tretinoin and Leukocytosis

With the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) acute promyelocytic leukemia (APL) has become from a detrimental to one of the most curable malignant diseases in humans. In particular, the chemotherapy-free regimen with ATO/ATRA has been proven to be highly effective in de novo APL and has become standard first-line therapy in younger adult, non-high-risk patients. Nevertheless, early death is still a major issue in APL, particularly in older patients, emphasizing the need of rapid diagnostics and supportive care together with immediate access to ATRA-based therapy. Despite the dramatic progress achieved in therapy of APL challenging situations occur, particularly in patients excluded from controlled studies with clinical knowledge mainly based on case reports and registries. Rapid identification and treatment of newly diagnosed patients as well as the management of toxicities and complications remain challenging. We offer up-to-date information and guidance regarding treatment of APL. Based on a literature review of existing scientific evidence we also discuss the approach to high-risk, elderly, pregnant and pediatric patients, treatment in patients with renal failure as well as of therapy-related or relapsed/refractory APL.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Electrocardiography; Female; Fetus; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasms, Second Primary; Pregnancy; Recurrence; Renal Dialysis; Renal Insufficiency; Tretinoin

Molecularly targeted therapies have transformed the management of PML-RARA+ acute promyelocytic leukaemia (APL), with survival rates now exceeding 80% in clinical trials. This raises questions about the relevance of post-remission monitoring for PML-RARA transcripts, which has been widely used to predict relapse, guiding early intervention to prevent disease progression and the inherent risk of fatal bleeding. Given the treatability of haematological relapse, survival benefits would only be seen if monitoring could identify patients who could be salvaged if treated early but not later on, although it could be argued that early deployment of arsenic trioxide (ATO) can avoid inducing hyperleucocytosis and the associated differentiation syndrome, which frequently complicate treatment of frank relapse. However, given the low rates of relapse now observed in patients presenting with standard risk disease (i.e. presenting WBC<10×10(9)/l) who achieve early molecular remission, subsequent sequential minimal residual disease (MRD) monitoring confers only a marginal benefit, so could be avoided in this group. However, sequential MRD monitoring may still be of value in patients with high risk APL, although evidence tends to come from historically controlled studies. Therefore, there may remain a role for MRD monitoring in the most clinically challenging subsets of APL, but the continuing debate highlights the need for robust evidence in developing a more individualized approach to management of other subtypes of acute leukaemia.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Cell Differentiation; Clinical Trials as Topic; Disease Management; Drug Monitoring; Drug Resistance, Neoplasm; Historically Controlled Study; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Real-Time Polymerase Chain Reaction; Remission Induction; Salvage Therapy; Tretinoin

Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARalpha oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Dyspnea; Fever; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Models, Biological; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Transcription, Genetic; Treatment Outcome; Tretinoin

Leukocytosis or hyperleukocytosis occurs during ATRA or arsenic trioxide differentiation therapy, which is related to the RA syndrome. The number of WBC often increased by ten or more times as high as that of pretreatment, around 7 to 20 days after treatment with ATRA or arsenic trioxide. Usually, when number of WBC tended to peak, there was concomitance with down-regulation of promyelocytes, up-regulation of myelocytes and more mature neutrophils. The same trend of classification of BM was observed in most of the patients with APL to whom leukocytosis happened. Although the mechanism of leukocytosis has not been demonstrated clearly, so far the proliferation hypothesis by cytokines and rheological hypothesis by adhesion molecules were taken into consideration. Otherwise, hypothesis about more divisions of differentiated myelocytes induced by ATRA or arsenic trioxide remains unclear. Usually, this kind of leukocytosis or hyperleukocytosis itself requires no additional cytotoxic treatment.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cytokines; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Oxides; Tretinoin

Extramedullary disease (EMD) is a rare clinical event in acute promyelocytic leukemia (APL). Although the skin is involved in half of the reported EMD cases, the occurrence of cutaneous promyelocytic sarcoma (PS) has been described very rarely. We report here three cases of PS which have the peculiarity of appearing at sites of punctures for arterial and venous blood and marrow samples (sternal manubrium, antecubital fossa, wrist over the radial artery pulse, catheter insertion scar). At presentation, all patients had hyperleukocytosis and a morphologic diagnosis of microgranular acute promyelocytic leukemia variant confirmed at the genetic level by demonstration of the specific chromosomal translocation t(15;17). A BCR3 type PML/RARa transcript was documented in the two patients for whom diagnostic RT-PCR was available. Patients had morphologic bone marrow remission at the time the PS appeared. A predilection for the development of cutaneous PS at sites of previous vascular damage has been noted, but the pathogenesis remains largely unknown. A potential role for all-trans retinoic acid has been advocated, although one of the three patients in our series had received no ATRA. A review of the literature revealed six similar cases and hyperleukocytosis at diagnosis was a consistent finding in all of them. A careful physical examination of these particular sites in the follow-up of patients at risk, as well as cutaneous biopsy and laboratory examination of suspected lesions are strongly recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy, Needle; Catheterization, Central Venous; Endothelium, Vascular; Female; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Leukocytosis; Male; Middle Aged; Punctures; Sarcoma; Skin Neoplasms; Tretinoin

Topics: Acetylation; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Child; China; Chromatin; Drug Evaluation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gastrointestinal Diseases; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Melarsoprol; Neoplasm Proteins; Neoplasms; Nervous System Diseases; Oxides; Phenylbutyrates; Protein Processing, Post-Translational; Salvage Therapy; Tretinoin

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Differentiation; China; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Europe; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Middle Aged; Mitoxantrone; New York; Pilot Projects; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA, tretinoin) is a natural metabolite of retinol and is normally found in plasma, at concentrations of approximately 0.5-1.5 ng/ml. The in vivo and in vitro studies has demonstrated that in pharmacological doses it can differentiate leukemic cells in acute promyelocytic leukemia (APL). ATRA has been shown to induce complete remission (CR) rates of approximately 90% in newly diagnosed and first relapsing APL. However, CR induced by ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission. ATRA followed by intensive chemotherapy has improved the outcome of newly diagnosed APL, by increasing the CR rate and by reducing the risk of relapse. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene is a marker for sensitivity to this agent. ATRA therapy is associated with the risk of rapidly rising leukocyte counts, leading to the retinoid acid syndrome which may be fatal if the increase in leukocytes is not reversed. A side effects from these complications ATRA therapy is generally well tolerated.

Topics: Animals; Antineoplastic Agents; Humans; In Vitro Techniques; Leukemia, Promyelocytic, Acute; Leukocytosis; Myelodysplastic Syndromes; 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

The major cause of early death in acute promyelocytic leukemia (APL), the high risk of a bleeding diathesis is now successfully counteracted within a few days by differentiation therapy using ATRA. Moreover, no resistance to this drug has been recorded during induction when the usual presence of PML/RAR alpha was confirmed by molecular study (some M3 cases do lack rearrangement of PML/RAR alpha). Paradoxically, a hypercoagulable clotting tendency may occur in these patients during the first month of ATRA treatment. Leucocyte activation (retinoic acid syndrome), often secondary to hyperleukocytosis, is prevented by early addition of chemotherapy when WBCs exceed defined limits, and is successfully treated by high dose corticosteroids. Routine acquired progressive in vivo resistance to all trans retinoic acid (ATRA) requires consolidation of ATRA-induced complete remission (CR) with intensive chemotherapy. Prevention of relapses using maintenance therapy is questionable and has not been tested in randomized trials. Actually the event-free survival of APL patients treated by the combination of ATRA and chemotherapy is 80% at 1 year, and the cure of 50% of patients is within our reach.

Topics: Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Prognosis; Time Factors; Tretinoin

Topics: Carrier Proteins; Cell Differentiation; Drug Resistance; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

Perhaps the most important advance in this field is not the specific actions of all-trans-retinoic acid in acute promyelocytic leukemia, but rather the conclusive documentation of differentiation as a practical and consistently effective method of treating human cancer. As a drug, all-trans-retinoic acid has certain undesirable pharmacologic properties that might be overcome by the use of alternative retinoids, such as 9-cis-retinoic acid, that are equally active against acute promyelocytic leukemia cells in vitro. In addition to retinoids that selectively activate RARs or RXRs, other ligands of the steroid-thyroid receptor superfamily, such as vitamin D3, glucocorticoids, and sex steroids also have cytodifferentiating actions in model systems. Numerous other agents can effect differentiation of neoplastic cells in such systems, including sodium butyrate, hexamethylene bisacetamide and its analogues, colony-stimulating factors, and interferons. Each of these compounds apparently acts through different pathways, and their activity may be greatly amplified when they are used in combination. Just as the practical usefulness of all-trans-retinoic acid in combination with conventional treatments continues to evolve, the use of differentiation agents in combination represents a novel and promising approach for oncologic therapy in the next decade. Although acute promyelocytic leukemia remains an "orphan" disease, its importance as a model for human neoplasia should not be minimized. The specific molecular lesion of acute promyelocytic leukemia is not shared by other cancers, but the physiologic actions of retinoids, their documented cytodifferentiating activity against a variety of human cancer cells in vitro, and their usefulness in cancer chemoprevention are clearly not mediated by identifiable mutations of retinoid receptors. The insights into transformation and leukemogenesis gained in acute promyelocytic leukemia may be a harbinger of further clinical applications and offer a glimpse into the next generation of cancer therapy.

Topics: Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Remission Induction; RNA, Neoplasm; Tretinoin

All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL. Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Edema; Fever; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung Diseases; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10(9) /l at presentation (median WBC 85·5 × 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4-week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukapheresis; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Oxides; Retrospective Studies; Survival Rate; 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

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-gamma. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzoates; Cell Differentiation; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Female; Gastrointestinal Diseases; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Pain; Prospective Studies; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor gamma; Retinoids; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin

Two hundred fifty-three patients with newly diagnosed acute promyelocytic leukemia (APL) were eligible to enter the multicentric GIMEMA-AIEOP "AIDA" trial during the period July 1993 to February 1996. As a mandatory prerequisite for eligibility, all patients had genetic evidence of the specific t(15;17) lesion in their leukemic cells confirmed by karyotyping or by reverse transcription-polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene (the latter available in 247 cases). Median age was 37.8 years (range, 2.2 to 73.9). Induction treatment consisted of oral all-trans retinoic acid (ATRA), 45 mg/m2/d until complete remission (CR), given with intravenous Idarubicin, 12 mg/m2/d on days 2, 4, 6, and 8. Three polychemotherapy cycles were given as consolidation. Hematologic and molecular response by RT-PCR was assessed after induction and after consolidation. At the time of analysis, 240 of the 253 eligible patients were evaluable for induction. Of these, 11 (5%) died of early complications and 229 (95%) achieved hematologic remission. No cases of resistant leukemia were observed. Of 139 cases studied by RT-PCR after induction, 84 (60.5%) were PCR-negative and 55 (39.5%) PCR-positive. One hundred sixty-two patients were evaluable by RT-PCR at the end of consolidation. Of these, 159 (98%) tested PCR-negative and 3 (2%), PCR-positive. After a median follow up of 12 months (range, 0 to 33), the estimated actuarial event-free survival for the whole series of 253 eligible patients was 83% +/- 2.6% and 79% +/- 3.2% at 1 and 2 years, respectively. This study indicates that the AIDA protocol is a well-tolerated regimen that induces molecular remission in almost all patients with PML/RAR alpha-positive APL. Preliminary survival data suggest that a remarkable cure rate can be obtained with this treatment.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Child; Child, Preschool; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Prospective Studies; Remission Induction; Syndrome; Translocation, Genetic; Treatment Outcome; Tretinoin

A clinical trial was conducted in order to evaluate the therapeutic effect and side-effects of low-dose ATRA in the treatment of acute promyelocytic leukemia (APL). We compared the pharmacokinetic features in normal individuals with single oral ATRA at 15 mg/m2 and 45 mg/m2, respectively. The results showed that maximal plasma concentration (Cpmax) with oral 15 mg/m2 ATRA was high enough (10(-6) M) to induce APL cell differentiation. Based on these results, 27 cases of de novo APL patients were treated with continuous oral ATRA at the dose of 15-20 mg/m2/day and 24/26 evaluable cases (92%) achieved clinical CR after 13 to 67 days of ATRA treatment. No patient experienced RAS and DIC. The Cpmax with a single dose of ATRA on day 1 of treatment and immediately at CR obtained with continuous ATRA in three cases demonstrated similar values in one patient and an approximately two-fold decrease in two patients. More importantly, compared with a relatively well-matched historic group of 20 APL patients treated with high-dose ATRA, our results suggest that low-dose ATRA is as effective as high-dose in treating APL patients and may provide advantages through decreased hyperleukocytosis and other side-effects.

Topics: Administration, Oral; Adult; Female; Half-Life; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Remission Induction; Tretinoin

Retinoids can inhibit the spontaneous in vitro growth of CFU-GM observed in juvenile chronic myeloid leukemia (JCML) and, when administered in vivo, have shown some clinical benefit in this disease. Because adult chronic myelomonocytic leukemia (CMML) has many features in common with JCML, we treated 10 cases of advanced adult CMML with ATRA (45 mg/m2/day). Five of them were also tested in vitro. After two patients had a rapid increase in WBC counts and clinical signs reminiscent of the 'ATRA syndrome' seen in acute promyelocytic leukemia, with fatal outcome in one of them, it was decided to add hydroxyurea (HY) to ATRA to patients with high WBC at inclusion or during ATRA treatment, and no more cases of ATRA syndrome were seen. Overall, six patients received ATRA + HY and four ATRA alone. Four patients had a minor but significant response with reduction of transfusion requirement (two cases) or increase in platelet counts (two cases). Apart from the ATRA syndrome, no other side-effect of ATRA was seen. Bone marrow mononuclear cells showed spontaneous growth of CFU-C in methylcellulose in the five patients tested in vitro, with a predominance of CFU-M. ATRA (10(-7) M) inhibited CFU-M growth in all cases, but increased CFU-G growth in one patient who developed the ATRA syndrome. No differentiation of bone marrow myeloid cells after short-term liquid culture with ATRA was observed. A decrease of CFU-C growth was observed in the four patients reevaluated during follow-up. In some cases of CMML, ATRA can improve anemia or thrombocytopenia but not other parameters. Furthermore, it can also induce hyperleukocytosis and ATRA syndrome in some patients, requiring the rapid addition of cytoreductive agents such as HY.

Topics: Aged; Antineoplastic Agents; Bone Marrow; Colony-Forming Units Assay; Female; Hematopoietic Stem Cells; Humans; Hydroxyurea; Leukemia, Myelomonocytic, Chronic; Leukocytosis; Male; Middle Aged; Pilot Projects; Platelet Count; Syndrome; Tretinoin; Tumor Cells, Cultured

Laboratory evidence of disseminated intravascular coagulation (DIC) and/or fibrinolysis is present in the majority of patients with acute promyelocytic leukemia (APL). Historically, early hemorrhagic death (EHD) occurred in 10% to 30% of patients treated with chemotherapy. All-trans retinoic acid (ATRA), a differentiating agent, has a CR rate above 80% in patients, with ATRA-associated leukocytosis. We studied thrombotic events in this population and compared it to patients treated with chemotherapy alone. The results of studies using ATRA in patients with APL were reviewed. Patients received ATRA 45-50 mg/m(2) orally in two divided doses daily until complete remission. In newly diagnosed patients, Idarubicin 12 mg/m(2)/day was given intravenously for 4 to 5 days beginning on the fifth day of ATRA therapy or when the white blood cell count (WBC) was over 10x 10(3)/mu l. Thrombotic complications were noted in 3 of 31 patients during induction. Two died from thrombotic events during therapy with multiple thromboses documented at autopsy. ATRA syndrome was suspected in 2 of the patients with thromboses and only 1 of the patients without thrombosis. In previous studies, 1 of 25 APL patients treated with chemotherapy alone had thrombotic events during therapy. In conclusion, treatment of APL with ATRA may decrease the incidence of hemorrhagic complications, but does not eliminate thrombosis. While thrombotic events were not significantly increased in patients treated with ATRA, they were more common in patients suspected of having ATRA syndrome.

Topics: Adult; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Cohort Studies; Cytarabine; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Germinoma; Hemorrhage; Humans; Idarubicin; Incidence; Infarction; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Melanoma; Middle Aged; Myocardial Infarction; Neoplasms, Multiple Primary; Remission Induction; Retrospective Studies; Spleen; Thrombosis; Treatment Outcome; Tretinoin

From February 1992 to February 1995, 77 patients with APL were treated with ATRA in induction (59 patients de novo, 6 in first relapse, 1 with APL secondary to a mielodisplastic syndrome). The dose used was 45 mg/k/day-30 mg/k/day until complete remission (CR) was achieved; of the 66 evaluable patients, 50 achieved complete remission (78%). Among the 14 patients who did not attain CR, 13 died, 10 of bleeding episodes and 3 of retinoic syndrome; one was rescued with chemotherapy. We proposed consolidation treatment with high dose Ara-C and Idarubicin to the 49 patients in complete remission; 6 could not receive it and 5 died; the disease free survival period of the other patients was 81% (CI95 90%-66%) at one year and 74% (CI95 91%-52%) at two years. We consider that our results are similar to those of other groups and we are inclined to continue with this treatment protocol.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Argentina; Child; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Remission Induction; Tretinoin

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Differentiation; China; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Europe; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Middle Aged; Mitoxantrone; New York; Pilot Projects; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Immunologic Factors; Japan; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Male; Mercaptopurine; Middle Aged; Prednisolone; Prospective Studies; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) is currently being used as remission induction treatment for acute promyelocytic leukemia (APL). Conventional chemotherapy is added both during and after ATRA treatment, in order to avoid the occurrence of hyperleukocytosis, and to improve the duration of complete remission. In this study we analysed the hematopoietic recovery of 18 consecutive APL patients after standard Idarubicin or Daunorubicin +/- Cytosine-Arabinoside regimens. 9 of the patients were at the onset of the disease, (CHT group) while 9 had been pre-treated with ATRA 45 mg/sqm/day for at least 3 months (ATRA group). 500 PMN/mmc were reached after 20.8 day from the end of treatment in CHT group and after 12.0 days in ATRA group (p = 0.007). Platelets recovery was faster, even though not significantly in ATRA group. Interestingly, PMN recovery in ATRA group was even shorter (p = 0.004) than that obtained in CHT group, after the first course of chemotherapy (treatment in CR vs treatment in CR). If these results are confirmed in a larger study, a protective effect of ATRA on normal residual hemopoiesis should be postulated.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Hematopoiesis; Humans; Idarubicin; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Neutrophils; Platelet Count; Premedication; Remission Induction; Salvage Therapy; Treatment Outcome; Tretinoin

To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia.. Phase II evaluation and comparison with historical control patients.. Tertiary care cancer referral center.. Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again.. 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior.. All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Leukopenia; Male; Middle Aged; Recurrence; Remission Induction; Survival Analysis; Time Factors; Tretinoin

In acute promyelocytic leukemia (APL), increased cell burden in the peripheral blood due to either the disease itself or early treatment with all-trans retinoic acid could cause hyperleukocytosis (HL) before induction chemotherapy. However, therapeutic leukapheresis has seldom been used because of concerns of subsequent coagulopathy after this invasive procedure. The aim of this study was to evaluate the effects of leukapheresis in APL, especially for efficacy and safety.. There was a trend toward favorable 30-day survival rate for the leukapheresis group compared with the non-leukapheresis group (76.9% and 67.4%; P = 0.24). The complications including subsequent intensive unit care (P = 0.23), severe hemorrhagic events (P = 0.13) showed no significant differences between the two groups. The patients were divided into subcohorts, and the survival rates of the leukapheresis and non-leukapheresis groups were 92.3% (95% confidence interval [CI], 77.8%-100.0%) versus 58.3% (95% CI, 38.6%-78.1%) (P = 0.03) in "sequential HL" and 76.7% (95% CI, 61.5%-91.8%) versus 54.8% (95% CI, 37.3%-72.4%) (P = 0.03) in "symptomatic HL," respectively. Moreover, in the "sequential HL" subcohort, the cumulative incidence of differentiation syndrome and following adverse events were significantly lower in the leukapheresis group.. In APL with "sequential HL" or "symptomatic HL" from either the disease itself or the effect of all-trans retinoic acid, therapeutic leukapheresis could be applied to reduce leukemic cell burden without significant risks.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Retrospective Studies; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique clinical presentation and prognosis. This study aimed to investigate the epidemiology, clinical characteristics, treatments, and clinical outcomes of Thai APL patients dominantly treated with all-trans-retinoic acid (ATRA) combined with a chemotherapy-based therapy.. This was an eight-year prospective, observational study from nine academic hospitals in the Thai Acute Leukemia Working Group (TALWG) of the Thai Society of Hematology, which included newly diagnosed Thai APL patients, aged 18 years or older. The web-based registration collected baseline charateristic, and clinical outcomes.. APL; acute promyelocytic leukemia; ATRA; all-transretinoic acid; CR; complete remission; DS; differentiation syndrome; ECOG; Eastern Cooperative Oncology Group; ED; early death; HR; hazard ratio; IQR; interquartile range; LFS; leukemia-free survival; OS; overall survival; WBC; white blood cell.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Prospective Studies; Treatment Outcome; Tretinoin

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Diagnosis, Differential; Dyspnea; Female; Fever; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung Diseases; Oxides; Risk Factors; Severity of Illness Index; Syndrome; Treatment Outcome; Tretinoin

Transfusion-related acute lung injury (TRALI) is a clinical syndrome characterized by sudden onset of respiratory distress due to pulmonary edema during or following transfusion. Two proposed pathophysiologic mechanisms for TRALI were proposed: the antibody hypothesis and the two-event hypothesis. The two-event hypothesis postulates that a pathway to neutrophil activation and aggregation can occur without leukocyte antibodies. We report a case of TRALI occurring during remission induction course of acute myeloid leukemia in a 27-year-old woman who received All-transretinoic-acid (ATRA). We postulate that ATRA may have played a role in this life-threatening complication by priming neutrophil and enhancing their adherence and their activation in the pulmonary endothelium. TRALI improved with non-invasive ventilation support and use of high dose corticosteroids.

Topics: Adult; Anemia; Antineoplastic Agents; Female; Flow Cytometry; Humans; Leukemia, Myeloid, Acute; Leukocytosis; Remission Induction; Respiratory Distress Syndrome; Transfusion Reaction; Tretinoin

In order to investigate the occurrence of hyperleukocytosis in treating acute promyelocytic leukemia (APL) patients with all trans retinoic acid (ATRA) and to explore the influence of the level of leucocyte on curative effect of ATRA, the APL patients were divided into three different groups according to the count of leucocyte in peripheral blood. Patients with WBC count less than 30x10(9)/L were administered with ATRA alone (the first group), patients with WBC count more than 30x10(9)/L were administered with ATRA alone (the second group) and patients with WBC count more than 30x10(9)/L were treated with ATRA+cytotoxic drugs (the third group). The results showed that hyperleukocytosis were found in 23 out of 39 patients (58.97%). Total remission rates in the second group and in the third group were 91.3%. The remission rates in the first, second and third groups were 100%, 87.5% and 90.9%, respectively. It is concluded that the ATRA in combination with cytotoxic drugs can efficiently control the occurrence of hyperleukocytosis during ATRA-treating APL and reduce the early mortality.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Treatment Outcome; Tretinoin; Young Adult

All-trans retinoic acid (ATRA) is used as differentiation therapy for acute promyelocytic leukemia (APL). The two major adverse effects of ATRA therapy are hyperleukocytosis and retinoic acid syndrome. In order to prevent these adverse effects, low-dose ATRA therapy (25 mg/m2/d) has been tried in adults. Accordingly we assessed the pharmacokinetics of low-dose ATRA in children with cancer. Four children (one with APL and three with other advanced cancer) were administered ATRA and its pharmacokinetics were evaluated. In three patients, the pharmacokinetic parameters of ATRA were similar to those previously determined for APL patients in remission, but the values were lower in one patient. Low-dose ATRA was effective for APL, but not for the solid tumors. This therapy did not cause any severe toxicity. Further studies are needed to determine the optimum ATRA regimen and to evaluate low-dose ATRA combined with chemotherapy in children with APL.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Neoplasms; Remission Induction; Tretinoin

We describe a patient with acute promyelocytic leukemia (APL) who developed pulmonary embolism (PE) and thrombotic thrombocytopenic purpura (TTP) during remission induction all-trans retinoic acid (ATRA) therapy. A 44-year-old man was diagnosed with APL and was treated with ATRA. On day 14, he developed PE, and on day 24, he developed TTP. Both PE and TTP occurred in association with leukocytosis due to ATRA administration. The PE responded to dexamethasone and TTP responded to plasma infusion. The PE and TTP remitted, and he achieved complete remission of APL. To our knowledge, there have been no reports of TTP occurring as a complication of ATRA therapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Pulmonary Embolism; Purpura, Thrombotic Thrombocytopenic; Remission Induction; Tretinoin

Topics: Antineoplastic Agents; Digestive System; Endothelium, Vascular; Fatal Outcome; Humans; Kidney; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Myocardium; Neoplastic Stem Cells; Respiratory System; Syndrome; Testis; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Hypotension; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung; Male; Respiratory Distress Syndrome; Syndrome; Tretinoin

Topics: Acute Kidney Injury; Antineoplastic Agents; Dexamethasone; Humans; Hypertension; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Leukostasis; Mortality; Premedication; Respiratory Distress Syndrome; Risk Factors; Syndrome; Tretinoin

Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena.. Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg.. Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37).. Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Dyspnea; Fever; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Oxides; Pleural Effusion; Syndrome; Tretinoin

To explore the mechanism of leukocytosis.. Enzyme linked immunosorbent assay (ELISA) method was used for detecting levels of serum granulocyte colony-stimulating factor (G-CSF) in 47 cases of acute promyelocytic leukemia (APL) during the treatment with all-trans retinoic acid (ATRA).. The peak of increased serum G-CSF level occurred on the 9th day, and WBC number was the highest on the 11th day. After ATRA treatment, both serum G-CSF level and WBC number increased in 68.1% of the cases. In 19.2% of the cases treated, serum G-CSF level was increased but without obvious change in WBC number, and the reverse was true in 12.7% of the cases.. Serum G-CSF level was statistically correlated to the number of WBC, promyelocytes and its late stage by Spearman's rank-order correlation coefficient.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Tretinoin

Of 82 patients with acute promyelocytic leukemia (APL) who were treated with all-trans retinoic acid (ATRA), 35 developed leukocytosis and 22 fatal side-effects(15 with retinoic acid syndrome and 7 intracranial bleeding). There was a high mortality in the patient with fatal side-effects. The relationship between leukocytosis and fatal side-effects was analyzed and the effect of therapeutic interventions on the development and prognosis of the fatal side-effects was investigated. The results showed that leukocytosis was a risk factor of the development of fatal side-effects in APL treated with ATRA. ATRA combined with small dose of harringtonin in treating APL can reduce the incidence of intracranial bleeding resulted from leukocytosis and corticosteroid can decrease the mortality of retinoic acid syndrome.

Topics: Adolescent; Adult; Aged; Cerebral Hemorrhage; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Tretinoin

Topics: Cytarabine; Humans; Leukemia, Myelomonocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Syndrome; Tretinoin

To investigate the cellular biological mechanism of leukocytosis produced by all-trans retinoic acid (ATRA).. BALB/C mice were fed by ATRA. The effects of ATRA on BALB/C mice hematopoiesis was studied by 3H-TdR, semi-solid progenitor culture, and CFU-S number.. ATRA increased the peripheral blood cells count in vivo. The effect on WBC count was obvious. The peak of the elevation (183% of the control) occurred at the 16th day. Correspondingly, 3H-TdR was increased and CFU-S was enhanced in BM, and the peak of the elevation (190% and 200% of the control, respectively) occurred at the 8th day. The progenitor cell CFU-GM was proliferated and the maximum elevation (215% of control) was observed at the 12th day.. ATRA could produce leukocytosis in normal BALB/C mice. The effect was possibly related to the proliferation of CFU-GM and CFU-S and to ATRA-induced CSA such as G-CSF in vivo.

Topics: Animals; Cell Division; Hematopoietic Stem Cells; Leukocytosis; Male; Mice; Mice, Inbred BALB C; Random Allocation; 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

We report on two girls, 3 and 13 years old, with acute promyelocytic leukemia (APL) who were successfully treated with all-trans retinoic acid (ATRA) 45 mg/m2/day. "Retinoic acid syndrome" was prevented with short-time treatment of high dose (4 x 1.5 g/m2) cytarabine. This regimen was well tolerated, although both children were critically ill. They achieved a complete remission confirmed by light microscopy, but reverse transcriptase polymerase chain reaction remained positive after ATRA, underlining the need of further chemotherapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents; Child, Preschool; Critical Illness; Cytarabine; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Remission Induction; Syndrome; Tretinoin

The mechanism of the cause of hyperleukocytosis induced by differntiation induction therapy of acute promyelocytic leukemia (APL) by all-trans retinoic acid (ATRA) was studies. Of 11 patients treated by ATRA in our hospital, 3 developed hyperleukocytosis. Moreover, 2 out of 4 patients with retinoic acid syndrome (ATRA syndrome) had hyperleukocytosis. Using the patients' leukemia cells as test material, we obteined the following results. In the presence of ATRA at a concentration that induced differentiation in vitro, promotion or supression of differentiation and lineage determination during the differentiation of APL cells involved factors other than ATRA, such as cytokines. Moreover, APL cells that differentiated into monocytoid cells possessed the capability of producing endogenous cytokines such as TNF alpha, which might be involved in the development of ATRA syndrome. Compared to cells from patients without hyperleukocytosis they had a stronger TNF alpha producing capability and lower sensitivity to TGF beta, showing hyperdifferentiation in response to ATRA. Depending on the case, those with the same sensitivity to ATRA might show different sensitivities to cytokines.

Topics: Adult; Antineoplastic Agents; Cell Differentiation; Cytokines; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Tretinoin; Tumor Cells, Cultured

During the treatment with all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL), leukocytosis occured in 33%-75% of the treated cases. ELISA method was used in detecting levels of serum granulocyle colony-stimulating factor (G-CSF) in 47 cases of APL during treatment with ATRA. It was found that the peak of increased serum G-CSF level occurred on the 9th day, and WBC number was highest on the 11th day. After ATRA treatment, both serum G-CSF level and WBC number increased in 68.1% of the cases. In 19.2% of the cases treated, serum G-CSF level was increased but without obvious change in WBC number, and the reverse was true in 12.7% of the cases. Serum G-CSF level was statistically correlated to the number of WBC, promyelocytes and its late stage by Spearman rank correlation analysis.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Tretinoin

According to French and European experience, hyperleukocytosis occurs during ATRA differentiation therapy in about 70% of de novo and 25% of relapsed APL cases. The most frequently suggested cause for this side-effect is an ATRA-induced proliferation of APL cells. However, no definite explanation for such a proliferative effect has been clearly established. Another mechanism directly related to the differentiation of marrow leukemic cells could be a change in their microrheology, allowing their release from the bone marrow and their transfer toward peripheral blood (PB) and tissues. Using a single cell aspiration assay into a glass restrictive channel, we measured APL cell viscosity values in five de novo APL patients. A deformability index (DI) was defined as the ratio of mean normal neutrophil viscosity x 100/mean APL cell viscosity. Results were the following: (1) at diagnosis, two patients had high marrow DI (96 and 250%) and three patients had low marrow DI (16, 17, and 40%); (2) when PB and marrow APL cells were simultaneously tested, PB APL cells display higher DI than marrow APL-cells; (3) the two patients with high initial marrow DI experienced an ATRA-induced hyperleukocytosis after only 1 day of treatment; (4) in the three patients with low initial marrow DI, the DI was increasing during ATRA therapy and hyperleukocytosis seemed to occur when a large amount of maturing APL cells reached a viscosity value similar to that of mature neutrophils. These results suggest that an asynchronism between rheological and morphological maturation in each APL cell might explain the occurrence of hyperleukocytosis in some patients during ATRA differentiation therapy.

Topics: Adult; Aged; Blood Viscosity; Bone Marrow; Cell Differentiation; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Rheology; Tretinoin; Viscosity

The effect of all-trans-retinoic acid (ATRA) on extramedullary acute promyelocytic leukemia (APL) has not been fully delineated. We report an unusual case of APL in which a patient relapsed in the skin and central nervous system. Cytodifferentiation of leukemic cells from these extramedullary sites was demonstrated following treatment with ATRA.

Topics: Bone Marrow; Cell Differentiation; Central Nervous System; Female; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Leukocytosis; Middle Aged; Skin; Tretinoin

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of the t(15;17) translocation and the resulting PML/RAR alpha fusion proteins. To date APL is the only AML which is sufficiently sensitive to all-trans retinoic acid (ATRA) differentiating effect. We have recently reported that APL express and secrete hematopoietic growth factors (HGF) such as IL-1 beta, TNF alpha, and IL-6. In vivo ATRA alone allows achievement of complete remission in APL patients. One of ATRA therapy's drawbacks is the increase of peripheral blast cells often associated with the ATRA leukocyte activation syndrome. To determine if this specific side-effect was linked to an increase of HGF release by APL cells, we studied the modulation of cytokine production by APL cells, we studied the modulation of cytokine production by APL samples (n = 12) before and after incubation with ATRA. ATRA failed to modulate TNF alpha, IL-6 or GM-CSF secretion levels; however, IL-8 levels decreased in 11 cases, and in four cases up-regulation of IL-1 beta and G-CSF protein expression was observed. These modulations were found to be linked to ATRA sensitivity as ATRA failed to modulate cytokine production in non-APL cells (n = 8). Interestingly, the increase of IL-1 beta and G-CSF production in the presence of ATRA was highly correlated to an increase in APL cell count in vitro and in vivo hyperleukocytosis, resulting in fatal outcome. IL-1 beta, TNF alpha, IL-6, and IL-8 are known to be implicated in leukocyte activation. The results of this study suggest that ATRA-induced hyperleukocytosis and ATRA leukocyte activation syndrome in APL may be inherent to the secretion of specific hematopoietic growth factors by the APL cells.

Topics: Blotting, Northern; Blotting, Southern; Cell Differentiation; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-8; Leukemia, Promyelocytic, Acute; Leukocytosis; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Tretinoin; Tumor Cells, Cultured; Up-Regulation

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Combined Modality Therapy; Cytarabine; Daunorubicin; Dexamethasone; Disease Progression; Fatal Outcome; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Renal Dialysis; Respiration, Artificial; Respiratory Insufficiency; Syndrome; Tretinoin

Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Resistance; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Multiple Myeloma; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Tretinoin

Topics: Adult; Child, Preschool; Drug Tolerance; Dyspnea; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Pseudotumor Cerebri; Tretinoin

Topics: Child, Preschool; Cytarabine; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Papilledema; Remission Induction; Tretinoin

Topics: Aged; Dyspnea; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Pseudotumor Cerebri; Tretinoin

Induction of remission of acute promyelocytic leukaemia (APL) needs intensive blood support (16) to prevent bleeding attributed to disseminated intravascular coagulation. Between 1989 and 1991, at the University Hospital in Kuala Lumpur, Malaysia, the remission rate of APL was only 27% with conventional chemotherapy as a result of inadequate transfusion resources. The use of all trans retinoic acid in induction therapy followed by consolidation and maintenance chemotherapy has improved the situation dramatically. Twelve patients entered the study. Ten patients achieved remission (83%), indicating how ATRA had significantly improved the results (p = 0.003). Blood component transfusions were also significantly reduced (p = 0.003). Two ethnic Chinese patients developed pulmonary leucostasis. Published Chinese (2, 6) and Japanese (11) studies have not reported this serious adverse effect. We can now state that leucostasis is not a phenomenon limited to the Western population. ATRA has proved to be extremely beneficial for patients at this centre. Early analysis also suggests that consolidation and maintenance chemotherapy has prolonged remission duration. ATRA should be made available for the treatment of APL in all countries where there are inadequate transfusion services.

Topics: Adolescent; Adult; Blood Banks; Blood Transfusion; Female; Health Services Needs and Demand; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Remission Induction; Tretinoin

Acute promyelocytic leukaemia (APL) (FAB-M3) is associated with fatal haemorrhagic complications in 10 to 20% of patients. Recently ALL-Trans Retinoic acid (ALL-Trans RA) therapy has been used with rapid correction of the coagulopathy. Although minimal haematologic toxicity has been reported, a number of potentially serious side-effect have been described. We report a case of bone marrow necrosis occurring in a patient with APL treated with ALL-Trans RA. The possible relationship of this complication to retinoid therapy is discussed. This patient subsequently recovered and not only achieved complete remission but tolerated two cycles of chemotherapy without problems.

Topics: Bone Marrow; Female; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Middle Aged; Mitoxantrone; Necrosis; Pain; Prednisone; Remission Induction; Tretinoin

Topics: Adult; Dyspnea; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Syndrome; Tretinoin

Topics: Adult; Heparin; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Thrombophlebitis; Thrombosis; Tretinoin

Topics: Administration, Oral; Adult; Female; Humans; Hydroxyurea; Leukapheresis; Leukemia, Promyelocytic, Acute; Leukocytosis; Stereoisomerism; Syndrome; Tretinoin

Topics: Bone Marrow; Humans; Infarction; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Pancytopenia; Tretinoin

Topics: Adenocarcinoma; Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Leukocytosis; Liver Neoplasms; Lung Neoplasms; Middle Aged; Tretinoin

Topics: Adult; Antineoplastic Agents; Basophils; Bone Marrow; Cell Differentiation; Histamine; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Peptic Ulcer; Tretinoin

Topics: Antineoplastic Agents; Basophils; Cell Differentiation; Histamine; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Tretinoin

To describe a novel complication of therapy with all-trans retinoic acid in patients with acute promyelocytic leukemia.. Case series.. Comprehensive cancer center.. Consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia who underwent remission induction treatment with all-trans retinoic acid, 45 mg/m2 body surface area per day.. Nine of 35 patients (26%; 95% CI, 9% to 52%) with acute promyelocytic leukemia who were treated with all-trans retinoic acid developed a syndrome consisting primarily of fever and respiratory distress. Additional prominent signs and symptoms included weight gain, lower-extremity edema, pleural or pericardial effusions, and episodic hypotension. The onset of this symptom complex occurred from 2 to 21 days after starting treatment. Three deaths occurred; post-mortem examinations in two patients showed pulmonary interstitial infiltration with maturing myeloid cells. Six other patients survived, each achieving complete remission (five patients with all-trans retinoic acid only; 1 patient with chemotherapy). In six of the nine cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes to a level of at least 20 x 10(9) cells/L. Certain therapeutic interventions, including leukapheresis, temporary cessation of therapy with all-trans retinoic acid, and cytotoxic chemotherapy in moderate doses were not useful after respiratory distress was established. However, the administration of high-dose corticosteroid therapy (dexamethasone, 10 mg IV intravenously every 12 hours for 3 or more days) early in the course of the syndrome resulted in prompt symptomatic improvement and full recovery in three of four patients.. The use of all-trans retinoic acid to induce hematologic remission in patients with acute promyelocytic leukemia is associated in some patients with the development of a potentially lethal syndrome that is not uniformly accompanied by peripheral blood leukocytosis. Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome.

Topics: Adult; Aged; Autopsy; Dyspnea; Edema; Female; Fever; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Remission Induction; Syndrome; 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: Adult; Air Pollutants, Occupational; Anemia; Blood Cell Count; Blood Cells; Dark Adaptation; Diterpenes; Drug Industry; Female; Humans; Hypersensitivity, Delayed; Leukocytosis; Middle Aged; Retinyl Esters; Tretinoin; Vitamin A

The neutrophil function and plasma leukotactic activity of a patient with Sweet's syndrome and cystonodular acne were evaluated during a 2 1/2-year period. These studies demonstrated that chemotaxis was frequently slightly increased, especially during an exacerbation of Sweet's syndrome, but showed some decrease during isotretinoin therapy. Other functions, such as phagocytosis, metabolic activation, and bacterial killing, also were slightly increased. In addition, the patient's serum contained a heat-stable, nonlipid chemoattractant that was present at all times except during a course of isotretinoin. Although his symptoms responded to aspirin, the plasma continued to show this chemoattractant. These findings are consistent with the hypothesis that excess chemoattractant in Sweet's syndrome attracts neutrophils, which then mediate an inflammatory response. In addition, aspirin may be used to control Sweet's syndrome symptoms, although it does not suppress the plasma chemoattractant.

Topics: Adult; Aspirin; Chemotaxis, Leukocyte; Dialysis; Hot Temperature; Humans; Isotretinoin; Leukocytosis; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pentose Phosphate Pathway; Phagocytosis; Plasma; Skin Diseases; Syndrome; Tretinoin; Zymosan

Topics: Amides; Anemia; Animals; Blood Glucose; Diterpenes; Enzymes; Female; Fractures, Bone; Granulocytes; Leukocytosis; Liver; Male; Mice; Retinyl Esters; Serum Albumin; Tretinoin; Vitamin A