RUNX1 ALL Reveals That NCI Risk, Rather Than Secondary Genetic Abnormalities, Is the Key Risk Factor
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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 receptor 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. 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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 transcription-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 mutations 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 deletion) 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  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  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  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.