Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study.

BACKGROUND: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate. OBJECTIVES: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity. METHODS: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool. RESULTS: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%. CONCLUSIONS: The pCR rate was insufficient to justify phase III investigation of imiquimod vs. SURGERY: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

Home-based Reach-to-Grasp training for people after stroke is feasible: a pilot randomised controlled trial.

OBJECTIVE: To determine feasibility of a randomised controlled trial (RCT) of home-based Reach-to-Grasp training after stroke. DESIGN: single-blind parallel group RCT. PARTICIPANTS: Residual arm deficit less than 12 months post-stroke. INTERVENTIONS: Reach-to-Grasp training in 14 one-hour therapist's visits over 6 weeks, plus one hour self-practice per day (total 56 hours). CONTROL: Usual care. MAIN MEASURES: Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), pre-randomisation, 7, 12, 24 weeks post-randomisation. RESULTS: Forty-seven participants (Reach-to-Grasp=24, usual care=23) were randomised over 17 months. Reach-to-Grasp participants received a median (IQR) 14 (13,14) visits, and performed 157 (96,211) repetitions per visit; plus 30 minutes (22,45) self-practice per day. Usual care participants received 10.5 (5,14) therapist visits, comprising 38.6 (30,45) minutes of arm therapy with 16 (6,24) repetitions of functional tasks per visit. Median ARAT scores in the reach-to-grasp group were 8.5 (3.0,24.0) at baseline and 14.5 (3.5,26.0) at 24 weeks compared to median of 4 at both time points (IQR: baseline (3.0,14.0), 24 weeks (3.0,30.0)) in the usual-care group. Median WMFT tasks completed at baseline and 24 weeks were 6 (3.0,11.5) and 8.5 (4.5,13.5) respectively in the reach-to-grasp group and 4 (3.0,10.0), 6 (3.0,14.0) in the usual care group. Incidence of arm pain was similar between groups. The study was stopped before 11 patients reached the 24 weeks assessment. CONCLUSIONS: An RCT of home-based Reach-to-Grasp training after stroke is feasible and safe. With ARAT being our preferred measure it is estimated that 240 participants will be needed for a future two armed trial.

Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia.

Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO's licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto's odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84-0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90-1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.

A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma.

BACKGROUND AND PURPOSE: For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODS: Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTS: Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0-36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7-35.9 Gy). CONCLUSION: IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

Haematological changes at altitude.

Hypobaric hypoxia is associated with an increase in erythropoesis and an increased thrombotic risk. This is true of long haul air travel, mountaineering expeditions and longer stays at altitude. Studies looking at clotting on mountaineering expeditions are further complicated by the effects of exercise, plasma volume changes and the catecholamine response to hypoxia. This review examines the evidence for changes in clotting factors and functional clotting at altitude and considers the implications of altitude travel for those with pre-existing medical conditions.

FLT3 inhibitors in acute myeloid leukaemia: assessment of clinical effectiveness, adverse events and future research-a systematic review and meta-analysis.

BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. PURPOSE: To assess the clinical effectiveness of FLT3 inhibitors in AML patients. METHODS: Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. RESULTS: Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. CONCLUSIONS: There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years' time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055581.

Pilot randomised controlled trial of occupational therapy to optimise independence in Parkinson's disease: the PD OT trial.

OBJECTIVE: To perform a pilot trial of occupational therapy (OT) to optimise functional independence in Parkinson disease (PD) to assess accrual/withdrawal rates, acceptability, outcome measures, and inform sample-size calculation. METHOD: Non-demented patients with idiopathic PD and difficulties with activities of daily living (ADL) were recruited provided they had not received OT in the last 2 years and/or physiotherapy in the last year. Patients were randomised to immediate OT or OT after completion of the trial. Patients randomised to OT were assessed at home by an experienced therapist and then received six home treatment sessions over 2 months. Interventions were targeted at functional independence and mobility goals. Outcome measures were: Nottingham Extended Activity of Daily Living Scale, Rivermead Mobility Index, Unified Parkinson's Disease Rating Scale ADL scale, Parkinson's Disease Questionnaire 39, EuroQol-EQ-5D, Hospital Anxiety and Depression Scale, and health economics analysis. RESULTS: 39 patients (25 male; mean age 73 years) were recruited from four centres over 16 months. The mean difference in NEADL at 8 months was 3.5 (95% CI -3.2 to 10.2). The mean difference in PDQ-39 Summary Score was 3.8 (95% CI -4.94 to 12.6). There were strong correlations between the PDQ-39 and other outcomes. The intervention was acceptable to patients, with a low withdrawal rate and good questionnaire completion. CONCLUSION: Randomisation to a trial of OT in PD is feasible. NEADL and PDQ-39 are relevant outcomes and provided data to inform sample size for an adequately powered randomised trial for which there is pressing need.

Dopamine agonist therapy in early Parkinson's disease.

BACKGROUND: Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa. OBJECTIVES: This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. SELECTION CRITERIA: Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality. MAIN RESULTS: Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. AUTHORS' CONCLUSIONS: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.

Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far.

Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive renal dysfunction, and eventually to end-stage renal failure. Revascularization has been used in an attempt to prevent progression of ARVD, despite a lack of evidence for a benefit on kidney function. Therefore, large-scale randomized trials are needed to determine reliably whether or not there is any worthwhile benefit. The Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients randomized to either revascularization or medical management alone was designed to provide this evidence. ASTRAL started recruiting in November 2000 and, as of the end of 2006, 731 patients have been randomized into the trial (19 patients short of its minimum target of 750 patients). A pooled analysis (not split by treatment arm) of all patients shows that serum creatinine increased in the first 6 months then remained relatively steady, whereas blood pressure has decreased from baseline. The trial is due to close to recruitment in April 2007, with the first presentation of the results of the randomized treatment comparison planned for the spring of 2008. To date ASTRAL is by far the largest randomized trial in ARVD, and will provide the most reliable and timely evidence on the role, if any, of revascularization in ARVD with which to guide the treatment of future patients.

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.

Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.

PURPOSE: To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS: In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS: The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION: The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

Intensive chemotherapy with or without additional bone marrow transplantation in paediatric AML: progress report on the MRC AML 10 trial. Medical Research Council Working Party on Childhood Leukaemia.

The Medical Research Council's AML 10 Children Trial commenced in 1988. It is a multicentre collaborative study based on 4 courses of intensive chemotherapy with additional allogeneic bone marrow transplantation for children with a matched sibling donor. The remaining children are randomised either to an autologous transplant using unpurged marrow or stopping therapy. To date 156 eligible patients have been entered with a CR rate of 91%. 56% of children are still alive 2 years after trial entry and 57% are in CR 3 years after achieving CR. The treatment regimen is intensive but mortality and morbidity are acceptable. The study will need to accrue patients for a further 2 to 3 years in the hope of defining the role of allogeneic and autologous marrow transplantation.

The significance of ultrastructural features in acute myeloid leukemia: a study of 220 patients entered into the Medical Research Council's ninth acute myeloid leukemia trial.

Samples of peripheral blood or bone marrow obtained before treatment from 220 patients entered into the Medical Research Council's ninth acute myeloid leukemia (AML) trial were examined by electron microscopy. Several ultrastructural features showed strong correlations with each other, with variants of AML defined by the Hayhoe classification scheme, and with FAB type. However, no ultrastructural feature was found either uniquely in association with any other or specifically in any variant of AML. Each ultrastructural feature was tested for association with achievement of remission, remission duration, and survival time. Only Auer rods were associated with a high remission rate (p = 0.01), but even this association was not quite conventionally significant when the analysis was not quite conventionally significant when the analysis was stratified for age (p = 0.055). Shorter duration of remission was associated with cytoplasmic projections (p = 0.04 stratified for age). Overall survival was worse when convoluted or lobed nuclei were present but only when stratified for age and Hayhoe type (p = 0.04). The possibility of testing combinations of ultrastructural features for correlation with diagnosis or prognosis is discussed but would require data from more than the present 220 patients to be meaningful.

Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia.

The expression of bcl-2 protein that is involved in preventing apoptosis in hemopoietic and other cells was evaluated by quantitative flow cytometry in various subpopulations in the normal fetal bone marrow (FBM) and in different types of acute myelogenous leukemias (AML). In the FBM the highest bcl-2 levels (mean antibody binding capacity 51 x 10(3) molecules/cell) were found in CD34+ intermediate sized blasts and myeloblasts, while a CD34+ subset of CD10+ lymphoblasts had low bcl-2 content (8-10 x 10(3) molecules/cell) and the CD34-, CD10+ lymphoblasts were, as expected from previous studies, bcl-2- (< 5 x 10(3) molecules/cell). Variable levels of bcl-2 (5.1-222 x 10(3)) were found in 43 tested cases of AML. The bcl-2 levels decrease with granulocytic and monocytic differentiation and, accordingly, cases of AML with M1 and M2 features showed significantly higher mean bcl-2 levels than the leukemias with promyelocytic (M3) or myelo-monocytic (M4/M5) features. Nevertheless, in seven cases of AML the bcl-2 levels were higher than seen in the normal FBM cells and none of these patients remain in remission after 2 years. Furthermore, in several AML cases intraclonal heterogeneity was observed. The undifferentiated smaller blasts with Class-IIdim display had higher bcl-2 content than the more differentiated larger blasts with more granular side scatter and Class-bright expression. In the same subsets of AML blasts the proliferative S-G2-M fractions showed a reciprocal correlation to bcl-2 content. Thus the higher bcl-2 levels may give a survival advantage and confer some degree of drug resistance to the least differentiated blast populations. The multi-parameter analysis described in this paper, including a combined bcl-2 and cytokinetic analysis of phenotypically defined subgroups of AML blasts, may detect early population shifts during relapse and also guide combination drug therapy.

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).

Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party.

The clinical features, cytogenetics and response to treatment have been examined in 180 infants (aged <1 year) with acute leukaemia; 118 with acute lymphoblastic leukaemia (ALL) and 62 with acute myeloid leukaemia (AML). Comparison of clinical features showed no difference in age or sex distribution between infants with ALL and AML but infants with ALL tended to have higher leucocyte counts at presentation. Cytogenetic abnormalities involving 11q23 were found in 66% of ALL and 35% of AML cases, the commonest, t(4;11) being found only in ALL. The other recognised 11q23 translocations were found in both types of leukaemia. Few patients had the common cytogenetic abnormalities associated with ALL in older children and few with AML had good risk abnormalities. Four year event-free survival 60% cf 30% (P = 0.001) and survival 65% cf 41% (P = 0.007) were significantly better in AML than ALL. These results were due to a lower risk of relapse 27% cf 62% at four years. Superior event-free survival was also seen in the subgroup of patients with 11q23 abnormalities and AML (55% cf 23%). The reasons for superior response in AML are unknown but may be related to the intensity of treatment, lineage of the leukaemia or other as yet unidentified factors.

Adjuvant interferon-alpha in malignant melanoma: current status.

High-risk surgically resected primary or loco-regional cutaneous malignant melanoma, although uncommon, can be associated with less than 50% 5-year survival; adjuvant therapy of proven efficacy is therefore appropriate. Since immunological control mechanisms seem to be important in the natural history of melanoma, biological agents have been the subject of many adjuvant studies. Most popular has been recombinant interferon. Well over 4000 patients have been entered into randomized studies. Results suggest that there may be a clinical benefit, most clearly in relapse-free but also perhaps in overall survival. More precise estimates of the magnitude of any benefits are needed. The doses, schedules and cost-benefits have yet to be fully evaluated. Interferon cannot yet be recommended as standard adjuvant therapy in high-risk malignant melanoma.

Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial.

The increasing success of intensive consolidation chemotherapy (CCT) as an alternative to bone marrow transplant (BMT) in acute myeloid leukaemia (AML) necessitates comparison of the impact on quality of life (QoL) of these two treatment modalities. Most QoL studies following BMT involve small patient numbers and provide ambivalent results. The present study examines QoL in a large number of patients 1 year from the end of treatment within the United Kingdom Medical Research Council (UK MRC) AML10 trial of BMT versus CCT. Allogeneic-BMT (Allo-BMT) was observed to have an adverse impact on most QoL dimensions compared with Autologous-BMT (A-BMT) and CCT. More patients receiving BMT had mouth dryness problems and worse sexual and social relationships, professional and leisure activities than CCT patients. QoL in A-BMT patients was less impacted than Allo-BMT. Intention-to-treat analysis showed similar results. These results indicate that a reconsideration of treatment strategies is warranted, and that further, good prospective studies are needed to evaluate more clearly the effects of these treatments in long-term survivors.