Sweet's syndrome associated with retinoic acid syndrome in a patient with promyelocytic leukemia

We report a case of Sweet's syndrome associated with retinoic acid syndrome in a patient with acute promyelocytic leukemia treated with all- trans retinoic acid (ATRA). Sweet's syndrome appeared on day 6 of ATRA therapy for promyelocytic leukemia. It was associated with a mild retinoic acid syndrome, an inflammatory syndrome occurring in 25% of patients treated with ATRA and characterized by features of capillary leakage with systemic inflammatory signs. The ATRA therapy was discontinued for 11 days and treatment with corticosteroids improved the systemic and cutaneous signs. Only 11 cases of Sweet's syndrome associated with ATRA have been previously reported in the literature, involving only the skin in eight cases, the skin and muscles in two cases, and the lung, kidney, fascia, and muscles in one case. Sweet's syndrome was followed by retinoic acid syndrome in one of these cases. The previously reported cases are reviewed, and the mechanisms of Sweet's and retinoic acid syndromes and the link between them are discussed.     

All-trans retinoic acid-induced erythema nodosum in acute promyelocytic leukemia

A 24-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid (ATRA) as a remission induction therapy. After pneumonia in the neutropenic period was successfully treated with antibiotic treatment, there was recurrence of high fever alone, followed by the appearance of erythema nodosum with pain in her upper limbs on day 25 of ATRA therapy. Skin biopsy neither revealed infiltration of leukemic cells nor suggested Sweet's syndrome. We considered the eruptions to be associated with ATRA, and prednisolone (30 mg/day for 5 days) was administered. Although the administration of ATRA was continued until complete remission of the leukemia, the erythema nodosum rapidly disappeared following short-term steroid therapy and no recurrence was observed. ATRA-induced erythema nodosum is rare, however it should be recognized as a possible adverse effect in ATRA therapy.     

Ellagic acid,a natural polyphenolic compound,induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells

All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK. EA activated the caspase-3 pathway and enhanced the expressions of myeloid differentiation markers (CD11b, MRP-14 protein, granulocytic morphology) induced by ATRA treatment. These results indicate that EA is a potent apoptosis inducer and also effectively potentiates ATRA-induced myeloid differentiation of HL-60 cells.     

Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia

Valproic acid (VPA) has been demonstrated to be able to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in inducing the differentiation of acute myeloid leukemia (AML) cells. A pilot study of the VPA/ATRA combination was performed in 11 elderly patients with de novo AML (median age, 82 years). Complete marrow response was observed in 3 patients, including 1 complete remission. Two additional patients had hematologic improvement.     

Acute myelogenous leukemia with a t(2;17;4)(p13;q21;p16) aberration: effective treatment with all-trans retinoic acid and granulocyte colony-stimulating factor

The efficacy of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL) has been well documented. However, ATRA is not as effective against other types of acute myelogenous leukemia (AML) or myelodysplastic syndromes. We present a patient with AML (FAB: M2) associated with a t(2;17;4)(p13;q21;p16) chromosomal defect in which the 17q21 breakpoint was not within the retinoic acid receptor alpha locus which is typically rearranged in APL. This patient was successfully treated with ATRA and granulocyte colony-stimulating factor and improvement of hematological parameters lasted for 19 months without the use of cytotoxic agents.     

All-trans retinoic acid in acute promyelocytic leukemia: Preliminary results in Cuba

Summary Seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Five (71.4%) achieved complete remission (CR). Most side effects were transient and well tolerated. Hyperleukocytosis was the major adverse effect. These observations confirm the efficacy of ATRA for inducing CR in APL.     

Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children

All-trans retinoic acid (ATRA) is a known inducer of differentiation in acute promyelocytic leukemia. To improve the outcome of children with acute promyelocytic leukemia, ATRA has been applied since 1994 as an additional induction element inthe AML-BFM 93 study. In a retrospective study, we compared 22 children treated with ATRA (median age: 9.3 years; range: 1.8-16.3) with 22 patients receiving conventional therapy (median age: 12.3 years; range: 3.2-16.7). Twenty-one of the children achieved complete remission. Only one patient died early from bleeding complications after 3 days administration of ATRA. In the control group, seven early deaths occurred (Fisher exact test; p<0.04). Two children died from intracerebral hemorrhages. Two patients suffered from sepsis during aplasia after induction therapy, and one child did not respond to treatment. The 5-year overall survival (OS) and event-free survival (EFS) of the children who received ATRA followed by chemotherapy were significantly bettercom-pared with conventionally treated children [OS: 0.87 +/- 0.9 vs 0.45 +/- 0.11, p (log rank) <0.003; EFS: 0.76 +/- 0.11 vs 0.43 +/- 0.11 p (log rank) <0.02]; the median observation time was 2.8 years (19-76 months). However, nearly all children suffered from common side effects such as headache, fever, joint, muscle and bone pain, weight gain, or dermatitis. In three patients, a retinoic acid syndrome was observed. Interruption of ATRA treatment and application of dexamethasone, necessary in 12 children, controlled theadverse effects. ATRA treatment could be resumed in 18 patients. In conclusion, ATRA treatment during induction could avoid early deaths in children with acute promyelocytic leukemia with considerable but manageable toxic side effects.     

All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells

The expressions of thrombomodulin (TM) and tissue factor (TF) by all- trans retinoic acid (ATRA) were studied in human leukemic cell lines including NB4 (acute promyelocytic leukemia) and U937 (monoblastic leukemia). ATRA remarkably upregulated TM antigen expression in cell lysates as well as TM cofactor activity on the cell surfaces of NB4. The level of TM mRNA in NB4 cells was increased by ATRA. Inherently procoagulant NB4 cells contained markedly higher content of TF, which was efficiently reduced by ATRA. Modest increase of TM and decrease of TF were observed when NB4 cells were treated with dibutyryl cyclic adenosine monophosphate (dbcAMP). On the other hand, both ATRA and dbcAMP showed dramatic increase of TM antigen level and modest decrease of TF antigen in U937 cells. These results suggest that ATRA regulates expressions of TM and TF antigens and activity in NB4 and U937 cell lines, and provide evidence for a potential efficiency of ATRA as a preventive and therapeutic agent for disseminated intravascular coagulation in promyelocytic and monocytic leukemia.     

The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia

Cyclin A1 is a newly discovered cyclin that is overexpressed in certain myeloid leukemias. Previously, the authors found that the frequency of cyclin A1 overexpression is especially high in acute promyelocytic leukemia (APL). In this study, the authors investigated the mechanism of cyclin A1 overexpression in APL cells and showed that the APL-associated aberrant fusion proteins (PML-retinoic acid receptor alpha [PML-RAR alpha] or PLZF-RAR alpha) caused the increased levels of cyclin A1 in these cells. The ectopic expression of either PML-RAR alpha or PLZF-RAR alpha in U937 cells, a non-APL myeloid cell line, led to a dramatic increase of cyclin A1 messenger RNA and protein. This elevation of cyclin A1 was reversed by treatment with all-trans retinoic acid (ATRA) in cells expressing PML-RAR alpha but not PLZF-RAR alpha. ATRA also greatly reduced the high levels of cyclin A1 in the APL cell lines NB4 and UF-1. No effect of ATRA on cyclin A1 levels was found in the ATRA-resistant NB4-R2 cells. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RAR alpha. Reporter assays showed that PML-RAR alpha led to activation of the cyclin A1 promoter. Addition of ATRA inhibited PML-RAR alpha-induced cyclin A1 promoter activity. Taken together, our data suggest that PML-RAR alpha and PLZF-RAR alpha cause the high-level expression of cyclin A1 seen in acute promyelocytic leukemia. (Blood. 2000;96:3894-3899)     

Development of Sweet's syndrome during all-trans retinoic acid therapy for acute promyelocytic leukemia

A 54-year-old woman visited our hospital because of gingival bleeding on May 31, 1998. After hematological and bone marrow examinations, she was diagnosed as having acute promyelocytic leukemia (APL) and given all-trans retinoic acid (ATRA) therapy starting on June 1. Anti-cancer drugs were administered for 5 days from June 12 because of an increase in the number of APL cells. The patient developed fever on June 20, and nodular erythematous eruptions appeared on June 23. Sweet's syndrome was diagnosed from biopsy samples of the eruption. ATRA was therefore discontinued, and prednisolone was started on June 29. The fever and skin eruptions improved rapidly, and complete remission was obtained on July 13. Sweet's syndrome due to ATRA may be a partial form of retinoic acid syndrome, in which the differentiated leukemic neutrophils increase and invade various organs. However, Sweet's syndrome must be considered regardless of the WBC count because in this case the syndrome occurred even when the WBC count was not high.     

Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein

In most cases of acute promyelocytic leukemia (APL), a fusion of the promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha) genes occurs, resulting in the expression of a PML-RARalpha chimeric protein. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found fusing RARa with other genes. Four variant mutations have been described, and the t(11;17)(q21;q23) translocation generating a promyelocyte leukemia zinc finger (PLZF)-RARalpha fusion gene is the most common. PLZF-RARalpha-positive APL forms a clinically distinct group because unlike PML-RARalpha-positive leukemia, it does not respond to retinoic acid with terminal granulocytic differentiation of the cells, and remissions cannot be achieved with retinoids alone. At the molecular level, this has been explained by the retinoic acid-insensitive binding of corepressor proteins to the PLZF part of the fusion protein, leading to sustained repression of target genes that are important for cellular differentiation. Targeting of the PLZF-RARalpha-bound corepressor complexes using a combination of all-trans retinoic acid (ATRA) and deacetylase inhibitors has shown that the repression of target genes can be relieved, allowing differentiation of the cells. In addition, when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) is applied, the cells may be forced to undergo terminal differentiation, both in vitro and in vivo. This suggests that signals from the activated G-CSF receptor may induce the release of corepressor proteins from PLZF. Together, these findings indicate that PLZF-RARalpha-positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given.     

蟾蜍灵增强全反式维甲酸对急性早幼粒细胞白血病原代培养细胞的诱导分化

目的 研究蟾蜍灵与全反式维甲酸（ATRA）联合对急性早幼粒细胞白血病（APL）原代培养细胞的诱导分化作用。方法12例初诊的APL患者的骨髓经单个核细胞分离后进行原代培养。细胞存活率测定采用锥虫蓝拒染法,细胞凋亡及诱导分化采用形态学分析、四唑氮蓝（NBT）还原试验及细胞分化抗原CD11b的流式细胞仪分解。结果蟾蜍灵5nmol／L与ATRA30nmol／L联合应用明显诱导APL原代培养细胞向成熟粒细胞分化、联合应用较单独应用ATRA时NBT还原率增加了15％-52％及CD11b表达增加了16％～69％,同时分化时间从7d缩短至4d,而且ATRA用量可减少至单用时的30％。结论蟾蜍灵与ATRA联合应用可显著增强ATRA对APL原代培养细胞的诱导分化作用。     

Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways

Use of all-trans-retinoic acid (ATRA) in combinatorial differentiation therapy of acute promyelocytic leukemia (APL) results in exceptional cure rates. However, potent cell differentiation effects of ATRA are so far largely restricted to this disease and long-term survival rates in non-APL acute myelogeneous leukemia (AML) remain unacceptably poor, requiring development of novel therapeutic strategies. We demonstrate here that myelomonocytic growth factors (granulocyte colony-stimulating factor [G-CSF] and/or granulocyte macrophage colony-stimulating factor [GM-CSF]) potentiate differentiation effects of ATRA in different AML cell lines and primary cells from patients with myeloid leukemia. The ligand-dependent activities of endogenous and transiently expressed retinoic acid receptor alpha (RARalpha) isoforms can be potentiated by G/GM-CSF in U-937 cells and correlate with increased expression of ATRA-inducible RARalpha2 isoform. Specific inhibitors of mitogen mitogen-activated protein kinase (MAPK) (MEK)-1/-2 or p38 extracellular signal-related kinase (ERK) kinase diminish the ATRA as well as ATRA and G/GM-CSF-induced activation of the RARalpha proteins and decreased the differentiation-induced decline in cell numbers. Our data demonstrate that acting, at least in part, via the MAP kinase pathways, myelomonocytic growth factors enhance ATRA-dependent activation of the RARalpha isoforms and maturation of myeloid leukemia cells. These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML.     

Retinoic acid in the treatment of acute promyelocytic leukemia: Inefficacy of the 13-cis isomer and induction of complete remission by the all-trans isomer complicated by thromboembolic events

Summary The clinical course of three patients with acute promyelocytic leukemia receiving all-trans retinoic acid (ATRA) as a single agent is reported. The first two patients were in first and second relapse of their leukemia that had occurred despite maintenance treatment with 13-cis retinoic acid after chemotherapy-induced complete remission (CR). A switch to ATRA was followed by achievement of a CR in two patients. The third patient received ATRA as first-line therapy. Two patients experienced thromboembolic complications during the phase of ATRA-induced leukocytosis. One of them died of pulmonary embolism on day 16 of treatment. The two responding patients who did not receive consolidation chemotherapy relapsed after 6 and 9 months, respectively. Increase of the ATRA dose failed to induce a new remission.     

CNS relapse in a low risk acute promyelocytic leukemia patient treated with ATRA-based regimen: is there a role for prophylactic CNS therapy in acute promyelocytic leukemia?

Though the incidence of CNS relapse in acute promyelocytic leukemia (AML-M3 FAB classification) has increased following the advent of all-trans retinoic acid (ATRA), still CNS relapse accounts for only 2–3% of all relapses in AML-M3 trated with standard ATRA plus chemotherapy regimen. We report a case of low risk AML-M3 treated with standard therapy, developing CNS relapse while on maintenance therapy with ATRA + 6-mercaptopurine (6-MP) + methotrexate (MTX).     

Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia

It has been shown that all-trans retinoic acid (ATRA) at doses of 45 to 100 mg/m2/d induces complete remission (CR) of acute promyelocytic leukemia (APL) by a differentiation process. To date, ATRA dose-ranging studies have not yet been evaluated. Thus, we initiated in May 1990 a multicenter study with ATRA at a lower dose of 25 mg/m2/d until CR. Thirty patients with APL were treated with ATRA, of whom 12 were previously untreated, 14 were in first relapse, and 4 had failed after conventional first induction chemotherapy. Twenty-four of 30 achieved CR, 3 failed, and 3 died before day 30. Median time to CR was 45 days. Hyperleucocytosis (14 to 43 x 10(9) white blood cells per liter) was observed in 9 patients between days 10 and 23. Clinical complications that may have been related to the retinoic acid syndrome were observed in 8 patients, of whom 3 died. Pharmacokinetics studies were performed in 5 patients. Peak plasma concentrations and mean area under the concentration-time curve were not lower than previous levels obtained under the 45 mg/m2 dose. Overall, our study shows that there is no difference in terms of therapeutic efficacy, triggering of hyperleukocytosis, or retinoic acid syndrome and pharmacokinetic results with ATRA at 25 or 45 mg/m2/d.     

A third complete remission of acute promyelocytic leukemia achieved by administering a gradual increase of all-trans retinoic acid following massive ascites due to retinoic acid syndrome

A 69-year-old man was diagnosed as having acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin plus cytarabine. He achieved cytogenetic complete remission (CCR). Relapse occurred 1 year after CCR. Treatment with Am80 gave him a second CCR. However, a second relapse occurred. Re-induction therapy with ATRA was started at 70 mg per day. On day 14, abdominal fullness rapidly increased and massive ascites appeared as a symptom of retinoic acid syndrome (RAS). We ceased the ATRA treatment and started administration of methylprednisolone. The ascites decreased, but an increase of ascites was recognized again temporarily after having re-started ATRA treatment. Thus we gradually increased ATRA administration from 40 mg/day to 70 mg/day of ATRA. RAS did not occur and the patient achieved a third CCR. This case indicates that a gradual increase in ATRA administration is beneficial for RAS occurring in APL patients.     

Acute promyelocytic leukemia: from highly fatal to highly curable

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia. Morphologically, it is identified as the M3 subtype of acute myeloid leukemia by the French-American-British classification and cytogenetically is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARalpha). It seems that the disease is the most malignant form of acute leukemia with a severe bleeding tendency and a fatal course of only weeks. Chemotherapy (CT; daunorubicin, idarubicin and cytosine arabinoside) was the front-line treatment of APL with a complete remission (CR) rate of 75% to 80% in newly diagnosed patients. Despite all these progresses, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT. Since the introduction of all-trans retinoic acid (ATRA) in the treatment and optimization of the ATRA-based regimens, the CR rate was raised up to 90% to 95% and 5-year disease free survival (DFS) to 74%. The use of arsenic trioxide (ATO) since early 1990s further improved the clinical outcome of refractory or relapsed as well as newly diagnosed APL. In this article, we review the history of introduction of ATRA and ATO into clinical use and the mechanistic studies in understanding this model of cancer targeted therapy.