scholarly journals Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet

Blood ◽  
2019 ◽  
Vol 133 (15) ◽  
pp. 1630-1643 ◽  
Author(s):  
Miguel A. Sanz ◽  
Pierre Fenaux ◽  
Martin S. Tallman ◽  
Elihu H. Estey ◽  
Bob Löwenberg ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Expert Panel ◽  
Genetic Diagnosis ◽  
Early Death ◽  
Promyelocytic Leukemia ◽  
Response To Treatment ◽  
All Trans Retinoic Acid ◽  
High Risk Disease ◽  
Frontline Therapy

Abstract Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

scholarly journals Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 1875-1891 ◽  
Author(s):  
Miguel A. Sanz ◽  
David Grimwade ◽  
Martin S. Tallman ◽  
Bob Lowenberg ◽  
Pierre Fenaux ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Genetic Diagnosis ◽  
Treatment Strategies ◽  
Promyelocytic Leukemia ◽  
Cytotoxic Agents ◽  
Response To Treatment ◽  
International Panel ◽  
All Trans Retinoic Acid ◽  
Disease Biology ◽  
Life Threatening

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion–based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto

2001 ◽  
Vol 19 (20) ◽  
pp. 4023-4028 ◽  
Author(s):  
Giorgina Specchia ◽  
Francesco Lo Coco ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Paola Fazi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Increased Risk ◽  
Junction Type ◽  
Wbc Count

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

Modern Approaches to Treating Acute Promyelocytic Leukemia

2011 ◽  
Vol 29 (5) ◽  
pp. 495-503 ◽  
Author(s):  
Miguel A. Sanz ◽  
Francesco Lo-Coco
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Virtual Absence ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Improved Outcomes ◽  
Experimental Trials ◽  
Cure Rates ◽  
Standard Risk

The advent of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy have contributed in the past 2 decades to optimize the antileukemic efficacy in acute promyelocytic leukemia (APL), leading to complete remission rates greater than 90%, virtual absence of resistance, and cure rates of nearly 80%. Recently reported studies from large cooperative trials have also shown that more rational delivery of treatment and improved outcomes may derive from the use of risk-adapted protocols. In particular, patients at higher risk of relapse (ie, those presenting with WBC > 10 × 109/L) seem to benefit from treatments that include cytarabine in the ATRA-plus-chemotherapy scheme, whereas patients with standard-risk disease can be successfully managed with less-intensive regimens that contain ATRA and anthracycline-based chemotherapy. After the outstanding results with arsenic trioxide (ATO) in the treatment of APL relapse, several experimental trials have been designed to explore the role of ATO in front-line therapy with the aim not only of minimizing the use of chemotherapy but also to reinforce standard ATRA-plus-chemotherapy regimens and additionally improve therapeutic efficacy. In this review article, we discuss most recent advances in the treatment of patients with newly diagnosed and relapsed APL.

scholarly journals Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2098-2108 ◽  
Author(s):  
Robert E. Gallagher ◽  
Barry K. Moser ◽  
Janis Racevskis ◽  
Xavier Poiré ◽  
Clara D. Bloomfield ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Active Role ◽  
Promyelocytic Leukemia ◽  
Chromosome Abnormalities ◽  
White Blood Count ◽  
Internal Tandem Duplication ◽  
All Trans Retinoic Acid ◽  
Additional Chromosome ◽  
Selection Of

Abstract Mutations in the all-trans retinoic acid (ATRA)–targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1078-1084 ◽  
Author(s):  
Lionel Adès ◽  
Miguel A. Sanz ◽  
Sylvie Chevret ◽  
Pau Montesinos ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Cumulative Dose ◽  
Promyelocytic Leukemia ◽  
Joint Analysis ◽  
High Dose ◽  
Newly Diagnosed ◽  
All Trans Retinoic Acid ◽  
High Cumulative Dose ◽  
Wbc Count

Abstract All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3171-3179 ◽  
Author(s):  
Francesco Lo-Coco ◽  
Giuseppe Avvisati ◽  
Marco Vignetti ◽  
Massimo Breccia ◽  
Eugenio Gallo ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Risk Group ◽  
High Risk Group ◽  
Promyelocytic Leukemia ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
All Trans Retinoic Acid ◽  
Risk Patients

AbstractAfter the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)–like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non–risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group. This trial was registered at www.clinicaltrials.gov as #NCT 001064570.

scholarly journals ACUTE PROMYELOCYTIC LEUKEMIA IN CHILDREN: A SINGLE CENTRE EXPERIENCE FROM TURKEY

2018 ◽  
Vol 10 (1) ◽  
pp. e2018045 ◽  
Author(s):  
Tekin Aksu
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Death Rate ◽  
Clinical Symptoms ◽  
Early Death ◽  
Pseudotumor Cerebri ◽  
Promyelocytic Leukemia ◽  
Severe Bleeding ◽  
Pediatric Hematology ◽  
All Trans Retinoic Acid ◽  
Problem Awareness

Background and objectives: Acute promyelocytic leukemia (APL), characterized by tendency to hemorrhage and excellent response to all-trans retinoic acid (ATRA), is a distinct subtype of acute myeloid leukemia (AML). In this retrospective study, we aimed to determine the incidence, clinical symptoms, toxicities and outcome of children with APL in our center. Methods: We retrospectively reviewed the medical records of children (age < 18 years) diagnosed with APL at our pediatric hematology department between January 2006-December 2016.Results: Pediatric APL represents 20.5% of AML cases in this cohort. Most of the cases presented as classical M3, albeit hypogranular variant was described in 12% of the cohort. Patients with hypogranular variant APL were differed from classical APL by co-expression of CD2 and CD34. About ¾ of APL patients had hemorrhagic findings at admission or at initial phase of the treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients and intracranial arterial thrombosis was present in one. Five patients showed side effects of ATRA such as pseudotumor cerebri, dilated cardiomyopathy, and pulmonary infiltrates. Six year overall survival (OS) and early death rate was found to be 82.5% and 12% respectively.Conclusions: A high frequency (20.5%) of APL was noted among children with AML in this single center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life threatening bleeding was the major problem, awareness and urgent treatment are critical factors to reduce early losses.

scholarly journals Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1248-1254 ◽  
Author(s):  
Jae H. Park ◽  
Baozhen Qiao ◽  
Katherine S. Panageas ◽  
Maria J. Schymura ◽  
Joseph G. Jurcic ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Death Rate ◽  
Early Death ◽  
Promyelocytic Leukemia ◽  
Care Providers ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Wide Range

Abstract The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ≥ 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ≥ 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.

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