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.     

全反式维甲酸治疗急性早幼粒细胞性白血病致Sweet综合征--病例报告及文献复习

目的:提高对全反式维甲酸(ATRA)治疗急性早幼粒细胞性白血病(APL)少见副作用的认识。方法:报告1例ATRA治疗APL致Sweet综合征的病例及治疗过程,并对相关文献进行复习总结。结果:ATRA治疗APL可以导致Sweet's综合征,采用糖皮质激素治疗有效。结论:Sweet综合征是维甲酸的少见副作用,临床上应提高对该综合征的早期诊断。     

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.     

A case of all-trans retinoic acid-induced myositis in the treatment of acute promyelocytic leukaemia

The use of all-trans retinoic acid (ATRA) is now standard therapy for the treatment of acute promyelocytic leukaemia (APML). There have been increasing reports of ATRA-induced myositis, with its frequent association with retinoic acid syndrome and Sweet's syndrome. We report a case of a young man with APML who developed ATRA-induced myositis characterized by unexplained fevers, bilateral leg swelling and a non-painful purpuric, petechial rash, with prompt resolution of symptoms and signs with high-dose steroids and cessation of ATRA. Rapid recognition of this adverse reaction and prompt institution of steroids is of prime importance given its potentially fatal course.     

Scrotal Ulcers Arising during Treatment with All-trans Retinoic Acid for Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) is effective in approximately 90% of the cases of acute promyelocytic leukemia (APL) with a low incidence of adverse effects. We report a patient with APL who developed skin ulcers of the scrotum concomitant with high fever during treatment that included ATRA. Severe fever was promptly alleviated with discontinuation of ATRA, while the ulcers improved gradually over 3 months. As the clinical features are similar to those of Sweet's syndrome, we should be aware of the possibility that this rare adverse effect may occur in the treatment with ATRA.     

Sweet's syndrome followed by retinoic acid syndrome during the treatment of acute promyelocytic leukemia with all-trans retinoic acid.

We present here the case of a 49-year-old female with acute promyelocytic leukemia (APL) who, after first developing all-trans retinoic acid (ATRA)-related Sweet's syndrome, was later diagnosed as having retinoic acid (RA) syndrome. Preceding the RA syndrome diagnosis, she developed a fever as well as erythematous nodules on her upper arms. These symptoms were observed on day 18 of treatment with ATRA. Ten days later, she began to develop respiratory distress. There was no indication of infection, and her condition did not improve with empiric therapy. At this time, the diagnosis of RA syndrome was made, resulting in the initiation of steroid pulse therapy, and within 24 hours her elevated fever and respiratory distress improved markedly. In addition, the erythematous nodules gradually began disappearing. A skin biopsy revealed a dense dermal infiltrate consisting of neutrophils.     

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.     

Bilateral Osteonecrosis of the Head of the Femur during Treatment with Retinoic Acid in a Young Patient with Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) is the drug of choice for the treatment of acute promyelocytic leukemia (APL). In general, ATRA is well tolerated, but it does have side effects, the most severe of which is ATRA syndrome. We report the case of a young patient with APL treated with ATRA for induction and maintenance therapy who then developed avascular necrosis of both femoral heads. We also review cases of APL patients with osteonecrosis of the femoral head after ATRA therapy.     

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.     

Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA

All-trans-Retinoic acid (ATRA) has been shown to improve survival in patients with acute promyelocytic leukemia (APML). It is a well-tolerated drug except for the serious side effect of ATRA syndrome. Dryness of the skin, cheilitis, and xerostomia are the common mucocutaneous side effects. Occurrence of scrotal ulceration is very rare. We report a 13-year-old boy who had scrotal ulceration caused by ATRA during the induction therapy of APML.     

Acute promyelocytic leukemia: evolving therapeutic strategies.

Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.     

Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)     

All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.     

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.     

The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL), once highly fatal, has emerged as the most curable subtype of acute myeloid leukemia in adults. Cure is now expected in approximately 70 to 90% of patients when treatment includes all- TRANS retinoic acid (ATRA) combined with anthracycline-based chemotherapy. Early mortality most often is due to a severe and often catastrophic bleeding, often intracerebral in location, and remains a major cause of treatment failure. Thrombosis, either at diagnosis or during the course of treatment, may be unrecognized and reflects the complexity of the coagulopathy. The dual phenomenon of bleeding and thrombosis is attributable to at least three processes: disseminated intravascular coagulation; fibrinolysis (generated in part by expression of annexin-II on the APL cell surface); and direct proteolysis of several proteins including fibrinogen and von Willebrand factor. Both ATRA and arsenic trioxide are associated with rapid resolution of the coagulopathy. The use of heparin, once a mainstay of therapy for patients with APL, has been all but abandoned. Preliminary studies suggest no role for the routine use of antifibrinolytic agents. The most important therapeutic strategy is early institution of ATRA at the first suspicion of the diagnosis (without waiting for genetic confirmation) and aggressive blood product support during induction.     

all-trans-Retinoic acid-induced expression and regulation of retinoic acid 4-hydroxylase (CYP26) in human promyelocytic leukemia

all-trans-Retinoic acid (ATRA) induces complete remission in majority of patients with acute promyelocytic leukemia (APL). However, accelerated metabolism of ATRA that is induced by chronic daily administration of oral ATRA has been implicated as one of the mechanisms leading to a reduced sensitivity or resistance to ATRA therapy. We investigated the expression and regulation of CYP26, a novel p450 enzyme, which is highly specific for ATRA, in promyelocytic leukemia cells (NB4 and HL-60). We found that treatment of NB4 cells with a pharmacological concentration of ATRA (1 microM) induced rapid and dose-dependent expression of CYP26 mRNA. The CYP26 expression returned to pretreatment levels in both cells after ATRA was removed from the media. Retinoic acid receptor-alpha (RARalpha) specific antagonist (CD2503) totally abolished the ATRA-induced expression of CYP26 mRNA in HL-60 and NB4 cells. Furthermore, HL-60R, a HL-60 subclone expressing nonfunctional RAR because of a point mutation in the ligand-binding domain of RARalpha, failed to show CYP26 mRNA expression in response to ATRA. ATRA-induced expression of CYP26 was restored in HL-60R cells retrovirally transduced with RARalpha, but not in those cells transduced with the other retinoid receptors. In conclusion, ATRA induces expression of CYP26 in myeloid and promyelocytic leukemia cells and this expression is modulated by RARalpha. The induction of CYP26 expression by ATRA treatment might be related to a substrate-driven feedback mechanism to regulate intracellular concentrations of ATRA and its over expression in some clones may be partly responsible for reduced sensitivity or resistance to ATRA therapy.     

Retinoids--"differentiation agents" for cancer treatment and prevention.

The ability of vitamin A and its derivatives to induce differentiation in certain target tissues has been appreciated for nearly a century. Recently, oral all-trans retinoic acid (ATRA), a vitamin A metabolite, has been shown to induce terminal differentiation of leukemic cells in patients with acute promyelocytic leukemia (APL). Complete remissions are obtained and normal hematopoiesis is established in an outpatient setting with minimal side effects in the majority of cases. Although remissions are not durable, disseminated intravascular coagulation, a frequent complication of remission induction in APL, is avoided by oral ATRA prior to definitive chemotherapy. The molecular basis for the efficacy of ATRA in APL appears to be the involvement of the retinoic acid receptor alpha locus in the t(15;17) translocation breakpoint characteristic of APL.     

All trans-retinoic acid decreases early mortality in patients with promyelocytic leukemia and can be given entirely on an outpatient basis.

The results of the treatment of 43 patients with acute promyelocytic leukemia (PML) are reported: 27 were treated initially with all-trans-retinoic acid (ATRA), whereas 16 were treated with conventional chemotherapy. All patients received myelosuppressive chemotherapy after the initial treatment. Respectively, the complete remission rate was 92% and 37% (P < 0.01), the 5-day mortality rate was 0% and 44% (P < 0.001), and the 28-day mortality rate was 4% and 44% (P < 0.001). The median disease-free survival was 12 and 1 months (P < 0.01), whereas the 12-month disease-free survival was 50% and 13% (P < 0.01) and the 36-month disease-free survival was 41% and 9% (P < 0.01). Thirteen of the patients treated with ATRA were given the treatment fully as outpatients. ATRA given as initial therapy decreased significantly early mortality in promyelocytic leukemia patients; because some promyelocytic leukemia patients given ATRA as initial therapy can be treated as outpatients, the costs of this treatment modality may be diminished.     

A case of all‐trans retinoic acid‐induced myositis in the treatment of acute promyelocytic leukaemia

The use of all‐trans retinoic acid (ATRA) is now standard therapy for the treatment of acute promyelocytic leukaemia (APML). There have been increasing reports of ATRA‐induced myositis, with its frequent association with retinoic acid syndrome and Sweet's syndrome. We report a case of a young man with APML who developed ATRA‐induced myositis characterized by unexplained fevers, bilateral leg swelling and a non‐painful purpuric, petechial rash, with prompt resolution of symptoms and signs with high‐dose steroids and cessation of ATRA. Rapid recognition of this adverse reaction and prompt institution of steroids is of prime importance given its potentially fatal course.     

Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid

All-trans-retinoic acid (ATRA) induces complete remission (CR) in up to 90% of acute promyelocytic leukemia (APL) patients with rapid amelioration of the bleeding syndrome. Previous studies indicate that ATRA treatment in vitro of the APL NB4 cell line can affect their procoagulant activity (PCA). To assess whether ATRA has this effect also in vivo, we prospectively studied the PCA of bone marrow blasts from APL patients on therapy with ATRA alone or associated with chemotherapy. Samples were obtained before, during, and after ATRA. To characterize the coagulopathy, we measured a series of plasma hemostatic variables before and during the first two weeks of therapy, as follows: (1) markers of hypercoagulability; (2) natural anticoagulants; (3) fibrinolysis proteins; and (4) elastase. The results by enzymatic and immunologic methods show that both total (tissue factor-like) and factor VII-independent (cancer procoagulant- like) blast cell PCAs, present before therapy, were reduced during (69% and 65% decrement, respectively) and virtually undetectable after ATRA. The plasma hemostatic assessment of patients before treatment was elevated hypercoagulability markers, low mean protein C, normal fibrinolysis proteins, and increased elastase. After starting ATRA, hypercoagulability markers were reduced within 4 to 8 days, protein C augmented, the overall fibrinolytic balance was unmodified, and elastase remained elevated. These results were not different either with or without chemotherapy and are consistent with the clinical findings of rapid improvement of the coagulopathy.