Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients

Abstract Abstract 765 Background: The combination of ATRA and idarubicin (AIDA) for induction therapy of acute promyelocytic leukemia (APL) yields complete remission (CR) rates of > 90%. If this is followed by intensive consolidation treatment, about 85% of patients are disease free and alive after 6 years. In fact, three cycles of consolidation treatment are considered the therapeutic standard; however, it is unclear how much treatment intensity is necessary for long-term survival. In order to address this question, we analyzed the clinical course of patients enrolled into the APL study of the German Study Alliance Leukemia (SAL), which contained only two courses of consolidation. Patients and Methods: All patients ≥ 18 years diagnosed with cytogenetically confirmed APL were eligible for inclusion in the risk-adapted SAL-AIDA-2000 trial. Enrolled patients received standard induction treatment with ATRA (45 mg/m2/d until CR) and idarubicin (12 mg/m2 for 4 doses every other day). After CR, non-high-risk patients (WBC ≤ 10,000/μL) received daunorubicin (45/60 mg/m2 days 1–3, dose depending on age) as first consolidation and mitoxantrone (10 mg/m2 days 2–4) as second consolidation. High-risk patients received additional cytarabine in both consolidation cycles (100/200 mg/m2 continuous infusion over 7 days in 1st consolidation and 1000/3000 mg/m2 twice daily on 4 days in 2nd consolidation, dose depending on age). After 2 cycles of consolidation, all patients were scheduled for 24 months of maintenance with 6-mercaptopurin (90 mg/m2 daily), methotrexate (15 mg/m2 weekly), and ATRA (45 mg/m2 for 15 days every 3 months). The following outcomes were analyzed: CR rate, induction deaths, disease-free survival (DFS), and overall survival (OS). Results: Between January 1999 and October 2010, 141 patients were enrolled in the trial. The median age at diagnosis was 51 years (range, 19–82), and 41 (29%) patients had a WBC >10,000/μL (high risk). The CR rate was 92% in the entire cohort; 95% in patients ≤ 60 and 86% in patients > 60 years (p=0.082). No significant differences in CR rates were seen between high-risk and non-high-risk patients (88% vs 94%, p=0.213). Three patients died during induction treatment (2%). After a median follow up of 55 months, the median DFS and OS were not reached. The estimated 6-year DFS was 80% (95%–CI 72%–88%) in all patients; 84% in patients ≤ 60 and 72% in patients > 60 years (p=0.140). The estimated 6-year OS was 77% in all patients; 84% (95%–CI 76%–92%) in the younger and 62% (95%–CI 47%–78%) in the elderly group (p=0.004). No significant survival differences between the high-risk and the non-high-risk patients were observed, neither for DFS (6-year DFS 78% (95%–CI 64–93%) vs 81% (95%–CI 72%–91%), p=0.625) nor for OS (6-year OS 71% (95%–CI 57%–86%) vs 79% (95%–CI 70–89), p=0.207). Conclusions: Our results confirm the efficacy of a risk-adapted approach both in high-risk and non-high-risk APL patients. The similarity for DFS and OS times between these two groups demonstrate the efficacy of cytarabine added to anthracyclines during consolidation in high-risk patients. Both CR rates and survival outcomes are comparable to the results obtained in the AIDA0493 and AIDA2000 trials by the GIMEMA group, which used three cycles of higher-dosed consolidation. In light of the data, modification in number and intensity of consolidation cycles may result in a less toxic but equally effective option for the treatment of APL and should be considered for further evaluation in a randomized clinical trial. Disclosures: No relevant conflicts of interest to declare.

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GIMEMA-AIEOP AIDA Protocols for the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) In Children: Analysis of 247 Patients Enrolled In Two Sequential Italian Multicenter Trials

Blood ◽

10.1182/blood.v116.21.871.871 ◽

2010 ◽

Vol 116 (21) ◽

pp. 871-871 ◽

Cited By ~ 3

Author(s):

Anna Maria Testi ◽

Robin Foa ◽

Gabriella Tomei ◽

Francesco Lo Coco ◽

Andrea Biondi ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Acute Promyelocytic Leukemia ◽

Remission Rate ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Intermediate Risk ◽

Newly Diagnosed ◽

High Risk Patients ◽

Risk Patients

Abstract Abstract 871 Since 1993, Italian pediatric patients (age <18 years) with newly diagnosed acute promyelocytic leukemia (APL) have been enrolled in two consecutive multicenter Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) - Italian Pediatric Hematology and Oncology Group (AIEOP) AIDA 0493 and 2000 trials. The AIDA 0493 protocol consisted of an induction including ATRA (25 mg/m2/day) and idarubicin, followed by three polychemotherapy consolidation courses without ATRA and a four-arm randomized maintenance therapy for patients who were PCR- after consolidation. The AIDA 2000 trial, which started in September 2000, included the same induction followed by a risk-adapted (Sanz criteria, Blood 2004) consolidation. Low and intermediate risk children received three less intensive anthracycline-based courses plus ATRA; for high risk patients, consolidation was intensified by adding ATRA to the three polychemotherapy consolidation courses of the previous protocol. Maintenance therapy consisted of standard daily mercaptopurine and weekly methotrexate given for two years. ATRA was administered for fifteen days every three months during all maintenance therapy. Between January 1993 and June 2000, 124 children were enrolled in the AIDA 0493 protocol. The results of this study have been previously reported (Testi et al, Blood 2005). From July 2000 to January 2009, 123 children with newly diagnosed APL were enrolled in the AIDA 2000 risk-adapted trial. We have now performed an updated analysis of the results of the first study and compared these results with those achieved with the AIDA 2000 study. The median follow-up is 12 and 5 years for the AIDA 0493 and 2000 studies, respectively. No differences in the main clinical and biologic diagnostic patients' characteristics - M/F ratio, median age, median WBC count, FAB M3/M3v, BCR1/BCR2/BCR3, low-intermediate/high risk - were observed between the two groups; the median platelet count was higher in the AIDA 2000 group (27.5 vs 20 × 109/L, p 0.05). The complete remission rate was 96% and 100% in the AIDA 0493 and 2000 protocols, respectively, with no patient showing resistant disease. No toxic death was recorded during the consolidation phase in both protocols; at recovery from the third consolidation course, 97% and 99% of the two groups of patients, tested by RT-PCR, achieved molecular negativity. The 6-year Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) are 89.7% (CI 95%: 84.7–95) vs 96% (CI 95%: 91.7–100), (p 0.05) and 73.1% (CI 95%: 66.7–80.2) vs 82.5% (CI 95%: 75.9–89.8), (p 0.28) in the AIDA 0493 and 2000 protocols, respectively. For low/intermediate risk children, OS and DFS at 6 years are 94.2% (CI 95%: 89.1–99.5) and 76.7% (CI 95%: 68.9–85.4) in the AIDA 0493 vs 95.6% (CI 95%: 90.0–100) and 82.7% (CI 95% 74.9–91.3) in the AIDA 2000 trial, respectively (p 0.57 and 0.73); considering high risk patients, OS and DFS at 6 years are 81.6% (CI 95%: 72.1–92.3) and 65.2% (CI 95%: 54.7–77.6) in the AIDA 0493 vs 96.8% (CI 95%: 90.9–100) and 82.3% (CI 95%: 70.1–96.5) in the AIDA 2000 trial (p 0.05 and 0.20). These results confirm the high anti-leukemic efficacy of the ATRA + idarubicin induction combination. For low/intermediate risk children, the anthracycline-based plus ATRA consolidation is equally effective as the previous cytarabine-containing regimen. The risk-adapted strategy including ATRA for consolidation resulted into a significant improvement in OS for all children. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group. Disclosures: Foa: Roche: Consultancy, Speakers Bureau.

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Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia: Results From a Randomized Controlled Trial

Journal of Clinical Oncology ◽

10.1200/jco.2013.53.3570 ◽

2014 ◽

Vol 32 (33) ◽

pp. 3729-3735 ◽

Cited By ~ 35

Author(s):

Katsuji Shinagawa ◽

Masamitsu Yanada ◽

Toru Sakura ◽

Yasunori Ueda ◽

Masashi Sawa ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Acute Promyelocytic Leukemia ◽

Controlled Trial ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

High Risk Patients ◽

All Trans Retinoic Acid ◽

Risk Patients ◽

Wbc Count

Purpose The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. Patients and Methods Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. Results A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 109/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non–high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. Conclusion In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

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Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome

Blood ◽

10.1182/blood-2010-01-266007 ◽

2010 ◽

Vol 115 (25) ◽

pp. 5137-5146 ◽

Cited By ~ 189

Author(s):

Miguel A. Sanz ◽

Pau Montesinos ◽

Chelo Rayón ◽

Alexandra Holowiecka ◽

Javier de la Serna ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Intermediate Risk ◽

Consolidation Therapy ◽

High Risk Patients ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Risk Patients

AbstractA risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMA LPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 × 109/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high- risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission after ATRA plus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in the LPA99 (26%; P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Registered at http://www.clinicaltrials.gov as NCT00408278.

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Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome

Yearbook of Oncology ◽

10.1016/s1040-1741(10)79526-9 ◽

2010 ◽

Vol 2010 ◽

pp. 125-126

Author(s):

R.J. Arceci

Keyword(s):

Treatment Outcome ◽

Retinoic Acid ◽

High Risk ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

High Risk Patients ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Risk Patients

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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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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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Outcome of Adult AML at First Relapse Following a Risk-Oriented Strategy: An Update of the Northern Italy Leukemia Group (NILG) Experience

Blood ◽

10.1182/blood.v112.11.4385.4385 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4385-4385 ◽

Cited By ~ 1

Author(s):

Irene Cavattoni ◽

Enrico Morello ◽

Elena Oldani ◽

Tamara Intermesoli ◽

Ernesta Audisio ◽

...

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Risk Category ◽

High Dose ◽

High Risk Patients ◽

Risk Patients ◽

First Relapse ◽

Group 2 ◽

Standard Risk ◽

Group 1

Abstract INTRODUCTION The impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) was retrospectively analyzed in 172 patients (patients) with relapsed non-APL AML, who had been initially treated with standard induction and risk-adapatiented consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All 172 patients were at first recurrence following consolidation of CR1 with high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinical-cytogenetic criteria) or allo-SCT in case of high-risk prognostic profile. Median age at relapse was 55 y (range 21–70). CR1 duration was <6 months in 50 patients (29%), ranging from 0.6 to 52,7 mo (median 9,1). High risk patients were 128/172 (74%) and 43/172 patients (25%) had an unfavourable cytogenetics (CG). One hundred-eleven patients (64%) received HiDAC and 24 (14%) an allo-SCT according to study design. RESULTS 140 patients (81%) received salvage treatment. The remaining 32 patients (19%) received palliation and all of them died. The median OS was 17.1 mo, with a 2yOS of 34%. Favorable prognostic factors identified by univariate analisys were: favourable or intermediate CG (p=0,007), standard risk category according to first line protocol (p=0.004), availibility of a HLA matched donor (p= 0.048), achievement of an early CR1(p=0,000), HiDAC as first line therapy(p=0,000), alloHSCT perfomed at relapse (p=0,000) and a DFS from CR1>12 mo (p=0,000). In multivariate analysis favourable or intermediate CG and DFS >12 mo were confirmed as independent prognostic factors (p=0,036 and p=0,001 respectively). Among the 140 patients, 50 received an allo-SCT following relapse (36%, group 1), and the remaining 90 (64%, group 2) received high dose chemotherapy alone (85), autologous SCT (2), or DLI (3, in case of previous alloSCT). Both groups were comparable regarding age >55 y, prior allo-SCT and risk class at diagnosis. After salvage therapy, 44 patients(88%) in the group 1 achieved CR2, compared to 26 patients (29%) in the group 2. The median duration of CR2 was 9 mo (range 2–64) and 3 mo (range 1–34) in group 1 and 2 respectively. NRM was 17/140: 12 patients (24%) in the allo-SCT group and 5 (6%) in group 2. The 2yOS was 57% and 23% respectively (p=0,000). Moreover, among 50 alloSCT patients, survival was affected by risk category at diagnosis: 2yOS of 19 (38%) standard risk patients was 83% compared to 42% in 31 high risk patients (62%) (p=0.01). This risk stratification has no impact on OS in the group 2. CONCLUSIONS DFS > 12 mo and standard risk category at diagnosis, according to NILG protocol, are the most important independent positive prognostic factors impacting OS of AML relapsed patients. The availibility of a HLA matched donor and a subsequent intensification with alloSCT may offer substantial salvage rates and its outcome is affected by the risk stratification at diagnosis. Nevertheless, high risk patients could benefit from alloSCT, reaching an 2yOS of 42%.

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