Richard F. Stevens

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.

A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients

One hundred and thirty‐four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c‐AMB), liposomal amphotericin B 1 mg/kg/d (L‐AMB1) or liposomal amphotericin B 3 mg/kg/d (L‐AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38°C or more, not responding to 96 h of systemic broad‐spectrum antibiotic treatment, and neutropenia (< 0.5 × 109/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38°C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L‐AMB treated patients had a 2–6‐fold decrease in the incidence (P  0.01) of test‐drug‐related side‐effects, compared to c‐AMB. Severe trial‐drug‐related side‐effects were seen in 1% of L‐AMB treated patients, in contrast to 12% of patients on c‐AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L‐AMB1 arm whereas the incidence was 3% in patients on L‐AMB3 and 23% in those on c‐AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L‐AMB arms than c‐AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L‐AMB arms (P < 0.01).

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.

Guidelines for the diagnosis and management of hereditary spherocytosis

Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non‐dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.

Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10)

Between 1988 and 1995, 341 children with acute myeloid leukaemia (AML) were treated on the Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10). The 5‐year overall survival was 57%, much improved on previous trials. However, there were 47 deaths (13.8%), 11 of which were associated with bone marrow transplantation (BMT). The treatment‐related mortality was significant at 13.8%, but decreased in the latter half of the trial from 17.8% in 1998–91 to 9.6% in 1992–95 (P = 0.03%). The main causes of death were infection (65.9%), haemorrhage (19.1%) and cardiac failure (19.1%). Fungal infection was a significant problem, causing 23% of all infective deaths. Haemorrhage occurred early in treatment, in children with initial white cell counts >100 × 109/l (P = 0.001), and was more common in those with M4 and M5 morphology. Cardiac failure only occurred from the third course of chemotherapy onwards, with 78% (7/9) in conjunction with sepsis as a terminal event. Some deaths could be prevented by identifying those most at risk, and with prompt recognition and aggressive management of complications of treatment. Future options include the prophylactic use of antifungal agents, and the use of cardioprotectants or alternatives to conventional anthracyclines to decrease cardiac toxicity.

The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.

We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event‐free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40–52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five‐year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5‐year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5‐year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5‐year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed – 103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied – 44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates – children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).

Bone-marrow transplantation for congenital erythropoietic porphyria

Congenital erythropoietic porphyria, a disorder of haem synthesis, is caused by uroporphyrinogen III synthase deficiency in bone-marrow normoblasts. Uroporphyrins and coproporphyrins accumulate and cause oxidative damage to cells exposed to sunlight. Uroporphyrin overproduction was greatly reduced and skin changes reversed in a girl who received a bone-marrow graft from an HLA-identical sibling at 10 years of age. The patient died 11 months after transplantation because of severe progressive pneumonitis and encephalopathy associated with cytomegalovirus infection, but the encouraging response up to 8 months after engraftment indicates a possible benefit of bone-marrow transplantation in the treatment of this rare but usually fatal inherited disease.

Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen.

In three children with haemolytic uraemic syndrome (HUS), evidence of red cell polyagglutinability due to Thomsen Friedenreich antigen (T-antigen) exposure was demonstrated. This was suspected after difficulties in ABO typing and was confirmed using specific antisera. Further supportive evidence included elevation of plasma sialic acid, alteration in red cell surface charge and evidence of T-antigen exposure in the renal biopsy specimen of one patient. Although involvement of this antigen in the pathogenesis of HUS has been associated with a high mortality, all three children have made a complete recovery. With early recognition and subsequent avoidance of plasma products, prognosis of this condition may be improved.