Haematological oncology
B. E. Roberts, A. H. Smith
Following the development of the cyclotron in 1932,radio-isotopes became available for use in
medicine both as tracer substancesand therapeutic agents.The father of nuclear medicine, Dr J. H.
Lawrence, pioneered their use in a range of diseasestatesand found that radio-isotopes were of
enormous value in the diagnosis and treatment of haemopoetic disease,particularly the
myeloproliferative disorders. Radioactive phosphorus 32Pemergedas the radio-isotope of choice for
the myelosuppressivetreatment of myeloproliferative disorders. This article also describesthe use of
radio-isotopes in the treatment of other disorders: chronic myeloid leukaemia, chronic lymphocytic
leukaemia and myeloma, work that is now largely forgotten. All myeloproliferative disorders may
evolve without treatment into myelodysplastic syndrome or blast-cell transformation. It is accepted
that life is prolonged in myeloproliferative disorders treated with 3Por alkylating agents,yet both are
leukaemogenic. The ideal form of treatment for polycythaemia vera is unknown and will remain so,
for patients with this disorder often outlive their physician and achieve90% of normal life
expectation. P remains the treatment of choice for elderly patients with polycythaemia Vera.
Radio-isotopes for use in medicine became available
in 1934, some 38 years after the discovery of X-rays
by Riintgen in 1896. They were first made in quantities sufficient for medical work from the cyclotron
developed by Ernest Lawrence and colleagues in
Berkeley, California in 1932.
The exploitation of the use of isotopes in medicine
was made by a team of workers in California associated with the cyclotron project led by John Lawrence,
brother of Ernest. It is generally acknowledged that
John Lawrence was the founding father of nuclear
medicine as a discipline and much of his pioneering
work was in the field of haematology. Lawrence used
radio-isotopes as both tracer substances and as a
form of therapeutic irradiation. The agent Lawrence
used most commonly for therapy was radioactive
phosphorus 32P
RADIOACTIVE
THERAPEUTIC
PHOSPHORUS:
AGENT
THE
Current knowledge
32P is a pure beta-emitter of maximum energy
1.71 Mev. with a mean range in tissue of 3 mm and a
maximum of 8 mm. It has a half-life of 14.3 days.
Administered
intravenously as sodium orthophosphate, it is taken up preferentially by bone,
spleen and liver. Within 6-24 h of parenteral administration of ?:P as sodium orthophosphate, bone concentration exceeds that of muscle, fat or skin by a
factor of 4-6; this ratio increases to 610 after 3 days.
Liver and spleen *P ratios to muscle, fat or skin are
of the same order of magnitude. Initially, P is selectively concentrated in the mitotically active cells in the
bone marrow and, within the first few days, is incorporated in the calcium phosphate of the bone lying
adjacent to the endosteum.
The effective dose of 32Pfor adults is given by the
International Commission on Radiological Protection
Dr B. E. Roberts, Department
of Haematology;
Dr A. H. Smith,
Department
of Medical
Physics, General Infirmary.
Leeds
LSI 3EX. UK
146
Radioactive
ohosohorus
ANALYSIS
in haematologv
147
OF TREATMENT
used by Lawrence
from I).
et al:
148
Blood
Reviews
Fig. 2 Median
permission
from
survival in polycythaemia
Vera. (Reproduced
I), including
original caption).
with
Radioactive phosphorus was also used in the treatment of chronic myeloid leukaemia (CML). In 1948,
Lawrence and co-workers6 reported their experience
of treating 129 patients from 1936 to 1947, a period of
11 years.
From its earliest availability, P was used in the treatment of chronic lymphocytic leukaemia (CLL) and 100
patients treated between 1936 and 1948 were reported
by Lawrence et al in 1949; 58 of the patients also had
localized radiotherapy to local lymph nodes or spleen.
It is interesting to read that, in contrast to the 3
patients who died of miliary tuberculosis in CML,
there was none in patients with CLL. There were 71
males and 29 females and the age difference was
between 20 and 60 years with a mean of 53 years.
The method of treatment was by giving 3774 MBq for 48 weeks repeated when the blood count
or symptoms warranted it.
The changes sought with therapy were an improved
red-cell count and decrease in lymphadenopathy and
splenomegaly. No attempt was made to bring the lymphocyte count to normal for fear of bone-marrow
damage. The response to therapy in this article is
shown by examples and indicates how the lymphocyte
counts can be controlled over several years (Fig. 5.)
Survival is shown in Figure 6 and, from this, the
authors calculated that the average survival was 4.5
years. An interesting comparison in terms of relationship with acute leukaemia to radiation therapy was
made between CML and CLL. At least one-third of
patients with CML died of a blast cell transformation,
whereas only 2 with CLL died with this picture. It was
noted that the total amount of j2P given to patients
with CLL was lower than with CML. This series
established for the first time that haemoglobin level is
a very important prognostic feature in CLL (Fig. 7).
Radioactive
Clinical
follow-up
in a patient
with chronic
myeloid
leukaemia.
(Reproduced
with
LIVING,
p32
LIVING,
Duration
Pig.
8.---Chronic
myelogenous
p;~tient living eleven years after
xcar, when some ~NXI~roentwl
I~tcrtd. The nvcrnge duration to
Fig. 4 Survival
in chronic
myeloid
leukaemia.
(Reproduced
with
1 including
from
permission
DEAD,
p32
DEAD,
~32,
in haematology
of the
of a small
Fig. S.-RI.
R.,
57 year
old woman.
Definite
improvement
white cell count
and size of the spleen foilowing
administration
nnloutlt
of P=.
Fig. 3
phosphorus
and X-ray
IO
II
(years)
from
lo, including
original
caption)
original
caption).
149
Fig.
Z.-By
infrequent
ntllllillihtr;tti(lll
of
I:
intrnvcnr,uslg,
in (loses
from
0.5 to 4 millicuries,
the I\ liitc
rc>ll> lxivc
tIcen
kcljt
llcar
nornl;tl
it,
nunil)er
anti
the patient,
a 41 +cr
oltl n1a11 L\ it!] chronic
Ivml~li;~tic leukcmin,
has
carried
on a normal
liie withtOut synilItc0ilh
(i,:: shf~n
in
millicurics,
ret1
Mood
cells
in millions.
hcmogl~~l~in in xr;rms
:tntl
\vhitc
I~l~od
cells
Zild
thronil)ocytrs
in til0~~s~l~tl~).
Fig. 5 Clinical
follow-up
origin al caption).
in a patient
with
chronic
lymphocytic
leukaemia
treated
by P. (Reproduced
with
permission
from
, including
in 37 cases of chronic
lymphatic
leuFig.
5.---l<esults
of pl* therapv
The
nwmher of patients -is plotted against average length of life
kemia.
the average
At present (May
15, 1949)
after onset (September
1948).
for the whole groull is 4.5 years, and the 22 living patients now have an
(These durations
have been
average duration
since onset of 6.8 years.
calculated
from the individual
patient charts by a disinterested
medical
observer.)
The vertical values show the number of cases studied and the
horizontal
values the duration in years.
Fig. 6 Survival
in patients
with chronic
lymphocytic
leukaemia
treated
by Y? (Reproduced
with permission
from
Ii, including
original
caption).
Radioactive
uhosuhorus
in haematoloev
15 1
Fig. 6.yConlpariso?
of. duration of disease !in years) -with percentage of
~~~hog$~m on adnnsslo? 11195 cases of chronic lymphatic leukemia treated
. The dotted lines are for average duration of deceased patlents.
Fig. 7 Survival
and haemoglobin
Ie~el in chronic
lymphocytic
leukaemia.
(Reproduced
with
permission
from
-. including
original
caption).
152
Blood
Reviews
of aleukaemic
myelosis
from
Heller,
A Leukaemia
Aleukemic
myelosis
Aleukemic
leukaemia
Pseudoleukaemia
Osteosclerotic
leukaemia
Atypical
myelosis
Megakaryocytic
myelosis
B Anaemia
Leukaemia
Myeloid
2
Duration
-I+H+H+
.. . . . . . . .
- - - - - -
8
of disease
Untreated
Veaesection
alone
X-ray therapy alone
Various combinations
Fig. 8 Survival
of patients with
forms of treatment.
(Reproduced
IO
12
14
anaemia
16
C Spleen and/or
Wears)
with X-ray
splenic
Leuko-erythroblastic
anaemia
Leuko-erythroblastosis
Osteosclerotic
anaemia
therapy
polycythaemia
vera with different
with permission
from ).
liver
Splenomegaly
with anaemia and myeloma
Myelophthisic
splenomegaly
Aleukemic
hepatosplenic
myelosis
Agnogenic
myeloid metaplasia
of the spleen
Myeloid
megakaryocytic
hepatosplenomegaly
Splenomegaly
with sclerosis of the bone marrow
Splenomegaly
with myeloid transformation
Splenomegaly
with anaemia
Myeloid
splenomegaly
without
myelocytaemia
D Bone marrow
Myelofibrosis
Myelosclerosis
Osteosclerosis
Table 2 Methods
Wasserman)
of treatment
of polycythaemia
vera (after
Variations
on bloodletting
General or topical
Phlebotomy
Scarifying
Cupping
Leeching
Iatrogenic
hookworm
infestation
Miscellaneous
Gastric lavage (to remove Castles Intrinsic
Factor (IF))
Gastrectomy
to remove IF (stimulus
to bone marrow)
Diet (iron-free,
high-fat,
low-purine)
Splenic extracts, liver extracts, splenectomy
a interferon
Chemical
Benz01 and derivatives
Phenylhydrazine:
acetylphenylhydrazine
(aniline derivative)
Onions (onion oil: N-propyldisulphide);
Arsenic:
Fowlers solution
(10 drops); Oxygen inhalation
(for bone-marrow
anoxia)
Radiation:
Total-body.
splenic, long bones, stomach
Radium,
thorium
X, Grenzstrahlen
Radioactive-phosphorus,
sodium, gold, zirconium,
yttrium.
Chemotherapy
Nitrogen
mustard,
busulfan,
thiotepa,
triethylene
melamine,
daraprim,
alkeran, chlorambucil,
cyclophosphamide,
procarbazine,
pipobroman
(Vercyte).
azaribine,
dibromannitol,
hydroxyurea
Radioactive
phosphorus
in haematologv
153
4. International
Committee
on Radiation
Protection
Publication
53. Vol 18 No 14. Radiation
Dose to Patients from
Radiopharmaceticals
p 15. Oxford:
Pergamon
Press. 1987.
5. Spiers FW. Beddoe AH, King SD et al. The absorbed
dose to
bone marrow
in the treatment
of polycythaemia
by P. Br J
Radio1 1976: 49: 133.
6. Seltzer RA. Kereiakes
JG. Sacnger EL. Pediatric radiation
cxnosures.
N Enel J Med 1964: 271: 84.
7. Low-Beer
BVA. Bliss RS. Schofield NE. Estimation
of dosage
for intravenously
administered
:I? Am J Roetgenol
1952; 67: 28.
8. International
Committee
on Radiological
Protection
Publication
17. Protection
of the patient in radionuclide
investigations.
p 64. 1971.
9. Berk PD. Goldberg
JD. Donovan
PB, Fruchtman
SM. Berlin
NI. Wasserman
LR. Therapeutic
recommendations
in
polycythaemia
vcra based on polycythaemia
vera study group
orotocols.
Sem Haematol
1986: 23: 132.
10. Vaquez MH. Sur un form speciale de cyanose
saccompagnant
dhyperglobulie
excessive et persistante.
CR
Sot Biol 1892: 44: 384.
11. Osler W. Chronic
cyanosis with polycythaemia
and enlarged
spleen: a new clinical entity. Am J Med Sci 1903: 126: 187.
12. Osler W. Erythraemia
(polycythaemia
with cyanosis, maladie
de Vaquez).
Lancet 1908: 1: 143.
13. Lawrence
JH. Berlin NI. Huff RL. The nature and treatment
of polycythaemia.
Medicine
1953; 32: 323.
14. Gaisbock
F. Die Polycythaemia.
Ergeb inn Med u Kindrrheilk
1922; 21: 234.
15. Videback
A. Polycythaemia
Vera: course and prognosis.
Acta
Med Stand 1950; 138: 179.
16. Lawrence
JH, Dobson
RL. Low-Beer
BVA, Brown BR.
Chronic
myelogenous
leukaemia.
A study of 129 cases in
which treatment
was with radioactive
phosphorus.
JAMA
1948; 136: 672.
17. Lawrence
JH. Low-Beer
BVA, Carpender
JWJ. Chronic
lymphatic
leukaemia.
A study of 100 patients treated with
radioactive
ohosuhorus.
JAMA
1949: 140: 585
18. Lawrence
JH. Wasserman
LR. Multiple
myeloma:
a study of
74 patients treated with radioactive
isotopes P and SR. Ann
Int Med 1950; 33: 41.
19 Chievitr
E, Thiede T. Complications
and causes of death in
polycythaemia
Vera. Acta Med Stand 1962: 172: 513.
JH, Winchell
HS. Donald
WG. Leukaemia
in
20 Lawrence
polycythaemia
era: relationship
to splenic myeloid metaplasia
and therapeutic
radiation
dose. Ann Intern Med 1969; 70: 763.
MG, Palin WE. Aleukaemic
myelosis.
21. Heller EL. Lewisohn
Am J Path01 1947; 23: 377.
22. Wasserman
LR, Polycythaemia
Vera Study Group. A
historical
perspective.
Sem Haematol
1986: 23: 183.
23. Kaplan ME. Mack K. Goldberg
JD. Donovan
PB. Berk PD.
Wasserman
LR. Long-term
management
of polycythaemia
vera with hydroxyurea:
a progress report. Sem Haematol
1986:
23: 167.
24. Tatarsky
I, Sharon R Management
of polycythaemia
vera
with hydroxyurea.
Sem Haematol
1997: 34: 24
25. Najeaii Y, dresch C. Rain JR. The very long term course of
polycythaemia:
a complement
to the previously
published
data
of the Polycythaemia
Vera Study Group.
Br J Haematol
1994;
86: 233.
26. Najean Y. Rain JR. The very long term evolution
of
polycythaemia
Vera: an analysis of 328 patients initially
treated by phlebotomy
on P between 1969 and 198 I. Sem
Haematol
1997: 34: 6.
H. Fischer SG et al. Leukaemic
27. Nand S. Messmore
transformation
in PV. Am J Haematol
1990: 34: 32.