Blootl Rrvitw,s ( 1997) 11, 146-153

11 1997 Pearson Professional

Ltd

Haematological oncology

Use of radioactive phosphorus in haematology

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

(ICRP) as 2.4 mSv per MBq administrated, with

the absorbed dose to bone surfaces and marrow as
11 mGy/MBq. These calculations are based on the
metabolic model from ICRP Publication 53. which
assumes that a fraction of 0.3 of the injected activity
goes to mineral bone and to be permanently retained,
and 0.70 is distributed in soft tissue. Activity distributed in soft tissue is assumed to be excreted with
half-times of 12 h, 2 days, and 19 days.
Studies with whole blood and plasma retention of
P in nine patients with polycythaemia. reported by
Spiers et al, revealed a two-compartment
exponential
function, with biological mean half-lives of 1.7 f 0.7
days and 22.5 f 5.9 days for whole blood; 0.8 + 0.5 and
20.0 f 5.1 days for plasma. The biological half-life in
iliac marrow (approx 9 days) and sternal marrow
(approx 7 days) did not differ significantly. However,
whole-body retention curves measured using a wholebody radiation counter were found to be monoexponential. with a mean biological half-life of 39.2 f 4.5
days. This is in broad agreement with the value of 49
days given by Seltzer.
Spiel-s et ali calculated a total absorbed dose to
marrow in trabecular bone as approximately 6.5 mGy
per MBq injected, with 2.7 mGy per MBq from
trabecular bone, 3.5 mGy per MBq from marrow and
0.3 mGy per MBq from cortical bone. These dosimetry
calculations took allowance for the existence of the
two interpenetrating
nonequilibrium
depositions (in
marrow and trabecula bone) and the small contribution to the marrow dose in trabecula bone by P in the
cortex.
Other investigators have given a range for the P
dose to bone, marrow, liver and spleen from 5.4 to
13.5 mGy per MBq injected, depending on such
variable as the size of the various compartments and
variations in phosphate turnover.
Protocols determining the quantity of P administrated vary, but usually range between 110 MBq and
220 MBq. Berk et al used 100 MBq m in the
PVSGOS protocol, with a limit of 185 MBq initially.
If this was not sufficient at 3 months, it was increased
by 25%1,with a further increase of 25% if improvement was not observed over the next 3 months; the
maximum dose suggested was 260 MBq.

The use of radioactive phosphorus in the treatment of

polycythaemia Vera
One of the diseases Lawrence chose to treat with
radio-isotopes was polycythaemia Vera. This disorder
was first described by Vaquez in 1892 and subsequently by Osler in 1903. Osler, describing a further
case at a Clinical Pathological Conference at the John

ohosohorus

ANALYSIS

Fig. 1 The range of isotopes

(Reproduced
with permission

in haematologv

147

OF TREATMENT

used by Lawrence
from I).

et al:

Radcliffe Hospital in Oxford in 1908, stated that the

patient would be treated with inhalations of oxygen
and radiotherapy to the spleen. Thus, one of the first
cases of polycythaemia vera described in the literature
was treated with radiotherapy and it became accepted
as one of a range of therapies for this disorder.
It was logical, therefore, to use radio-isotopes in
this disorder and the range used by Lawrence and
colleagues can be seen in Figure 1.
One of the most comprehensive reviews of polycythaemia vera is that of Lawrence, Berlin and Huff
(1953). This described the clinical picture in 263
patients of whom 207 were cases of polycythaemia
Vera.
The other cases included those of secondary polycythaemia related to anoxia and a further group of
patients whom they labelled relative polycythaemia or
the polycythaemia of stress, which they accepted
showed symptoms similar to Gaisbocks syndrome.
This review also presented the use of tracer isotopes
for the investigation of polycythaemia. Blood volumes were measured using red cells labelled with P.
Studies on red-cell survival and red-cell production
were carried out using N labelled glycine and Fe
iron. Using a scintillation counter, splenic erythropoiesis was detected in some cases. From the range of
isotopes evaluated for therapy of polycythaemia Vera,
radioactive phosphorus P emerged as the isotope of
choice.
The mode of administration of P was to start
with a dose of 111 MBq followed by a careful followup and phlebotomy if necessary. After IO-12 weeks
following re-evaluation,
a further dose of 11 l118 MBq was given. The mean amount of 12Pgiven in

148

Blood

Reviews

FIG. 19. Permntage muviva in 201c-of

polyoythemis vera treated with Pa hued on
67 deceamd caneaplum tbm living rho hew survived at lsvt to the time for whiob the
percentage ia calculated. Contact with seven onea hu hem lat, but their dumtiolu me
measured only to the date at which they were 1-t knom to be alive. The sutival ia plotted
on II probability scale. Sines the point. lie uentially on a atmight line, the longwvitia
follow a normal distribution.
The median survival is abom to bs 13.9 y-.

Fig. 2 Median
permission

from

survival in polycythaemia
Vera. (Reproduced
I), including
original caption).

with

an initial six-month period averaged 251 MBq. The

response of patients was variable. Some patients only
appeared to require one course of therapy, a group of
20 patients lasted longer than 5 years without treatment and 5 patients 10 years. The results of treatments were a virtual relief of symptoms and
resolution of physical signs.
The number of patents treated and the length of
follow-up enabled the authors to estimate the median
survival of patients with polycythaemia vera treated by
32Pas 13.2 years (Fig. 2.) This contrasted with the data
of Videbaek (1950), which showed survival time half
this value with venesection, phenyl-hydrazine and
radiotherapy. Lawrence and colleagues also showed a
reduction in thrombotic events; in the studies, there
were 144 patients living and 57 dead. Of the dead
patients, 15 died of what was called at the time chronic
myeloid leukaemia of whom a proportion, difficult to
estimate, transformed into acute leukaemia.

The use of radioactive phosphorus in the treatment of

chronic myeloid leukaemia

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.

Some patients had been previously treated with

X-ray therapy, either total body irradiation. fashionable at the time, or to the spleen. It is interesting to
note that 3 patients died of miliary tuberculosis with
no previous history. Treatment was often given as
37-74 MBq per week over 4-8 weeks, with care being
taken not to induce a cytopenia.
Because of the mixed nature of the cases,the authors
were able to make general comments only but some
good clinical results were obtained (Fig. 3). They noted
that it was not possible to extend life by irradiation.
They noted that approximately
one-third of
patients died of acute leukaemia. At the time of publication, 33 of the 129 patients were alive 5 years after
presentation. One patient lived for 11 years controlled
successfully by P (Fig. 4.)
It would appear overall that the results of P injections were very similar to radiotherapy to the spleen
and for whole body irradiation.

Radioactive phosphorus in chronic lymphocytic

leukaemia

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,

p32 and X-ray

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)

leukemia with radiation

therapy.
The
onset received only Ps2 until this past
radiation to the spleen has been admindate is 3.7 years.
permission

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.

The use of radioactive phosphorus in the treatment of

myeloma
An evaluation of the use of radio-isotopes in the
treatment of multiple myeloma (MM) was published
by Lawrence and Wasserman in 1950. The alternative treatment at the time was X-ray therapy to local
sites of disease, stilbamidine or urethane.
In all, 24 patients were recorded in detail and the
small literature on the subject reviewed. The authors
also evaluated radioactive strontium Sr but found
that it was too toxic for haemopoietic bone marrow
because of its relatively long half-life of 50.5 days.
Overall, the results were no better than X-ray therapy
or stilbamidine.
However, in a limited number of cases, the symptomatic relief was striking and remissions lasting
months were obtained.
Protein electrophoresis was not available at the time
and effects on paraprotein remain unknown. Dosage
was 37 MBq once or twice a week for 4-6 weeks.

Radioactive phosphorus treatment and the development

of leukaemia
The series of Lawrence Berlin and Huff in 1953 was
the largest and most significant in the world literature.
It represented the long-term follow-up of 207 patients
with polycythaemia
vera and it was noted that

(Reproduced

with

permission

from

-. including

original

caption).

15 patients at the time of publication developed what

was called chronic myelogenous leukaemia and went
on to develop acute leukaemia but the median survival of polycythaemia vera treated with radioactive
phosphorus was 13.2 years (Fig. 2). Thus, it would
appear that radioactive phosphorus prolongs life in
polycythaemia vera but at the risk of leukaemic transformation. This contrasted with the work of Chievitz
and Theide, (Fig. 8), which illustrates the virtue of
myelosuppressive therapy. Thus began a controversy
on the use of P in polycythaemia Vera, which may be
summarized as follows:
I. Radiation is leukaemogenic and therefore P
should not be used in the treatment of
polycythaemia Vera.
2. Patients with polycythaemia not treated with
myelosuppressive therapy may develop leukaemia
but treatment with radioactive phosphorus
enhances this tendency.
3. Treatment with P allows the patients to live long
enough to develop leukaemia.
The condition of CML referred to by Lawrence et al in
1953 is in fact a very different condition from the Phchromosome-positive leukaemia to which this term is
now applied. The patient no longer has a high red-cell
count and may become anaemic, the anaemia is leucoerythroblastic in type, the marrow is hypercellular and
shows ineffective erythropoiesis and may evolve to

152

Blood

Reviews

Table 1 The synonyms

Lewisohn
and Palin

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 ).

myelofibrosis. There is usually hepatosplenomegaly

due to extramedullary haemopoiesis. This syndrome
is referred to by many as spent polycythaemia but
in 1947 at least 24 synonyms could be found in the
literature (Table l).>
Since the original series of Lawrence et al in 1953,j
a large volume of literature has accumulated on the
various modes of treatment of polycythaemia vera
and their effects on the thrombotic and haematological sequelae. However, the series of patients published
are not strictly comparable because of different
diagnostic criteria and treatment. Various alternative
modes of therapy have been used; many bizarre and
with severe side-effects (Ref.*; Table 2).
In an attempt to solve this problem, the Polycythaemia Vera Study Group (PVSG) was set up in
the USA in the 1960s under the leadership of Louis
Wasserman.?
Diagnostic criteria were established and a threeway randomization between phlebotomy, radioactive
phosphorus and chlorambucil was instituted.
After five years of the study, it was appreciated that
chlorambucil was leukaemogenic and this arm of the
trial was terminated. In his review, Wassermann2
noted that the median survival with phlebotomy was
13.9 years, chlorambucil 9.1 years and 32P11.8 years.
In 1979, the PSVG went on to evaluate hydroxyurea
but this therapeutic trial was terminated after 5 years
because of lack of funds. However, Tatarsky and
Sharon 1997 continued to follow up the patients
entered into this trial, added further ones and
reviewed the literature.
They reported 71 patients followed up for a minimum of 5 years and noted that acute leukaemia
occurred in 4 patients. This is not significantly different

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

from the phlebotomy group but the numbers are

small. In a review of the literature, however, the incidence of acute leukaemia varied from 2% to 10.5%.
A similar series that followed on from the PSVG
trial was reported by Najean et alzi and extended
further in 1997. As in other series, the number of
patients receiving phlebotomy alone diminished with
time as patients were transferred to myelosuppression and patients on IP therapy were given hydroxyurea as the total dose of IzP given increased. These
authors also found that in the phlebotomy arm the
incidence of myelofibrosis increased confirming the
findings of Nand et al. The authors also found
that the introduction
of myelosuppressive therapy
reduces this tendency.
It is now highly unlikely that another trial evaluating the use of P in polycythaemia will ever be undertaken. The median survival for patients treated with
?P in polycythaemia was 13.5 years in the series of
Najean and Rain6 comparing very well with the findings of Lawrence et al in the past. What is most
significant, however, is that the life-expectancy of a
similar group of people in France is 15.2 years, representing a difference of only 10%. Perhaps the potentially harmful effects of myelosuppressive therapy are
balanced by regular medical supervision and control
of haematocrit and platelet count.
Although
hydroxyurea is probably the recommended treatment on the younger patients. the fact
that P represents a very effective, complication-free,
form of treatment for the elderly with long periods of
remission makes it the treatment of choice for patients
over the age of 65.
The use of P in CLL and CML was superseded by
alkylating therapy. The results obtained by Lawrences
group at the Donner Laboratories with jzP in retrospect do not seem all that bad in comparison to agents
such as chlorambucil and busulphan respectively,
though strict comparisons on a historical basis are not
possible.
REFERENCES
1. Lawrence
JH. Some tracer and therapeutic
studies with
articial radioactivity.
Br J Radio1 1948; 21: 53 1.
2. Silberstein
EB. Radionuclide
therapy
of hematologic
disorders.
Sem Nucl Med 1979: 9: 100.
3. Annals of the International
Committee
on Radiation
Protection
Publication
62, Vol 22. No 3. Radiological
Protection
in Biomedical
Research - Addendum
1 to ICRP
Publication
53. p 25. Oxford:
Pergamon
Press 1991.

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in haematologv

153

4. International
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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
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for intravenously
administered
:I? Am J Roetgenol
1952; 67: 28.
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Committee
on Radiological
Protection
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17. Protection
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investigations.
p 64. 1971.
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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
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CR
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and enlarged
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Medicine
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Ergeb inn Med u Kindrrheilk
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A. Polycythaemia
Vera: course and prognosis.
Acta
Med Stand 1950; 138: 179.
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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
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E, Thiede T. Complications
and causes of death in
polycythaemia
Vera. Acta Med Stand 1962: 172: 513.
JH, Winchell
HS. Donald
WG. Leukaemia
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polycythaemia
era: relationship
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radiation
dose. Ann Intern Med 1969; 70: 763.
MG, Palin WE. Aleukaemic
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21. Heller EL. Lewisohn
Am J Path01 1947; 23: 377.
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LR, Polycythaemia
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Sem Haematol
1986: 23: 183.
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JD. Donovan
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1986:
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24. Tatarsky
I, Sharon R Management
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Sem Haematol
1997: 34: 24
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Br J Haematol
1994;
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