Using the in vitro drug sensitivity test to identify candidate treatments for transient abnormal myelopoiesis.

Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.

A Case of Novel GATA-1 Mutation-positive Transient Abnormal Myelopoiesis With Life-threatening Complications in a Neonate With Down Syndrome.

Transient abnormal myelopoiesis is a transient myeloproliferative disorder seen in ∼15% to 20% of infants with Down syndrome. These infants are usually asymptomatic, requiring only monitoring, but they can have variable severity of symptoms up to multisystemic dysfunction requiring chemotherapy. GATA-1 somatic mutations acquired in utero are pathognomic of this entity and present nearly in all cases. Herein, we present a case of Down syndrome in a neonate who presented within her first week of life with life-threatening features of transient abnormal myelopoiesis requiring chemotherapy support. In addition, next-generation sequencing revealed a small mutant clone (8%) positive for a novel frameshift GATA-1 mutation.

Paraneoplastic Leukemoid Reaction in Gastroesophageal Junction Adenocarcinoma: A Case Report.

BACKGROUND The presence of leukocytosis associated with non-hematological malignancy after ruling out other causes is defined as paraneoplastic leukemoid reaction (PLR). PLR is a rare manifestation of various solid tumors. It is associated with poor prognosis unless receiving effective antineoplastic treatments. CASE REPORT A 72-year-old female was referred to a hematologist/oncologist for the evaluation of leukocytosis with neutrophilia. Initial workup was unremarkable; however, she had progressively worsening leukocytosis with neutrophilia, associated with severe anemia and dysphagia. Computed tomography (CT) scan revealed wall thickening at the gastroesophageal junction (GEJ) and multiple hypodensities of the liver. Esophagogastroduodenoscopy (EGD) confirmed the diagnosis of GEJ tumor and biopsy returned as adenocarcinoma with human epidermal growth factor receptor 2 (HER2) overexpression. Leukocytosis resolved after the first round of chemotherapy and the patient remains progression-free with the addition of trastuzumab to her chemotherapy regimen. CONCLUSIONS We report a rare case of PLR caused by GEJ adenocarcinoma. This is the first case of PLR in a patient with metastatic GEJ adenocarcinoma with HER2 overexpression in the Caucasian population. It is important to workup leukocytosis promptly, to keep malignancy in the differential diagnosis and to seek early hematology/oncology consultation.

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment-related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed. PROCEDURE: To identify potential novel therapeutic targets for myeloid disorders in children, including DS-AMKL and non-DS-AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre-)leukemic pediatric patient cells. RESULTS: Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan-histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation. CONCLUSION: NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS-AMKL.

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study.

Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.

Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement.

This brief communication reports on a patient with an exceedingly rare "8p11 (eight-p-eleven) myeloproliferative syndrome" (EMS) with CEP110-FGFR1 rearrangement who responded to treatment with the multi-tyrosine kinase inhibitor (TKI) dasatinib. Dasatinib improved quality of life substantially by increasing blood counts and reducing the need for transfusions. This report demonstrates that the second-generation TKI may provide a therapeutic option for elderly and frail EMS patients who cannot be offered aggressive therapy, including allogeneic hematopoietic cell transplantation. The Oncologist 2017;22:480-483.

Leukemoid reaction in cervical cancer: a case report and review of the literature.

BACKGROUND: The presentation of a leukemoid reaction in cervical cancers is rare. A leukemoid reaction is defined as leukocytosis associated with a cause outside the bone marrow, with the white blood cell count (WBC) exceeding 50*109/L. Two cervical cancers presenting with leukemoid reactions were previously reported. However, the cancers in these cases were mainly in the advanced stages and had a poor outcome. CASE PRESENTATION: Here we report a 40-year old patient with clinical stage (FIGO IIA1) cervical squamous carcinoma suffering from vaginal cuff recurrence with a leukemoid reaction two months after laparoscopic radical hysterectomy. The patient suffered from persistent fever and leukocytosis after one month of antibiotic treatment accompanied by rapid growth of the vaginal mass indicated that the leukocytosis could not be caused only by infection. After paclitaxel injection, the WBC count increased to 70.37*109/L. Bone marrow aspirates and biopsy showed left-shift neutrophilia, which confirmed leukemoid reaction. After two courses of paclitaxel and cisplatin treatment, the white blood cell counts decreased to normal, the fever disappeared, and the vaginal mass was reduced dramatically. She achieved completed remission after subsequent chemo-radiation and two additional courses of chemotherapy. CONCLUSION: In our case, leukemoid reaction was related to recurrent cervical carcinoma and sensitive to chemotherapy. To our knowledge, this is the third case to be reported in the literature. Furthermore, this is the only case described that shows an unequivocal correlation between tumor response and leukemoid reaction.

Leukemoid reaction, a rare manifestation of autoimmune hemolytic anemia in a case of small duct primary sclerosing cholangitis.

A 48 year old lady presented with jaundice and exertional breathlesness. Her laboratory reports showed anaemia, reticulocytosis, leucocytosis, elevated Lactate Dehydrogenase (LDH), alkaline phosphatase levels, hyperbillirubinemia and positive direct Coomb's test. After ruling out all the other causes of autoimmunity and hemolytic anemia, she was diagnosed as leukemoid reaction due to autoimmune hemolytic anemia with primary sclerosing cholangitis. Patient showed immediate improvement after corticosteroids.

Cancer-associated myeloproliferation: old association, new therapeutic target.

The association between malignancy and development of a paraneoplastic leukocytosis, the so-called leukemoid reaction, has long been appreciated. Although a leukemoid reaction has conventionally been defined as a peripheral blood leukocytosis composed of both mature and immature granulocytes that exceeds 50,000/microL, a less profound leukocytosis may be appreciated in many patients harboring a malignant disease. More recent insights have shed new light on this long-recognized association, because research performed in both murine models and cancer patients has uncovered multiple mechanisms by which tumors both drive myelopoiesis, sometimes leading to a clinically apparent leukocytosis, and inhibit the differentiation of myeloid cells, resulting in a qualitative change in myelopoiesis. This qualitative change leads to the accumulation of immature myeloid cells, which due to their immune suppressive effects have been collectively called myeloid-derived suppressor cells. More recently, myeloid cells have been shown to promote tumor angiogenesis. Cancer-associated myeloproliferation is not merely a paraneoplastic phenomenon of questionable importance but leads to the suppression of host immunity and promotion of tumor angiogenesis, both of which play an integral part in tumorigenesis and metastasis. Therefore, cancer-associated myeloproliferation represents a novel therapeutic target in cancer that, decades after its recognition, is only now being translated into clinical practice.

Alcoholic hepatitis with leukemoid reaction after surgery.

Alcoholic hepatitis (AH) is a clinicopathologic syndrome resulting from an excessive intake of alcohol. Leukemoid reactions (LRs) are characterized by a strikingly elevated granulocyte count over 40,000-50,000 cells/mm(3). Although a leukocytosis of 15,000-18,000 cells/mm(3) is frequently seen in AH, LRs are rare in this context. AH-associated LRs are a sign of poor prognosis and have a high mortality. A 64-year-old male with a history of heavy alcohol intake underwent a right hemicolectomy for cecal carcinoma. Preoperative laboratory data were normal with the exception of an albumin of 2.1 g/dL. Liver biopsies that were taken because of a nodular appearance revealed micronodular cirrhosis, steatohepatitis, and Mallory bodies. Postoperatively, the patient developed a leukocytosis that progressively increased to 72.6 cells/mm(3). He also developed signs of impaired hepatic and renal function. Extensive workup failed to reveal a source of infection. A trial of intravenous antibiotics had no impact on the leukocytosis. Methylprednisolone at a dose of 40 mg IV daily was started on postoperative day 9. The patient experienced a progressive decline in white blood count (WBC), which reached 25.2/mm(3) on postoperative day 14. However, he died on postoperative day 16. We conclude that the patient had AH-associated LR in the postoperative period, but died despite successful treatment of the LR with steroids.

[Leukemoid reaction with uncommonly high leucocytosis in the course of serious infection]. / Odczyn bialaczkowy z niespotykanie wysoka leuko- cytoza w przebiegu ciezkiego zakazenia.

We present a case of 51-year old female patient with gastrointestinal perforation and septic shock leading to leukemoid reaction with WBC 155 x 109/l. Leukemoid reaction in neoplasms and infections can mimic chronic myelogenous leukaemia and is an important diagnostic problem.

Steroidal management and serum cytokine profile of a case of alcoholic hepatitis with leukemoid reaction.

Leukemoid reactions (LRs) are rare in alcoholic hepatitis (AH), but they are a sign of poor prognosis. The treatment of AH with corticosteroids is controversial, though several reports suggest that these should be used in severe cases of AH. We report a case of AH-associated LRs that presented with an increase of the serum concentrations of the proinflammatory cytokines interleukin (IL)-18 (an initiator of inflammation) and IL-1beta (likely responsible for the neutrophilia of the LRs). These findings provided a pathogenic indication for the use of corticosteroids (that block the transcription of IL-1beta), and this approach achieved a clinical and analytical recovery in our patient. This pathogenic mechanism might also underlie other cases of LRs and other complications of AH, thus providing a rationale for the benefits of corticotherapy in these rare but severe conditions.

Agranulocytosis, plasmacytosis, and thrombocytosis followed by a leukemoid reaction due to acute acetaminophen toxicity.

OBJECTIVE: To describe a patient who developed hepatotoxicity, reactive plasmacytosis with thrombocytosis and life-threatening agranulocytosis, followed by a leukemoid reaction, apparently caused by acute acetaminophen toxicity. SETTING: University-affiliated hospital. CASE SUMMARY: A 19-year old white women who took an overdose of acetaminophen developed hepatotoxicity and reactive plasmacytosis with thrombocytosis and life-threatening agranulocytosis, followed by a leukemoid reaction. Symptoms, signs, and laboratory findings regressed with symptomatic therapy during the follow-up period. CONCLUSIONS: We believe that acute acetaminophen toxicity was responsible for these hematologic abnormalities. This profile of hematologic adverse effects associated with acetaminophen toxicity has not been reported previously.

[The prolymphocytic-lymphocytic leukemization of B-cell lymphosarcomas]. / Prolimfotsitarno-limfotsitarnaia leikemizatsiia B-kletochnykh limfosarkom.

The paper presents clinical, hematological, morphological and immunological characteristics of B-cell lymphosarcoma with prolymphocytic-lymphocytic type of leukemization in 50 adult patients (9 females and 41 males aged 29-86 years). In B-cell immunological subvariant of prolymphocytic-lymphocytic leukemization changes in the primary tumor always corresponded to prolymphocytic variant of lymphosarcoma. This distinguishes B-cell lymphosarcomas from previously described T-cellular ones in which the type of eventual leukemic changes did not always correspond to the kind of initial tumor. The presence or absence of prolymphocytes with split nuclei in bone marrow puncture samples was neither of clinical nor of prognostic significance. In leukemization of B-cell prolymphocytic lymphosarcoma from the cells with split nuclei or cells with different configuration of the nuclei, immunological phenotype typical for B-cell chronic lymphoid leukemia did not occur. In prolymphocytic lymphosarcoma from cells with round nuclei one-third of patients had immunological phenotype more typical for B-cell chronic lymphoid leukemia. However, among them were patients with aggressive course with predominant extranodal location of tumor and prolymphocytic type of leukemization. Tumor nodes in B-cell prolymphocytic lymphosarcomas, irrespective of leukemization morphological variant, proved rather resistant to therapy. A complete clinicohematological remission according to the international criteria occurred in 2 of 50 patients, only.

[The prolymphocytic-lymphocytic leukemization of T-cell lymphosarcomas]. / Prolimfotsitarno-limfotsitarnaia leikemizatsiia T-kletochnykh limfosarkom.

The paper presents a detailed clinical, hematological, morphological, ultrastructural and immunological characterisation of T-cell lymphosarcoma with prolymphocytic-lymphocytic leukemic transformation (PLLT). In PLLT the proportion of T-cell immunological subvariant of lymphosarcoma came to 15% being detected only in 8 out of 52 examinees. The patients (6 males and 2 females) varied in age from 24 to 76 years (median 49 years) and had the following histological forms of primary tumor tissue: lymphoblastic lymphosarcoma (n = 3), pleiomorphic small cell lymphosarcoma (n = 1), large-cell anaplastic lymphosarcoma (n = 1), prolymphocytic lymphosarcoma. Immunological characteristics of these 8 cases were heterogeneous: in lymphoblastic variant there was immature T-immunological phenotype. In pleomorphic small-cell lymphosarcoma there were also signs of T-cell activation. In large-cell anaplastic lymphosarcoma an immunological phenotype of lymphoid cells from the primary tumor tissue and bone marrow differed in more advanced immunological differentiation of bone marrow tumor cells. In prolymphocytic variant tumor cells had features of T-helpers or T-suppressors. Most of the patients received polychemotherapy according to the schemes for high-grade lymphosarcomas despite PLLT though the latter is not a universal indicator of late tumor progression, more aggressive course of the disease and poor prognosis.

[Clinical variants in the course of a fungal disease caused by a fungus in the genus Paecilomyces]. / Klinicheskie varianty techeniia gribkogo zabolevaniia, vyzvannogo gribom roda Paecilomyces.

The data are available on 23 cases of eosinophil-type leukemoid reaction to infection with Paecilomyces fungi treated in 1980-1987. The clinical course presented with high fever on the onset followed by the subfebrile temperature later, symptoms of upper respiratory tract catarrh, enlargement of peripheral lymph nodes, involvement of other organs, 78-84% eosinophilia, leukocytosis at the onset. Upon establishment of accurate diagnosis by specific laboratory tests, the etiopathogenetic treatment was administered. The response was achieved in 94% of the patients.