Comparison on Treatment Outcomes on Paediatric Acute Promyelocytic Leukaemia: ICC APL 2001 Versus HKPHOSG AML 1996 Protocol
Acute promyelocytic leukaemia (APL) is a biologically and clinically distinct variant of acute myeloid leukaemia (AML). Patients often presented as a medical emergency with lethal haemorrhages. Despite high early mortality rate, APL has superior event-free survival (EFS) with prompt administration of all-trans retinoic acid (ATRA). This study is a retrospective review comparing outcomes of paediatric APL patients in Hong Kong treated with the two previously adopted protocols (HKPHOSG AML 1996 versus ICC APL 2001) over past 20 years. Total 53 eligible patients were identified, 30 and 23 were treated with HKPHOSG AML 1996 and ICC APL 2001 protocol respectively. Five-year overall survival and EFS for HKPHOSG AML 1996 versus ICC APL 2001 protocol were 80% versus 82.6% and 66.7% versus 75.1% with a median follow up period of 193.4 versus 56.7 months. To conclude, local data reveals that ATRA-based therapy demonstrate better outcome than AML-based chemotherapy in treating paediatric APL patients.
Keyword : Child; Drug therapy; Hong Kong; Leukaemia; Survival
Acute promyelocytic leukaemia (APL) is a rare form of acute myeloid leukaemia (AML) with only around 2 to 4 paediatric cases annually in Hong Kong. APL was classified as AML-M3 in the older French-American-British (FAB) classification system and is currently classified as APL with t(15;17)(q24.1;q21.2); PML-RARA in the World Health Organization (WHO) classification system.1 APL is a biologically and clinically distinct variant of AML. Patients often presented as a medical emergency with lethal pulmonary or cerebrovascular haemorrhage due to coagulopathies (disseminated intravascular coagulation and primary hyperfibrinolysis) induced by leukaemic promyelocytes. Despite high rate of early mortality, APL has superior EFS of above 70% to nearly 100% across all age and risk groups once the differentiation agent all-trans retinoic acid (ATRA) is promptly administered when diagnosis is timely suspected or confirmed.2
Due to rare local incidence of paediatric APL, the Hong Kong Paediatric Haematology and Oncology Study Group (HKPHOSG) had adopted the HKPHOSG AML 1996 protocol based on UK MRC AML 10/12 protocol in treating territory-wide paediatric APL patients in all local paediatric oncology centres during 1997 to 2008, followed by joining the International Consortium for Childhood (ICC) APL 2001 protocol as one of the participating regions in the ICC since 2009 till present.
With the establishment of the Hong Kong Children's Hospital (HKCH) as the single territory-wide paediatric oncology centre in Hong Kong after merging the five existing paediatric oncology units - Queen Mary Hospital (QMH), Prince of Wales Hospital (PWH), Queen Elizabeth Hospital (QEH), Tuen Mun Hospital (TMH) and Princess Margaret Hospital (PMH); together with advancements in understanding on biology and treatments of paediatric APL, this study serves as a retrospective review on the outcomes of paediatric APL patients in HK treated with the two previously adopted protocols (HKPHOSG AML 1996 and ICC APL protocol 2001) providing scientific evidence before initiation of new treatment protocol.
All children diagnosed to have APL at age 18 or below at the time of diagnosis during the period between January 1, 1996, and December 31, 2017 in the 5 local paediatric oncology centres were included. Accrual of demographic data and outcomes were conducted by HKPHOSG data officers. Cross-checking of clinical information was conducted via the Electronic Patient Record (ePR) through the Clinical Management System (CMS). Clinical Data Analysis and Reporting System (CDARS) was also searched using the diagnostic code for Acute Myeloid Leukaemia, M3 (ICD-10 205.00) for any missing cases.
Statistical analyses were performed with the Statistical Package of Social Sciences version 24.0 (IBM SPSS 24.0). Continuous variables were expressed as mean and standard deviation. Overall survival (OS) was calculated from the date of diagnosis to the date of death of any cause or last follow-up (censored). Event-free survival (EFS) was calculated from the date of diagnosis to date of relapse, death of any cause, or last follow-up (censored). The probabilities of OS and EFS were calculated using the Kaplan-Meier estimation and log rank test was used to compare the survival of different groups. P-values <0.05 were deemed statistically significant.
This study complies with the Declaration of Helsinki and approval from Institutional Review Board of the University of Hong Kong / Hospital Authority Hong Kong West Cluster had been sought (UW 14-890).
Total 53 eligible patients were identified, 30 and 23 were recruited and treated with HKPHOSG AML 1996 and ICC APL Study 2001 protocol respectively (see Table 1). Median age of diagnosis was 12.2 years (range 2.4-17.8 years). Male-to-female ratio was 1.1 to 1. Two patients died before treatment in both treatment arms. Another two patients died during induction phase chemotherapy in both treatment arms, contribute to 6.7% and 8.7% of eligible patients in each cohort respectively. Remission was achieved in the remaining 26 (86.7%) (20 in CR1, 4 in >CR2 with 6 deaths) and 19 (82.6%) (15 in CR1, 1 in >CR2 with 4 deaths) respectively. There were total 5 (16.7%) and 1 (4.3%) patients relapse respectively. The 5-year OS and EFS for HKPHOSG AML 1996 versus ICC APL Study 2001 protocol was 80% vs 82.6% and 66.7% vs 75.1% with a median follow up period of 193.4 vs 56.7 months (see Table 2).
APL, FAB classification M3 or M3v, represents approximately 4-8% of paediatric AML1 but the incidence may be higher in children of Hispanic and Mediterranean origin. The median age at presentation is probably similar as that of other AML subtypes, but APL has rarely been reported in the first year of life. It can arise de novo or be therapy related (t-APL). The characteristics and outcome of t-APL appear similar to those of de novo APL.3
APL accounts for 5 to 20 percent of AML depending on geographical location, with higher incidence among Hispanics in Central and South America, Italy, and Spain. Blacks had lower lifetime incidence rates than non-Hispanic Whites, Hispanics, and Asians.4-8 In Hong Kong, four or less cases were diagnosed every year, which accounts for 16.7 percent (23 out of 138) of all AML cases diagnosed in recent 10 years (see Table 1). Various studies have reported a modest increase in incidence of APL in the last two decades8,9 but this trend is not observed in our locality. As for age distribution, its incidence is rare in the first decade of life, it then increases during second decade, reaches plateau during early adulthood, and then remains constant until it decreases after the sixth decade.9 For local paediatric cohort, two-thirds of them presented in second decade of life. There is no gender predilection. APL sometimes occur as a subgroup of therapy-related myeloid neoplasms (t-MDS/t-AML) after cytotoxic therapy (especially topoisomerase-II inhibitors such as etoposide, doxorubicin, and mitoxantrone) or radiation therapy.10
B. Clinical features (see Table 3)
Apart from typical presentation of pancytopenia as in other subtypes of AML (except microgranular APL which tends to present with higher peripheral blast counts) (see Table 3 case 50), APL has unique presentation of bleeding secondary to severe coagulopathy (especially for hypergranular APL variant) contributed by both disseminated intravascular coagulation (DIC) and primary fibrinolysis, which can cause life-threatening pulmonary or cerebrovascular haemorrhage (up to 40 percent) and even early haemorrhagic death (10 to 20 percent).11,12 In local paediatric APL cohort, clinical bleeding features (conjunctival or retinal haemorrhage, intracranial or subdural haemorrhage, oral mucosal bleeding, gum bleeding, epistaxis, bruising, petechiae, pulmonary haemorrhage, menorrhagia, haematuria, per rectal bleeding or haemarthrosis) was noted in 85 percent (39 out of 46) of patients on initial presentation. In our locality, 4 out of 53 patients (7.5 percent) died of haemorrhagic complications before initiation of treatment, all due to massive intracerebral haemorrhage (ICH). Infective symptoms (fever, coryzal symptoms or gastroenteritis), anaemic symptoms (pallor, fatigue, malaise, dizziness, palpitation, shortness of breath) and constitutional symptoms (loss of appetite, weight loss) and were noted in 37 percent (17 out of 46), 24 percent (11 out of 46) and 17 percent (8 out of 46) respectively. Other clinical presentations include gum hypertrophy, bone pain, hepatomegaly and splenomegaly. It is of interest to note that one of the patients present with fever and diarrhoea which later evolve into intestinal obstruction, appendicitis with gangrene formation, sepsis and disseminated intravascular coagulation (DIC) (see Table 3 Case 51). Acute colonic pseudo-obstruction (ACPO)(Ogilvie's syndrome) had been reported in several case reports or small series13-16 to be associated with acute myeloid (including APL) and lymphoblastic leukaemia during induction chemotherapy presumably due to use of vincristine which can cause autonomic neuropathy, but its association with APL on initial presentation before starting chemotherapy has not been described in literature. As general paediatricians or practitioners, it is important to recognise the clinical presentations of this rare, potentially lethal yet highly treatable disease entity as prompt referral to paediatric oncology specialists for diagnosis and treatment could significantly improve patient outcome as repeatedly reiterated in this article.
C. Diagnosis and Pathologic Features
(a) Morphology in marrow and peripheral blood smear
APL is characterised by the presence of atypical promyelocytes in bone marrow and/or peripheral blood. Promyelocytes are large (usually larger than 20 microns in diameter) myeloid precursors of variable morphologies, usually with high nucleus to cytoplasmic ratio, fine chromatin, and prominent nucleoli. Cardinal feature of promyelocyte is the presence of numerous violet cytoplasmic granules in a dense or coarse pattern obscuring the nucleus.
(b) Conventional karyotyping
Conventional karyotyping is an essential part of the standard workup. It is highly specific but time-consuming (takes approximately two days for results). Around two-thirds (32/53) of local paediatric APL patients have cytogenetics result available. APL is characterised by translocation t(15;17)(q22;q21) involving fusion of gene encoding the retinoic acid receptor alpha (RARa) and promyelocytic leukaemia (PML).17,18 In local paediatric APL cohort, t(15;17) is demonstrated in 80 percent (26 out of 32 patients) with cytogenetics results available (see Table 3). PML-RAR fusion gene predicts a favourable response to molecularly targeted therapies ATRA and arsenic trioxide (ATO).
(c) Molecular genetics
Determination of the underlying molecular fusion is critical for the appropriate clinical management of APL. Approximately 10% of APL cases with an underlying PML-RAR fusion have no detectable t(15;17) at diagnosis, either due to unsuccessful cytogenetic analysis, cryptic rearrangements or more complex rearrangements including simple variant translocations.19,20 Patients with molecularly but not cytogenetically detected PML-RAR fusion have an equally favourable outcome to those with overt t(15;17).21 Four out of thirty-two local paediatric APL patients showed normal cytogenetics. Cryptic translocation was detected by reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridisation (FISH) (see Table 3).
It is important to define PML-RAR isoform as a basis for subsequent MRD monitoring. In minority of cases (<5%), RARa is fused to alternative partners, commonest being nucleophosmin (NPM1) resulting from the t(5;17)(q35;q21) translocation20,22 and NuMA as a result of t(11;17)(q13;q21). These rare paediatric retinoid-sensitive subtypes of APL, with NPM1-RARA and NuMA-RARA fusions,20,22,23 may not be sensitive to ATO3; whereas APL involving PLZF and STAT5b as a result of t(11;17)(q23;q21) and interstitial deletion of chromosome 17 respectively, are resistant to ATRA3. These fusions were not identified in local cohort.
(d) FMS-like tyrosine kinase-internal tandem duplications (FLT3-ITD)
Among local cohort, FLT3-ITD was detected in one patient, but its prognostic significance is uncertain.24,25 (see Table 3)
APL phenotype is considered CD34 negative/partial or weak positive, HLA-DR negative, CD13 positive, CD33 positive, CD11b negative, CD15 weak or negative, CD117 weak/variable, and sometimes CD2 positive and CD56 positive.
(a) Drawbacks of anthracycline-based protocol (HKPHOSG AML 1996)
In Hong Kong, HKPHOSG had adopted the HKPHOSG AML 96 protocol based on UK MRC AML 10/12 protocol in treating territory-wide paediatric APL patients in all local paediatric oncology centres during 1997 to 2008. While the outcome is generally favourable with 5-year OS of 80%, 5-year EFS is just 66.7% with relapse rate of 16.7%. This drawback is also being identified from overseas experience.26-28 Using anthracycline-based chemotherapy protocols with ATRA followed by maintenance with ATRA, 6-mercaptopurine (6-MP) and methotrexate (MTX), relapse rates for patients with a WBC <10x109/L at diagnosis are typically 10% or less, while rates may exceed 20% for patients with a WBC ≥10x109/L, which echoed with local situation.
(b) Rationale of changes in ICC APL 2001 protocol
ICC APL 2001 protocol based on the results of AIEOP-AIDA 93 trial demonstrating promising results with combined use of ATRA and anthracyclines. GIMEMA-AIEOP AIDA 93 study recruited 983 patients with newly diagnosed APL between January 1993 and June 2000 of whom 124 (13%) were aged less than 18 years. Induction chemotherapy consisted of Idarubicin 12 mg/m2/day x 4 given with ATRA 25 mg/m2/day (compared to an adult dose of 45 mg/m2/day) until remission or maximum of 90 days. Consolidation consisted of 3 monthly courses: Cytarabine (Ara-C) 1 gm/m2/day x 4 with Idarubicin 5 mg/m2/day x 4 (course 1), Mitoxantrone 10 mg/m2/day x 5 with etoposide (VP-16) 100 mg/m2/day x 5 (course 2), and Idarubicin 12 mg/m2/day x 1, Ara-C 150 mg/m2/8 hourly x 5 and 6-thioguanine (6-TG) 70 mg/m2/8 hourly x 5 (course 3). Molecular response by RT-PCR was assessed following the third consolidation course and PCR-negative patients were initially randomised to one of four maintenance arms (6-MP+MTX; ATRA alone; ATRA+6-MP+MTX; no maintenance) but subsequently to ATRA alone or ATRA+6-MP+MTX. One hundred and three (96%) of the 107 evaluable children achieved haematological complete remission (CR) and 4 died during induction (1 sepsis; 3 intracranial haemorrhage). Overt ATRA syndrome occurred in two cases and pseudotumor cerebri in 10 children. The OS, disease-free-survival (DFS) and EFS, at more than 10 years, were 89%, 78% and 76% respectively. The only significant predictor of haematological CR was the WBC; 100% vs 89% (p=0.01) for WBC less than 10x109/L and equal to or greater than 10x109/L respectively. A WBC at diagnosis of equal to or greater than 10x109/L also had a significant impact on EFS (59% vs 83% at 10 years). Ninety-four children were evaluable for RT-PCR at the end of consolidation; of these, 91 (97%) tested PCR-negative and 3 PCR-positive. Children who were in molecular remission after consolidation therapy and randomised to receive ATRA and maintenance chemotherapy were significantly more likely to remain in molecular remission than those children who received ATRA alone (77% vs 42% respectively; p=0.0177).
GIMEMA-AIEOP AIDA 93 study reduced dose of ATRA as compared to adults in view of the apparent increase in ATRA-related side effects observed in children. Besides, cumulative dose of cardiotoxic anthracyclines is also lowered. Cytarabine is delivered in consolidation assuming its role in patients with high WBC, which is a commoner situation in childhood APL, though its benefit remained unproven.29,30 The combination of intermittent ATRA and chemotherapy may reduce rates of molecular and frank relapse and hence improve outcome, particularly for patients with a high whit WBC at presentation.30-33 With ICC APL 2001 protocol, superior outcomes had been demonstrated with 5-year OS and EFS of 82.6% and 75.1% respectively with a median follow up period of 56.7 months for local cohort.
(c) Minimal residual disease (MRD) directed pre-emptive therapy
Monitoring of minimal residual disease (MRD) has been shown to be an independent risk factor for relapse34 as demonstrated in studies from Italy28,35-37 and the United Kingdom.21 German AML Cooperative Group also demonstrated that patients who failed to achieve a 3-log reduction in PML-RARa transcript level within the first 3-4 months of therapy as detected by quantitative RT-PCR had an increased risk of early relapse.38
Pre-emptive therapy for patients with positive MRD impending relapse confers survival benefit than retreating patient when they have progressed to frank relapse due to the well-recognised risk of induction death due to associated coagulopathy as evidenced by the GIMEMA and PETHEMA groups.36,39,40 Patients with persistent PCR positivity or molecular relapse will receive molecularly targeted therapy, with ATO and may proceed to stem cell transplantation. For patients achieving molecular remission and with a PCR negative stem cell harvest, good results have been achieved with autologous stem cell transplantation.41,42 Allogeneic transplant is generally reserved for APL patients in whom harvest of PCR negative stem cells is unsuccessful or who fail to achieve second molecular remission.
(d) Arsenic Trioxide (ATO)
Therapeutic use of ATO has well been documented in treatment of various diseases across centuries despite its historical reputation as a toxin and a poison. ATO has now emerged as a treatment of choice for patients with refractory/relapsed PML-RAR+ APL.43,44
Although second remission could be achieved through re-induction with ATRA alone or in combination with chemotherapy, 2 cycles of ATO at recommended dose of 0.15 mg/kg/day enables induction of molecular remission in majority of patient without significant myelosuppression,43 which allows outpatient-based therapy and reduction in anthracycline exposure.
The optimal dosing schedule for ATO is not known. At least three dosing regimens are currently in use: (i) continuous dosing at 0.15 mg/kg/day, (ii) intermittent dosing at 0.15 mg/kg/day for 5 days, off for two days, weekly x 4 with a two week break when daily ATRA is given and the cycle repeated x 2 and (iii) intermittent dosing starting with a loading dose of 0.3 mg/kg for 5 days followed by 0.25 mg/kg twice weekly. These dosing schedules are comparable in terms of efficacy and toxicity profiles.45,46 The ICC-APL Study 2001 protocol is based on the conventional continuous dosing schedule recommended by the manufacturer, Cephalon. However, alternative equivalent dosing schedules may be preferred for logistic reason. ATO has also been evaluated as part of first-line therapy of APL in the recent US Intergroup trial C971042. Safety and effectiveness in paediatric patients under 5 years of age has not been studied to any great extent. From personal communications with local adult haematologists, promising result had been demonstrated with the use of oral arsensol in adult APL patients in Hong Kong. Usage of oral arsenol has been proposed as a monotherapy in selected low risk paediatric APL patients, sparing the use of anthracyclines. Future studies could be proposed related to this.
(e) ATRA syndrome / retinoic acid syndrome (RAS) / differentiation syndrome
Despite high efficacy of ATRA and ATO in treating APL patients, their usage could lead to retinoic acid syndrome (RAS) manifested as fever, dyspnoea, weight gain, hypotension and pulmonary infiltration. The mechanism of RAS is unknown but it is speculated that capillary leak syndrome due to cytokine release from differentiating myeloid cells and mediation by cathepsin G could play a role.47 In local cohort, nearly one-tenth (5 out of 53 cases) developed RAS after ATRA/ATO. Symptoms usually subside after ATRA/ATO is discontinued in conjunction with administration of short course intravenous dexamethasone as in all 5 local cases.
(f) Gemtuzumab Ozogamicin (Mylotarg®)
Gemtuzumab ozogamicin (GO) is an anti-CD33 targeted therapy with significant anti-leukaemic activity against APL due to high CD33 expression in APL cells.48-50 Its conjugate contains the intercalating anthracycline calicheamicin, which links the antibody to the cytotoxic agent, enables calicheamicin to be released only intracellularly, thereby avoiding much of the anthracycline-related toxicity. Its major side-effects include myelosuppression, allergic reactions and sinusoidal obstruction syndrome (SOS).
Strengths and Limitations
This territory-wide retrospective study summarised initial clinical presentations, treatment responses, clinical outcomes and complications HK children and adolescents at age 18 or below suffering from this rare subtype of APL in the last 2 decades. It also made comparisons between the two previously adopted protocols (HKPHOSG AML 1996 versus ICC APL 2001), which consolidated local clinical experience from 5 children oncology centres in HK. The intrinsic limitation of this study is that the two groups compared are at different time points (1997-2008 vs 2009 till present). The follow up time for the newer protocol is much shorter. The secular trend of improvement is hard to be discerned whether ATRA-based therapy demonstrates better outcome than AML-based chemotherapy in treating paediatric APL patients is due to treatment itself as there could be variants and confounders like the team's learning curve, expertise mix, supportive care by intensivists as well as multidisciplinary nursing and pharmacy team care which could potentially led to better outcome.
Retrospective review of local paediatric APL cohort reveals that ATRA-based therapy demonstrate better outcome than AML-based chemotherapy in treating paediatric APL patients. With the establishment of HKCH, it is hoped that a unified updated treatment protocol in collaboration with adult haematologists and international centres would be formulated, with incorporation of more accurate and wider panel of molecular diagnostics. Besides, it is anticipated that with the newly formed hub-and-spoke clinical service model, prompt referral of suspected or diagnosed paediatric APL cases from regional hospitals to HKCH could be enhanced.
Declaration of Interest
All the authors report no conflicts of interest.
The authors would like to thank HKPHOSG data officers for data accrual and the medical, nursing and pharmacy team involved in patient care.
1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391-405.
2. Asou N, Adachi K, Tamura J, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol 1998;16:78-85.
3. Beaumont M, Sanz M, Carli P, et al. Therapy-related acute promyelocytic leukemia. J Clin Oncol 2003;21:2123-37.
4. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control 2008;19:379-90.
5. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 2012; 119:34.
6. Matasar MJ, Ritchie EK, Consedine N, Magai C, Neugut AI. Incidence rates of acute promyelocytic leukemia among Hispanics, blacks, Asians, and non-Hispanic whites in the United States. Eur J Cancer Prev 2006;15:367-70.
7. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-91.
8. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. Cancer 2012;118:5811-8.
9. Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011;118:1248-54.
10. Beaumont M, Sanz M, Carli PM, et al. Therapy-related acute promyelocytic leukemia. J Clin Oncol 2003;21:2123-37.
11. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993;82:3241-9.
12. Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990;75:2112-7.
13. Wells CI, O'Grady G, Bissett IP. Acute colonic pseudo-obstruction: A systematic review of aetiology and mechanisms. World J Gastroenterol 2017;23:5634-44.
14. Jessop M, Choo K, Little M. Acute colonic pseudo-obstruction in paediatric oncology patients. J Paediatr Child Health 2010;46:698-9.
15. Kurtz J, Andres E, Maloisel F, et al. Acute colonic pseudoobstruction in acute promyelocytic leukemia. Gastroenterol Clin Biol 1997;21:629-30.
16. Park JA, Yun JH, Kang HJ, Shin HY, Ahn HS. Acute intestinal pseudo-obstruction after induction treatment of relapsed acute promyelocytic leukemia with arsenic trioxide. Pediatr Blood Cancer 2008;50:872-4.
17. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999;93:3167-215.
18. Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 1991;66:663-74.
19. Grimwade D, Gorman P, Duprez E, et al. Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood 1997;90:4876-85.
20. Grimwade D, Biondi A, Mozziconacci MJ, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t (15;17): results of the European Working Party. Blood 2000;96:1297-308.
21. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid:result of the Randomized MRC Trial. Blood 1999;93:4131-43.
22. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996;87:882-6.
23. Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nature genetics 1997;17:109-13.
24. Poire X, Moser BK, Gallagher RE, et al. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 2014;55:1523-32.
25. Kutny MA, Moser BK, Laumann K, et al. FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012;59:662-7.
26. de Botton S, Coiteux V, Chevret S, et al. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 2004;22:1404-12.
27. Ortega JJ, Madero L, Martin G, et al; PETHEMA Group Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 2005;23:7632-40.
28. Testi AM, Biondi A, Lo Coco F, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2005;106:447-53.
29. Sanz MA, Lo Coco F, Martin G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96:1247-53.
30. Sanz MA, Martin G, Rayon C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/ RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999;9:3015-21.
31. Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002;99:759-67.
32. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999;94:1192-200.
33. Sanz MA, Martin G, Lo Coco F. Choice of chemotherapy induction, consolidation and maintenance in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 2003;16:433-51.
34. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 2002;16:1959-73.
35. Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. Blood 1998;92:784-9.
36. Lo Coco F, Diverio D, Avvisati G, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999;94:2225-9.
37. Lo Coco F, Romano A, Mengarelli A, et al. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia 2003;17:930-3.
38. Schnittger S, Weisser M, Schoch C, et al. New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood 2003;102:2746-55.
39. Esteve J, Escoda L, Martin G, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 2007;21:446-52.
40. Lo Coco F, De Santis S, Esposito A, Divona M, Diverio D. Molecular monitoring of hematologic malignancies:current and future issues. Semin Hematol. Semin Hematol 2002;39(2 Suppl 1):14-7.
41. Meloni G, Diverio D, Vignetti M, et al. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission:prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 1997;90:1321-5.
42. Thomas X, Dombret H, Cordonnier C, et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. Leukemia 2000;14:1006-13.
43. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-60.
44. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999;94:3315-24.
45. Grimwade D, Jovanovic J, Diverio D, et al. Real-time detection of PML-RARA and RARA-PML fusion transcripts in high risk acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO): Implications for realization of pre-emptive therapy for molecular relapse. Am Soc Hematol 2006.
46. Fox E, Razzouk BI, Widemann BC, et al. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 2008;111:566-73.
47. Tallman MS. Retinoic acid syndrome: a problem of the past? Leukemia 2002;16:160-1.
48. Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol 2006;4:57-62.
49. Lo-Coco F, Cimino G, Breccia M et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004;104:1995-9.
50. Petti MC, Pinazzi MB, Diverio D, et al. Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (MylotargTM CMA-676). Br J Haematol 2001;115:63-5.