemia 2006; 20: 410–416. is noteworthy that all six IKZF1-deleted patients have remained in 4 Attarbaschi A, Mann G, Konig M, Dworzak MN, Trebo MM, Muhlegger N et al. first CR for 49.5 years. This observation supports previous data, Incidence and relevance of secondary chromosome abnormalities in childhood 14 indicating that the prognostic effect of IKZF1 deletions is pleiotropic. TEL/AML1 þ acute lymphoblastic leukemia: an interphase FISH analysis. Leukemia In conclusion, ETV6–RUNX1 ALL patients have an excellent 2004; 18: 1611–1616. outcome when treated with contemporary regimens irrespective 5 Ko DH, Jeon Y, Kang HJ, Park KD, Shin HY, Kim HK et al. Native ETV6 deletions of the presence of additional genetic abnormalities. However, the accompanied by ETV6-RUNX1 rearrangements are associated with a favourable adverse effects of NCI risk group based on age and WCC remain prognosis in childhood acute lymphoblastic leukaemia: a candidate for prog- pertinent. A limitation of this study was the lack of data on nostic marker. Br J Haematol 2011; 155: 530–533. (MRD), which was not measured in this 6 Barbany G, Andersen MK, Autio K, Borgstrom G, Franco LC, Golovleva I et al. Additional aberrations of the ETV6 and RUNX1 genes have no prognostic trial. MRD at various time points (for example, end of induction, impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic end of consolidation, etc) has been shown to be predictive of leukaemias treated according to the NOPHO-ALL-2000 protocol. Leuk Res 2012; outcome in ALL generally and among ETV6–RUNX1-positive 36: 936–938. 15 cases. However, the majority of ETV6–RUNX1 patients are MRD 7 Forestier E, Andersen MK, Autio K, Blennow E, Borgstrom G, Golovleva I et al. negative post induction, and the clinical utility of MRD is highly Cytogenetic patterns in ETV6/RUNX1-positive pediatric B-cell precursor acute protocol specific. Therefore, the prognostic impact of static risk lymphoblastic leukemia: A Nordic series of 245 cases and review of the literature. factors available at the time of diagnosis (for example, NCI risk Genes Cancer 2007; 46: 440–450. status) is still useful in the clinical setting. Even though this study 8 Mitchell C, Payne J, Wade R, Vora A, Kinsey S, Richards S et al. The impact of risk was large, the rarity of many secondary abnormalities restricted stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 our ability to adequately assess their impact and this was and ALL97/99. Br J Haematol 2009; 146: 424–436. compounded by a low relapse rate and the effect of NCI risk 9 Al-Shehhi H, Konn ZJ, Schwab CJ, Erhorn A, Barber KE, Wright SL et al. Abnorm- group. Therefore, it is unlikely that the genetic heterogeneity alities of the der(12)t(12;21) in ETV6-RUNX1 acute lymphoblastic leukemiaGenes existing within this subtype will yield clinically relevant risk factors. Chromosomes Cancer 2013; 52: 202–213.

Leukemia (2013) 2242 – 2267 & 2013 Macmillan Publishers Limited Letters to the Editor 2259 10 Forestier E, Heyman M, Andersen MK, Autio K, Blennow E, Borgstrom G et al. 13 Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A et al. Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival. Institute Consortium Protocol 95-01. Blood 2006; 107: 4508–4513. Br J Haematol 2008; 140: 665–672. 14 Waanders E, van der Velden VH, van der Schoot CE, van Leeuwen FN, 11 Rubnitz JE, Wichlan D, Devidas M, Shuster J, Linda SB, Kurtzberg J et al. van Reijmersdal SV, de Haas V et al. Integrated use of minimal residual disease Prospective analysis of TEL gene rearrangements in childhood acute lympho- classification and IKZF1 alteration status accurately predicts 79% of relapses in blastic leukemia: a Children’s Oncology Group study. J Clin Oncol 2008; 26: pediatric acute lymphoblastic leukemia. Leukemia 2011; 25: 254–258. 2186–2191. 15 Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL et al. 12 Bhojwani D, Pei D, Sandlund JT, Jeha S, Ribeiro RC, Rubnitz JE et al. ETV6-RUNX1- Clinical significance of minimal residual disease in childhood acute lymphoblastic positive childhood acute lymphoblastic leukemia: improved outcome with leukemia and its relationship to other prognostic factors: a Children’s Oncology contemporary therapy. Leukemia 2012; 26: 265–270. Group study. Blood 2008; 111: 5477–5485. Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count

Leukemia (2013) 27, 2259–2262; doi:10.1038/leu.2013.137 Ten patients (5%) died within the first month of treatment, of whom eight were older than one year at diagnosis and seven of these had T-ALL. Four patients died 13–27 days after admission because of neutropenic septic complications, whereas the Patients with white blood cell (WBC) count in peripheral blood remaining six patients died within 14 days from admission X200 Â 109/l at diagnosis of acute lymphoblastic leukemia (ALL) because of intracranial hemorrhage (N ¼ 5) or massive intracranial constitute 5–8% of all childhood ALL patients and are known to infiltrates with secondary brain edema and herniation (N ¼ 1). have significantly lower survival rates.1,2 Hyperleukocytosis at Coagulation disturbances were not demonstrated. Four of these 9 diagnosis of childhood ALL is an oncological emergency latter six patients had initial WBC of 577, 768, 825 and 925 Â 10 /l associated with early morbidity and mortality related both to and presented with severe central nervous system symptoms microcirculatory leukostasis and hyperviscosity and to severe already at admission. Whereas the last two patients developed metabolic and electrolyte derangements due to tumor lysis.3,4 such symptoms on the third day after the rise in WBC from 305 to 9 2 Since the introduction of urate oxidase, the risk of tumor lysis 625 Â 10 /l within 3 days on a prednisolone dose of 11.7 mg/m / 9 syndrome (TLS) has been markedly reduced.5–8 However, 24 h, or after a limited reduction in WBC from 395 to 291 Â 10 /l. clinicians may still reduce the dose of anticancer agents or delay Furthermore, in two of these six patients corticosteroids (CS) were 9 9 the antileukemic therapy to avoid TLS, but the impact of such not started (WBC 768 Â 10 /l) or were delayed (WBC 925 Â 10 /l) modifications on the risk of developing of early complications due to efforts to carry out leukapheresis. related to hyperleukocytosis and on survival is uncertain. In multivariate logistic regression analysis, only WBC (OR We performed a population-based multicenter study of 221 (95% CI): 1.004 (1.001–1.006), (P ¼ 0.007)) and the presence of children aged 0–14.9 years with ALL and WBC X200 Â 109/l at neurological symptoms at admission (OR (95% CI): 5.8 (1.3–25.2), diagnosis treated in Denmark, Finland, Iceland, Lithuania, Norway (P ¼ 0.018)) were independently and significantly associated with or Sweden from January 1992 to October 2011. This constituted risk of early death, whereas neither gender, age, immunopheno- 92% of all 241 ALL patients with WBC X200 Â 109/l during that type, leukemic karyotype and administration of antileukemic period, and 6% of all 3985 newly diagnosed ALL patients. therapy within 24 h after admission versus later, nor hemoglobin The diagnosis of ALL was based on histo-/cytomorphology, at admission or administration of packed red blood cell 9 immunophenotyping, karyotyping and molecular cytogenetics as transfusion when WBC was still X200 Â 10 /l were found to be previously reported.9 For two infants and four non-infants, of significance. immunophenotype was lacking or ambiguous. Informed consent Initial therapy was heterogeneous and center-dependent as to antileukemic treatment was obtained according to the there was no common Nordic/Baltic tumor burden reducing Declaration of Helsinki. The regional or national ethics strategy for patients with hyperleukocytosis (Figure 1 and committees approved the study. Supplementary Figure 2). The majority (85%) of the patients were 2 Data were retrieved from the Nordic Society for Paediatric initially hydrated with X3000 ml/m /24 h, and urine was alkali- Hematology and Oncology (NOPHO) leukemia registry and from nized and allopurinol given to 89% and 97%, respectively, of those patient files. Morbidity and mortality within a month after who did not receive urate oxidase. The urate oxidase was admission was registered and analyzed in detail. Of 12 patients administered from 1 to 10 (median: 5) days. It was initiated registered in the NOPHO leukemia registry with induction deaths, before or on the same day as the administration of any two occured 45 and 59 days after admission, and thus were not antileukemic treatment for 96% of the 71 patients who received included into the present study as early deaths. this treatment with available information on timing of the first Overall, the clinical presentation and the pattern of leukostasis dose. Administration of a CS prephase was optional for the seven or hyperviscosity associated complications were similar to those infants and 159 older patients who were enrolled in NOPHO ALL- previously reported4,10–12 (Table 1). In total, 40% (N ¼ 92) 92, ALL-2000 or ALL-2008 clinical trials, and was mandatory both experienced one or more complications associated with hyper- for 38 Nordic infants who were enrolled in the Interfant-99 or leukocytosis (Table 1 and Supplementary Figure 1). Their initial À 06 clinical trials, and for the 17 Lithuanian patients who were WBC was moderately higher than for patients without such treated according to BFM-based chemotherapy. Intrathecal MTX complications (median (75% range): 396 (245–794) Â 109/l vs 317 had to be initiated no later than on the first day of any other (219–603) Â 109/l, (P ¼ 0.001)). Thus, the absolute risk of antileukemic therapy (Supplementary Table 1). complications increased 1.5-fold with every WBC increase of Indications for exchange transfusion or leukapheresis were 100 Â 109/l. according to local guidelines, and were performed in 24 and 12

Accepted article preview online 2 May 2013; advance online publication, 21 May 2013

& 2013 Macmillan Publishers Limited Leukemia (2013) 2242 – 2267