J. M. Chessells

Haematological abnormalities in Shwachman‐Diamond syndrome

We have analysed the haematological parameters in 21 patients with Shwachman‐Diamond syndrome (SDS) seen over a 25‐year period at our institution. Neutropenia, although present in all patients, was intermittent in two‐thirds, constant in the rest and was associated with impaired chemotaxis in all of those patients tested. Fetal haemoglobin (HbF) was elevated in 80% of the patients at some stage, and anaemia and thrombocytopenia was documented in 66% and 24% respectively. Bone marrow samples were taken in over half of the patients. Myelodysplastic syndrome (MDS) developed in seven (33%) patients, five of whom had acquired clonal structural chromosome abnormalities in their bone marrows. In five of the patients with MDS (24%) transformation to acute myeloid leukaemia occurred. Like other constitutional bone marrow failure syndromes, SDS has a predilection to leukaemic transformation hitherto assumed to be in the region of 5–10%. The data presented here suggest that this figure probably represents an underestimate. Shwachman‐Diamond syndrome is an interesting model of leukaemia development and greater understanding of the clinical spectrum of this rare disorder should produce further insights into its pathobiology.

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically‐defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event‐free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph‐positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event‐free survival of 87.5% at 5 years. A number of other non‐random abnormalities were identified with no clear prognostic significance.

Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia

Summary. We have reviewed the outcome after relapse in a cohort of 505 children with acute lymphoblastic leukaemia (ALL) seen at a single institution. The majority of relapses (74%) occurred within 3 years from diagnosis, and most involved the bone marrow alone or with overt extramedullary relapse. Early relapse was more common in children with T‐ALL and those with unfavourable cytogenetics. Factors influencing second remission included length of first remission and type of relapse. Children who had not received previous cranial irradiation had a superior survival. The German relapse score involving length of first remission, site of relapse and immunophenotype was highly predictive of outcome: event‐free survival with 95% confidence intervals at 6 years for patients who received modern treatment [intensive chemotherapy or bone marrow transplantation (BMT)] was 78% (51–92%) for standard risk, 41% (33–49%) for intermediate risk and 19% (10–31%) for highest risk. Retrospective comparison of BMT with chemotherapy showed no difference in the intermediate‐risk group but a possible advantage in the highest risk group. Follow‐up of 235 patients who relapsed after chemotherapy and received a third course of treatment showed an extremely high early attrition rate, but a small number of patients survived in third remission. We conclude that new approaches are needed to individualize therapy in intermediate‐risk patients and to improve the outcome for those in the highest risk group. Only a small number of children can be treated effectively in third remission.

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia : the MRC UKALL X experience

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event‐free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT).

An investigation of the t(12;21) rearrangement in children with B‐precursor acute lymphoblastic leukaemia using cytogenetic and molecular methods

The t(12;21) is the commonest recurrent translocation in childhood acute lymphoblastic leukaemia (ALL), the presence of which has been suggested to be a good prognostic feature. We have studied 22 childhood cases of B‐precursor ALL with this rearrangement, and have found no significant differences in event‐free survival between these and a control group of patients with similar phenotypes. Using a variety of cytogenetic and molecular techniques, we have confirmed a strong association with co‐expression of myeloid markers, frequent deletions of the short‐arm of the untranslocated chromosome 12 homologue and duplication of the derivative chromosome 21. Intragenic deletion of the untranslocated ETV6 gene in 3/12 informative patients points to the likelihood of this gene being a target for deletion.

Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990–99

Summary. Between 1990 and 1999, 36 children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), not associated with Downs syndrome, were diagnosed in Britain. A total of 31 children received intensive chemotherapy, six of whom proceeded to a bone marrow allograft in first remission, whereas two received an autograft. Of the 23 given chemotherapy only, four died of toxicity, 10 relapsed and nine are alive in first remission. Out of the 10 who relapsed, four are alive and disease‐free following an allograft. Out of the 6 children given an allograft in first remission, two died of disease and four are alive in first remission. Both children given an autograft died of disease. Two children received an allograft without prior chemotherapy but died of toxicity. Three children received supportive care only, and one child survived. The overall survival was 51% at 5 years, and was superior in children with RAEBt (63%) compared with RAEB (28%, P = 0·03). Cytogenetics were available in 35 cases. Monosomy 7 was the most common abnormality (33% of cases). Survival in children with monosomy 7 was 22% at 5 years compared with 66% for the other patients (P = 0·05). Allowing for cytogenetics, outcomes of therapy appear similar to those for de novo acute myeloid leukaemia (AML), and it is appropriate for children with RAEB/RAEBt to be registered in AML trials.

Cytomorphology of childhood lymphoblastic leukaemia: a prospective study of 2000 patients

Blast cell morphology of children with lymphoblastic leukaemia (ALL) entering two national multicentre trials was prospectively reviewed by three haematologists to define the clinical importance of (a) French–American–British (FAB) classification, (b) the presence of cytoplasmic vacuoles, and (c) the presence of ‘hand‐mirror’cells.

Cryptic deletions and inversions of chromosome 21 in a phenotypically normal infant with transient abnormal myelopoiesis: a molecular cytogenetic study

A case of transient abnormal myelopoiesis in a normal newborn without features of Down syndrome is described. The majority of bone marrow cells analysed belonged to a chromosomally abnormal clone with trisomy for chromosomes 18 and 21. Complex intrachromosomal rearrangements of one chromosome 21, demonstrated by fluorescence in situ hybridization using locus‐specific probes, were found in a minor population of the clonal cells. These rearrangements involved loci previously shown to be rearranged in the leukaemic cells from patients with Down syndrome and leukaemia. However, the childs myeloproliferation resolved rapidly, with disappearance of the abnormal clone, and 3.5 years later she remains well.

Deletions of chromosome 21 restricted to the leukemic cells of children with Down syndrome and leukemia

Down syndrome (DS) is associated with an increased risk of developing hematological malignancies, but the basis for this predisposition is so far unknown. Using fluorescence in situ hybridization with a panel of locus-specific probes on normal and leukemic metaphases, we have found long-arm interstitial deletions of one of the chromosome 21s in the leukemic cells from five patients with DS and leukemia. This finding provides strong evidence for a gene or genes present on chromosome 21 having an important function in the development of leukemia in individuals with Down syndrome.

Medical cost of curing childhood acute lymphoblastic leukaemia

Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure. In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups. These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.