Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute

Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time

Association of acute myeloid leukemias most immature phenotype with risk groups and outcomes

The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the “gold standard” immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells in a large prospective cohort. The leukemic clone’s most primitive hematopoietic cellular phenotype was prospectively identified in 109 newly-diagnosed acute myeloid leukemia patients, and analyzed against clinical risk groups and outcomes. Most (80/109) patients harbored CD34+CD38− leukemia cells. The CD34+CD38− leukemia cells in 47 of the 80 patients displayed intermediate aldehyde dehydrogenase expression, while normal CD34+CD38− hematopoietic stem cells expressed high levels of aldehyde dehydrogenase. In the other 33/80 patients, the CD34+CD38− leukemia cells exhibited high aldehyde dehydrogenase activity, and most (28/33, 85%) harbored poor-risk cytogenetics or FMS-like tyrosine kinase 3 internal tandem translocations. No CD34+ leukemia cells could be detected in 28/109 patients, including 14/21 patients with nucleophosmin-1 mutations and 6/7 acute promyelocytic leukemia patients. The patients with CD34+CD38− leukemia cells with high aldehyde dehydrogenase activity manifested a significantly lower complete remission rate, as well as poorer event-free and overall survivals. The leukemic clone’s most immature phenotype was heterogeneous with respect to CD34, CD38, and ALDH expression, but correlated with acute myeloid leukemia risk groups and outcomes. The strong clinical correlations suggest that the most immature phenotype detectable in the leukemia might serve as a biomarker for “clinically-relevant” leukemia stem cells. ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01349972","term_id":"NCT01349972"}}NCT01349972

Genetic Variants of Ehrlichia phagocytophila1, Rhode Island and Connecticut

Primers were used to amplify a 561-bp region of the 16S rRNA gene of Ehrlichia phagocytophila from Ixodes scapularis ticks and small mammals collected in Rhode Island and Connecticut. DNA sequences for all 50 E. phagocytophila-positive samples collected from 1996 through 1998 in southwestern Connecticut were identical to the sequence reported for E. phagocytophila DNA from confirmed human cases. In contrast, the sequences from 92 of 123 E. phagocytophila-positive Rhode Island samples collected from 1996 through 1999 included several variants differing by 1-2 nucleotides from that in the agent infecting humans. While 11.9% of 67 E. phagocytophila-positive ticks collected during 1997 in Rhode Island harbored ehrlichiae with sequences identical to that of the human agent, 79.1% had a variant sequence not previously described. The low incidence of human ehrlichiosis in Rhode Island may in part result from interference by these variant ehrlichiae with maintenance and transmission of the true agent of human disease

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts

The development of pevonedistat in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): hope or hype?

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder clinically defined by cytopenias, bone marrow failure, and an increased risk of progressing to acute myeloid leukemia (AML). Traditionally, first-line treatment for patients with higher-risk MDS has been hypomethylating agents (HMAs). However, these agents have modest clinical activity as single agents. A one-size-fits-all treatment paradigm is insufficient for such a heterogeneous disease in the modern era of precision medicine. Several new agents have been developed for MDS with the hopes of improving clinical outcomes and survival. Pevonedistat is a first-in-class, novel inhibitor of neuronal precursor cell-expressed developmentally down-regulated protein-8 (NEDD8) activating enzyme (NAE) blocking the neddylation pathway leading to downstream effects on the ubiquitin–proteosome pathway. Pevonedistat ultimately leads to apoptosis and inhibition of the cell cycle in cancer cells. Studies have demonstrated the safety profile of pevonedistat, leading to the development of multiple trials investigating combination strategies with pevonedistat in MDS and AML. In this review, we summarize the preclinical and clinical rationale for pevonedistat in MDS and AML, review the clinical data of this agent alone and in combination with HMAs to date, and highlight potential future directions for this agent in myeloid malignancies

Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute

BACKGROUND: Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time. METHODS: A retrospective analysis was performed on 711 adult AML patients enrolling in 45 phase I clinical trials supported by the Cancer Therapy Evaluation Program of the National Cancer Institute from 1986 to 2009. Changes in ORR and mortality rates for patients enrolled in 1986 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009 were estimated with multivariable logistic regression models. All statistical tests were two-sided. RESULTS: There was a statistically significant increase in AML patients enrolling in phase I clinical trials over time (1986 to 1990: n = 61; 2006 to 2009: n = 256; P = .03). The ORR for the entire cohort was 15.4% (1986 to 1990: 8.9%, 1991 to 1995: 21.1%; 1996 to 2000: 7.0%; 2001 to 2005: 10.0%; 2006 to 2009: 22.6%), and it statistically significantly improved over time (P < .001). There was a statistically significant improvement in ORRs with novel agents in combination vs single agents (ORR = 22.8% vs 4.7%, respectively, odds ratio = 5.95, 95% confidence interval = 3.22 to 11.9, P < .001). The 60-day mortality rate for the entire cohort was 22.6%, but it statistically significantly improved over time (P = .009). CONCLUSIONS: There has been an encouraging increase in AML patients enrolling in phase I clinical studies over time. The improvement in ORRs appears to be partly because of the increase in combination trials and the inclusion of previously untreated poor-risk AML. Continued enrollment of AML patients in early phase clinical trials is vital for drug development and improvement in therapeutic outcomes