tretinoin and Respiration-Disorders

Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well-known treatment-related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Antineoplastic Agents; Arsenic Trioxide; Cell Differentiation; Clinical Trials as Topic; Cytokine Release Syndrome; Edema; Enzyme Inhibitors; Epigenesis, Genetic; Fever; fms-Like Tyrosine Kinase 3; Humans; Hypotension; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Myelopoiesis; Neoplasm Proteins; Pleural Effusion; Respiration Disorders; Tretinoin

All-trans retinoic acid (ATRA) is a potent differentiation agent that is effective therapy in acute promyelocytic leukaemia. Although ATRA is generally well tolerated, some patients develop retinoic acid syndrome. This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. However, if identified early enough, effective therapy can be administered. This chapter discusses the clinical aspects and pathogenesis of retinoic acid syndrome.

Topics: Chemotaxis, Leukocyte; Dexamethasone; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Respiration Disorders; Syndrome; Tretinoin

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/microL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-->CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/microL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/microL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/-

Topics: Acute Kidney Injury; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Cytarabine; Dexamethasone; Disease-Free Survival; Female; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Life Tables; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Proportional Hazards Models; Remission Induction; Respiration Disorders; Survival Rate; Syndrome; Treatment Outcome; Tretinoin

All-trans retinoic acid (RA) treatment of patients with acute promyelocytic leukemia (APL) induces complete remission in more than 90% of the cases. Although RA therapy is well tolerated, about 25% of APL patients develop a potentially fatal condition called retinoic acid syndrome (RAS). Molecular mechanisms underlying the development of RAS pathogenesis, especially those that result in the damage of endothelial cells remain elusive. In the present study, we found that RA treatment induces the expression of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in peripheral blast cells from APL patients. IFN-gamma and IL-1beta also exerted synergistic effect in driving human umbilical cord endothelial cells (HUVECs) and human lung microvascular endothelial cells (HLMVECs) into apoptosis. RA also upregulated the expression of CD38, an ectoenzyme responsible for the generation of the calcium messenger cyclic ADP-ribose. Importantly, RA-induced CD38 expression promoted strong attachment of leukemia cells to endothelial cells, and incubation of endothelial cells with either high concentration (100 ng/ml) of IFN-gamma alone or low concentration of IL-1beta and IFN-gamma (10 ng/ml, each) induced strong apoptotic responses as revealed by caspase-8 activation and DNA fragmentation. Our results suggest that these RA-induced events could contribute to the development of RAS pathogenesis in patients with APL.

Topics: ADP-ribosyl Cyclase 1; Antineoplastic Agents; Apoptosis; Blast Crisis; Blotting, Western; Cell Adhesion; Cell Differentiation; Cells, Cultured; Endothelium, Vascular; Humans; Interferon-gamma; Interleukin-1beta; Leukemia, Promyelocytic, Acute; Lung; Nitric Oxide; Receptors, Retinoic Acid; Respiration Disorders; Syndrome; Tretinoin; Umbilical Veins

Retinoic acid syndrome (RAS) is the clinical syndrome that occurs after treatment of acute promyelocytic leukemia with all-trans-retinoic acid (ATRA). The patients experience fever, dyspnea, hypotension, respiratory distress, edema and weight gain. Chest x-ray will show pulmonary infiltrates and pleuropericardial effusion. The onset of this syndrome is usually 5-21 days after ATRA treatment when white blood cell counts are rising more than 10,000/cu.mm. The authors have reported a case of RAS. The patient was a 29-year-old man who had been working in a battery manufacturing factory for 7 years. He presented with easily bruising for one month. The initial blood test showed hematocrit of 36.2%, white blood cells count of 3,200/cu.mm with 28% neutrophils, 20% lymphocytes, 2% eosinophils and 50% promyelocytes and platelet of 20,000/cu.mm. Peripheral blood smear revealed numerous fragmented red blood cells. Bone marrow examination showed hypercellularity with abnormal promyelocytes of 95% and bone marrow cytogenetics was translocation of chromosome 15 and 17 [t (15;17)(q22;q12)]. The diagnosis was acute promyelocytic leukemia and the patient was treated with ATRA 45 mg/m2/day per oral starting on day 1 and intravenous idarubicin 10 mg/n2 on day 4, 5 and 6. On day 13, he had a body temperature of 39 degrees C and a dry cough. The white blood cells were rising to 7,400/cu.mm with 16% neutrophils. On day 18, he had oliguria, high grade fever, hypotension, cough with chest pain and white blood cells rose to 21,300/cu.mm with 65% neutrophils and rising of blood urea nitrogen and creatinine. Chest x-ray showed enlarged cardiac shadow with pleural effusion. Echocardiogram revealed moderate amount of pericardial effusion. The diagnosis of RAS was made and ATRA was withdrawn. Intravenous dexamethasone 4 mg every 6 hours and hemodialysis was started. The patient's symptoms improved dramatically and bone marrow examination was in complete remission. He was subsequently given cytarabine and idarubicin as consolidation. This patient had clinical manifestation consistent with RAS, which improved after prompt treatment.

Topics: Acute Kidney Injury; Adult; Dexamethasone; Glucocorticoids; Humans; Leukemia, Promyelocytic, Acute; Male; Respiration Disorders; Syndrome; Tretinoin

A case is reported of a pregnant 16-year-old-woman diagnosed with Acute promyelocytic leukaemia (APL) at 25 weeks gestation and treated with all-trans retinoic acid (ATRA) (45 mg/m2) for 25 days in combination with chemotherapy. She achieved a complete cytogenetic and molecular remission. Clinical course was complicated, with an intracerebral bleed, respiratory failure requiring ventilation and prolonged pancytopenia following initial chemotherapy. A live female infant was born at 28 weeks gestation who survived to discharge with significant pulmonary complications. She remains oxygen dependent at 6 months of age. ATRA has been used from the 3rd week of gestation, but fetal malformations are common during the first trimester. In contrast it seems to be safe in the second and third trimesters with regard to teratogenesis but can cause other side-effects. Most successful outcomes in treatment of APL during pregnancy are seen after treatment with ATRA and delivery of the baby at as late a stage as possible. Pregnancies terminated before remission has been obtained or those treated in the first trimester have a poor maternal outcome.

Topics: Adolescent; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Cesarean Section; Dexamethasone; Diuretics; Epilepsy, Tonic-Clonic; Female; Fetal Growth Retardation; Humans; Idarubicin; Infant, Newborn; Leukemia, Promyelocytic, Acute; Lung; Neutropenia; Nutrition Disorders; Oxygen; Parenteral Nutrition, Total; Pregnancy; Pregnancy Complications; Pregnancy Complications, Neoplastic; Remission Induction; Respiration Disorders; Tranexamic Acid; Tretinoin