Refractory Anemia with Excess of Blasts in Transformation Clinical, Hematologic, and Cytogenetic Findings in Nine Patients

Nicole Smadja, Marcel Krulik, Aimery de Gramont, Gustavo Gonzalez-Canali, Alain A. Audebert, and Jacques Debray

ABSTRACT: Clinical, hematologic, and cytogenetic data of nine patients with refractory anemia with excess of blasts in transformation (RAEB-t), classified according to the French-American- British Cooperative Group/or myelodysplastic syndrome (MDS), are reported. At diagnosis, eight out of nine cases, had chromosomal abnormalities and three out of nine developed acute leukemia. Karyotype studies allowed individualization of two groups of patients: five with nonrandom major karyotype abnormalities (MAKA) including hypodiploidy, chromosomes 5 and 7 involvement, at least four other abnormalities, and a poor prognosis (survival always under 3.5 months); and four patients with either normal karyotypes or minor karyotype abnor- malities (MIKA) (no more than three abnormalities) and a better prognosis (survival from 14 to 38 months). Karyotype appears to be a major prognostic factor among RAEB-t.

INTRODUCTION

Myelodysplas t ic syndromes (MDS) are a heterogenous group in which hematologic status and outcome differ from one category to another. Recently, a new category has been defined by the FAB Cooperat ive Group [1]: refractory anemia wi th excess of blasts in t ransformat ion (RAEB-t). This RAEB-t group has a worse survival than RAEB [2-5]. Some authors [6-8] have found that the cytogenetic findings are an i ndependen t prognost ic factor in MDS.

We report n ine pat ients wi th RAEB-t and cytogenetic studies showing that cytoge- netic f indings have a major prognostic value in RAEB-t.

PATIENTS AND METHODS

Nine pat ients wi th de nova RAEB-t and cytogenetic studies at diagnosis are reported. The fol lowing criteria of the FAB classification [!] were used for diagnosis of RAEB-t: more than 20% and up to 30% of blasts in the bone marrow, presence of Auer rods in granulocyte precursors, and 5% or more blasts in the per iphera l blood.

From the Clinique M6dicale, H6pital Saint-Antoine, Paris, France.

Address reprint requests to: Madame N. Smodja, Clinique M~dieale, Service du Professeur M. Krulik, HOpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.

Received November 28, 1988; accepted April 4, 1989.

55 O 1989 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 42:55-65 (1989) 655 Avenue of the Americas, New York, NY 10010 0165-4608/89/$03.50

56 N. Smadja et al.

There were seven females and two males with an age range of 35-88 years at diagnosis. Two had a possible professional exposure to mutagenic and/or carcino- genic chemical agents: a country woman (case 2), and a metal welder worker (case 6).

Three patients received chemotherapy: one mitoxantrone (case 2) and the two others low doses of cytosine arabinoside (cases 4 and 8). Treatment was only sympto- matic in six patients. Progression to acute leukemia (AL) was observed in three cases. Six patients remained in RAEB-t; two of them had a complete remission of short duration (chemotherapy induced) (cases 2 and 8). Four patients experienced major pulmonary infections (cases 1, 2, 4, and 5). Death was related to progression to AL in three patients, and with RAEB-t in six patients. Survival duration from diagnosis was 1 to 38 months.

Cytogeuetic studies were carried out on bone marrow cells without mitogens. Each specimen was processed after 24- and 48-hour cultures with RPMI medium and 20% fetal calf serum (Laboratoire Eurobio). Mitoses were accumulated with colchi- cine, and hypotonic shock was performed with citrate and hyaluronidase. Chromo- somes were stained using an RHG-banding techniques. Karyotypes were described according to the ISCN 1985 [9]. For each patient, eight to 33 metaphases were exam- ined. All patients had a cytogenetic study at diagnosis. Six patients had one to three karyotypic follow-ups during the disease course (Table 1, cases 1, 2, 3, 6, 8, and 9).

RESULTS

Cytogenetic Results

According to the cytogenetic results, two groups of patients may be described (Table 1).

Group 1. Five patients (cases 1-5) with nonrandom MAKA all had hypodiploidy with a range from 43 to 45 chromosomes; involvement of chromosome 5 consisting of monosomy and/or partial deletion of the long arm; and involvement of chromosome 7 as monosomy (case 1, Fig. 1; and case 3) or partial or total deletion of long arm (cases 2, 4, and 5). This deletion was followed by translocation of long arm of chromosome 17 (case 2, Fig. 2) and by trauslocation of part of the long arm of chromosome 15 (case 4, Fig. 3). All had at least four other numerical or structural abnormalities including involvement of chromosome 12 (case 2, Fig. 2; case 4, Fig. 3; and case 5), involvement of chromosome 20 (case 1, Fig. 1; case 2, Fig. 2 and case 5), monosomy 3 (case 3; case 4, Fig. 3; and case 5), and structural abnormality of chro- mosome 11 (case 2; case 4, Fig. 3).

In summary, all five patients had monosomy for chromosomal region 5q15-*5q34 and for 7q13-*7qter. Among other nonrandom chromosomal abnormalities, we did not find any specific involved chromosomal region. None of the five patients had trisomy 8, which is frequently found in myelodysplastic syndromes.

Group 2. Four patients (cases 6-9) had either normal karyotype or MIKA. Cases 8 and 9 have been published previously [10, 11]. None of these patients had hypodi- ploidy. Two patients had involvement of chromosome 7 of the same kind as in the first group: case 6 presented a partial loss of the long arm, and case 8 had complete loss of the long arm of this chromosome followed by translocation of the long arm of chromosome 1 to the deleted chromosome 7. Case 8 had trisomy 8. Two patients had normal karyotypes at diagnosis; one of these (case 9) acquired a chromosomal abnor- mality during acute leukemic transformation (Table 1).

57

Table I Cytogenetics results in nine patients with RAEB-t °

Patient Date

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GROUP 1

1. 1/31/84 17 6

2/8/84 16 0 2. 12/5/84 24 O

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5. 6/17/86 13 3

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6. 2/12/85 17 12

11/6/85 12 8 4/8/86 17 9

7. 9/18/84 9 9 8. 9/1/81 18 0

9.

12/22/81 20 0 2/23/82 19 0

12/30/79 19 19 11/18/80 33 O

4/28/81 33 10 5/4/82 2 2 0

43,XX,-4,-7,-16,inv(4)(p15q11?),del(5) (q14q34),r(18),del(20)(q12),del(21) (q l lq21?) /42 ,XX,-4 , - 7 , - 16 , - 18,inv(4) (p15q11?),del(5)(q14q34),del(20) (q12),del(21)(qllq217)

Same as 1/31/1984 karyotype (above) 44,XX,- 1 , - 4 , - 7 , - 12 , - 17 , - 20,

+ der(1)t(1;4)(q11;p11),+der(1)t(1;7) (p11;p11),del(5)(q14q34),+der(7)t(7;17) (q11;q11),dup(11)(q12-~q13), + mar l

Same as 12/5/1984 karyotype (above) 45,XX,- 3 , - 5 , - 7 , - 15,+ der(2)t(2;?)

(q31;?),del(6)(q23),+mar1,+mar2/45, XX,-3,-7,-12,+der(2)t(2;?)(q31;?),del(5) (q12q34),del(6)(q23),+mar1

Same as 8/12/1985 karyotype (above) 45 ,XX, -3 , - 7 , - 12 , - 14 , - 22,de1(5)

(q14q34),+der(7)t[del(7)(p15);15] [q31;q21],+i(11q),+ der(12)t(12;?) (q21;?),del(15)(q21),+ der(22)t(?;22)(?;p12)

44,XX,- 3 , - 5 , - 12 , - 17 , - 20,-22,de1(7) (q12q34),+ der(22)t(?;22)(?;p12),+mar1, +mar2,+mar3

46,XY,del(20)(q12}/46,XY,del(20){q12),del(7) (q21q31)

46,XY,del(2O)(q12) 46,XY,del(2O}(q12),del(7)(q21q31)

46,XX,inv(9)b/47,XX,- 7,+8,+t(1;7) (p11;p11),invp(9) b

46,XX,inv(9) b 46,XX,inv(9)b/47,XX,- 7,+ 8,+t(1;7)

(p11;p11},inv(9) b (further karyotypes were identical)

- - (still normal at 5/7/1980) 46,XY,t(9;22)(q34;q11) 46,XY,t(9;22)(q34;q11)/47,XY, + 11 46,XY,t(9;22)(q34;q11)

° Group 1 had nonrandom MAKA; group 2 had a normal karyotype or MIKA.

b Congenital pericentric inversion of chromosome 9.

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Hematologic Results

Group 1. These patients had major karyotype abnormalities (Table 2, cases 1-5). All patients were females, with an age range from 60 to 88 years. Peripheral blood blast count ranged from 6% to 20% (median 12%); no blasts had Auer rods, and the bone marrow blast count ranged from 8% to 20% (median 13.5%). Bone marrow showed major alterations of the three cell lineages in all five patients. Major pulmonary infection occurred in four out of five patients. Case 2 had a complete remission of short duration obtained after chemotherapy; during this remission the karyotype was normal (Table 1). Transformation to acute leukemia occurred in one case. Survival was short: all died from 1 to 3.5 months after diagnosis.

Group 2. These patients had normal karyotypes or no more than three abnormalities (case 6-9). There were two females and two males, with an age range from 35 to 71 years. Peripheral blood blast count ranged from 1% to 8% (median 4%), none had Auer rods, the bone marrow blast count ranged from 1% to 28% (median 20%), bone marrow failure was moderate, major infections were not observed, and two patients evolved to acute leukemia. Case 8 had a complete remission obtained after chemo- therapy; during this remission the karyotype was normal (Table 1). Survival in these cases was longer, being 14, 23, 30, and 38 months, respectively.

Cytogenetic and Hematologic Correlations

The two groups of patients identified by karyotype results also had different clinical and hematologic characteristics. Group 1, with MAKA, was composed of older pa- tients presenting with major bone marrow failure with a higher average of peripheral blood blasts, serious infections, and a very poor prognosis, with a survival under 3.5 months.

The second group, with either normal karyotypes or MIKA, was composed of younger patients with minor bone marrow involvement, a lower average of periph- eral blood blasts, no major infections, and better prognosis, with survival between 1 to 3 years.

DISCUSSION

RAEB-t is the fifth subtype of myelodysplastic syndromes of the FAB classification [1]. Some patients are borderline, with RAEB features but with more peripheral blood blasts and/or more bone marrow blasts [10]. Most often RAEB-t is the first hematologic diagnosis; uncommonly, it results from the evolution of another MDS. RAEB-t represents 9% [5] to 22% [3] of MDS. In a personal series [4] of 168 patients with MDS, the frequency of de novo RAEB-t was 11.9%. Some patients are young, with features and evolution similar to classic acute myelocytic leukemia (AML). However, the majority of patients are old, refractory to chemotherapy, and have an outcome like RAEB.

In the literature, median survival for RAEB-t is 9-11 months [2-5], whereas it is 12-24 months for simple RAEB [4, 5, 11]. RAEB-t is a heterogenous group that either evolves to medullary failure or to blastic transformation and acute leukemia [3].

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Cytogenetic Findings in RAEB-t 63

rence was not significantly different in the two groups; thus, the poor prognosis of the first group does not appear to be related to evolution to AL.

In the literature, cytogenetic studies on RAEB-t have been reported among series of de novo MDS. Cytogenetic clonal abnormalities were found in 50% to 100% of the cases [6-8, 12-14]. RAEB-t is in the MDS category where abnormal clones were most frequently found [7, 8, 14]. Hypodiploidy appeared inconstantly: three out of four cases [6], four out of 14 cases [8], three out of three cases [14], and none out of four cases [15]. Hyperdiploidy was noted in two cases out of four [8], in one case out of three [14], and in two cases out of four [15].

In three series [7, 8, 14], major karyotype abnormalities were reported in approxi- mately 50% of cases, whereas in three other, different, series [6, 15,16] the percentage was between 20% and 40%. In one of these series [8], four cases presented with MAKA with the same chromosome involvement as in our patients. In RAEB-t, as in other MDS forms, the most frequent abnormalities reported are involvement of chro- mosomes 5 and 7.

MAKA were also found in de novo MDS different from RAEB-t: RAEB [6, 8, 17, 18], unclassified preleukemia [19, 20], and acute nonlymphocytic leukemia (ANLL) [21, 22]. Survival of these patients was always poor (from 0.3 to 3.5 months when specified). Other MAKA different from our cases have been reported in some MDS or ANLL; they also have a poor prognosis [23-27].

Similarities between some RAEB, RAEB-t, and ANLL expressed by MAKA in older patients could mean that some MDS and ANLL are intimately related disorders [14, 28, 29]. Thus, the presence of MAKA seems to be a hallmark of a poor prognosis in some categories of MDS including RAEB, RAEB-t, and in ANLL some cases [6, 8, 14, 15, 30-34]. In the first group (MAKA), peripheral blood blast count was higher than in the second group (MIKA), and this could also be a prognostic factor.

It is also striking that MAKA reported here are similar to chromosome abnormali- ties described in therapy-related MDS and ANLL [35-39]. Hypodiploidy and chro- mosome 5 and/or 7 involvement were the first chromosomal abnormalities reported in therapy-related leukemia [40, 41]. Other abnormalities involved chromosomes 3 and 17 [37], and more recently involvement of chromosomes 12 and 21 was demon- strated [39]. Besides hypodiploidy, three of our patients had involvement of chromo- somes 5 and 7, monosomy 3, and involvement of chromosome 12, and in one patient had involvement of chromosome 21 as well.

In conclusion, the presence of MAKA is an independent prognostic factor in RAEB-t as in some other MDS, in de novo ANLL, and in therapy-related leukemia.

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