erythroleukemia: a comparison between the previous fab approach and the who classification

Leukemia Research 26 (2002) 423–429

Erythroleukemia: a comparison between the previous FABapproach and the WHO classification

Sophie Parka,∗, Françoise Picardb, Zahia Azguic, Franck Viguied, Annabelle Merlata,Martine Guesnub, Véronique Leblonde, François Dreyfusaa Service d’hématologie, Hôpital Cochin, 27 rue du Faubourg St-Jacques, 75014 Paris, France

b Laboratoire d’hématologie, Hôpital Cochin, 27 rue du Faubourg St-Jacques, 75014 Paris, Francec Laboratoire d’hématologie, Hôpital Pitié-Salpétrière, Paris, France

d Laboratoire de cytogénétique, Hôpital Hôtel-Dieu, Paris, Francee Service d’hématologie, Hôpital Pitié-Salpétrière, Paris, France

Received 8 March 2001; accepted 13 August 2001

Abstract

Erythroleukemia is, within FAB classification, a proliferation of erythroblasts superior to 50% and of myeloblasts superior to 30%. Thenew WHO classification abolishes the frontier between RAEB-t with 20% and leukemia with 30% of blasts. AML6 variant is a new entitycharacterized by the proliferation of immature erythroblasts and the absence of non-erythroid blast cells. We analyzed 16 erythroleukemia,5 RAEB-t and 2 AML6 variants to clarify their relationship.

We suggest on survival, karyotype and cytologic characteristics that secondary erythroleukemia are the same entity as RAEB-t, confirmingthe WHO classification and that amongst de novo erythroleukemia, there is ‘AML6 variant’ with pure erythroid lineage proliferation.© 2002 Elsevier Science Ltd. All rights reserved.

Keywords:Erythroleukemia; WHO classification; FAB classification; Acute myeloid leukemia 6 variant; Myelodysplasia

1. Introduction

Leukemias of erythroid lineage represent a heterogeneousentity. There are AML6 variants [1,2] in which essen-tially erythroid lineage proliferates, FAB-M6 and RAEB-twhere myeloblastic cells coexist with erythroid cells. The1985 FAB classification defined AML6 as a proliferationof immature erythroblasts >50% and of myeloblasts >30%amongst non-erythroid cells [3]. But the new WHO clas-sification considers that RAEB-t with 20% of myeloblastsare the same disease as leukemia with 30% of blasts [4].So RAEB-t and erythroleukemia (ERL) could be a singledisease evolving through different phases from dyserythro-poiesis to proliferation of myeloid lineage.

In an attempt to clarify criteria for cytological diagnosis,differential diagnosis and prognostic factors, we studiedretrospectively 16 patients with ERL fitting the definitionof AML6 in the FAB group, 5 patients with RAEB-t (>50%of erythroblasts and<30% of myeloblasts), and 2 patients

Abbreviations:ERL, erythroleukemia∗ Corresponding author. Tel.:+33-1-43263397; fax:+33-1-43263397.E-mail address:[email protected] (S. Park).

having AML6 variants. We classified them in multilin-eage AML/MDS and secondary AML/MDS according tothe WHO classification and we conclude that this WHOapproach is relevant.

2. Patients and methods

2.1. Patients

We reviewed and re-examined the bone marrow files oftwo institutions between 1985 and January 2000; 16 patientsfulfilled the AML6-FAB criteria, i.e. >50% of erythroblastsand >30% of myeloblasts amongst non-erythroid cells [1].Five RAEB-t with more than 50% of erythroblasts and>20% of myeloblasts were also included. There were twoAML6 variants with undifferentiated blasts that lately revea-led to be erythroblasts on immunophenotypage (CD36+,glycophorin positive). Therefore, 23 patients were studied.Medical records were reviewed to examine occupationalexposure or previous exposure to carcinogenic agents. Twogroups of patients were identified: one for primary and onefor secondary AML6.

0145-2126/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.PII: S0145-2126(01)00146-1

424 S. Park et al. / Leukemia Research 26 (2002) 423–429

2.2. Cytochemical analysis

Besides the percentage of erythroblasts and of the remai-ning non-erythroid blasts, we calculated the ratio of thenumber of immature against end-stage differentiation ery-throblasts to detect a maturation arrest. When this E1+E2/E3 + E4 ratio (pronormoblasts+ basophilic normoblasts/polychromatophilic+acidophilic normoblasts) was superiorto 0.3, it correlated with a maturation arrest [5].

Cytomorphology of abnormal cells was described foreach patient. We stressed the myelodysplastic featuresinvolving myeloid lineage and megakaryocytes as wellas erythroid lineage. Hyposegmentation, degranulation,micromegakaryoblasts, basophilic stippling, abnormalitiesof the nuclei were noted.

Table 1Clinical features of patients with AML6a

Patient Sex/age Diagnosis Toxic exposure Treatment/outcome Survival(months)

1 M/35 M4 then M6 Chemotherapy: alkylantsand cytarabine

Chemotherapy 9

2 M/67 M5 then M6 Chemotherapy for RAEB-t Chemotherapy 53 M/29 M6 NA Chemotherapy: CR, allo

BMT in CR1Alive, +29

4 M/71 M6 Hydroxyurea for polycythemia vera NT, dead (infectious disease) 15 F/49 M6 Nitrosourea and topoisomerase II

inhibitor agent and radiotherapy45 Gy for uterine cancer

NT, dead (infectious disease) 1

6 M/58 M6 Benzene, rubber, bitumen Chemotherapy, failure,dead (hemorrhage)

11

7 M/70 M6 No Chemotherapy, failure,dead of RL

5

8 F/44 M2 then M6 Chemotherapy for AML2 NT, dead 49 M/59 M6 Anthracyclin and alkylating

agent for NHLChemotherapy, failure, dead 3

10 M/20 M6 NA Chemotherapy, non-sensitiveRL 12 months later

17

11 M/67 M6 Benzene Chemotherapy, failure, dead 212 M/30 M6 No Chemotherapy: CR, allo BMT in CR1 Alive:+3013 M/26 M6 Dyes Chemotherapy, failure; second

intention chemotherapy: CR2related allo BMT: CR; dead

9

14 M/69 t-AML then M6 Chemotherapy for AML Chemotherapy, CR, dead of RL 515 M/58 M6 Pesticides Chemotherapy, CR, RL 10 months later 1116 F/67 M6v No NT 317 M/55 M6v Chemotherapy for myeloid

metaplasia (hydroxyurea,pipobroman, CCNU)

Chemotherapy, failure 6

18 M/54 RAEB-t NA Chemotherapy, CR, RL 8 months later 1919 M/49 RAEB-t NA20 F/75 RAEB-t Antipyrimidines and alkylating

agents and radiotherapy forbreast cancer

NT, dead 2

21 F/64 RAEB-t No Chemotherapy: CR, dead 622 M/64 RAEB-t then M6 No Chemotherapy, CR, dead of RL 1423 M/37 RAEB-t No Chemotherapy, failure, died of

M6 and aspergillosis5

a M6: AML6; M6v: AML6 variant; CR: complete remission; allo BMT: allo bone marrow transplantation; RL: relapse; t-AML6: therapy-relatedAML6; RAEB-t: refractory anemia with excess of blasts in transformation; NA: not available; NT: no treatment.

2.3. Cytogenetic studies

Chromosome studies were performed at leukemia pre-sentation for all patients on cultured bone marrow cells.Metaphases were R-banded by heat denaturation. At least20 mitoses were studied for each patient. Karyotypes wereclassified in three risk groups as described previously [6].

2.4. Statistical analysis

Survival distribution at the cut-off date of June 2000 wasestimated using the Kaplan and Meier method. Survivalcurves were compared between cytogenetic groups andbetween RAEB-t and FAB-AML6 leukemia with the logrank test [7]. AML6 variants were excluded for this latter

S. Park et al. / Leukemia Research 26 (2002) 423–429 425

comparison as they represent a particular subset. A signifi-cance level of 0.05 was used.

3. Results

3.1. Clinical findings

Patients’ ages ranged between 20 and 75 years old, median51.2 years old. All patients presented with a severe anemia(mean hemoglobin rate at 7.25 g/dl). None showed hyper-leukocytosis. Peripheral erythroblasts were common with amean of 86 erythroblasts/100 white blood cells. None pre-sented with hepatosplenomegaly or adenopathy (Table 1).

Thirteen patients out of 23 had a previous history ofexposure to mutagenic agents. Four patients had receivedanthracyclines and cytosine arabinoside for acute leukemia(AML2, AML5, AML4, and undetermined AML). Thedelays between previous leukemic disease and the onset ofAML6 were, respectively, of 9, 11, 12 and 33 months. Onepatient had been treated for non-Hodgkin lymphoma beforethe onset of AML6. Four patients had occupational exposureto benzene, toluene, rubber and bitumen for 14 years. Onepatient received hydroxyurea for polycythemia vera for 2years, and another one received pipobroman for agnogenicmyeloid metaplasia for 4 years, two patients had receivedchemotherapy and radiotherapy for breast cancer and uterinecancer, respectively. So 10 patients presented with de novoAML6, whereas in 13 patients, leukemia was preceded byeither significant occupational exposure or chemotherapy.

3.2. Cytology

Two groups could be defined according to erythroid lin-eage maturation. The first one with five patients (patientsnos. 2, 14, 15, 17, 20) was characterized by maturationarrest with accumulation of early erythroid precursors,and the ratio proerythroblasts+ basophilic erythroblasts/acidophil erythroblasts+ polychromatophilic erythroblastswas superior to 0.3. One of these patients had AML6v andthe other four ones had therapy-related AML6. In the secondgroup (18 patients), maturation to the later stages of ery-throid differentiation was quantitatively preserved (Table 2).

Erythroid lineage was very dysplastic in all patients, withmacroblasts (abnormal nucleo-cytoplasmic asynchrony) andbasophilic stippling.

Multilineage dysplasia was present. Megakaryocyteswere also dysplastic, with abnormalities of the nuclear seg-mentation or abnormalities of size (micromegakaryocytes innine patients). Dysgranulopoiesis was described in six pa-tients. There was no correlation between dysgranulopoiesisand previous exposure to cytotoxic agents. Two patients hadAML6 variants on these criteria: a predominant populationof erythroblasts (>50%) infiltration without a clear cyto-logical maturation, immunophenotyping compatible witherythroblasts markers as glycophorin and CD36.

Table 2Bone marrow findings in AML6 patients at initial presentationa

Patient % ER/% blasts E1+ E2/E3+ E4 Maturationarrest

1 54/32 6/48 No2 67/35 16/51 Yes3 48/27 12/36 No4 61/31 6/55 No5 68/49 11/57 No6 83/40 19/64 No7 73/30 11/62 No8 55/27 10/45 No9 84/30 15/69 No

10 50/46 2/48 No11 50/40 12/38 No12 62/27 10/40 No13 49/11 11/38 No14 40/40 35/72 Yes15 65/13 24/60 Yes16 28/29 5/23 No17 19/47 10/19 Yes18 77/12 9/68 No19 47/17 9/38 No20 53/19 20/33 Yes21 90/9 20/70 No22 52/21 7/45 No23 62/22 9/53 No

a ER: erythroblasts; E1: pronormoblasts, expressed as %; E2: baso-philic normoblasts; E3: polychromatophilic normoblasts; E4: acidophilicnormoblasts; E1+ E2/E3 + E4: ratio between early and late erythroidprecursors.

3.3. Cytogenetics

Karyotype at presentation was abnormal in all but fourpatients. For four other patients, the karyotype was unavail-able (not done or unsuccessful). For six patients (32%),there were less than two chromosome rearrangements (themost frequent abnormalities were duplication of chromo-some 1, trisomy 10, trisomy 8, deletion of chromosome9, chromosome 7 derivative). Complex karyotype occurredin nine patients (47%), four cases of whom had erythroidmaturation arrest.

There were bad prognosis cytogenetic abnormalities inthis latter group (loss of part or totality of chromosome 5was found in four patients with an unbalanced translocationresulting in a deletion of 5q, monosomy of chromosome7 in three patients, monosomy 17 in three patients), andespecially complex chromosome alterations which matchwell with secondary leukemia (eight patients out of ninewith complex karyotype had previous exposure to mutagenicagents) (Table 3).

3.4. Outcome

Chemotherapy was given to 15 patients and consisted ofan anthracycline and cytarabine in 13 patients. Five patientswere not treated (too old, refusal or PS >2) and died with amedian delay of 2 months. There were five failures and 10


Table 3Cytogenetic studies in 19 patients with AML6+ RAEB-ta

Patient Diagnosis Karyotype

1∗ M4 then M6 47, XY,+102∗ M5 then M6 44–45, XY, der(2) t(2;5) (p11; q?32),−3, der(5) t(2;5) (p?23; q?13), der(7) t(7;8) (p12; q13),

add (16) (q?23),−19, +min, +variations [20]3 M6 47, XY, +8 [20]4∗ M6 45, X, −Y, −5, −7, −17, −17, +der(22) t(22;7) (p11; q11),+mar1,+mar2,+mar3 with variation [20]5∗ M6 45, XX, del(4) (q25; q34),−7,+10, −12, add (16) (q22),−17, +mar [21]/46, XX [1]6∗ M6 41–44, XY, add (4) (qter),−5,−12,? der(16),−17, −17, −22, +mar1,+mar2,+variation [17]/46, XY [6]7 M6 47, XY, +8, del(9) (q?32; q?34) [23]/48, XY, idem,+del(9q) [1]8∗ M2 then M6 46, XX, del(9) (q21; q32) [6]/46, XX [82]9∗ M6 48, XY, +del(1) (q31), del(2) (p23),+i(7q), −12, del(12) (p12),−17, der(17?),+19, der(21)

t(21;?) (q22;?) with variations [22]10 M6 46, XX [16]11∗ M6 46, XY [23]12 M6 46, XY, t(11;19) (q23; p13) [20]13∗ M6 NA14∗ t-AML then M6 42, XY, del(1) (q11),−5, add (6) (p?), add (7) (p?),+der(9),+10, +der(11),−15, −16,

−17, −18, −19, −20 [11]/46, XY [29]15∗ M6 NA16 M6v 46, XY, dup(1) (p?p?) [20]17∗ M6v 46, XY [8]/47, del(X) (q22), Y, t(2;7) (q11; p13), del(4) (q21), der(7), der(8), der(9), der(10), der(19) [8]18 RAEB-t NA19 RAEB-t NA20∗ RAEB-t 45, XX, der(4), del(5) (q?22;? q32), idic(5) (q12),−6,−7, add (11) (p12), add (12) (p11),

r(14) (p?q?) [20]21 RAEB-t 46, XY [14]22 RAEB-t then M6 46, XY [20]23 RAEB-t 46, XY, del(7) (q22; q34) [6]/92, idem X2 [2]/46, XY, der(7) [8]/92, idem X2 [4]

a NA: not available; asterisk (*) denotes previous exposure to cytotoxic agents before diagnosis of AML6. Numbers in square brackets denotes numberof mitosis.

complete remissions after chemotherapy with disappearanceof dysplastic features. Six patients relapsed after CR1, witha mean delay of 8.6 months. Two patients received topote-can as an induction therapy but they died 4 months laterwithout remission. Three patients (patients nos. 3, 12 and13) had HLA matched-related allograft after CR1 or CR2(Table 1).

Mean survival was 5± 2.4 months (Fig. 1). Long-termsurvival included two allotransplantated patients who sur-vived longer than 29 months after diagnosis and were still

Fig. 1. Kaplan–Meier curve of overall survival of patients with erythroleukemia;n = 16 events on 18 patients.

alive at the cut-off point. One patient died of allografttoxicity with a survival of 6 months. Fifteen patients diedof persistent disease after chemotherapy failure. Three pa-tients died of infectious disease. Two patients died withouttreatment of their disease. High-risk karyotype group ofpatients had a poor mean survival of 5 versus 8.5 months inthe normal—intermediate risk karyotype group (P < 0.1,Fig. 2). AML6 had a mean survival of 5 versus 5.5 monthsfor RAEB-t (P < 0.5, Fig. 3). The two AML6 variants hada median survival of 4.5 months.


Fig. 2. Survival according to karyotypic risk on 19 patients (log rank test: 0.1).

Fig. 3. Comparison of overall survival between RAEB-t and AML6;n = 17, P < 0.5.

4. Discussion

AML6 is a heterogeneous entity amongst AML. It rep-resents 3–4% of AML [8–10]. Immature erythroid prolif-eration consists of (1) AML6 with coexistence of erythroidproliferation >50% of erythroblasts and presence of 30%of myeloblasts as described in the FAB classification; (2)M6 variants with only immature erythroid proliferation.We stress the fact that AML6 is a cytological diagnosisaccording to the FAB classification. Therefore, despitethe heterogeneous origins of this entity (de novo AML,therapy-related AML or phenotypic shift from other kindof myeloproliferative disease), we studied all these pa-tients. Roggli and Saleem described 15 cases with a mediansurvival of 4 months but the cytological description was

heterogeneous: they retained erythroleukemia or erythremicmyelosis in their 1982 study [8]. Atkinson et al. in a studyof 15 cases of FAB-AML6, mentioned the idea of a pro-gression from myelodysplastic syndrome to acute myeloidleukemia [9]. Since the new WHO classification whichabolishes the frontier between AML and RAEB-t, there isonly one updated description of AML6 as we know [11].Kowal-Vern et al. divided erythroleukemia into three groupsaccording to the WHO classification (M6A: myeloblast pre-dominance, M6B: proerythroblast predominance and M6C:mixed >30% myeloblasts and >30% proerythroblasts), andthey found that M6B and M6C had a poorer prognosis thanM6A. Interestingly, in their study, they outlined the factthat M6A patients had a higher incidence of myelodyspla-sia preceding the erythroleukemia. As AML6 and RAEB-t


are represented by a coexistence of a variable proportion oferythroblasts and myeloblasts, our hypothesis is that thesetwo entities are the evolution of a same disease, that thecytologic difference between AML6 and RAEB-t does nothave a prognostic impact and that there is no difference interms of karyotype abnormality and survival.

We studied 23 cases of erythroleukemia occurring in twohematological centers between 1985 and 2000 to clarify therelationship between AML6, RAEB-t and AML6 variants.Sixteen patients had AML6 in the FAB classification, fivepatients had RAEB-t with 20% of myeloblasts and at least50% of erythroblasts and two patients had AML6 variants.Thirteen patients had a previous history of an exposure tochemotherapy or mutagenic agents. Ten patients had denovo AML6. This is consistent with the rate of secondaryerythroleukemia described by Atkinson in 1993 (53 ver-sus 47% for secondary ERL). Our high rate of secondaryAML6 (60%) suits well with the complex karyotype foundin therapy-related AML/MDS as del 5q, monosomy 7 andmonosomy 17 (as after high dose exposure to alkylat-ing agents). In the WHO classification, these secondaryleukemia are called ‘therapy-related AML/MDS’.

Karyotype can be classified into three groups: (a) patientswith normal karyotype; (b) patients with less than two chro-mosome abnormalities; (c) patients with complex karyotype(>2 chromosome rearrangements). We observed that AML6have the same complex karyotype abnormalities as RAEB-twith deletion of chromosomes 5, 7, 17 as described inEstey et al. series [12]. Nakamura showed on a series of 10patients having AML6-FAB leukemia that the progress ofthe disease in the complex karyotypic abnormalities groupwas more aggressive and resulted in a poorer prognosis,compared with patients having normal karyotype (mediansurvival of>15.5 versus 4.5 months) [13]. But our series of23 patients did not show any difference of survival betweenthe karyotype groups even after excluding RAEB-t. It couldbe due to a lack of power of statistical tests on a little se-ries and to the fact that two patients having bad prognosiskaryotype survived longer because of allografting. A fewstudies have shown that allogeneic bone marrow transplan-tation could improve disease-free survival in young patientshaving myelodysplasia with excess of blasts after first re-mission by chemotherapy [14,15]. Even for therapy-relatedmyelodysplasia, transplantation seems to be favorable forlong-term disease-free survival [16].

Trilineage dysplastic features, which are observed in65% of our patients, are of bad prognosis according toBrito-Babapulle et al. [17,18]. The new WHO classifica-tion, according to our results, defines amongst AMLs, thosewith dysplastic features because of their bad prognosis.The variable percentage of myeloblasts (between 20 and30% or >30%) would be of no importance in terms of sur-vival and rate of complete remission between AML6 andRAEB-t, abolishing the barriers between RAEB-t and acuteleukemia. The number of myeloblasts did not influence sur-vival in our study (P < 0.5, Fig. 3). In our erythroleukemia,

median survival rate in treated patients is similar to Wattelet al. [19] and Aul et al. [20] rate within myelodysplasticsyndromes (8 and 9 months of median survival) [19,20].Moreover, Estey et al. have shown that there was no differ-ence of survival between RAEB-t and AML, consideringstratification on karyotype and age [12].

Our cytological results showed that there were two pat-terns of erythroid maturation. We noticed that the patientswho had a maturation arrest at the earliest stage of erythro-poiesis, carried major karyotype abnormalities and a shortersurvival (2.5 versus 10.4 months for those who finished theirmaturation to the later stages of differentiation). Kowal-Vernet al. [5] in 1992 suggest that an excess of proerythroblastsis a negative prognostic factor in acute erythroleukemia.However, our AML6 variants had a median survival of 4.5months similar to AML6 or RAEB-t.

The typical AML6 with 50% of erythroblasts and 30%of myeloblasts is probably the same entity as RAEB-t with20% of myeloblasts. Both entities have the same excess oferythroblasts with more or less myeloblasts, the same me-dian survival, the same complexity of karyotype and mostFAB-AML6 are secondary to chemotherapy or mutagenicagents as RAEB-t. Our report supports arguments to abolishthe RAEB-t entity and stresses the aspect of multilineagedysplasia found in this kind of AML6 and the impact ofkaryotypic risk on the prognosis. We think that the soleprimary de novo AML6 is leukemia with undifferentiatedblasts in cytology, that immunophenotypically fit erythrob-lasts [21]. A larger study must be undertaken to characterizethis subgroup of ‘true erythroleukemia’.

Acknowledgements

S. Park provided the design, collected and analyzed thedata, and provided the statistical expertise of the data, draftedthe paper. F. Picard, M. Guesnu and Z. Azgui providedthe study materials. F. Viguié analyzed the karyotypes. V.Leblond and F. Dreyfus provided the conception and thecritical revision and the final approval of the article.

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erythroleukemia: a comparison between the previous fab approach and the who classification

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