Realgar Indigo Formula Plus ATRA As Postremission Treatment in an Rral and Chemo-Free Model for High-Risk Acute Promyelocytic Leukemia Patients: A Prospective, Multicenter, Phase II Study

Abstract Background: Low-risk patients with acute promyelocytic leukemia (APL) can be cured using only ATRA and arsenic trioxide (ATO), without chemotherapy(Lo-Coco F, et al. NEJM 2013) .Our group simplified the protocol by replacing iv ATO with oral arsenic, referred to as RIF, allowing for outpatient, oral and chemotherapy-free treatment for an increasing number of APL patients (Zhu HH, et al. NEJM 2014; 371:2239-41;Zhu HH, et al. Lancet Oncol 2018;19:871-879; Zhu HH, et al. Blood 2019;134:597-605). We also reported a promising single-center results using chemo-free postremission treatment for high-risk APL patients (Zhu HH, Blood 2018;131:2987-2989), which need to be confirmed in a well designed multi-center trial. Objective: To evaluate the efficacy of safety Realgar indigo formula plus retinoic acid as postremission treatment in an oral and chemo-free model for high-risk APL patients . Design, setting and participants: a prospective, multicenter, single-arm, phase II clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (>18 years old) with newly diagnosed APL and achieved complete remission(CR) were enrolled since May 2019, with final follow-up in July 31,2021. Interventions: The consolidation therapy included realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and4-week-off regimen for 4 cycles and ATRA (25 mg/m 2 daily in anoral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary endpoint was the 2-year DFS. Secondary endpoints included complete molecular remission (CMR) defined as the absence of detectable PML-RARA transcripts., event-free survival (EFS), OS, and safety. Main outcomes and measures: 38 eligible patients were enrolled including 18 males and 20 females and the median age was 41 years old (18-77 years). The median of WBC count is 25.39（10.2-113.9）×109/L[ >50×10 9/L n=10; (20-50)×10 9/L n=14，(10-20)×10 9/L n=14].All the patients achieved CMR during post-remission treatment phase (7 months). Until now, no molecular, hematologic recurrence,and central nervous system leukemia has happened with median follow-up of 13 months. What's more, this chemotherapy-free, completely oral regimen was well tolerated. C onclusions: These exciting results proved that RIF plus retinoic acid as postremission treatment of high-risk APL was effective, safe and convenient. The study is ongoing, and the effective of this regimen need to be evaluated by more patients and longer time. Figure 1. The overall survival(OS) and disease-free survival (DFS) of high-risk APL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.6130 ◽

2009 ◽

Vol 27 (4) ◽

pp. 504-510 ◽

Cited By ~ 248

Author(s):

Farhad Ravandi ◽

Eli Estey ◽

Dan Jones ◽

Stefan Faderl ◽

Susan O'Brien ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Gemtuzumab Ozogamicin ◽

Promyelocytic Leukemia ◽

Platelet Recovery ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Purpose We examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO) but without traditional cytotoxic chemotherapy. Patients and Methods From February 2002 to March 2008, 82 patients with APL were treated with a combination of ATRA plus ATO. The first cohort of 65 patients received ATRA and ATO (beginning on day 10 of ATRA). High-risk patients (WBCs ≥ 10 × 109/L) received GO on the first day. From July 2007, the second cohort of 17 patients received ATRA and ATO concomitantly on day 1. They also received GO on day 1, if high risk, and if their WBC increased to more than 30 × 109/L during induction. Monitoring for PML-RARA fusion gene was conducted after induction and throughout consolidation and follow-up. Results Overall, 74 patients achieved complete remission (CR) and one achieved CR without full platelet recovery after the induction, for a response rate of 92%. Seven patients died at a median of 4 days (range, 1 to 24 days) after inclusion in the study from disease-related complications. The median follow-up is 99 weeks (range, 2 to 282 weeks). Among the responding patients, three experienced relapse at 39, 52, and 53 weeks. Three patients died after being in CR for 14, 21, and 71 weeks, all from a second malignancy. The estimated 3-year survival rate is 85%. Conclusion The combination of ATRA and ATO (with or without GO) as initial therapy for APL was effective and safe and can substitute chemotherapy-containing regimens.

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ACUTE PROMYELOCYTIC LEUKEMIA (APL) IN PATIENTS AGED > 70 Years.

Blood ◽

10.1182/blood.v114.22.4160.4160 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4160-4160

Author(s):

Paola Finsinger ◽

Massimo Breccia ◽

Clara Minotti ◽

Ida Carmosino ◽

Laura Cannella ◽

...

Keyword(s):

Overall Survival ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

Case Reports ◽

Promyelocytic Leukemia ◽

Very Elderly ◽

Free Survival ◽

All Trans Retinoic Acid ◽

Lost To Follow Up

Abstract Abstract 4160 Acute Promyelocytic Leukemia (APL) is a rare subtype of Acute Myeloid Leukemia (AML) more common in younger adults, with a median age of 45 – 50 years at onset. The use of All-trans Retinoic Acid (ATRA) as tailored treatment has made APL a very curable disease also in patients aged > 60 years; however, there are only few case reports in very elderly APL patients. To address this issue, we revised clinical data and treatment results in 12 patients aged > 70 years with newly diagnosed APL followed at our Institution from 1/91 to 12/2008. Clinical characteristics at onset were as follows: M/F 7/5, median age 74.7 years (range 70.0 – 80.8), M3/M3v 11/1, median WBC 1.3 × 109/l (range 1.0 – 7.4), median PLTS 53 × 109/l (range 12 – 302), BCR1/BCR3 6/6. According to Sanz risk score, 7 patients were at low-risk and 5 at intermediate-risk; 6/12 patients had arterial hypertension, 4/12 a concomitant cardiologic disease, 3/12 a cerebro-vascular disease and 2/12 a previous neoplasia. Induction therapy consisted of ATRA + Idarubicin in 8 patients (2/8 with reduced Idarubicin dosage) and ATRA alone in 4 patients; in this latter group, however, 2/4 needed to add chemotherapy (CHT) based on Mitoxantrone + AraC due to hyperleukocytosis during ATRA treatment. All patients achieved both morphological and molecular Complete Remission (CR) after a median time of 50 (range 29 – 65) and 105 (range 51 – 239) days, respectively. Infective complications were observed in 10/12 patients (4 episodes of FUO, 6 sepsis, 2 cystitis and 1 oral abscess) while ATRA syndrome occurred in 2/12 patients; in addition, there were 3 episodes of cardiac ischemia and 3 episodes of paroxystic atrial fibrillation. All but one patient received consolidation therapy (based on CHT alone in 7 patients, CHT + ATRA in 3 patients and ATRA alone in 1 patient), followed by maintenance treatment in 8 patients. Four patients had a relapse (hematological in 3 cases and molecular in 1 case) after 8, 11, 35 and 56 months respectively. At present, 6 patients are still alive, 4 died due to disease progression (3) or senectus while in CR (1) and 2 were lost to follow-up while in CR: mean event-free survival and overall survival were 89.2 months (95%CI 52.6 – 125.8) and 99.9 months (95%CI 65.0 – 134.7), respectively. In conclusion, ATRA-based treatment of APL is safe and effective also in very elderly patients, with long-lasting disease-free and overall survival. Disclosures: No relevant conflicts of interest to declare.

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Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials

Blood ◽

10.1182/blood.v130.suppl_1.641.641 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 641-641

Author(s):

Honghu Zhu ◽

Depei Wu ◽

Xi Zhang ◽

Lin LIU ◽

Jun Ma ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

White Cell Count ◽

Promyelocytic Leukemia ◽

Clinical Trial Registry ◽

Phase 3 ◽

Rate Difference ◽

Noninferiority Trial

Abstract Objective Intravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients. Methods We conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%. Results Complete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p= 0.12). The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p >0.05). Conclusions RIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054). Disclosures No relevant conflicts of interest to declare.

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Clinical Profile, Complications and Outcomes of Patients with Acute Promyelocytic Leukemia: Indian Perspective

Blood ◽

10.1182/blood-2021-152874 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4385-4385

Author(s):

Tejasvini Vaid ◽

Mukul Aggarwal ◽

Pradeep Kumar ◽

Rishi Dhawan ◽

Jasmita Dass ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Risk Group ◽

High Risk Group ◽

Promyelocytic Leukemia ◽

Low Risk ◽

P Value

Abstract Background: The introduction of all-trans-retinoic-acid (ATRA) and arsenic trioxide (ATO) has changed acute promyelocytic leukaemia (APL) from a highly fatal malignancy to a major success in the sphere of haemato-oncology, with long-term survival exceeding 90% in some studies [1]. While literature from the developed world boasts of outstanding outcomes of patients with APL, there is a paucity of data on management strategies, complications and outcomes from the developing world in general and India in particular [2]. With a large population residing in rural areas, high infection rates and limited access to healthcare, we aim to delineate the challenges faced in curing APL in the developing world. Methods: We retrospective collected data from medical records of all patients diagnosed with APL between January 2016 to December 2020 in the department of Hematology. A presumptive diagnosis of APL was made based on the presence of abnormal promyelocytes in peripheral blood or bone marrow and flow cytometry (CD13, CD33 positive, HLADR, CD34 negative). The diagnosis was confirmed by the presence of PML-RARα fusion gene by RT-PCR. Data on baseline characteristics, therapy, complications and outcome was collected. Overall survival (OS) was defined from the date of diagnosis to death or date of last follow up. Disease free survival (DFS) was defined from the date of first remission to date of first relapse, death or date of last follow up. Results: 64 patients were treated during the study period. Baseline characteristics, therapy administered and induction outcomes are mentioned in Table 1. Complications: 56.25% patients developed differentiation syndrome (DS). The incidence was higher in Sanz high-risk group as compared to Sanz-low risk group (68.8% vs 43.2%, p value 0.044). The incidence of infection at presentation was similar in Sanz high-risk and low-risk groups (55.2% vs 59.4%, p value 0.7). The incidence of new episode of febrile neutropenia during therapy was 62.5% and was higher in Sanz high-risk group as compared to low-risk group (75% vs 50%, p value 0.039). On multivariate analysis, development of infection during induction was a significant predictor of death or relapse (p value 0.02 HR:0.3; 95% CI 0.12-0.84). 17.2% patients developed pseudotumor cerebri. All of them were treated with acetazolamide, 6 patients' symptoms persisted despite acetazolamide and the dose of ATRA was lowered to 25mg/m2. 3 patients developed thrombosis. One patient had superior sagittal sinus thrombosis at presentation and two patients developed central line related thrombosis during therapy. 15.6% patients developed hepatotoxicity of which 3 had an underlying chronic liver disease. The remaining had a normal liver echotexture on ultrasonography and viral markers were normal; the liver dysfunction was attributed to drug induced liver injury. One patient who received AIDA protocol developed PSVT and improved with adenosine. Another patient who received ATRA+ATO+Daunorubicin developed accelerated hypertension and was managed symptomatically. Outcomes 75% patients attained complete remission after induction. 9 patients died from infection, 6 from bleeding and one from DS. At a median follow up of 26 months, 2 patients belonging to high-risk group had relapsed. They received reinduction with ATRA and ATO; one succumbed to pancreatitis during induction, the other attained CR2 and is on maintenance therapy. The 4-year DFS and OS was 71.25% (95% CI 59.9 to 82.5) and 73.13% (95% CI 62.2 to 84.1) respectively. Patients in Sanz low risk group had a better 4-year DFS (84.9% vs 58.3%, p value 0.026) and OS (84.9% vs 62.5%, p value 0.044) as compared to the Sanz high-risk group. There was a trend towards improved outcomes in high-risk patients with the use of ATRA+ATO+Daunorubicin. Conclusion: APL patients in India have a higher incidence of DS, pseudotumor cerebri, hepatotoxicity, baseline infections & new infections during induction complicating therapy. CR rate, DFS, OS were comparable to other population-based studies. ATRA, ATO and daunorubicin combination is the preferred protocol for treating high-risk patients. REFERENCES: 1. Iland HJ et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120(8):1570-80 2. Lo-Coco F et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-21. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Treatment of Acute Promyelocytic Leukemia (APL) At Tawam Hospital UAE

Blood ◽

10.1182/blood.v120.21.4347.4347 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4347-4347

Author(s):

Arif Alam ◽

Harimohan Narayanan ◽

Shanaaz Sonday ◽

Sabir Hussain ◽

Amar Lal ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Supportive Care ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

Early Death ◽

Promyelocytic Leukemia ◽

Published Data ◽

Female Ratio

Abstract Abstract 4347 Acute Promyelocytic Leukemia (APL) is a unique sub-type of Acute Myeloid leukemia associated with a balanced reciprocal translocation between chromosomes 15 and 17 and 80% of the cases present with bleeding diathesis caused by severe coagulopathy. The translocation generates a fusion transcript joining the PML(promyelocyte) and RAR-α (retinoic acid receptor-α) genes. The therapy of APL has been revolutionized by the introduction of differentiating agents All Trans Retinoic Acid (ATRA) and Arsenic Trioxide. All patients were treated as per Pethema protocol. Initially LPA99 (Sanz MA. Blood. 1999 Nov 1;94(9):3015-21) and since January 2012 a risk adapted therapy based on LPA2005 (Sanz MA et al. Blood June 24, 2010 vol. 115 no. 25 5137–5146). Treatment included induction followed by 3 cycles of consolidation and two years of maintenance. Nineteen patients were diagnosed with APL between January 2009 and June 2012. Three patients are excluded from the analysis as karyotyping and/or PCR did not confirm the diagnosis. The median age was 35 years (range 22–53 years). Male to female ratio was 4:1. Nine (56%) patients were stratified as high risk (WBC ≥ 10 ×109/l) while, seven (44%) as intermediate risk and low risk (WBC < 10 ×109/l). Three (19%) patients had early death despite treatment and supportive care. The cause of death was intracranial hemorrhage (1) pulmonary hemorrhage (1) and multi-organ failure (1). Thirteen patients achieved a complete morphological and molecular remission (80%). There has been only 1 case of treatment failure (high risk at presentation). This patient was successfully re-induced with arsenic trioxide and achieved second molecular complete remission. Unfortunately he relapsed a second time and is currently alive in third morphological remission but remains PCR positive for PML/RARα 33 months after diagnosis. Our limited experience shows favorable outcome (CR 80%) for the treatment of APL using the Pethema protocol compared to published data (Tallman MS. Blood 2002;99(3):759–767). Early death rate remains high despite intensive supportive care. The only variable is the availability and initiation of ATRA at the clinical suspicion of diagnosis both at the referring hospitals and treatment center. 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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Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia

Blood ◽

10.1182/blood-2018-02-834051 ◽

2018 ◽

Vol 131 (26) ◽

pp. 2987-2989 ◽

Cited By ~ 15

Author(s):

Hong-Hu Zhu ◽

Yan-Rong Liu ◽

Jin-Song Jia ◽

Ya-Zhen Qin ◽

Xiao-Su Zhao ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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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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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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Preliminary Results of a Consolidation Therapy Consisting Single Anthracycline Agent and Alternative All-Trans Retinoic Acid in Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4284.4284 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4284-4284

Author(s):

Zhang Jie ◽

Xiaojian Meng ◽

Zhen Cai ◽

Xiujin Ye ◽

He Huang

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Treatment Strategies ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

Preliminary Results ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Abstract 4284 Background: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with distinctive biologic and clinical features that is now highly curable. However, there are complicated issues in treatment strategies for induction, consolidation and maintenance that remain to be studied. The optimal regimen and the duration of consolidation is one of the above controversies. Patients and methods: Six patients (4 males, 2 females) were enrolled in this observation with a median age of 28 years (18–36). All were diagnosed de novo APL with demonstration of the abnormal increased promyelocytes of 53–90% accompanied with detection of t(15;17) or PML/RARα rearrangements. At diagnosis, WBC counts were 0.9–4.6×109/L and platelet counts were 13–84×109/L. Induction therapy was composed of all-trans retinoic acid (ATRA) with or without anthracycline or homoharritonine. After achieving complete remission (CR) following the above regimens, consolidation therapy was given monthly consisting single anthracycline agent of idarubincin (8–10 mg/m2/d, day 1–3) or aclarubicin (8–12 mg/m2/d, day 1–7) and alternative ATRA (25 mg/m2/d, day 1–15). After 12–18 months of consolidation, patients received maintenance therapy including methotrexate (12 mg/m2/d, per week) plus 6 mercaptopurine (30 mg/m2/d, qod ×12 days) and alternative ATRA (25 mg/m2/d, day 1–15) for one year. Results and conclusions: At present, all of the six patients are in continuous CR status, four of whom ceased treatment and are undergoing regular monitoring. Preliminary results from our experience demonstrates that single anthracycline and alternative ATRA can act as a valid option with limited toxicity for APL and might be used as a consolidation strategy, particularly for low and intermediate-risk patients. Disclosures: No relevant conflicts of interest to declare.

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