Management of Relapse in Acute Promyelocytic Leukemia Treated with Upfront Arsenic Trioxide Based Regimens

Abstract The standard of care for patients with acute promyelocytic leukemia (APL) relapsing after frontline treatment with arsenic trioxide (ATO) based regimens remains to be defined. Available data on response and survival outcomes in patients who had received ATO as part of upfront therapy suggests that there is a high incidence of resistance to ATO and ATRA resulting in inferior response and survival (Zhu HH et al. N Engl J Med. 2014). We present our experience on management of relapse in APL patients treated with frontline ATO based therapy. Data on all consecutive patients with relapsed APL diagnosed and treated in the Depatment of Haematology, Christian Medical College, Vellore, from January, 1998-December, 2015 were included in this retrospective analysis. One hundred and four (29%) out of the total 358 APL patients diagnosed during the study period had relapsed. Out of these 73 (70%) patients received upfront ATO based therapy. Six out of 73 refused treatment and got discharged at request following the diagnosis of relapse, the remaining 67 (91.8%) were included in the analysis. Median age of patients was 28 years (range: 4-54), 44 (65.7%) were males. Median time to relapse from initial diagnosis was 19.6 months (range: 6 - 128). Relapses were isolated molecular in one, isolated CNS in 6 [9%], bone marrow + CNS in 13 [19.4%] and medullary only in 47 [70.1%] patients. All 67 patients received ATO based therapy (ATO ± ATRA +/- Anthracycline/Bortezomib) as re-induction. 63/67 (94%) achieved molecular remission post re-induction, while 3 (4.5%) died during re-induction and one discontinued treatment. An autologous SCT was offered to all patients who achieved molecular remission, however only a proportion of cases opted for SCT due to financial constraints. Those that did not opt for an autologous SCT were given ATO+ATRA maintenance therapy. 35/63 (55.6%) opted for autologous SCT while 28 (44.4%) continued on maintenance therapy alone. Median time to autologous SCT from relapse was 5.8 months (range: 2 - 32). There were no treatment related deaths following autologous SCT. At a median follow up of 46 months (range: 1-224), the 5 year estimate of OS and EFS (Fig 1) of the whole cohort (n=67) was 73.6% ± 5.7% and 67% ± 6.1%. The 5 year estimate of OS and EFS (Fig 2) of those who received autologous SCT vs those who were on chemotherapy were 90.3% ±5.3 vs 58.6±10.4 %, (P=0.004) and 87.1% ±6.0% vs. 47.7% ±10.3%, (P=0.001) respectively. In unadjusted analysis, those who received chemotherapy as post relapse consolidation had 5.73 (95%CI: 1.86 - 17.65) times risk of relapse as compared to those who received autologous SCT, which was statically significant (P=0.002). In the adjusted analysis (Table 1) those who received chemotherapy the risk of relapse was 7.6 (95%CI: 1.98 - 28.87) times compared to those who received autologous SCT, which was statically significant (P=0.003) after adjusting for age, total WBC at relapse and duration of CR1. Remission induction with ATO based regimens followed by an autologous SCT in patients with relapsed APL who were treated with frontline ATO based regimens is associated with excellent long term survival and should be considered the standard of care even in this setting. 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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Final Analysis of a Multi-Center Randomized Controlled Trial (IAPLSG04) to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v118.21.426.426 ◽

2011 ◽

Vol 118 (21) ◽

pp. 426-426 ◽

Cited By ~ 1

Author(s):

Vikram Mathews ◽

Biju George ◽

Farah Jijina ◽

Cecil Ross ◽

Reena Nair ◽

...

Keyword(s):

Maintenance Therapy ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Low Cost ◽

Single Agent ◽

Promyelocytic Leukemia ◽

Newly Diagnosed ◽

Molecular Remission ◽

Short Period

Abstract Abstract 426 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 who achieved molecular remission were randomized to 6 vs. 12 months of ATO maintenance. From July, 2004 to December, 2008, 186 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septicemia/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 for up to 60 days in induction; this was followed by 28 day consolidation after a 4 week break following induction. 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. 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. Hydroxyurea was permitted for control of leucocytosis. Of the 159 patients who could be evaluated 138 (86.8%) achieved hematological remission (CHR), one patient had primary induction failure and was removed from the study the rest were induction deaths at a median of 17 days (range: 4 – 69). 52 (32.7%) received an anthracycline in induction while 116 (73%) received hydroxyurea in induction. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.3%), in the majority they resolved after discontinuing ATO for a short period. 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 48 months the 5 year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free surivival (DFS) was 75.7±3.9%, 68±4% and 76.9±4.2% respectively. Twenty five patients relapsed, the median time to relapse was 19.2 months (range: 8.2–51). There were no relapses beyond 4 years of follow up. 136 patients who achieved molecular remission after consolidation were randomized in to 6 months (n=63) or 12 months (n=73) of maintenance therapy. The baseline characteristics of the two groups were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS (Figure 1) and DFS of the two groups were not statistically different. There was no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity. This study confirms that this low cost, low intensity single agent ATO based regimen, as reported previously, is well tolerated and results in durable remissions. However, there is no apparent clinical benefit from increasing the duration of maintenance from 6 to 12 months. Disclosures: No relevant conflicts of interest to declare.

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Arsenic Trioxide-Based Therapy Of Relapsed Acute Promyelocytic Leukemia: Updated Results Of The European Registry Of Relapsed APL (PROMYSE)

Blood ◽

10.1182/blood.v122.21.1406.1406 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1406-1406 ◽

Cited By ~ 1

Author(s):

Eva Lengfelder ◽

Francesco Lo-Coco ◽

Lionel Ades ◽

Pau Montesinos ◽

David Grimwade ◽

...

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Salvage Therapy ◽

Performance Status ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Clinical Relapse ◽

Consolidation Therapy ◽

Term Survival ◽

Frontline Therapy

Abstract Background Arsenic trioxide (ATO) is regarded as the treatment of choice for relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). In 2008, a European online registry of rAPL based on uniform CRFs was established under the auspices of the European LeukemiaNet (ELN) to gain insights in the clinical and biological characteristics of rAPL treated with ATO and to allow an assessment of the different options for postconsolidation therapy. Methods Eligibility criteria for prospective or retrospective registration were PML-RARA+ 1st or successive molecular or clinical relapse of APL from the year 2003 onwards. The treatment should be based on the European recommendations for treatment of rAPL (www.leukemia-net.org/content/), which offer induction and consolidation therapy with ATO and several options for post-consolidation therapy including autologous or allogeneic stem cell transplantation or chemotherapy consolidation followed by various modifications of maintenance therapy ± ATO - to be selected depending on several variables including patient age, performance status, PCR status after consolidation, type of frontline therapy, first CR duration and donor availability. Results By 30 June 2013, of 220 registered cases, 198 were evaluable (172 in 1st, 26 in ≥2nd relapse). Of these, 149 patients (pts) in 1st relapse received ATO-based salvage therapy after standard frontline therapy based on all-trans retinoic acid (ATRA) and anthracyclines (98 hematological (hematol) relapses of bone marrow combined with CNS relapse in 5 pts, 40 molecular (mol), 11 isolated extramedullary, mainly CNS). Clinical characteristics: median age at relapse 44 years (y) (4 to 81), 67% males, Sanz Risk Score at 1st diagnosis: low 23%, intermediate 48% and high 29% of pts. Median duration of first remission was 565 d (105 d to 7.0 y). The median treatment duration of ATO (0,15 mg/kg/day) plus ATRA (44% of pts) for remission induction (ind) was 30 days (d) and for consolidation (cons) 25 d. CNS relapses received ATO and additional intrathecal chemotherapy ± irradiation. WBC white blood cell count; Leuko.: leukocytosis requiring hydroxyurea; ADS: APL differentiation syndrome; 1 median; 2 hematological; 3 RT-PCR of PML-RARA negative. In non-hematological relapses, no early deaths occurred and no major side effects of ATO were seen. Median follow up of the 149 pts was 2.8 y (6 d to 10 y). Three-year overall survival (OS) was 70%, 95%CI [61;79] and 6-year OS 56% [42;70]. Three-year OS of hematological, molecular and extramedullary relapse was 69% [58;80], 66% [48;84] and 90% [81;99], respectively (p=0.2). Concerning outcome after transplantation, 3-year OS after autologous was 82% [70;94] (n=55), after allogeneic 75% [58;92] (n=32) and without transplantation 66% [48;84] (n=55) (p=0.4). Conclusions With ATO-based salvage therapy over 50% of patients in 1st relapse of APL can probably be cured. Pts in molecular relapse have a lower rate of early complications and death. Long-term survival is possible with transplantation-free approaches, but transplantation seems to improve the outcome. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding. Lo-Coco:TEVA: Speakers Bureau.

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A Prospective Study on the Effectiveness of Arsenic Trioxide (ATO) in Remission Induction of Acute Promyelocytic Leukemia (APL)

Chattagram Maa-O-Shishu Hospital Medical College Journal ◽

10.3329/cmoshmcj.v14i2.25709 ◽

2015 ◽

Vol 14 (2) ◽

pp. 5-10

Author(s):

Mohammad Abdullah Al Anis ◽

Mohiuddin Ahmed Khan ◽

Salma Afrosa ◽

M Sirajul Islam ◽

Akhil Ranjan Biswas ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Single Agent ◽

Young Patients ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Induction Phase ◽

Newly Diagnosed ◽

Molecular Remission

Background: Arsenic Trioxide (ATO) as a single agent, has proven efficacy in inducing molecular remission in patients with Acute Promyelocytic Leukemia (APL). It is commonly used to treat relapsed APL. But there is Limited study on ATO in the management of newly diagnosed cases of APL. The concerned study was done to evaluate the effectiveness and outcome of ATO in remission induction of new cases of APL in the context of a limited resource hospital in Bangladesh.Methods: From March 2008 to March 2010, 20 patients with Promyelocytic Leukemia (PML) / Retinoic Acid Receptor ? (RAR ?) + newly diagnosed APL were enrolled. All patients were treated with a regimen of single-agent arsenic trioxide till remission at our center. After remission the regimen was administered on outpatient basis.Results: Overall 15 (75%) patients achieved complete hematological remission. 12 (80%) patients achieved molecular remission after induction phase and 3 (20%) after completion of consolidation phase. At a median follow up of 36 months (Range 25 -44 months), Disease Free Survival (DFS) and Overall Survival (OS) 86.6% and 85.3% respectively. Relatively young patients with long form of t (15;17) had shown good response with this response. However, the response is slower than All Trans Retinoic Acid (ATRA). Patients presenting with high White Blood Cell (WBC) count, low platelet count, variable form of t (15;17) are found to respond poorly. The toxicity profile, in the majority, was mild and reversible. Treatment cost was also reduced than that of conventional regimen.Conclusion: Single-agent arsenic trioxide as used in this study in the management of newly diagnosed cases of APL is safe, cost beneficent and is associated with durable responses. But additional interventions as combining ATRA with ATO would probably required in high risk cases.Chatt Maa Shi Hosp Med Coll J; Vol.14 (2); Jul 2015; Page 5-10

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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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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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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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Walking a Tightrope: Dosage Modifications and Treatment Outcomes of All-Trans-Retinoic Acid, Arsenic Trioxide, and Daunorubicin for High-Risk Acute Promyelocytic Leukemia

JCO Global Oncology ◽

10.1200/go.20.00226 ◽

2020 ◽

pp. 1749-1756

Author(s):

Madhav Danthala ◽

Krishna Reddy Golamari ◽

Arun Seshachalam ◽

Anupama Mikkilineni ◽

Sitalata Chappidi ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Tertiary Care ◽

Standard Of Care ◽

Drug Dosage ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

PURPOSE The use of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) in the treatment of low- and intermediate-risk acute promyelocytic leukemia (APL) is the standard of care. We report the combined use of ATRA, ATO, and daunorubicin (DNR) in patients newly diagnosed with high-risk APL. The primary focus was to describe the drug dosage modifications made in the real-world scenario. METHODS In this descriptive study, we included 16 out of 28 patients with high-risk APL from two tertiary care centers in South India (Vijayawada and Trichy) between January 2015 and December 2018. A unique approach of initiating ATRA at a dose of 25 mg/m2 on day 1 and escalation to 45 mg/m2 after cytoreduction with DNR and hydroxyurea was followed in all patients to avert differentiation syndrome, in the setting of hyperleukocytosis at presentation. RESULTS All patients who survived the first 3 days of admission achieved complete remission after a median duration of 29 days. There were no deaths during induction or consolidation, and the regimen was well tolerated; two patients developed grade 3/4 peripheral neuropathy requiring treatment modification. After a median follow-up duration of 1.9 years, there were no hematologic or molecular relapses. CONCLUSION The study sheds light on the modifications made to recommended dosages of ATRA, ATO, and DNR to optimize outcomes in high-risk APL and reaffirms the importance of ATO use in the front-line setting to achieve durable responses with minimal toxicity.

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Oral Arsenic Trioxide without Chemotherapy as Maintenance Therapy for Patients with Acute Promyelocytic Leukemia in First Complete Remssion

Blood ◽

10.1182/blood.v112.11.2959.2959 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2959-2959

Author(s):

Wing-Yan Au ◽

Sidney Tam ◽

Anskar Y.H. Leung ◽

Eric Tse ◽

Cyrus Kumana ◽

...

Keyword(s):

Maintenance Therapy ◽

Arsenic Trioxide ◽

Solid Tumors ◽

Acute Promyelocytic Leukemia ◽

Cytosine Arabinoside ◽

Promyelocytic Leukemia ◽

Salivary Gland Cancer ◽

Queen Mary Hospital ◽

Carcinoma Of Colon ◽

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Abstract ORAL arsenic TRIOXIDE without chemotherapy as MAINTENANCE THErAPY for patients with Acute promyelocytic leukemia in first complete remssion Wing-Yan Au, Sidney Tam, Anskar Y.H. Leung, Eric Tse, Cyrus Kumana, Yok-Lam Kwong. Departments of Medicine and Clinical Biochemistry, Queen Mary Hospital, Hong Kong Background. Conventional maintenance therapy for acute promyelocytic leukemia (APL) in first complete remission (CR1) comprises all-trans retinoic acid (ATRA), mercaptopurine and methotrexate. Arsenic trioxide (As2O3) is used predominantly in relapsed cases. The efficacy and safety of earlier use of As2O3 in maintenance remain undefined. The availability of oral-As2O3 makes As2O3 maintenance practical. Materials and methods. From 2001–2008, 49 patients (24 men, 25 women, median age: 44 (16–73) years) with APL in CR1 (achieved after induction with ATRA, daunorubicin and cytosine arabinoside, and consolidated with daunorubicin and cytosine arabinoside) were studied. The following 2-year oral-As2O3 maintenance regimens were used: oral- As2O3 (10 mg/day × 14 Tevery 2 months, n=20), oral-As2O3 + ATRA (22.5–45 mg/m2/day × 14 every 2 months, n=20), and oral-As2O3 + ATRA + ascorbic acid (1 gm/day × 14, every 2 months, n=9). As2O3 regimens were approved by the institutional review board at Queen Mary Hospital. All As2O3 maintenance regimens were orally administered at home. Results. At diagnosis, the presenting leucocyte count was > 10 × 109/L in 9 cases, and platelet count < 40 × 109/L in 32 cases. At a median follow-up of 25 (2–87) months, there were 4 relapses (risk group: high, n=3; low, n=1; relapse site: bone marrow, n=4; central nervous system, CNS, n=2; maintenance protocol: As2O3, n=2, As2O3+ATRA, n=2). CR2 was achieved in all patients with further As2O3-based therapy, although 2 patients ultimately relapsed again and died of refractory leukemia. Of the 45 patients in continuous CR1, 3 patients had died of unrelated causes (stroke at 62 months, nasopharyngeal carcinoma at 24 months, carcinoma of colon at 86 months). Three other solid tumors (carcinoma of colon, n=2; salivary gland cancer, n=1) were diagnosed. Of the 5 solid tumors found in this cohort, only 1 was diagnosed after commencement of As2O3-maintenance. The 3-year leukemia-free-survival and overall-survival were 89% and 77%. There was no difference in survival between patients receiving different oral-As2O3 maintenance regimens, and stratified according to risk factors. Adverse effects of the oral-As2O3 maintenance included headache (n=18), gastric discomfort (n=7), herpes zoster reactivation (n=10), reversible liver function derangement (n=12), menorrhagia (n=3), and rash (n=8). Clinical arrhythmias were not observed. There were no defaults in treatment due to side effects. Conclusion. Oral-As2O3 maintenance is a simple regimen that is well tolerated, entirely oral and administered at home. This regimen considerably reduces exposure to anthracyclines, topoisomerase II inhibitors and anti-metabolites as used in other protocols, which is potentially advantageous for a curable leukemia, in view of chemotherapyinduced long-term complications. Although >60% of our patients belonged to intermediate and high-risk groups, this regimen was comparable to other multi-chemotherapy regimens in maintaining remission.

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Single Cycle of Arsenic Trioxide–Based Consolidation Chemotherapy Spares Anthracycline Exposure in the Primary Management of Acute Promyelocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.5158 ◽

2010 ◽

Vol 28 (6) ◽

pp. 1047-1053 ◽

Cited By ~ 68

Author(s):

Steven D. Gore ◽

Ivana Gojo ◽

Mikkael A. Sekeres ◽

Lawrence Morris ◽

Marcel Devetten ◽

...

Keyword(s):

Maintenance Therapy ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Cytotoxic Agents ◽

Single Cycle ◽

Free Survival ◽

All Trans Retinoic Acid ◽

Primary Management

Purpose Event-free survival following all-trans-retinoic acid (ATRA) –based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. Patients and Methods After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m2, cardiac ejection fraction decreased by ≥ 20% in 20% of patients. Conclusion These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

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