Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion.

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.

Phase-2 trial of an intensified conditioning regimen for allogeneic hematopoietic cell transplant for poor-risk leukemia.

Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase-2 trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was i.v. BU, targeted to a first-dose plasma area under the curve (AUC) of 700-900 µM min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated TBI (FTBI) at 1200 cGy in 10 fractions. GVHD prophylaxis was CsA and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade II mucositis in 29 patients (97%) and grade III in one patient, grade II-III sinusoidal obstructive syndrome in 2 patients (7%), and grade 2-3 (CTC) skin toxicity in 8 patients (27%). The 30- and 100-day TRMs were 0 and 7% respectively. The median follow-up was 83.7 months (60.7-96.4) for surviving patients. The 5-year overall and disease-free survival was 40% for all patients. Cumulative 5-year relapse incidence (RI) was 23% and TRM was 37%. We have shown promising OS and RI in these poor-risk patients, who typically have few curative options.

Mast cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His.

Mast cell disease (MCD), a proliferation of mast cells (MC), is occasionally associated with hematologic malignancies. Neoplastic MC have activating c-kit mutations. c-kit is a receptor tyrosine kinase required for the development, proliferation, and survival of MC. Interaction of c-kit with its ligand stem cell factor induces dimerization, receptor phosphorylation, and signal transduction. The most common c-kit mutation detected in neoplastic MCD is Asp816Val, which results in ligand-independent autophosphorylation of the receptor leading to MC proliferation. We describe the rare occurrence of MCD associated with acute myeloid leukemia, report a novel c-kit mutation Asp816 His, and discuss the pathogenesis of MCD associated with hematologic malignancies.

Ticlopidine-induced aplastic anemia: development of chromosomal abnormalities and response to immunosuppressive therapy.

Severe aplastic anemia is a well-recognized complication of ticlopidine therapy that carries a high mortality. Therapy with colony-stimulating factors or corticosteroids has been largely ineffective in this disorder. We report a case of ticlopidine-induced aplastic anemia that was successfully treated with cyclosporine and high-dose dexamethasone. The patient rapidly responded to immunosuppressive therapy and had a normal hemogram after cessation of immunosuppression. On long-term follow-up, the patient developed a progressive macrocytic anemia. Repeat bone marrow evaluation demonstrated myelodysplasia with erythroid hypoplasia. An associated chromosomal abnormality consisting of a t(3;16) (q21; p13.3) translocation was detected. This is the first report of a chromosomal abnormality associated with ticlopidine induced marrow aplastic anemia.

Intraspinal hemorrhage complicating oral anticoagulant therapy: an unusual case of cervical hematomyelia and a review of the literature.

Intraspinal hemorrhage is a rare but dangerous complication of anticoagulant therapy. It must be suspected in any patient taking anticoagulant agents who complains of local or referred spinal pain associated with limb weakness, sensory deficits, or urinary retention. We describe a patient with hematomyelia, review the literature on hematomyelia and other intraspinal hemorrhage syndromes, and summarize intraspinal hemorrhage associated with oral anticoagulant therapy. The patient (a 62-year-old man) resembled previously described patients with hematomyelia in age and sex. However, he was unusual in having cervical rather than thoracic localization. As with intracranial bleeding, the incidence of intraspinal hemorrhage associated with anticoagulant therapy might be minimized by close monitoring and tight control of the intensity of anticoagulation. However, it is noteworthy that many of the reported cases were anticoagulated in the therapeutic range. If intraspinal hemorrhage is suspected, anticoagulation must be reversed immediately. Emergency laminectomy and decompression of the spinal cord appear mandatory if permanent neurologic sequelae are to be minimized. A high index of suspicion, prompt recognition, and immediate intervention are essential to prevent major morbidity and mortality from intraspinal hemorrhage.