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Leukemia (2003) 17, 1600–1604 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu after acute promyelocytic : the European APL group experience I Lobe1, F Rigal-Huguet2, A Vekhoff3, B Desablens4, D Bordessoule5, C Mounier6, A Ferrant7, M Sanz8, M Fey9, C Chomienne10, S Chevret11, L Degos12 and P Fenaux13 for the European APL group 1Service des Maladies du Sang, CHU Lille, France; 2Service d’He´matologie, CHU Toulouse, France; 3De´partement d’He´matologie et Oncologie Me´dicale, Hoˆpital Hoˆtel-Dieu, Paris, France; 4Service des Maladies du Sang, CHU Amiens, France; 5Service d’He´matologie Clinique, CHU Limoges, France; 6De´partement d’He´matologie, CHU Saint-Etienne, France; 7Service d’He´matologie, UCL Bruxelles, Belgium; 8Hospital Clinico de Valencia, Espagne; 9Medical Institute (INSEL), Bern, Switzerland; 10Laboratoire de Biologie Cellulaire He´matopoı¨e´tique, Hoˆpital Saint-Louis, Paris, France; 11DBIM, Hoˆpital Saint-Louis, Paris, France; 12Institut d’He´matologie, Hoˆpital Saint-Louis, Paris, France; and 13Service d’he´matologie clinique, Hoˆpital Avicenne, Bobigny, France

With improved treatment of acute promyelocytic leukemia major emerging problem in the follow-up of APL. Those findings (APL) by all trans retinoic acid (ATRA) combined to anthracy- prompted us to review cases of MDS or AML (non-APL) cline–aracytin (CT), a larger number of those patients may be at risk of late complications. Recently, the occurring during the evolution of APL patients included in Rome group reported five cases of myelodysplastic syndrome multicenter trials of our European group. (MDS) or acute (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete (CR). From 1991 to 1998, we treated 677 newly Patients and treatment diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n ¼ 579) or CT alone (n ¼ 38); 246 of Patients them received subsequent maintenance CT with 6 mercapto- purine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13–74 months after Between 1991 and 1998, we included 677 newly diagnosed the diagnosis of APL. In all six cases, t(15;17) and PML- cases of APL in APL 91 and APL 93 trials. Inclusion criteria were: RARalpha rearrangement were absent at the time of MDS diagnosis of APL based on morphological criteria and subse- diagnosis, and mainly showed complex cytogenetic quently confirmed by presence of t(15;17) or PML-RAR alpha abnormalities involving 5 and/or 7, typical of rearrangement,8 age 75 years or less, and a minimum MDS observed after treatment with alkylating agents, although follow-up of 3 years. none of the six patients had received such agents for the treatment of APL. Our findings suggest that MDS can indeed be a long-term complication in APL, although probably at lower 9–11 incidence than that previously reported. Treatment Leukemia (2003) 17, 1600–1604. doi:10.1038/sj.leu.2403034 Keywords: acute promyelocytic leukemia-myelodysplastic APL 91 trial design: Patients were randomized to receive syndrome; therapy related chemotherapy alone (CT group) or ATRA followed by CT (ATRA group). In the CT group, patients received two successive courses of (DNR) 60 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days (courses I and II). Those who Introduction achieved complete remission (CR) after course I received a final course of DNR 45 mg/m2/day for 3 days and AraC 1 g/m2 every Acute promyelocytic leukemia (APL) is a specific type of acute 12 h for 4 days (course III). Patients who achieved CR only after myeloid leukemia (AML) characterized by the morphology of course II received two cycles of course III. blast cells (M3 according to FAB classification), t(15;17) In the ATRA group, patients received ATRA 45 mg/m2/day translocation that fuses the PML gene on 15 to orally until CR, or for a maximum of 90 days. After CR the RAR alpha gene on , and by specific achievement, they received the same three CT courses as in the 1,2 . –aracytin (AraC) chemotherapy CT group. (CT), introduced in the 1960s, has yielded cure rates of 35–40% in APL, whereas combination of anthracycline–Ara C or APL 93 trial design: Induction treatment was stratified on anthracycline alone CT to all trans retinoic acid (ATRA), age and initial WBC. Patients aged less than 65 years with WBC introduced in the early 1990s, has improved this cure rate to 3 less than 5000/mm were randomized between ATRA followed 65–70%,3–6 thereby increasing the number of patients poten- by CT (ATRA-CT group) similar to the ATRA group of APL 91 tially at risk of late side effects of treatments. In the last 2 years, trial, and ATRA plus CT (ATRA+CT) differing from ATRA-CT several case reports of myelodysplastic syndrome (MDS) or AML by the fact that CT was started on day 3 of ATRA treatment. (different from APL), occurring during the course of APL, have 3 7 Patients with WBC45000/mm at presentation or aged 66 to been made. Recently, the Rome group reported five cases of 3 75 years and with WBC less than 5000/mm were not MDS in 77 (6.5%) APL patients treated with CT alone or ATRA randomized and received ATRA plus CT course I from day 1 combined to CT, suggesting that MDS/AML was possibly a and the same treatment as in the ATRA-CT group, respectively. Patients who achieved CR received two CT consolidation ´ Correspondence: Dr P Fenaux, Service d’hematologie clinique/ Paris courses (similar to courses II and III of APL 91 trial). The elderly XIII Universite´,Hoˆpital Avicenne 125 rue de Stalingrad, 93009 Bobigny, France; Fax :+33 0 140875487/0148955499; pierre.fe- group, however, only received course II. Patients were then [email protected] offered a second randomization testing maintenance treatment Received 11 February 2003; accepted 8 April 2003 with intermittent ATRA (45 mg/m2/day, 15 days every 3 months) Myelodysplastic syndrome after APL I Lobe et al 1601 and continuous CT with 6 mercaptopurine (6 MP, 90 mg/m2/day and 22, dup (12)(q12;q22), and patient no. 5 had monosomy 8 orally) and methotrexate (MTX, 15 mg/m2/week), both sched- and t(8;11)(q32;q21). At the time of MDS diagnosis, no t(15;17) uled for 2 years. was found, and PML-RARalpha was negative in five patients. In the remaining patient (patient no. 3), where the research of the Follow-up transcript was a failure, FISH analysis was negative for t(15;17). Three of the six patients progressed to AML (MoAML in all three cases) 1, 6 and 18 months after diagnosis of MDS. Patients were followed up until January 1st 2000 (sixth interim Treatment of MDS/AML was symptomatic in four patients and analysis) for APL 91 trial and January 1st 2002 (third interim consisted of intensive chemotherapy in the remaining two cases analysis) for APL 93 trial. MDS and AML were classified (nos. 1 and 6). Patient no. 1 did not achieve CR and died a few according to FAB group criteria.12 months later of progressive ; patient no. 6 achieved CR and was receiving consolidation courses. Results After diagnosis of RA, one patient (no.2) relapsed from her APL. Karyotype showed both t(15;17) and rearrangements In total, 677 patients were included in APL 91 trial (n ¼ 101) and observed during the MDS phase. PML-RARalpha rearrangement APL 93 trial (n ¼ 576). Of these 617 of them achieved CR, after was present. The patient was treated by ATRA and chemotherapy alone (n ¼ 38) or ATRA combined to or followed AraC. APL blasts, t(15;17) and PML-RARalpha rearrangement by chemotherapy (n ¼ 579). After consolidation chemotherapy, disappeared, but cytopenias, myelodysplastic features in bone 117, 76 and 129 of the complete remitters received main- marrow and cytogenetic rearrangements other than t(15;17) tenance treatment with 6MP+MTX, intermittent ATRA or both persisted, the diagnosis being still that of RA; she evolved 3 treatment modalities, respectively. The other patients received months later to RAEB and died of progressive disease. no maintenance treatment. With a median follow-up of 51 months (range: 39–118), six patients (0.97%) developed MDS or AML including one of the Discussion patients included in APL 91 trial and five of the patients included in APL 93 trial. The incidence of MDS/AML after APL we report, close to 1%, Clinical and hematological characteristics of the patients who was lower than in the Rome group experience, although the developed MDS or AML are shown in Table 1. Median age was follow-up was similar. 56.5 years (range: 52–73) at diagnosis of APL, and 59.5 years If one includes the five patients reported by the Rome group, (range: 57–76) at diagnosis of MDS/AML and there were two the six patients presented here and previous case reports, 22 females and four male patients. Five patients initially had cases of MDS or AML (other than APL) occurring during the classical APL and one had the microgranular variant APL. course of APL have been reported,14–25 and their characteristics Patient 1 had been previously reported.13 are shown in Table 2. Cytogenetic study at diagnosis of APL showed isolated Median age of those 22 patients at diagnosis of APL was 52 t(15;17) translocation in three patients. Patients nos. 1 and 4 years (range: 8–73) and they included 12 male and 10 female had additional clonal abnormalities: del(9) (q21q31) in patient patients. Their features were similar to those of APL patients no. 4, del(3) (q24q26), del(5) (q23q32), t(7;11) (p11;p12) in included in APL 91 and 93 trials in general:9–11 four initially had patient no. 1. Patient no. 5 had cytogenetic failure, but PML- WBC counts greater than 10,000/mm3, one had the M3V RARalpha rearrangement was present. All six patients had microgranular variant and three had cytogenetic abnormalities achieved CR with ATRA combined to (patient nos. 1, 2 and 5) or in addition to t(15;17); four of the 22 patients had APL relapse followed by chemotherapy (patient nos.3, 4 and 6). None of the before developing MDS. Our six patients who developed MDS six patients who initially received four courses of intensive had received DNR and AraC, and three of them had also chemotherapy (two successive courses no. III) experienced received 6MP and MTX. In the 16 previously reported cases, in subsequent MDS or AML. t(15;17) and additional abnormalities addition to an anthracycline, 12 had also received VP16, nine had disappeared after CR achievement and RT-PCR analysis had had received 6MP and MTX, five 6TG, but only six had received become negative in all patients. Patient no. 3 had relapsed 40 an alkylating agent, as part of a conditioning regimen for an months after CR achievement and had been treated by autograft in three cases. The fact that all patients, in GIMEMA chemotherapy with ATRA and mitoxantrone-AraC, he achieved group trials had received VP 16 for consolidation (although the CR, received two consolidation courses with – cumulative dose was only 500 mg/m2) whereas no VP 16 was , followed by autologous transplan- administered in APL 91 and 93 trials could have explained in tation (ASCT) preceded by – conditioning. part the lower incidence of AML/MDS we observed in those MDS developed 13–74 months (median: 46.5) after diagnosis trials. of APL. The six MDS cases included three cases of refractory Median interval from diagnosis of APL to that of MDS was 43 (RA), two cases of RA with excess blasts (RAEB), one months (range: 13–111). 17 patients initially had MDS, three case of RAEB in transformation (RAEB-t). In one case of RA had AML without a preceding MDS phase (and information on (patient no. 4), the patient had cytogenetic features of MDS preceding MDS was not available for two patients). Karyotype at without cytopenias or any during 42 the time of MDS/AML, was abnormal in all but one case, months before a diagnosis of RA could be made. In this patient, included partial or complete deletion of chromosomes 7 and 5 cytogenetic study had been made for a preheart transplant in 10 and nine cases respectively, and complex karyotype in evaluation 69 months after the diagnosis of APL; karyotype at eight cases. Balanced translocations were observed in seven the time of RA diagnosis was unchanged. patients and, in two of them, involved 21q22 typical breakpoints Cytogenetic analysis at MDS diagnosis showed rearrange- observed in therapy related AML occurring after topoisomerase ments of chromosomes 5, 17 and 7 in five, four and two II inhibitors.26,27 In all, 11 of the patients progressed to AML. patients, complex (three chromosomal rearrangements or Median survival was 7 months (range: 1–26), only eight greater) in four of them. Patient no. 3 had monosomy 17, 18 patients surviving more than 1 year. Of note was that two of the

Leukemia Myelodysplastic syndrome after APL I Lobe et al 1602 patients had APL recurrence after diagnosis of MDS (after 2 and 7 months, respectively), including our case no.2. In this patient, karyotype and RT-PCR at the time of MDS diagnosis and after a Survival from MDS diagnosis (months) 11.5 0.8 7.5 new CR of APL had been reached showed no t(15;17) and no PML-RARalpha fusion transcript. In the other patient, t(15;17) was not found at the time of MDS diagnosis by conventional (which showed typical MDS findings: monosomy 5 Progression to AML 6 months No 25.4 M0 AML after 1 month No 24+ 18 months Noand 4+ 7) but by FISH analysis, and relapse of APL rapidly occurred. Our new cases, review of the previously published literature and discussions raised by publication of the Rome group’s experience, help give a better understanding of cases of MDS occurring during the course of APL.28,29 In most reported cases, diagnosis of MDS/AML was made at a stage of MDS ; furthermore, cytogenetic findings were generally typical of therapy-related MDS, showing rearrangements of chromosomes Karyotype at diagnosis of MDS t(15;21)(p11;q21), -17, +mar 43, XY, del(5)(q12q35), add(11)(q23), dup(12) (q12q22), -17, -18, -22 (q11;p? or q?), der(10)t(7;10;20) (q3?;q2?; p? or q?),der(17)t(10;17)(q2?;p11), -13, -20, del(20)(q11), +mar1, +mar3/ 47, idem, del (X) (q26),(1;?)(p36;?), der(1) +8, +mar2 del(5)(q13q33), del(6)(p22),-17 5 and/or 7, often complex. Those findings suggested that MDS/ AML were indeed secondary to treatment of APL and did not by a a correspond to clonal evolution of APL, or fortuitous association of another leukemia. On the other hand, therapy-related MDS with and/or 7 deletion or complex karyotype are 26,27 PML-RAR RT-PCR at MDS diagnosis FISH for PML-RAR negative generally reported after prolonged use of alkylating agents, which was generally not the case in MDS that occurred during APL evolution. Therefore, Klarskov Andersen and Pedersen- Bjergaard,23 suggested the hypothesis that those MDS/AML FAB type of MDS RA Negative 46, XX, del(5)(q22q34), RAEB Failure could correspond, at least in some cases, to APL relapse in a cytogenetically unrelated , as sometimes described in other AML types. There is however limited evidence to support this hypothesis. Furthermore, in at least one case of MDS/AML Interval from APL to MDS diagnosis (months) 13 (relapse occurred 7 months after MDS diagnosis) 46 (6 months after relapse) following APL, demonstration by RFLP analysis that the two disorders emerged from different clones was made.28 A final possibility could be that, in some cases, APL was the acute transformation of a previously undiagnosed underlying MDS, which continued its evolution, after APL remission or cure, to full-blown MDS. Although no features of MDS were treatment APL relapse and its ATRA combined to CT by ASCT No relapsereported 47 in RAEB-t 21 Negative of the 45, XY, t(3;17)(p11;q11), 22 cases at APL diagnosis or after CR achievement for APL, small arguments in favor of this hypothesis, in MDS/AML after APL, could be the re-evolution of APL in two of the 22 MDS cases, after MDS diagnosis, and the presence of del(3q) and del(5q) (typical of MDS) at diagnosis of Maintenance treatment MTX-6MP No relapse 32 RAEB Negative 45, XX, del(5)(q21q34)-7 M0 AML after ATRA+ MTX-6MP None CT followed None No relapse 111 RA Negative 45, XY, -5, der(7)t(7;20) None No relapse 74 RA Negative 45, XY, -8, t(8;11)(q32;q21) M0 AML after ATRA+ MTX-6MP APL in our patient no.1. Furthermore, we recently observed a patient with MDS who progressed to APL, with return to a typical MDS phase after achieving CR of APL (unpublished Front line therapy trial trial trial trial trial trial data). In conclusion, the occurrence of tMDS/AML after APL seems a to be a rare event, with no clearly identified risk factors. It is of concern in a highly curable form of leukemia and further works at APL diagnosis Positive APL 93 Positive APL 93 Positive APL 93 Positive APL 91 Positive APL 93 Positive APL 93 on the subject are certainly encouraged.

Acknowledgements FAB type PML-RAR Classical APL Classical APL Classical APL Micro- granular variant APL APL Classical APL This work was supported by the Ligue Nationale Centre le (Comile´ du Nord). The Association de Accheriche Centre le Cancer and the Programme Hospitalion de Recherche Clinique. Karyotype at APL diagnosis del(3)(q24q26), del(5 )(q23q32), t(7;11)(p11;p12), t(15;17)(q22;q21) t(15;17)(q22;q21) t(15;17)(q22;q21) del(9)(q21q31), t(15;17)(q22;q21) t(15;17)(q22;q21) References /l) 9 1 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, 10

 Gralnick HR et al. Proposals for the classification of the acute Main clinico-biological characteristics of patients with MDS/AML after APL at APL diagnosis WBC ( leukaemias. French–American–British (FAB) co-operative group. Br J Haematol 1976; 33: 451–458. Sex/ age 2 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. A variant form of hypergranular promyelocytic Table 1 Patient no. 1 F/61 148 46, XX, 2 F/56 0.8 46, XX, 3 M/52 0.7 46, XY, 4 M/57 1.4 46, XY, 5 M/73 1.3 Failure Classical 6 M/54 0.9leukemia 46, XY, (M3). Ann Intern Med 1980; 92: 261.

Leukemia Table 2 Review of previously published cases of MDS/AML occurring during the course of APL

Reference Age/ WBC Karyotype Drugs used duringAPL Number of APL Interval from FAB type of PML-RARa Karyotype at Progression to MDS/AML Survival from sex ( Â 109/l) at at APL treatment (other than relapse/ APL to MDS MDS/ AML at MDS/ diagnosis AML therapy MDS diagnosis APL diagnosis diagnosis anthracyclins) (treatment of diagnosis AML of MDS/ AML (months) relapse) (months) diagnosis

15 48/M 1.05 46, XY, 6MP, VP16 0 33 RAEB Negative 46, XY, t(7;21)(q31;q22) M1 AML after ATRA then 17 t(15:17)(q22;q21) 11 months CT 16 61/M 1.7 NA AraC, 6MP, VP16 0 43 NA NA 46, XY, t(3;21)(q26;q22), NA ATRA 5 der(4)t(4;?)(q27;?), der(7)t(4;7)(q27;q22), der(16)t(16;?)(p11;?) 17 57/F 0.6 46, XX, t AraC, CY, VCR, 6TG, 0 24 RAEB Negative 45, XX, dic(5;17) M2 AML after NA 6 (15;17)(q22;q21) MTX/6MP (q11;p11)/ 43, idem, 2 months -7, -20 18 15/F 1.4 46, XX, AraC, VP16, 6TG, 0 49 No MDS phase Negative 46, XX, t(10;11)(p14;q21) M4 AML CT then 2 (died on t(15;17)(q22;q21) MTX/6MP alloBMT D50 of GVHD) 19 26/F 8.4 46, XX, ATRA, VCR, MTX/6MP 0 34 RAEB-t ND 45, XX, -7, der(7)del(7)(p10) No CT NA t(15;17)(q22;q21) del (7)(q21) 20 31/M NA 46, XY, AraC Busulfan + CY 1/ ATRA+CT then 51(CR 1) 38 NA Negative 45, XY, -7 NA NA NA t(15;17)(q22;q21) (for autologous SCT autologous SCT (CR2) 36 (post conditioning) autoBMT) 21 55/M NA 46, XY, AraC, 6MP, VP16, CY 0 43 No MDS phase NA 46, XY, t(10;11)(q23;p15) M2 AML CT 26+ t(15;17)(q22;q21)

22 48/M NA 46, XY (PML-RAR +) ATRA, AraC, VP16 0 25 RAEB Negative 47, XY, +8 M2 AML after CT then 12+ Lobe I APL after syndrome Myelodysplastic 10 months autoSCT 23 43/F NA 46, XX, AraC, VP16 0 84 RAEB NA 43, XX, del(5)(q15), -7, No NA 3 t(15;17)(q22;q21) add(9)(q34), -18, -21 al et 24 8/M NA 46, XY, ATRA, AraC, VP16, 6MP, 0 34 No MDS phase ND 45, XY, -7 Acute CT 15+ t(15;17)(q22;q12) VCR, CY, 6TG biphenotypic leukemia 25 51/F NA 46, XX, ATRA, AraC, VP16, 0 26 RA Negative 46, XX, -5, add(6)(p23-25), M6 AML after CT 10 t(15;17)(q22;q21) 6TG MTX/6MP +8, add(17)(p13) 4 months 13,14 61/F 22.9 47, XX, +8, ATRA, AraC, MTX/ 6MP 1 (occurred 29 RAEB ND (FISH 45, XX, -5, -7, +11 No ATRA 3 t(15;17)(q22;q21) 2 months after was + for MDS) t(15;17) 7 52/F 1.5 46, XX, ATRA, VP 16, 6TG, 0 43 MDS negative 45, XX, -7 AML after Supportive 18+ t(15;17)(q22;q21) Ara C, MTX/6MP 18 months care 7 63/M 6.3 46, XY ATRA, VP 16, 6TG, 0 46 MDS Negative Failure AML after Supportive 1 t(15;17)(q22;q21 Ara C, MTX/6MP 1 month care 7 35/M 43.7 46, XY, AraC, VP16, 6TG, 1/ATRA, AraC, 48 (33 from 2nd MDS Negative 46, XY, del(5)(q?) AML after Supportive 5 t(15;17)(q22;q21) MTX/6MP AutoSCT CR) 2 months care 7 31/F 19.5 46, XX, ATRA, VP 16, 6TG, 2/1st: ATRA, CT, 24 (2 from 2nd MDS Negative 46, XX AML after Supportive 12+ t(15;17)(q22;q21) Ara C, MTX/6MP AutoSCT 2nd: CR) 5 months care then ATRA, CT alloSCT Leukemia 1603 Myelodysplastic syndrome after APL I Lobe et al 1604 3 De Botton S, Chevret S, Sanz M, Dombret H, Thomas X, Guerci A. 16 Miyazaki H, Ino T, Sobue R, Kojima H, Wakita M, Nomura T et al. Additional chromosomal abnormalities in patients with acute Translocation (3;21)(q26;q22) in treatment-related acute leukemia promyelocytic leukaemia (APL) do not confer poor : secondary to acute promyelocytic leukemia. Cancer Genet results of APL 93 trial. Br J Haematol. 2000; 111: 801–806. Cytogenet 1994; 74: 84–86. 4 Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and 17 Hatzis T, Standen GR, Howell RT, Savill C, Wagstaff M, Scott GL. chemotherapy in the treatment of acute promyelocytic leukemia. 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