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Acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by proliferation of morphologically abnormal promyelocytes and a severe bleeding diathesis. The abnormal promyelocyte is characterized by abundant, large granules, many of which are spindle-shaped. Electron microscopic appearance of the granules closely resembles that of Auer rods. The granules appear to possess tissue thromboplastin activity by both immunologic and clotting assays. Coagulation studies in APL are generally consistent with disseminated intravascular coagulation. Prolongation of the prothrombin time and elevation of fibrinogen degradation products are the tests that are most commonly abnormal. Although occasional reports indicate a favorable response of the coagulopathy to drugs that inhibit fibrinolysis, the use of prophylactic heparin appears to be the treatment of choice. The response rate of APL to chemotherapy regimens that contain an anthracycline is comparable to that of acute myelogenous leukemia. The recent description of the 15;17 chromosomal translocation which may be pathognomonic for APL is only the second example of a chromosomal marker of human neoplasia. Marked elevation of serum vitamin B12 and B12 binding proteins appears to be another characteristic feature of APL. An in vitro cell line of APL cells has been demonstrated to have the capacity to differentiate to functional polymorphonuclear leukocytes, but the cause for the maturation arrest is unknown.

Blood Coagulation Disorders

Acute promyelocytic leukemia. A review of literature.

Acute promyelocytic leukemia is a form of acute myeloblastic leukemia characterized by hemorrhagic episodes, severe thrombocytopenia and infiltration of the marrow with "hypergranular" promyelocytes, often with multiple Auer bodies. Ultrastructurally. the promyelocytes show many splinter granules and Auer bodies with characteristic hexagonal arrangement of tubules with a periodicity of 250 A. Serum vitamin B12 and B12-binding proteins, in particular, transcobalamin I, are abnormally high. Karyotypic abnormalities include pseudodiploidy and partial deletion of the long arm of chromosome 17. Coagulation profile during bleeding episodes is usually consistent with disseminated intravascular coagulation. Greatly improved prognosis in recent years as a result of aggressive chemotherapy and anticoagulation emphasizes the need of early recognition of this clinical entity.

Adult

Prophylactic heparin therapy in acute promyelocytic leukemia.

Twenty-four patients with acute promyelocytic leukemia were reviewed. Group I, treated between July 1970 and September 1973, received arabinosylcytosine and 6-thioguanine, and there was one complete remission, with 4/7 dying during induction with intracerebral hemorrhages, and 2/7 dying within one month. Group II, treated between May 1974 and March 1975, received daunomycin and arabinosylcytosine without heparin and 2/8 went into remission, with 6/8 dying during induction, 5 with intracerebral hemorrhages. Group III, treated between March 1975 and November 1976, received the identical chemotherapy as group II but with the addition of prophylactic heparin and there were 7/9 complete remissions, with 2/9 dying with intracerebral hemorrhages. In Group III there was an increased incidence of remission induction when compared to Group II (p less than .05) or when compared to Groups I and II combined (p less than .05). There was also a decreased incidence of fatal hemorrhage in Group III. This suggests that prophylactic heparin is useful during remission induction in acute promyelocytic leukemia.

Adolescent

Oral manifestations of acute promyelocytic leukemia.

A study was conducted of 16 patients with acute promyelocytic leukemia. The most common oral manifestations were hemorrhagic diathesis and leukemic involvement. There was gingival bleeding, petechiae, and ecchymosis of the oral mucosa, massive infiltration-induced gingival swelling, ulcerative glossitis, swelling of the tonsils, and facial palsy. Inflammatory stomatitis also occurred. Patients with acute promyelocytic leukemia had a higher incidence and severity of oral bleeding than those with other types of acute leukemia. However, the oral findings in our series were not necessarily specific for acute promyelocytic leukemia because the same oral symptoms occur in other forms of acute leukemia.

Humans

Acute promyelocytic leukemia: results of therapy and analysis of 13 cases.

Acute promyelocytic leukemia (APL) was diagnosed in 13 of 84 adult patients (15.4%) with acute myeloid leukemia (AML) first admitted between 1972 and 1976. All patients had clinical and/or laboratory evidence of defibrination syndrome. Four patients died of cerebral hemorrhage within 2 days of admission. Two patients died of generalized infection on days 7, and 16, respectively, after admission. The remaining 7 patients (54%) underwent complete remission (CR) with daunomycin, arabinosyl cytosine, and adriamycin. All patients received massive platelet transfusion, no heparin, and no granulocyte transfusion. CR was more frequent in patients with a very low blast cell count and a fibrinogen level higher than 100 mg/100 ml. Median survival of these seven CR patients with APL is similar (15 months) to that of CR patients with other types of AML treated at the same institution during the same period.

Adolescent

Shortened platelet survival in acute promyelocytic leukemia.

A platelet kinetic study in 2 patients with acute promyelocytic leukemia (APL) associated with disseminated intravascular coagulation (DIC) demonstrated that the platelet survival was characteristically shortened. These findings suggest increased platelet consumption during the process of DIC in APL.

Blood Platelets

Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia.

We have previously reported on two patients with acute promyelocytic leukemia (APL) who had what appeared to be a deletion of chromosome No. 17. We now describe a third patient with APL. All three patients had a structural rearrangement involving No. 15 and No. 17. Our current interpretation of the chromosomal abnormality is that it is a reciprocal translocation, t (15;17) (q22; q21). Evidence that this is a consistent rearrangement associated with APL comes not only from our three patients, but also from two other published cases of APL, studied with banding, who also had an identical abnormality.

Adult

Unusual configurations of endoplasmic reticulum in cells of acute promyelocytic leukemia.

An ultrastructural study of leukemia cells from 8 patients with acute promyelocytic leukemia revealed several features that have not previously been emphasized: prominent dilated rough endoplasmic reticulum and two unusual configurations of endoplasmic reticulum (ER). The two membrane structures, multilaminar ER and complex stellate arrangements of ER, appeared to be morphogenetically related. The multilaminar ER was observed in every mitotic cell and less frequently in interphase cells. The stellate ER complex was observed only in interphase cells. Ultrastructural evidence is presented to support the possible evolution of the stellate ER complex from the multilaminar ER.

Endoplasmic Reticulum

Disseminated intravascular coagulation in acute promyelocytic leukemia. Possibility of treatment with glucocorticoids at high doses.

Seven patients affected by acute promyelocytic leukemia and presenting a hemorrhagic syndrome with hypofibrinogenemia have been treated with Daunorubicin and high doses of Glucocorticoids. In three out of the seven patients we also added an antiprotease agent (Trasylol, Bayer). Hemorrhagic diathesis has been controlled in all patients but one without massive platelet transfusions. A complete hematologic remission with prolonged survival was achieved in five patients.

Daunorubicin

Acute promyelocytic leukemia presenting as a pelvic mass.

The case history of a child with acute promyelocytic leukemia (APL) is reported to illustrate both an unusual presentation of APL as a pelvic mass and to review the pathophysiology and treatment of the disease. Therapy of APL consists of chemotherapy, namely adriamycin/daunomycin for remission induction, and of control of disseminated intravascular coagulation. A chloroma, if present, may require local irradiation in addition to chemotherapy. With aggressive management, the number of prolonged remissions may be greater for APL than for any other form of acute myelogenous leukemia (AML), with significant numbers of patients achieving five-year survival.

Antineoplastic Agents

Acute promyelocytic leukemia. Management of the coagulopathy during daunorubicin-prednisone remission induction.

Seven adults with acute promyelocytic leukemia (APL) and disseminated intravascular coagulation were treated for remission induction with daunorubicin hydrochloride and prednisone. In all patients the coagulopathy was managed with continuous-infusion heparin sodium and vigorous transfusion with platelets, cryoprecipitate, and fresh frozen plasma. Five patients survived induction; they all achieved complete remission (CR). Median duration of CR was 27 + months; two patients presently survive in their initial CR at 28 and 48 months. Recognition of APL as a distinct type of acute leukemia and prompt initiation of treatment aimed at rapid cytoreduction and control of the coagulopathy has resulted in a prolonged disease-free survival for the majority of patients.

Adolescent

Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia.

In a prelminary communication, we described the establishment of a continuous human myeloid cell line (HL-60). Here we report the detailed properties of this cell line and document its derivation from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia. As characterized by light and electron microscopy, the predominant cell type in both the fresh and cultured sources is a neutrophilic promyelocyte with prominent nuclear/cytoplasmic asynchrony. Up to 10% of the cultured cells spontaneously differentiate beyond the promyelocyte stage, and the proportion of terminally differentiated cells is markedly enhanced by compounds known to stimulate differentiation of mouse (Friend) erythroleukemia cells. The HL-60 cells lack specific markers for lymphoid cells, but express surface receptors for Fc fragment and complement (C3), which have been associated with differentiated granulocytes. They exhibit phagocytic activity and responsiveness to a chemotactic stimulus commensurate with the proportion of mature cells. As characteristic of transformed cells, the HL-60 cells form colonies in semisolid medium and produce subcutaneous myeloid tumors (chloromas) in nude mice. A source of colony-stimulating activity stimulated the cloning efficiency in soft agar 5--30-fold. Despite adaptations to culture, the morphological phenotype and responsiveness to chemical induction of differentiation is essentially unchanged through at least 85 passages. Cytogenetic studies reveal aneuploidy. Metaphases with 44 chromosomes predominated in vivo and in early culture passages; however, clones with 45 or 46 chromosomes became predominant with continued passaging. The most consistent karyotypic abnormalities were the deletion of chromosomes 5, 8, and X and the addition of a marker resembling a D-group acrocentric and of a submetacentric marker, most likely an abnormal E-group chromosome. No DNA herpesvirus or RNA retrovirus was isolated in the fresh or cultured cells. The HL-60 cultured cell line provides a continuous source of human cells for studying the molecular events of myeloid differentiation and the effects of physiologic, pharmacologic, and virologic elements on this process.

Adult

Acute promyelocytic leukemia in childhood. Report of a case with a review of the literature.

A rare case of acute promyelcytic leukemia (APL) is reported in a 7-year-old boy. The patient displayed the typical features of APL including impaction of the marrow with promyelocytes, marked elevation of the serum vitamin B12 and transcobalamin I levels and a hemorrhagic diathesis. The bleeding diathesis in the case was due to thrombocytopenia, and there was no evidence for disseminated intravascular coagulation.

Bone Marrow