With improved treatment of acute promyelocytic leukemia (APL) by all trans retinoic acid (ATRA) combined to anthracycline–aracytin chemotherapy (CT), a larger number of those patients may be at risk of late complications. Recently, the Rome group reported five cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete remission (CR). From 1991 to 1998, we treated 677 newly diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n=579) or CT alone (n=38); 246 of them received subsequent maintenance CT with 6 mercaptopurine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13–74 months after the diagnosis of APL. In all six cases, t(15;17) and PML-RARalpha rearrangement were absent at the time of MDS diagnosis, and karyotype mainly showed complex cytogenetic abnormalities involving chromosomes 5 and/or 7, typical of MDS observed after treatment with alkylating agents, although 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 incidence than that previously reported.
Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia (AML) characterized by the morphology of blast cells (M3 according to FAB classification), t(15;17) translocation that fuses the PML gene on chromosome 15 to the RAR alpha gene on chromosome 17, and by specific coagulopathy. 1,2 Anthracycline–aracytin (AraC) chemotherapy (CT), introduced in the 1960s, has yielded cure rates of 35–40% in APL, whereas combination of anthracycline–Ara C or anthracycline alone CT to all trans retinoic acid (ATRA), introduced in the early 1990s, has improved this cure rate to 65–70%,3,4,5,6 thereby increasing the number of patients potentially at risk of late side effects of treatments. In the last 2 years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL, have been made. Recently, the Rome group7 reported five cases of MDS in 77 (6.5%) APL patients treated with CT alone or ATRA combined to CT, suggesting that MDS/AML was possibly a major emerging problem in the follow-up of APL. Those findings prompted us to review cases of MDS or AML (non-APL) occurring during the evolution of APL patients included in multicenter trials of our European group.
Patients and treatment
Between 1991 and 1998, we included 677 newly diagnosed cases of APL in APL 91 and APL 93 trials. Inclusion criteria were: diagnosis of APL based on morphological criteria and subsequently confirmed by presence of t(15;17) or PML-RAR alpha gene rearrangement,8 age 75 years or less, and a minimum follow-up of 3 years.
APL 91 trial design
Patients were randomized to receive chemotherapy alone (CT group) or ATRA followed by CT (ATRA group). In the CT group, patients received two successive courses of daunorubicin (DNR) 60 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days (courses I and II). Those who 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 12 h for 4 days (course III). Patients who achieved CR only after course II received two cycles of course III.
In the ATRA group, patients received ATRA 45 mg/m2/day orally until CR, or for a maximum of 90 days. After CR achievement, they received the same three CT courses as in the CT group.
APL 93 trial design
Induction treatment was stratified on age and initial WBC. Patients aged less than 65 years with WBC less than 5000/mm3 were randomized between ATRA followed by CT (ATRA → CT group) similar to the ATRA group of APL 91 trial, and ATRA plus CT (ATRA+CT) differing from ATRA → CT by the fact that CT was started on day 3 of ATRA treatment.
Patients with WBC>5000/mm3 at presentation or aged 66 to 75 years and with WBC less than 5000/mm3 were not randomized and received ATRA plus CT course I from day 1 and the same treatment as in the ATRA → CT group, respectively.
Patients who achieved CR received two CT consolidation courses (similar to courses II and III of APL 91 trial). The elderly group, however, only received course II. Patients were then offered a second randomization testing maintenance treatment with intermittent ATRA (45 mg/m2/day, 15 days every 3 months) and continuous CT with 6 mercaptopurine (6 MP, 90 mg/m2/day orally) and methotrexate (MTX, 15 mg/m2/week), both scheduled for 2 years.
Patients were followed up until January 1st 2000 (sixth interim analysis) for APL 91 trial and January 1st 2002 (third interim analysis) for APL 93 trial. MDS and AML were classified according to FAB group criteria.12
In total, 677 patients were included in APL 91 trial (n=101) and APL 93 trial (n=576). Of these 617 of them achieved CR, after chemotherapy alone (n=38) or ATRA combined to or followed by chemotherapy (n=579). After consolidation chemotherapy, 117, 76 and 129 of the complete remitters received maintenance treatment with 6MP+MTX, intermittent ATRA or both treatment modalities, respectively. The other patients received 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 patients included in APL 91 trial and five of the patients included in APL 93 trial.
Clinical and hematological characteristics of the patients who developed MDS or AML are shown in Table 1. Median age was 56.5 years (range: 52–73) at diagnosis of APL, and 59.5 years (range: 57–76) at diagnosis of MDS/AML and there were two females and four male patients. Five patients initially had classical APL and one had the microgranular variant APL. Patient 1 had been previously reported.13
Cytogenetic study at diagnosis of APL showed isolated t(15;17) translocation in three patients. Patients nos. 1 and 4 had additional clonal abnormalities: del(9) (q21q31) in patient no. 4, del(3) (q24q26), del(5) (q23q32), t(7;11) (p11;p12) in patient no. 1. Patient no. 5 had cytogenetic failure, but PML-RARalpha rearrangement was present. All six patients had achieved CR with ATRA combined to (patient nos. 1, 2 and 5) or followed by chemotherapy (patient nos.3, 4 and 6). None of the six patients who initially received four courses of intensive chemotherapy (two successive courses no. III) experienced subsequent MDS or AML. t(15;17) and additional abnormalities had disappeared after CR achievement and RT-PCR analysis had become negative in all patients. Patient no. 3 had relapsed 40 months after CR achievement and had been treated by chemotherapy with ATRA and mitoxantrone-AraC, he achieved CR, received two consolidation courses with idarubicin–cyclophosphamide, followed by autologous stem cell transplantation (ASCT) preceded by busulfan–melphalan conditioning.
MDS developed 13–74 months (median: 46.5) after diagnosis of APL. The six MDS cases included three cases of refractory anemia (RA), two cases of RA with excess blasts (RAEB), one case of RAEB in transformation (RAEB-t). In one case of RA (patient no. 4), the patient had cytogenetic features of MDS without cytopenias or any bone marrow dysplasia during 42 months before a diagnosis of RA could be made. In this patient, cytogenetic study had been made for a preheart transplant evaluation 69 months after the diagnosis of APL; karyotype at the time of RA diagnosis was unchanged.
Cytogenetic analysis at MDS diagnosis showed rearrangements of chromosomes 5, 17 and 7 in five, four and two patients, complex (three chromosomal rearrangements or greater) in four of them. Patient no. 3 had monosomy 17, 18 and 22, dup (12)(q12;q22), and patient no. 5 had monosomy 8 and t(8;11)(q32;q21). At the time of MDS diagnosis, no t(15;17) was found, and PML-RARalpha was negative in five patients. In the remaining patient (patient no. 3), where the research of the 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. Treatment of MDS/AML was symptomatic in four patients and consisted of intensive chemotherapy in the remaining two cases (nos. 1 and 6). Patient no. 1 did not achieve CR and died a few months later of progressive disease; patient no. 6 achieved CR and was receiving consolidation courses.
After diagnosis of RA, one patient (no.2) relapsed from her APL. Karyotype showed both t(15;17) and rearrangements observed during the MDS phase. PML-RARalpha rearrangement was present. The patient was treated by ATRA and mitoxantrone AraC. APL blasts, t(15;17) and PML-RARalpha rearrangement disappeared, but cytopenias, myelodysplastic features in bone marrow and cytogenetic rearrangements other than t(15;17) persisted, the diagnosis being still that of RA; she evolved 3 months later to RAEB and died of progressive disease.
The incidence of MDS/AML after APL we report, close to 1%, was lower than in the Rome group experience, although the follow-up was similar.
If one includes the five patients reported by the Rome group, the six patients presented here and previous case reports, 22 cases of MDS or AML (other than APL) occurring during the course of APL have been reported,14,15,16,17,18,19,20,21,22,23,24,25 and their characteristics are shown in Table 2.
Median age of those 22 patients at diagnosis of APL was 52 years (range: 8–73) and they included 12 male and 10 female patients. Their features were similar to those of APL patients included in APL 91 and 93 trials in general:9,10,11 four initially had WBC counts greater than 10,000/mm3, one had the M3V microgranular variant and three had cytogenetic abnormalities in addition to t(15;17); four of the 22 patients had APL relapse before developing MDS. Our six patients who developed MDS had received DNR and AraC, and three of them had also received 6MP and MTX. In the 16 previously reported cases, in addition to an anthracycline, 12 had also received VP16, nine had received 6MP and MTX, five 6TG, but only six had received an alkylating agent, as part of a conditioning regimen for an autograft in three cases. The fact that all patients, in GIMEMA group trials had received VP 16 for consolidation (although the cumulative dose was only 500 mg/m2) whereas no VP 16 was administered in APL 91 and 93 trials could have explained in part the lower incidence of AML/MDS we observed in those trials.
Median interval from diagnosis of APL to that of MDS was 43 months (range: 13–111). 17 patients initially had MDS, three had AML without a preceding MDS phase (and information on preceding MDS was not available for two patients). Karyotype at the time of MDS/AML, was abnormal in all but one case, included partial or complete deletion of chromosomes 7 and 5 in 10 and nine cases respectively, and complex karyotype in eight cases. Balanced translocations were observed in seven patients and, in two of them, involved 21q22 typical breakpoints observed in therapy related AML occurring after topoisomerase II inhibitors.26,27 In all, 11 of the patients progressed to AML.
Median survival was 7 months (range: 1–26), only eight patients surviving more than 1 year. Of note was that two of the 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 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 cytogenetics (which showed typical MDS findings: monosomy 5 and 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 5 and/or 7, often complex. Those findings suggested that MDS/AML were indeed secondary to treatment of APL and did not correspond to clonal evolution of APL, or fortuitous association of another leukemia. On the other hand, therapy-related MDS with chromosome 5 and/or 7 deletion or complex karyotype are generally reported after prolonged use of alkylating agents,26,27 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 could correspond, at least in some cases, to APL relapse in a cytogenetically unrelated clone, 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 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 reported in 21 of the 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 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 data).
In conclusion, the occurrence of tMDS/AML after APL seems 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 on the subject are certainly encouraged.
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This work was supported by the Ligue Nationale Centre le Cancer (Comilé du Nord). The Association de Accheriche Centre le Cancer and the Programme Hospitalion de Recherche Clinique.
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Lobe, I., Rigal-Huguet, F., Vekhoff, A. et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia 17, 1600–1604 (2003) doi:10.1038/sj.leu.2403034
- acute promyelocytic leukemia-myelodysplastic syndrome
- therapy related
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