- Email: [email protected]
Cytogenetic, morphologic, and clinical correlations in acute nonlymphocytic leukemia with t(8q−;21q+)
Second International Workshop
99
Cytogenetic, Morphologic, and Clinical Correlations in Acute Nonlymphocytic Leukemia with t(8q-;21q+) 1 The cytogenetic pattern of the bone marrow cells, the bone marrow morphology, and the clinical data obtained before treatment of 48 acute nonlymphocytic (ANLL) patients with t(8q-;21q+) were reviewed. The criteria for inclusion in this study were similar to those described under Materials and Methods of the General Report on this workshop (p. 93). RESULTS
Morphology Bone marrow smears were available from 44 of the 48 patients. The slides were reviewed by four hemtologists and classified according to the FAB criteria (see companion paper in this series). In 43 patients, the leukemic cells were classified as M2. The material was inadequate for diagnosis in I patient.
Sex and Age Twenty-six patients were females and 22 were males. The sex distribution in the various subgroups was similar (Table 1). The median age was 45 years with a range of 5 - 8 3 years; the median age in the subgroups varied between 31 and 52 years (Table 1).
Chromosome Aberrations In all patients, the break point was in band q22 of chromosome #8 and in q22 of chromosome of #21. In 18 patients (38%), t(8;21) was the only chromosome abnormality (Group I). Loss of one sex chromosome in addition to the t(8;21) was found in 16 patients (33%) (Group II). In 14 patients (29%), other chromosome abnormalities in addition to the t(8;21) were observed (Group III); these included variant, three-way translocations, in which the break points in chromosomes # 8 and #21 were similar to those observed in the standard translocation. Some patients had an extra chromosome #8 and others had additional structural rearrangements, particularly an interstitial deletion of 9q that was noted in 3 patients.
Remissions The frequency of a complete remission(CR) in all patients was 74% (34 of 46 patients for w h o m there was adequate follow-up). It varied between 63 and 85 % in the different subgroups (Table 1). q n referring to this report the following format should be used: Second International W o r k s h o p on C h r o m o s o m e s in Leukemia (1979): Cytegenetic, Morphologic, a n d Clinical Correlations in Acute N o n l y m p h o cytic Leukemia w i t h t(Sq-;21q+). Cancer Genet Cytogenet 2, 99 - 102 1980.
100
Correlations in Nonlymphocytic
Table 1
Leukemia
Clinical data on 48 patients with t(8q-;21q+)
Response" (No. of patients) CR PR NR
Median survival (months)
Cytogenetic category
No. of patients
M e d i a n age (years)
Total group Group I 46,XX,t+ 46,XY,t+ G r o u p II 45,X, - X,t+ 45,X,-Y,t+ G r o u p III t+ a n d other
48 11 ~'
45 52
34 8
3 1
9 1
11.5 14
7
52
5
1
1
15
9 7
40 47
5 5
1 0
3 2
5 6
14 b
31
11
0
2
15.5
"CR = complete remission; NR = no remission; PR = partial remission. bone patient lost to follow-up.
Table 2
Survival time and cytogenetic pattern in 46 patients
No. of patients Group I female male Group II female male G r o u p III
10 7 9 7 13 (6F,8M)
M e d i a n survival in m o n t h s (No. of patients) AN+AA AN AA
Patients alive at 1 year/2 years
14 15
21.5+(6) 26+(3)
9.5(4) 6.5+(4)
6,,/3 ~ 4,,/2 b
5 6 15.5
11+(5) 7(5) 18+(10)
2(4) 3.5+(2} 14(3)
2~/0 2~/2 ~ 9,'/4 b
"All except one patient had an AN pattern. t'All AN. "All except two patients had an AN pattern.
Table 3
F r e q u e n c y a n d g e o g r a p h i c d i s t r i b u t i o n o f t(8;21), o t h e r abnormalities, and normal karyotype in patients with an M2 marrow pattern N u m b e r of p a t i e n t s Other abnormalities
Laboratory
Total M2
t(8;21)
Normal
Buffalo, U S A Chicago, USA Essen, W. G e r m a n y Helsinki, F i n l a n d Lund, Sweden London, England Paris, France Saitama, Japan Melbourne, Australia
112 21 35 27 44 35 23 23 109
12 5 5 2 3 1 1 7 5
39 11 17 12 25 16 14 2 52
61 5 13 13 16 18 9 14 52
TOTAL
429
41
188
201
Second International Workshop
10 1
Survival Data on survival were available for 46 patients. The m e d i a n survival time was 11.5 -months for the whole group. In Groups I and III, the m e d i a n survival was 14 and 15.5 months, respectively. In Group II, i.e., in the patients with a missing sex chromosome, a considerably shorter time of survival was observed, namely, a m e d i a n of 5.5 months (Tables 1 and 2). Within Groups I, II, and III, no significant sex difference in survival was noted. W h e n survival time was related to the presence of some normal metaphase cells, the m e d i a n survival was 9 months for all patients with only abnormal metaphase cells (AA) and 14.5 months for those with some normal metaphase cells (AN). The survival of A A and AN patients w i t h i n the subgroups is shown in Table 2. In Group I, AN patients had a survival time at least twice that of A A patients; the difference was especially large in males. In Group II, the u n u s u a l l y short survival time was evident in both sexes, but AN patients did better than A A patients. In Group III, little difference in survival between A A and AN patients was observed. The i m p r o v e d response of AN patients is reflected in the number of patients who were alive 1 year after diagnosis. Of 23 such patients, 19 had an AN pattern; 11 patients were alive at 2 years, and all of these had an AN pattern.
DISCUSSION The t(8q-;21q+) aberration was present in about 5% of patients with ANLL reviewed at the First International Workshop on Chromosomes in Leukemia in 1977 [1]. The results of the present review of a fairly large group of such patients demonstrate that this abnormality is often associated with other c h r o m o s o m e aberrations, most comm o n l y with loss of one sex chromosome. In all 43 cases with t(8;21) and adequate bone marrow material available for review, the diagnosis of M2 (myeloblastic leukemia w i t h maturation) was made. This karyotypic aberration and the t(15;17) in acute promyelocytic leukemia (APL) are, thus, two translocations that a p p e a r to be closely associated with a block in a particular stage of leukemic cell maturation. The clinical course was characterized by a remission of almost 75% of the cases and a m e d i a n survival time of about I year. As was observed at the First Workshop [1], patients with a t(8;21) had the best prognosis of any group of a n e u p l o i d leukemic patients, and their m e d i a n survival time of 11.5 months was equal to or better than that of patients with only normal metaphase cells. Some patients, particularly those with only the translocation or with the translocation and other abnormalities not related to loss of a sex chromosome, had survival times of about 15 months. However, the patients who had a missing sex c h r o m o s o m e in a d d i t i o n to t(8;21) were found to form a special group with regard to prognosis. The remission frequency was lower and the m e d i a n survival time was considerably shorter than in the other patients with t(8;21). The poor prognosis associated with a missing sex c h r o m o s o m e was equally evident in both sexes. As expected, the absence of normal metaphases (AA) was associated with an unfavorable outlook. In the patients with a missing sex chromosome, the AA pattern indicated an extremely poor prognosis with a m e d i a n survival time of only 2 months, i.e., shorter than that previously found in ANLL patients who had no normal bone marrow metaphases at diagnosis [1]. On the other hand, patients in Groups I and III with an AN pattern have a comparatively good outlook; w i t h i n Group I, 8 of 9 AN patients were alive at i year, and 5 of 9 were alive at 2 years. Within Group III, 7 of 10 AN patients were alive at 1 year, and 4 of 10 were alive at 2 years. Three of the Group I and III AN patients lived longer than 45 months. Information was available from most laboratories about their total pool of patients with M2 (Table 3). Forty patients among a total of 429 with M2 had a t(8;21). Two h u n d r e d one patients (47%) had a normal karyotype. Clear geographic differences in
102
Correlation in N o n l y m p h o c y t i c Leukemia
the occurrence of the t(8;21) exist. The frequency in Saitama (Japan) is 7 out of 23 (30.4%), whereas it is 24% in Chicago, 2.8% in London, and 1 out of 23 in Paris. The reason for this variation is unclear. In conclusion, the cytogenetic, morphologic, and clinical review of patients with ANLL and t(8;21) has revealed the following characteristic features: 1. The typical bone marrow m o r p h o l o g y in ANLL with t(8;21) is M2, i.e., myeloblastic with some maturation. 2. The t(8;21) in ANLL is associated with loss of one sex c h r o m o s o m e in a significant n u m b e r of patients. 3. Overall, the t(8;21) is associated with a good prognosis, particularly for patients w h o have some normal metaphase cells. 4. The acute leukemia is of an especially aggressive type, however, in patients with t(8;21) and a missing sex chromosome. 5. The findings to-date suggest a geographic difference in the occurrence of the t(8; 21).
REFERENCES 1. First International Workshop on Chromosomes in Leukemia, 1977 (1978): Chromosomes in Phi-positive chronic granulocytic leukaemia. Br. J Haemato139:305 - 309, 1978.
99
Cytogenetic, Morphologic, and Clinical Correlations in Acute Nonlymphocytic Leukemia with t(8q-;21q+) 1 The cytogenetic pattern of the bone marrow cells, the bone marrow morphology, and the clinical data obtained before treatment of 48 acute nonlymphocytic (ANLL) patients with t(8q-;21q+) were reviewed. The criteria for inclusion in this study were similar to those described under Materials and Methods of the General Report on this workshop (p. 93). RESULTS
Morphology Bone marrow smears were available from 44 of the 48 patients. The slides were reviewed by four hemtologists and classified according to the FAB criteria (see companion paper in this series). In 43 patients, the leukemic cells were classified as M2. The material was inadequate for diagnosis in I patient.
Sex and Age Twenty-six patients were females and 22 were males. The sex distribution in the various subgroups was similar (Table 1). The median age was 45 years with a range of 5 - 8 3 years; the median age in the subgroups varied between 31 and 52 years (Table 1).
Chromosome Aberrations In all patients, the break point was in band q22 of chromosome #8 and in q22 of chromosome of #21. In 18 patients (38%), t(8;21) was the only chromosome abnormality (Group I). Loss of one sex chromosome in addition to the t(8;21) was found in 16 patients (33%) (Group II). In 14 patients (29%), other chromosome abnormalities in addition to the t(8;21) were observed (Group III); these included variant, three-way translocations, in which the break points in chromosomes # 8 and #21 were similar to those observed in the standard translocation. Some patients had an extra chromosome #8 and others had additional structural rearrangements, particularly an interstitial deletion of 9q that was noted in 3 patients.
Remissions The frequency of a complete remission(CR) in all patients was 74% (34 of 46 patients for w h o m there was adequate follow-up). It varied between 63 and 85 % in the different subgroups (Table 1). q n referring to this report the following format should be used: Second International W o r k s h o p on C h r o m o s o m e s in Leukemia (1979): Cytegenetic, Morphologic, a n d Clinical Correlations in Acute N o n l y m p h o cytic Leukemia w i t h t(Sq-;21q+). Cancer Genet Cytogenet 2, 99 - 102 1980.
100
Correlations in Nonlymphocytic
Table 1
Leukemia
Clinical data on 48 patients with t(8q-;21q+)
Response" (No. of patients) CR PR NR
Median survival (months)
Cytogenetic category
No. of patients
M e d i a n age (years)
Total group Group I 46,XX,t+ 46,XY,t+ G r o u p II 45,X, - X,t+ 45,X,-Y,t+ G r o u p III t+ a n d other
48 11 ~'
45 52
34 8
3 1
9 1
11.5 14
7
52
5
1
1
15
9 7
40 47
5 5
1 0
3 2
5 6
14 b
31
11
0
2
15.5
"CR = complete remission; NR = no remission; PR = partial remission. bone patient lost to follow-up.
Table 2
Survival time and cytogenetic pattern in 46 patients
No. of patients Group I female male Group II female male G r o u p III
10 7 9 7 13 (6F,8M)
M e d i a n survival in m o n t h s (No. of patients) AN+AA AN AA
Patients alive at 1 year/2 years
14 15
21.5+(6) 26+(3)
9.5(4) 6.5+(4)
6,,/3 ~ 4,,/2 b
5 6 15.5
11+(5) 7(5) 18+(10)
2(4) 3.5+(2} 14(3)
2~/0 2~/2 ~ 9,'/4 b
"All except one patient had an AN pattern. t'All AN. "All except two patients had an AN pattern.
Table 3
F r e q u e n c y a n d g e o g r a p h i c d i s t r i b u t i o n o f t(8;21), o t h e r abnormalities, and normal karyotype in patients with an M2 marrow pattern N u m b e r of p a t i e n t s Other abnormalities
Laboratory
Total M2
t(8;21)
Normal
Buffalo, U S A Chicago, USA Essen, W. G e r m a n y Helsinki, F i n l a n d Lund, Sweden London, England Paris, France Saitama, Japan Melbourne, Australia
112 21 35 27 44 35 23 23 109
12 5 5 2 3 1 1 7 5
39 11 17 12 25 16 14 2 52
61 5 13 13 16 18 9 14 52
TOTAL
429
41
188
201
Second International Workshop
10 1
Survival Data on survival were available for 46 patients. The m e d i a n survival time was 11.5 -months for the whole group. In Groups I and III, the m e d i a n survival was 14 and 15.5 months, respectively. In Group II, i.e., in the patients with a missing sex chromosome, a considerably shorter time of survival was observed, namely, a m e d i a n of 5.5 months (Tables 1 and 2). Within Groups I, II, and III, no significant sex difference in survival was noted. W h e n survival time was related to the presence of some normal metaphase cells, the m e d i a n survival was 9 months for all patients with only abnormal metaphase cells (AA) and 14.5 months for those with some normal metaphase cells (AN). The survival of A A and AN patients w i t h i n the subgroups is shown in Table 2. In Group I, AN patients had a survival time at least twice that of A A patients; the difference was especially large in males. In Group II, the u n u s u a l l y short survival time was evident in both sexes, but AN patients did better than A A patients. In Group III, little difference in survival between A A and AN patients was observed. The i m p r o v e d response of AN patients is reflected in the number of patients who were alive 1 year after diagnosis. Of 23 such patients, 19 had an AN pattern; 11 patients were alive at 2 years, and all of these had an AN pattern.
DISCUSSION The t(8q-;21q+) aberration was present in about 5% of patients with ANLL reviewed at the First International Workshop on Chromosomes in Leukemia in 1977 [1]. The results of the present review of a fairly large group of such patients demonstrate that this abnormality is often associated with other c h r o m o s o m e aberrations, most comm o n l y with loss of one sex chromosome. In all 43 cases with t(8;21) and adequate bone marrow material available for review, the diagnosis of M2 (myeloblastic leukemia w i t h maturation) was made. This karyotypic aberration and the t(15;17) in acute promyelocytic leukemia (APL) are, thus, two translocations that a p p e a r to be closely associated with a block in a particular stage of leukemic cell maturation. The clinical course was characterized by a remission of almost 75% of the cases and a m e d i a n survival time of about I year. As was observed at the First Workshop [1], patients with a t(8;21) had the best prognosis of any group of a n e u p l o i d leukemic patients, and their m e d i a n survival time of 11.5 months was equal to or better than that of patients with only normal metaphase cells. Some patients, particularly those with only the translocation or with the translocation and other abnormalities not related to loss of a sex chromosome, had survival times of about 15 months. However, the patients who had a missing sex c h r o m o s o m e in a d d i t i o n to t(8;21) were found to form a special group with regard to prognosis. The remission frequency was lower and the m e d i a n survival time was considerably shorter than in the other patients with t(8;21). The poor prognosis associated with a missing sex c h r o m o s o m e was equally evident in both sexes. As expected, the absence of normal metaphases (AA) was associated with an unfavorable outlook. In the patients with a missing sex chromosome, the AA pattern indicated an extremely poor prognosis with a m e d i a n survival time of only 2 months, i.e., shorter than that previously found in ANLL patients who had no normal bone marrow metaphases at diagnosis [1]. On the other hand, patients in Groups I and III with an AN pattern have a comparatively good outlook; w i t h i n Group I, 8 of 9 AN patients were alive at i year, and 5 of 9 were alive at 2 years. Within Group III, 7 of 10 AN patients were alive at 1 year, and 4 of 10 were alive at 2 years. Three of the Group I and III AN patients lived longer than 45 months. Information was available from most laboratories about their total pool of patients with M2 (Table 3). Forty patients among a total of 429 with M2 had a t(8;21). Two h u n d r e d one patients (47%) had a normal karyotype. Clear geographic differences in
102
Correlation in N o n l y m p h o c y t i c Leukemia
the occurrence of the t(8;21) exist. The frequency in Saitama (Japan) is 7 out of 23 (30.4%), whereas it is 24% in Chicago, 2.8% in London, and 1 out of 23 in Paris. The reason for this variation is unclear. In conclusion, the cytogenetic, morphologic, and clinical review of patients with ANLL and t(8;21) has revealed the following characteristic features: 1. The typical bone marrow m o r p h o l o g y in ANLL with t(8;21) is M2, i.e., myeloblastic with some maturation. 2. The t(8;21) in ANLL is associated with loss of one sex c h r o m o s o m e in a significant n u m b e r of patients. 3. Overall, the t(8;21) is associated with a good prognosis, particularly for patients w h o have some normal metaphase cells. 4. The acute leukemia is of an especially aggressive type, however, in patients with t(8;21) and a missing sex chromosome. 5. The findings to-date suggest a geographic difference in the occurrence of the t(8; 21).
REFERENCES 1. First International Workshop on Chromosomes in Leukemia, 1977 (1978): Chromosomes in Phi-positive chronic granulocytic leukaemia. Br. J Haemato139:305 - 309, 1978.