Lpukemra Research Vol. 9, No. 6. pp. 755-763. 1985 Printed in Great Britam.

0145-?IZ6/X5S1 W + 0.00 Pergmlon PW\S L Id

IMMUNOPHENOTYPIC CLASSIFICATION OF LYMPHOBLASTIC LEUKAEMIA AND LYMPHOCYTIC

LYMPHOMA - AN EXPERIENCE IN THE SOUTH- WESTERN AREA OF THE CAPE PROVINCE OF

SOUTH AFRICA

PETER JACOBS

The University of Cape Town Leukaemia Centre and Department of Haematology, Groote Schuur Hospital, Observatory, The Cape, South Africa.

Abstract-Adequate tumour material was obtained for phenotypic classification using a standard library of monoclonal antibodies from 81 previously untreated patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), or lymphocytic lymphoma (LL). Sixty- one individuals were adults and 20 were children of 14 yr or younger. Fifty-eight of the patients (72%) had acute lymphoblastic leukaemia and the remaining 23 (28%) had chronic lymphocytic leukaemia or lymphocytic lymphoma.

Considering only the patients with acute lymphoblastic leukaemia (n = 58) the median age was 19 yr (range 3-69 yr): 9% were black, 43% were coloured, 48% were white, and the distribution between adult (n = 38) and paediatric patients (n = 20) was comparable.

Complete remission rate in the adults was 58% and in the paediatric group 85%. For the total group (n = 58) median duration of survival was 59 weeks for common, 39 weeks for null, 63 weeks for T-ALL, and I3 weeks for B-ALL subtypes. In both the common and the null groups overall and disease-free survival was superior in the children. In contrast, no difference was evident in the T-ALL group, which was also notable for its high incidence in young coloured males.

The I5 patients with CLL and eight with LL were adults and all the cells were phenotypically of B lineage: in view of the small numbers no comments are possible about ethnic differences. A multi-centre collaborative study is needed to define the epidemiology of haematologic malignancy in South Africa, with emphasis on differences among ethnically distinct subpopulations.

INTRODUCTION

THE NATURAL history and response to treatment of the haematologic malignancies varies between different races. Scientific information about these neoplasms is strikingly deficient from Africa. This is unfortunate in view of the unique opportunities that exist for such epi- demiological study. In part, this may reflect reluctance of patients to leave their families and travel long dis- tances to attend specialised clinics where the diagnostic and therapeutic expertise is available, and in part to the formidable problems of maintaining records when follow-up is unreliable, particularly once any improve- ment in symptoms has occurred [l]. Superimposed on these difficulties may be local cultural influences, in- cluding those of traditional healer or medicine-man, low-level of medical information, and a generally accepting philosphy to symptoms and signs of disease.

Abbreviations: ALL, acute lymphoblastic leukaemia; CU., chronic lymphocytic leukaemia; LL, lymphocytic lymphoma.

Correspondence IO: Peter Jacobs, Department of Haema- tology - Research Centre, University of Cape Town Medical School, Anzio Road, Observatory 7925, Cape, South Africa.

Key words: Immunologic typing, leukaemia, lymphoma, Southwestern Cape.

Systematic protocol studies since 1972 have been used to explore the presentation and management of haema- tologic malignancies at our institution. In view of the unique composition of our patient population, data has been accumulated on ethnic differences during the course of studies on acute leukaemia [2-4], chronic granulocytic leukaemia [5], myeloma [6], chronic lym- phocytic leukaemia and the indolent lymphomas [7], and diffuse large cell lymphoma [8]. In general terms, three observations occur consistently. Firstly, median age at presentation is between 10 and 15 yr lower in black when compared to white patients with the coloured population being intermediate. Secondly, from a catchment area of between 3 and 4 million people, of whom 12% are black, 53% are coloured, 33% are white, and 2% are Indian or Asian, the attendance at the specialised haematology clinic is approximately 10% for black, 40% for coloured, and 50% for white. This small but significant deviation from the composition of the overall population is probably attributable to limited availability of specialised services for haematologic disorders. Thirdly, many of our patients present late in the course of their disease with high tumour bulk and sub-optimal nutritional status: such fundamental dif- ferences make direct comparison of results from other centres having a more affluent patient load and earlier stage disease unreliable. These factors can only be con-

755

756 PETER JACOHS

trolled for by randomised studies within a single institu- tion where treatment programmes are being compared. However, relatively small numbers of patients at each centre are a compelling argument for collaborative group studies where treatment would be standardised and variables such as ethnic differences defined.

We report initial experience from our currently active study at the University of Cape Town and Groote Schuur Hospital in which immunophenotypic classifica- tion was used to explore the incidence and response to standardised treatment programmes between the three major race groups in the southwestern Cape.

MATERIALS AND METHODS

The reference population The Groote Schuur Hospital drains between 3 and

4 million people, of whom approximately 12% are black, 53% are coloured, 33% are white and 2% are Asian. The average annual admissions approximate 75,000 and outpatient visits close to I million; in general medical or surgical beds approximately 10% of patients are black, 63% are coloured and 27% are white. The Department of Haematology admits, on average, 360 patients and sees 7200 outpatients annually. of whom 10% are black, 40% are coloured [9], and 50% are white. This latter pattern has been constant over the past decade and the differences between it and both the over- all population and that for patients on the general hospital services probably reflects a referral pattern which has developed around the special interest and pro- vision of diagnostic and therapeutic services for patients with haematologic problems, including myeloma, lym- phoma and leukaemia.

No reliable national or local figures are available for the overall incidence of the major categories of haema- tologic malignancy. An approximation can be derived from the population in the catchment or drainage area and the statistics for the hospital department for the period January 1980 through June 1984 with an average annual new patient accrual rate for patients over the age of 14 yr being 30 for non-Hodgkin’s lymphoma, 12 for Hodgkin’s disease, 14 for chronic lymphocytic leu- kaemia, 6 for chronic granulocytic leukaemia, 30 for non-lymphoblastic leukaemia and 13 for acute lym- phoblastic leukaemia. Within each of these disease- types, the ratio of black to coloured and white patients was 9:43:48, with an additional 1% Asian patients, with these figures being relatively constant. Furthermore, within each of these ethnic groups, the male to female ratio was 3.4:1, 1.22:1, and 1.24:l. The predominance of black males may reflect local cultural practice where larger numbers of males make up the work force and there is generally greater reticence of the more conser- vative rural black woman to leave her family, even to attend regional hospitals.

Study population (n = 8 I) Fifty-eight patients with previously untreated ALL,

I5 with CLL. and eight with LL were phenotypically classified using a standardised library of monoclonal

antibodies provided by the LRF Centre as part of the collaborative group study of leukaemia subtypes (see paper by &eaves et al., in this issue).

All patients were previously untreated and entered onto study with informed consent. Fifty-eight had ALL, 15 had CLL and five had miscellaneous lymphocytic lymphoma.

Patient evaluation All patients had detailed history taken and underwent

full physical examination. Complete blood counts were carried out on the Coulter Counter Model S Plus [lo] and using May-Griinwald-Giemsa staining were classi- fied as ALL on the basis of the French- American- British (FAB) Co-operative Group’s proposal [I I-131. The diagnosis of chronic lymphocytic leukaemia was based on established criteria [14] and staged according to the Rai recommendations [15]. Lymphocytic iym- phoma was classified according to the recommendations of the International Working Formulation [16]. Bio- chemical profile was determined using established methodology [ 171. In vitro bone marrow culture studies were performed on aspiration samples. Blasts were ex- amined by sheep erythrocyte rosette formation [ 181 and by direct and indirect immunofluorescence using an- tibodies against terminal deoxynucleotidyl transferase (TdT) [19] and a standardised library of monoclonal antibodies, including demonstration of surface im- munoglobulin [20, 211, Dr and CALL antigens [22, 231.

Patient exclusions The I5 patients with CLL are excluded from further

analysis but are reported elsewhere [7,24, 251. The eight patients with miscellaneous lymphocytic lymphomas are not suitable for further analysis because the numbers are too small.

Chemotherapy programme The adults were managed with conventional doses of

vincristine, prednisone, I-asparaginase and adriamycin. Those achieving complete remission underwent cranio- spinal prophylaxis and entered a three-year maintenance programme of oral 6-mercaptopurine and methotrexate with monthly drug intensification. The children were stratified into low or high risk; the former were treated with a St Jude regimen [26] and the latter with a modified LSA-L2 protocol [27].

Statistical analyses These were carried out using established methods [28,

291.

RESULTS (TABLE 1)

Age The median age of the patients with ALL (n = 58) was

19 yr (range 3-69). There were 38 adults with a median age of 24.5 yr (range 16-69); the corresponding figures for blacks were 24 yr (range 19-48), coloureds 20.5 yr (range 16-62), whites 28 yr (range 16-69), and Asians 37 yr (range 34-64). Twenty of the patients were 14 yr or

TAIX

E I.

AC

UTE

LYM

PHOB

LAST

IC

LEUK

AEM

IA

Phen

otyp

e N

umbe

rs

and

age

Adu

lts

Chi

ldre

n

Perc

ent

Mal

e C

ompl

ete

Surv

ival

N

umbe

rs

Perc

ent

Mal

e C

ompl

ete

Surv

ival

to

re

mis

sion

(w

eeks

) an

d to

re

mis

sion

(w

eeks

) B

lack

C

olou

red

Whi

te

fem

ale

(070

) ag

e B

lack

C

olou

red

Whi

te

fem

ale

V.0

)

Com

mon

12

9

I6

75

9:3

50

23

5 20

20

60

3:

2 10

0 76

31.5

5

Nul

l IO

0

50

50

5:5

70

30

28.5

T-C

ell

I2

8 67

25

9:

3 67

46

22.5

7 14

29

51

1:

6 86

62

-, 9

..- :z

6 0

66

34

5:l

100

47.5

6.5

B-C

ell

4 25

50

25

2:

2 25

4

33.5

_

~~ ~~

2 0

50

50

1:I

0 7.

5

7.5

Com

paris

on

of p

atie

nt

popu

latio

n,

com

plet

e re

spon

se,

and

actu

aria

lly

pred

icte

d su

rviv

al

by p

heno

type

be

twee

n ad

ults

an

d ch

ildre

n ag

ed

I4 y

r or

you

nger

. Th

e sm

all

num

bers

m

ake

stat

istic

al

anal

ysis

unre

liabl

e bu

t ch

ildre

n ar

e se

en

IO g

ener

ally

ha

ve

high

er

resp

onse

ra

tes

and

bette

r su

rviv

al

than

ad

ults

. A

not

able

ex

cept

ion

is T

-ALL

w

here

, de

spite

hi

gher

re

spon

se

rate

s in

pae

diat

ric

patie

nts,

surv

ival

is

com

para

ble

to t

hat

foun

d in

the

ad

ults

. B

-ALL

is

an

unco

mm

on

grou

p bu

t pa

tient

s do

un

iform

ly

poor

ly.

Ediro

rs

note

: Se

vera

l of

the

se

case

s w

ere

re-c

lass

ified

by

the

re

fere

nce

cent

re

(see

Tab

le

2 in

the

pa

per

by G

reav

es

ef a

l.).

In p

artic

ular

5

of

the

I7 c

ases

of

N

ull-A

LL

wer

e cl

assi

fied

as A

LL

of

unce

rtain

su

btyp

e.

Thre

e ad

ditio

nal

case

s w

ere

cons

ider

ed

uncl

assi

fiabl

e A

LL

subt

ypes

.

758 PETER JACOBS

younger with a median age of 6.5 yr (range 3-14); the corresponding figures for blacks were 11 yr (range 9-13). coloureds 6 yr (range 3-12), and whites 6.5 yr (range 4-14).

Race

The 58 patients with ALL were made up of five (8%) blacks, 22 (40%) coloured, 28 (48%) white and three (4Vo) Asians. When subdivided into adult and paediatric individuals this distribution was constant.

Common acute lymphoblastic leukaemia (Table 2) The median age of these 17 patients was 27 years; two

were black, two were coloured, 12 were white and there was one Asian. There were I2 adults having a median age of 37.5 yr; one was black, one was coloured, nine were white and there was one Asian. Five of the patients were children, having a median age of 5 yr; one was black, one was coloured and three were white. The male to female ratio was 12.5; for the adults it was 9:3 and for the children 3:2.

The complete response rate for adults was 50%. and median survival was 23 weeks; for the children complete remission rate 100% and median survival was 76 weeks.

Null acute lymphoblastic leukaemia (Table 3) The median age of these 17 patients was 19 yr; one

was black, five were coloured, nine were white and two were Asians. There were 10 adults having a median age of 28.5 yr; there were no black patients, three were coloured, five were white and two were Asian. Seven of the patients were children, having a median age of 9 yr; one was black, two were coloured and four were white. The male to female ratio was 6: 11; for the adults it was 5:5 and for the children it was 1:6.

The complete response rate for adults was 70% and median survival was 30 weeks; for the children complete remission rate was 86% and median survival was 62 weeks. T-acute lymphoblastic leukaemia (Table 4)

The median age of these 18 patients was 18 yr; one was black, 12 were coloured and five were white. There were 12 adults, having a median age of 22.5 yr; one was black, eight were coloured and three were white. Six of the patients were children, having a median age of 6.5 yr; there were no black patients, four were coloured and two were white. The male to female ratio was 14:4, for the adults it was 9:3 and for the children 5:l.

TABLE 2. COMMON ACUTE LYMPHOBLASTIC LEUKAEMIA

Haemoglobin White blood count

Blasts Platelets

33%

(O-87%)

77

(< 10-394)

8.7

(2.1-71.2)

10.0 7.8

(6.6-14.8) (2.1-71.2)

10.3

(8.4-14.8)

9.1 7.0

(6.6-12.6) (4.2-27.2)

11.9 5.8

(I 1.3-12.6) (4.7-6.9)

9.1 7.0

(8.4-12.9) (2.7-7.8)

9.5 10.8

(6.6-14.8) (2.1-71.2)

26%

(O-87%)

80

(< 10-356)

68%

(14-75%)

40

(I l-394)

47%

(27-68’70)

25

(<10-40)

26%

(ll-33%)

117

(77-394)

45%

(O-87%)

56.5

(11-356)

Total

Median

Range

Adults

Median

Range

Children

Median

Range

Black

Median

Range

Coloured

Median

Range

White

Median

Range

Leukaemia and lymphoma in the Southwestern Cape

TABLE 3. NULL ACUTE LYMPHOBLASTIC LEUKAEMIA

Haemogiobin White blood count

Total

Median

Range

Adults

Median

Range

Children

Median

Range

Black

Median Range

Coloured

Median

Range

White

Median

Range

8.1 9.1

(4.2-12.9) (1.8-290)

87 15.3

(5.2-12.9) (1.8-127)

7.4 6.5

(4.2-12.0) (4.2-290)

5.0 13.0 - -

10.7 12.3

(5.2-12.9) (1.8-127)

8.0 7.7

(4.2-l 1.6) (4.2-290)

Blasts Platelets

58% 88

(O-97070) (5-517)

63%

(O-95%)

88

(27-517)

43%

(O-97%)

63

(5-194)

65% -

54 -

19%

(O-95%)

71

(5-517)

58%

(O-97%)

92

(53461)

759

The complete response rate for adults was 67% and median survival was 46 weeks; for the children complete remission rate was 100% and median survival was 47.5 weeks.

B-acute lymphoblastic leukaemia (Table 5) The median age of these six patients was 19.5 yr; one

was black, three were coloured and two were white. There were four adults, having a median age of 33.5 yr; one was black, two were coloured and one was white. Two of the patients were children, having a median age of 7.5 yr; one was coloured and one was white. The male to female ratio was 2:4; for the adults it was 2:2 and for the children it was I : I.

The complete response rate for adults was 25% and median survival was 4 weeks; in the children there were no responders and median survival was 7.5 weeks.

Survival by phenotype Pooling the data from adults and children (Fig. 1)

median survival is 59 weeks for common ALL, 39 weeks for null ALL, 63 weeks for T-ALL, and 13 weeks for B-ALL. Disease-free survival is 56 weeks for common ALL, 20 weeks for null ALL, and 66 weeks for T-ALL.

DISCUSSION

Ethnicity is a powerful prognostic factor influencing the natural history and response to treatment of patients with haematologic malignancy. Thus, comparisons between blacks and whites in New York State with Reef Towns in the Southern Transvaal reveal differences, suggesting that disease expression may be strongly in- fluenced by the social milieu [30]. In a period now ex- ceeding a decade, striking consistent differences have emerged between black, coloured and white patients at our institution. Of these, age has been most clearly documented, with the median for black being between 10 and I5 yr lower than white patients with the same disease, and the coloured population generally occupy- ing an intermediate position.

Furthermore, although response rates for standar- dised management protocols are not different for race groups matched for other variables, late presentation with high bulk disease, often with sub-optimal nutri- tional status, show a trend to more frequent occurrence among referred black patients, although similar features may be found in less sophisticated individuals from the coloured and white race groups. In addition, sex distri-

760 PETER JACOBS

TABLE 4. T-ACUTE LYMPHOBLASTIC LEUKAEMIA

Haemoglobin White blood count

Blasts Platelets

Total

Median

Range

Adults

Median

Range

Children

Median

Range

Black

10 78.1

(U-15.8) (1.7-338)

11.4 105.9

(7.6-15.8) (1.7-263)

8.9 86

(5.5-14.0) (19.9-338)

Median Range

Coloured

7.8 13.5 - -

Median

Ran8e

White

Median

Range

10.0 87

(7.6-14.1) (1.7-263)

11.6 41.6

(5.5-15.8) (2.7-338)

71%

(O-100%)

73.5%

(O-100%)

72.5%

(2-100%)

544io -

86.5 (7-421)

86.5

(<IO-245)

88.5

(7-421)

67 -

594

(O-IOOsro)

94

(15-421)

75vo

(O-100%)

81%

(7-245)

bution is a less striking but clearly demonstrable variable and, as in chronic granulocytic leukaemia, cytogenetic differences also appear to exist [5], although clinical presentation, haematologic features, response to treat- ment and survival rates could not be correlated with this finding.

Conventional morphology is insufficiently sensitive to reliably separate immunobiologically distinct subtypes of lymphoid neoplasia within the French-American- British (FAB) classification [12]. Mottoclonal antibodies were used for this purpose to prospectively study the in- fluence of age and race on remission rate and survival using standardised protocols for treatment in patients stratified by phenotypic subtype.

In the patients with common and null ALL the pheno- type was distributed similarly, both between the adult and the paediatric age groups and, furthermore, there was no significant variation between black, coloured and white patients. Two additional points require com- ment. Firstly, both complete remission rate and median duration of survival is already showing a trend in favour of patients expressing the common acute leukaemia

antigen. Secondly, age is predictably emerging as a favourable prognostic factor for both these immuno- phenotypic subgroups.

T-ALL is a particularly interesting cohort. Thus, while the age disiribution is comparable to the other im- munologically defined subgroups, the value of immuno- phenotypic classification is reflected in an unexpected finding with a clear predominance in young coloured males. Unlike other series reporting a prominence of mediastinal tumour, this finding was unusual in these patients. The complete response rate to standard chemo- therapy was also not significantly different from com- mon and null ALL patients, with adults achieving this status in 67% of cases and the children in 100%. How- ever, survival shows two important differences. Firstly, as generally expected. in the paediatric age group this is inferior to the common and null ALL variants; a finding consistent with reports that the T-cell phenotype is an unfavourable prognostic factor in this age group (311. Secondly, and by way of contrast, adults survive better than any of the other subtypes. To pursue this latter dif- ference in more detail, comparative analysis has been

Leukaemia and lymphoma in the Southwestern Cape

TABLE 5. B-ACUTE LYMPHOBLASTIC LEUKAEMIA

761

Haemoglobin White blood count

Blasts Platelets

Median

Range

Adults

Median

Range

Children

Median

Range

Black

Median

Range

Coloured

Median

Range

White

Median

10.2

(6.3-12.9)

Il.0

(8.5-12.9)

8.3

(6.3-10.4)

8.5

-

10.4

(10-11.5)

9.6

(6.3-12.9)

20.0

(4.6-98.2)

17.0

(4.6-98.2)

22.4

(22.1-22.8)

98.2 62%

- -

18.0

(16.0-22.8)

13.3

(4.6-22.1)

49.5%

(2-70%)

41%

(2-70%)

39%

(l9-59%)

40%

(19-70%)

30.5%

(2-59%)

27.5

(19-221)

21.5

(19-159)

126.5

(32-221)

I9

-

23

(20-221)

95.5

(32-159)

0 Common ??Null

b

0’ I I I I 20 40 60 80

1 100

WEEKS FIG. 1. Acute lymphoblastic leukaemia. Actuarially predicted survival by phenotype for pooled data from adults (n=38) combined with children aged 14 yr or younger (n=20). The notable feature is similarity in the curves for patients with com- mon and T-ALL; the major influence being that of an unusu- ally high occurrence of T-ALL in a subgroup of young col- oured males. It is also notable that no plateau is yet evident for the overall population. Separate analysis by age is precluded by small numbers of patients in each immunophenotypically

distinct subclass.

762 PETEK JACOBS

undertaken against a control group of patients im- munologicaily classified as common or null-ALL [32].

In this study the complete remission rates were 71% for the T-ALL and 75% for the common or null group while actuarially predicted median duration of survival is 49 and 39 weeks, respectively. While these differences may reflect geographical and racial factors, they may equally well be explained by the thymic phenotype becoming a less reliable marker of poor prognosis with increasing age, and this is likely to be the result of the more aggressive clinical course of all phenotypic sub- groups of acute lymphoblastic leukaemia in the adult.

CONCLUSION

Three points are emphasized by this study. Firstly, apparently homogeneous tumour morphology in lym- phoproliferative disorders can be misleading and im- munologic techniques provide a suitable methodology to more reliably define phenotypically distinct sub-popula- tions. Secondly, the unexpected high incidence of T-ALL in young coloured males is in keeping with other evidence that ethnicity can exert an important and dis- tinctive influence on disease expression. Thirdly, irres- pective of race, age emerges as a favourable prognostic factor. Finally, there remains a striking paucity of properly assembled scientific data from countries in Africa, where a unique opportunity exists to define the potential impact of ethnic differences upon the natural history of different disease categories. The importance of the latter information is becoming increasingly appreciated as the role of viral infections and oncogene activation in the pathogenesis of human tumours such as the T-cell leukaemia-lymphoma syndrome is clarified [33]. All these cogent reasons for centres having the necessary expertise and patient populations collaborate in studies to explore this relatively neglected but im- portant facet of geographical haematopathology.

Acknowledgemenrs-Supported by the University of Cape Town Leukaemia Centre and Staff Research Fund, the National Cancer Association and the Medical Research Coun- cil. Data on the paediatric patients were contributed by Dr Cyril Karabus, Dr Paddy Hartley, Dr Arthur Bird and laboratory staff. Monoclonal antibodies were supplied by Dr M. F. Greaves from the Leukaemia Research Fund Centre. Appreciation is expressed to Gail McLellan for marker studies, Lucille Wood and Karen Edwards for data collection and analysis, Jackie Davies for typing, and the Medical Superinten- dent of Groote Schuur Hospital for permission to publish.

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Africa. A review. Leukemia Res. 3, 51. Dubovsky D., Kernoff L. &Jacobs P. (1978) Rapid remis-

sion induction in adult acute non-lymphoblastic leu- kaemia. Eur. J. Cancer 14, 1179. Jacobs P., Dubovsky D. W. & Wood L. (1984) In adult

acute nonlymphoblastic leukaemia extended maintenance chemotherapy has no benefit. Am. J. Hemar. 16, 255.

4.

5.

6.

7.

8.

9.

10.

II.

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14.

IS.

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18.

19.

Jacobs P. (1984) The epipodophyllotoxin VPl6-213 in

combination chemotherapy for adults with acute nonlym-

phoblastic leukaemia. Proc. Modern Trends in Human Leukemia VI, Wilsede, 17-21 June 1984 (in press).

Jacobs P., King H. S. & Dent D. M. (1983) Chronic

granulocytic leukaemia. A IO-year experience in the Black,

Coloured and White populations of the south-western

Cape Province. S. Afr. med. J. 63, 879. Jacobs P., King H. S., le Roux I. & Scaly R. S. (1984)

Comparison of sequential half-body irradiation to chemo-

therapy as primary treatment for myeloma. Proc. 13th Annual Meeting of rhe Int. Sot. for Experimental Hema- tology, Atlanta, Georgia. Jacobs P., King H. S., le Roux I. & Sealy R. S. (1984) A

comparison of total body irradiation to combination

chemotherapy in the treatment of lymphoproliferative

disorders. Proc. 2nd Int. Con. on Malignant Lymphoma, Lugano. Jacobs P., King H. S., Cassidy F., Dent D. M. &Harrison

T., (1981) VP-16-213 in the treatment of stage 111 and IV

diffuse lymphocytic lymphoma of the large cell (histio-

cytic) variety: an interim report. Cancer Treat. Rep. 65, 987. Beighton P. (1976) Genetic disorders in southern Africa.

S. Afr. Med. J. 50, 1125.

Rowan R. M., Fraser C., Gray J. H. & McDonald G. A.

(1979) The Coulter Counter Model S Plus - the shape of

things to come. Clin. Lab. Haemal. 1, 29.

Bennett J. M., Catovsky D., Daniel M., Flandrin G.,

Galton D. A. G., Gralnick H. R. & Sultan G. (1976)

Proposals for the classification of the acute leukaemias.

French-American-British (FAB) Co-operative Group. Er. J. Haemar. 33, 45 1. Burns C. P., Armitage J. O., Frey A. L., Dick F. R.,

Jordan J. E. & Woolson R. F. (1981) Analysis of the, presenting features of adult acute leukemia: The French-

American-British classification. Cancer 47, 2460. Flandrin G. & Daniel \I.-T. (1981) Cytochemistry in the

classification of leukemias. In The Leukemic Cell. (Catovsky D., Ed.), pp. 29-48. Churchill Livingstone,

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