Judith M. Chessells

Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population‐based study of incidence and survival

Summary.u2002 We aimed to identify and classify cases of paediatric myelodysplastic syndromes (MDS) occurring in Britain to estimate the incidence of this rare group of diseases, investigate the results of therapy and identify prognostic risk factors. Patients aged below 15u2003years at diagnosis were collected from England, Scotland and Wales, inclusively between 1990 and 1999. One hundred and thirty‐five patients were accepted as de novo MDS or juvenile myelomonocytic leukaemia (JMML). The incidence for this period was 1·35 per million (age standardized rate) which is below that reported outside the UK. The overall survival was 45%[standard error (SE)u2003=u20034%] at 5u2003years: 40% (SEu2003=u20036%) for JMML and 50% (SEu2003=u20036%) for other MDS. Significant adverse prognostic factors for JMML were a platelet count <u200a40u2003×u2003109/l, raised fetal haemoglobin, FPC score and age above 2u2003years at diagnosis, for other MDS only monosomy 7 was significant. To conclude, the incidence of MDS/JMML in children in the UK appears to be lower than that reported outside the UK. This may be either a real difference in incidence or variation in reporting. Monosomy 7 is associated with poor outcome in MDS other than JMML. The prognosis of JMML depends on age, platelet count and fetal haemoglobin.

Chromosomes and other prognostic factors in acute lymphoblastic leukaemia: a long‐term follow‐up

Summary. Cytogenetic, clinical and laboratory features at diagnosis were examined in a group of 80 children with acute lymphoblastic leukaemia (ALL) who had been followed up for a minimum of 5 1/2 years. The 17 (21%) with high hyperdiploidy tended to have low leucocyte counts and common ALL, but their favourable outcome (75% event‐free survival) was independent of these factors. No patient with hypodiploidy survives while the pseudodiploid and normal groups have an intermediate prognosis. Cytogenetic analysis showed examples of patients with the well‐recognized translocations and a number with apparently unique ones. Among the latter were some long‐term survivors. We conclude that Cytogenetic analysis identifies a good risk group of patients who remain well on long‐term follow‐up, but that the presence of a translocation does not necessarily imply a poor outcome.

The use of DNA probes to monitor minimal residual disease in childhood acute lymphoblastic leukaemia

DNA probes to both the joining region (JH) of the immunoglobulin heavy chain gene (IgH) and to the β chain of the T‐cell antigen receptor complex (TCR) have been used as tumour‐specific markers to monitor the rearrangements of the IgH chain gene and the TCR β gene in the blast cells of children presenting with acute lymphoblastic leukaemia (ALL) of B or T cell origin. Blast cells from 68 children with early B cell ALL and eight with T‐ALL were examined at presentation, at day 28 after commencement of therapy and at varying times thereafter. An additional 43 patients (42 with B cell ALL, one with T‐ALL) were studied both at presentation, at completion of their 2‐year treatment course and 3 months later. Twelve patients, drawn from both these groups, were studied at relapse as were a further eight patients in whom an extramedullary relapse had occurred. Persistence of clonally‐derived cells as a predictor of early relapse was seen in the day 28 bone marrows of 11/76 newly‐diagnosed children (nine early B and two T‐ALL) followed by rapid, overt relapse in four of the early B ALL cases. No minimal residual disease (MRD) was detected in bone marrows from any of the 43 patients completing their 2‐year treatment course, but six of these subsequently relapsed at varying time periods thereafter. Identical patterns of rearrangement at both presentation and relapse were seen in most cases. Oligoclonality, or multiple IgH chain gene rearrangements was seen in the blast cells of 15% of patients with early B cell ALL. No correlation between oligoclonality, high white count, unfavourable phenotype, or abnormal karyotype could, however, be ascertained.

Childhood monosomy 7 revisited

Summary. Monosomy 7 is found in acute myeloid leukaemia (AML) and myelodysplasia and is characteristic of a rare chronic myeloproliferative disease (MPD) of young children. We have seen 16 children with monosomy 7. Their clinical features and response to treatment are discussed.

Possible evidence for genomic imprinting in childhood acute myeloblastic leukaemia associated with monosomy for chromosome 7

Monosomy or deletion of chromosome 7 is a frequent finding in both de novo and secondary acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Based on analysis of deletions of chromosome 7 in such patients, it has been suggested that there is a critical region of the chromosome lying within bands q21‐q31. We have examined bone marrow and peripheral blood samples from 10 patients with MDS, AML and biphenotypic acute leukaemia who had monosomy for or rearrangement of chromosome 7, seeking evidence of non‐random allele loss that might suggest the presence of imprinted genes on the chromosome.

Acute myeloid leukaemia in childhood: clinical features and prognosis.

Clinical and laboratory features at presentation were correlated with morphological (FAB) subclass of AML in a group of 112 children diagnosed between 1972 and 1982. Patients with a monocytic component of AML (M4, M5) had higher initial leucocyte counts, a higher incidence of extramedullary infiltration and of CNS involvement. In M4 AML CNS relapse occurred in patients with a high initial leucocyte count whereas in M5 AML CNS involvement tended to occur at presentation in children with low initial counts. Two‐thirds of patients treated achieved remission and most failures were due to inadequate chemotherapy, although haemorrhage, leucostasis or metabolic complications caused early death in patients with M4 and M5 AML. With a minimum follow up of 3 years only 12% of patients are alive; these figures have not improved in consecutive series despite increasing intensity of induction and more recent availability of bone marrow transplantation. No features predictive of long‐term survival were identified, but patients with myeloid differentiation (M1, M2, M3) did better than those with a monocytic or erythroid component (M4, M5, M6).

The (4;11) translocation in acute leukaemia of childhood: the importance of additional chromosomal aberrations.

Summary. Case reports of four girls and one boy with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) and t(4;11) are presented. The incidence of t(4;11) ascertained at diagnosis in ALL was 2.6% and in AML 5.3%. Four of the children were under 2 years and one was 11 years at diagnosis. Leucocyte counts above 71 × 109/1 and liver, spleen and node enlargement were found in all cases. Blasts of the four cases tested at diagnosis were negative to the c‐ALL antigen and either TdT+ (ALL) or TdT‐ (AML M1). Maximum survival was less than 8 months. Additional chromosomal change was found at diagnosis in two cases and in relapse in a third. In the case of AML t(4;11) (q21;p15) was present as a second translocation. Additional numerical changes, in these and other reported cases, included +6, commonly found in ALL, +8, +19, more often reported in AML. It is suggested that additional chromosomal changes in these cases support cytochemical and surface marker evidence that t(4;11) has a pluripotent target cell, similar to that of the Philadelphia translocation.

A second course of treatment for childhood acute lymphoblastic leukaemia: long-term follow-up is needed to assess results

We report the results of long‐term follow‐up of 94 children who completed treatment for acute lymphoblastic leukaemia (ALL) between 1974 and 1986 and subsequently experienced a bone marrow relapse before 1992. 91 children received further induction, intensification and CNS directed therapy; 19 proceeded to BMT or ABMT and the remainder were treated on one of three protocols which increased in intensity. The duration of second remission improved significantly with increasing intensity of treatment and bone marrow transplantion was followed by fewer relapses than chemotherapy. Analysis of factors influencing the duration of second remission showed that only length of first remission was of additional significance; the median duration of second remission being only 19 months in children with a first remission of less than 4 years and 62 months in those with longer first remissions. 29 children electively stopped chemotherapy a second time but only 11 of these remain still in second remission with recurrences occurring for up to 7 years from the the time first relapse. Only three of the 24 longterm survivors had no significant late effects of treatment; these were most marked in children who had received a second course of radiotherapy. We conclude that very long follow‐up is necessary to determine whether patients may be successfully re‐treated following late bone marrow relapse and that all such treatment is associated with a high incidence of late effects.

Infant acute lymphoblastic leukaemia with t(11;19)

Seven cases of infant acute lymphoblastic leukaemia with t(11:19) (q23;p13) are described. They are characterized by a high white cell count, organomegaly, early central nervous system (CNS) disease, and a poor prognosis. Blasts are usually of an immature early B‐cell lineage although monocytoid features are present in some cases. The characteristics of infant acute leukaemia with t(11;19) are very similar to those found with t(4;11), and the presence of t(11;19) may indicate the same poor prognosis.

Leukaemia arising in donor cells following allogeneic bone marrow transplantation for β thalassaemia demonstrated by immunological, DNA and molecular cytogenetic analysis

Summary Combined DNA analysis, molecular cytogenetic and immunological techniques have been used to identify the donor origin of common acute lymphoblastic leukaemia (cALL) which arose in a male patient with β thalassaemia major, 5 years after an allogeneic bone marrow transplant from his HLA‐matched sister. The necessity of using multiple techniques in this and similar cases is emphasized and the possible mechanisms for the development of donor leukaemia and the leukaemic transformation of donor cells are discussed.