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Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin. We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77–1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73–0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82–0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31–0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75–0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83–1·18; p=0·9). Doses of 3 mg/m2 were associated with fewer early deaths than doses of 6 mg/m2, with equal efficacy. Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed. None.

This comparison of outcomes of allogeneic hematopoietic stem-cell transplantation in 1993–1997 and 2003–2007 shows that although patients had a somewhat poorer overall prognosis in the more recent period, the rate of death not preceded by relapse, the risk of relapse, and overall mortality decreased. Infections, graft-versus-host disease (GVHD), and liver, kidney, and pulmonary complications have been associated with high mortality after allogeneic hematopoietic-cell transplantation since the introduction of this procedure 40 years ago. 1 Changes in practice have decreased organ toxicity, 2 – 5 and improved prevention and treatment strategies have decreased the severity of acute GVHD. 6 – 9 The control of infectious complications has improved since the development of molecular methods for the detection of viral and fungal infections, the use of preemptive treatments, the introduction of new antifungal agents, and the prevention of nosocomial infection. 10 – 13 To examine the hypothesis that changes in the care of . . .

The graft-versus-tumour effect seen after allogeneic (genetically different) haematopoietic cell transplantation for human malignancies represents the clearest example of the power of the human immune system to eradicate cancer. Recent advances in our understanding of the immunobiology of stem-cell engraftment, tolerance and tumour eradication are allowing clinicians to better harness this powerful effect.

This invited commentary contains original material that has not been published or submitted elsewhere. Contributions were made by a single author. I have no conflict of interests involving the subject or material.

September 12 marked the 50th anniversary of E. Donnall Thomas's initial report of a radical new approach to cancer treatment: radiation and chemotherapy followed by the intravenous infusion of bone marrow. Dr. Frederick Appelbaum writes that Thomas's persistence in the face of criticism and clinical failure ultimately paid off. September 12, 2007, marked the 50th anniversary of E. Donnall (Don) Thomas's initial report of a radical new approach to cancer treatment: radiation and chemotherapy followed by the intravenous infusion of bone marrow. 1 That publication represented the beginning of a long series of laboratory and clinical investigations; more than a decade would pass before the procedure achieved its first successes. Yet Thomas's persistence in the face of criticism and clinical failure ultimately paid off in a new form of therapy that was used to treat approximately 50,000 people worldwide in 2006 (see timeline). Thomas's interest in the possibility of hematopoietic-cell . . .

A physician's unrelenting commitment made bone marrow transplantation an effective cancer therapy. With the death of E. Donnall (Don) Thomas on 20 October, the field of oncology lost an inspiring figure and the individual most responsible for developing human bone marrow transplantation. Don had what seemed to him a simple idea: Because normal marrow was easily destroyed by irradiation, shouldn't it be possible to destroy an abnormal marrow and replace it with marrow from a normal donor? Although simple in concept, Don's struggle to make marrow transplantation a clinical reality was long and difficult. Early attempts were unsuccessful, either because the transplanted marrow was rejected, or because the marrow rejected its new host. These failures led many to criticize Don's efforts as dangerous and futile. But his persistence paid off in the development of a therapy that has saved hundreds of thousands of lives.

Patients with minimal residual disease who received a cord-blood transplant had a higher probability of survival than those receiving a transplant from mismatched unrelated donors and a lower risk of relapse than those receiving a transplant from matched or mismatched unrelated donors. The preferred donor for patients who are in need of an allogeneic hematopoietic-cell transplant remains an HLA-identical sibling. Such a donor is not available for the majority (approximately 70%) of patients, and alternative donor sources are necessary. 1 At the Fred Hutchinson Cancer Research Center, the first alternative choice for patients who do not have an HLA-identical sibling has been an unrelated donor who has been matched with the patient at the allele level for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (a so-called 10/10 match, or an HLA-matched unrelated donor). However, approximately 50% of white patients who do not have an . . .

Background The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. Methods In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort, N  = 185) who received intensive chemotherapy. Models were validated in an independent set of similarly treated patients (validation cohort, N  = 166). Results Models using European LeukemiaNet guidelines were significantly associated with clinical outcomes and, therefore, utilized as a baseline for comparisons. Models incorporating age and expression of select transcripts with biomarkers from European LeukemiaNet guidelines demonstrated higher area under the curve and C-statistics but did not show a substantial improvement in performance in the validation cohort. Subset analyses demonstrated that models using only the European LeukemiaNet guidelines were a better fit for younger patients (age < 55) than for older patients. Models integrating age and European LeukemiaNet guidelines visually showed more separation between risk groups in older patients. Models excluding results for ASXL1 , CEBPA , RUNX1 and TP53 , demonstrated that these mutations provide a limited overall contribution to risk stratification across the entire population, given the low frequency of mutations and confounding risk factors. Conclusions While European LeukemiaNet guidelines remain a critical tool for triaging patients with acute myeloid leukemia, the findings illustrate the need for additional prognostic factors, including age, to improve risk stratification.

Background Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers. Methods To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes. Results Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations ( CEP70 , COMMD7 , DNMT3B , ECE1 , LNX2 , NEGR1 , PIK3C2B , SEMA4D , SMAD2 , TAF8 , ZNF444 ). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes ( CEP70 , DNMT3B , ECE1 , and PIK3CB ) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells. Conclusions This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.

Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.