A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.

BACKGROUND: The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach. METHODS: Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA). RESULTS: Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms. CONCLUSIONS: Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.

The debate: The trials have told us very little.

The original trials of empiric intravenous amphotericin-B in the 1980s failed to prove conclusively its efficacy in the treatment of febrile neutropenia. Despite that, all subsequent studies of the therapy of presumed, possible, probable and proven invasive aspergillosis have assumed that this drug, either as deoxycholate or in lipid-based form, is the gold standard treatment against which all newcomers should be compared. This has led to a series of further inconclusive randomized controlled trials of empiric therapy as a result of which the most we can say is that nearly all new drugs are less toxic but also no more effective than amphotericin-B deoxycholate. The toxicity of the non-lipid formulation of this drug should have led us to withdraw it from both RCTs and routine clinical practice some years ago in view of the increasing evidence of equivalent efficacy and lower toxicity of other agents including lipid amphotericin formulations.Recent studies of the use of newer diagnostic techniques (i.e., CT and serology) reinforce the need to abandon the empiric trial approach in which we have repeatedly shown lack of superiority in the treatment of an infection which most patients do not have. Even in the small number of trials of the therapy of proven or probable invasive aspergillosis, results have been inconclusive or at best confusing in trying to find a better option than amphotericin-B. The trial of voriconazole versus amphotericin-B deoxycholate for this indication is a model for study for all those interested in the difficulties of designing trials which lead to convincing results.Effective prophylaxis trials and their analyses began by following a more rational pathway, first showing convincingly that fluconazole reduced the risk of C. albicans systemic infection in transplant patients. Unfortunately the widespread faith in the ability of this drug to prevent a wider range of systemic fungal infections in a wider range of patients is simply not supported by the data from many subsequent single trials and meta-analyses. This attachment to fluconazole has been mirrored by unwillingness to accept the evidence that itraconazole is superior in prophylaxis to fluconazole which is inactive against Aspergillus spp. In this case the trials have not told us enough because we have not believed the results. Results of trials of extended range azoles such as posaconazole are interesting but there are insufficient data to claim that posaconazole is superior to itraconazole.The progress in therapy and prophylaxis of systemic fungal infection has been unsatisfactory and slow. A new approach is needed for the design of clinical trials for these indications. There is good evidence that supportive investigations should now be used routinely in clinical practice and trials to increase certainty about the presence of invasive infection, to limit unnecessary use of expensive and toxic drugs and to improve analysis of efficacy of old and new antifungal agents.

A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia.

The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT [daunorubicin, ara-C, thioguanine], DA [daunorubicin, ara-C], or FLAG-Ida [fludarabine, ara-C, G-CSF, idarubicin]) with GO on day 1. It was possible to give GO 3 mg/m2 with course 1, but 6 mg/m2 with course 1 or GO in a dose of 3 mg/m2 with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P =.007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years.