tretinoin and Thrombocytopenia

Topics: Anticoagulants; Disseminated Intravascular Coagulation; Gabexate; Heparin; Humans; Leukemia; Platelet Transfusion; Serine Proteinase Inhibitors; Thrombocytopenia; Tretinoin; Vitamin K Deficiency

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.. We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.. Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.. ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Consolidation Chemotherapy; Disease-Free Survival; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Middle Aged; Neutropenia; Oxides; Thrombocytopenia; Tretinoin; Young Adult

The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.. Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).. Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.. In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Hydroxamic Acids; Hypokalemia; Male; Maximum Tolerated Dose; Neoplasms; Neutropenia; Thrombocytopenia; Tretinoin; Vorinostat

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Neutrophils; Platelet Count; Recombinant Proteins; Thrombocytopenia; Treatment Outcome; Tretinoin; Young Adult

Twenty-two patients with high-risk myelodysplastic syndrome (HRMDS) were treated with a 10-day course of oral all trans retinoic acid (45 mg/m2) and s.c. low-dose cytosine arabinoside (LDARAc) given at the dose of 20 mg twice per day. The courses were repeated monthly until response or progression, in the case of response, the therapy was administered until relapse. Morphologic diagnoses were refractory anemia with excess blasts (RAEB) in nine, RAEB in transformation (RAEB-t) in nine, and chronic myelomonocytic leukemia (CMMoL) in four patients; in all cases, bone-marrow blast infiltration was greater than 10% (median 20%, range 12-30%). When the international prognostic scoring system was applied, all the cases qualified as intermediate/high-risk categories. Nineteen patients were males and three were females; the median age was 69 years (range 25-90 years); three patients had previously been treated with conventional chemotherapy, and one of them had also undergone autologous bone-marrow transplantation. The criteria of response were defined as follows: (1) complete response: normalization of blood counts and bone-marrow blasts (<5%), and (2) partial response: decrease in bone-marrow blast infiltration by 50%, and two of the following parameters - improvement in hemoglobin level by 1.5 g/dl or decrease by 50% in transfusional requirement, increase by 50% in absolute neutrophil count, and increase by 50% in platelet count. Overall, 7 (32%) of 22 patients achieved a response, with 5 (23%) being classified as complete responders and 2 (9%) as partial responders. Fifteen (68%) patients did not achieve any response, and 14 died of progressive disease or infectious disease. The overall median survival was 8 months (range 1-27 months), whereas the median survival of responders was 16 months (range 8-27 months); the median duration of response was 11 months (range 2-21 months). Moderate to severe hematological toxicity and infections were the most common side effects. In conclusion, it seems that the association of ATRA and LDARA-C may be effective in approximately 30% of HRMDS patients. Optimizing this approach might be pursued by selecting, on a biological basis, those cases more likely to respond or by incorporating other differentiating agents or growth factors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Hypertriglyceridemia; Infections; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Thrombocytopenia; Tretinoin

Early death remains a major factor in survival in APL. We aimed to analyze the risk factors for differentiation syndrome and early death in acute promyelocytic leukemia (APL).. The clinical data of APL patients who were newly diagnosed at Mianyang Central Hospital from January 2013 to January 2022 were retrospectively analyzed.. Eighty-six newly diagnosed APL patients (37 males and 49 females) were included in this study. The median age was 46 (17-75) years. Sixty-one patients (70.9%) had low/intermediate-risk APL, and 25 patients (29.1%) had high-risk APL. The incidence of differentiation syndrome (DS) was 62.4%. The multivariate analysis showed that a peak white blood cell (WBC) count ≥16 × 10^9/L was an independent risk factor (OR = 11.000, 95% CI: 2.830-42.756, P = 0.001) for DS in all APL patients, while a WBC count ≥10 × 10^9/L on Day 5 was an independent risk factor for DS in low-intermediate risk APL patients (OR = 9.114, 95% CI: 2.384-34.849, P = 0.001). There were 31 patients (36.5%) with mild DS and 22 patients (25.9%) with severe DS. The multivariate analysis showed that WBC count ≥23 × 10^9/L at chemotherapy was an independent risk factor for severe DS (OR = 10.500, 95% CI: 2.344-47.034, P = 0.002). The rate of early death (ED) was 24.4% (21/86). The multivariate analysis showed that male gender (OR = 7.578,95% CI:1.136-50.551, P = 0.036), HGB < 65 g/L (OR = 16.271,95% CI:2.012-131.594, P = 0.009) and WBC count ≥7 × 10^9/L on Day 3(OR = 23.359,95% CI:1.825-298.959, P = 0.015) were independent risk factors for ED. The WBC count at diagnosis, WBC count on Day 3 and WBC count on Day 5 had moderate positive correlations with tumor necrosis factor-α (TNF-α) at diagnosis, and the correlation coefficients were 0.648 (P = 0.012), 0.615 (P = 0.033), and 0.609 (P = 0.035), respectively. The WBC count had no correlation with IL-6.. During induction treatment, cytotoxic chemotherapy may need to be initiated to reduce the risk of DS for APL patients with a low-intermediate risk WBC count ≥10 × 10^9/L on Day 5 or for all patients with a peak WBC count ≥16 × 10^9/L. Patients with WBC > 7 × 10^9/L on Day 3 have a higher risk of ED. Leukocyte proliferation is associated with TNF-α rather than IL-6, and TNF-α may be a potential biomarker for predicting ED.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interleukin-6; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytes; Leukopenia; Male; Middle Aged; Retrospective Studies; Syndrome; Thrombocytopenia; Tretinoin; Tumor Necrosis Factor-alpha; Young Adult

Acute promyelocytic leukemia (APL) is a medical emergency because of associated lethal early bleeding, a condition preventable by prompt diagnosis and therapeutic intervention. The mechanisms underlying the hemostatic anomalies of APL are not completely elucidated. RNA-sequencing-based characterization of APL (n = 30) was performed and compared to that of other acute myeloid leukemia (n = 400) samples and normal promyelocytes. Perturbations in the transcriptome of coagulation and fibrinolysis-related genes in APL extend beyond known culprits and now include Thrombin, Factor X and Urokinase Receptor. Most intriguingly, the Podoplanin (PDPN) gene, involved in platelet aggregation, is aberrantly expressed in APL promyelocytes and is the most distinctive transcript for this disease. Using an antibody panel optimized for AML diagnosis by flow cytometry, we also found that PDPN was the most specific surface marker for APL, and that all-trans retinoic acid therapy rapidly decreases its expression. Functional studies showed that engineered overexpression of this gene in human leukemic cells causes aberrant platelet binding, activation and aggregation. PDPN-expressing primary APL cells, but not PDPN-negative primary leukemias, specifically induce platelet binding, activation and aggregation. Finally, PDPN expression on leukemia cells in a xenograft model was associated with thrombocytopenia and prolonged bleeding time in vivo. Together our results suggest that PDPN may contribute to the hemostatic perturbations found in APL.

Topics: Adult; Aged; Animals; Female; Flow Cytometry; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Membrane Glycoproteins; Mice; Middle Aged; Platelet Aggregation; Thrombocytopenia; Transcriptome; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Membrane Glycoproteins; Platelet Aggregation; Thrombocytopenia; Tretinoin

Topics: Adult; Danazol; Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Tretinoin

Acute promyelocytic leukemia (APL) is a rare but particularly malignant form of acute leukemia that is characterized by a rapid progression to fatal hemorrhage. Survival rates of patients with APL have increased with the introduction of all-trans retinoic acid (ATRA), but early deaths caused by hemorrhage still persist.. A man with undiagnosed APL presenting with focal neurologic findings and deteriorating altered mental status caused by an intracranial hemorrhage is discussed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important to consider APL when diagnosing etiologies for intracranial hemorrhage. In addition to standard care, early administration of ATRA is recommended upon clinical suspicion of the disease.

Topics: Blood Platelets; Consciousness; Emergency Service, Hospital; Factor VIII; Fibrinogen; Humans; Intracranial Hemorrhages; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Nervous System Diseases; Thrombocytopenia; Tomography, X-Ray Computed; Tretinoin

Topics: Diagnosis, Differential; Electrolytes; Female; Hemolytic-Uremic Syndrome; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Phenotype; Remission Induction; Syndrome; Thrombocytopenia; Treatment Outcome; Tretinoin

Disseminated intravascular coagulation in humans is frequently associated with Gram-negative bacterial sepsis. Therefore, to examine the role and time frame of the in vivo induction of tissue factor (TF) by bacterial endotoxin, a reverse transcription polymerase chain reaction and a solid-phase ELISA assay were developed to monitor the in vivo production in rabbits, of TF mRNA and TF antigen by peripheral blood leukocytes (PBL).. : Healthy rabbits were injected intravenously with either 1, 10 or 50 microg/kg of Salmonella endotoxin. Blood samples were obtained both before endotoxin administration and at various time points thereafter, up to 24 h. Some experiments were also done to determine whether all-trans retinoic acid would ameliorate the signs of the endotoxin-induced disseminated intravascular coagulation.. PBL counts dropped significantly within 2 h of rabbits receiving the endotoxin, recovering to baseline levels by 24 h. Platelet counts decreased gradually over this same time frame. Fibrin deposition was noted in renal glomerular capillaries at 24 h. An increase (P<0.001) in PBL-associated TF mRNA levels was observed 2 h post-endotoxin (10 microg/kg, n = 8), followed by a gradual decline over the subsequent 24 h. The average increase in TF mRNA at 2 h was approximately 4.6-fold (P<0.001) over that seen at time 0. The amount of mononuclear cell associated TF antigen demonstrated a peak at 2 h post-endotoxin (10 microg/kg, n = 13), with levels approximately 9.6-fold greater than (P<0.001) baseline. Pre-treatment of rabbits with all-trans retinoic acid significantly (P<0.001) ameliorated the PBL-associated increase in TF mRNA and TF antigen levels.. These results suggest that low dose endotoxin (10 microg/kg) faithfully reproduces the non-overt activation of coagulation observed in primates and human volunteers, supporting the hypothesis that TF expression is involved in the in vivo initiation and propagation of disseminated intravascular coagulation. Moreover, all-trans retinoic acid may be effective in modulating in vivo the TF transcription induced by endotoxin.

Topics: Animals; Antithrombin III; Blood Cell Count; Disseminated Intravascular Coagulation; Drug Evaluation, Preclinical; Endotoxemia; Fibrin; Fibrinogen; Gene Expression Regulation; Kidney Glomerulus; Leukocytes; Lipopolysaccharides; Male; Rabbits; RNA, Messenger; Thrombocytopenia; Thromboplastin; Tretinoin

To study hemostasis in ATRA treatment of acute promyelocytic leukemia (APL).. Hemostasis was studied in 8 newly admitted APL patients treated with ATRA. All of them had hemorrhages, thrombocytopenia 5-15 x 10(9)/l at diagnosis, laboratory signs of the DIC syndrome at induction therapy.. Hemorrhage arresting was seen on the ATRA therapy day 14 to 30. Duration of thrombocytopenia under 20 x 10(9)/l was 5.8 +/- 1.8 days. After 7 days of ATRA therapy coagulation tests improved with some hypercoagulation tendency. Subsequent condition of hemostasis was considered as normo/hypercoagulation accompanied by constant thrombin persistence (in the presence of FDP) and depression of hageman-dependent fibrinolysis even in remission. A case of ileofemoral thrombosis followed by fatal thromboembolism of the pulmonary artery is reported.. It is suggested to use heparin, especially low molecular weight heparin when there are signs of hypercoagulation in APL patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Female; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Thrombocytopenia; Time Factors; Tretinoin

We studied serum thrombopoietin (TPO) levels and circulating numbers of platelet during five courses of myelosuppressive post-remission chemotherapy in three patients with acute leukemia in complete remission. Serum TPO levels were measured by a newly developed and sensitive sandwich enzyme-linked immunosorbent assay. In all courses, serum TPO levels changed reciprocally with the platelet counts. When platelets were transfused into patients near the time of platelet nadir, the TPO levels dropped temporarily, while platelet counts temporarily increased. In addition, platelets obtained after transfusion in a thrombocytopenic patient showed lower binding to biotinylated TPO than donor platelets prior to the transfusion. The finding indicated that the TPO receptors were saturated with endogenous TPO of the patient with a high serum TPO level. These results suggest that the platelet mass directly regulates serum TPO levels by receptor-mediated absorption and is one of the major regulators of serum TPO levels in humans.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Blood Transfusion; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Platelet Count; Predictive Value of Tests; Thrombocytopenia; Thrombopoietin; Translocation, Genetic; Tretinoin

In 26 acute promyelocytic leukaemia (APL) patients treated with all-trans retinoic acid (ATRA), 23% had platelet counts between 459 and 800 x 10(9)/I during treatment. These values, observed between days 28 and 45 of ATRA treatment, were transient and asymptomatic. We report two APL cases with platelet counts > 1000 x 10(9)/I during ATRA therapy who were treated with recombinant interferon alpha. In both cases ATRA doses were not modified, no complications secondary to thrombocytosis were seen, and they subsequently achieved complete remission. It is suggested that IL-6 may play an important role in the pathogenesis of the thrombocytosis induced by ATRA. To our knowledge, this is the first report of thrombocytosis occurring during ATRA treatment.

Topics: Adolescent; Adult; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Pancytopenia; Thrombocytopenia; Thrombocytosis; Tretinoin

To determine the activity of fenretinide in patients with myelodysplastic syndromes, 15 patients were treated (300 mg/d starting dose, escalated to 400 mg/d) for a 12-week course. No responses were observed in 14 evaluable patients. Exacerbation of thrombocytopenia occurred in one patient with chronic myelomonocytic leukemia, who succumbed to an intracerebral hemorrhage after 3 weeks of treatment. Two patients with long-standing stable sideroblastic anemia experienced interval leukemic progression. In one patient, clinical features of chronic myelomonocytic leukemia appeared, characterized by a striking rise in peripheral monocyte count (0.49 x 10(9)/l to 10.8 x 10(9)/l) and hepatosplenomegaly, which resolved promptly after cessation of treatment. The second patient experienced evolution into acute myelomonocytic leukemia with cytogenetic progression. The drug was well tolerated with no patient having to discontinue treatment because of toxicity. We conclude that fenretinide lacks clinical efficacy in the treatment of myelodysplasia and in some patients may enhance leukemic progression.

Topics: Acute Disease; Aged; Cerebral Hemorrhage; Drug Evaluation; Fenretinide; Humans; Leukemia; Leukocytosis; Male; Middle Aged; Monocytes; Myelodysplastic Syndromes; Thrombocytopenia; Tretinoin

Topics: Acne Vulgaris; Adolescent; Humans; Isotretinoin; Platelet Count; Thrombocytopenia; Tretinoin

Topics: Adult; Humans; Isotretinoin; Male; Thrombocytopenia; Tretinoin

Treatment of chronic phase chronic myelogenous leukemia with hydroxyurea or busulfan rarely induces cytogenetic (true) remissions. Intensive chemotherapy induces brief true remissions in approximately 50% of patients. We added 13-cis-retinoic acid to daunorubicin, cytosine arabinoside, and thioguanine to determine if it could increase the incidence and duration of remission induced by cytotoxic chemotherapy. Of the 17 evaluable patients, one patient (6%) achieved complete remission, and seven patients (41%) achieved partial remissions. The median duration of remission was 1.6 months. We conclude that 13-cis-retinoic acid does not increase the incidence and duration of remission in chronic phase chronic myelogenous leukemia.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, 21-22 and Y; Cytarabine; Daunorubicin; Humans; Isotretinoin; Leukemia, Myeloid; Leukopenia; Liver; Middle Aged; Stomatitis; Thioguanine; Thrombocytopenia; Time Factors; Tretinoin

Eighteen patients with myelodysplastic syndrome received 13-cis-retinoic acid (1.0-mg/kg/day starting dose with 0.5-mg/kg increment escalations) in a phase I-II trial. Two partial responses involving the erythroid series were observed in four patients with primary refractory anemia with ring sideroblasts. One of two patients with chronic myelomonocytic leukemia also achieved a partial response. No other responses were found in the remaining patients, which included eight with refractory anemia with excess blasts. In six patients drug toxicity necessitated termination of the trial. Four patients had unexpected drug-induced thrombocytopenia; three of these had low platelet counts before treatment. Two of the six patients had other toxic effects. Further studies are warranted to evaluate the effectiveness of 13-cis-retinoic acid in patients with refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia. At moderate doses significant toxic effects, including thrombocytopenia, are not uncommon.

Topics: Anemia, Refractory; Blood Cell Count; Drug Evaluation; Erythropoiesis; Hematopoietic Stem Cells; Hemoglobins; Humans; Isotretinoin; Leukemia, Myeloid; Myelodysplastic Syndromes; Thrombocytopenia; Tretinoin