Acute lymphoblastic leukemia subtypes in israel: The sheba medical center experience

Leukemia Research Vol. 6, No. 5, pp. 669-673. 1982. Printed in Great Britain.

ACUTE

0145-2126/82/050669-05103.00/0 © 1982 Pergamon Press Ltd.

LYMPHOBLASTIC LEUKEMIA ISRAEL: THE SHEBA MEDICAL

SUBTYPES CENTER

IN

EXPERIENCE* BRACHA RAMOT,'I" ISAAC BEN-BASSAT, AMIRA MANY, GEORGE KENDE, YORAM NEUMAN, FRIDA BROK-SIMONI, ESmER ROSENTHAL a n d SHLOMIT ORGAD~ The Joseph and Caroline Gruss Institute of Hematology and ~Tissue Typing Laboratory, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University. Israel (Received 15 March 1982. Accepted 3 June 1982) Abstract--During the period from 1978 to 1981, 52 patients with ALL were diagnosed and treated at the Chaim Sheba Medical Center. Using standard cell markers to subtype the blasts, 49 of the patients could be classified: 16 were found to be T-cell ALL, 10 common ALL, five null ALL, four pre-B and 14 were partially characterized as non-B, non-T. Analysis of the series revealed two distinctive features: high prevalance (30%) of T-cell ALL among both Jews and Arabs and a high proportion, two-thirds, of high risk patients due to high initial WBC counts, unfavourable age or T-cell characteristics. The minimal incidence of ALL among the Gaza Strip Arab children during the study period is 4: 100,000, which is close to the incidence in the Western world. During previous years the leukemia incidence in the Gaza Strip was very low while the most common lymphatic malignancies were Burkitt tumor and other non-Hodgkin lymphomas. Key words: ALL, subtypes of ALL, effect of environment on lymphatic malignancies.

INTRODUCTION MARKED differences in the incidence of various childhood tumors and leukemias have

been observed between developed and developing countries. B-Cell tumors in children were found to be relatively common in Africa and rare in Western Europe and the U.S.A., while acute lymphoblastic leukemia (ALL) is the most common childhood malignancy in the Western world l5, 11, 21]. These differences could be related to environmental and genetic factors [10, 12, 17] or to the differences in medical care between developed and undeveloped countries. As there are no reports on ALL subtypes in the Middle East, it is of interest to summarize our experience. The Gaza Strip is a fast-developing region with a population of about 500.000. As all patients with hematological malignancies from this area are referred to the Chaim Sheba Medical Center, it seems to be an important source of information on the effect of a rapidly changing environment on the prevalence of the different subtypes of lymphoma and leukemia. PATIENTS A N D METHODS Fifty-two ALL patients were diagnosed and treated between the years 1978 and the end of 1981. The following studies were done on blast ceils obtained either from the peripheral blood or bone marrow: E-rosette formation [20]; surface immunoglobulins using a directly fluoreseinated F(ab'h fragment; adenosine deaminase {ADA~ [3J: nucleoside phosphorylase (NP) [9]: as well as the standard staining reactions for PAS, peroxidase and acid phosphatase. From 1980 onwards the common ALL antigen (cALLA) was tested in a cytotoxicity *This study was supported by the Israel Cancer Association. +Holder of the Yechiel and Helen Lieber Chair for Cancer Research at the Tel-Aviv University, Tel-Aviv, Israel. 669

670

BRACHA RAMOTet al.

assay using the J5 monoclonal antibody [14] (supplied by Dr. J. Ritz) and TdT (terminal deoxynucleotidyl transferase) by an immunofluorescent method [4] (using an antibody supplied by Dr. F. Bollum). 5'-Nucleotidase 1"13]and cytoplasmic immunoglobulins 1"19] were assayed in some of the cases. Burkitt cell leukemia cases were excluded from this study.

RESULTS Except for three in whom the studies were incomplete and who could not be subtyped, 49 ALL patients were classified into the known ALL subtypes. The relevant clinical and laboratory data are presented in Tables 1 and 2. Thirteen patients, three of them adults, had T-cell ALL with high E-rosette forming blasts and seven of them had mediastinal tumors. Three patients had probable T-cell ALL: all had mediastinal tumors, two had high ADA activity and the third had 10% E-rosette forming blasts. These three patients TABLE 1.

Patient

CLINICAL AND LABORATORY DATA OF PATIENTS WITH

Age

Ethnic WBC Mediastinal origin* ( x 1 0 9 / 1 ) tumor

ERr (%)

No.

Sex

(yr)

1 2 3 4 5 6 7 8 9 10 11 12 13

M M M M M M M M M M F M F

NR¶ 5 50 43 14 8 34 2 16 15 3 15 1

A J A J J A J A A J A A A

310 24 110 12 250 950 140 400 180 17 213 35 50

NR + NR + 0 + 0 + 0 + + + 0

64 30 87 35 76 30 95 89 99 33 81 95 72

64.4 35.3 27.1 102.2 17.9 29.6 18.8 59.3 59.1 49.4 33.1 20.7 13.6

11 14 18

J A J

I00 32 2

+ + +

10 0 0

37.1 76.6 72.3

Probable T-cell 14 F 15 M 16 M

T-CELLALL

ADA++ NP~ 10,5 10.6 5.6 10.0 7.4 5.5 2.4 17.4 19.2 11.5 9.3 19.3 51.5

5'-N~

TdT4I

0.0004

50

0.00006 0 0.0026 0.015

50 40

5.4 61.2 12.9 0.0041

100 20

100

*A = Arab, J = Jew.

tPercentage of E-rosette forming blasts. ~/tmol/h/10 a cells. §nmol/min/lO 6 cells. [IPercentage of positive cells. ¶NR = Not recorded.

are included for further analysis in the T-cell ALL group, The non-B, non-T group comprised of 10 patients with common ALL (cALLA positive), five patients with null ALL (cALLA negative), four patients with pre-B ALL and 14 patients partially characterized as non-B, non-T on the basis of an absence of mediastinal tumor, no E-rosette forming blasts and no surface immunoglobulins. As these patients were diagnosed prior to the introduction of tests for cALLA or cytoplasmic immunoglobulins, this is probably a more heterogeneous group than the others. This is also evident in the wide range of ADA activities seen in this group. Table 3 summarizes the clinical and laboratory characteristics of the two major subtypes of T- and non-B, non-T ALL. Similar to previous reports the T-ALL patients when compared to the non-B, non-T group were older, had a male sex bias and had higher initial WBC counts. In addition the mean ADA activity of the T-cell ALL blasts was significantly higher while no such difference was observed in the N P activity.

671

ALL subtypes TABLE 2. CLINICAL AND LABORATORY DATA OF PATIENTS WITH NON-B, NoN-T ALL Patient No.

Sex

Age (yr)

Ethnic origin*

Common ALL antigen positive l 2 3 4 5 6 7 8 9 10

M F M F F F M M F F

3 13 4 26 3 6 10 19 9 6

WBC ERr (× 10/1) % ADA~ NP~

A J A J A J J A A J

16 8 9 90 5 3 12 35 40 40

0 0 0 0 0 0 0 0 0 0

25.9 37.1 20.7 16.2 33.9 4.4 18.2 17.1 14.8 22.3

19.3 32.2 19.3 10.5 11.1 3.5 15.6 12.6 12.1 20.6

5'-N§ TdTII Clg** 80 50 0.047 0.03 0.087 0.076 0.065

80 40 50

80

Common ALL antigen negative (null) 11 12 13 14 15

F F F M F

11 ¼ 2½ 23 3

J J A A A

540 75 5 288 300

0 0 0 0 0

61.7 14.8 18.9 30.7 15.7

32.1 11.1 68.7 19.3 9.1

0.0051 0.0036 0.06 0.039 0.025

F M F M

9 5 " 2½ 10

J A A J

4 350 10 6

0 0 0 0

59.3 0.1 3.2 56.3

2 7 . 6 0.02 6.9 0.0003 2 2 . 5 0.03 25.1

A J A A J A A A A A J A A A

140 300 6 44 22 19 18 54 207 360 22 220 29 4

6 0 0 0 6 0 0 2 14 5 8 6 1 2

9.8 6.4 12.6 31.7 13.4 53.5 8.5 24.2 18.5 13.4 15.8 15.4 22.5 1.8 17,5 28.3 4.3 74.1 40,5 22.4 15,6 16.9 12.5 1.5 1.7 25.1 89.3

80 80 60

Pre-B 16 17 18 19

0 5 25 50

90 15 60 50

Partially characterized 20 21 22 23 24 26 27 28 29 30 31 32 33

M F M M M M M F M M F M M F

8 ¼ 1 8 2 15 5 4 15 I1 4 3 4 7

0.02

For abbreviations see Table 1. **°,o Cytoplasmic #-chain positive cells.

DISCUSSION By the use of standard immunological and enzymatic markers, most of our patients could be classified into the known subtypes of ALL. It was found that the frequency of T-ALL in our series, using strict criteria, is about 30~ both in Jews and Arabs, which is higher than the reported 10-20~o in the Western countries [6, 15, 18]. This is a minimal estimate as it is conceivable that some of the partially studied patients seen in the early part of the study period, especially those with high ADA activity, were they studied with anti-T antisera, would be found to belong to the E-rosette negative T-cell subtype. No definite conclusions can be drawn on the countrywide prevalence of T-cell leukemia among Jewish children from the data of one centre only. However, the data in Arabs from the Gaza Strip, an area served almost exclusively by The Sheba Medical Center, indicate a genuine high prevalence of T-cell ALL in this population, although lower than

BRACHA RAMOT et al.

672

TABLE 3. CHARACTERISTICSOF ALL PATIENTS Non-B, non-T ALL

T-ALL

No. of patients Arabs Jews Children ( < 16 yr) Adults

16 9 7 12 4

33 21 12 30 3

Male :female* Mean age *(yr) Median initial WBC ( × 10 g/l) No. of patients with WBC ( × 10g/l):

4.3:1

1.1:1 6,2 29 14 (42°,0) I0 (30°,o) 9 (28°./0)

ADA activity$

100 100

3 (19%o) 4 (25%) 9 (56°) 44.8 + 6.3

24.3 + 3.2 Ip < 0.0005)

N P activityt

16.2 + 4.1

20.2 + 3.2 (p = 0.2)

*Adults ( > 16 yr) excluded from analysis. "l'gmol/h/10 s cells. Mean + S.E.

reported previously in a smaller group [12]. The Arab population in the Gaza Strip is approx. 500,000 and the population below the age of 14 years is 45~o [7], so it can be estimated that the minimal incidence of ALL is about 4:100,000, which is the range observed in the U.S.A. [16]. Compared to the years 1972-1977 during which period only six cases of childhood ALL were referred to us, the number of cases diagnosed during the last four years is definitely higher. The cause of this apparent increase could be related to changing environmental conditions which occurred in this fast-developing area [12], an assumption supported by the fact that a concomitant decrease in the incidence of Burkitt tumor occurred in the same period (unpublished data). About two-thirds of the patients in our series are in the high risk category, either due to T-cell characteristics or to a high initial WBC count ( > 2 0 x 109/1) or an unfavourable age group ( < 2 or > 10 years). This is in contrast to most series from the Western world where the low risk category predominates [6, 8, 15]. In this study there is further confirmation of our previous work on ADA as a useful discriminating enzymatic parameter of T-cell vs non-B, non-T ALL [1], while NP lacked significance as a marker of the different subgroups of ALL [2]. Of interest are the patients diagnosed as pre-B ALL: two had unexpectedly high ADA activities in the range found in T-cell leukemia, while the other two had very low activity, similar to the findings in B-cell leukemia. It should be interesting to gather more information on this group of pre-B ALL since it appears to be heterogeneous and could possibly imply that the high ADA pre-B cells are less differentiated while the low ADA cases are more differentiated along the B-cell line. Acknowledgements--The technical help of Rivka Melik and Fanny Holtzmann is greatly appreciated.

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