Ian M. Hann

Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial

BACKGROUND Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. METHODS After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse. FINDINGS 381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2). INTERPRETATION The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.

A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk‐directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5‐year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good‐risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial

359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A‐BMT) or allogeneic (allo‐BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A‐BMT versus not. Allo‐BMT was recommended for patients with a HLA‐matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo‐BMTs, 1/60 A‐BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long‐term outcome was excellent with survival at 7 years from entry of 56% and event‐free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A‐BMT and allo‐BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long‐term side‐effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.

Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials.

Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.

Adolescents with acute lymphoblastic leukaemia: Outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials

Adolescents with acute lymphoblastic leukaemia (ALL) have languished in the shadow of success of the outcome of therapy in childhood ALL. Their treatment has always been incorporated into either paediatric or adult clinical trials depending on the mode of referral and hence there is a need to address an age and risk specific strategy for improving the outcome of this neglected group of patients. This article has summarised the recent and updated retrospective comparative analysis of adolescents treated on the Medical Research Council (MRC) trials. This analysis adds further emphasis to the treatment approach and the merits and limitations of treatment of adolescents on paediatric and adult trials.

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.

The impact of prophylactic treatment on children with severe haemophilia

Twenty‐seven children with severe haemophilia receiving regular prophylactic factor concentrate were evaluated to examine the overall effectiveness of prophylaxis in modern haemophilia care. The median age at the start of prophylaxis was 6.2 years (range 1.3–15.9 years) and the cumulative length of follow‐up was 808 months (mean 30, range 7–76 months).

The use of recombinant factor VIIa in children with inherited platelet function disorders

Summary. Inherited deficiencies of platelet surface glycoproteins such as Glanzmanns thrombasthenia (GT) or Bernard–Soulier syndrome (BSS) can lead to a severe bleeding diathesis. In the past, bleeding episodes in these patients have often required platelet transfusion to secure haemostasis but recently a number of patient reports have suggested that recombinant factor VIIa (rVIIa) may also be effective. We have used rVIIa on 33 occasions in seven children with inherited platelet function disorders over a 2‐year period: five had GT, one had BSS and one had storage pool disease with a severe phenotype. Bleeding ceased with rVIIa alone in 10 of 28 acute bleeding episodes, but recurred in two of these. The two features that predicted response to rVIIa were the severity of the bleeding and the delay from the onset of bleeding to treatment. Five episodes of planned surgical intervention were treated successfully with rVIIa. Eighteen out of the 28 acute episodes and none of the planned surgical episodes required blood product support. We have found variable efficacy of rVIIa for acute bleeding episodes in this small series of children with inherited platelet function defects but larger studies are warranted, particularly as rVIIa is a relatively low‐risk treatment approach for these disorders.

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.

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

Summary.  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 15 years 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) = 4%] at 5 years: 40% (SE = 6%) for JMML and 50% (SE = 6%) for other MDS. Significant adverse prognostic factors for JMML were a platelet count < 40 × 109/l, raised fetal haemoglobin, FPC score and age above 2 years 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.