tretinoin and Hemorrhagic-Disorders

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-

Topics: Aged; Arsenic Trioxide; Disease Management; Female; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Practice Guidelines as Topic; Pregnancy; Recurrence; Tretinoin

All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

Topics: Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Chromosome Aberrations; Disseminated Intravascular Coagulation; DNA-Binding Proteins; fms-Like Tyrosine Kinase 3; Hemorrhagic Disorders; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Leukocyte Count; Nuclear Proteins; Oncogene Proteins, Fusion; Oxides; Prognosis; Risk Factors; Tandem Repeat Sequences; Treatment Outcome; Tretinoin; Tumor Protein p73; Tumor Suppressor Proteins

Coagulopathy is a unique component of the pathology of acute promyelocytic leukaemia (APL). Though many causative factors have been elucidated, therapies to rectify the coagulopathy are far from being realised. Thrombotic and bleeding complications remain the major causes of early deaths. In this chapter, the known causes of abnormalities in haemostatic function, namely the coagulopathy and changes in the fibrinolytic system, will be reviewed. Major risk factors for these complications are identified. Current available measures for correction of the coagulopathy and their effectiveness are critically examined. Unless the coagulopathy can be effectively controlled, bleeding complications will remain an obstacle to achieving a cure for this disease. The issues that need to be addressed in next phase of investigations are also discussed.

Topics: Annexin A2; Anticoagulants; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Blood Coagulation Tests; Carboxypeptidase B2; Disseminated Intravascular Coagulation; Fibrinolysis; Forecasting; Granulocyte Precursor Cells; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recombinant Proteins; Risk Factors; S100 Proteins; Thrombomodulin; Thrombophilia; Thromboplastin; Tretinoin; Urokinase-Type Plasminogen Activator

Despite the development of highly effective treatment strategies for acute promyelocytic leukaemia around 10% of patients die in the presentation period as a consequence of the associated bleeding diathesis. The cause of the coagulopathy is complex resulting from a combination of tissue factor (TF) and cancer procoagulant (CP) induced disseminated intravascular coagulation, exaggerated fibrinolysis due predominantly to enhanced expression of annexin II on APL blast cell membranes and blast cell production of cytokines. All-trans retinoic acid (ATRA) has revolutionised the treatment of APL. When combined with chemotherapy long term survival rates of up to 80% can be achieved. Commencement of ATRA induces APL blast cell differentiation and is associated with a rapid resolution of the bleeding tendency through a combination of effects which include up regulation of thrombomodulin and down regulation of TF and CP production and cell surface expression of annexin II.

Topics: Cell Differentiation; Combined Modality Therapy; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Life-threatening bleeding, which remains a challenging complication of acute leukaemia, is particularly characteristic of the subtype, acute promyelocytic leukaemia (APL). The clinical picture and laboratory abnormalities are most compatible with the diagnosis of disseminated intravascular coagulation (DIC). Evidence for diffuse activation of the coagulation system, hyperfibrinolysis and systemic elaboration of non-specific protease activity can usually be demonstrated and occurs most commonly during induction chemotherapy. While both host- and tumour-associated mechanisms can be implicated in the pathogenesis of the coagulopathy, leukaemic cell properties appear to be the proximate cause of activation of the haemostatic mechanisms. In this chapter we summarize the current state of knowledge of the pathogenesis of the coagulopathy of APL and the therapeutic approaches that have proved most useful for the management of this complication. Special attention is devoted to the use of all-trans-retinoic acid (ATRA), which has revolutionized the treatment of APL and markedly ameliorated the APL-related coagulopathy.

Topics: Disseminated Intravascular Coagulation; Hemorrhagic Disorders; Heparin; Humans; Leukemia, Promyelocytic, Acute; Platelet Transfusion; Tretinoin

Induction of differentiation and/or apoptosis is a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukaemia with all-trans-retinoic acid and arsenic compounds. Treatment with all-transretinoic acid results in complete remission in 92 - 95% of patients with this disease. Using the recently advocated combination of all-transretinoic acid and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. Chemotherapy in combination with all-trans-retinoic acid seems to be the best postremission treatment protocol, with a 5-year relapse-free survival rate of 50 - 60%. Arsenic compounds have recently proved effective in newly diagnosed and relapsed acute promyelocytic leukaemia, with complete remission rates of 80 - 90% according to most reports. As2O3, the most studied arsenic compound, can be given by intravenous infusion at a dose of 0.08 - 0.16 mg/kg daily. A course of 28 - 44 days is required to induce remission. Although the drug is safe in patients who have relapsed, severe liver damage has been observed in some newly diagnosed patients. Combined use of chemotherapy and arsenic as postremission treatment results in longer survival than arsenic alone. Although their mechanisms of action are distinct, both all-trans-retinoic acid and arsenic can modulate PML-RARalpha, an oncoprotein that has a central role in leukaemogenesis, and both can relieve ranscriptional repression by modifying chromatin structure.

Topics: Animals; Antineoplastic Agents; Apoptosis; Arsenicals; Cell Differentiation; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Tretinoin

Bleeding complications are often associated with acute promyelocytic leukemia (APL) they occur frequently at the onset of APL and become more serious during chemotherapy. The increased bleeding tendency of APL is caused by a massive proteolytic state, triggered by procoagulant substances, plasminogen activators and proteinases released into the circulation from leukemic cells. The introduction of all-trans-retinoic acid (ATRA) into the treatment of APL has reduced bleeding complications. However the mechanisms of the hemostatic defects in patients with APL and their modifications during ATRA with or without chemotherapy are still incompletely understood. Attempts at characterizing and monitoring these hemostatic abnormalities have been made by using several laboratory parameters. Among them we have studied the structural modifications of von Willebrand Factor (vWF). In APL, plasma vWF is massively degraded, with specific fragments produced by the action of plasmin and elastase. After ATRA therapy, proteolysis diminishes progressively in parallel with the improvement of other hemostatic measurements. We conclude that abnormalities of vWF structure and function might adversely affect hemostasis in APL and that their improvement after ATRA administration might explain in part the effectiveness of this drug in reducing hemorrhagic complications.

Topics: Antineoplastic Agents; Biopolymers; Blood Coagulation Tests; Cysteine Endopeptidases; Endopeptidases; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Macromolecular Substances; Models, Biological; Molecular Weight; Neoplasm Proteins; Pancreatic Elastase; Plasminogen Activators; Platelet Adhesiveness; Tretinoin; von Willebrand Factor

Topics: Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Lymphocyte Subsets; Tretinoin

Topics: Cell Division; Cell Transformation, Neoplastic; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Risk Factors; Thrombosis; Tretinoin

From January 1990 to August 1997, 29 consecutive patients were treated with newly diagnosed primary acute promyelocytic leukemia (APL) at the authors' Institution. Of these, 27 (16 boys and 11 girls) were evaluable. Median age at diagnosis was 6.3 (range: 1.9-15.7) years. This population was treated with two consecutive protocols: 13 patients were included in the AML-HPG-90 protocol and 14 in the AML-HPG-95. The initial treatment was the same for both protocols: an induction 8-day phase with cytarabine, idarubicin, and etoposide was followed by a consolidation with cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, doxorubicin, and prednisone. Two courses of intensification with high-dose (HD) cytarabine and etoposide were given in the first study. Only one intensification course was administered in the second study, with HD cytarabine plus idarubicin or etoposide decided by randomization. Complete remission was achieved in 67% (18/27) of cases. Mortality on induction was quite high, 30% (8/27) mainly due to hemorrhages from disseminated intravascular coagulation (DIC). The event-free survival estimate for all patients was 0.47 (SE: 0.1). From April 1994, all-trans-retinoic acid (ATRA) was administered just during the first days of the induction phase (median: 9, range: 2-27) to stop or prevent DIC. Eighteen patients received ATRA and 9 did not. Three patients developed signs of ATRA syndrome during the first days of administration but no one died due to this toxicity. The impact of a short course of ATRA on early control of DIC was studied by analyzing the number of platelet, cryoprecipitate, and fresh frozen plasma transfusions during the induction phase in both groups. No statistical differences in complete remission rate, early mortality, need of transfusion of blood components for DIC, and survival estimates could be established between patients who received ATRA and those who did not. ATRA used in a short-course schedule during induction of APL did not stop early mortality due to DIC. Moreover, survival results did not improve with this method of ATRA usage. Longer periods of ATRA administration during APL therapy are strongly recommended.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytogenetics; Dexamethasone; Disease-Free Survival; Disseminated Intravascular Coagulation; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemorrhage; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Male; Platelet Count; Retrospective Studies; Risk Factors; Survival; Time Factors; Tretinoin

Acute promyelocytic leukemia (APL) is associated with a hemorrhagic disorder of unknown cause that responds to treatment with all-trans-retinoic acid.. We studied a newly described receptor for fibrinolytic proteins, annexin II, in cells from patients with APL or other leukemias. We examined initial rates of in vitro generation of plasmin by tissue plasminogen activator (t-PA) in the presence of APL cells that did or did not have the characteristic translocation of APL, t(15;17). We also determined the effect of all-trans-retinoic acid on the expression of annexin II and the generation of cell-surface plasmin.. The expression of annexin II, as detected by a fluorescein-tagged antibody, was greater on leukemic cells from patients with APL than on other types of leukemic cells (mean fluorescence intensity, 6.9 and 2.9, respectively; P<0.01). The t(15;17)-positive APL cells stimulated the generation of cell-surface, t-PA-dependent plasmin twice as efficiently as the t(15;17)-negative cells. This increase in plasmin was blocked by an anti-annexin II antibody and was induced by transfection of t(15;17)-negative cells with annexin II complementary DNA. The t(15;17)-positive APL cells contained abundant messenger RNA for annexin II, which disappeared through a transcriptional mechanism after treatment with all-trans-retinoic acid.. Abnormally high levels of expression of annexin II on APL cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications of APL.

Topics: Adolescent; Adult; Annexin A2; Antibodies; Child; Child, Preschool; Female; Fibrinolysin; Fibrinolysis; Hemorrhagic Disorders; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Male; Middle Aged; RNA, Messenger; Transcription, Genetic; Transfection; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured

The mechanisms underlying acute promyelocytic leukemia (APL) coagulopathy and its reversal by administration of all-trans retinoic acid (ATRA) have been investigated. Bone marrow promyelocytic blasts from nine patients with APL were cultured with or without ATRA 1 mumol/L. Cultured blasts (days 0, 3, 6, and 9) were washed, resuspended in phosphate buffer, lysed by freezing and thawing, and then assayed for procoagulant activity (PCA), elastase activity, tissue factor (TF) antigen, tissue-type plasminogen activator (t-PA) antigen and urokinase-type plasminogen activator (u-PA) antigen. PCA was determined by a recalcification assay. Elastase was measured by an amidolytic assay (S-2484). TF, t-PA, and u-PA antigens were measured by an enzyme-linked immunosorbent assay (ELISA). Malignant promyelocytes isolated from the patients had increased levels of PCA and TF as compared with the control polymorphonucleates, and low levels of elastase, t-PA, and u-PA; the patient blast PCA level was significantly related to the degree of hypofibrinogenemia. In this system, blast PCA depended on the tissue factor and was significantly correlated to the TF antigen values. In the cultures without ATRA, PCA, TF, and u-PA progressively increased, whereas elastase and t-PA levels remained essentially unchanged. In the presence of ATRA, all parameters (except u-PA) decreased during the culture time. Thus, a major role of the promyelocytic blast cell PCA in the pathogenesis of M3-related coagulopathy is suggested; the ATRA effect on coagulopathy seems mainly mediated by a downregulation of the PCA.

Topics: Adolescent; Adult; Aged; Aprotinin; Blood Coagulation; Cell Differentiation; Cysteine Endopeptidases; Female; Fibrinolysis; Gene Expression Regulation, Leukemic; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Neoplastic Stem Cells; Pancreatic Elastase; Thromboplastin; Tissue Plasminogen Activator; Tretinoin; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator