Elevated Serum Transaminase Activity at Diagnosis is Associated With Rapidly Progressing Disease in

Children With Acute Lymphoblastic Leukemia

JUKKA RAUTONEN. MD, AND MARl-fI A. SIIMES. MD

The authors study whether quantitative measurement of serum glutamate pyruvate transaminase (SGPT) activity might serve as an indicator of liver involvement at diagnosis of acute lymphoblastic leukemia (ALL) and could be used as a parameter in predicting the prognosis of individual patients. The series consisted of 123 children with newly diagnosed untreated ALL. The mean follow-up time was 69 months (range, 22-140 months). The SGPT activity at diagnosis was significantly associated with the duration of event-free survival (P < 0.0001). For the 13 patients with SCPT activity > 40 IU/I the 5-year event-free survival was only 9%. All 1 1 patients with the lowest SGPT activities (<8 IU/l) remain in primary remission (24 to 81 months). The relative risk of relapse or death for children with SGPT activities of <8 lU/l, 8-40 W/l, and >40 IU/I were 0.2 (95% confidence limits 0.09-0.45), 1, and 4.8 (2.2-10.7), respectively (P < 0.001). The SGPT activity at diagnosis was not associated with clinically assessed liver enlargement. The authors speculate that high SGPT activities at diagnosis are associated with a rapidly progressing, fulminant form of ALL.

Cuncer 61:754-757, 1988.

VIDENCE OF organ infiltration, such as hepatomeg- E aly, was one of the first recognized prognostic fac- tors in childhood acute lymphoblastic leukemia (ALL).’,* Liver enlargement is one of the risk group cri- teria in the German BFM protocols3 that also are widely used in the Scandinavian countries. However, it appears to be a rather crude estimate of the leukemic involve- ment of the liver, and in most studies hepatomegaly has not been an independent prognostic f a ~ t o r . ~ - ~

It is known that serum glutamate pyruvate transami- nase (SGPT) activity originates almost exclusively from the liver. whereas a certain proportion of serum gluta- mate oxaloacetate transaminase (SGOT) can be traced to other tissues, such as cardiac or skeletal muscle. In this report we study whether quantitative measurement of SGPT activity at diagnosis of ALL might serve as an indicator of liver involvement and could be used as a parameter in predicting the prognosis of individual pa- tients. Measurement of the less-specific SGOT activity was included in the protocol mainly as a control, for

From the Children’s Hospital. University of Helsinki, Helsinki. Finland.

Supported by Foundation for Pediatric Research and Sigrid JuGlius Foundation.

Address for reprints: Jukka Rautonen, MD. Children’s Hospital. University of Helsinki, Stenbackinkatu 1 I , SF-00290 Helsinki, Fin- land.

Accepted for publication September 4. 1987.

SGPT would be expected to be a more accurate and reliable index of liver involvement than SGOT in pa- tients with ALL.

Patients and Methods

Of the 167 patients with newly diagnosed, untreated ALL admitted to the Children’s Hospital, University of Helsinki, during the 10-year period from 1975 to 1984, 124 (74%) had both their initial SGPT and SGOT activi- ties recorded. One of these patients was excluded from the analysis, as it seemed likely that his SGPT activity had been erroneously recorded, SGPT 0 IU/I and SGOT 39 IU/l, and the original laboratory lists were no longer available. At the time of diagnosis the median age of the 123 patients was 4.8 years (range, 2 months-I5 years). The number of boys and girls was 61 and 62, respec- tively. The patients excluded for lack of SGPT values did not differ in characteristics or outcome from the other patients.

The diagnosis of ALL was based on a bone marrow aspirate in all cases. In addition, a successful bone mar- row needle biopsy, surface marker, and karyotype analy- sis were available from 119, 87, and 70 cases, respec- tively. The therapeutic regimens used are routine Scan- dinavian protocol^.^^^ Maintenance therapy was electively discontinued after the patient had remained 3 years in remission.

754

No. 4 TRANSAM~NASES IN ALL - Rautonen and Siimes 755

TABLE 1. Associations Between SGPT Activity and Other Factors at Diagnosis

SGPT IU/I

<8 8-13 14-40 >40 (n = 1 1 ) (n = 46) (n = 53) (n = 13) P

Sex (W males) 36 41 60 Age (yr) 5.4 5.5 4.0 Maternal age (yr) 24.0 21.6 21.6 Paternal age (yr) 25.9 29.2 29.1 Leukocyte count X 109/1 4.9 11.9 8.5 Hemoglobin (d1) 88 83 76

Periph blasts (W) 15 40 30 BUN (mmol/l) 7 10 8

Femtin &I 33 I 173 26 1

Hatelets x 109/1 151 66 53

IgG W of normal I24 115 I12

Symptoms z 14 d ('-70) 73 50 34 Enlarged spleen (9%) 27 39 33 Enlarged liver (%) 46 60 61 Enlarged kidneys (%) 9 24 I I Enlarged lymph nodes (9%) 46 44 40 CNS leukemia ('70) 0 1 1 0 Roentgenologic signs of bone involvement 50 46 28 Cell type (n)

Non-T. non-B 7 30 32 T or B 0 4 5 C ALLA-positive 516 15/23 25/27

<46 0 2 1 46, normal 0 5 8 46, abnormal 2 10 6 47-50 0 4 8 >so 5 7 8

Chromosome modal no. (n)

The numerical values represent either medians or percentages of positive findings, unless otherwise indicated. The P values refer to overall differences between the four groups.

The closing date of follow-up for this study was Oc- tober 31, 1986. The mean follow-up time was 69 months (range, 22- 140 months). One low-risk patient in primary remission of 36 months duration was lost to follow-up because the family emigrated.

Both SGPT and SGOT activities were measured be- fore the initiation of chemotherapy by routine methods.' The upper limit of normal values used in our hospital is 40 IU/1 for both SGPT and SGOT.

All statistical analyses were performed with the BMDP statistical software package.'' Differences be- tween groups were analyzed with likelihood ratio chi- square (G2) test or variance analysis. The resulting P values (Table 1) were not corrected for multiple compar- isons. Survival analyses were calculated by the product- limit method; groups were compared by Mantel-Cox's test. All deaths during induction (n = 7), deaths during complete remission (n = 9), and relapses (n = 35) were considered as failures. The results were not changed ap- preciably if only relapses were considered as failures. The independence of prognostic variables was assessed with Cox's proportional hazards model. Risk ratios were

46 5.3

28.5 33.9 14.7 88 25 42

8 93

374 23 31 17 23 46 0 7

8 1

313

0 1 3 0 0

0.2 1 0.7 I 0.08 0.009 0.84 0.88 0.06 0.52 0.13 0.99 0.6 1 0.008 0.97 0.45 0.46 0.88 0.02 0.009 0.26

0.32 0.10

SGPT: serum glutamic pyruvate transaminase; Periph: peripheral; CNS: central nervous system.

calculated as exp (coefficient) and 95% confidence limits as exp (coefficient k 1.96 SE).

Results

Thirteen (9%) patients had elevated SGPT activities, above 40 IU/l, at diagnosis. The median activity was 14 1U/1 (range, 4-736 IU/l). The SGOT activity was ele- vated in 34 (28%) patients, the median activity being 28 IU/l (range, 1 1-800 IU/l). The mean SGOT/SGPT ratio was 2.8 (range, 0.2-10.0).

All data on SGPT and SGOT activities of the 106 patients followed for more than 3 years are shown in Figure 1 ; their transaminase activities did not differ sig- nificantly from those of the 17 patients excluded from the figure for insufficient follow-up time. A clear associ- ation exists between SGPT activity and prognosis. Only one of the patients with elevated SGPT activity at diag- nosis remained in remission for 3 years. This finding is confirmed by the survival analysis (Fig. 2).

For the 13 patients with SGPT activity > 40 IU/l, the 5-year event-free survival was only 9%. A detailed analy-

756 CANCER February 15 1988 Vol. 61

l o o 0 l

4 0

- . 2 I- 0 (3 fn

1 I

0

1 1 7 4 0 100 1000

SGPT lull

w I’

0

0 0

0 0 .

0 w

0

1 7 4 0 100 1000

SGPT lull FIG. I . SGPT and SGOT activities in children with ALL who achieved remission and have remained at least 3 years in remission (left) or who

relapsed or died within 3 years of diagnosis (right).

sis further showed that all 1 1 patients with the lowest SGPT activities (<8 IU/l) were alive in primary remis- sion of 24 to 8 1 months’ duration. In the remaining 99 patients with intermediate (8-40 IU/I) SGPT activities no clear relationship between SGPT activity and prog- nosis could be demonstrated. When this group was di- vided into two subgroups, as equal in size as possible, the resulting graphs of event-free survival almost were iden- tical.

The overall differences in the prognoses of the four above-mentioned groups were statistically highly signifi-

100

80

c5

8 60 Y

v) c 2

U n 40

SGPT 0-7 lull (nsll) k-l

Pl %l.--- SGPT 8-13 lull (n=46)

I 7 1 SGPT 14-40 lull (n=53) I \

‘1 SGPT r40 lull (n=13)

0 1 I I I I I I

0 2 4 6 8 10 1 2

YEARS AFTER DIAGNOSIS

FIG. 2. The effect of initial SGFT activity on the length of event-free survival in children with ALL (P < 0.OOOI).

cant ( P < 0.0001). Although the risk of relapse was higher in patients with high SGPT activity, the sites of relapse in these patients were not different from those in the other patients.

Elevated SGPT activity also affected the chances of achieving remission. Only 76.9% of the patients with SGPT activity > 40 IU/l attained a complete remission as compared with 96.4% of the other patients (P = 0.02).

The SGPT activity at diagnosis showed no clear rela- tionship with patient’s age or sex or with leukocyte count (Table 1). Low paternal age (at the child’s birth), long duration of symptoms preceding the diagnosis, and occurrence of roentgenologic signs of bone involvement all were correlated with low SGPT activities (for each, P < 0.0 I ) , as was the occurrence of initial central nervous system (CNS) leukemia (P < 0.05). In addition, there existed a clear linear relationship between SGPT activity and platelet count, although this association did not reach statistical significance (P = 0.06) because of the wide variation in individual platelet count values.

Like paternal age, maternal age (ie. , mother’s age at the time when the patient was born) was associated with SGPT activity, although not significantly (P = 0.08). The association between liver size and SGPT activity was not significant (P = 0.45).

Initial SGPT activity retained its prognostic signifi- cance in multivariate analysis even when all the factors listed in Table 1 were taken into account. The relative risk of relapse or death for children with SGPT activities of <8 IU/l, 8 to 40 IU/l, and >40 IU/1 were 0.2 (95% confidence limits 0.09-0.45), 1, and 4.8 (2.2-10.7). re-

No. 4 TRANSAMINASES IN ALL

spectively (P < 0.001). Thus, SGPT seems to be of prog- nostic value if it is either elevated or very low. Interme- diate values are not helpful. The other independent ad- verse prognostic factors were initial CNS-leukemia, age younger than 1 year, and hemoglobin concentration over 80 g/l.

Elevated activities of the other transaminase enzyme, SGOT, also were associated with a poorer prognosis. The 5-year event-free survivals of patients with SGOT activities of 140 IU/1 and >40 IU/I were 62% and 4 I%, respectively (P = 0.004). In contrast to the patients with very low SGPT activities, the patients with the lowest SGOT activities did not have a better prognosis than the other patients with SGOT activities within the normal range. In contrast to SGPT, SGOT activity was not an independent prognostic factor in multivariate analysis.

Discussion

The superiority of the liver-specific SGPT as a prog- nostic indicator suggests that liver involvement at diag- nosis has some prognostic significance. Surprisingly, the mechanism underlying this observation seems to oper- ate within both the low and the high range of activity of the enzyme, although most of the values were within the normal range. The unique association between very low SGPT activities and excellent prognosis deserves em- phasis.

It should be questioned whether the association be- tween SGPT activity and event-free survival is genuine or merely a coincidence. There exist no previous studies on this subject. The only enzyme in serum that has been reported to affect the prognosis of children with ALL is lactate dehydrogenase (LD); elevated LD activity was found to be associated with a poor prognosis in 293 children with standard risk ALL.” Thus, the idea of an association between serum enzyme activities and prog- nosis of ALL is not entirely new. Unfortunately, LD values were not obtained on our patients. In our study, the linearity of the risk and lack of other explanatory factors suggest that SGPT activity has a genuine, inde- pendent, and strong influence on prognosis. It is clear, however, that further prospective studies are needed to confirm these findings.

Italian researchers have noticed that 8% to 12%’2-’4 or even 41%” of children with leukemia show signs of in- fectious hepatitis at diagnosis and associated elevated serum transaminase levels. Concomitant hepatitis is not likely, however, to be responsible for the elevated en- zyme activities found in this study, since none of our patients had a documented hepatitis infection during the study period. Furthermore, hepatitis is a rare disease in Finland.

. Rautonen and Siimes 757

We speculate that, in an analogous fashion to Down’s syndrome, the association between parental age and ini- tial SGPT activity is not necessarily a coincidence. The association between Down’s syndrome and high mater- nal age and also with a poor prognosis in leukemia is well recognized.I6 Similarly, it is not impossible that high parental age may be associated with a yet unrecog- nized type of ALL in which patients often have elevated SGPT levels and a poor prognosis. The interpretation of the associations between elevated SGPT activity and short duration of symptoms or absence of roentgeno- logic signs of bone involvement cannot be aided by ear- lier observations. However, the current findings might lend support to a speculation that high SGPT activities at diagnosis are associated with a rapidly developing and progressing, fulminant form of ALL.

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