tretinoin and Pulmonary-Edema

Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.

Topics: Acute Kidney Injury; Arsenic Trioxide; Cell Differentiation; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Pulmonary Edema; Steroids; Syndrome; Tretinoin

The introduction of all-trans retinoic acid (ATRA) into routine clinical practice changed the outcome of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML). Patients who do not survive generally succumb within the first 30 days after presentation or diagnosis, often from intracranial or pulmonary hemorrhage caused by the characteristic coagulopathy associated with this disease. For the majority of patients who avoid hemorrhagic complications, the goals of decreasing the side effects of diagnosis and treatment-including pain, inpatient hospital days, and late sequelae of cytotoxic chemotherapy-have emerged as paramount. Here, we discuss novel and provocative observations regarding diagnostic and treatment strategies for APL that are likely to emerge as standards of care in the next 5 years, and that may improve the rate of early hemorrhagic death and decrease diagnosis- and treatment-related morbidity.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Arsenic Trioxide; Arsenicals; Biopsy, Fine-Needle; Bone Marrow; Clinical Trials as Topic; Dexamethasone; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Oxides; Practice Guidelines as Topic; Prognosis; Pulmonary Edema; Remission Induction; Respiratory Insufficiency; Tretinoin

Noncardiogenic pulmonary edema, and, to a lesser extent, acute respiratory distress syndrome (ARDS), are common clinical manifestations of drug-induced lung diseases. Clinical features and radiographic appearances are generally indistinguishable from other causes of pulmonary edema and ARDS. Typical manifestations include dyspnea, chest discomfort, tachypnea, and hypoxemia. Chest radiographs commonly reveal interstitial and alveolar filling infiltrates. Unlike pulmonary edema that is due to congestive heart failure, cardiomegaly and pulmonary vascular redistribution are generally absent in cases that are drug-related. Rare cases of drug-induced myocarditis with heart failure and pulmonary edema have been described. Results from laboratory evaluation and respiratory function tests are nonspecific.

Topics: Antineoplastic Agents; Chlorothiazide; Contrast Media; Diuretics; Ethchlorvynol; Humans; Hypnotics and Sedatives; Iatrogenic Disease; Immunosuppressive Agents; Lung; Pulmonary Edema; Respiratory Distress Syndrome; Sodium Chloride Symporter Inhibitors; Tocolytic Agents; Tretinoin

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or

Topics: Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cause of Death; CD13 Antigens; Cerebral Hemorrhage; Combined Modality Therapy; Gene Expression Regulation, Leukemic; Humans; Leukapheresis; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasm Proteins; Pulmonary Edema; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Retrospective Studies; Survival Analysis; Syndrome; Treatment Outcome; Tretinoin

Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-alpha) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-alpha, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-alpha plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-alpha 5 MU/m2 s.c. daily, low-dose ara-C 10 mg s.c. daily and ATRA 45 mg/m2 orally daily, for 7 consecutive days every other week. Overall, 76% of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59% (major in 38% and complete in 17%). Compared with patients treated with IFN-alpha and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64%), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-alpha and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Combined Modality Therapy; Cytarabine; Drug Administration Schedule; Female; Femur Head Necrosis; Humans; Immunologic Factors; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocytosis; Life Tables; Male; Middle Aged; Paranoid Disorders; Pilot Projects; Pseudotumor Cerebri; Pulmonary Edema; Red-Cell Aplasia, Pure; Remission Induction; Survival Analysis; Syncope; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Diagnosis, Differential; Dyspnea; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Middle Aged; Mitoxantrone; Pleural Effusion; Pulmonary Edema; Thioguanine; Tomography, X-Ray Computed; Tretinoin

Use of all-transretinoic acid (ATRA) with other chemotherapeutic agents in the treatment of acute promyelocytic leukemia (APL) has been shown to cause the differentiation of abnormally granulated specific blast cells into mature granulocytes by acting on the t(15; 17) fusion gene product. The complete remission rate is increased and survival time is prolonged in APL patients who receive chemotherapy plus ATRA, whereas ATRA syndrome and other ATRA-related adverse effects including pseudo tumor cerebri, headache, severe bone pain, mucosal and skin dryness, hypercholesterolemia, and cheilitis may be observed especially during induction phase of the treatment. In this paper, we report a 9-year-old girl with APL who developed pancarditis while receiving the APL-93 treatment protocol. In our patient, endocarditis and myocarditis were initially determined after ATRA treatment during the induction part of the protocol. All findings disappeared after ATRA was discontinued. When ATRA was readministered in the maintenance part of the treatment protocol, she developed pancarditis and severe pulmonary edema. As her symptoms decreased dramatically with the discontinuation of ATRA and the initiation of steroid treatment, the clinical picture strongly suggested the ATRA treatment as the causative factor. To the best of our knowledge, this clinical picture of pancarditis secondary to ATRA treatment has not been reported earlier in the English literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Myocarditis; Pulmonary Edema; Severity of Illness Index; Tretinoin

All-trans retinoic acid (ATRA) induces complete remission in patients with acute promyelocytic leukemia (APL). However, ATRA sometimes causes retinoic acid syndrome (RAS) characterized by respiratory distress, pleural effusions, fever and weight gain. To investigate the pathophysiology of RAS, we generated an animal model by injecting an APL cell line, NB4, into immunodeficient mice. When NOD/scid mice were injected intravenously with fully differentiated NB4 cells (1 x 10(7)) and then given a daily administration of ATRA, three of 12 mice died of pulmonary edema within 14 days. Pathologically, dilated lung capillary vessels and alveolar effusions were observed. After the injection, NB4 cells were detected in the lung within 2 days and in the pleural effusion later on. The gene expression levels of CXC chemokines (MIP-2 and KC) and ICAM-1 were increased in the lung and heart by the ATRA administration. In immunohistochemical analyses, MIP-2 was clearly detected in alveolar macrophages of the lung in mice with RAS. Dexamethasone treatment prevented the development of RAS and decreased the CXC chemokine mRNA expression in the lung. These findings suggested that the activation of adhesion molecules for leukocytes and expression of CXC chemokines in the lung are closely involved in triggering RAS.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Chemokines, CXC; Doxorubicin; Heart; Humans; Injections, Intravenous; Leukemia, Promyelocytic, Acute; Lung; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Pulmonary Edema; Remission Induction; Syndrome; Tretinoin; Tumor Cells, Cultured

To describe the retinoic acid syndrome, a complication of therapy with all-trans retinoic acid (ATRA) in acute promyelocitic leukemia (APL).. Retrospective study of five patients with a morphologic diagnosis of APL by the French-American-British (FAB) classification that were treated for remission induction with ATRA and developed the ATRA syndrome.. Three patients in newly diagnosed APL and two in leukemia relapse were analyzed. All patients received with ATRA 45 mgrs/m2/day, and three of them also received chemotherapy. Patients developed fever, respiratory distress, pulmonary infiltrates, weight gain and edemas. The onset of this symptom complex occurred from 1 to 11 days after starting treatment and was preceded by an increased in peripheral blood leukocytes. Infections or congestive heart failure were ruled out. The clinical course progressed while patients being treated with wide spectrum antibiotics. Four patients were treated with high doses corticosteroid therapy (dexametasone 10 mgrs intravenously every 12 hours), in three of them full recovery was attained and one died. One patient that did not received steroids died.. The use of all-trans retinoic acid to induce hematologic remission in APL patients is associated in same patients with the development of ATRA syndrome, a life threatening complication. Symptoms begin in the first days of treatment. If this syndrome is suspected, early treatment with high dose steroids should be initiated.

Topics: Adolescent; Antineoplastic Agents; Female; Humans; Leukemia, Myeloid, Acute; Lung Diseases, Interstitial; Male; Middle Aged; Pulmonary Edema; Respiratory Insufficiency; Retrospective Studies; Syndrome; Tretinoin

All-trans retinoic acid (ATRA) has been used successfully in inducing remission in patients with acute promyelocytic leukemia (APL). Its overall toxicity is considerably less compared to standard induction chemotherapy; however, it is associated with a high incidence of a potentially fatal symptom complex referred to as "retinoic acid syndrome." This report describes a patient with APL who developed the syndrome a few weeks after initiating induction therapy with ATRA despite being treated for hyperleukocytosis. The case illustrates the classic features of the syndrome and its dramatic response to corticosteroid treatment.

Topics: Antineoplastic Agents; Dexamethasone; Dyspnea; Glucocorticoids; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Pulmonary Edema; Syndrome; Tretinoin