Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Results of the PETHEMA LPA2005 Trial Using All-Trans Retinoic Acid and Anthracycline with Cytarabine for High-Risk Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 138-138 ◽  
Author(s):  
Miguel A. Sanz ◽  
Pau Montesinos ◽  
Aleksandra Holowiecka ◽  
Gustavo Milone ◽  
Chelo Rayon ◽  
...  

Abstract Background: A previous report of the PETHEMA Group (Sanz et al, Blood 2004) showed that a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation (LPA99 trial), followed by ATRA and low dose methotrexate and mercaptopurine for maintenance therapy, resulted in high antileukemic efficacy, moderate toxicity, and a high degree of compliance. A critical analysis of this study led us to consider the following opportunities for improvement in a new trial: the observation of a lack of relapses in non high-risk patients (WBC counts <10 × 109/L) who had received incomplete consolidation therapy due to the occurrence of severe complications, led us to consider that there was room for a reduction of chemotherapy in this potentially overtreated setting; the outstanding results reported by the Italian GIMEMA Group in high-risk patients < 60 years combining ATRA, anthracycline and cytarabine in consolidation (Lo- Coco et al, ASH 2004) led us to investigate a similar strategy looking for a synergistic effect of this triple combination of drugs. Thus, a new risk-adapted PETHEMA trial (LPA 2005) was designed and initiated in July 2005. Methods: AIDA regimen (ATRA 45 mg/m2/d ATRA until CR and idarubicin 12 mg/m2/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: i.”low-risk” patients (WBC <10×109/l and platelets >40×109/l) received ATRA (45 mg/m2/d × 15) simultaneously with idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 3 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); ii.”intermediaterisk” patients (WBC <10×109/l and platelet <40×109/l) received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (idarubicin 7 mg/m2/d in the course #1 and 2 days instead of 1 in the course #3). Both risk groups received mitoxantrone × 3 in course #2 instead of × 5 in the LPA99 trial; and iii.”high-risk” patients (WBC >10×109/l) < 60 years received ATRA (45 mg/m2/d × 15) and idarubicin in courses #1 and #3 at the same dose than for low-risk patients but with the addition of cytarabine (1000 mg/m2/d × 4 in course #1 and 150 mg/m2/8 h days 1 to 4 in course #3) and 2 more days of mitoxantrone in course #2 (5 days instead of 3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months during 2 years. Results: Of 319 patients enrolled in the LPA 2005 trial between July 2005 and July 2008, data on baseline characteristics and induction outcome was available from 290 patients. CR was achieved in 268 patients (92%). No resistant cases were observed. Toxicity was manageable during consolidation and there were 2 deaths in CR during consolidation. The median follow-up of the cohort was 21 months (range, 2–38). Six patients presented hematological relapse and 3 molecular relapse. Overall, the 2-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 5%, 94%, and 92%, respectively. The 2-year CIR for low-, intermediate- and high-risk patients were 0%, 6% and 8%, respectively. A comparison of these results with those obtained with the LPA99 trial show a statistically significant lower CIR in high-risk patients (p=0.047). Conclusions: The significant improvement of the outcome observed in high-risk patients suggests a synergistic effect of the triple combination of ATRA, anthracycline and cytarabine.

2021 ◽  
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Donghua He ◽  
Yi Zhao ◽  
...  

Abstract Background: According to different patients’ subgroups choose optimal maintenance therapy. Methods: 226 Newly Diagnosed Multiple Myeloma (NDMM) patients in our center were included, the patients’ characteristics, survival, response, subgroup analysis, adverse reactions were compared between the patients with or without maintenance, proteasome inhibitor (PI) or immunomodulators (IMiDs) maintenance. And the survival of different maintenance duration of bortezomib-based regimens was also analyzed.Results: The maintenance therapy not only upgraded more patients’ response (34.3 vs. 13.3%, p= 0.006), but also significantly prolonged the patients’ PFS (median PFS: 41.1 vs. 10.5 months, p < 0.001) and OS (median OS: not reached vs. 38.6 months, p < 0.001). Compared with IMiDs, the PFS (median PFS: 43.7 vs. 38.5 months, p = 0.034) and OS (median OS: not reached vs. 78.5 months, p = 0.041) can both benefit from bortezomib-based maintenance. The patients younger than 65 years old with bortezomib-based maintenance significantly prolonged the OS (p= 0.032). Patients achieving the only partial response (PR) after induction and consolidation therapy experienced a significantly longer PFS and OS with bortezomib-based maintenance compared to IMiDs (p= 0.007, 0.002). Besides, the high-risk patients (ISS 2-3, DS 2-3 and RISS 2-3) with bortezomib-based maintenance can benefit PFS (p= 0.002, 0.02, 0.06, respectively) and OS (p=0.059, 0.047, 0.044, respectively) compared with IMiDs. The OS was significantly prolonged in the patients who received ≥12 months of bortezomib-based maintenance than those with maintenance < 12 months (p< 0.001), but no difference was observed in OS between the patients who received the 12-24 or ≥ 24months of bortezomib-based maintenance (p= 0.292).Conclusion: Maintenance therapy can significantly improve the survival of NDMM patients. Bortezomib-based regimens maintenance was more superior to IMiDs in overall PFS and OS. The beneficial effect is most evident in patients achieving the only PR after induction and consolidation therapy, and the high-risk patients. Moreover, younger patients also could benefit from bortezomib-based maintenance in OS. The bortezomib-based maintenance duration lasting 12-24 months after induction and consolidation therapy can reach a satisfactory OS.


BMJ Open ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. e034892
Author(s):  
Rachel E Harris ◽  
Marina Aloi ◽  
Lissy de Ridder ◽  
Nicholas M Croft ◽  
Sibylle Koletzko ◽  
...  

IntroductionImmunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn’s disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups.AimsTo compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation.Methods and analysisREDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6–17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk).Ethics and disseminationClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access.Trial registration numberNCT02852694; Pre-results.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 871-871 ◽  
Author(s):  
Anna Maria Testi ◽  
Robin Foa ◽  
Gabriella Tomei ◽  
Francesco Lo Coco ◽  
Andrea Biondi ◽  
...  

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.


2014 ◽  
Vol 32 (33) ◽  
pp. 3729-3735 ◽  
Author(s):  
Katsuji Shinagawa ◽  
Masamitsu Yanada ◽  
Toru Sakura ◽  
Yasunori Ueda ◽  
Masashi Sawa ◽  
...  

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.


2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 39-39
Author(s):  
Paul L. Nguyen ◽  
Jingbin Zhang ◽  
Kasra Yousefi ◽  
Elai Davicioni ◽  
Robert Benjamin Den ◽  
...  

39 Background: Prior studies suggested integrated clinical-genomic risk grouping can more accurately prognosticate prostate cancer (PCa) outcome than NCCN clinical risk. We evaluated the potential for genomic testing to reclassify patients in a manner that could change management compared to NCCN risk groups. Methods: We evaluated 4,474 consecutive patients with PCa who received the Decipher Biopsy test between 01/2016-08/2017 and had information to determine NCCN risk. Genomic categorizations with the potential to change management were defined as NCCN very low/low to genomic intermediate or high (active surveillance to active treatment), NCCN favorable intermediate to genomic high (radiation therapy [RT] alone to RT plus androgen deprivation therapy [ADT]), NCCN unfavorable intermediate to genomic low (RT + ADT to RT alone), NCCN high risk to genomic low (RT + long term ADT to RT + short term ADT). Results: There were 927 NCCN low-risk, 2,427 intermediate, and 1,120 high-risk patients. Among NCCN low-risk, the incidence of genomic low, intermediate, and high risk was 58.7%, 25.0%, and 16.3% respectively, for NCCN intermediate it was 36.5%, 27.6%, and 35.8%, and for NCCN high risk it was 15.9%, 17.1%, and 67.1%. Management could have been changed in the 41.3% of NCCN low risk patients with intermediate or high genomic risk, 26.7% of favorable intermediate risk patients who had high genomic risk, 32.4% of unfavorable intermediate risk patients with low genomic risk, and 15.9% of high risk patients with low genomic risk. Conclusions: A slight majority (54%) of Decipher Biopsy users have NCCN intermediate-risk disease, likely reflecting a need for further prognostic information to refine recommendations in intermediate risk. Reclassification of NCCN groups by genomic risk was common and an integrated clinical-genomic risk system could have altered treatment recommendations in 41.3% of NCCN low, 26.7% of favorable intermediate, 32.4% of unfavorable intermediate risk, and 15.9% of high risk patients.


2017 ◽  
Vol 67 (665) ◽  
pp. e881-e887 ◽  
Author(s):  
Samuel Finnikin ◽  
Ronan Ryan ◽  
Tom Marshall

BackgroundStatin prescribing should be based on cardiovascular disease (CVD) risk, but evidence suggests overtreatment of low-risk groups and undertreatment of high-risk groups.AimTo investigate the relationship between CVD risk scoring in primary care and initiation of statins for the primary prevention of CVD, and the effect of changes to the National Institute for Health and Care Excellence (NICE) guidance in 2014.Design and settingHistorical cohort study using UK electronic primary care records.MethodA cohort was created of statin-naïve patients without CVD between 1 January 2000 and 31 December 2015. CVD risk scores (calculated using QRISK2 available from 2012) and statin initiations were identified. Rates of CVD risk score recording were calculated and relationships between CVD risk category (low-, intermediate-, and high-risk: <10%, 10–19.9%, and ≥20% 10-year CVD risk) and statin initiation were analysed.ResultsA total of 1.4 million patients were identified from 248 practices. Of these, 151 788 had a recorded CVD risk score since 2012 (10.67%) and 217 860 were initiated on a statin (15.31%). Among patients initiated on a statin after 2012, 27.1% had a documented QRISK2 score: 2.7% of low-risk, 13.8% of intermediate-risk, and 35.0% of high-risk patients were initiated on statins. Statin initiation rates halved from a peak in 2006. After the 2014 NICE guidelines, statin initiation rates declined in high-risk patients but increased in intermediate-risk patients.ConclusionMost patients initiated on statins had no QRISK2 score recorded. Most patients at high risk of CVD were not initiated on statins. One in six statin initiations were to low-risk patients indicating significant overtreatment. Initiations of statins in intermediate-risk patients rose after NICE guidelines were updated in 2014.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Donghua He ◽  
Yi Zhao ◽  
...  

IntroductionWe analyzed different patient subgroups to determine optimal maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients.MethodsA total of 226 NDMM patients in our center were included in the study. The characteristics, survival, and adverse reactions were compared among patients who received maintenance therapy or not, and patients who received proteasome inhibitors (PIs) or immunomodulators (IMiDs) maintenance. The survival of different maintenance durations of bortezomib-based regimens was also analyzed.ResultsThe maintenance therapy not only upgraded more patient responses (34.3 vs 13.3%, P = 0.006), but also significantly prolonged their progression-free survival (PFS) (median PFS: 41.1 vs 10.5 months, P &lt; 0.001) and overall survival (OS) (median OS: not reached vs 38.6 months, P &lt; 0.001). Compared with IMiDs, the PFS (median PFS: 43.7 vs 38.5 months, P = 0.034) and OS (median OS: not reached vs 78.5 months, P = 0.041) were both enhanced by PIs maintenance. Patients younger than 65 years who received PIs had a significantly prolonged OS (P = 0.032). Patients achieving only a partial response (PR) after induction and consolidation therapy had significantly longer PFS and OS after PIs maintenance compared to IMiDs (P = 0.007, 0.002). High-risk patients (ISS 2–3, DS 2–3, and RISS 2–3) given PIs maintenance benefit from a prolonged PFS (P = 0.002, 0.02, 0.06) and OS (P = 0.059, 0.047, 0.044, respectively) compared with IMiDs therapy. OS was significantly prolonged in patients who received ≥ 12 months of bortezomib-based maintenance therapy compared to those who were treated for &lt; 12 months (P &lt; 0.001), but no difference was observed in OS between patients who received 12 to 24 or ≥ 24 months of bortezomib-based maintenance therapy (P = 0.292).ConclusionPIs maintenance was superior to IMiDs in overall PFS and OS. The beneficial effect was most evident in patients achieving PR after induction and consolidation therapy, and in high-risk patients. Moreover, younger patients also benefited from PIs maintenance with an increased OS. A bortezomib-based maintenance therapy duration of 12 to 24 months after induction and consolidation therapy produced satisfactory OS.


2021 ◽  
Vol 24 (3) ◽  
pp. 680-690
Author(s):  
Michiel C. Mommersteeg ◽  
Stella A. V. Nieuwenburg ◽  
Wouter J. den Hollander ◽  
Lisanne Holster ◽  
Caroline M. den Hoed ◽  
...  

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.


Sign in / Sign up

Export Citation Format

Share Document