A case of AML characterized by a novel t(4;15)(q31;q22) translocation that confers a growth-stimulatory response to retinoid-based therapy

Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-transretinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving theTMEM154andRASGRF1genes. Analysis of primary cells from the patient revealed the expression ofTMEM154-RASGRF1mRNA and the resulting fusion protein, but no expression of the reciprocalRASGRF1-TMEM154fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML

Powered bone marrow biopsy procedures produce larger core specimens, with less pain, in less time than with standard manual devices

Bone marrow sampling remains essential in the evaluation of hematopoietic and many non-hematopoietic disorders. One common limitation to these procedures is the discomfort experienced by patients. To address whether a Powered biopsy system could reduce discomfort while providing equivalent or better results, we performed a randomized trial in adult volunteers. Twenty-six subjects underwent bilateral biopsies with each device. Core samples were obtained in 66.7% of Manual insertions; 100% of Powered insertions (P=0.002). Initial mean biopsy core lengths were 11.1±4.5 mm for the Manual device; 17.0±6.8 mm for the Powered device (P<0.005). Pathology assessment for the Manual device showed a mean length of 6.1±5.6 mm, width of 1.0±0.7 mm, and volume of 11.0±10.8 mm3. Powered device measurements were mean length of 15.3±6.1 mm, width of 2.0±0.3 mm, and volume of 49.1±21.5 mm3 (P<0.001). The mean time to core ejection was 86 seconds for Manual device; 47 seconds for the Powered device (P<0.001). The mean second look overall pain score was 33.3 for the Manual device; 20.9 for the Powered (P=0.039). We conclude that the Powered biopsy device produces superior sized specimens, with less overall pain, in less time

Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111220/1/bjh13323.pd

In elderly patients with AML, which patients should be considered fit or unfit for standard induction therapy?

A 75-year-old man visits his primary care physician for a routine checkup and a complete blood count reveals pancytopenia. BM examination confirms the diagnosis of acute myeloid leukemia. No dysplastic features were noted and his karyotype results are pending. The patient has well-controlled hypertension and his last hospital admission was 20 years ago for repair of a rotator cuff injury. His Eastern Cooperative Oncology Group performance status is 0/4 and he has no cognitive impairment. You believe the patient is fit for standard acute myeloid leukemia induction, but you are concerned because of his older age and you are considering less-intensive approaches

Troxacitabine in leukemia

Troxacitabine (Troxatyl; BCH-4556; (−)−2′-deoxy-3′-oxacytadine) is the first synthetic L-nucleoside enantiomer to demonstrate broad spectrum cytotoxic activity. It was obtained by exchanging the sulphur endocyclic atom with oxygen in the structure of lamivudine, following the discovery that this agent had cytotoxic, as well as anti-viral activity. The unique "unnatural" stereochemistry of troxacitabine has produced impressive cytotoxic potency against a wide range of malignancies in the laboratory which led to its selection for clinical development. The initial trials with troxacitabine have established its efficacy in both solid and haematological malignancies, including those resistant to ara-C (cytarabine). This review will consider troxacitabine in terms of its pharmacology, mode of action, pharmacokinetics, toxicities, and clinical efficacy

Novel Abl Kinase Inhibitors in Chronic Myeloid Leukemia in Blastic Phase and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib being the first and most successful of these. Resistance to imatinib results in some patients from Abl kinase point mutations. Overcoming imatinib resistance represents one of the biggest challenges facing clinicians in the modern management of CML. In this review, we discuss the current understanding of CML pathophysiology and mechanisms of imatinib resistance and how advancing this knowledge has led to the design of novel therapies in the area of blastic phase CML and Philadelphia chromosome–positive acute lymphoblastic leukemia with previous imatinib failure

Recent advances in the diagnosis and therapy of Richter's syndrome

Richter's syndrome (RS) denotes the development of aggressive lymphoma that arises in patients with chronic lymphocytic leukemia (CLL). Presenting features typically include a rapid clinical deterioration with fever in the absence of infection, progressive lymph node enlargement, and an elevation in serum LDH. Diagnostic biopsy of affected sites usually reveals large cell lymphomas; however, Hodgkin variant cases have been described. Richter's transformation occurs in approx 5% of CLL patients and may be associated with infection with Epstein-Barr virus (EBV). Chromosome 11 and 14 abnormalities have also been described as well as tumor suppressor gene defects involving p53, p21, and p27. Treatment options for these patients are limited and include combination chemotherapy with or without the addition of monoclonal antibodies and stem cell transplantation. Response to therapy is variable and generally short-lived. Median survival is usually in the order of 5-8 mo. More effective management for RS is needed as well as prognostic models that will identify CLL patients at risk of transformation. This review will address the current status of RS and deal with the pathophysiology, diagnostic approach, and treatment of this challenging disease

Amonafide: a future in treatment of resistant and secondary acute myeloid leukemia?

Development of the novel topoisomerase II inhibitor, amonafide, began almost 40 years ago. The drug was selected for further investigation owing to evidence of marked antineoplastic efficacy in preclinical models of cancer. When its usefulness in the treatment of various solid malignancies proved limited, focus was shifted to establishing its use as an antileukemic agent, specifically against secondary and treatment-associated acute myeloid leukemia (AML). While Phase I and II studies gave rise to hopes that amonafide might hold the key to treating older patients, including those with multidrug resistant, cytogenetically unfavorable secondary and treatment-associated AML, when used in combination with cytarabine, it failed to demonstrate a survival advantage over standard-of-care therapy in randomized studies. This article will outline the development of amonafide from the laboratory to the bedside and discuss the potential place that this agent has in the current management of AML