Causes and prognostic factors for early death in patients with acute promyelocytic leukemia treated with single-agent arsenic trioxide

Early death (ED) is one of the most critical issues involved in the current care of patients with acute promyelocytic leukemia (APL). Factors identified as independent predictors of ED varied among published studies. We retrospectively analyzed the incidence, causes, and prognostic factors of ED in a series of 216 patients with newly diagnosed APL who received arsenic trioxide (ATO) as induction therapy. Multivariate logistic regression analysis was used to determine the association of clinical factors with overall ED, hemorrhagic ED, death within 7 days, and death within 8–30 days. In total, 35 EDs (16.2%) occurred that were caused by hemorrhage, differentiation syndrome (DS), infection, and other causes, in order of prevalence. The independent prognostic factors for overall ED and death within 8–30 days were the same and included serum creatinine level, Eastern Cooperative Oncology Group (ECOG) score, sex, and fibrinogen level. The risk factors for hemorrhagic ED and death within 7 days were similar and included serum creatinine level, ECOG score, and white blood cell count, while hemorrhagic ED was also associated with D-dimer. Our findings revealed a high rate of ED, and the causes of ED were similar to those among patients who received ATRA-based therapy. Increased creatinine level was the most powerful predictor, and an ECOG score greater than 2 was another strong prognostic factor for all four types of ED.     

Successful treatment of a case of relapsed acute promyelocytic leukemia with arsenic trioxide.

We report a patient with an initial relapse of acute promyelocytic leukemia (APL) who achieved a second complete remission (CR) after treatment with arsenic trioxide. The patient, a 66-year-old woman diagnosed as having relapsed APL, received arsenic trioxide intravenously at a dose of 10 mg/day. At day 36, the patient achieved a second CR. The side effects were slight neuralgia and mild skin erythematous changes, which improved following cessation of the drug. Although arsenic trioxide may be effective for relapsed APL, it should be used with caution because of various complications.     

Oral administration of arsenic trioxide induced molecular remission in relapsed acute promyelocytic leukemia

I report on a 21-year-old man with acute promyelocytic leukemia (APL) which relapsed after a therapeutic regimen consisting of tretinoin, daunorubicin, enocitabine, mitoxantrone, and cytarabine. The patient also had severe mental retardation caused by a congenital central nervous system malformation. Administration of arsenic trioxide (As2O3) is indicated for patients with APL, however, daily intravenous infusion of As2O3 presented problems because of the patient's violent resistance to venous access. Accordingly, 10mg of an oral solution of As2O3 was given once daily for 70 days. No adverse events were observed with the exception of transient hyperleukocytosis and fever. The patient achieved molecular remission 103 days after the start of oral As2O3, and remains in remission after an additional 2 courses of oral As2O3 as consolidation chemotherapy. Oral As2O3 may be useful in the treatment of relapsed APL as an alternative to intravenous As2O3.     

Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy

The extent of and factors controlling arsenic penetration into the central nervous system (CNS) remain unclear. Elemental arsenic levels in 67 paired cerebrospinal fluid (CSF) and plasma samples from 9 patients with acute promyelocytic leukemia (APL) on oral arsenic trioxide (As2O3), obtained during intrathecal chemotherapy (treatment of CNS APL, n = 6; prophylaxis, n = 3) were measured. Median arsenic levels of CSF and plasma were 95.8 nmol/L (range, 3.5-318.9 nmol/L) and 498.9 nmol/L (range, 36.3-1892.8 nmol/L). As a group, CSF and plasma arsenic was linearly correlated (P < .001), with CSF at 17.7% the plasma level. The CSF/plasma arsenic ratio, which reflected the arsenic CSF penetration efficiency, varied significantly in individual patients (P < .001). Repeated intrathecal chemotherapy and presence of blasts in CSF did not affect the CSF/plasma arsenic ratio. Plasma arsenic was the only significant determinant of CSF arsenic levels. CSF arsenic was present at therapeutically meaningful levels, implying that As2O3 therapy might be beneficial in CNS APL.     

Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia

Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses.     

Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide.

Arsenic trioxide has been shown to be effective in treating acute promyelocytic leukemia (APL), with minimal overall toxicity reported to date. A phase I/II study was initiated in June 1998 using arsenic trioxide for relapsed APL to determine the maximum tolerated or minimal effective dose and to determine the efficacy of treatment at that dose. Ten patients received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day intravenous arsenic trioxide. Six of 7 patients evaluable for response achieved cytogenetic or molecular complete remission. However, 3 patients died suddenly during the first cycle of treatment. Autopsies obtained on 2 of these failed to identify a cause of sudden death, despite evidence of pulmonary hemorrhage in one. A third patient, for whom an autopsy was not performed, became asystolic and died while on continuous cardiac telemetry. These observations suggest that arsenic trioxide may be significantly or even fatally toxic at doses currently used and that caution is warranted in its use.     

Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation

BACKGROUND AND OBJECTIVES: Arsenic trioxide (ATO) has been reported to be a safe and effective treatment for relapsed acute promyelocytic leukemia (APL). The aim of this study was to evaluate the efficacy and toxicity as well as the eligibility to stem cell transplantation (SCT) in a series of 7 patients with relapsing APL, managed with ATO. DESIGN AND METHODS: Seven patients with relapsing APL while on maintenance treatment with all-trans-retinoic acid (ATRA) or who were ATRA refractory-received ATO at a dose of 10 mg daily by 2-hour intravenous infusion until complete remission (CR). After consolidation chemotherapy, patients were programmed to receive autologous or allogeneic stem cell transplantation (SCT) according to donor availability. The median age of the patients was 55 (21-71) years: 2 patients presented with concomitant extramedullary relapse. RESULTS: Six patients (86%) achieved CR after a median of 35 ATO doses (20-49) with negligible toxicity; one patient died from pneumonia. After consolidation with a four-day course of cytarabine at 1 g/m2 and mitoxantrone 6 mg/m2, two patients underwent allogeneic SCT, two received PML/RARa negative autologous peripheral blood stem cells collected after consolidation plus granulocyte colony-stimulating factor, one failed mobilization and received a second consolidation course. One elderly patient refused further treatment and relapsed 6 months later. After a median follow-up of 15 months from CR2 achievement, 5 patients are alive in continuous CR. INTERPRETATION AND CONCLUSIONS: The high CR rate and the mild toxicity confirm that ATO represents a valid alternative to salvage chemotherapy for patients relapsing while on ATRA treatment or who are ATRA-refractory. Allogeneic or autologous SCT after ATO-induced CR is feasible in the majority of patients.     

Successful treatment of relapsed and refractory acute promyelocytic leukemia with arsenic trioxide (As2O3)

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.     

Successful cyclosporine treatment for thrombocytopenia after salvage therapy with arsenic trioxide therapy followed by autologous hematopoietic stem cell transplantation in acute promyelocytic leukemia

A 55-year-old man with acute promyelocytic leukemia in the first relapse was treated with arsenic trioxide as salvage therapy. After obtaining molecular remission, he underwent autologous peripheral blood stem cell transplantation (PBSCT) with busulfan and melphalan conditioning. The transplant dose of CD 34-positive cells was sufficient, and engraftment was prompt. Platelet count increased to 320 x 10(9)/1 on day 21; however, it rapidly decreased to 27 x 10(9)/l on day 37. Despite treatment with corticosteroid, the platelet count decreased to 6 x 10(9)/l on day 55. About one month after cyclosporine administration, thrombocytopenia gradually improved. This clinical course suggests immune-mediated thrombocytopenia following autologous PBSCT.     

Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic leukemia previously treated with ATRA and chemotherapy

Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21–128 months), the 4-year OS probability was 0.85 (95% CI 0.61–0.94), DFS was 0.74 (95% CI 0.49–0.88), and EFS 0.68 (95% CI 0.45–0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.     

Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.