Mast cell leukemia.

Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation-involvement of the liver, spleen, peritoneum, bones, and marrow-are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.

Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression.

Apart from indolent systemic mastocytosis (SM), which is associated with a favorable prognosis, other subtypes of SM (SM with associated clonal hematologic non-mast cell lineage disease, aggressive SM, and mast cell leukemia - collectively referred to in this review as advanced SM) can be debilitating. The complexity of SM makes both the diagnosis and design of response criteria challenging for clinical studies. The tyrosine kinase KIT has been shown to play a crucial role in the pathogenesis of SM and has been a focal point in the development of targeted therapy. Mutations within various domains of the KIT receptor that lead to constitutive activation have been identified in patients, and those involving the activation loop of the KIT receptor are the mutations most frequently detected in patients with mastocytosis. Aberrant activation of the KIT receptor results in increased production of mast cells in extracutaneous organs that may lead to organ failure or early death. This review discusses the diagnosis and management of patients with advanced SM, including the relevance of KIT in this disease, potential therapies targeting this kinase, and criteria for measuring responses to these therapies.

[Mast cell leukemia--case report]. / Mastocitna leukemija--prikaz bolesnice.

UNLABELLED: Mast cell leukemia is extremely rare, more often arises de novo and in 15% of cases developes from preexistence mast cell diseases. It is a high malignant leukemia with bad prognosis and a short survival. A 72-year old female was admitted to hospital with clinically suspected plasmocytoma. She had eccematoid changes on her trunk and underarms. Radiogramm showed osteolytic lesions of the right thigh and pelvis. FNA of the bone marrow revealed hypercellular smear with 80% of mast cells and immature mast cells which were cytochemically positive to toluidin (Figure 1. and 2.), chloracetate, alcian blue, acid fosphatase and Sudan black and negative to periodic acid Schiff (PAS) and peroxidase (POX). The peripheral blood smear showed single mast cells which were positive to toluidin. The bone marrow biopsy confirmed mast cell leukemia. The chariogramm of the bone marrow showed numerical and structural chromosomal changes. Two month after the diagnosis the patient suffered from right thigh fracture and was treated with local radiotherapy, antihistaminic and analgetic therapy. The patient died within 6 month after the diagnosis. CONCLUSION: Mast cell leukemia is very rare and high grade leukemia with short survival time. Cytological diagnosis is possible, when there is more then 20% of atypical mast cells in the bone marrow aspirate. The diagnosis of aleukemic variant of mast cell leukemia could be stated if there is less then 10% of mast cells in the peripheral blood.

Myelomastocytic Leukemia With t(8;21) in a 3-year-old Child.

Here we report a 3-year-old boy with myelomastocytic leukemia. The patient presented with fatigue and right eye proptosis. Bone marrow revealed acute myeloid leukemia with t(8;21) and trisomy 8. Induction therapy produced marked reduction in marrow myeloblasts with the emergence of 13% atypical mast cells. These cells were subsequently identified in retrospect in the diagnostic marrow consistent with myelomastocytic leukemia. His clinical course was notable for the difficulty in the eradication of the leukemic process and resembled that of adults with systemic mastocytosis with associated hematologic non-mast cell lineage disease. To the best of our knowledge, this is the youngest individual reported. The implications of mast cell lineage involvement in acute myeloid leukemia are reviewed.

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Extramedullary Involvement of Mast Cell Leukemia Detected by 18F-FDG PET/CT.

Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis, characterized by the leukemic expansion of immature mast cells. We present a case of MCL with extramedullary involvement of cervical lymph node and lung demonstrated by the initial F-FDG PET/CT scan. After a transient complete remission by induction chemotherapy and allogeneic hematopoietic stem cell transplantation, the follow-up PET/CT showed extensive extramedullary relapse involving multiple lymph nodes and small bowel. F-FDG PET/CT may be a useful tool to comprehensively stage and follow-up MCL.

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy.

Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development leads to systemic mastocytosis (SM), a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused MC accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.

Evidence for a graft-versus-mast-cell effect after allogeneic bone marrow transplantation.

Mast cell leukemia (MCL) is a rare form of aggressive mastocytosis with a reported median survival below 6 months. Casuistic reports suggest the effectiveness of allogeneic bone marrow transplantation (BMT) for MCL. However, these reports lack clear evidence for a graft-versus-mast-cell (GvMC) effect. We prospectively investigated the GvMC at different time points after allogeneic BMT and donor-lymphocyte infusions (DLI). Samples were gathered from a patient with MCL treated with allogeneic BMT from an unrelated HLA identical donor. Parameters for detection of a GvMC effect included flow cytometrical analysis of mast cell (MC) populations in peripheral blood and BM, BM smear and histology, chimerism analysis of flow cytometrically sorted BM CD117+/CD34- MC and testing for anti-mast cell reactivity of donor lymphocytes by interferon (IFN)-gamma ELISPOT. DLIs reduced MC from 5 to 0.5%. MC chimerism analysis demonstrated a complete recipient genotype after BMT, suggesting that the persistent mastocytosis was part of residual neoplastic disease. At 3.7 years after BMT, there is some evidence for relapse. In summary, BMT and DLIs attenuated the mastocytosis from an aggressive to an indolent form and may have improved the patients' prognosis. The in vitro data of our study indicate for the first time the existence of a GvMC effect.

Rapid engraftment of mast cells of donor origin in a case of acute myeloid leukemia with mast cell leukemia after allogeneic stem cell transplantation.

Mastocytosis is a rare disease characterized by an abnormal increase of mast cells in tissues. We report a case of acute myeloid leukemia (AML) with t(8;21) and mast cell leukemia (MCL) in which the mastocytosis persisted after standard chemotherapy and allogeneic stem cell transplantation, although the myeloid leukemia achieved molecular complete remission soon after induction chemotherapy. Donor-type mast cells were noted on d31 after transplant. No c-kit mutation was found before or after the transplant. This represents the first reported case in which rapid engraftment of mast cells of donor origin was documented. Thus, the possibility that the mast cell originates from a common myeloid precursor cell may be questioned and a reactive process should be considered in some cases of systemic mastocytosis.

Treatment of systemic mast cell disorders.

The heterogeneous nature of disease manifestations in mastocytosis requires the individualization of therapy to each patient's clinical presentation and prognosis. The mainstay of treatment for most categories of mastocytosis are H1 and H2 antihistamines with the addition of corticosteroids for more severe symptoms. This article presents a summary of treatment strategies for indolent and aggressive forms of mastocytosis along with a discussion of future therapeutic directions.

Biology, classification and treatment of human mastocytosis.

Mastocytosis is a term collectively used for a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells. Clinical symptoms occur from the release of chemical mediators and the pathologic infiltration of cells. Three major groups of patients with mastocytosis can be distinguished: i) cutaneous mastocytosis, ii) mastocytosis involving the skin and one or more extracutaneous organ(s), and iii) visceral mastocytosis without involvement of the skin. Groups ii) and iii) account for approximately 15-20% of all cases and have been referred to as systemic mastocytosis. Cutaneous mastocytosis typically presents as urticaria pigmentosa or diffuse cutaneous mastocytosis. These patients usually have a benign course. In contrast, systemic mastocytosis is a diffuse hematologic process with an increased risk to develop aggressive disease. In these patients, additional hematologic abnormalities or a second hematologic process, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia, may develop. Malignant mastocytosis and mast cell leukemia are rare forms of mastocytosis and characterized by uncontrolled and progressive proliferation and infiltration of mast cells in diverse organs. These patients often present without cutaneous lesions and have a very unfavorable prognosis. Because of the immature morphology of the cells it is often difficult to establish the diagnosis in such patients. However, the use of antibodies to mast cell antigens has recently improved the diagnostic efficiency in patients with suspected mast cell disease. No effective therapy for patients with malignant mastocytosis is known, although some patients may benefit from corticosteroid and interferon alpha treatment. The present article gives an overview of current knowledge about the biology, heterogeneity and treatment of human mastocytosis.

Proteomics in the search for biomarkers of animal cancer.

The prevalence of cancer in companion animals has increased in the recent decade, making this disease one of the major causes of deaths. As in human medicine, veterinary medicine faces the problem of cancer prevention as well as early diagnosis and effective therapy. Early diagnosis of cancer is crucial for the successful treatment of the disease and there is a need for biomarkers that could be used as a diagnostic tool, and to guide a targeted therapy or monitor a therapeutic response. Proteomic technologies that were introduced to human cancer research over a decade ago provide the opportunity to identify distinct protein patterns for cancer diagnosis and therapy monitoring. These also have potential to be utilised in veterinary medicine. The present paper summarises the current knowledge about proteomic studies on animal cancer biomarker research published to date.