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Objective/background: Anti-T lymphocyte globulin Fresenius (rATG-F; ATG-Fresenius) and antithymocyte globulin (thymoglobulin), which are included in transplant protocols, are used to reduce the risk of chronic graft-versus-host disease (cGVHD) or suppress allograft rejection. Available clinical studies have been conducted in heterogenous patient populations and with different administration protocols including stem cell sources. Additionally, the pharmacokinetics of ATG is variable, and the clinically effective dose of rATG-F, in particular, is not exactly known. The aim of the study was to investigate the clinical outcomes of acute myeloid leukemia (AML) patients who underwent hemopoietic peripheral stem cell transplantation from full-matched sibling donors and given two different doses of r-ATG-F. Methods: This was a single-center, retrospective chart review conducted between July 2005 and July 2016. Sixty-nine consecutive AML patients who underwent transplant with fludarabine- and busulfan-based conditioning were included in the study. Patients in Group 1 received 15 mg/kg body weight rATG-F to 2013 (n = 46), and Group 2 received 30 mg/kg of rATG-F dose begining in 2013 to reduce to cGVHD (n = 23). Cyclosporine and methotrexate were used to treat acute GVHD (aGVHD) prophylaxis. Outcome parameters were compared between the groups. Results: Although the recommended dose r-ATG-F had led to a decrease in the cumulative incidence of cGVHD (27 [58.7%] vs. 8 [34.8%]; p = .03), it also increased the infection rate at 1 year (3 [6.5%] vs. 4 [17.4%]; p = .02). The two groups were similar in terms of engraftment time, aGVHD, relapse, nonrelapse mortality, and rATG-F-related toxicity. A Cox regression model revealed that aGVHD III–IV was associated with increased nonrelapse mortality at 1 year (hazard ratio = 18.2; 95% confidence interval, 1.667–199.255; p =

[EN] Within the European Network for Cancer research in Children and Adolescents (ENCCA), SIOPE and the European paediatric haematology-oncology community have established a long-term sustainable Strategic Plan to increase the cure rate and the quality of survivorship for children and young people with cancer over the next ten years. The ultimate goal is to increase the diseaseand late-effect- free survival after 10 years from the diagnosis, and beyond. As a result of several initiatives to involve all stakeholders and ensure that all their points of view would be taken into account in the document, this long-term sustainable Strategic Plan has achieved a broad consensus, and will serve as the "European Cancer Plan for Children and Adolescents"., This publication has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under the project ENCCA (European Network for Cancer research in Children and Adolescents), grant agreement nr. HEALTH-F2-2011-261474.

Reciprocal translocations involving the long arm of chromosome 7 are relatively rare cytogenetic aberrations in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). A 44-year-old woman was initially given a diagnosis of de novo AML M6A with a normal karyotype. After achieving complete remission, she received allogeneic bone marrow transplantation from an unrelated male donor. Seven months later, pancytopenia appeared with 14.8% myeloblasts and dysplastic changes of neutrophils and megakaryocytes in the bone marrow. Chromosome analysis revealed complex karyotypes, with add(7)(q22) and add(9)(q34) detected in all abnormal metaphase spreads; spectral karyotyping revealed these chromosomal aberrations to be derived from a reciprocal translocation t(7;9)(q22;q34). Fluorescence in situ hybridization analyses showed that D7S486 at 7q31 was translocated to the der(9)t(7;9), and that the ABL gene at 9q34 remained on the der(9)t(7;9). Because the same translocation reappeared and sustained for more than 8 months after second stem cell transplantation, we revised the diagnosis as therapy-related MDS after allogeneic transplantation. The t(7;9)(q22;q34) was supposed to have a crucial role in the pathogenesis of MDS. Considering two other such reported cases of AML, the t(7;9)(q22;q34) may be a novel recurrent translocation in myeloid malignancies.

La leucemia mieloide aguda (LMA) es poco frecuente en la infancia, pero cuando se presenta suele revestir mayor gravedad que las formas linfoides. Las principales complicaciones, íntimamente relacionadas con su peor pronóstico, son la hemorragia aguda, la infección y las secundarias a leucostasis. Se presentan 2 pacientes pediátricos con LMA tipo M 5 a y M 2 en los que la enfermedad se manifestó con un proceso agudo grave (distrés respiratorio agudo y hemorragia cerebral, respectivamente), secundario a leucostasis y que motivó su ingreso en la unidad de cuidados intensivos pediátricos. Mientras que la evolución fue favorable en el primer paciente, permitiendo con posterioridad el trasplante de medula ósea, el segundo falleció a las pocas horas de su ingreso. Se discute la fisiopatología de cada caso, el tratamiento y el uso de leucoferesis como alternativa terapéutica en pacientes con hiperleucocitosis y leucostasis. Se insiste en la necesidad de mantener un alto grado de sospecha para realizar un diagnóstico lo más precoz posible que impida que un porcentaje elevado de pacientes fallezca aun antes de iniciar el tratamiento citostático. : Acute myeloblastic leukemia (MLA) is an uncommon disease in childhood and its prognosis is worse than that of lymphoblastic leukemia. Severe hemorrhage, infections and perfusion disorders secondary to leukostasis are the main complications leading to its high mortality rate. Two pediatric patients with MLA (M 5 a and M 2 ) are presented. Both patients were admitted to the pediatric intensive care unit with acute respiratory distress syndrome and intra-cranial hemorrhage respectively, secondary to leukostasis. The first patient showed favorable clinical course and underwent bone marrow transplantation four months later; in contrast, the second patient died a few hours after admission. The physiopathology of each case, the therapeutic approach and the use of leukopheresis as a therapeutic alternative in patients with hyperleukocytosis and leukostasis are discussed. A high degree of suspicion is required to make a diagnosis as early as possible in order to avoid the death of a large percentage of patients before cytostatic treatment begins.

Publisher Summary Most cases of leukemia do not stem from an inherited genetic predisposition but from somatic genetic alterations. The etiology of acute leukemia is unknown. The factors are important in the pathogenesis of leukemia have been highlighted in this chapter. Acute leukemias represent a clonal expansion and arrest at a specific stage of normal myeloid or lymphoid hematopoiesis. They constitute 97% of all childhood leukemias and consist of the following types: acute lymphoblastic leukemia (ALL) ─ 75%, acute myeloblastic leukemia (AML), also known as acute nonlymphocytic leukemia (ANLL) ─ 20%, acute undifferentiated leukemia (AUL) ─

Publisher Summary Acute myeloid leukemia (AML) represents a group of hematopoietic neoplasms derived from the bone marrow precursors of myeloid lineage. The neoplastic process is the result of clonal proliferation of an aberrant, committed stem cell at the level of CFU-S or later stages of differentiation leading to the accumulation of immature forms without, or with limited, maturation. Other terms used to denote AML include acute nonlymphoid leukemia (ANLL), acute myelogenous leukemia, and acute myeloblastic leukemia. According to this classification, AML is divided into four major categories as: AML with recurrent genetic abnormalities, AML with multilineage dysplasia, AML and myelodysplastic syndromes (MDS), therapy related, AML not otherwise categorized. Three major environmental insults have been implicated in the increased incidence of AML: ionizing radiation, chemotherapeutic agents, and occupational exposure to chemicals. Ionizing radiation induces DNA damage leading to chromosomal breaks which may cause mutations, deletions, and translocations. The extent of this damage depends on the type of radiation, the amount and rate of absorption, distribution of the absorbed energy in the tissue, and the intervals between the radiation exposures. Therapy-related AML (t-AML) and therapy-related MDS (t-MDS) represent spectrums of a progressive clonal hematopoietic disorder that is evolved following cytotoxic chemotherapy and/or irradiation. The reason for chemotherapy or irradiation is usually a primary malignancy.

Immunophenotyping of leukemia cells is generally performed on cells in suspension. These suspensions are usually prepared from anticoagulated peripheral blood or bone marrow samples but when anticoagulation is suboptimal clotted samples may reach the laboratory. In this study cell suspensions were prepared from clotted blood and bone marrow samples of leukemia patients by lysis of the clots with streptokinase. The cell suspensions were then labeled with monoclonal or polyclonal antibodies and examined by flow cytometry or fluorescence microscopy. Enough cells could be isolated from small volumes of clotted blood or bone marrow aspirate to determine the immunophenotype of the cells. The morphology of the cells was well preserved and accurate identification of the cells was possible. The immunophenotypes determined on clotted samples from four patients with acute myeloblastic leukemia, five with acute lymphoblastic leukemia and two with chronic lymphocytic leukemia were identical to those established using EDTA anticoagulated samples of the same patients. When no unclotted samples are available this approach may avoid the necessity for a new sample and the concomitant delay in treatment of the patient.

The lipid composition of immature myeloid cells from the bone marrow of normal persons and myeloblasts from patients with acute myeloblastic leukemia was studied and compared with the lipid composition of normal mature human neutrophils. Total cholesterol, phospholipid, and fatty acid composition was determined on each cell type. The leukemic cells showed decreased total cholesterol and cholesterol-to-phospholipid ratio, increase phosphatidylcholine and phosphatidylinositol, decreased phosphatidylethanolamine, and an increased percentage of unsaturated fatty acids when compared to normal mature neutrophils. A nearly identical pattern was seen in the normal immature myeloid precursors from normal bone marrow. We conclude that the altered lipid composition of acute myeloblastic leukemia cells is related to unexplained factors related to cell age and not to malignancy per se.

Publisher Summary This chapter focuses on the immunotherapy of acute myeloblastic leukemia (AML). On the surface of many AML cells, there are some foreign proteins, which may distinguish them from the normal cells of the tissue of origin. The most logical way in which to immunize an animal against a tumor is to do so using the specific tumor antigen. Membrane extracts may be used for this purpose, but this method suffers from the disadvantage that fragile antigenic determinants may be damaged in the extraction procedure. Viable cell suspensions irradiated to prevent implantation offers an alternative means of presenting tumor antigen. To justify the term immunotherapy, an observed therapeutic effect must follow an immunological manipulation. There has been new speculation about the possible mechanism of action of BCG, that is, it stimulates the normal bone marrow and enables the balance between the normal cells and the leukaemic cells to be changed in favor of the former.

Publisher Summary This chapter describes the purification procedure of cytidine deaminase enzyme from leukemic mouse spleen. Cytidine deaminase is widely distributed among mammalian tissues. This enzyme is responsible for the inactivation of cytosine arabinoside––one of the most useful chemotherapeutic agents available for the treatment of acute myeloblastic leukemia. In the mouse spleen, a marked increase in the specific activity of cytidine deaminase occurs following infection with Friend leukemia virus. Elevated levels of cytidine deaminase are also found in regenerating mouse liver, in human leukemic cells, following the treatment of the patient with cytosine arabinoside, and in HeLa cells cultured in the presence of cytosine arabinoside. The activity of cytidine deaminase is assayed by measuring the amount of labeled uridine formed by the deamination of 2-14C-labeled cytidine. High levels of cytidine deaminase are found in human polymorphonuclear leukocytes.

Publisher Summary This chapter discusses the new anticancer drug with significant activity in acute myeloblastic leukemia known as “5-azacytidine.” 5-Azacytidine has the empirical formula C 8 H 12 N 4 O 5 . 5-Azacytidine for injection can be obtained from the Cancer Therapy Evaluation Program, DCT, NCI, and is supplied in 100-mg vials with 100-mg mannitol (USP). The product is prepared as a white lyophilized powder in 20-ml vials. When reconstituted with 19.9 ml of sterile water for injection (USP), each milliliter of solution contains five mg of 5-azacytidine and five mg of mannitol at pH 6.0–7.5. The reconstituted solution hydrolyzes at room temperature and should be used within 30 minutes. The reconstituted solution can be further diluted with lactated Ringer's injection (USP) providing optimum pH for solution stability. The pH of this solution at a concentration of 100 mg/500 ml is approximately 6.37. The reconstituted solution further diluted in this manner should be used within two to three hours. Over this period of time, 10–15% decomposition occurs based on ultraviolet and nuclear magnetic resonance assay methods.

Publisher Summary This chapter discusses the measurement of the effect of interferons on the proliferative capacity and cloning efficiency of normal and leukemic human myeloid progenitor cells in culture. In the case of human leukemic myeloblasts, interferon has been shown to decrease colony formation in leukemic myeloblasts from patients with acute myeloblastic leukemia as well as clonigenicity in soft agar of various leukemic cell lines, such as HL-60, KG-1, and K-562 cells. Interferon also induces a decrease in the self-renewal capacity of leukemic myeloblasts––that is, the ability of cloned cells to form secondary colonies when recultured. Growth inhibition induced by crude and recombinant interferon (IFN)-α and IFN-β in the established human promyelocytic leukemic cell line HL-60, does not involve an induction of terminal differentiation, whereas recent studies indicate that IFN-γ can induce antigenic and biochemical changes normally associated with the differentiation of HL-60 cells into monocytes and granulocytes. The methods employed for evaluating the effect of interferon on colony formation of normal and leukemic myeloid progenitor cells, as well as for continuously cultured human leukemic cell lines, share several common features.

Publisher Summary This chapter focuses on the new developments in the field of cancer active immunotherapy (AI). Al of cancer is a form of manipulation of the patient's; immune machinery composed of T- and B-lymphocytes and of macrophages. It was introduced in an attempt to kill tumor cells left by chemotherapy, which is unable to kill the last cell because it obeys the first-order kinetics. Al is being applied on a few solid tumors for residual imperceptible disease after surgery in cases for which prognosis was poor. The most recent results for melanoma patients show that, as in acute myeloblastic leukemia (AML) patients, this treatment is significantly effective but only of slight benefit to patients.