Leukemia (2004) 18, 939–947 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $25.00 www.nature.com/leu Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: a report from the Children’s Cancer Group

NA Heerema1,10, JB Nachman2, HN Sather3,MKLa3, R Hutchinson4, BJ Lange5, B Bostrom6, PG Steinherz7, PS Gaynon8 and FM Uckun9

1The Ohio State University, Columbus, OH, USA; 2University of Chicago, Chicago, IL, USA; 3Children’s Cancer Group, Arcadia, CA, USA; 4University of Michigan, Ann Arbor, MI, USA; 5Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 6Children’s Hospitals and Clinics, Minneapolis, MN, USA; 7Sloan Kettering Cancer Center, New York, NY, USA; 8University of California, Los Angles, CA, USA; and 9CCG ALL Biology Reference Laboratory, Hughes Institute, St Paul, MN, USA

Monosomy 7 or deletions of 7q are associated with many with an array of genetic disorders including Fanconi anemia, myeloid disorders; however, the significance of such abnorm- neurofibromatosis type 1, severe congenital neutropenia, and alities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses Schwachman–Diamond syndrome. involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) Chromosome 7 deletions and monosomy 7 have also been with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), reported in adult acute lymphoblastic leukemia (ALL), in which and two (3%) with losses involving both arms. Patients with they frequently occur as secondary aberrations associated with a losses involving chromosome 7 were more likely to be X10 Philadelphia (Ph) chromosome and predict a poor prognosis.11 years old, National Cancer Institute (NCI) poor risk, and However, losses of chromosome 7 are not predictive of a worse hypodiploid than patients lacking this abnormality. Patients prognosis when Ph-positive patients are excluded from the with or without these abnormalities had similar early response 11 to induction therapy. Event-free survival (EFS) and survival for analyses. Although generally infrequent in childhood ALL, patients with monosomy 7 (Po0.0001 and P ¼ 0.0007, respec- monosomy 7 or structural abnormalities resulting in the deletion tively) or del(7p) (Po0.0001 and P ¼ 0.0001, respectively), but of 7p have been reported to confer increased risk of treatment not of patients with del(7q), were significantly worse than those failure in Ph-positive cases, and it has been hypothesized that a of patients lacking these abnormalities. The poorer EFS was TSG on 7p may contribute to the poor outcome of these maintained after adjustment for a Philadelphia (Ph) chromo- 12 some, NCI risk status, ploidy, or an abnormal 9p. However, the patients. The significance of chromosome 7 losses, including impact on survival was not maintained for monosomy 7 after monosomy 7, deletions of 7p, and deletions of 7q, in the overall adjustment for a Ph. These results indicate that the critical population of children with ALL is unknown. Therefore, we have region of loss of chromosome 7 in pediatric ALL may be on the analyzed a large cohort of 1880 children with ALL treated on p-arm. recent risk-adjusted trials of the Children’s Cancer Group (CCG) Leukemia (2004) 18, 939–947. doi:10.1038/sj.leu.2403327 for losses of all or part of chromosome 7. Published online 4 March 2004 Keywords: childhood acute lymphoblastic leukemia; chromosome 7; prognosis; monosomy 7; deletion 7p Materials and methods

Patients

Introduction Diagnosis of ALL required determination of lymphoblastic morphology by Wright–Giemsa staining of bone marrow smears, Complete or partial loss of chromosome 7, predominantly negative lymphoblast staining for myeloperoxidase, and cell monosomy 7 or deletions of 7q, is associated with a variety of surface expression of two or more lymphoid differentiation myeloid disorders, including cases of preleukemic myelodys- antigens.13 Immunophenotyping was performed centrally in the plastic syndrome (MDS) and acute myelogenous leukemia CCG ALL Biology Reference Laboratory by immunofluorescence (AML) in children1 and de novo and therapy-related MDS and and flow cytometry, as described previously.13,14 Patients were AML in adults.2 Monosomy 7 or deletion of 7q in these disorders classified as B-lineage if X30% of their leukemic cells were is associated with poor prognosis.3–6 It has been hypothesized positive for CD19 and/or CD24 and o30% were positive for one that there is a tumor suppressor gene (TSG) on chromosome arm or more of the T-cell-associated antigens CD2, CD3, CD5, or 7q that contributes to the pathogenesis of these diseases, and CD7. Likewise, patients were classified as having T-lineage ALL several chromosomal bands have been identified that contain if X30% of the isolated blasts were positive for one or more of commonly deleted segments, including 7q22 and different the T-cell-associated antigens CD2, CD3, CD5, or CD7 and nonoverlapping regions in 7q31–q35.7–10 However, a putative o30% were positive for CD19 and/or CD24. TSG has not yet been identified on 7q. Childhood monosomy 7, The current study involved 4986 children entered in CCG or ‘monosomy 7 syndrome’, is a unique disorder that frequently risk-adjusted ALL protocols between 1988 and 1995. Children progresses to AML, with poor outcome.1 It may be associated aged 2–9 years with white blood cell (WBC) counts o10 000/ml were treated on CCG-1881 for low-risk patients,15 and children Correspondence: Dr NA Heerema, c/o Children’s Oncology Group, aged 2–9 years with WBC counts 10 000–49 999/ml or aged 12– Attention Shaun Mason, PO Box 60012, Arcadia, CA 91066-6012, 24 months and WBC counts o50 000/ml were enrolled on CCG- USA; Fax: þ 1 651 628 9891; E-mail: [email protected] 16 10 1891 for intermediate-risk patients. After completion of these Supported in part by research grants, including CCG Chairman’s studies, children with low- or intermediate-risk ALL were Grant No. CA-13539 and CA-60437, from the National Cancer 17 X Institute, National Institutes of Health enrolled on CCG-1922. High-risk patients (age 10 years Received 14 May 2003; accepted 26 January 2004; Published online and/or with WBC counts X50 000/ml) were treated on CCG- 4 March 2004 188218,19 or CCG-1901, for patients with multiple unfavorable Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 940 features (lymphomatous syndrome).20 Infants aged o1 year after review. Full karyotypes of children with ALL and losses were excluded from this analysis. All protocols were approved involving chromosome 7 are given in Table 1, and the losses are by the National Cancer Institute (NCI) and the institutional shown graphically in Figure 1. More than half (N ¼ 59; 79%) of review boards of the participating CCG-affiliated institutions. these patients had loss of the p-arm of chromosome 7, including Informed consent was obtained from parents, patients, or both, 16 with monosomy 7, 41 with structural rearrangements in accordance with the Declaration of Helsinki. resulting in deletions of 7p, and two with losses of both 7p and 7q. (Note: Losses of 7p that extended into 7q11.2 were Cytogenetic analysis considered as 7p losses.) In all, 12 cases with loss of 7p had an i(7)(q10), and five had –7,der(v)t(v;7)(v;q11.2), where ‘v’ is any Cytogenetic analyses were performed at diagnosis by institu- chromosome. Although no consistent region of loss was tional laboratories. A minimum of two original karyotypes from identified, most 7p losses included p15–pter (Figure 1). Losses each abnormal clone were reviewed centrally by at least two involving the q-arm of chromosome 7 occurred in 34 cases members of the CCG Cytogenetics Committee. Abnormalities (45%) including 16 with monosomy 7 and two with losses of were designated using the International System for Human both 7p and 7q, and most losses included 7q32–qter. Cytogenetic Nomenclature (ISCN, 1995).21 Abnormal clones Hypodiploidy (N ¼ 27) and pseudodiploidy (N ¼ 27) were more were defined as two or more metaphase cells with identical frequent than low hyperdiploidy (47–50 chromosomes; N ¼ 9) structural abnormalities or extra chromosomes, or three or more or high hyperdiploidy (450 chromosomes, HH; N ¼ 12) among metaphase cells with identical missing chromosomes. Accep- the patients with losses involving chromosome 7 (Table 2). tance of a normal karyotype required analysis of a minimum of However, losses of the p-arm of chromosome 7 occurred with 20 cells from unstimulated bone marrow only. A total of 1880 similar frequencies in hyperdiploid, pseudodiploid, and HH cases had centrally reviewed and accepted cytogenetic data; 75 karyotypes; whereas losses involving the q-arm of chromosome (4%) had losses of all or part of chromosome 7. 7 were most frequent in patients with pseudodiploidy. Of the 16 cases with monosomy 7, 12 were hypodiploid. Only one of the 11 HH (one patient was near-tetraploid) patients had trisomy of Statistical methods chromosomes 4, 10, and 17, identified as associated with a superior outcome in Children’s Oncology Group (COG) studies Data were current to August 31, 2001. Clinical, demographic, (unpublished COG data31,32). Of the 75 patients, 72 (96%) had and laboratory features of patients with and without deletions of 2 structural abnormalities. Only one patient had a sole abnorm- chromosome 7 were compared using w tests for homogeneity of ality, monosomy 7. A high percentage of patients with losses proportions. Outcome was analyzed using life table methods involving chromosome 7 also had an abnormal 9p (N ¼ 27; and associated statistics. The primary end point examined was 36%) and/or an abnormal 12p (N ¼ 16; 21%). Five patients had event-free survival (EFS) from study entry; events included a Philadelphia (Ph) chromosome: three with monosomy 7 and induction failure (nonresponse to therapy or death during two with del(7p). A t(1;19) was present in six patients, five with induction), leukemic relapse at any site, death during remission, an unbalanced der(19)t(1;19). No patient had a t(4;11). or second malignant neoplasm, whichever occurred first. Patients who did not have an event at the time of EFS analysis were censored at the time of last contact. The Kaplan–Meier life 22 Comparison of clinical and biological characteristics of table estimate of EFS and its standard deviation (s.d.) at children with ALL with or without losses involving specific time points are given. An approximate 95% confidence chromosome 7 interval (CI) can be obtained from the life table estimate 71.96 23,24 s.d. Life table comparisons used the log rank statistics. The clinical and biological characteristics at diagnosis of ALL in P-values are based on the pattern of outcome across the entire children with losses involving chromosome 7 were compared period of patient follow-up; values p0.05 are referred to as with those without this abnormality (Table 2). Patients with statistically significant. losses involving chromosome 7 were more likely than patients The current cohort of patients with accepted cytogenetic data without this abnormality to be X10 years of age (P ¼ 0.004), to was similar to concurrently enrolled patients who did not have have NCI poor risk33 status (P ¼ 0.002), a t(1;19) translocation accepted cytogenetic data with respect to many presenting (P ¼ 0.03), or a Ph chromosome (P ¼ 0.01). Patients with losses features, although patients with accepted data were more likely involving chromosome 7 were more likely to have hypodiploidy to be white, have high WBC counts, high platelet and and less likely to have HH (Po0.0001) than patients without hemoglobin levels, large mediastinal masses, lymphadenopa- losses involving chromosome 7. Leukemic cells from patients thies, T-lineage immunophenotypes, and non-L1 FAB morphol- with losses involving chromosome 7 were no more likely than ogies. The actual percentages of patients with or without those without this abnormality to express the myeloid markers accepted cytogenetic data in these categories, however, did CD13 (P ¼ 0.73) or CD33 (P ¼ 0.30). not appear to differ; thus, the statistical differences may be due to the large sample size. Early treatment response, induction outcome, and EFS were nearly identical for concurrently Response to induction therapy of children with ALL and enrolled patients with or without accepted cytogenetic data. losses involving chromosome 7

Results Early marrow status (blasts percentage on day 7 of induction therapy), which is a significant prognostic factor for ALL Cytogenetic features of children with ALL and complete patients,34 was not significantly different for patients with or or partial losses of chromosome 7 without losses involving chromosome 7 (P ¼ 0.15), although a lower percentage of patients with (39%) versus without (50%) Complete or partial losses of chromosome 7 were found in 75 of losses involving chromosome 7 had M1 marrow status (o5% 1880 (4%) childhood ALL patients with accepted cytogenetics blasts). A higher frequency of patients with losses involving

Leukemia Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 941 Table 1 Karyotypes of children with ALL and losses involving chromosome 7

Patient # ISCN

1 45,XX,À7

2 45,XX,À7,del(9)(p22)

3 45,XY,t(3;22)(p25;q11.2),À7/46,idem,+X/44,idem,À9/45,idem,+X,À9

4a 34,X,+Y,+1,+5,+6,+8,+10,+11,+18,+19,+21,+22

5b 45,XX,À7,t(9;22)(q34;q11)

6b 45,XY,À7/45,idem,t(9;22)(q34;q11)

7c 46,XY,À7,add(9)(q34),del(11)(q13),À13,+2mar

8 51,XY,+X,+5,À7,+11,+13,+20,+21

9a 40,X,ÀY,À3,der(4)t(3;4)(p21;p16),À7,À9,À15,À16,À17,À18,+2mar

10 47,XX,add(1)(q11),+der(1)t(1;1)(p13;q22),À4,À6,À7,+add(8)(q24),À10,del(10)(p1?2),add(11)(p1?2),À12,add(13)(q32),À19,À19,À20,+22,+6mar

11a 36,XX,À3,À4,À5,À7,À9,À13,À15,À16,À17,À17,À20,+mar/72,idemx2

12 46,XY,del(4)(p14p16),À7,À9,+10,add(12)(p11.2),À15,À18,add(20)(q11.2),+3mar[6]/46,XY[29]

13 54,XY,+X,+2,+6,À7,+14,+15,+18,+21,+21,+mar

14 45,XY,À7,À7,add(9)(p22),À14,+2mar

15b 45,X,ÀY,À7,del(9)(p22),t(9;22)(q34;q11.2),del(10)(q22q24),der(12)t(Y;12)(q12;p13),+mar

16a 43,X,ÀX,add(1)(p3?4),t(2;12)(p21;p13),À7,t(7;9)(p13;p22),add(12)(p11),À15

17d 55,XX,+X,del(2)(q21),+4,+5,+6,i(7)(q10),+14,+add(15)(q13),+21,+21,+mar/55,idem,Àdel(2)(q21),der(9)t(2;9)(p11.2;p13) or der(9)t(2;9)(p13;p22),+10,+18,Àmar

18 59,XX,+X,+X,+4,+5,i(7)(q10),+8,+9,+10,+14,+17,+18,+21,+21,+mar

19 46,XX,+der(1)t(1;9)(p13;q13),i(7)(q10),À9,der(19)t(1;19)(q23;p13.3)[2]/46,idem,del(6)(q1?1)

20e 46,XX,i(7)(q10),der(19)t(1;19)(q23;p13)

21e 46,XY,t(1;19)(q23;p13),i(7)(q10)

22e 48,XX,+5,i(7)(q10),+8,der(19)t(1;19)(q23;p13)/46,XX,+1,der(1;9)(q10;q10),i(7)(q10),der(19)t(1;19)(q23;p13)

23 46,X,ÀY,i(7)(q10),+8

24 46,XX,i(7)(q10),der(19)t(1;19)(q23;p13.3)

25 56,XY,+X,+Y,+5,+6,i(7)(q10),+9,+10,+11,+18,der(20)t(1;20)(q12;q13.3),+21,+22

26 47,XY,?i(7)(q10),+12

27e 51,XX,+4,+5,i(7)(q10),+8,+18,+der(19)t(1;19)(q2?3;p13)

28 51,XY,+X,i(7)(q10),+?15,+20,+21,+21

29 59,XY,+X,+4,+5,+6,der(7)t(1;7)(q11;p11),+10,+11,+11,+14,+15,+18,+21,+21,+mar

30 47,XX,+5,del(6)(q13q21),add(7)(p11.2),dic(9)(p12),del(14)(q22q24)

31b 45,XY,dic(7;9)(p11;p11),t(9;22)(q34;q11)

32 45,XX,dic(7;9)(p11.2;p13)

33 45,XY,dic(7;9)(p11;p11)

34 53,XY,+X,?del(1)(q?42),del(3)(q2?5),+4,+6,add(7)(p11.2),+21,+21,+22,+0À3mar

35 46,XX,add(7)(p1?2),add(19)(p13)

36d 45,XX,t(4;15)(p14;q1?4),del(6)(q16q26),add(7)(p12),add(12)(q13),À18

37 45,XY,t(1;11)(q21;p15),del(7)(p12p15),add(13)(q34),À20

38 46,XY,dic(7;9)(p13;p11),der(12)t(9;12)(p11;p13),+21c

39 46,XY,del(6)(q1?5q25),add(7)(p1?3)

40 45,XY,dic(9;12)(p1?3;p1?2)/44,idem,der(7)t(7;17)(p1?3;q?21),À17

Leukemia Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 942 Table 1 Continued

Patient # ISCN

41d 46,XX,+X,der(7)t(7;15)(p1?3;q1?3),À15

42 45,XY,À5,del(6)(q1?5q21),der(7)t(5;7)(q1?3;p1?3)

43 67o3n4,XXX,+X,À1,À2,À3,del(6)(q15q23),À7,del(7)(p13p22),+10,À12,À17,+18,À19,+der(?)t(?;1)(?;q2?1),+r

44 61o3n4,XXY,À1,À2,À3,del(7)(p14)x2,À9,À9,À10,À11,À12,À13,À15,À16,+17,À20,+3mar

45c 46,XX,del(6)(q2?q2?),add(7)(p15),del(9)(p1?3),À11,?del(14)(q1?3q2?2),+mar

46 46,X,t(X;12)(q24;p13),inv(2)(p13q37)/46,idem,t(9;19)(q34;q13.1)/46,idem,der(7)t(1;7)(q23B25;p15B22),t(8;10)(q24.1;q22), t(9;19)(q34;q13.1)

47 46,XX,del(7)(p15),add(11)(q22),add(21)(q22)

48d 49,XY,+6,t(10;11)(p13;q13),add(19)(p13),+21,+21/ 46,XY,der(6)t(6;10)(q21;q11.2),der(7)t(7;15)(p15;q15),der(10)t(10;11)(q11.2;q12),del(11)(q12),del(12)(p11.2),add(15)(q?21),add(19)(p13)

49 46,XY,add(7)(p21),del(15)(q22)

50 47,XY,À1,del(2)(p13p23),+5,der(7)t(1;7)(p22;p21),del(9)(p22),+mar

51 46,XX,add(7)(p22),del(9)(p21p24)

52 48,XY,der(2)t(2;12)(q33;q13),add(7)(p?22),del(8)(p21),+10,À12,À15,add(17)(p11.2),+21,+2mar

53 45,XX,del(5)(p?13p?15),À7,der(9)t(7;9)(q11.2;p11.2),del(12)(p1?2),add(21)(q?22)

54 45,XY,del(1)(q32),À7,del(8)(q22),add(12)(p13),der(12)t(7;12)(q11.2;p13)

55 46,XY,À7,der(11)t(7;11)(q11.2;q21),add(19)(q13.4),+21c/45,idem,À15,der(22)t(15;22)(q11;p11)

56a,b 42,XY,À3,À5,der(6)t(6;7)(p25;q11.2),À7,add(8)(p21),der(9)t(9;12)(p22;p13)t(9;22)(q34;q11),der(12)t(9;12)(p22;p13),À13, der(15;17)(q10;q10),add(22)(p11),+mar

57a 44,XX,der(2)t(2;7)(q31;p15),À7,psudic(9;16)(p2?2;p1?1.2),der(12)t(7;12)(q1?1.2;p11.2)/45,idem,+mar

58 45,XY,del(7)(q11),der(9)t(9;14)(p13;q24),À14,À16,+mar

59c 46,XY,inv(1)(q23q42),dup(5)(q31q34)x2,del(7)(q11.2q36),t(10;14)(p13;q11.2)

60 47,XX,+X,add(7)(q22),add(21)(q22)

61 48,XY,del(6)(q15q23),der(7)t(7;11)(q22;q13),add(9)(p22),À10,+21,i(21)(q10)x2,+2mar

62 46,XX,t(1;12)(q21;p13),del(7)(q22q36),t(12;18)(p13;q21)

63 46,XX,del(5)(q15q31),del(7)(q?22q?34)

64 46,XY,del(4)(q12q27 or q21q31),À5,del(7)(q22q32),+8,add(12)(p11.2),add(13)(q3?2),add(14)(q?11.2)

65 46,XY,del(7)(q22q31.2) or del(7)(q31.2q32)/47,idem,+mar

66 96,XXY,+del(X)(q2?4),ÀY,add(2)(q3?7)x2,del(3)(p11)x2,À5,À5,add(7)(q32)x2,À12,À12,À13,À14,À17,+19,add(19)(p13)x2,?del(20)(q11.2),À22,+11mar

67 46,XX,del(7)(q32),der(21)t(?15;21)(q15;q22)

68 45,X,ÀX,add(7)(q3?2)/48,idem,+3mar

69 46,XY,del(6)(q21q2?5),add(7)(q3?2)

70c 46,XY,del(7)(q?32),del(9)(p13),À10,add(11)(p13),i(17)(q10),+mar

71c 46,XY,del(5)(q15q35),del(6)(q15q25),?del(7)(q34),del(9)(q21q34)/44,idem,+6,Àdel(6)(q15q25),À16,À18,À20,+mar/46,idem,del(17)(p11.2)

72 46,XX,add(7)(q3?4)

73 45,XX,del(1)(q25),der(7)psu dic(7;7)(q11.2;p22)t(7;15)(q32;q22),À11,À12,del(13)(q12.3q22),add(14)(p11),À15,À22,+r,+2mar

74f 46,XY,add(1)(q44),t(4;12)(q12;p13),del(5)(q15q35),add(6)(p22),r(7),i(9)(q10),add(14)(q32),t(14;16)(q11.2;q24),add(15)(p11.2),À17, add(18)(p1.?3),+mar

75 48,XY,del(7)(p13),del(7)(q22),+10,À15,+21,+mar aPreviously described in Heerema et al.25 bPreviously described in Uckun et al.26 cPreviously described in Heerema et al.27 dPreviously described in Heerema et al.28 ePreviously described in Uckun et al.29 fPreviously described in Heerema et al.30

Leukemia Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 943 difference in EFS was maintained when the analyses were adjusted for the presence of a Ph (P ¼ 0.008), NCI risk status including (P ¼ 0.0007) and excluding (P ¼ 0.03) Ph patients, ploidy when Ph patients were included (P ¼ 0.01), and an abnormal 9p including (P ¼ 0.002) and excluding (P ¼ 0.04) Ph patients. However, the worse OS was not maintained when Ph patients were excluded from the adjusted analyses (Table 3). Significantly, EFS and OS were significantly worse for patients with del(7p) than for patients with normal 7p (Po0.0001 and P ¼ 0.0001, respectively; Table 3; Figures 2 and 3). Moreover, these differences were maintained when the analyses were adjusted for a Ph chromosome (Po0.0001 and P ¼ 0.0004, respectively), NCI risk status including (Po0.0001 and P ¼ 0.0004, respectively) and excluding Figure 1 Losses of Chromosome 7. An ideogram of chromosome 7 (P ¼ 0.0001 and 0.001, respectively) Ph cases, ploidy includ- showing losses in individual patients. Each line to the right of the ing (P ¼ 0.004 and 0.01, respectively) and excluding ideogram represents the chromosome 7 loss in a single patient. (P ¼ 0.003 and 0.01, respectively) Ph cases, and an abnormal Selected band designations are given on the left of the ideogram. 9p including (P ¼ 0.0007 and 0.004, respectively) and excluding (P ¼ 0.0005 and 0.004, respectively; Table 3) Ph cases. However, outcome for patients with deletions of 7q but with apparently normal 7p’s was not significantly different from that chromosome 7 failed induction than patients without this of patients lacking this abnormality in any of the analyses abnormality (3 and 1%, respectively, P ¼ 0.04). (Table 3; Figures 2 and 3).

Outcome of children with ALL and losses involving Discussion chromosome 7 We have examined the frequency and prognostic significance EFS was significantly worse for patients with a loss involving of losses and deletions of chromosome 7 in a large cohort chromosome 7 compared with patients without this of children with ALL. Loss of all or part of chromosome aberration, with 7-year EFS estimates of 48 (s.d. ¼ 6%) and 7 was found in 75 of 1880 (4%) patients studied. Unlike 75% (s.d. ¼ 1%), respectively (Po0.0001; Table 3). Overall adults with ALL and losses involving chromosome 7,11 children survival (OS) was also significantly worse for patients with with losses involving chromosome 7 in this cohort were not a loss involving chromosome 7 than for patients without more likely than those without this abnormality to express this abnormality with 7-year OS estimates of 62 (s.d. ¼ 6%) myeloid markers. and 84% (s.d. ¼ 1%), respectively (Po0.0001; Table 3). Patients Dabaja et al11 found no difference in survival rates for adult with a loss involving chromosome 7 had higher frequencies of ALL patients with or without deletions of chromosome 5 or 7; both marrow and central nervous system relapses than patients both groups, however, had a very poor outcome (3-year survival without this aberration. The poorer EFS and OS were retained of approximately 36%). Monosomy 7 and del(7q) have been when Ph patients were excluded from the analyses (Po0.0001 associated with an adverse outcome in AML,3–6 suggesting that for both comparisons), after adjustment for NCI risk status the critical region(s) in AML may be in the q-arm.7–10 In this (Po0.0001 for both comparisons) and after adjustment for study, both EFS and OS were significantly worse for children ploidy (P ¼ 0.0002 and 0.004, respectively; Table 3). An with ALL with a loss involving chromosome 7 than for patients abnormal 9p in this overall cohort of 1880 patients was lacking this abnormality. However, when the patients were associated with a poor prognosis.35 After adjustment for an grouped by those with monosomy 7, deletions of 7p resulting abnormal 9p, EFS and OS maintained significance (Po0.0001 from structural rearrangements, and deletions of 7q resulting and P ¼ 0.0001, respectively). The poorer outcome was main- from structural rearrangements, only deletions of 7p were tained when Ph patients were excluded from the adjusted consistently associated with an inferior outcome. Additionally, analyses (Table 3). children with ALL with a loss involving chromosome 7 were more likely than patients without this abnormality to be of age 10 or greater, have NCI poor risk status, have a Ph chromosome, Outcome of children with ALL and monosomy 7, hypodiploidy and/or have an abnormal 9p, all adverse risk deletions of 7p, and deletions of 7q factors in this cohort of children with ALL.25,26,32,33 After adjustment for each of these features, the poorer EFS and OS of To determine if monosomy 7 conferred a different prognostic children with del(7p) were maintained, indicating that del(7p) is risk than deletions of 7p (del(7p)) and deletions of 7q (del(7q)), a significant adverse prognostic factor regardless of the presence outcome for patients with monosomy 7 (16 patients), patients of other adverse risk factors. Patients with monosomy 7 also had with del(7p) only (41 patients, including those with break- a worse EFS, which was maintained after adjustment for each of points in 7q11.2), and patients with del(7q) only (16 patients, these factors including and excluding Ph patients except when including patient 66 with near-tetraploidy and loss of 7q in the analysis was adjusted for ploidy and Ph patients were two chromosomes 7) was analyzed. Patients 74 and 75 were excluded from the analysis. However, monosomy 7 did not omitted from these analyses as they had deletions of both 7p confer a worse OS when patients with a Ph were excluded from and 7q. Patients with monosomy 7 had a worse EFS and the analyses nor when the analyses were adjusted for ploidy and OS than patients lacking this abnormality (Po0.0001 and Ph patients were included in the analysis, although a difference P ¼ 0.0007, respectively; Table 3; Figures 2 and 3). The was suggested for the latter (P ¼ 0.06). Importantly, patients with

Leukemia Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 944 Table 2 Presenting features of children with ALL and losses involving chromosome 7

Patients with losses involving Patients without losses involving chromosome 7 (N ¼ 75) chromosome 7 (N ¼ 1805)

Variable Category N (%) N (%) P-valuea

Age (years) 1–9 48 (64) 1412 (78) 0.004 X10 27 (36) 393 (22)

WBC ( Â 109/l) o20 40 (53) 1130 (63) 0.25 20–49 15 (20) 268 (15) X50 20 (27) 407 (23)

Sex Male 43 (57) 1000 (55) 0.74 Female 32 (43) 805 (45)

Race White 60 (80) 1466 (81) 0.19 Black 3 (4) 145 (8) Other 12 (16) 194 (11)

Liver Normal 33 (45) 898 (50) 0.67 Mod. enlargedb 38 (51) 839 (47) Markedly enlarged 3 (4) 64 (4)

Spleen Normal 30 (41) 867 (48) 0.29 Mod. enlarged 37 (50) 830 (46) Markedly enlarged 7 (9) 108 (6)

Lymph nodes Normal 40 (53) 911 (50) 0.48 Mod. enlarged 28 (37) 775 (43) Markedly enlarged 7 (9) 119 (7)

Mediastinal mass Absent 70 (93) 1639 (91) 0.39 Small 4 (5) 82 (5) Large 1 (1) 84 (5)

Hemoglobin (g/dl) 1–7.9 42 (57) 946 (52) 0.6 8.0–10.9 21 (28) 614 (34) X11.0 11 (15) 243 (13)

Platelets ( Â 109/l) 1–49 35 (47) 844 (47) 0.64 50–149 25 (34) 542 (30) X150 14 (19) 419 (23)

CNS disease at Yes 3 (4) 50 (3) 0.52 diagnosis No 71 (96) 1738 (97)

Down’s syndrome Yes 2 (3) 31 (2) 0.54 No 73 (97) 1773 (98)

NCI risk groupc Standard 33 (44) 1120 (62) 0.002 Poor 42 (56) 685 (38)

Immunophenotype B-lineage 50 (85) 1040 (84) 0.91 T-lineage 9 (15) 195 (16)

CD10 negative 13 (20) 263 (19) 0.79 CD10 positive 52 (80) 1146 (81)

CD13 negative 31 (84) 581 (86) 0.73 CD13 positve 6 (16) 96 (14)

CD33 negative 41 (87) 707 (92) 0.3 CD33 positive 6 (13) 65 (8)

Cytogenetic abnormalities

Ploidyd Normal FF579 F o0.0001 Hypodiploid 27 (36) 83 (7) Pseudodiploid 27 (36) 469 (38) Low hyperdiploid 9 (12) 194 (16) (47–50 chromosomes)

Leukemia Monosomy 7 and del(7p) in childhood ALL NA Heerema et al 945 Table 2 Continued

Patients with losses involving Patients without losses involving chromosome 7 (N ¼ 75) chromosome 7 (N ¼ 1805)

Variable Category N (%) N (%) P-valuea

High hyperdiploid 12 (16) 480 (39) (450 chromosomes)

Translocations t(1;19) positive 6 (8) 59 (3) 0.03 t(1;19) negative 69 (92) 1746 (97)

t(4;11) positive 0 (0) 14 (1) 0.44 t(4;11) negative 75 (100) 1791 (99)

t(9;22) positive 5 (7) 39 (2) 0.01 t(9;22) negative 70 (93) 1766 (98) aGlobal w2 test for homogeneity. bMod., moderately; degree of organomegaly and size of mediastinal mass were determined as described by Steinherz et al.20 cBased on Smith et al.33 dBased in the simplest clone; P-value refers to comparison of abnormal ploidy only. Significant values are in bold.

Table 3 Outcome analyses of children with ALL and losses involving chromosome 7

Any loss 7 Monosomy 7 del(7p)a del(7q)a

Ph included EFS o0.0001 o0.0001 o0.0001 0.21 OS o0.0001 0.0007 0.0001 0.77 Ph excluded EFS o0.0001 0.008 o0.0001 0.17 OS o0.0001 0.13 0.0004 0.68

NCI risk adjusted EFS o0.0001 0.0007 o0.0001 0.36 Ph included OS o0.0001 0.01 0.0004 0.97 NCI risk adjusted EFS o0.0001 0.03 0.0001 0.28 Ph excluded OS 0.0008 0.35 0.001 0.93

Ploidy adjusted EFS 0.0002 0.01 0.004 0.62 Ph included OS 0.004 0.06 0.01 0.75 Ploidy adjusted EFS 0.0003 0.14 0.003 0.45 Ph excluded OS 0.01 0.52 0.01 0.91

Abnormal 9p adjusted EFS o0.0001 0.002 0.0007 0.25 Ph included OS 0.0001 0.02 0.004 0.85 Abnormal 9p adjusted EFS o0.0001 0.04 0.0005 0.19 Ph excluded OS 0.0009 0.32 0.004 0.74 aExcludes two patients with p and q deletions. P-values for the analyses are given. Any loss 7 ¼ patients with any loss involving chromosome 7; del(7p) ¼ patients with structural rearrangements resulting in deletion of 7p; del(7q) ¼ patients with structural rearrangements resulting in deletion of 7q. Comparisons were with patients without losses involving chromosome 7. Ph ¼ Philadelphia chromosome; EFS ¼ event-free survival; OS ¼ overall survival. deletions of 7q did not have a significantly worse EFS or OS Conclusion compared with patients with no losses involving chromosome 7, with or without adjustment for other features. These results Losses involving chromosome 7 are relatively frequent in suggest that the critical region of loss of chromosome 7 that is childhood ALL. Deletions of 7p confer an inferior outcome in associated with an inferior outcome in childhood ALL may be children with ALL, regardless of the presence of other poor located on the p-arm. Russo et al12 suggested that a tumor prognostic features, whereas deletions of 7q are not associated suppressor gene on 7p might contribute to the poor outcome of with a worse outcome. Monosomy 7 is also associated with an children with Ph ALL and monosomy 7 or losses involving 7p. inferior EFS in children with ALL, except when the analysis is Our results are consistent with this hypothesis, and extend the adjusted for ploidy and Ph patients are excluded. Monosomy 7 significance of loss of 7p to Ph-negative childhood ALL. Thus and del(7p) in childhood ALL appear to represent a form of although losses involving chromosome 7 are associated with a leukemia distinct from monosomy 7 and losses involving poor prognosis in both ALL and AML, the critical region of chromosome arm 7q observed in myeloid disorders in children chromosome 7 may differ. or adults.

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