morphological diagnoses of the japan adult leukemia study group acute myeloid leukemia protocols:...

1. Introduction

The French-American-British (FAB) classification foracute myeloid leukemia (AML) [1,2] has been widelyaccepted because of its simple morphological criteria,although it includes some immunological findings in diag-nosing AML M0 and M7 [3,4]. It has been adopted by a

Morphological Diagnoses of the Japan AdultLeukemia Study Group Acute Myeloid

Leukemia Protocols: Central ReviewKazutaka Kuriyama,a,* Masao Tomonaga,a Tohru Kobayashi,b Jin Takeuchi,c

Toshiteru Ohshima,d Shinppei Furusawa,e Kenji Saitoh,e Ryuzo Ohno,ffor the Japan Adult Leukemia Study Group

aDepartment of Hematology and Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University School ofMedicine, Nagasaki; bSecond Department of Internal Medicine, Mie University School of Medicine, Tsu; cFirst Department

of Internal Medicine, Nihon University School of Medicine, Tokyo; dSekishindo Hospital, Kawagoe; eDepartment of Hematology, Dokkyo University School of Medicine, Tochigi; fDepartment of Medicine III,

Hamamatsu Medical School, Hamamatsu, Japan

Received July 6, 2000; received in revised form July 31, 2000; accepted August 1, 2000

*Correspondence and reprint requests: Kazutaka Kuriyama,MD, Department of Hematology and Molecular Medicine, AtomicBomb Disease Institute, Nagasaki University School of Medicine,1-12-4 Sakamoto, Nagasaki 852-8102, Japan; 81-95-849-7110;fax: 81-95-849-7113 (e-mail: [email protected]).

AbstractA morphological review system of the Japan Adult Leukemia Study Group has developed from the AML-87 through the

AML-92 experience.We reviewed 1427 (90%) of 1592 cases enrolled in the AML-87, -89, or -92 protocols for morphology; 1408(88%) were eligible. The rate of diagnostic concordance between each institute and the Committee on Morphological Diagno-sis ranged from 76% to 80%. Acute myeloid leukemia (AML) subtypes were as follows: AML M0, 27 (2%); M1, 179 (13%);M2, 472 (34%); M3, 358 (25%); M4, 265 (19%); M5, 57 (4%); M6, 39 (3%); and M7, 11 (1%). The reason for the high numberof patients with AML M3 is that many M3 patients were enrolled in the AML-92 protocol, which contained all-trans-retinoicacid. AML M0, M6 and M7 belonged to the poor prognostic groups. Auer bodies were found in 284 (53%) of 538 patients whosurvived significantly longer than those without Auer bodies in AML-87/-89. In AML-92 except for AML M3, 259 (43%) of602 cases were Auer+ and also showed better survival rates. The survival of patients with >50% myeloperoxidase (MPO)-positive blast cells was better than those with ≤50% MPO+ blast cells in AML-87/-89. This trend was also seen in AML-92excluding M3. AML with trilineage dysplasia (AML/TLD) is characterized as a subtype of de novo AML that shows morpho-logical dysplasia of mature hematopoietic cells on a background of leukemic blast cells.The number of patients with AML/TLDwas 89 (16.5%) of 545 patients reviewed in AML-87/-89. AML-92, except for M3, showed a higher rate of patients with TLD(161 cases; 27.6%) because there were no patients with TLD in the AML M3 group. Survival rates for AML/TLD were worsethan those for AML/non-TLD in both the AML-87/-89 and -92 protocols. Eighty percent of all cases (793/986) entered inAML-92 were analyzed cytogenetically. Fifty-one cases were not available for karyotyping because of a lack of mitoses or inap-propriate preparations.The most frequent karyotype was normal, which accounted for 34.2%.The t(15;17), t(8;21), and inv(16)karyotypes, which are regarded as good risk factors, were 23.8%, 9.2%, and 1.6%, respectively. Abnormal chromosomes 5, 7,t(9;22), and t(6;9) were considered to be poor or intermediate risk factors. As a new system of karyotyping begins in the ongo-ing AML protocol, useful chromosomal data will be obtained in the near future. Int J Hematol. 2001;73:93-99.©2001 The Japanese Society of Hematology

Key words: Adult AML; Morphological review; FAB classification; Myeloperoxidase; Trilineage myelodysplasia

International Journal ofHEMATOLOGY

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94 Kuriyama et al / International Journal of Hematology 73 (2001) 93-99

number of cooperative study groups such as the Japan AdultLeukemia Study Group (JALSG), established in 1987. In clin-ical trials, it is important to assess the morphological diagnosesmade by each of the institutes. At the same time that JALSGwas established, the Committee on Morphological Diagnosis,which consisted of 5 hematologists, was also founded. Theinstitutes were required to send several peripheral blood andbone marrow smears stained with May-Grünwald-Giemsa,myeloperoxidase (MPO), esterase chloroacetate, and esterasebutyrate to the center for morphological review.The membersof the committee examined the smears morphologically andmade the final diagnoses after discussion concerning patientswhose diagnoses were not identical to those determined bythe institute. It became clear that this review system had somedrawbacks. First, there were differences in the quality of stain-ing of smears between institutes. Second, it was time consum-ing for each institute to stain smears and send them to the cen-ter.Third, it was difficult for the members of the committee tomeet 2 or 3 times a year. To solve these problems, we decidedto stain the smears at the Center for Morphological Review(located at the Department of Hematology, Nagasaki Univer-sity School of Medicine) and send the diagnoses to the insti-tutes immediately. The center then circulated the smears ofthe patients whose diagnoses differed from those of each insti-tute among the members. Thus, each institute received a finaldiagnosis more quickly.

We now report the results of the diagnoses made underour central review system.

2. Patients and Methods

Ninety percent (1427/1592) of patients enrolled in theAML-87, -89, and -92 protocols, described in detail elsewhere[5-7], were reviewed for morphology by the Committee onMorphological Diagnosis and were analyzed (Table 1). Ineach protocol, the cases not reviewed were excluded from thisanalysis. In the AML-87 and -89 protocols, each institute sentsmears stained with May-Grünwald-Giemsa, MPO, esterasechloroacetate,and esterase butyrate to the center. In the AML-92 protocol, unstained smears were sent to the center and werestained there. Only 19 of 1427 cases reviewed were not eligiblebecause of misdiagnoses (Table 1). The diagnosis and classifi-cation of AML were according to the FAB criteria [1-4].

Clinical data including the analysis of karyotypes from 20or more cells stained using G-banding staining methods wereobtained from the data sheets sent by 41 institutions. Overallsurvival was calculated according to the Kaplan-Meiermethod and compared by the two-sided log-rank test, usingthe Phreg procedure in the SAS program (SAS Institute, Cary,NC, USA). Patients who received allogeneic bone marrowtransplantations were censored on the date of transplantation.

Table 1.Number of Patients in Japan Adult Leukemia Study Group Acute

Myeloid Leukemia (AML) Protocols*

AML-87 AML-89 AML-92 Total

Entry 265 341 986 1592Review 242 (91) 313 (91) 872 (88) 1427 (90)Eligible 234 (88) 311 (91) 863 (88) 1408 (88)Without M3 192 (72) 246 (72) 611 (62) 1049 (66)

*Data are n or n (%).

Table 2.Concordance of Morphological Diagnoses Between Each Institute andthe Committee on Morphological Diagnoses*

Cases Same Concordance,Protocol Reviewed Diagnosis %

AML-87 242 190 79AML-89 313 251 80AML-92 872 664 76Total 1427 1105 77

*AML indicates acute myeloid leukemia.

Table 3.Concordance of Morphological Diagnoses of the Japan Adult Leukemia Study Group AML-92 Between Each Institute and the Committee on Mor-

phological Diagnosis*

Diagnosis by Institute

M0 M1 M2 M3 M4 M5 M6 M7 Total

n 33 144 226 260 117 60 24 8 872Diagnoses reviewed, n (%)

M0 22 (67) 4 1 0 0 0 0 0M1 1 68 (47) 8 2 0 4 0 0M2 4 46 192 (85) 7 21 0 5 1M3 0 0 1 250 (96) 1 0 0 0M4 1 17 22 0 94 (80) 33 1 1M5 1 2 0 0 1 21 (35) 0 1M6 0 3 2 0 0 0 17 (71) 0M7 3 0 0 0 0 1 0 4 (50)Total 663 (76)

MLL 1 0 0 0 0 0 0 0HL 0 0 0 0 0 1 0 0ALL-L2 0 1 0 0 0 0 0 0Others 0 1 0 0 0 0 1 1Impossible 0 2 0 1 0 0 0 0

*AML indicates acute myeloid leukemia; MLL, mixed lineage leukemia; HL, hypoplastic leukemia; ALL-L2, acute lymphoid leukemia-L2 subtype.

3. Results

3.1. Concordance of Morphological Diagnoses

Table 2 shows the concordance of morphological diag-noses between each institute and the Committee on Mor-phological Diagnosis. The rate of concordance ranged from76% to 80% (mean, 77%).As shown in Table 3, the best con-cordance rate was 96% for AML M3 and the worst was 35%for AML M5 in AML-92.

3.2. FAB Subtypes

AML subtypes according to FAB classification were as fol-lows: AML M0, 27 (2%); M1, 179 (13%); M2, 472 (34%); M3,358 (25%); M4, 265 (19%); M5, 57 (4%); M6, 39 (13%); andM7, 11 (1%) (Table 4). In the AML-92 protocol,AML M0 wasthe first to be adapted, and the M3 patients enrolled weretreated with an all-trans-retinoic acid (ATRA)-containingregimen [8,9]. Because ATRA was available only through thisprotocol in Japan, not only participating institutions but alsotheir affiliated hospitals enrolled a number of patients withAML M3 to the AML-92 protocol, and this is probably whythe overall rate of M3 reached 25%.Therefore, the actual fre-quency of the M3 subtype seems to be 18% to 21%, as shownin AML-87 or -89. Survival rates for the FAB subtypes inAML-87/-89 and those except for M3 in AML-92 are shownin Figure 1. AML M0, M6, and M7 belonged to the poor-riskgroup, and AML M7 showed the worst survival rate.

3.3. Auer Bodies and MPO Reaction as PrognosticFactors

The Auer body is established as a morphological leukemicmarker and presents in leukemic myeloblasts in many AMLcases [10,11]. Clinicians analyze about 500 cells in a bonemarrow smear and decide that AML is Auer+ if an Auerbody is found in at least 1 blast cell, but it is possible that apatient is diagnosed as both Auer+ and Auer– because thepercentage or number of blast cells examined is different ineach sample.Therefore, data on Auer body positivity must beinterpreted carefully. We examined 300 blast cells in a bonemarrow smear for Auer bodies.Auer+ AML was found in 284(53%) of 538 patients examined, and they survived signifi-cantly longer than those who were Auer– in AML-87/-89

(Figure 2). In AML-92, except for AML M3, most of whomhad Auer rods and/or faggots, 259 (43%) of 602 cases wereAuer+ and exhibited better survival rates (Figure 2B), as wasseen in AML-87/-89 (Figure 2A).

MPO activity is positive in monocytic and granulocytic cellsbut is rarely detected in monoblasts. Therefore, the blast cellspositive for MPO can be identified as myeloblasts [12]. MPO+

AML is diagnosed if MPO+ blasts are >3% of all blast cellsaccording to the FAB criteria [1]. MPO+ blast cells were foundin AML M1, M2, M3, M4, and M6, but MPO+ blast cells or

Morphological Diagnoses of AML in the JALSG Protocols 95

Table 4.Acute Myeloid Leukemia (AML) Subtypes According to French-American-British Classification*

Subtype AML-87 AML-89 AML-92 Total

M0 — — 27 (3) 27(2)M1 43 (18) 53 (17) 83 (10) 179 (13)M2 83 (36) 113 (36) 276 (32) 472 (34)M3 42 (18) 65 (21) 251 (29) 358 (25)M4 46 (20) 49 (16) 170 (20) 265 (19)M5 13 (6) 18 (6) 26 (3) 57 (4)M6 6 (3) 11 (4) 22 (3) 39 (3)M7 1 (0.4) 2 (1) 8 (1) 11 (1)Total 234 311 863 1408

*Data are n (%) or n.

Figure 1. Overall survival of patient groups defined by the French-American-British subtypes in AML-87/-89 (A) and AML-92 except M3(B). JALSG indicates Japan Adult Leukemia Study Group;AML, acutemyeloid leukemia.


leukemic promyelocytes in AML ranged from 100% of mostAML M3 to a very low percentage in M6 (data not shown).The patients with >50% MPO+ blast cells showed better prog-noses than those with ≤50% MPO+ blast cells in AML-87/-89(Figure 3A) or in AML-92 without M3 (Figure 3B).

3.4. AML With Trilineage Dysplasia

The number of patients with AML with trilineage dyspla-sia (TLD) was 89 (16.5%) of 545 patients reviewed in AML-87/-89. This percentage is almost identical to the reportedrates, including ours [13-16]. Because we have never found aTLD in AML M3 patients, AML-92 except for M3 showed ahigher rate of patients with TLD (161 cases; 27.6%; data notshown). The complete remission rates of the TLD cases inAML-87/-89 and in AML-92 were 65% and 64%, whichwere significantly worse than the 77% and 79% of non-TLDrates, respectively (data not shown). Figure 4 shows a lowersurvival for AML/TLD compared with AML/non-TLD inboth the AML-87/-89 and -92 protocols.

3.5. Chromosomal Analysis

Having some information on karyotypes in the AML-87and -89 protocols, we were able to estimate the karyotypes in

AML-92 (Table 5). Eighty percent of all cases (793/986)entered were analyzed cytogenetically. Fifty-one cases werenot available for karyotyping because of a lack of mitoses orinappropriate preparations. The most frequent karyotypewas normal, accounting for 34.2%. The karyotypes havingt(15;17), t(8;21), and inv(16), which are regarded as good riskfactors [17-20], accounted for 23.8%, 9.2%, and 1.6%,respectively. For example, in AML-92 without M3, thepatients with t(8;21) survived significantly longer than thosewith other karyotypes (Figure 5A). On the other hand, thechromosome 5 abnormality indicated a poor prognosis (Fig-ure 5B). Other karyotypes having the chromosome 7 abnor-mality, t(9;22), and t(6;9) were considered poor or interme-diate risk factors (data not shown) [18-20].

4. Discussion

Our morphological review system has been in place fromAML-87 through AML-92. Cases entered numbered 1592;1427 (90%) were reviewed morphologically, and 1408 (88%)were eligible. In each protocol, the cases not reviewed wereexcluded from this analysis but were included in someJALSG reports [5-7]. They should ideally be omitted fromany analyses as reported by the Southwest Oncology Group,

Figure 2. Overall survival of Auer+ or Auer– acute myeloid leukemia(AML) patients in AML-87/-89 (A) and AML-92 except M3 (B). Thedifference between the Auer+ and Auer– patients was highly significant.JALSG indicates Japan Adult Leukemia Study Group.

Figure 3. Overall survival of patients with >50% versus ≤50% blastcells having myeloperoxidase (MPO) activity in AML-87/-89 (A) and inAML-92 except M3 (B). The patients having >50% MPO+ blast cellssurvived significantly longer. JALSG indicates Japan Adult LeukemiaStudy Group; AML, acute myeloid leukemia.


where the patients without morphological review totaled16% of all the patients enrolled and were excluded [21].

The morphological concordance rates varied widely inthe FAB subtypes, from 96% for AML M3 to 24% for AMLM5b in AML-92. These percentages suggest that the mor-phological characteristics of M3, such as hypergranularity,frequent faggots in cytoplasm, and kidney- or dumbbell-shaped nuclei, can be easily identified.They also suggest thatit is difficult for many hematologists to identify exactlymonocyte-lineage cells, especially promonocytes or mono-blasts present in AML M4 or M5. Additionally, we foundthat 10% to 15% of monocytic cells were completely nega-tive for esterase butyrate in our AML series, which made itmore difficult to distinguish between the subtypes.

The actual frequency of the M3 subtype that seems to be18% to 21% is higher than that reported from Europe[22,23] or the United States [24,25]. Although Douer et al[26] reported that the frequency of M3 is 24.3% in Latinopatients, which is higher than in non-Latino patients, it is notclear whether there is a significant difference between racesor ethnicities. Our data showed that AML M7 had the worstsurvival rate. Many reports [27-29] support this result.

The patients with Auer+ and/or >50% MPO+ blast cellsshowed better prognoses than those with Auer– and/or ≤50%MPO+ blast cells in AML-87/-89. This trend was also recog-nized in AML-92 except M3. Higher survival rates in patientswith >50% MPO+ blast cells were reported in the MedicalResearch Council [30] and the Eastern Cooperative Oncol-ogy Group [31] studies, although Sudan black stain was usedinstead of MPO in the former, and MPO was used in the caseof AML M1. By multivariate analysis, Auer body positivitywas not significant, and presence of >50% MPO+ blast cellswas the most significant factor for predicting survival (datanot shown). This result means that most AML cases withAuer bodies are included in those with >50% MPO+ blastcells. The reason why Auer positivity or a higher percentageof MPO+ blast cells show better survival rates is not known.

AML/TLD is characterized as a subtype of de novo AMLthat shows morphological dysplasia of mature hematopoieticcells on a background of leukemic blast cells [13,14,32].Although dysplastic features seen in AML/TLD are similarto those in myelodysplastic syndrome (MDS) [33], theabsence of preceding hematologic abnormalities distinguishesAML/TLD from leukemias following MDS. Although thiscategory was not included in the FAB classification, theWorld Health Organization classification for AML, newlyproposed in 1999, named it AML with multilineage dysplasiaconsisting of 2 subtypes: with or without prior MDS [34,35].Our findings suggest that AML/TLD is refractory to con-ventional chemotherapy. On the other hand, we found thatthe outcome of allogeneic BMT for AML/TLD was compa-rable to that for non-TLD [36].

Karyotype is one of the most important factors in plan-ning the treatment strategy for AML [37]. For example,cytarabine intensification seems to contribute to a substan-tial prolongation of survival time in patients with favorablekaryotypes, especially t(8;21) [38,39]. Therefore, to maintaina high standard of chromosomal analyses, the JALSG alsoneeded to review the karyotypes. We thus started a newreview system for the karyotypes in the ongoing AML-97protocol. From this, we will soon obtain higher quality

Figure 4. Overall survival of patients with acute myeloid leukemia(AML) with or without trilineage dysplasia (TLD) in AML-87/-89 (A)and in AML-92 except M3 (B). The difference between the patientswith and without TLD was highly significant. JALSG indicates JapanAdult Leukemia Study Group.

Table 5.Cytogenetic Findings in the Japan Adult Leukemia Study Group AML-

92 Protocol

Cytogenetic Results n (%)

Normal karotype 270 (34.2)t(15;17) 190 (23.8)t(8;21) 73 (9.2)Chromosome 5 abnormality† 21 (2.6)Chromosome 7 abnormality 17 (2.1)inv(16) 13 (1.6)t(9;22) 12 (1.5)Chromosome 12 abnormality 8 (1.0)t(6;9) 4 (0.5)Other abnormalities 133 (16.8)Not available 51 (6.4)Total 793

*AML indicates acute myeloid leukemia.†Includes 3 cases additionally having chromosome no. 7 and no. 12

abnormalities and 2 cases having no. 12 abnormality.

information on chromosomal abnormalities in AML. Becausethe JALSG is the largest and best-established group in Japannow, its data may be regarded as representative of Japan.Thus,JALSG is obligated to maintain high standards and to providetreatment protocols based on clinical evidence–based therapyfor AML. To fulfill these obligations, it is essential to reviewthe data gathered by each institute.

Acknowledgments

We thank participating physicians from the 69 institutionsof the JALSG for their cooperation. We also thank Drs. S.Honda and M. Mine for advice on statistical analyses.

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