Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and ...

Leukemia (1999) 13, 376–385  1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu

Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7 H Hasle1, M Arico`2, G Basso3, A Biondi4, A Cantu` Rajnoldi4, U Creutzig5, S Fenu6, C Fonatsch7, OA Haas8, J Harbott9, G Kardos10, G Kerndrup11, G Mann8, CM Niemeyer12, H Ptoszkova13, J Ritter5, R Slater14, J Stary´15, B Stollmann-Gibbels16, AM Testi6, ER van Wering17 and M Zimmermann5 for the European Working Group on MDS in Childhood (EWOG-MDS) 1

Department of Pediatrics, Aarhus University Hospital, Denmark; 2Department of Pediatrics, University IRCCS S Matteo, Pavia, Italy; Department of Pediatrics, University of Padova, Italy; 4Department of Pediatrics, University of Milan, Italy; 5Department of Pediatrics, University of Mu¨nster, Germany; 6La Sapienza, Rome, Italy; 7Institute of Medical Biology, University of Vienna, Austria; 8St Anna Children’s Hospital, Vienna, Austria; 9Oncogenetic Laboratory, Children’s Hospital, Giessen, Germany; 10Department of Pediatrics, Free University of Amsterdam, The Netherlands; 11Department of Pathology, Odense University Hospital, Denmark; 12Department of Pediatrics, University of Freiburg, Germany; 13Department of Pediatrics, Ostrava, Czech Republic; 14Netherlands Working Party on Cancer Genetics and Cytogenetics, Rotterdam, The Netherlands; 152nd Department of Pediatrics, Prague, Czech Republic; 16Department of Pediatrics, University of Essen, Germany; 17Dutch Childhood Leukemia Study Group, The Hague, The Netherlands

3

We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (−7) or deletion of the long arm of chromosome 7 (7q−). Patients with therapyinduced disease were excluded. The morphologic diagnoses according to modified FAB criteria were: MDS in 72 (refractory anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML in 28. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year). Loss of chromosome 7 as the sole cytogenetic abnormality was observed in 75% of those with MDS compared with 32% of those with AML. Predisposing conditions (including familial MDS/AML) were found in 20%. Three-year survival was 82% in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEBT. Children with −7 alone had a superior survival than those with other cytogenetic abnormalities: this was solely due to a better survival in MDS (3-year survival 56 vs 24%). The reverse was found in AML (3-year survival 13% in −7 alone vs 44% in other cytogenetic groups). Stable disease for several years was documented in more than half the patients with RA or RAEB. Patients with RA, RAEB or JMML treated with bone marrow transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest prognostic factor. Only patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. Our data give no support to the concept of monosomy 7 as a distinct syndrome. Keywords: myelodysplastic syndrome (MDS); acute myeloid leukemia (AML); children; monosomy 7

Introduction Myelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis often with prominent morphologic abnormalities. MDS is rare in childhood with an annual incidence of only four/million.1 The French–American–British (FAB) group proposed a classification of MDS comprising five subgroups: refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML).2,3 The FAB classification has become widely accepted for MDS in adults. The classification of childhood MDS has remained rather controversial and inconsistent.4–6 Correspondence: H Hasle, Department of Pediatrics, Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark; Fax: 45 8949 6023 Received 13 July 1998; accepted 20 November 1998

The most conflicting area in the classification of childhood MDS has been the pediatric equivalent of what the FAB group termed CMML. These children have most often been referred to as juvenile chronic myeloid leukemia (JCML) in the British and American literature,7,8 whereas others have favored the FAB term CMML.4,9–11 An International Working Group concluded that the different terminology did not reflect the existence of different disorders and proposed the term juvenile myelomonocytic leukemia (JMML). The term has attained international acceptance6,12–14 and will be used throughout this paper. Although we acknowledge that JMML often shows myeloproliferative features different from other MDS types, we have included JMML in the group of childhood MDS in accordance with the practice by other cooperative groups. Loss of chromosome 7 material, either as complete monosomy 7 (−7) or as deletion of the long arm (7q−), is the most common cytogenetic abnormality in childhood MDS seen in approximately 30% of cases.4,5,15 Only 4–5% of childhood AML cases show −7/7q−.16–19 AML patients with −7/7q− have a very poor prognosis,16,17,19 but due to the infrequency of the association there are very few data on the clinical characteristics of these patients. Children with MDS and −7 have often been considered a distinct hematologic disorder described as the monosomy 7 syndrome, characterized by young age, male predominance, hepatosplenomegaly, and leukocytosis.20–23 The monosomy 7 syndrome has many similarities with JMML and the distinction between the two nosological entities has not been clear-cut. In a previous study we did not find any major clinical differences between JMML in children with and without −7.11 Furthermore, −7 has been considered to represent a late event or an opportunistic cytogenetic abnormality.24 Therefore, it may be questioned whether a classification solely based on the loss of chromosome 7 is of clinical relevance. The aim of the present study was to describe the clinical characteristics, the predisposing conditions, survival and response to treatment of a large number of children with −7/7q−. Materials and methods Data on children with −7/7q− and myeloid malignancies were collected retrospectively through members of the European Working Group on MDS in Childhood (EWOG-MDS). Patients previously exposed to chemotherapy or radiation, as well as patients with Fanconi anemia or congenital granulocytopenia

Monosomy 7 and myeloid leukemia H Hasle et al

were excluded. The study group consisted of 100 children from Austria (n = 5), Czech Republic (n = 8), Denmark (n = 20), Germany (n = 40), Italy (n = 15) and the Netherlands (n = 12). Data on 28 of the patients have been included in previous studies from EWOG-MDS.11,25 Inclusion required a diagnosis of MDS or AML and bone marrow (BM) or peripheral blood (PB) karyotype by standard technique showing at least three cells with loss of a whole chromosome 7 or at least two cells with identical structural abnormalities leading to loss of chromosome 7q material. Confirmatory fluorescence in situ hybridization (FISH) studies were performed in a few cases, but the classification of the patients relied solely on standard cytogenetics. The first reported abnormal karyotype involving chromosome 7 was used to classify the patients as −7 alone, −7 plus other abnormalities (−7 + other), 7q− alone, or 7q− plus other abnormalities (7q− +other). Karyotypes were described according to the International System for Human Cytogenetic Nomenclature 1995.26 All cases were categorized according to the FAB classification of MDS and AML, with the following two modifications: for a diagnosis of JMML up to 20% myeloblasts in the blood was accepted.11,27,28 AML was diagnosed when myeloblasts in PB were ⬎30%, regardless of the number of myeloblast in BM.29 White blood cell count (WBC) was corrected for the presence of nucleated red blood cells in PB. Reference values for corpuscular volume (MCV) were taken from Dallman and Siimes30 and for hemoglobin F (HbF) from Huehns and Beaven.31 Due to the retrospective nature of the study some data could not be retrieved. The number of patients with evaluable data was: hemoglobin (n = 99), MCV (n = 68), HbF (n = 41), WBC (n = 100), platelets (n = 99), complete PB differential count (n = 97), complete BM differential count (n = 96), spleen size (n = 100). The date of diagnosis was defined as the date of first BM examination suggesting a diagnosis of MDS or AML, also in patients in whom −7/7q− was detected only later. Date of diagnosis ranged from November 1976 to March 1997. Patients 26 and 88 were lost to follow-up at 115 and 59 months, respectively. They were censored at the date of last follow-up. The ␹2 test was used to test statistical significance in contingency tables. Fisher’s exact test was applied when appropriate for small sample size. Age distribution was compared using Wilcoxon rank sum test. Survival was calculated from the date of diagnosis to the date of death of any cause or last followup. The Kaplan–Meier method was used to estimate survival rates with comparisons based on the two-sided log-rank test.32 Standard errors (s.e.) were calculated using Greenwood’s formula. Prognostic factors were analyzed using Cox regression and the method of recursive partition.33,34 The following variables were included in the analyses: sex, age, hemoglobin, WBC, platelets, morphologic diagnosis (RA, RAEB, RAEB-T, JMML, AML) and karyotype (−7, −7 +other, 7q−, 7q− +other). The recursive partition was performed according to the method used by Trueworthy et al.35 Quantitative variables were categorized using the cutpoint which resulted in the highest risk-ratio in univariate Cox regression. The classification was repeated for each subgroup. The variable chosen for partition was the one with the largest estimated hazard ratio meeting the criterion of a P value ⬍5%. Partitioning was restricted to splits which resulted in subgroups including more than 10 patients.

Results

Clinical characteristics RA was diagnosed in 11 patients, RAEB in eight, RAEB-T in 10, JMML in 43 and AML in 28 (MO two, M1 four, M2 12, M4 two, M5 one, M6 three, M7 two, unclassified two). The clinical characteristics according to morphologic diagnosis are shown in Table 1. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year) (P ⬍ 0.001). JMML predominated among the youngest children accounting for 83% of the 23 cases occurring in infants below 1 year of age (Figure 1). Boys dominated in all MDS subgroups with an overall boy/girl ratio of 2.4. In contrast, a predominance of girls with AML resulted in a boy/girl ratio of 0.75 (P ⬍ 0.01). At presentation 49 patients had fever ⬎38°C, an active infection was documented in 34 children. Hepatosplenomegaly and lymphadenopathy were associated with JMML. Of the seven children with JMML who did not present with splenomegaly, five developed splenomegaly during the clinical course. Skin rash was described in 16 children, nine of these had JMML. Blasts in the cerebrospinal fluid at presentation were noticed in five patients, all with AML. Diabetes insipidus was present in two patients, both had JMML with −7. Chloroma occurred in five children with JMML, two with RAEB-T, and two with AML.

Hematologic findings Hematologic characteristics at diagnosis are given in Table 2. Anemia (hemoglobin ⬍11 g/dl) was present in 89% of the patients. Hemoglobin at presentation was highest among those with RA of whom two had a hemoglobin within normal reference for age; both showed macrocytosis, neutropenia, and thrombocytopenia. Macrocytosis was observed in seven of eight evaluable RA patients, but in only 27 of 60 non-RA patients (P ⬍ 0.05). HbF was elevated for age in 23 of 41 evaluable patients, but in only six of them did HbF exceed 10%; one each with RA (HbF = 12%), RAEB (HbF = 47%), RAEB-T (HbF = 70%) and two with JMML (HbF = 28% and 70%). The latter was a 2-month-old boy with HbF of 70%, which is just above the upper normal limit for age. The presenting WBC was low in RA, RAEB and RAEB-T; none of these patients presented with a WBC above 15 × 109/l. Absolute monocytosis (⬎1 × 109/l) was observed in all patients with JMML, in one with RAEB-T and in five with AML Neutropenia (⬍1.5 × 109/l) was seen in 43% of the patients and thrombocytopenia (⬍150 × 109/l) in 83%. Seven of 10 RAEB-T patients had BM blasts ⬍20%, but were classified as RAEB-T due to PB blasts ⬎5%. Auer rods were present in four cases, all diagnosed as AML due to BM blasts ⬎30%. BM erythropoiesis dominated in RA and RAEB with a median myeloid:erythroid ratio of 1.0 and 0.9, respectively, compared with 2.7 in RAEB-T and JMML and 11.2 in AML.

Cytogenetic findings Clinical characteristics according to karyotype are shown in Table 3. In MDS 75% of the patients had −7 as the sole abnormality; this was found in only 32% of the AML cases (P ⬍ 0.0001). 7q− was observed in 11% of those with MDS, but in

377


378

Table 1

Presenting features, treatment and survival in 100 children with complete or partial monosomy 7 according to diagnosis

Boys/girls Age at presentation (years) median range Hepatomegaly (%) Splenomegaly (%) Lymphadenopathy (%) Neurofibromatosis Down syndrome Treatment None or low-dose AML-like AML like + BMT BMT alone 3-year survival (%)

RA n = 11

RAEB n=8

RAEB-T n = 10

JMML n = 43

AML n = 28

7/4

6/2

7/3

31/12

12/16

4.5 1.9–12.5 0 (0) 0 (0) 2 (18)

3.7 0.5–13.7 4 (50) 2 (25) 4 (50)

6.5 2.4–15.7 5 (50) 4 (40) 3 (30)

1.1 0.2–11.4 38 (88) 36 (83) 27 (63) 4

2.8 0.6–15.1 18 (64) 15 (54) 12 (43)

15 12 8 8 45

2 23 3 0 34

2 4 2 2 3 82

2 3 1 2 63

1 3 5 1 8

32% of those with AML (P ⬍ 0.05). A striking sex-difference was observed with male sex being associated with −7 as the sole cytogenetic abnormality (boy/girl ratio 3.2). In contrast, girls dominated among those with 7q− and in those with additional cytogenetic abnormalities (boy/girl ratio 0.7) (P ⬍ 0.001). Loss of chromosome 7 with additional cytogenetic abnormalities or 7q− occurred in 37 patients (Table 4). All those with AML and 7q− had simple deletions, which was seen in only one with MDS (P ⬍ 0.001). The remaining MDS patients had more complex abnormalities, add(7) (n = 2), der(7) (n = 4), ring(7) (n = 1). Trisomy 8 was the most common additional aberration noted in eight patients (two RAEB, one RAEB-T, five AML). Of the eight patients with trisomy 8 one had constitutional trisomy 21, three acquired trisomy 21, and one acquired pentasomy 21q. A total of seven had acquired additional copies of chromosome 21 (one RA, two RAEB, two RAEB-T, two AML) one with tetrasomy 21 and another with pentasomy 21q. In patient 421 with Down syndrome the acquired extra chromosome 21 was present in a separate clone to the −7. Six of the patients with −7 and other cytogenetic abnormalities had marker chromosomes. An interstitial deletion of 7q was demonstrated in patient 128 by standard cytogenetics and by FISH analysis in patient 79. The commonly deleted segments of 7q located at 7q22 and 7q32–3336 were deleted in 11 and 13 of the 15 evaluable patients with 7q−, respectively. Only patients 121 and 312 had deletions outside the commonly deleted regions. Serial cytogenetic examinations were performed in 49 patients. In seven children a normal karyotype preceded the detection of −7/7q−. One patient with RAEB and a patient with JMML had −7 documented at follow-up without morphologic evolution. In four patients −7/7q− was detected at progression. In one patient with JMML −7 was documented only at relapse following BMT. Eight patients presenting with −7 showed clonal evolution (data not shown).

Associated conditions Figure 1

Age distribution according to diagnosis.

Four children were known to have neurofibromatosis type 1 (NF1) and two had Down syndrome. One of the patients with NF1 and two additional JMML patients without NF1 had


Table 2

Hemoglobin (g/dl) MCV elevated for age (% of evaluable) HbF elevated for age (% of evaluable) WBC (109/l)a Platelets (109/l) a

379

Hematologic characteristics at diagnosis given as median and range

RA

RAEB

RAEB-T

JMML

AML

10.5 (7.6–12.5) 7 (88)

7.4 (1.8–10.5) 3 (60)

7.8 (5.6–10.9) 3 (60)

9.2(3.5–12.4) 13 (38)

68 (3.2–15.4) 8 (50)

4 (100)

3 (75)

2 (100)

12 (41)

2 (100)

3.8 (1.5–8.6) 64 (6–211)

4.4 (1.5–10.8) 76 (6–140)

4.9 (1.4–14.4) 48 (10–390)

21.1 (3.1–259) 58 (10–496)

13.6 (1.8–109) 45 (7–324)

WBC corrected for the presence of nucleated red blood cells.

Table 3

Presenting features, treatment and survival in the 100 children according to karyotype

Boys/girls Age at presentation (years) median range Diagnosis RA RAEB RAEB-T JMML AML Hepatomegaly (%) Splenomegaly (%) Lymphadenopathy (%) Neurofibromatosis Down syndrome Familial cases Treatment None or low-dose AML-like AML-like + BMT BMT alone 3-year survival (%)

−7 n = 63

−7 + other n = 20

7q− n=4

7q + other n = 13

48/15

9/11

0/4

6/7

2.6 0.2–15.7

5.3 0.7–14.1

1.6 0.5–3.2

2.5 0.4–15.0

8 5 5 36 9 41 (65) 39 (62) 29 (46) 4

2 1 5 2 10 12 (60) 9 (45) 8 (40)

0 0 0 3 1 4 (100) 3 (75) 3 (75)

1 2 0 2 8 8 (62) 6 (46) 8 (62)

6

2 3

1

19 19 12 13 50

1 14 4 1 42

1 1 2 0 0

xanthogranuloma. One patient had a constitutional inv(9)(p12q12). One child had been treated with anti-thymocyte globulin and corticosteroid for aplastic anemia 6 years prior to the diagnosis of MDS. Another child had received treatment with corticosteroid and androgens since infancy for Diamond–Blackfan anemia. None of the children had received G-CSF. A variety of associated non-hematological abnormalities were reported; Silver–Russel syndrome, Rothmund-Thomson syndrome (described in details elsewhere),37 macrocephalus, hydrocephalus, facial dysmorphia (n = 3), mental retardation (n = 2), deafness, blindness, ptosis (n = 3), vermis cerebelli agenesis, atrial septal defect, and an undefined bleeding disorder in a pair of twins. The child with Silver–Russel syndrome presented at 8 months of age with synchronous AML and Wilms tumor.

Familial cases MDS or AML in siblings was identified in eight families (Table 5). Furthermore, leukemia was found in second or third degree relatives in two additional families, resulting in a total of 10 affected families (10%). Information on the type of leukemia in the family members was often incomplete, −7/7q− was

3 9 1 0 35

detected in four of six cytogenetically evaluated family members. JMML was diagnosed in one pair of homozygous twins, both children presenting at the age of 6 months with 45,XX,−7. The sister of patient 229 was evaluated as possible bone marrow donor and showed leukopenia and dysplastic granulocytopoiesis. Initial karyotype was normal, but followup 2 years later showed 47,XX,add(7)(q22), +mar. Those with affected family members presented at a higher age (6.4 vs 2.7 years, P ⬍ 0.05), but did not show any significant differences from the non-familial cases concerning sex, cytogenetics, and survival.

Treatment and survival Univariate analysis showed low platelet count, high WBC, RAEB-T, and 7q− to be significantly poor prognostic factors (Table 6). Cox regression analysis proved morphologic diagnosis to be the strongest prognostic factor (Table 6). Survival was superior in RA vs other subgroups (P = 0.02) with a 3year survival of 82% (s.e. = 0.09) in RA, 63% (s.e. = 0.17) in RAEB, 45% (s.e. = 0.08) in JMML, 34% (s.e. = 0.10) in AML, and only 8% (s.e. = 0.11) in RAEB-T (Figure 2). Children with −7 alone had a 3-year survival of 50% (s.e. = 0.06) vs 42% (s.e. = 0.12) in −7 other, 0% in 7q−, and 35%


380

Table 4

EWOG No.

Karyotypes in the 37 patients with abnormalities other that complete monosomy 7 alone

Diagnosis

Karyotype

119 229 605 117 118 250 421

RA RA RAEB RAEB-T RAEB-T RAEB-T RAEB-T

602 92 104 244 235 88 241 71 114 422 717 131 91

RAEB-T JMML JMML AML AML M0 AML M1 AML M1 AML M2 AML M2 AML M2 AML M2 AML M4 AML M6

Complete monosomy 7 with other aberrations (−7 + other) 47,XX,+21/46,XX,−7,+21 45,XX,add(2)(q32),−7,add(13)(q32) 46,XX,del(3)(q?),−7,+21/45,XX,del(3)(p?),−7 46,XY,−6,−7,+2mar 47,XY,−7,+11,del(12)(q?),add(18)(p?),+21c 47,XY,−7,+21,+21 46,XX,add(5)(p?),−7,+21c/47,XX,idem,+8/ 49,XX,t(4;4),(q3?1;q3?5),+8,+21c,+21 45,XY,−7,inv(9)(p12q12)c/near tetraploid 45,XY,inv(2)(p23q13),−7 45,XX,−7,i(17)(q10) 44–47,XX,−6,del(6)(q21),−7,add(9)(q33),−10,−11,−16,−19,−2mar[cp12] 45,XY,del(1)(q?),−7,add(11)(q?),−12,−14,add(17)(q?),+mar,+r/46,idem,+22 47,XX,−7,der(11)(q?),+r,+mar 46,XX,−7,+10 46,XX,−7,+22 46,XX,−7,+10 48,XX,−7,+8,−12,+18,+19,+mar/49,XX,−7,+11,−12,+18,+19,+22,+mar 46,XY,der(6)(?),−7,+8,der(11)(?),der(12)(?),−17,+2mar[cp8] 47,XY,−7,i(21)(q10),+i(21)(q10),+mar/48,idem,+8 45,XY,−7,add(12)(p?)

312 406 606 79

JMML JMML JMML AML M0

Deletion 7q (7q−) 46,XX,add(7)(q36) 46,XX,add(7)(q22) 46,XX,del(7)(q?) 46,XX,del(7)(q22),ish del(7)(q22q36)

248 120 719 15 107 121 72 73 74 75 122 128 720

RA RAEB RAEB JMML JMML AML M1 AML M2 AML M2 AML M2 AML M4 AML M5 AML M7 AML M7

Deletion 7q with other aberrations (7q− + other) 46,XY,+1,der(1;7)(q10;p10) 47,XX,+8/46,XX,+1,der(1;7)(q10;p10) 48,XY,r(7),+8,+21 46,XY,der(7)t(7;20)(q11;q11),del(20)(q11) 46,XY,t(1;3)(p13;p21),der(7)t(7;12)(q21;q13) 46,XY,del(7)(q35),del(16)(q22) 51,XX,+X,del(7)(q32),+8,+20,+21,+22 46,XX,add(1)(p3?),add(5)(p15.1),del(5)(q22),del(7)(q22) 47,XX,del(7)(q22),+8 46,XY,t(6;8)(q?:q?),del(7)(q33),inv(16)(p13q22) 46,XX,del(7)(q22),add(9)(p?23),del(12)(p11) 45,XX,−5,der(7)del(7)(p21)del(7)(q22q33),−9,der(9)t(5;9)(q22;q34),dup(13)(q12q14),+mar 46,XX,t(8;16)(p11;q13),add(9)(q34.3)/46,XX,del(7)(q22),t(8;16)(p11;q13)

Table 5

EWOG No.

Hematological disorders in relatives

Sex/Age

Diagnosis

Cytogenetics

Relative

Age

70 79 80 91 226 229 250 419

M/4yr F/6mo M/15yr M/13yr M/12yr F/12yr M/7yr M/4yr

AML AML RAEB-T AML RAEB-T RA RAEB-T RA

−7 7q− −7 −7 +other −7 −7 +other −7 + other −7

714 715

M/3mo F/6mo

JMML JMML

−7 −7

Grandmother Twin sister Sister Cousin Sister Sister Sister Sister Father Aunt Uncle Half-aunt Half-cousin Brother Mono-Twin

ND 5mo ND ND ND 17yr 6mo 11yr ND 7yr 14yr 39yr 13yr ND 6mo

ND, no data; NS, not specified.

Diagnosis

Cytogenetics

Leukemia (NS) ND AML ND AML ND Leukemia (NS) ND Leukemia (NS) ND RA add(7)(q22) Leukemia (NS) ND Granulocytopenia Normal Granulocytopenia Normal AML ND AML ND AML ND RAEB −7 Died of bleeding, no diagnosis −7 JMML −7 = pt No. 716


Table 6

381

Analyses of prognostic factors

Factor

P (log-rank test)

Univariate analysis Sex Platelets ⬍100 × 109/l WBC ⬎60 × 109/l Age ⬍2 years Age ⬍3 years Age ⬍4 years RA RAEB RAEB-T AML −7 + other 7q− 7q− + other Cox regression analysis Platelets ⬍100 × 109/l WBC ⬎60 × 109/l RAEB-T

0.73 0.005 0.007 0.28 0.35 0.21 0.07 0.64 0.005 0.74 0.25 0.007 0.91

␹2 6.8 5.3 9.9

P 0.0092 0.0212 0.0017

Risk ratio 2.4 2.4 3.7

Figure 3 Survival in −7 alone vs other chromosome 7 abnormalities. (a) MDS; (b) AML.

Figure 2

Survival according to diagnosis.

(s.e. = 0.14) in 7q− + other. The superior survival in −7 was solely due to a better survival in MDS (3-year survival 56% (s.e. = 0.07) vs 24% (s.e. = 0.11) (P = 0.0003). Figure 3a). The reverse was found in AML, with a 3-year survival of only 13% (s.e. = 0.12) in −7 vs 44% (s.e. = 0.12) in other cytogenetic groups (P = 0.26) (Figure 3b). The difference was not statistically significant. A prognostic score for childhood MDS proposed by the British group5 assigned one point each for HbF ⬎10%, platelets ⬍40 × 109/l, and two or more cytogenetic abnormalities. Application of the scoring system was hampered by HbF being evaluable in only 39 of the MDS patients and therefore not included in the regression analyses. The 3-year survival was 63% in those with score zero (n = 19), 35% in those with score 1 (n = 13), and 17% when score ⬎1 (n = 6) (P ⬍ 0.01). Survival and treatment were both associated with diagnosis (Table 1). Treatment is therefore presented separately according to diagnosis. We did not find any difference in survival between RA and RAEB and the two groups are presented together. It should be noted than only one of the RAEB patients had BM blasts ⬎15%.

RA and RAEB: Four of the six patients who did not receive any treatment showed stable disease during a median followup of 42 months (range 33–74). Of the eight patients treated with AML regimens, three were treated within 3 months without signs of progression, five received AML therapy after progression following a median interval of 28 months. Five received BMT following a median period of observation of 18 months. None of them showed signs of progression. None of the five patients treated with intensive chemotherapy not followed by BMT survives. However, a 2-year-old boy with RAEB and −7 received AML therapy and remained in remission for 7 years. He then relapsed with acute lymphoblastic leukemia with complex cytogenetic abnormalities, but without any detectable abnormalities of chromosome 7. Death from infection during therapy-induced cytopenia occurred in two of eight patients receiving AML-like therapy. BMT without prior chemotherapy was given to five children, two of them are surviving. JMML: Fifteen patients received no or only low-dose therapy. These patients had more favorable prognostic factors11 by presenting at a lower median age (9 months) and only three showing platelets ⬍33 × 109/l. Six of the patients receiving no intensive therapy are alive. Patients 417 and 704 have shown stable disease for 110 and 28 months, respectively. Four patients (26, 714, 715, 716) had a normal karyotype at latest


382

follow-up, despite persistent hematologic abnormalities and organomegaly in the latter three patients. These three children presented below 6 months of age, two were monozygotic twin brothers and the third had an affected brother. The evolution was considered to represent spontaneous cytogenetic remission since the patients received supportive therapy only, except splenectomy in patient 26. The latter patient has been described previously.38 None of the 12 patients treated with intensive chemotherapy not followed by BMT and only two of the eight patients receiving AML therapy followed by BMT survive. Death from complications of the therapy-induced cytopenia occurred in six of the 20 patients receiving AML-like therapy. BMT without prior chemotherapy was performed in eight children at a median of 7 months (range 1–15) from diagnosis, six of these children survive.

RAEB-T: The median survival was only 11 months (Figure 2). Only two of the 10 patients survive (250 and 316). Both patients received AML therapy followed by BMT and have remained in continued remission 4 and 18 months post BMT.

AML: Almost all patients received AML therapy (Table 1). The overall survival at 3 and 5 years was 34%, being considerably lower, although not statistically significant, in those with −7 alone (Figure 3b). Four children (one 7q−, three −7) received autologous BMT, three died of relapse, patient 422 has remained in complete remission 4. year post autologous BMT.

Monosomy 7 syndrome? The ‘infantile monosomy 7 syndrome’ has been defined as −7 in a child under 4 years of age with any type of MDS.5 Of the 63 children with −7, 35 were below 4 years of age and had the following diagnoses according to the modified FAB criteria: RA (n = 4), RAEB (n = 3) and JMML (n = 28). Male sex dominated (boy/girl ratio 4.0) in all morphologic subgroups. The patients with JMML below 4 years of age frequently had hepatomegaly (93%), splenomegaly (89%) and lymphadenopathy (58%). Splenomegaly was not found in any of those with RA or RAEB. Two of three with RAEB had modest hepatomegaly and lymphadenopathy. Increased WBC was associated with JMML (median 21 × 109/l, range 5.2–135), in contrast to a median WBC of 3.7 × 109/l (range 2.1–5.5) in RA and 4.8 × 109/l (range 3.9–5.5) in RAEB. Only one JMML patient overlapped the WBC range found in RA/RAEB. Children with RA or RAEB had a 3-year survival of 86 vs 54% in JMML (not statistically significant). Of the nine patients receiving AMLlike therapy all died, however, one survived 7 years in remission. Morphologic diagnoses in the 19 children aged 4–15 years with MDS and −7 showed RA (n = 4), RAEB (n = 2), RAEB-T (n = 5) and JMML (n = 8). With the exception of RAEB-T being associated with age ⬎4 years, no significant differences were observed between those below or above 4 years of age. Hepatomegaly, splenomegaly and leukocytosis were also associated with JMML in older children, although the median WBC in JMML (14 × 109/l) was lower than in younger patients. The 3-year survival was 71% in RA, 50% in RAEB, 25% in JMML and 13% in RAEB-T.

Discussion Loss of chromosome 7 material occurs in 30% of childhood MDS4,5,15 and in 4–5% of childhood AML.16–19 The annual incidence of childhood AML is 5.4/million vs 4.0 for MDS.1 Thus, the ratio of MDS vs AML should, accepting the Danish population-based figures, be 4.9. In the present series the ratio was 2.6, which may indicate a selection bias towards relatively more AML cases. However, there may also have been a positive selection bias for JMML, due to recruitment of cases for the foregoing EWOG-MDS study on JMML.11 RARS does occur in children, but is very rare4 and was not found in our series. RARS has previously been reported in one patient with −7.39 We found fewer cases with AML M4 and M5 and more with M2 and M6 than in unselected series of AML.18 JMML occurred almost exclusively in young children below 4 years of age. The age at presentation in JMML was only 13 months, in accordance with previous studies including mainly JMML patients with normal karyotype.9,11 No age peak was observed for the other MDS types. AML showed a peak in infants below 2 years of age. The age distribution appears similar to what is found in MDS and AML without −7/7q−.1,40 There was a strong male predominance in MDS, whereas girls dominated in AML. A female predominance has previously been reported among children below 2 years of age with AML.41 However, in the present study the male predominance in MDS and female predominance in AML was observed among both infants and older children. Male sex was strongly associated with −7 alone and female sex with additional cytogenetic abnormalities. Qualitative defects of the neutrophils have been documented in patients with −7.20,21,42 Fever at presentation was noted in 49% of our patients and infection in 34%, comparable to what was found in a larger series of JMML mainly with normal karyotype.11 Our previous study showed a similar proportion of patients with fever or infection at diagnosis in JMML with or without −7.11 In addition, the risk of infection-related death following intensive chemotherapy in MDS seems to be comparable in patients with and without −7.43 HbF was increased above 10% in five patients. Increased HbF has been one of the hallmarks of JMML. Only two of our JMML cases had HbF ⬎10%, one of them had 7q− and in the other it was just above the normal limit for age. This is in accordance with our previous study,11 showing that significantly increased HbF is very uncommon in JMML associated with −7. Seven patients showed −7/7q− at follow-up investigations only, underscoring the importance of repeated cytogenetic examination in children with MDS.15 Six of those with −7 and additional aberrations had marker chromosomes. It is likely that some of the marker chromosomes contained chromosome 7 material.44,45 Most of the patients with 7q− had what on standard cytogenetics appeared to be terminal deletions. However, FISH studies in such patients frequently show interstitial deletions or cryptic translocations,46 as documented in one of our patients. Four children had NF1, two Down syndrome, one aplastic anemia, and one Diamond–Blackfan anemia. Familial leukemia occurred in 10 children. A variety of non-hematological abnormalities were reported. If we include the two children with Silver–Russel syndrome and Rothmund–Thomson syndrome a total of 20 patients had predisposing conditions (21% in MDS and 18% in AML). Predisposing conditions (including previous chemotherapy and Fanconi anemia, not included here) was found in 30% in an unselected series of MDS.1 In


contrast, only 4% of children with AML are known to have predisposing genetic disorders.47 Down syndrome with −7/7q− has only been reported in a few cases.48–50 As many as 20% of children with RA, RAEB or RAEB-T have Down syndrome.1 Finding only two cases of Down syndrome in the present series further indicates that −7/7q− is relatively uncommon in myeloid leukemias in children with Down syndrome.51,52 MDS and AML have been described in a few patients with Diamond–Blackfan anemia,53 although not previously associated with −7/7q−. The development of AML with 7q− in a child with Silver–Russel syndrome is interesting in light of recent data showing uniparental disomy for the entire chromosome 7 in some of these patients.54 Familial occurrence of MDS with −7/7q− has been reported in a number of cases10,24,55–57 and has been claimed to account for as many as one-third of the children with −7.55 We found MDS or AML in relatives of 10 patients. This frequency is in contrast to a population-based study58 and a single institution study5 including a total of 28 children with −7 showing no relatives with MDS/AML. Familial MDS does also occur without −7/7q−5,59 and it is uncertain whether −7 per se increases the risk for familiar cases. There were no conspicuous clinical characteristics, except for higher age, as reported previously,24 of those with affected family members compared with the non-familial cases. Some data indicate that the inherited predisposing locus in familial MDS or AML with −7/7q− is not located on chromosome 7.56 This is in accordance with the absence of leukemia cases in a cohort study of 183 persons with constitutional aberrations of chromosome 7.60 Spontaneous regression of −7 has occasionally been reported in the literature.38,39,61–63 We add three new cases, all presenting with JMML, to this very unusual phenomenon. It has been suggested that spontaneous remission occurs when MDS is a polyclonal expression of a multiorgan disease.64 Our cases with spontaneous cytogenetic remission had clonal hematopoiesis and no signs of associated systemic disease, although patient 714 had atrial septal defect and the twins Nos 715 and 716 had an undefined bleeding disorder. None of the 20 children with MDS treated with AML-like chemotherapy not followed by BMT is surviving, although one patient remained in remission for 7 years until secondary malignancy occurred. Eight of 28 patients with RA. RAEB or JMML receiving AML-like therapy died during therapyinduced cytopenia. Previous studies5,39,43 showed similar poor outcome following intensive chemotherapy, although one study reported favorable outcome following intensive chemotherapy in RAEB and RAEB-T.65 As the overall remission rate and survival in childhood MDS is low −7 may not be an independent prognostic factor.43 In patients with RA or RAEB −7 alone may indicate a fair chance for a long stable period without progression and a favorable outcome following BMT without prior chemotherapy. This is in contrast to MDS with −7/7q− in adults, which is associated with a very poor prognosis.66 The survival in RA, RAEB, and JMML following BMT without prior chemotherapy was superior to that of patients treated with AML therapy alone or AML therapy followed by BMT. Although the comparison was hampered by the fact that children who received AML-like regimens as first-line therapy may represent more aggressive disease, our data suggest that BMT is the treatment of choice for these patients. The indolent nature of RA and RAEB often allows sufficient time searching for an optimal donor. Regression analyses showed morphologic diagnosis to be the strongest prognostic factor. Children with RA had a parti-

cular favorable prognosis, as was also shown in a series from St Jude Children’s Hospital.39 Children with MDS and −7 alone had a significantly better survival than those with other cytogenetic abnormalities. AML patients with −7/7q− had a poor prognosis as in previous studies.17,47 The present study indicates that the inferior survival in AML may only be related to those with −7 as the sole abnormality. The male predominance and the poor survival in AML with −7 is comparable to what is found in MDS. AML with −7 may represent an advanced stage (blast crisis) of MDS rather than truly de novo AML. Due to the low number of patients AML studies have traditionally lumped together −7 and 7q−.16–19,24 The present study suggests major differences in survival and biology and we recommend that −7 and 7q− be analyzed separately in future studies. Complete loss of chromosome 7 occurred in all morphologic subgroups. The patients differed in clinical features at presentation and in outcome. Only those patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. A previous EWOG-MDS study of children with JMML11 showed no major clinical differences between JMML in children with and without −7. Spontaneous growth in vitro and GM hypersensitivity are characteristics of JMML and are observed regardless of whether −7 is present or not13 (P Emanuel, unpublished data). NF1 has served as a model for the understanding of the pathogenesis of JMML. Mutation in the NF1 gene results in a lack of neurofibromin leading to a persistent activation of the Ras protein and hence disturbed signal transduction as if the ras gene had been mutated.67,68 Ras mutations are found in 15% of children without NF1 who have MDS associated with −7.67 The fact that −7 is seen at about the same frequency when JMML develops in NF1 as when it occurs in children without predisposing conditions11 is further evidence that monosomy 7 should not be considered a discrete entity. It may be more appropriate to consider children with clinical features of JMML as one disorder regardless of the presence of −7. Loss of chromosome 7 occurs in a heterogeneous group of myeloid disorders and our data give no support to the concept of monosomy 7 as a distinct syndrome.

Acknowledgements Alexandra Fischer, Department of Pediatrics, University of Freiburg, Germany is greatly appreciated for excellent management of the database. We are indebted to the many doctors who generously contributed data to the study.

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