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Acute Non-Lymphocytic Leukemias

Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy


We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26 950/mm3 (7700–162 000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARα isoform (P=0.0003) and high WBC counts (10 000/mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P=0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (10 000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC 10 000/mm3 at diagnosis remains to be established.


The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT) and maintenance treatment has improved the outcome of acute promyelocytic leukemia (APL), but relapse still occurs in 10–25% of the patients.1, 2, 3, 4, 5, 6, 7, 8 Although very rare in APL in the past,9, 10, 11 cases of extramedullary (EM) relapse have been increasingly reported in the last few years.12, 13, 14, 15, 16, 17, 18 Those EM relapses largely predominate in the central nervous system (CNS) and the skin, followed by other sites (testes, sites of vascular access, external ear and auditory canal).12, 13, 14, 15, 16, 17, 18 It has been suggested that EM relapse may be associated with initial adverse prognostic features (including high WBC counts, microgranular morphology and bcr3 isoform),12, 15, 17 but risk factors for EM relapse have not been precisely defined. Because of its rarity, the outcome of patients with EM relapse remains undetermined and only one study reported that the outcome was similar to that of patients who experienced isolated BM relapse.16

We studied the incidence, presenting features, risk factors and outcome of EM relapse occurring in APL patients initially treated with ATRA and CT in three multicenter trials with prolonged follow-up.

Patients and methods

Between 1991 and 1999, 806 patients were included in APL91 and APL93 trials (European APL group)1, 5 and PETHEMA 96 trial (Spanish group)4 and received ATRA combined to or followed by CT, consolidation with CT, with or without maintenance with low-dose 6 mercaptopurine (6MP)+methotrexate (MTX), intermittent ATRA or both.

In APL91 trial, open from 1991 to 1992, patients were randomized for induction treatment between CT alone and ATRA followed by CT (ATRA → CT group). Only patients randomized to ATRA → CT (n=54) were included in the present study. In this ATRA → CT group, patients received ATRA 45 mg/m2/day orally until CR or for a maximum of 90 days. After CR achievement, they received three courses of daunorubicin (DNR) and AraC, the last course with high-dose AraC (Figure 1). In APL93 trial (n=576), open between 1993 and 1998, patients aged 65 years or less with WBC <5000/μl were randomized between ATRA followed by CT (ATRA → CT group; as in APL91 trial) and ATRA+CT (ATRA+CT) with the same combination of ATRA and CT, but with CT started on day 3 of ATRA treatment. Patients with WBC>5000/mm3 at presentation received ATRA plus CT from day 1 (high WBC group) and patients 66–75 years of age were not randomized and received ATRA+CT started on day 1 of ATRA treatment and the same schedule as in the ATRA → CT group (elderly group). Patients who achieved CR received two further DNR–AraC consolidation courses similar to those of APL91 trial (with the exception of the elderly group that only received one consolidation course). There was no maintenance treatment in APL91 trial. In APL93, there was a randomization for maintenance testing both intermittent ATRA and continuous CT with 6 mercaptopurine (6MP) and (MTX), both scheduled for 2 years.

Figure 1

Estimation of the cumulative incidence functions of extramedullary (EM) relapse and isolated medullary relapse over time (a) and of the overall survival following the occurrence of relapse (b).

In PETHEMA 96 trial (n=176), open from 1996–1999, induction therapy consisted of oral ATRA 45 mg/m2/day, until CR or for a maximum of 90 days, and four intravenous (i.v.) bolus of idarubicin 12 mg/m2 on days 2, 4, 6, and 8. Patients who achieved CR received 3 monthly consolidation courses consisting of idarubicin 5 mg/m2 i.v. daily for 4 days (course no. 1), mitoxantrone 10 mg/m2 i.v. daily for 5 days (course no. 2), and idarubicin 12 mg/m2 i.v. on only 1 day (course no. 3). After completion of consolidation, patients who tested polymerase chain reaction (PCR)-negative for the PML/RARα hybrid gene were started on maintenance therapy (intermittent ATRA and continuous CT with 6MP and MTX). The main differences between the trials were that CT combined DNR and AraC (at 200 mg/m2 during the two first CT courses, and 1 g/m2/12 h during third CT course) in APL91 and APL93, whereas CT was an anthracycline alone in PETHEMA 96 trial. None of the patients included in those trials received intrathecal (IT) CNS prophylaxis or cranial irradiation.


Bone marrow molecular relapse was assessed by using a previously described19, 20 nested RT-PCR technique for PML-RAR amplification, whose sensitivity ranges from 10−5 to 10−4.

Statistical methods

The cumulative incidence of relapse with EM localization (measured from the date of hematological remission to that of diagnosis of relapse with EM involvement) was calculated according to the competing-risk method, where hematological relapses with no apparent EM involvement and deaths prior to relapse were considered as competing risks outcomes.21 Comparisons of specific cumulative incidences across groups used the Gray test,22 with multivariable analysis performed using the Fine and Gray model.23 Finally, overall survival after relapse was estimated by the Kaplan–Meier method, and then compared between groups by the log-rank test.24, 25

All tests were two-sided, with P-values of 0.05 or less denoting statistical significance. Analyses were performed using the SAS 8.2 (SAS, Inc., Cary, NC, USA) and Splus2000 (MathSoft, Inc., Seattle, WA, USA) software packages.


Incidence and characteristics of EM relapses

Of the 806 patients included in APL91 and APL93 trials and PETHEMA 96 trial (Table 1), 740 (92%) patients achieved CR, of whom 169 (23%) subsequently relapsed, including 10 EM relapses. Three additional EM relapse occurred in second (n=2) or third relapse (n=1). Subsequent analyses were only made on first relapses. Median follow-up was 70 months (Q1–Q3=53–90).

Table 1 Patient characteristics according to protocol treatment

EM relapse occurred after a median CR1 duration of 411 days (range 140–1488) as compared to 547 days (range 178–2936) for isolated BM relapse. Of the 10 EM relapses, nine involved the CNS, with meningeal signs or symptoms in all cases, and one was a cutaneous relapse both at a site of vascular access and at a site of trephine BM biopsy (Table 2). Patients with EM relapse included six males and four females and their median age was 35 years (range 6–60). Their median WBC count at diagnosis was 26 950/mm3 (range 7700–162 000) with eight patients having WBC 10 000/mm3, the last two patients also having relatively high WBC counts for APL (7700 and 8600/mm3, respectively). Three patients had M3v. PML-RARα breakpoint was available in nine of the 10 patients: three had the bcr1 isoform and six the bcr3 isoform. Simultaneous BM involvement was documented in eight of the nine CNS relapses (89%), by morphology in seven cases, and RT-PCR only in one case. Only one (10%) patient with EM relapse had experienced retinoic acid (RA) syndrome.

Table 2 Pretreatment characteristics and outcome of patients with extramedullary disease at first relapse

The cumulative incidence of EM disease at first relapse and of isolated BM relapse were 0.62 and 5.0% after one year, and 1.1 and 15.5% after 3-year, respectively (Figure 1a).

Risk factors for EM relapse

Univariate analysis (Table 3) identified age less than 45 years (P=0.05) (Figure 2a), the presence of the bcr3 PML-RARα isoform (P=0.0003) and high WBC counts (P<0.0001) (Figure 2b) as risk factors for EM relapse after CR achievement. Occurrence of RA syndrome was not associated with an increased risk of EM relapse (P=0.69). As detailed knowledge of PML-RARα isoforms was available in only 332 cases, the variable bcr was excluded for multivariate analysis. Multivariate analysis only retained high WBC counts (P=0.0014) as associated with EM relapse (Table 3).

Table 3 Main comparison of cumulative incidences of extramedullary or isolated medullary relapses according to initial patient characteristics
Figure 2

Estimation of the cumulative incidence of extramedullary relapse according to age (a), white blood cells (WBC) count (b), PML-RARα isoforms (c).

Patients included in the PETHEMA protocol were characterized by younger age (P=0.006), higher incidence of the bcr3 PML-RARα isoform (P=0.001) as compared with patients included in the APL91 and APL93 trials (Table 1). Therefore, the higher incidence of CNS relapses we observed in the PETHEMA 96 protocol (26% of the relapses versus 3% in the APL91 and APL93 trials) could have been explained, at least in part, by the initial characteristics of those patients. Multivariate analysis indeed found no difference between the APL91 and APL93 trials and the PETHEMA 96 trial for the incidence of CNS relapse (P=0.73). On the other hand, PETHEMA patients had shorter follow-up than APL91 and APL93 trial patients, and therefore less time at risk of EMD.

In univariate analysis, risk factors for isolated BM relapse included male gender (P=0.0018), high WBC counts (P<0.0001), microgranular morphology (P=0.036) and the presence of the bcr3 PML-RARα isoform (P=0.023). In multivariate analysis, male gender (P=0.003) and high WBC counts (P<0.0001) remained independent predictors of isolated BM relapse.

Outcome of EM relapses

Treatment of CNS relapse included triple IT injections in all cases, followed by systemic salvage CT regimens (n=8, combined with ATRA, in five patients), and liposomal ATRA until CR followed by intensive consolidation therapy with high-dose AraC (n=1). Systemic salvage CT regimens combined an anthracycline (mitoxantrone or idarubicine) with high or intermediate dose AraC and, in two cases, VP 16. One patient received CNS irradiation after CR2 achievement. The patient with skin relapse was treated with cutaneous irradiation without systemic CT, followed by maintenance therapy combining low-dose CT and intermittent ATRA. Three patients died during salvage treatment (one CNS bleeding and two severe sepsis) and the remaining seven patients achieved CR2. Two of the seven patients who achieved CR2 had early BM relapse but achieved CR3. Three patients subsequently underwent allogeneic stem cell transplantation (two in CR2; one in CR3) but two of them died from transplant related mortality, and one had just been transplanted. Three patients underwent autologous stem cell transplantation (two in CR2; one in CR3), of whom two had early relapse and one was still in CR2. Overall, only three patients were still alive, in CR2, 5+, 38+ and 52+ months after first relapse (Table 1). Median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04 by the log-rank test; Figure 1b).


This study shows that EM relapse largely predominate in the CNS, are almost always associated with BM relapse and carry a poorer prognosis, as compared with patients with isolated BM relapse. Those relapses are significantly associated with high WBC counts at diagnosis. Some authors have suggested an increase in the incidence of EM relapse since the introduction of ATRA in the treatment of APL, and have speculated about a possible role of this drug through modulation of APL blasts and endothelial cells adhesion molecules.7, 8, 12, 17 However, more simple explanations can be considered. Indeed, the better outcome of APL patients treated with ATRA-based regimens have led to the emergence of leukemia from sanctuaries that otherwise did not have the opportunity to appear. This was why we analyzed the incidence of EM relapse using a competing risk method, which takes into account other events, such as hematological relapse and death prior to relapse, that can compete with the incidence of EMD. To our knowledge, this is the first study based on a large series of patients with APL, who were treated with ATRA-based regimens that analyzed the incidence of EM relapse using this suitable statistical method.

The 3-year cumulative incidence of EM relapse we observed (5% of the first relapses) is similar to that previously published,8, 13, 16 which ranged from 5 to 12%. As in the GIMEMA experience,16 CNS involvement greatly predominated. Of note is that the only skin relapse occurred at the site of BM aspiration and venous catheterism, as previously reported for some skin relapses.15 Several reports found, in patients with EM relapse,12, 13, 15, 16, 17 a high incidence of presenting features such as the microgranular M3 variant, the bcr3 PML-RARα isoform, both features being correlated to high WBC counts.26, 27, 28 However, those presenting features may also be absent in case of ear involvement.18 Finally, it has been suggested that occurrence of RA syndrome might be associated with an increased risk of EM relapse.14

In our study, patients with EM relapse had significantly higher WBC counts at diagnosis, a higher incidence of bcr3 PML-RARα isoform but, also, were significantly younger than the other APL patients included in the study. A relationship between hyperleucocytosis and bcr3 isoform and younger age had been previously reported.26, 29 Patients included in PETHEMA trial had a higher incidence of CNS relapses. However, they were significantly younger and had higher incidence of the bcr3 PML-RARα isoform than patients included in the APL91 and APL93 trials. Their higher incidence of EM relapse was not confirmed when other competing risk factors were taken into account. On the other hand, PETHEMA patients had shorter follow-up than APL91 and APL93 patients and therefore less time at risk of EM relapse. Those confounding factors make comparisons between PETHEMA and APL91 and APL93 trials for the incidence of EM relapse difficult to interpret.

We found no significant correlation between the occurrence of RA syndrome and subsequent EM relapse.14 CD56 may be associated with a worse outcome in APL patients30 and with an increased risk of CNS relapse in acute lymphoblastic leukemia,31 but we could not assess the impact of this parameter on the risk of EM relapse due to the low number of patients studied immunophenotypically.

EM relapse was associated with overt or molecular relapse in 80% of the cases. This is an incidence similar to that previously published.16 Despite intensive systemic therapy in addition to intrathecal therapy, followed by allogeneic or autologous stem cell transplantation in most cases, patients with an EM relapse had a poorer outcome as compared with isolated BM relapse (P=0.04), contrary to the AIDA experience.16

In conclusion, EM relapse occurred more frequently in younger patients, in patients with increased WBC counts (10 000/mm3) and bcr3 PML-RARα breakpoint. They largely predominated in the CNS, were often associated with marrow relapse and carried a poor prognosis. Whether CNS prophylaxis by intrathecal chemotherapy (and/or systemic high-dose AraC) should be systematically performed in patients with WBC 10 000/mm3 at diagnosis remains to be established.


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This work was supported by the Programme Hospitalier de Recherche Clinique (CHU Lille), the Association de Recherche contre le Cancer and the Ligue Nationale contre le Cancer (Comité du Nord).

Author information



Corresponding author

Correspondence to P Fenaux.

Additional information

Complete list of participants and addresses are given in appendix A.

Appendix A

Appendix A

The following clinical departments and personnel participated in the PETHEMA 96 trial:

Hospital Universitario La Fe, Valencia, Sanz MA, Martín G; Hospital Central de Asturias, Oviedo, Rayón C; Hospital Clínico San Carlos, Madrid, Díaz-Mediavilla J; Hospital Clínico Universitario, Valencia, Terol MJ; Hospital Insular de Las Palmas, Las Palmas, González JD; Hospital Clinic, Barcelona, Esteve J; Hospital General, Alicante, Rivas C; Hospital U. Germans Trias i Pujol, Badalona, Ribera JM; Complexo Hospitalario Xeral-Calde, Lugo, Arias J; Hospital Universitario, Salamanca, González M; Hospital de Cruces, Baracaldo, Alvarez MC; Complejo Hospitalario, León, Ramos F; Hospital Juan Canalejo, La Coruña, Debén G; Hospitales Ntra Sra del Pino/Sabinal, Las Palmas, Mataix R; Hospital Reina Sofia, Córdoba, Tabares S; Hospital Clínico Universitario, Valladolid, Fernández F; Hospital Universitario Vall D'Hebron, Barcelona, Bueno J; Hospital Son Dureta, Palma de Mallorca, Novo A; Hospital Xeral de Galicia, Santiago de Compostela, Pérez M; Hospital Ramón y Cajal, Madrid, Odriozola J; Hospital do Meixoeiro, Vigo, Loureiro C; Hospital Severo Ochoa, Leganés, Sánchez P; Hospital Dr Peset, Valencia, Sayas MJ; Hospital 12 de Octubre, Madrid, De la Serna J; Hospital General de Murcia, Murcia, Moraleda JM; H Universitario Virgen de la Victoria, Málaga, Pérez I; HU Puerta del Mar, Cádiz, Capote FJ Hospital San Pedro de Alcántara, Cáceres, Bergua JM; Hospital Materno-Infantil de Las Palmas, Las Palmas, Lodos JC Basurtuko Ospitalea, Basurto, Beltrán de Heredia JM; Hospital Rio Hortega, Valladolid, Peñarrubia MJ; Hospital Clínico Universitario Lozano Blesa, Zaragoza, Palomera L; Hospital General Jerez de la Frontera, Jerez de la Frontera, León A; Hospital General, Albacete, Romero JR; Hospital Xeral Cíes, Vitoria, Poderós C; Hospital Txagorritxu, Vitoria, Guinea JM; Hospital San Pau, Barcelona, Brunet S; Hospital General (Oncología Pediátrica), Alicante, Esquembre C; Hospital Rio Carrión, Palencia, Ortega F; Hospital U Marqués de Valdecilla, Santander, Conde E; H Universitario La Fe (Hospital Infantil), Valencia, Castell V

The following laboratories and personnel participated in the PETHEMA 96 trial:

Hospital Universitario La Fe, Valencia, Bolufer P, Barragán E; Hospital Universitario, Salamanca, González M, Chillón C; Hospital Clinic, Barcelona, Colomer D; Hospitales Ntra Sra del Pino/Sabinal, Las Palmas, Gómez T; Hospital Reina Sofia, Córdoba, Román J; Universidad de Navarra, Pamplona, Calasanz MJ; Hospital 12 de Octubre, Madrid, Bornstein R; Hospital Clínico San Carlos, Madrid, Villegas A; Hospital Clínico Universitario, Valencia, Marugán I; Hospital Ramón y Cajal, Madrid, Ferro C; Hospital do Meixoeiro, Vigo, Loureiro C; Hospital U Marqués de Valdecilla, Santander, Richard C.

Dr P Fenaux and Dr L Degos served as cochairmen, and Dr C Chastang and S Chevret-Chastang (Department of Biostatistics, Hopital St Louis, Paris), as biostatiscians. The following clinical departments participated in APL91 and APL93 trials:

French APL Group: S Castaigne, H Dombret (Paris), R Zittoun (Paris), E Archimbaud (Lyon), P Travade (Clermont Ferrand), C Gardin (Clichy), A Guerci (Nancy), S de Botton (Lille), AM Stoppa (Marseille), F Dreyfus (Paris), F Stamatoulas (Rouen), F Rigal-Huguet (Toulouse), H Guy (Dijon), JJ Sotto (Grenoble), F Maloisel (Strasbourg), J Reiffers (Pessac), A Gardembas (Angers), D Bordessoule (Limoges), N Fegueux (Montpellier), A Veil (Paris), T Lamy (Rennes), M Hayat (Villejuif), E Deconinck (Besancon), E Guyotat (St Etienne), M Martin (Annecy), E Cony-Makhoul (Bordeaux), JP Abgrall (Brest), O Reman (Caen), B Desablens (Amiens), JL Harousseau (Nantes), Y Bastion (Lyon), JP Pollet (Valenciennes), J Pulik (Argenteuil), M Lepeu (Avignon), M Renoux (Bayonne), P Morel (Lens), P Henon (Mulhouse), N Gratecos (Nice), P Colombat (Tours), D Machover (Villejuif), A Dor (Antibes), P Casassus (Bobigny), J Donadio (Castelnou), B Salles (Chalon), B Legros (Clermont Ferrand), P Audhuy (Colmar), A Dutel (Compiègne), N Philippe (Lyon), B Benothman (Meaux), C Christian (Metz), C Margueritte (Montpellier), F Witz (Nancy), A Pesce (Nice), A Baruchel (Paris), L Sutton (Paris), C Quetin (Pointe à Pitre), B Pignon (Reims), E Vilmer (Paris), E Bourquard (St Brieuc), JP Marolleau (Paris), P Robert (Toulouse), B Despax (Toulouse), G Nedellec, P Auzanneau (Paris), M Janvier (St Cloud).

Spanish AML Group: O Rayon (Oviedo), M Sanz (Valencia), J San Miguel (Salamanca), J Montagud (Valencia), E Condé (Santander), P Javier de la Serna (Madrid), G Martin (Valencia), M Perez Encinas (Santiago), JP Torres Carrete (Juan Canalejo), J Zuazu (Barcelone), J Odriozola (Madrid), E Gomez-Sanz (Madrid), L Palomera (Zaragoza), L Villegas (Almeria), A Deben (Juan Canalejo), P Besalduch (Palma de Mallorca).

Cooperative AML Study Group, Germany: H Link (Hannover), A Ganser (Frankfurt), E Wandt (Nurnberg), A Breitenbach (Stuttgart), B Brennscheidt (Freiburg), D Herrmann (Ulm), H Soucek (Dresden), H Strobel (Erlangen).

Swiss Group for Clinical Cancer Research AML group: K Geiser (Berne), M Fey (Berne), T Egger (Berne), E Jacky.

Belgian Group: JL Michaux (Bruxelles), A Bosly (Yvoir), E Meeus (Anvers), A Boulet (Mons).

Dutch group: P Daenen (Groningen), P Muus (Nijmegen).

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de Botton, S., Sanz, M., Chevret, S. et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia 20, 35–41 (2006).

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  • acute promyelocytic leukemia
  • extramedullary relapse
  • all-trans retinoic acid

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