Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

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Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211024727 ◽

2021 ◽

pp. 107815522110247

Author(s):

Kyle Zacholski ◽

Bryan Hambley ◽

Erin Hickey ◽

Sarah Kashanian ◽

Andrew Li ◽

...

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Survival Rates ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Free Survival ◽

All Trans Retinoic Acid ◽

Grade 3 ◽

Disease Free

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

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Studies on Treatment of Acute Promyelocytic Leukemia With Arsenic Trioxide: Remission Induction, Follow-Up, and Molecular Monitoring in 11 Newly Diagnosed and 47 Relapsed Acute Promyelocytic Leukemia Patients

Blood ◽

10.1182/blood.v94.10.3315.422k16_3315_3324 ◽

1999 ◽

Vol 94 (10) ◽

pp. 3315-3324 ◽

Cited By ~ 428

Author(s):

Chao Niu ◽

Hua Yan ◽

Ting Yu ◽

Hui-Ping Sun ◽

Jian-Xiang Liu ◽

...

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Pcr Analysis ◽

Remission Induction ◽

Newly Diagnosed ◽

First Choice ◽

Wbc Count

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

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Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Updated Results of the Spanish PETHEMA LPA99 Trial Using ATRA and Anthracycline Monochemotherapy.

Blood ◽

10.1182/blood.v110.11.590.590 ◽

2007 ◽

Vol 110 (11) ◽

pp. 590-590 ◽

Cited By ~ 1

Author(s):

Miguel A. Sanz ◽

Pau Montesinos ◽

Edo Vellenga ◽

Chelo Rayon ◽

Ricardo Parody ◽

...

Keyword(s):

High Risk ◽

Acute Promyelocytic Leukemia ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

Number Of Patients ◽

Risk Patients ◽

Low Toxicity ◽

High Degree

Abstract Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up. Methods: From November 1999 to July 2005, 564 patients (median age 40 years, range 2–83) with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months. Results: CR was achieved in 511 patients (91%). Except for three cases labelled as resistant, of the remaining 50 patients 56%, 24%, 16% and 4% died due to hemorrhage, infection, retinoic acid syndrome, and acute myocardial infarction, respectively. Multivariate analysis showed that WBC >10×109/l, age >60 years, male gender, and serum creatinine >1.4 mg/dl at presentation had independent predictive value of death during induction. The median follow-up of the cohort was 57 months (range 20–94 months). Thirteen patients (median age 72 years, range 4–81) died in remission and 99% of patients completed the entire assigned therapy. Thirty-six patients presented haematological relapse, 16 molecular relapse, and 8 secondary myelodysplastic syndrome or acute myeloid leukemia. Overall, the 5-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 11%, 85%, and 84%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 7% and 28%, respectively. Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL.

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Incidence of Secondary Neoplasms In Patients with Acute Promyelocytic Leukemia Treated with All-Trans-Retinoic Acid (ATRA) with Chemotherapy or with Arsenic Trioxide (ATO).

Blood ◽

10.1182/blood.v116.21.1085.1085 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1085-1085

Author(s):

Alireza Eghtedar ◽

Stefan Faderl ◽

Hagop Kantarjian ◽

Susan O'Brien ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Secondary Neoplasms ◽

Secondary Cancers ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Abstract 1085 Background: Progress in the treatment of patients (pts) with acute promyelocytic leukemia (APL) with the use of modern all-trans retinoic acid (ATRA)-containing regimens has resulted in the majority of pts achieving long-term disease-free survival. There is little data on the incidence and patterns of secondary neoplasms in pts treated with these regimens. Objective: To compare the incidence of secondary neoplasms in pts with APL treated with two different ATRA-containing regimens. Methods: We retrospectively examined the charts of 160 pts with APL treated with ATRA plus chemotherapy (n=54) or ATRA plus arsenic trioxide (ATO)(n=106) as their initial induction regimen at the University of Texas – M. D. Anderson Cancer Center from 1991 to 2009. Twenty seven (17%) pts had a remote history of a prior unrelated cancer. Pt characteristics and the incidence of secondary cancers per unit time of follow-up were compared. Results: The median age at diagnosis of the entire population was 44 years (range, 13 – 81) and the median age for the chemotherapy plus ATRA group was 38 years (range, 13–67) vs. 46 years (range, 14 – 81) for the pts treated with ATO plus ATRA (p= 0.001). Thirty (55%) and 54 (50.9%) in each cohort were women (p=0.52) and 2 (3.7%) and 26 (24.5%) were older than 60 years of age, respectively (p= 0.001). Twenty (37%) and 30 (28.3%) had high risk disease (WBC > 10 × 109/l)(p= 0.3), and 34 (62.9%) and 76 (71.6%) had low risk disease (WBC ≤ 10 × 109/l), respectively. Fifty one (94.4%) and 105 (99%) pts treated using the two regimens achieved a CR. The median follow-up time for the two cohorts was 136 and 29 months [ranges, (5 to 193) and (1 to 93), respectively]. Nine and 2 pts in the two groups developed secondary cancers including 2 breast cancers, 3 MDS/AML, 1 vulvar cancer, 1 prostate cancer, 1 colon cancer and 1 soft tissue sarcoma in the chemotherapy group vs. 1 melanoma and 1 pancreatic cancer in ATO group. The cumulative incidence of secondary cancers in the two cohorts is shown in figure 1. Conclusion: Treatment of pts with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time exposure. Disclosures: Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Ravandi:Cephalon: Honoraria, Research Funding, Speakers Bureau.

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Phase II Study of Single-Agent Arsenic Trioxide for the Front-Line Therapy of Acute Promyelocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.2107 ◽

2011 ◽

Vol 29 (20) ◽

pp. 2753-2757 ◽

Cited By ~ 137

Author(s):

Ardeshir Ghavamzadeh ◽

Kamran Alimoghaddam ◽

Shahrbano Rostami ◽

Seyed Hamidolah Ghaffari ◽

Mohamad Jahani ◽

...

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Residual Disease ◽

Single Agent ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Newly Diagnosed ◽

Long Term Follow Up

Purpose The long-term follow-up results of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy show high cure rates. Several studies have shown high efficacy of single-agent arsenic trioxide in newly diagnosed APL. However, long-term follow-up results are needed. Patients and Methods One hundred ninety-seven patients with newly diagnosed APL were treated with arsenic trioxide 0.15 mg/kg daily intravenous infusion until complete remission (CR). After achieving CR, the patients received one to four more courses of therapy with arsenic trioxide as consolidation and were observed with reverse-transcriptase polymerase chain reaction studies from peripheral blood (to detect of minimal residual disease) every 3 months or until relapse or death. Results The morphologic CR rate was 85.8%. The most common cause of remission failure was early death owing to APL differentiation syndrome (13.2%). The most important prognostic factor for early mortality was a high WBC count at presentation. The 5-year disease-free survival (DFS) rate was 66.7% ± 4% (SE). Relapse after 5 years in CR was rare. The 5-year overall survival (OS) rate by intention-to-treat analysis was 64.4% ± 4%. In patients who achieved CR, OS and DFS were identical. Conclusion The long-term follow-up of newly diagnosed patients with APL treated with single-agent arsenic trioxide shows high rates of DFS and OS.

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Oral Arsenic Trioxide in Front Line Therapy for Acute Promyelocytic Leukemia. A Prospective Costa Rican Study

Blood ◽

10.1182/blood-2019-122627 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3838-3838 ◽

Cited By ~ 1

Author(s):

Mariela Rodriguez ◽

Ronald Rojas ◽

Alejandra Vargas ◽

Miguel Angel Rodriguez ◽

Claudia Garcia ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Oral Formulation ◽

Promyelocytic Leukemia ◽

Front Line ◽

Line Therapy ◽

Grade 3

KEY WORDS: Acute Promyelocytic Leukemia, oral Arsenic Trioxide, ATRA, Front Line Therapy. CONTEXT: Studies showed the combination of all-trans-retinoic acid (ATRA) with Arsenic trioxide (ATO) as an effective treatment of patients with newly diagnosed Acute Promyelocytic Leukemia (APL), permitting a chemotherapy-free treatment approach. Oral formulations of ATO were developed with similar efficacy compared to the IV formulation, and a slightly safer profile. OBJECTIVE:To determine the effectiveness and safety of a locally produced oral ATO with ATRA as a first line therapy in APL. DESIGN:We designed the LPCR05 protocol based on established treatment protocols. Treatment regimen: Induction phase: all patients received ATRA (45 mg/m2 daily) and an locally produced oral formulation of ATO (10 mg daily), with a dose of Idarubicin (12 mg/m2 on days 1,3,5 and 7, if older than 60 years only given on day 1) added only to the high-risk patients. Consolidation Phase: 3 cycles of ATO + ATRA for 30days every 6 weeks. Maintenance Phase: 4 Cycles of ATRA+ATO daily for 15 days every 3 months. Oral formulation for ATO is prepared by the Laboratory of Pharmaceutical Products from our Social Security System according to the literature and approved by local health and pharmaceutical regulators. RESULTS: We report data on our first 26 APL patients enrolled on the LPCR05 protocol. Six patients were classified as high risk, eighteen intermediate and two low risk (Table 1). One high risk patient discontinued after first consolidation because of lost follow up. The median follow up is 12.5 months. Hematological complete remission was obtained after 30 days of treatment in all 26 patients. Molecular complete remission in 22 evaluated patients after first and third consolidation was achieved in 95% and 100% respectively (Table 2). None of the patients have relapsed. There were no withdrawals of the protocol because of side effects and no induction deaths because of coagulopathy. No severe cardiac or neurological toxicity was found. Grade 3 hepatic toxicity was seen in two patients, in both cases, temporary discontinuation of ATRA and ATO resolved the side effect. One patient developed non treatment related grade 3 renal toxicity and other one developed a probably related grade 3 skin toxicity. Severe infectious complications were seen in three patients, two had pneumoniae (one death) and one enteritis (Table 3). Patients are managed in the ambulatory setting, with fewer hospitalizations (mean hospitalization days per patient of 38,1 with ATRA + chemotherapy vs 14,1 with oral ATO and ATRA), and therefore the cost is three times lower (US$65 208 vs US$24 195) than our previous approach with ATRA + chemotherapy protocol. CONCLUSION: Our data demonstrate both efficacy and safety of oral ATO with ATRA as front line therapy in all risk groups. This strategy also demonstrated lower operational costs, fewer hospitalization days, and improved convenience for patients. We expect longer follow-up will confirm that treatment with oral ATO and ATRA is a curative therapeutic strategy for patients with APL that is particularly attractive for use in low and medium income countries. Disclosures No relevant conflicts of interest to declare.

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Remission in Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide (varitrinox) As the First Line in Colombia

Blood ◽

10.1182/blood-2020-137143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Gustavo Milone ◽

Samuel Sarmiento Doncel ◽

Carol Agudelo Rico ◽

Fabiola Vizcarra Reyes ◽

Gina Alejandra Diaz Mosquera ◽

...

Keyword(s):

High Risk ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Intermediate Risk ◽

Newly Diagnosed ◽

First Line ◽

Risk Patients

Acute promyelocytic leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) in which a chromosomal translocation t (15; 17) (q22; q12) is generated by fusing produces a hybrid PML / RARα gene, generating an altered signal . The combination of transretinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of newly diagnosed standard risk patients with acute promyelocytic leukemia (APL) in several countries. The objective of the present study is to describe the frequency of remission in patients with acute promyelocytic leukemia who were administered as a first line Arsenic Trioxide (varitrinox) during the period from November 2017 to June 2020 in Colombian patients. Methods: Retrospective observational and descriptive study of 12 patients diagnosed with acute promyelocytic leukemia treated with ATO Arsenic trioxide (Varitrinox) as first line, the source of information was provided by the treating hematologists (medical records) by filling out the technical concept format. Active pharmacovigilance scientist in Colombia, this format keeps the identification information of the patient anonymized and the confidentiality of the data is guaranteed as well as compliance with the rules of good clinical practice. Results: Twelve patients with age range between 22 and 69 years with a median age of 34.0 were analyzed. It was found in the analysis that 100% had induction hematologic remission with a median of 45 days. 75% of patients received ATO + ATRA and were at low and intermediate risk, the remaining 25% received ATRA + ATO + Chemotherapy and were at high risk, and intermediate risk. 91.7% of molecular remission in consolidation was obtained and it was measured in cycle 3 by means of PCR (undetectable), 8.3% (n = 1) was positive 3% and is finishing consolidation. Regarding the most frequent adverse events, intravascular coagulation (n = 9), neutropenia (n = 6) and thrombocytopenia (n = 6) were observed. 75% of patients are disease-free, 16.7% are on maintenance (they received ATO + ATRA + Induction chemotherapy) and 8.3% are on consolidation. So far, none of the patients under study have died. Conclusions: Our results support the use of ATO (Varitrinox) in newly diagnosed APL patients (as first line), as a care strategy for low, intermediate and high risk patients. The role of ATRA-ATO is guaranteed in other studies where they manage patients of different risks. Key words: Arsenic trioxide, leukemia promyelocytic acute, leukemia myeloid acute, remission induction, tretinoin. Disclosures No relevant conflicts of interest to declare.

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Treatment of Relapsed Acute Promyelocytic Leukemia with Oral Arsenic Trioxide: An Eleven-Year Experience

Blood ◽

10.1182/blood.v112.11.2958.2958 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2958-2958

Author(s):

Wing-Yan Au ◽

Sidney Tam ◽

Anskar Y.H. Leung ◽

Eric Tse ◽

Cyrus Kumana ◽

...

Keyword(s):

Ascorbic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Maintenance Treatment ◽

Histone Deacetylase Inhibitors ◽

Significant Proportion ◽

Gemtuzumab Ozogamicin ◽

Promyelocytic Leukemia ◽

Hematopoietic Stem

Abstract Background. For patients with relapsed acute promyelocytic leukemia (APL), the optimal therapy after arsenic trioxide (As2O3)-induced complete remission (CR) is unclear. Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) has been advocated. These strategies are associated with morbidity and considerable mortality, and not all patients are eligible. The role of maintenance therapy with As2O3 remains undefined. Materials and methods. From 1997–2008, 50 consecutive APL patients (25 men, 25 women, median age: 35 (12–72) years) in relapse (R1, n=47; R2, n=3) were treated with As2O3 until CR. This was followed by idarubicin consolidation (6 mg/m2/day × 9) in 43 patients. Seventeen patients did not receive maintenance treatment. Thirty-two patients received oral-As2O3 maintenance (10 mg/day × 14 every 2 months). All-trans retinoic acid (ATRA, 45 mg/m2/day) maintenance was used together with oral-As2O3 in 27 patients. As2O3 protocol was approved by the institutional review board at Queen Mary Hospital. All maintenance treatment was given in the outpatient clinic as oral medication. Results. Of 50 relapsed cases, As2O3-induced CR was achieved in 49 patients, 1 patient dying of pneumonia. At a median follow-up of 61 (6–122) months, 27 patients (19 with and 8 without As2O3 maintenance) had remained in remission. Further relapses (R2, n=20; R3, n=2.) occurred in 22 patients (13 with and 9 without As2O3 maintenance), at a median of 16 (6–28) months. Concomitant central nervous system (CNS) relapse occurred in 8 cases. Treatment of post-As2O3 relapses included oral-As2O3 (10 mg/day) + ATRA (45 mg/m2/day) with (n=10) or without (n=10) ascorbic acid (1 gm/day) until CR, and then maintenance with As2O3 + ATRA +/− ascorbic acid. Leucocytosis during treatment was controlled with mitoxantrone. In these 22 cases of post-As2O3 relapses, further remission was still achieved in 19 patients (CR3, n=18; CR4, n=1), with 3 patients dying from cerebral bleeding. At a median follow-up of 88 (8–98) months, 8 patients had remained in remission. Further relapses occurred in 11 patients. Salvage therapy consisted of As2O3+ATRA+ascorbic acid, together with chemotherapy (mitoxantrone, n=8; amascrine, n=3), gemtuzumab ozogamicin (n=4), and autologous HSCT (n=1). Eight patients finally died of refractory leukemia after a median of 6 (2–33) months. Three patients had remained in remission (CR4, n=2, CR5 n=1) at a median of 41 (26–102) months. On an intention-totreat basis, our oral-As2O3 treatment/maintenance regimen for patients with relapsed APL resulted in a 4-year overall survival of 71%, and event-free-survival of 53%. Conclusion. Our findings showed that an oral-As2O3-based treatment/maintenance strategy resulted in durable remission in a significant proportion of patients with relapsed APL. As most of the treatment is administered at home, this regimen involves much less financial, personnel and emotional costs as compared with HSCT strategies. Further improvement should be directed towards prevention of CNS relapses with appropriate prophylaxis in high-risk patients. For remissions at or beyond CR3, consideration of HSC harvest and storage at molecular remission should be considered. The use of demethylation agents and histone deacetylase inhibitors in combination with As2O3 remains to be investigated.

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Single Agent Arsenic Trioxide Regimen for the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Initial Results of a Multicenter Randomized Controlled Study From India to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy (IAPLSG04).

Blood ◽

10.1182/blood.v114.22.2082.2082 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2082-2082 ◽

Cited By ~ 2

Author(s):

Vikram Mathews ◽

Biju George ◽

Farah Jijina ◽

Cecil Ross ◽

Reena Nair ◽

...

Keyword(s):

Maintenance Therapy ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Single Agent ◽

Promyelocytic Leukemia ◽

Controlled Study ◽

Newly Diagnosed ◽

Free Survival ◽

Short Period

Abstract Abstract 2082 Poster Board II-59 Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen, a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients were randomized to 6 vs. 12 months of ATO maintenance (ClinicalTrials.gov Identifier:NCT00517712). From July, 2004 to December, 2008, 182 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Diagnosis was subsequently confirmed by molecular methods. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septic/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Hydroxyurea was permitted for control of leucocytosis. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Of the 155 patients who could be evaluated 136 (87.7%) achieved hematological remission (CHR). One patient had primary induction failure and was removed from the study while the other 18 were induction deaths at a median of 17 days (range: 4 – 69). During induction, 52 (33.5%) patients received an anthracycline and 116 (75%) received hydroxyurea. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.7%), which resolved in the majority after discontinuing ATO for a short period. One hundred and thirty six patients were randomized, 64 (47%) and 72 (53%) into a 6 and 12 month maintenance regimen respectively. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 24 months, the 3-year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 76.87±4.33%, 71.57±4.64% and 80.69±4.77% respectively. Fourteen patients relapsed, the median time to relapse was 19.3 months (range: 9-51). The baseline characteristics of the two groups (6vs12 months) were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS and DFS of the two groups were not statistically significantly different. There was also no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity. Single agent ATO based regimen as reported previously is well tolerated and results in durable remissions. Longer follow up is required to see if 12 months of maintenance therapy reduces risk of late relapses. Disclosures: No relevant conflicts of interest to declare.

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Maintenance therapy with arsenic after induction in an alternative and long-term case for the prevention of recurrence of acute promyelocytic leukemia during the period between November 2005 and December 2011.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6556 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6556-6556

Author(s):

Mozaffar Aznab ◽

Ghobad Salimi ◽

Jafar Navabi ◽

Touraj Jouybari ◽

Mansour Rezaei ◽

...

Keyword(s):

Maintenance Therapy ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Term Therapy ◽

First Line ◽

First Line Therapy

6556 Background: Arsenic trioxide has been used in the first line treatment of acute promyelocytic leukemia and also for recurrence after ATRA and chemotherapy. In this study, it we used it in induction of remission and maintenance therapy Methods: Between November 2005 to December 2011, 42 patients admitted in our department with APL diagnosis. There were 27 male and 15 women with a median age of 28 years. Arsenic trioxide started at 0.15 mg/kg intravenous infusion till patient’s bone marrows achieve to complete remission. Then, after 28 days rest, we did consolidation with Arsenic trioxide with the same dosage for 28 more days. We continued treatment with 14 days courses of Arsenic trioxide every 3-4 months for 2 years, as maintenance therapy Results: Four patients died during the first 20 days of treatment. Thirty-eight patients achieved to remission. Two patients refused to continue treatment after achieving to remission and excluded from this study. Thirty-six patients finished whole treatment. After a median follow-up of 54 months, 4 patients died due to disease relapse and one patient relapsed and initiated treatment with Arsenic and ATRA. Five patients faced leukocytosis over 100,000/ml. In these cases we were obligated to discontinue Arsenic for 3-4 days and did chemotherapy by Danourobicin for 2 days. Totally 8 patients died during remission induction and long-term follow up. One year, 3 and 5 years RFS were 97%, 87.1% and 79.4 respectively and we didn’t observe any relapse for patients who remained in remission after 5 years. Finally, 31 patients are alive and free of disease. The overall survival was 79.5% for our cohort. Conclusions: Arsenic trioxide is an effective treatment as the first line therapy for new cases of APL and long term therapy with will reduce the risk of diseases recurrence without any major toxicity in long time.

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