Congenital leukaemia - Wiley Online Library

British Journal of Haematology, 2002, 117, 513–524

Congenital leukaemia: the Dutch experience and review of the literature Dorine Bresters, 1 Angelino C. W. Reus, 1 Anjo J. P. Veerman, 1 Elizabeth R. van Wering, 2 Anna van der Does-van den Berg 2 and Gertjan J. L. Kaspers 1 1Department Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, and 2Dutch Childhood Leukaemia Study Group, Den Haag, The Netherlands Received 15 August 2001; accepted for publication 27 November 2001

Summary. We reviewed Dutch patients and those described in the literature with congenital leukaemia in the past 25 years, with the intention to obtain an overview of the characteristics of this rare disease. Among the 117 patients reviewed, acute myeloid leukaemia (AML) was more frequent (64%) than acute lymphoblastic leukaemia (ALL, 21%). Most patients had a high leukaemic cell load with hepatosplenomegaly, leukaemia cutis and hyperleucocytosis. Cytogenetic abnormalities were found in the majority of the patients tested (72%); 11q23 abnormalities were found in less than half of them (42%). The probability of overall survival at 24 months was only 23%. When congenital AML and ALL were compared, clinical characteristics and overall survival were not significantly different. However, in patients at risk, the probability of event-free survival (EFS)

Although leukaemia is the most common malignancy in childhood, congenital leukaemia, manifesting itself within the first 4 weeks of life, is rare and accounts for < 1% of all leukaemias in childhood (Pierce, 1959; Bader & Miller, 1979). The following diagnostic criteria have been proposed for congenital leukaemia: (i) presentation in the first 4 weeks of life; (ii) proliferation of immature myeloid, lymphoid or erythroid cells; (iii) infiltration of these cells into nonhaematopoietic tissues; and (iv) absence of other diseases which may explain this proliferation (Pierce, 1959; Resnik & Brod, 1993; Odom, 1995). Recently, Sande et al (1999) have published a more general review of congenital and neonatal leukaemia, without precise clinical data on all reported cases. Most other reports of congenital leukaemia until now have been case reports or focused on specific features, such as skin involvement or cytogenetic abnormalities. Correspondence: Ms Dorine Bresters MD PhD, Department Pediatrics/IHOBA (J6-S), Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] 2002 Blackwell Science Ltd

and disease-free survival (DFS) were significantly higher in AML than in ALL, 43% versus 13% and 68% versus 0% respectively. Among the congenital AML cases, six spontaneous remissions have been described. In conclusion, the clinical characteristics of congenital leukaemia differ from those of leukaemia in older children and prognosis is generally poor. Once complete remission is achieved, patients with AML fare better than those with ALL. Chemotherapy for congenital leukaemia needs improvement to increase the sustained remission rate. Keywords: congenital leukaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, prognosis, transient myeloproliferative disorder.

We present two patients with congenital leukaemia, as seen in our centre, to illustrate the clinical features and course of this disease. The rarity of congenital leukaemia and the dismal outcome in our patients prompted us to retrospectively review the clinical characteristics of the Dutch patients, as well as the patients described in the literature, who were diagnosed with congenital leukaemia in the past 25 years. The purpose of the review was to give a comprehensive overview of the clinical and cell-biological features of congenital leukaemia. The differentiation from transient myeloproliferative disorder (TMD) is extensively discussed as well as the remarkable phenomenon of spontaneous remission in some patients with congenital leukaemia. CASE REPORTS Patient 1. After an uneventful full-term pregnancy, a girl was born by Caesarean section because of a transverse lie and fetal distress. Her birthweight was 4Æ4 kg and Apgar scores were 5, 8 and 9 after 1, 5 and 10 min respectively. It was immediately noticed that the baby had a blueberry muffin appearance. She was in respiratory distress, but

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responded well to oxygen treatment. The child was referred to the intensive care unit for further evaluation. The family history revealed that the parents were consanguineous, but no cancer or blood diseases ran in the family. Physical examination showed a pale-greyish neonate with petechiae, several purpurae and purple nodules. The liver and the spleen were 4 and 2 cm palpable below the costal margin respectively. Otherwise, no physical abnormalities were noted. Laboratory tests showed: haemoglobin 15Æ1 g/dl, platelets 6 · 109/l and white blood cell (WBC) count 140 · 109/l, with 84% blasts in the differential count. Clotting tests were normal. Creatinine and urea were normal for the age, urinary acid was 118 mmol/l (normal), aspartate transaminase (AST) 118 U/l, alanine transaminase (ALT) 62 U/l (normal < 50 U/l) and lactate dehydrogenase (LDH) was 1526 U/l (normal < 400 U/l). Serology testing was not indicative of congenital infection with toxoplasma, rubella, cytomegalovirus, herpes virus or syphilis. A bone marrow aspirate revealed 66% lymphoblasts, immunophenotypically consistent with a pro-B acute lymphoblastic leukaemia (ALL) (TdT, HLA-DR and CD19 positive; CD10, cytoplasmic l and surface immunoglobulin negative; CD13, CD15 negative, CD33 25%). Cytogenetic investigation (including fluorescence in situ hybridization (FISH)) showed a 46, XX karyotype and MLL gene rearrangement by t(11;19)(q23;p13). Lumbar puncture did not reveal meningeal involvement. Chest X-ray was normal. Cerebral ultrasound was normal. Abdominal ultrasound showed hepatosplenomegaly with the liver measuring 8Æ2 cm and the spleen measuring 7Æ2 cm in the midclavicular line. Treatment was started with hyperhydration, alkalization and allopurinol, and prednisone was started and gradually increased until a dose of 40 mg/m2/day was reached according to the Interfant 99 protocol (an international collaborative treatment protocol for infants under 1 year with ALL). She also received methotrexate and prednisolone intrathecally on day 1. The patient was a so-called good responder at day 8 (less than 1 · 109 blasts/l in peripheral blood) and multiagent induction treatment according to the good responder arm of the Interfant protocol was started (consisting of dexamethasone, vincristine, daunorubicin, cytarabine, l-asparaginase and intrathecal prednisolone, methotrexate and cytarabine). The patient was dependent on oxygen therapy for 3 weeks. Repeated chest X-rays did not show any pulmonary pathology. Blood cultures were repeatedly negative and antibiotics were discontinued after 1 week. Bone marrow evaluation at day 15 and day 33 of induction therapy showed hypoplastic bone marrow without blasts. After recovering from the induction treatment, chemotherapy was continued according to the MARAM (6-mercaptopurine, high-dose methotrexate, cytarabine and l-asparaginase) protocol. After this course, bone marrow aplasia lasted for almost 4 weeks, however, without any serious mucous membrane toxicity and without serious infections. Unfortunately, when her blood cell count did increase, lymphoblasts were again detected in the peripheral blood. This indicated either resistant disease or an early

relapse on treatment and further chemotherapy was not considered useful. The patient died at 5 months of age. Patient 2. After an uneventful full-term pregnancy, resulting from in vitro fertilization, a boy was born with a birthweight of 3Æ03 kg and Apgar scores of 9 and 10 after 1 and 5 min respectively. Minor skin lesions were noticed, but physical examination was otherwise normal with no organomegaly or petechiae, and he was discharged without further investigation. At the age of 20 d he was readmitted to the hospital because of persistent skin lesions. He also had mild respiratory distress and an enlarged abdomen. Physical examination at this time revealed hepatosplenomegaly with the liver and spleen palpable 8 and 7 cm below the costal margin respectively. Multiple purple nodules were scattered over his chest, arms and legs. Petechiae were absent. Otherwise, physical examination was normal. Laboratory results were: haemoglobin 11Æ6 g/dl, platelets 62 · 109/l and WBC count 187 · 109/l, with 82% blasts in the differential count. Blood cultures were negative and serology testing was not indicative of congenital infection with toxoplasma, rubella, cytomegalovirus, herpes virus or syphilis. Bone marrow aspiration failed and all tests were performed on peripheral blood cells. The blasts were weakly positive for periodic acid–Schiff (PAS) stain, partly positive for peroxidase and a-naphtylacetate esterase, inhibited by natrium fluoride. Immunophenotyping showed a population of mononuclear cells expressing CD13, CD14, CD15 and CD33 positivity. Lymphoid markers were absent (CD 10 0%, CD19 14%, CD20 0%, CD2 0%, CD7 0%). A diagnosis of acute myeloid leukaemia (AML), French-American-British (FAB) type M4, was made. Cytogenetic investigation revealed a normal 46XY karyotype and MLL gene rearrangement by t(4;11) (q21;q23). A biopsy of one of the skin lesions demonstrated leukaemic infiltration. Lumbar puncture was not performed because of his unstable clinical condition. Antibiotics, allopurinol, hyperhydration and alkalization were initiated and the patient was treated with thioguanine and cytarabine intravenously, both at a dose of 10 mg. Despite treatment, the WBC count increased towards 450 · 109/l and he was transferred to the intensive care unit. An exchange transfusion was performed and platelet transfusion was given. After this procedure, his WBC count was 85 · 109/l. Because of respiratory insufficiency, he was ventilated mechanically. Several hours after the exchange transfusion he became hypotensive and did not respond to intravenous fluid resuscitation or inotropic medication. His condition deteriorated with absence of pupillary reflexes and a bulging fontanelle. Cerebral ultrasound showed oedema and intraparenchymal haemorrhages extending into the left lateral ventricle. A decision was made to stop further treatment and the patient died at the age of 22 d. THE DUTCH EXPERIENCE (TABLE I) Fifteen patients were diagnosed with congenital leukaemia in the Netherlands during the last 25 years. In the first year covered in this review (1975), 100 children between 0 and 14 years of age were diagnosed with leukaemia

2002 Blackwell Science Ltd, British Journal of Haematology 117: 513–524

M 1976

M 1979

F 1983

F 1999

F 1977

M 1981

F 1982

M 1982

F 1983

F 1988

M 1988

F 1993

2415

3001

6710**

937

2666

2875

2933

3059

3982

4506

5442

Sex/ Year of diagnosis

687

DCLSG number*


AML

AML

AML

AML

AML

AML

AML

AML

ALL

ALL

ALL

ALL

Type of leukaemia

M4

M5

M5

M5

M5

M5

?

M4

L1

L1

L1

L1

FAB type

+ + – + + + – + + – – –

–– + + + + + – + + – + + – + + – + + + + + + + +

Lymph nodes/ Hepatomegaly/ Splenomegaly

+

+

+

+

+

–

–

–

+

–

+

––

Leukaemia cutis

–

?

+

?

+

–

+

–

–

–

–

––

CNS

98Æ2

221

18

342Æ1

3Æ4

153Æ6

3Æ9

14Æ7

140

295

440

109

WBC count ( · 109/l)

Table I. Clinical data of the Dutch patients with congenital leukaemia, diagnosed between 1975 and 2000.

No abnormality

?

t(10; 11)(p13;q23)

t(4; 10)(p+ ; p))

?

?

?

t(11; 13)(?;?)

t(11; 19)(q23;p13)

?

?

?

Cytogenetics

+

–

–

–

+

–

+

–

+

+

+

+

Therapy

+ –

–

–

–

+ + (1 years)

–

–

–

+ + (4 months)

+ + (25 months)

–

+ + (6 months)

Remission/§ relapse

Alive at last follow-up (59 months)

0Æ1

2

0Æ5

Alive at last follow-up (187 months)

1

0Æ6

4Æ5

5

29

2

8Æ5

Survival (months)

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1Æ3

*Dutch Childhood Leukaemia Study Group number. Central nervous system involvement of leukaemia. +, chemotherapy according to the current protocols, with intention to cure; –, supportive care only. §Upper +, complete remission achieved; lower +, relapse (time after diagnosis). ––, absent; +, present; ?, not done or unknown. **Described in case reports as patients 1 and 2.

+ t(9; 11)(p23;q13) 41Æ6 – – M0 M 1995 5895

AML

M5 F 1995 5815

AML

(90 ALL, 10 AML) in the Netherlands, with incidences of 2Æ85 and 0Æ32 per 100 000 children for ALL and AML respectively. In the last year covered by this review (1999), 122 children between 0 and 14 years were diagnosed with leukaemia (104 ALL, 18 AML), with an incidence of 3Æ74 and 0Æ63 per 100 000 children, for ALL and AML respectively. As less than one patient per year is diagnosed with congenital leukaemia, congenital leukaemia makes up less than 1% of paediatric leukaemias each year. Four out of 15 (26Æ7%) patients had ALL and 11 out of 15 patients (73Æ3%) had AML. Six out of 11 patients with congenital AML had FAB type M5. Almost all patients had hepato- and/or splenomegaly (14 out of 15 patients), eight out of 15 (53%) patients had leukaemic infiltration of the skin, and 10 out of 15 (67%) patients had hyperleucocytosis (defined as WBC count > 50 · 109/l). Four out of eight patients in whom cytogenetic investigation was performed had an 11q23 abnormality. Nine out of 15 patients (60%) were treated with intention to cure. However, only two patients survived, one (no. 5442) without events, who was treated with chemotherapy and autologous bone marrow transplantation, and one (no. 2933) after an isolated meningeal relapse, who is still alive after subsequent chemotherapy.

–

1 – – –

+

304Æ5

t(11; 19) (q23; p12–13)

– + M 1994 5572**

AML

M4

+ + + – + – – + +

+

?

187

t(4; 11)(q21;q23)

Remission/§ relapse Therapy Cytogenetics WBC count ( · 109/l) CNS Leukaemia cutis Lymph nodes/ Hepatomegaly/ Splenomegaly FAB type Type of leukaemia Sex/ Year of diagnosis DCLSG number*

Table I. continued

0Æ7

D. Bresters et al Survival (months)

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REVIEW OF THE LITERATURE (INCLUDING THE DUTCH PATIENTS) (TABLES II AND III) A Medline search for English language papers on congenital and neonatal leukaemia between 1975 and 2000 was carried out. A total of 102 patients with congenital leukaemia, as defined by the diagnostic criteria stated above, were identified (Abe et al, 1983; Allan et al, 1989; Badhe & Sane, 1992; Bastard et al, 1985; Benedict et al, 1979; Bernstein et al, 1984; Bernstein et al, 1987; Brissette et al, 1996; Campbell et al, 1997; Carney et al, 1992; Chu et al, 1983; Clark et al, 1984; Dinulos et al, 1997; Djernes et al, 1976; Embon et al, 1995; Fernandez et al, 1999; Francis et al, 1989; Fugazza et al, 1992; Gale & Toledano, 1984; Gale et al, 1986; Garewal et al, 1993; Gilgenkrantz et al, 1983; Gottesfeld et al, 1989; Gray et al, 1986; Hagemeijer et al, 1981; Hanada et al, 1991; Hara et al, 1984; Hayashi et al, 1985; Hazani et al, 1993; Heikinheimo et al, 1994; Huret et al, 1993; Irwin & Campbell, 1978; Isaacs, 1987; Jadhav et al, 1988; Kojima et al, 1989; Kurosawa et al, 1987; Kushwaha et al, 1977; Lampkin et al, 1985; Las-Heras et al, 1986; Lasson & Goos, 1981; Liang et al, 1986; Liang et al, 1993; Lilleyman, 1980; Matamoros et al, 1994; Mayer et al, 1995; McCoy et al, 1995; Monpoux et al, 1996; Mori et al, 1997; Muchi et al, 1985; Odom & Gordon, 1984; Ohyashiki et al, 1988; Raney et al, 1979; Rechavi et al, 1988; Resnik & Brod, 1993; Ridge et al, 1995; Sainati et al, 1996; Sait et al, 1988; Seo et al, 1986; Shah et al, 1984; Shimizu et al, 1987; Shimizu et al, 1989; Shitara et al, 1992; Silberstein et al, 1979; Simon et al, 1984; Sippe, 1981; Spier et al, 1984; Van den Berghe et al, 1979; Van den Berghe et al, 1983; Warrier et al, 1983; Weis et al, 1985; Yen et al, 1996; Zandecki et al, 1988). Six patients, who


Congenital Leukaemia

517

Table II. Clinical data of the patients with congenital leukaemia reported in the literature from 1975 to 2000, and including the Dutch patients diagnosed in the same period (n ¼ 117). Type of leukaemia

Sex Extramedullary involvement

WBC count (·109/l) Cytogenetics§

Therapy

ALL AML AUL Biphenotypic/switch JMML/JCML Female Male Leukaemia cutis Hepatomegaly Splenomegaly Lymphadenopathy Meningeal involvement Median (range) (n ¼ 105) 11q23 abnormality - t(4; 11) - t(9; 11) - t(11; 19) - Other Other abnormality No abnormality found Chemotherapy (n ¼ 64)–

Died before start of treatment (n ¼ 20) Supportive care only (n ¼ 26)

24/114* (21Æ1%) 73/114 (64%) 6/114 (5Æ3%) 8/114 (7%) 3/114 (2Æ6%) 48/110 (43Æ6%) 62/110 (56Æ4%) 66/104 (63Æ5%) 76/95 (80%) 71/95 (74Æ7%) 18/74 (24Æ3%) 16/32 (50%) 104 (2Æ6–968)

5/72 (6Æ9%) 2/72 (2Æ8%) 7/72 (9Æ7%) 8/72 (11Æ1%) 30/72 (41Æ7%) 20/72 (27Æ8%) CR** 40/64 (62Æ5%) PD** 20/64 (31Æ3%) Unknown 4/64 (6Æ3%)

CR 6/26 (23Æ1%) PD 20/26 (76Æ9%)

P < 0Æ0001 (AML versus ALL)

P ¼ 0Æ18

pOS 31Æ6% (± 6Æ5%)

pOS 13Æ3% (± 5Æ1%)

*Number of patients with the characteristic/number of patients in which presence or absence of the characteristic is described. AUL, peroxidase positivity < 3% of blasts and neither lymphoid nor myeloid (< 20% positivity) surface markers. Biphenotypic (both lymphoid and myeloid markers) at presentation or switch from lymphoid to myeloid leukaemia or vice versa at relapse (see text). §Cytogenetic abnormalities, either with or without 11q23 abnormality. –Varies from single agent to multiagent chemotherapy and includes three AML patients who received a stem cell transplant. **CR, complete remission; PD, progressive disease; unknown, response to treatment unknown. pOS, probability of overall survival at 24 months in patients who received chemotherapy and in whom duration of survival after treatment was described (n ¼ 58). pOS, probability of overall survival at 24 months in patients who were not treated with chemotherapy (n ¼ 46). JMML, juvenile myelomonocytic leukaemia; JCML, juvenile chronic myeloid leukaemia.

were stillborn, but in whom autopsy confirmed leukaemia (with infiltration of leukaemic cells into non-haematopoietic tissue), were included. Another six patients, who were described as having congenital leukaemia, but in whom, owing to the lay-out of the papers concerned, information on criterion 3 (infiltration of leukaemic cells into nonhaematopoetic tissues) was lacking, were included. Some papers did not report whether other causes of the proliferation had been properly investigated and ruled out (criterion 4), but if the disease course suggested a leukaemoid reaction or TMD (see next paragraph), the patients were not included in the review. Differentiation from TMD A major problem in newborns can be to distinguish true congenital myeloid leukaemia from either a leukaemoid

reaction (as may occur with congenital infection, sepsis, haemolysis or severe asphyxia) or from TMD (Liang et al, 1986; Hayashi et al, 1988; Kurahashi et al, 1991; Zipursky et al, 1992; Liang et al, 1993, 1986; Lange et al, 1998; Lange, 2000). TMD is initially indistinguishable from congenital leukaemia, but always remits spontaneously. TMD has an almost universal association with Down’s syndrome or other manifestations of trisomy 21 (including mosaicism), a cytogenetic abnormality that occasionally may be found in blast cells only. In TMD, the blast cells typically have surface antigens characteristic of megakaryoblasts (FAB M7). What may make differential diagnosis difficult is that TMD has been described, although rarely, in patients without chromosome 21 abnormalities (Kalousek & Chan, 1987; Brissette et al, 1994). In several cases of TMD, the blast cells have been shown to be clonal in origin as in


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D. Bresters et al Table III. Clinical characteristics of patients with congenital ALL versus AML as described in the literature from 1975 to 2000 and including the Dutch patients.

ALL (n ¼ 24) Lineage/FAB classification

Leukaemia cutis WBC count (· 109/l), median (range) Cytogenetics: 11q23 abnormality

Other No abnormality found CR– pOS**

B lineage: pro-B cALL T lineage Unknown M0 M1 M2 M4 M5 M6 M7 Unknown

t(4;11) t(9;11) t(11;19) Other

AML (n ¼ 73)

8/11* (72Æ7%) 1/11 (9Æ1%) 2/11 (18Æ2%) 13/24

11/20 (55%) 114 (9Æ7–666) (n ¼ 21)

1/51 (2%) 1/51 (2%) 6/51 (11Æ8%) 9/51 (17Æ6%) 30/51 (58Æ8%) 3/51 (5Æ9%) 1/51 (2%) 22/73 46/66 (69Æ7%) 79Æ1 (3Æ4–900) (n ¼ 67)

0 0 3/13 (23%) 0 4/13 (30Æ8%) 6/13§ (46Æ2%) 11/16 (68Æ8%) 13Æ6% (± 7Æ3%) (n ¼ 22)

1/42 (2Æ4%) 2/42 (4Æ8%) 3/42 (7Æ2%) 4/42 (9Æ5%) 22/42 (52Æ4%) 10/42 (23Æ8%) 19/30 (63Æ3%) 24Æ4% (± 5Æ4%) (n ¼ 69)

P ¼ 0Æ22 P ¼ 0Æ30

P ¼ 0Æ71 P ¼ 0Æ52

*Number of patients with the characteristic/number of patients in which presence or absence of the characteristic described. One patient: blasts with both megakaryocytic and erythroid markers. Cytogenetic abnormalities, either with or without 11q23 abnormality. §Including two patients with germline trisomy 21. –Number of patients treated with curative intention, who achieved complete remission/number of treated patients in whom achievement of remission described. **pOS, probability of overall survival at 24 months of follow-up in patients for whom duration of survival was described (in two ALL and four AML patients, survival unknown). Including three patients treated with allogeneic bone marrow transplantation.

leukaemia (Kurahashi et al, 1991; Lange, 2000). Also, retrospective surveys indicate that as many as 30% of infants with TMD will develop AML (usually of M7 subtype) before 3 years of age (Homans et al, 1993). In our review, we excluded Down’s syndrome patients with probable TMD. Two patients with Down’s syndrome and congenital ALL, both stillborn (Gray et al, 1986), and a patient with mosaicism trisomy 21 and congenital AML (FAB M2), who died aged 2 weeks (Liang et al, 1986, 1993) were included. One patient with pentasomy 21 in blast cells only (ALL) responded well to mild chemotherapy and is in long-term remission (Van den Berghe et al, 1983). One patient with FAB M7 leukaemia who had no chromosome 21 abnormality but a t(1;22)(p13;q13) and one patient with mixed FAB M6/M7 leukaemia and normal cytogenetics were included in the review (Sait et al, 1988; Mori et al, 1997). The clinical characteristics of 102 patients with congenital leukaemia reported in the literature and 15 Dutch

patients of the last 25 years are shown in Table II. In Table III, the characteristics of congenital ALL compared with congenital AML are described. Statistical significance (P < 0Æ05) of differences in clinical characteristics of AML versus ALL was calculated with Pearson v2-test and for WBC with Mann–Whitney U-test. Not all information could be obtained for every reported patient because many case reports lacked critical information. Type of leukaemia, lineage/FAB classification As has been described before, congenital leukaemia, in contrast to leukaemia in older children, is more often of myeloid lineage (Wolk et al, 1974; Weinstein, 1978; Morse et al, 1979; Resnik & Brod, 1993). Among 114 neonates in whom the type of leukaemia was reported, AML is significantly more frequent (64%) than ALL (21Æ1%; P < 0Æ0001; Table II). The most frequent immunophenotype of ALL is


Congenital Leukaemia pro-B ALL (72Æ7%; Table III), which is much more frequent than in older children with ALL. The majority of patients with congenital AML have monoblastic leukaemia (FAB M5, 58Æ8%; Table III), which differs from the prevalence of this FAB type in older children with AML (15–25%) (Weinstein, 1999; Pui et al, 2000). FAB M2 is less frequent in congenital myeloid leukaemia, 12% compared with 28% in older children (Weinstein, 1999). Interestingly, four patients with congenital leukaemia have been described in the literature who showed a phenotypic switch from lymphoid to myeloid leukaemia (Hayashi et al, 1985; Ridge et al, 1995; Brissette et al, 1996) or vice versa (Shimizu et al, 1989) at relapse. In another four patients both myeloid and lymphoid surface markers (biphenotypic) were found on the blasts (Rechavi et al, 1988; Fugazza et al, 1992; Shitara et al, 1992; Matamoros et al, 1994) (Table II). It is assumed that these leukaemias develop from an early stem cell that can differentiate in both the myeloid and the lymphoid direction. Phenotypic switch and biphenotypic leukaemia have also been described in infants after the neonatal period (Greaves, 1996). Clinical presentation Although more boys than girls have been reported with congenital leukaemia, this difference was not statistically significant (Table II). The characteristic presentation of congenital leukaemia is that of leukaemia cutis, which is one of the causes of the so-called blueberry muffin baby (differential diagnosis of the blueberry muffin baby also includes rhabdomyosarcoma, neuroblastoma and histiocytosis), and hepatosplenomegaly. As a skin biopsy was seldom performed, it was difficult to be sure from the literature if skin lesions were indeed leukaemic infiltrates. However, when described as palpable and/or blue/red/purple lumps, we considered this leukaemia cutis. If skin lesions were described as petechiae or purpurae we did not consider them to be leukaemia cutis, but we may therefore have missed some cases with leukaemia cutis. By this definition, overall, 63Æ5% of the patients with congenital leukaemia had leukaemic skin infiltrates (Table II), which appeared to be present more often in AML than ALL, but this difference was not statistically significant (Table III). Hepatomegaly and splenomegaly were present in 80% and 74Æ7% of the patients respectively (Table II). Lymphadenopathy was less common (24Æ3%). Although lumbar puncture was described in only a minority of patients (n ¼ 32), central nervous system (CNS) involvement appeared to be common and occurred in 50%. Hyperleucocytosis is present in a majority of the patients with a median leucocyte count of 104 · 109/l. The median WBC count was higher in ALL compared with AML, but the range was similar (P ¼ 0Æ30; Table III). A high leukaemic cell load with extramedullary involvement is the rule rather than the exception in congenital leukaemia, as is reflected in the diagnostic criteria. Cytogenetics Cytogenetic investigations were performed in the majority of the patients (n ¼ 72), but the recently developed more

519

sensitive techniques such as fluorescent in situ hybridization (FISH) were not available in the earlier years of the study. Although the t(4;11)(q21;q23) translocation has been reported in up to 75% of all leukaemias diagnosed in the first year (Greaves, 1996), the MLL rearrangement may not be that common in congenital leukaemia. Overall, 30Æ6% (22 out of 72) of patients in whom cytogenetic investigations were performed had a translocation involving the chromosome region 11q23 (t(4;11), t(9;11), t(11; 19) and other 11q23 abnormalities (Table II). In most of them, the MLL rearrangement was confirmed using molecular biological techniques. Interestingly, six out of eight patients who had either biphenotypic leukaemia or a switch in type of leukaemia at relapse had an 11q23 abnormality/MLL rearrangement. It has been recognized that the classic form of infant ALL, characterized by an immature B-lineage immunophenotype with coexpression of myeloid markers, which probably also originates from an early stem cell, correlates with 11q23 abnormalities; (Chessells et al, 1994; Greaves, 1996; Biondi et al, 2000). In only two patients with congenital AML, a t(9;11)(p22;q23) was described, a translocation which in infants (aged 24 months or less) was shown to be associated with a favourable prognosis (Pui et al, 2000). These two patients were both responders to treatment, but one died after relapse and, in the other, survival was not described (Shimizu et al, 1987; Monpoux et al, 1996). Both in congenital ALL and AML other cytogenetic abnormalities have been described, which were very diverse and therefore are not given in more detail (Table III). The prognostically favourable cytogenetic abnormalities described in older children with AML [t(8;21), t(15;17), inv(16)] were not seen in any of the patients. None of the ALL patients had a t(12;21)(p12;q22) translocation. Treatment and prognosis For Kaplan–Meier analysis overall survival (OS) was defined as the time (in months) from diagnosis to death, and stillborn babies were included with an OS of 0 months. Event-free survival (EFS) was defined as the time from diagnosis to either recurrence of disease or death in complete remission. Patients who did not achieve complete remission (CR) were considered a failure on day 0 (EFS 0 months). Stillborn babies, patients who died before treatment could be instituted, and patients who received supportive care only, were censored for analysis of EFS. Spontaneous remissions were included in the analysis of EFS. Disease-free survival (DFS) was defined as the time from complete remission to either recurrence of disease or death in complete remission. The probability of OS/EFS/DFS (pOS/ pEFS/pDFS (± SE)) is given at 24 months, because the median follow-up in the group of patients at risk was 26 months (range: 4–187 months), 26 months and 25 months, respectively, and, except for one patient with ALL (recurrence of disease at 25 months and death at 29 months), all events occurred within 24 months from diagnosis or complete remission. Statistical significance (P < 0Æ05) for Kaplan–Meier analysis was calculated with a log rank test.


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A total of 64 out of 110 (58Æ2%) patients with congenital leukaemia were treated with chemotherapy with an intention to cure (in seven patients it was not described whether treatment was given; Table II). This treatment was quite heterogeneous, depending on the year of diagnosis, the type of leukaemia and the treatment centre. Therapies with single-agent as well as multiagent chemotherapy have been tried, the latter predominantly in recent years with better awareness of the dismal prognosis and with better supportive care. Although 62Æ5% of the treated patients achieved CR, the pOS in the treated group was only 31Æ6% (± 6Æ5%) (Table II). These results may be biased favourably by the fact that successfully treated patients were probably more likely to be reported. The remission rate on chemotherapy was similar for AML and ALL (Table III). Half of the patients who achieved CR with chemotherapy relapsed (meningeal in two patients and bone marrow in 19) and only three of them survived after further treatment. Relapse occurred after a median duration of remission of 6 months (range: 1–25 months). Three patients in the treated group died of infection. Among 46 patients who received supportive care only, including the ones who died before chemotherapy could be started, the pOS was 13Æ3% (± 5Æ1%). This was significantly less (P < 0Æ00001) than the pOS in the treated group. Among the patients who had received supportive care only, six patients showed a spontaneous remission (see next paragraph). Both the Dutch patients and our literature search confirm the poor prognosis of congenital leukaemia. Patients with congenital leukaemia who were stillborn or died in the first few days of life, even before treatment could be started, were described. The pOS (± SE) among 109 patients with congenital leukaemia for whom the duration of survival was described and including stillborns (with a survival of zero), was 22Æ7% (± 4Æ2%) at 24 months of follow-up (Fig 1). The pEFS in 64 patients at risk was 30Æ6% (± 5Æ9%) at 24 months of follow-up, and the pDFS in 44 patients at risk was 45Æ3% (± 8Æ4%) at 24 months of follow-up. The 64 patients analysed for EFS included the six spontaneous remissions and 58 out of 64 patients who had received chemotherapy (six treated patients were excluded from analysis; in four because response to treatment was not described and in two because survival after CR was not described). The 44 patients analysed for DFS included the six spontaneous remissions and 38 patients who achieved CR after chemotherapy (two patients excluded from analysis because survival after CR unknown). When pOS was analysed and compared in 69 congenital AML and 22 congenital ALL patients, for whom duration of survival had been described (including stillborns), overall survival appeared to be better in AML as compared with ALL, pOS 24Æ4% and 13Æ6% respectively (Table III and Fig 2). However, this difference was not statistically significant (P ¼ 0Æ52). This could well be due to a limited number of patients in follow-up. Among the AML group, 16 patients, including six spontaneous remissions, out of 69 survived with a median duration of follow-up of 35Æ5 months (range 10–187 months). Among the ALL

Fig 1. Overall survival in 109 congenital leukaemia patients in whom the duration of survival from diagnosis had been described.

Fig 2. Overall survival in 69 congenital AML patients as compared with 22 congenital ALL patients for whom duration of survival from diagnosis had been described.

group, two patients out of 22 survived with a duration of follow-up of 18 and 21 months. The pEFS in patients at risk at 24 months of follow-up was 42Æ7% (± 8Æ4%) and 13Æ3% (± 8Æ8%) in 35 AML and 15 ALL patients respectively (P ¼ 0Æ02). Although the numbers were small, pDFS, once patients have achieved complete remission (either after chemotherapy or spontaneously), also was significantly better in congenital AML as compared to congenital ALL, 67Æ9% (± 10Æ0%) and 0%, respectively (P ¼ 0Æ003; Fig 3). As many case reports lack information on long-term follow up and the numbers are small, it was not possible to draw a conclusion on any secular trend in outcome over the 25-year study period. However, overall survival in the treated patients in the five, 5-year periods covered by this review did not seem to be different (data not shown). Spontaneous remissions Interestingly, six patients with congenital AML in whom the disease remitted without having had any chemotherapy


Congenital Leukaemia

Fig 3. Disease-free survival in congenital AML patients (n ¼ 22, including six spontaneous remissions) as compared with ALL patients (n ¼ 10), analysed in the patients who achieved complete remission (CR) and in whom duration of (disease-free) survival after CR had been described. (In congenital ALL, two out of 10 patients who achieved CR had a recurrence of disease within 1 month of CR.)

have been described (Lampkin et al, 1985; Isaacs, 1987; Gottesfeld et al, 1989; Mayer et al, 1995; Sainati et al, 1996; Dinulos et al, 1997). The duration of follow-up in these patients is 10–48 months. Five of these patients had monoblastic leukaemia (FAB M5) and in one, FAB type was not described. All six patients had skin involvement and two patients had hepatosplenomegaly; in one patient the latter was not described. WBC count was above 50 · 109/l in three out of six patients. Cytogenetics was carried out in five patients and was normal in two. Cytogenetic abnormalities in three included t(5;6)(q31;q21), inv(9), and t(8;16) (p11;p13). So neither FAB type nor (cyto)genetics were characteristic for TMD (see paragraph on TMD). We must therefore assume that spontaneous remission, although rare, may occur in congenital AML. FUTURE PERSPECTIVES AND CONCLUSIONS Although there is, understandably, reluctance to treat neonates with high-intensity multiagent chemotherapy, the historically poor prognosis of the disease may warrant this approach. In vitro tests with the MTT assay have shown that infants with ALL are relatively resistant to steroids, vincristine and asparaginase, but relatively sensitive to cytarabine (Pieters et al, 1998). The new international protocol for infant lymphoblastic leukaemia (Interfant-99), which includes patients with congenital disease and consists of chemotherapy derived from both the treatment of myeloid and lymphoid leukaemia, will hopefully give a higher sustained remission rate. In congenital AML, if the clinical condition of the patient allows it, time should be taken to complete investigations needed for differentiation from a leukaemoid reaction and from probable TMD. At this time, patients with congenital myeloid leukaemia in the Netherlands are treated according to the national acute non-lymphoblastic leukaemia protocol also in use for older children. This subgroup is too small to

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reach a conclusion on results as compared with older children. The occurrence of spontaneous remissions, even in true congenital AML, could mean that a small proportion of patients receives intensive chemotherapy, whereas they would have recovered without treatment. Unfortunately however, there are currently no characteristics that identify these patients at diagnosis. In conclusion, the review of 117 patients with congenital leukaemia shows that the prognosis of this disease is generally poor and that improvements in the (chemotherapeutic) treatment of these patients are needed to achieve higher sustained remission rates. The disease must be distinguished from TMD. Rarely, spontaneous remissions appear to occur in congenital AML, especially in the FAB M5 subgroup. ACKNOWLEDGMENTS We thank the Dutch Childhood Leukaemia Study Group (DCLSG) for providing the data on the Dutch patients with congenital leukaemia. Board members of the DCLSG are: H. van den Berg, J. P. M. Bo¨kkerink, S. S. N. de Graaf, B. Granzen, P. M. Hoogerbrugge, W. A. Kamps, F. A.E. Nabben, R. Pieters, J. A. Rammeloo, T. Re´ve`sz and A. J. P. Veerman. REFERENCES Abe, R., Ryan, D., Cecalupo, A., Cohen, H. & Sandberg, A.A. (1983) Cytogenetic findings in congenital leukemia: case report and review of the literature. Cancer Genetics and Cytogenetics, 9, 139– 144. Allan, R.R., Wadsworth, L.D., Kalousek, D.K. & Massing, B.G. (1989) Congenital erythroleukemia: a case report with morphological, immunophenotypic, and cytogenetic findings. American Journal of Hematology, 31, 114–121. Bader, J.L. & Miller, R.W. (1979) US cancer incidence and mortality in the first year of life. American Journal of Diseases of Children, 133, 157–159. Badhe, P.B. & Sane, S.Y. (1992) Congenital leukemia: organ involvement in six autopsy cases. Journal of Postgraduate Medicine, 38, 127–129. Bastard, C., Vannier, J.P., Bizet, M., Lenormand, B. & Tron, P. (1985) Translocation (4;11;17) in a case of acute lymphoblastic leukemia (letter). Cancer Genetics and Cytogenetics, 17, 81–82. Benedict, F.W., Lange, M., Greene, J., Derencsenyi, A. & Alfi, O.S. (1979) Correlation between prognosis and bone marrow chromosomal patterns in children with acute nonlymphocytic leukemia: similarities and differences compared to adults. Blood, 54, 818–823. Bernstein, R., Macdougall, G.L. & Pinto, M.R. (1984) Chromosome patterns in 26 South African children with acute nonlymphocytic leukemia (ANLL). Cancer Genetics and Cytogenetics, 11, 199–214. Bernstein, R., Pinto, M.R., Spector, I. & Macdougall, L.G. (1987) A unique 8;16 translocation in two infants with poorly differentiated monoblastic leukemia. Cancer Genetics and Cytogenetics, 24, 213–220. Biondi, A., Cimino, G., Pieters, R. & Pui, C. (2000) Biological and therapeutic aspects of infant leukemia. Blood, 96, 24–33. Brissette, M.D., Duval-Arnould, B.J., Gordon, B.G. & Cotelingam, J.D. (1994) Acute megakaryoblastic leukemia following transient


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