Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:37-43

Original Article

Acute Leukaemia in Infants Less Than 18 Months of Age: A Retrospective Analysis of 13 Cases

SK Ma, SY Ha, GCF Chan, LC Chan, YL Lau


Abstract

Clinical features, blast cell immunophenotype, cytogenetic findings and treatment outcome were analyzed in a retrospective study of 13 cases of infant leukaemia diagnosed in Queen Mary Hospital, Hong Kong, over a ten-year period. There were 11 cases of acute lymphoblastic leukaemia (ALL) and two cases of acute myeloid leukaemia (AML). Bulky disease with organomegaly, central nervous system (CNS) involvement and high white cell count were prominent features at presentation. Four out of 11 cases (37%) of ALL were common ALL antigen (CALLA) negative assuming an early B-precursor phenotype. Translocation 4;11 was found in one case out of seven analyzed (14%), giving a lower incidence when compared with published data, though the sample size was small. Among ALL cases, we found a complete remission (CR) rate of 91%. Most of them relapsed, giving a probability of event-free survival (EFS) of 20.8% at 48 months. Nevertheless, a significant number was salvaged and the total survival was 56.8% at 84 months. The findings showed that infant leukaemia had distinctive clinical and biological characteristics. A high risk for relapse was noted but the probability of survival in our series was encouraging.

Keyword : Acute leukaemia; Cytogenetics; Immunophenotype; Infant; Outcome


Abstract in Chinese

Introduction

The clinical and biological features of acute leukaemia in infants differ markedly from that occurring in older children. Infants with AML generally have monoblastic or myelomonocytic subtypes with hyperleucocytosis and a propensity for extramedullary involvement.1 Acute lymphoblastic leukaemia in infants is usually characterized by hyperleucocytosis, hepatosplenomegaly, CNS disease and blast cells which are CALLA negative ("null" cell / early B-precursor ALL).2 Treatment outcome is uniformly poor in infants having both forms of acute leukaemia.3,4 Recent cytogenetic and molecular analysis of infants with acute leukaemia reveal a high incidence of non-random chromosomal translocation involving the 11q23 region5 with rearrangements of the MLL oncogene.6,7 Such genetic aberration has been shown to confer a poor prognosis to infants thus affected.8-10

A retrospective study was undertaken to examine the presentation, immunophenotype, cytogenetic data, response to treatment and clinical outcome of a series of infants with acute leukaemia seen at the Queen Mary Hospital over a ten-year period. We had included all cases below 18 months in the present study, since there were evidence that many of those between 12-18 months shared clinical and biological features with cases below a year of age, and the same age criterion was used in an ongoing multicentre case-controlled trial on molecular epidemiology of infant leukaemia which two of the co-authors (SYH, LCC) were involved in.

Methods

Patients

Between January 1985 to June 1995, a total of 13 infants below the age of 18 months were diagnosed as suffering from acute leukaemia. There were nine males and four females, giving a M:F ratio of 2.3:1. The mean age at presentation was 9 months. The leukaemia were classified according to French-American-British (FAB) Cooperative Group criteria11,12 based on morphology supplemented by cytochemistry and immunophenotyping. CNS disease was defined as more than 5 cells/mm3 in the cerebrospinal fluid (CSF) recognizable as leukaemic blasts. For the purpose of the present study, archival materials and records were retrieved and analyzed.

Immunophenotyping

Peripheral blood and bone marrow cells were separated on a Ficoll-Hypaque gradient (Nycomed, Oslo, Norway) and mononuclear cells harvested to enrich for blast cells. The cells were labeled with commercially available monoclonal antibodies to CD19, CD10, CD20, CD22 (Blineage associated, Coulter, Hialeah, FL), CD7, CD2, CD5, CD1, CD3 (T-lineage associated, Coulter), CD13, CD33 (myeloid-lineage associated, Coulter), CD41, CD42b (megakaryocytic-lineage associated, Coulter), CD45 (leucocyte common antigen, Coulter) and HLA-DR (Coulter). Detection of antibody binding was either by alkaline phosphatase anti-alkaline phosphatase (APAAP) method (Dako, Carpinteria, CA) or by flow cytometry using a Coulter EPICS Profile II flow cytometer (Coulter) equipped with a 15-mW (488 nm) laser. Isotypically matched immunoglobulins (Coulter) were used as negative controls for the monoclonal antibodies used for cell labeling. An antigen was considered positive when they were expressed in more than 20% of blast cells. Nuclear terminal deoxyribonucleotidyl transferase (Tdt) and cytoplasmic-μ chain were detected on cytospins of leukaemic blasts using kits (Supertech for Tdt; Dako for cytoplasmic-μ) or, alternatively, by flow cytometry after permeabilization of cell membrane according to the protocol as described.13 Leukaemic immunophenotype were classified where possible according to the recommendations of the First Morphologic, Immunologic and Cytogenetic (MIC) Co-operative Group.14

Chromosome analysis

Bone marrow samples were obtained at diagnosis and cytogenetic study was performed as previously described by Chan et al.15 Briefly, a direct harvest was done as soon as the sample was obtained. This was supplemented by short term overnight cultures with fluorodeoxyuridine and uridine as blocking agents, and thymidine as release. After washing, fixation, harvest and banding, at least 20 metaphases were counted and 10 metaphases were analyzed. The karyotype was reported according to ISCN 1991.16

Treatment

ALL

Patients diagnosed prior to 1989 were treated by United Kingdom (UK) ALL-VIII protocol. After 1989, chemotherapeutic regimens were modeled on the UK infant ALL protocols. In summary, vincrisitne, prednisolone, daunorubicin and L-asparaginase were used in induction phase while etoposide and cytarabine were used in first consolidation. CNS-directed treatment consisted of intrathecal methotrexate and high dose intravenous methotrexate. Cranial irradiation was avoided except in one patient (case no.3, see below) who had florid CNS involvement on presentation. Second consolidation was achieved with mitozantrone and cytarabine with 6-mercaptopurine, methotrexate, prednisolone and vinristine being used as interim continuation therapy. Late intensification consisted of dexamethasone, vincristine, L-asparaginase, cyclophosphamide, cytarabine and thioguanine. Treatment was continued to a total of two years from diagnosis. Relapsed patients were treated with UKALL-XI induction regimen followed by a continuous and intensive Berlin Frankfurt-Münster (BFM) type of chemotherapy. Patients who suffered from CNS relapse (isolated or combined) received, in addition, triple intrathecal therapy until CSF was clear of blasts while patients with testicular disease on relapse received, in addition, testicular irradiation.

AML

Patients were treated by a modified UK Medical Research Council (MRC) AML-10 protocol. Briefly, induction chemotherapy consisted of two courses of daunorubicin, cytarabine and etoposide together with triple intrathecal therapy. Amsacrine, etoposide, cytarabine and mitozantrone were used as consolidation.

Statistical methods

The method of Kaplan and Meier25 was used to construct projections of total as well as event-free survival (EFS). EFS was defined as the time to first occurrence of induction failure, relapses at any site or death. For patients not experiencing an event, EFS was the time to last follow-up.

Results

Clinical features at diagnosis

Among the 13 consecutive cases of infant leukaemia diagnosed and treated in Queen Mary Hospital in a tenyear period from 1985 to 1995, there were 11 cases of ALL and two cases of AML (Table I). The majority had hepatosplenomegaly (92%) and lymphadenopathy (62%) at presentation. Mediastinal mass was seen in the two patients suffering from T-ALL (cases 9 and 12) only. Three out of 13 (23%) had CNS disease at diagnosis while testicular involvement at diagnosis was seen in only one patient (7.7%). Two other common features on presentation were fever (77%) and bleeding tendency (46%).

Table I Clinical Features of 13 Consecutive Infant Leukaemias
Patient No Sex Age
(months)
Diagnosis LN Liver Spleen Mediastinal mass CNS disease Testicular disease Fever Bleeding
1 M 13 ALL + + + - - - - +
2 F 16 AML - - - - - - + -
3 M 9 ALL + + + - + - + -
4 F 6 ALL - + + - - - + +
5 M 6 ALL - + + - - - + -
6 M 13 ALL + + + - - - + -
7 F 5 AML - + + - + - - -
8 M 5.5 ALL - + + - - - + +
9 M 16 ALL + + + + - - + +
10 M 9 ALL + + + - + + - +
11 M 5 ALL + + + - - - + -
12 F 6 ALL + + + + - - + +
13 M 15 ALL + + + - - - + -
Key: +: present; -: absent; LN: lymphadenopathy

The white cell count at diagnosis ranged from 5.1 to 416.5 x 109/L with a median of 45.5 x 109/L (Table II). Three patients (23%) had a white cell count of over 100 x l09/L. There appeared to be no correlation between high white cell count at diagnosis and the presence of CNS disease. The median haemoglobin concentration at diagnosis was 7.7 g/dL (range: 5.1-10 g/dL) while the median platelet count was 48 x 109/L (range : 12-107 x 109/L). Among the 11 cases of ALL, nine (82%) were classified according to FAB criteria as L1 while the remaining two (18%) as L2. Of the two patients suffering from AML, one had acute megakaryoblastic leukaemia (FAB-M7) while the other acute myelomonocytic leukaemia (FAB-M4).

Table II Laboratory Findings of 13 Consecutive Infant Leukaemias
  Cytochemical reaction of blasts
Patient WBC
(x 109/L)
Haemoglobin
(g/dL)
Platelet
(x 109/L)
FAB MPO SBB PAS CAE NSE NSE-F ACP ACP-T
1 33.8 7.3 12 L2 ND - - - - ND - ND
2 11.2 9.5 104 M7 ND - +(34) - - ND +(90) -
3 25.4 10 107 L1 ND - +(29) - +(15) ND - ND
4 89.5 7 31 L1 - - +(24) - +(7) - - ND
5 416.5 7.2 72 L1 - - +(9) - - ND - ND
6 260 5.1 53 L1 - - - - - ND - ND
7 230 3.8 27 M4 +(90) +(90) - +(80) +(60) - +(50) -
8 28.3 8.2 65 L1 - - +(30) - - ND +(5) -
9 45.5 5.1 37 L1 - - +(15) - - ND +(55) -
10 69 9.1 48 L1 - - +(5) - - ND - ND
11 88 9.5 54 L1 - - +(60) - - ND - ND
12 21.2 7.7 20 L2 - - - - +(90) - +(100) -
13 5.1 9 45 L1 - - ND ND ND ND ND ND
Key: +: positive (% positivity in brackets); -: negative; ND: not done; FAB: French-American-British Group; MPO: Myeloperoxidase; SBB: Sudan Black B; PAS: Periodic acid schiff; CAE: Chloroacetate esterase; NSE: Non-specific esterase; NSE-F: NSE with fluoride inhibition; ACP: Acid phosphatase; ACP-T: ACP with tartrate inhibition

Blast cell immunophenotype

Immunophenotyping results with a panel of monoclonal antibodies were tabulated in Table III. Among the 11 cases of ALL, there were four CALLA-negative early B-precursor ALL (37%), three common ALL (27%), two pre-B ALL (18%) and two T-ALL (18%). In the two cases of common ALL (cases 1 and 4) diagnosed before 1989, cytoplasmic-μ chain detection was not performed, i.e. pre-B ALL could not be ruled out. No case of acute mixed lineage leukaemia was seen.

Table III Immunophenotype of Leukaemic Blasts
Patient No. CD13 CD33 CD19 CD20 CD22 CD10 Cyt-μ CD2 CD3 CD5 CD7 CDla Tdt HLA-DR CD45 Others Conclusion
1 ND ND ND ND + + ND - ND ND ND ND ND + ND ND Common ALL
2 ND - ND ND - - ND - ND - - ND ND - + CD42b+ AM7L
3 - ND + - - - ND - ND - ND ND ND + + ND Early B-precursor ALL
4 - - + - + + ND - - - - ND ND + ND ND Common ALL
5 - ND + - - - ND - - - - ND ND + ND CD41-
CD42b-
Early B-precursor ALL
6 - ND + ND - - ND - ND ND - ND + - ND ND Early B-precursor ALL
7 + - - ND - ND ND ND ND ND - ND - + ND CD34- AM4L
8 ND ND + ND - - ND ND ND - - ND ND + ND ND Early B-precursor ALL
9 - - - ND - - - - - + + + + - ND CD41-
CD14-
CD15
T-ALL
10 - ND + - + + + - - ND - ND + + + CD34- Pre-B ALL
11 ND - + - ND + - - - ND - ND ND + + ND Common ALL
12 - - - - - - - - + + + - + - + CD34- T-ALL
13 ND ND + ND + + + - - - - - ND + ND ND Pre-B ALL
Key: +: present; -: absent; ND: Not done

Karyotypic abnormality

Out of seven cases successfully karyotyped, two (29%) had clonal karyotypic abnormality, both of which were structural changes (Table IV). Patient no. 6, who harbored t(4;11)(q21;q23), was a 13-month old infant presenting with hepatosplenomegaly, generalized lymphadenopathy and a white cell count of 260 x 109/L. In addition he had pericentric inversion of chromosome 9, a common constitutional anomaly. He was diagnosed as having early B-precursor ALL (CALLA-negative) and a complete remission was attained after chemotherapy. However, he relapsed 34 months later and succumbed to infection (methicillin-resistant staphyloccocus aureus septicaemia) during prolonged neutropenia on re-induction. A rare translocation t(6;7)(q24;q36) was found in patient no. 9 who was diagnosed to suffer from T-ALL at the age of 16 months. He is still in complete remission after three years of follow-up.

Table IV Cytogenetic Data and Treatment Outcome
Patient No. Cytogenetic result Time to CR
(days)
Site of relapse EFS
(months)
Duration of follow-up
(months)
Disease status
1 ND 28 CNS 9 20 dead
2* ND No CR - 0 1 dead
3 ND 35 BM 8 10 dead
4 ND 60 CNS 15 84 CR2
5 ND 38 BM 4 84 CR2
6 46, XY, t(4;11) (q21;q23), inv(9) 35 BM 34 36 dead
  (p11q13)[3]          
7* No growth 50 BM 2 4 dead
8 46, XY[10] 35 - 48 48 CR1
9 46, XY, t(6;7) (q24;q34)[4]/46, XY[1] 28 - 36 36 CR1
10 46, XY[4] No CR - 0 2 dead
11 46, XY[7] 28 Testis 10 36 CR2, post-BMT
12 46, XX[5] 28 BM 4 7 R1
13 46, XY[9] 28 - 6 6 CR1
Key: ND: Not done; CR: complete remission; R = relapse; EFS: event free survival; *: AML cases, the rest are ALL

Treatment outcome

ALL

Although these infants were not treated with exactly the same protocol, induction chemotherapy was nearly identical. Complete remission (CR) was achieved in 10 out of 11 patients (91%) with a median time to CR of 32 days (range: 28-60 days). Patient no.10 who failed to achieve CR had primary resistant disease and persistent marrow failure Seven patients eventually relapsed at a median time of 9 months (range : 4-34 months). The site of relapse was systemic (bone marrow) in four patients (57%), isolated CNS in two (29%) and isolated testicular in one (14%). A second complete remission (CR2) was achievable in three patients (43%) and were to date still in CR2. Cases no. 1 and 3 died of refractory relapse while cases no. 6 suffered hypoplastic death post-chemotherapy. Case no. 12 was still under treatment for relapse but marrow examination on day 28 post-reinduction showed persistent leukaemia. She was scheduled for myeloablative therapy followed by allogeneic peripheral stem cell transplant. Case no. 11 had an allogeneic bone marrow transplantation (BMT) performed in CR1 with a HLA-matched sibling donor. He suffered an isolated testicular relapse 4 months after BMT but was salvaged with intensive re-induction chemotherapy. At present, he is still in CR2 with a total follow-up duration of 36 months.

AML

Both patients had a short survival. The patient with acute megakaryoblastic leukaemia suffered hypoplastic death post-chemotherapy due to disseminated aspergillus infection while the patient with acute myelomonocytic leukaemia enjoyed only a brief remission and succumbed on re-induction.

Kaplan-Meier estimates of survival probability (Figure) was carried out in patients with ALL only, since both AML cases had very brief survival times. The median EFS for this group of infants was 9 months. The probability of EFS was 20.8% (S.E.=13%) at 48 months with a median duration of follow-up of 36 months. The probability of total survival was 56.8% (S.E.=16.5%) at 84 months.

Discussion

In this retrospective analysis of 13 consecutive cases of infant leukaemia diagnosed and treated in a single institution in Hong Kong, we had included all patients below 18 months of age, since there were evidence that many of those between 12-18 months shared clinical and biological features of infant leukaemia.4 When analyzing the results one had to take into consideration the sample size which was small.

Our data showed that infants with acute leukaemia had a high incidence of adverse clinical characteristics that were associated with poor survival, namely hyperleucocytosis on presentation, hepatomegaly, splenomegaly, and CNS disease.17 Ninety-two percent of our patients had hepatosplenomegaly at diagnosis. Twenty-three percent had white cell count above 100 X 109/L, which was comparable to that reported by the Pediatric Oncology Group (POG),4 but lower than the 50.4% reported by the Children's Cancer Study Group (CCSG).3 CNS disease was seen in 23% of our patients and was slightly higher than the 11 % quoted by POG and CCSG, though our sample size was much smaller.

In agreement. with previous studies, the most prevalent immunophenotype among ALL was CALLA-negative early B-precursor ALL. Nevertheless, the incidence of common ALL in our series was higher, accounting for 43% of all cases that were not T, B or pre-B. As cytoplasmic-μ chain detection was not carried out in two CALLA-positive cases, pre-B phenotype could not be ruled out. The incidence of T-ALL appeared to be higher than reported, and no acute mixed lineage leukaemia was found.

Chromosomal translocations played an extremely important role in influencing treatment and prognosis in childhood acute lymphoblastic leukaemia.18 Cytogenetic abnormalities were reported in 55-70% of infant leukaemia.9,19 We detected structural abnormalities in 29% of our patients, which was much lower than that reported in the literature. The difference was probably spurious owing to the small sample size, but could represent true biological dissimilarities with the Caucasian population. A larger study was needed to further elucidate this point. One patient (case no. 6) had t(4;11)(q21;q23), which was reported in up to 30% of infants less than one year with leukaemia.9 Using molecular analysis, 11 q23/MLL oncogene rearrangement was detected in 68-70% of infant leukaemia8,10 and had convincingly been shown to confer a poor prognosis to patients thus affected. Among the 11q23 cytogenetic rearrangements, it had been shown by CCSG that patients with t(4;11) fared worse than others, for example those with t(9;11).9 Thus infant leukaemia probably formed a distinctive biological entity in terms of genetic defect. Our patient had a typical presentation of t(4; 11) cases that were reported20-22 Interestingly, he had a remission duration of 34 months before eventually relapsing in the marrow, which was long in comparison with the reported median EFS of 8 months.20

Fig. Event-free survival and total survival curves for infant ALL cases.

Another interesting cytogenetic abnormality is the occurrence of a rare translocation, t(6;7)(q24;q36), in case no. 9, Both our case and that of a non-infant childhood ALL reported in the literature23 were diagnosed as T-ALL. Our patient is now still in complete remission after 36 months of follow-up. No attempt was made to correlate CALLA-negativity and 11q23 abnormality with outcome since the number of cases included in this series was small and cytogenetic data was unavailable in six patients.

Treatment outcome was very poor for the two cases of AML who both had short survivals. For our infants with ALL, we recorded a CR rate of 91%. However, seven out of 10 (70%) who attained CR eventually relapsed. This showed that infants with leukaemia did not fail to achieve initial remission, but early disease recurrence was the factor responsible for the poor prognosis. The probability of EFS was 20.8% at 48 months, which was in accordance with a usually quoted EFS figure of 20-30% at four years.3,19 Surprisingly, we were able to salvage three cases out of seven that relapses, and they are still in CR2 at the time of study. Together with three patients in continuous CR1 and one recently relapsed case on treatment, a total of seven cases were alive at the time of study. The total (overall) survival was 56.8% at 84 month with a median follow-up duration of 36 months. This seemed to suggest that, although relapses were common, a significant proportion of our infants could be salvaged with chemotherapy with or without bone marrow transplantation. The fact that treatment protocols had changed over time had already been pointed out. Hence the apparently higher mortality among patients in the early study period could be related to less intensified protocols.

The distinct molecular aberration associated with poor prognostic features and the rate of early relapses would demand new therapeutic and monitoring strategies specially designed for this group of patients with leukaemia. One possibility would be to link specific treatment protocols with minimal residual disease detection using a reverse-transcriptase polymerase chain reaction for MLL gene rearrangement in t(4;11).24

In conclusion, we had shown that infant leukaemia constituted an entity with distinctive clinical, biological and genetic features. Although most cases relapsed giving a poor EFS, we found that a significant number of our cases were salvagable. Hence the overall survival outlook for our infants with leukaemia were not that grim. A larger series of cases in Hong Kong was needed to see if the biology and treatment outcome of local patients really differed from that in Caucasians. An on-going multicentre case-controlled trial on molecular epidemiology of infant leukaemia is being conducted by members of the Hong Kong Paediatric Haematology-Oncology Study Group in collaboration with overseas investigators and their results are eagerly awaited.

Acknowledgments

The authors thank Mr.Wilfred Wong, Department of Paediatrics, Queen Mary Hospital for statistical analysis and Ms. Juliana Kwok, Department of Pathology, Queen Mary Hospital for assistance in manuscript preparation. The technical support of Mr.Frankie Lee in immunophenotyping and Ms. L.M.Ching in cytogenetics, both staff of the Department of Pathology, Queen Mary Hospital, are also much appreciated.


References

1. Darbyshire PJ, Smith JHF, Oakhill A, et al. Monocytic leukemia in infancy. A review of eight children. Cancer 1985;56:1584-9.

2. Katz F, Malcolm S, Gibbons B, et al. Cellular and molecular studies on infant null acute lymphoblastic leukemia. Blood 1988;71:1438-47.

3. Reaman G, Zeltzer P, Bleyer WA, et al. Acute lymphoblastic leukemia in infants less than one year of age: A cumulative experience of the Children's Cancer Study Group. J Clin Oncol 1985;11:1513-21.

4. Crist W, Pullen J, Boyett J, et al. Clinical and biological features predict a poor prognosis in acute lymphoblastic leukemias in infants: A Pediatric Oncology Group Study. Blood 1986;67:135-40.

5. Pui CH, Raimondi SC, Murphy SB, et al. An analysis of leukemic cell chromosomal features in infants. Blood 1987;69: 1289-93.

6. Thirman MJ, Gill HJ, Burnett RC, et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocation, N Engl J Med 1993;329:909- 14.

7. Cimino G, Lo Coco F, Biondi A, et al. ALL-1 gene at chromosome 11q23 is consistently altered in acute leukemia of infancy. Blood 1993;82:544-6.

8. Chen CS, Sorensen PHB, Domer PH, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993;81:2386-93.

9. Heerema NA, Arthur DC, Sather H, et al. Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukaemia: Impact of the 11q23 breakpoint on outcome: A report of the Children's Cancer Group. Blood 1994;83:2274-84.

10. Pui CH, Behm FG, Downing JR, et at. 11q23/MLL rearrangement confers a poor prognosis U infants with acute lymphoblastic leukaemia. J Clin Oncol 1994;12:909-15.

11. Bennett JM, Catovsky D, Daniel MT, et at. French-American-British (FAB) Co-operative Group. Proposals for the classification of acute leukaemias, Br J Haematol 1976;33:451-8.

12. Bennett JM, Catovsky D, Daniel MT, et al, Proposed revised criteria for the classification of acute myeloid leukaemia. A report of the French-American-British Co-operative Group. Br J Haematol 1985;103:626-9.

13. Slaper-Cortenbach ICM, Admiraal LG, Kerr JM, et al. Flow cytometric detection of terminal transferase and other intracellular antigens in combination with membrane antigens in acute lymphoblastic leukaemias. Blood 1988;72:1639-46.

14. First MIC Co-operative Study Group. Morphologic, immunologic and cytogenetic (MIC) working classification of acute lymphoblastic leukaemia. Cancer Genet Cytogenet 1986;23:189-97.

15. Chan LC, Ha SY, Ching LM, et al. Cytogenetics and immunophenotypes of childhood acute lymphoblastic leukemia in Hong Kong. Cancer Genet Cytogenet 1994;76:118-24.

16. Mitelman F, editor. International System for Human Cytogenetic Nomenclature. Basel:Karger, 1991.

17. Robinson L, Sather H, Coccia P. Assessment of the interrelationship of prognostic factors in childhood acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1980;2:5-13.

18. Williams DL, Harber J, Murphy SB, et al. Chromosomal translocations play a unique role in influencing prognosis in childhood acute lymphoblastic leukaemia. Blood 1986;68:205-12.

19. Stark B, Vogel R, Cohen IJ, et al. Biologic and cytogenetic characteristics of leukemia in infants. Cancer 1989;63:117-25.

20. Pui CH, Frankel LS, Carroll AJ, et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;l1)(q21 ;q23): A collaborative study of 40 cases. Blood 1991;77:440-47.

21. Raimondi SC, Peiper SC, Kitchingman GR, et al. Childhood acute lymphoblastic leukemia with chromosomal breakpoint at 11q23. Blood 1989;74:1627-34.

22. Mirro J, Kitchingman G, Williams D, et al. Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation. Blood 1986;67:686-97.

23. Hayashi Y, Raimondi SC, Look AT, et al. Abnormalities of the long arm of chromosome 6 in childhood acute lymphoblastic leukemia. Blood 1990;76:1626-30.

24. Hilden JM, Frestedt JL, Moore RO, et al. Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4:11) (q21;q23). Blood l995;86:3876-82.

25 Kaplan EL, Meier P Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.

 
 

This web site is sponsored by Johnson & Johnson (HK) Ltd.
©2024 Hong Kong Journal of Paediatrics. All rights reserved. Developed and maintained by Medcom Ltd.