A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia.

The study was designed to compare clofarabine plus daunorubicin vs daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67 years; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; ± one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and ± azacitidine maintenance. The primary end point was overall survival. The overall response rate was 69% (complete remission (CR) 60%; CRi 9%), with no difference between DA (71%) and DClo (66%). There was no difference in 30-/60-day mortality or toxicity: significantly more supportive care was required in the DA arm even though platelet and neutrophil recovery was significantly slower with DClo. There were no differences in cumulative incidence of relapse (74% vs 68%; hazard ratio (HR) 0.93 (0.77-1.14), P=0.5); survival from relapse (7% vs 9%; HR 0.96 (0.77-1.19), P=0.7); relapse-free (31% vs 32%; HR 1.02 (0.83-1.24), P=0.9) or overall survival (23% vs 22%; HR 1.08 (0.93-1.26), P=0.3). Clofarabine 20 mg/m2 given for 5 days with daunorubicin is not superior to ara-C+daunorubicin as induction for older patients with AML/high-risk MDS.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial.

Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P<0.0001) was required in the MRC arm. GO did not provide benefit. High white blood cell count (>10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome.

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC+ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with >10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20 mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML.

Prophylactic treatment for cytosine arabinoside-induced keratoconjunctivitis.

High-dose cytosine arabinoside (Ara-C) is known to cause keratoconjunctivitis in a large proportion of patients. Topical steroids are a popular choice of prophylactic treatment. The objective of this survey was to evaluate the type, dose, frequency and duration of drops used in all centres (n = 117) participating in the acute myeloid leukaemia trial 15 (AML 15), and to assess adherence to the trial protocol prescribed guidelines. All centres used prophylactic treatment; however, the dose of Ara-C at which it was initiated varied from 100 to 6000 mg/m(2)/day. All centres used some form of steroid prophylaxis with prednisolone 0.5% being the most commonly used (98/117), but only 6 of the 117 centres initiated treatment at doses recommended in the trial protocol. Ten centres used lubricants in addition to steroids. No centre reported the use of non-steroidal anti-inflammatory drops. The duration of treatment ranged from 2 days prior to commencing Ara-C to 28 days post-treatment. Twenty-two centres reported complications of which preservative allergy was the commonest. There is a large variation in prophylactic treatment practice in the UK. Clear guidance on the use of prophylaxis and further studies are required to ascertain the most effective prophylactic treatment and regimen.

Clinical impact of enhanced diagnosis of invasive fungal disease in high-risk haematology and stem cell transplant patients.

AIMS: To investigate the impact of routine use of biomarkers for diagnosing fungal infection within a care pathway on antifungal usage and clinical outcomes. METHODS: A cohort of high-risk haematology and stem cell transplant patients was entered into a neutropenic care pathway in which targeted diagnostic testing replaced empiric antifungal treatment. Patients were screened twice a week by PCR and antigen testing during fever or when chronic graft versus host disease was present and were followed-up for a minimum of 1 year. RESULTS: No excess morbidity or mortality was seen in patients in whom empiric antifungal treatment was withheld, and there were substantial savings in antifungal drug expenditure. CONCLUSIONS: The introduction of a comprehensive diagnostic surveillance strategy to exclude invasive fungal infection in high-risk patients with haematological malignancy and those undergoing transplantation can result in improvements in clinical management. There are also potential additional benefits of improved patient survival, decreased morbidity and decreased hospital stay.

Invasive aspergillosis localised to the colon presenting as toxic megacolon.

Primary gut involvement by Aspergillus is an exceedingly rare and often a fatal complication of intensive chemotherapy in patients with acute leukaemia. We report a 46-yr-old patient with granulocytic sarcoma of the testis. He received acute myeloid leukaemia type treatment with ADE chemotherapy (Cytosine Arabinoside, Daunorubicin and Etoposide). While neutropenic he presented with pyrexia, abdominal pain and massive abdominal distention. He was treated with intravenous antibiotics and antifungals according to our usual institutional protocol without any response. He was found to have toxic megacolon on plain X-ray and subsequently underwent total colectomy and ileostomy. The colon histology showed Aspergillus fungal hyphae infiltrating the bowel wall. There was no any evidence of pulmonary, hepatic, splenic or renal lesions on the computerised tomography scan. Following colectomy, he was treated with 2 wk of antifungal treatment. He recovered well and was discharged home. The increased awareness, high degree of clinical suspicion of unusual presentation and early surgical intervention with aggressive antifungal treatment, has a key role in the management of these rare and often fatal cases.

Microstructural characterization of autogenous laser welds on 316L stainless steel using EBSD and EDS.

This research is concerned with autogenous welding of 316L stainless steel and the microstructure generated by such a process. Autogenous welding does not require a filler material and in this case relies on an initial shallow melt phase to maintain a conduction limited weld. Essentially, a high power laser beam traverses the substrate, with the beam shaped by conventional optics, which produces a Gaussian irradiance distribution; or with a diffractive optical element, used to produce a uniform irradiance distribution. Initial results have shown that due to the nature of the heating cycle, complex microstructures are developed. These fine, complicated microstructures cannot be satisfactorily resolved and quantified using standard optical microscopy techniques. Electron backscatter diffraction (EBSD) and energy dispersive spectroscopy (EDS) have been carried out on a number of different microstructures prepared using a range of welding parameters. It is demonstrated that the simultaneous determination of the chemistry and crystallography is a very useful tool for rapid identification of the different phases formed on solidification as a consequence of varying welding procedures.

Developmental approaches in immunological control of acute myelogenous leukaemia.

After many years of hope and disillusionment, the possibility of utilizing immune-mediated approaches to control neoplastic clones has become a reality in various haematological malignancies. This is largely a consequence of the continuous advances in knowledge and the progressive development of more refined technologies that have led to a better understanding of the biology of the malignant cells and of the host immune system, to a more precise definition of disease entities and to the design of innovative therapeutic programmes. In this chapter, we will review different immunological strategies that have reached clinical practice in patients with acute myelogenous leukaemia (AML), the focus of this volume, and discuss pre-clinical developments that may in the near future translate into the design of new immunotherapeutic protocols for the management of AML. Treatment of AML with antibody directed therapy will also be discussed.

Acute myeloid leukemia: therapeutic indications.

The main issue for younger patients with acute myeloid leukemia is the prevention of relapse. About 55% of patients relapse and the risk can partially be predicted by prognostic factors, particularly cytogenetics. A number of strategies can attempt to reduce the relapse risk. Intensification of induction therapy has been attempted but there is as yet no convincing evidence that survival is improved. Transplantation of either allogeneic or autologous stem cells does not seem to offer major survival advantage overall or within risk groups. Improved understanding of resistance mechanisms and the identification of new risk factors may enable the development of a more targeted approach to therapy.

High dose cytarabine or transplantation for consolidation of younger patients with acute myeloid leukemia.

Collaborative study groups have invested considerable effort in the last decade in defining the role of allogeneic and autologous bone marrow transplantation as consolidation treatment for first remission of acute myeloid leukemia in younger patients. These efforts have been able, more precisely, to quantitate the degree to which patients who receive transplantation are a selected group. There has been a trend in recent years to increase the intensity of chemotherapy, which has improved treatment results, and the factors which determine the risk of relapse have become more widely acknowledged. These developments have made the appropriate choice of consolidation treatment less clear. Transplantation significantly reduces the risk of relapse and in some trials has improved the disease-free survival. However, a clear benefit in overall survival has been less clear and more difficult to demonstrate, partly because some patients who fail first-line chemotherapy can be salvaged in second remission. The trials that included high-dose cytarabine (ara-C) in the chemotherapy schedule were the ones in which no survival benefit was seen.

Role of allogeneic and autologous hematopoietic stem cell transplantation in acute myeloid leukemia.

Most younger patients with acute myeloid leukemia will enter remission of disease. Prevention of relapse is now the central therapeutic issue. A number of factors predict the risk of relapse, the most powerful of which is cytogenetics. Both allogeneic and autologous transplantation have been extensively used as remission consolidation, but intensive chemotherapy has also provided improved results such that the choice of consolidation treatment is not clear. Recent prospective trials of allogeneic and autologous transplantation with careful analysis have not always shown a survival benefit, although both approaches have significantly reduced relapse risk. In analysis where relapse risk is taken into account based on cytogenetics, there is little evidence of the benefit of transplantation in good-risk patients, partly because patients in this group who relapse can then undergo successful salvage therapy. The results are still uncertain in standard-risk patients, so transplantation should continue to be used in the context of a trial. Poor-risk patients have a higher failure rate after transplantation, and for these patients novel approaches are required.

Extramedullary T lymphoblastic transformation of chronic myeloid leukaemia occurring after double allogeneic transplantation.

The clinical course of chronic myeloid leukaemia (CML) is characterised by a chronic phase followed by an acute phase or blast crisis. Lymphoid transformation accounts for 20-30% of such events, with the majority of cases being of B cell origin. Extramedullary transformation occurs in approximately 10% of cases. We report a case of T cell lymphoblastic transformation in CML presenting as an extramedullary mass after allogeneic stem cell transplant. This case supports the growing evidence that CML arises in the pluripotent stem cell.

Elevated glucose levels influence in vitro hatching, attachment, trophoblast outgrowth and differentiation of the mouse blastocyst.

A glucose concentration of 3.5 mg/ml is optimal for in vitro embryo attachment and trophoblastic cell outgrowth. Raising the concentration above 3.5 mg/ml does not improve embryo culture and can at certain concentrations be detrimental to embryo development.