Table Of ContentHemopoietic Dysplasias
(Preleukemic States)
Editors: Marcel Bessis and George Brecher
With 94 Figures
Springer-Verlag Berlin Heidelberg New York 1977
This monograph comprises Vol. 2 No. 1-2 of the jouroal Blood Cells
(Editor' Marcel Bessis, Associate Editor: Stephen B. Shohet)
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Table of Contents
JEAN BERNARD: Preleukemic States . . . . . . . . . 5
SECTION I: CLINICAL AND HEMATOLOGICAL DATA
J.W. UNMAN, G.c. BAGBY, JR.: The Preleukemic Syndrome: Clinical and
Laboratory Features, Natural Course, and Management . . . . . . . . 11
B. DREYFUS: Preleukemic States. I. Definition and Classification. II. Refrac
tory Anemia with an Excess of Myeloblasts in the Bone Marrow (Smoldering'
Acute Leukemia) . . . . . . . . . . . . . . . . . 33
Discussion of papers by LINMAN, BAGBY, and DREYFUS. . . . . . . . 45
N. KAMADA, H. UCHINO: Preleukemic States in Atomic Bomb Survivors
in Japan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
G. TCHERNIA, F. MIELOT, E .. SUBTIL, C. PARMENTIER: Acute Myeloblastic
Leukemia after Immunodepressive Therapy for Primary Nonmalignant Dis-
ease .................. . 67
Discussion . . . . . . . . . . . . . . . . 78
S.-A. KILLMANN: Preleukemia: Does it Exist? . 81
Discussion . . . . . . . . '. . . . . . . . 96
SECTION II: NEW TECHNIQUES AND SPECIAL INVESTIGATIONS
M.A.S. MOORE: Prediction of Relapse and Remission in AML by Marrow
Culture Criteria ......................... 109
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
K.A. DICKE, G. SPITZER, A. CORK, M.J. AHEARN: In vitro Colony Growth
of Acute Myelogenous Leukemia . . . . .' . . . . . . . . . . . . . 125
G. SPITZER, K.A. DICKE, E.A. GEHAN, T. SMITH, K.B. MCCREDIE: The
Use of the Robinson in vitro Agar Culture Assay in Adult Acute Leukemia 139
G. SPITZER, M.A. SCHWARZ, K.A. DICKE, J.M. TRUJILLO, K.B. MCCREDIE:
Significance of PHA Induced Clonogenic Cells in Chronic Myeloid Leuke-
mia and Early Acute Myeloid Leukemia . . . . . . . . . . . . . . . 149
Discussion of papers by DICKE et al. and SPITZER et al. . . . . . . . . 157
J.S. SENN, G.B. PRICE, T.W. MAK, E.A. MCCULLOCH: An Approach to
Human Preleukemia Using Cell Culture Studies ......... .. 161
Discussion .. . . . . . . . . . . . . . . . . . . . . . . . . . . 164
J.E. MALDONADO, J. MAIGNE, D. LECOQ: Comparative Electron-Micro
scopic Study of the Erythrocyt~c Line in Refractory Anemia (Preleukemia)
and Myelomonocytic Leukemia ................... 167
4
J. BRETON-GORIUS, Y. COQUIN, J.L. VILDE, B. DREYFUS: Cytochemical and
Ultrastructural Studies of Aberrant Granules in the Neutrophils of Two
Patients with Myeloperoxidase Deficiency during a Preleukemic State. Rela
tionship to Abnormal Bactericidal Activity . . . . . . . . . . .. 187
Discussion of papers by MALDONADO et al. and BREToN-GORIUS et al. .. 207
CH. SALMON: Blood Groups Changes in Preleukemic States ...... 211
M.F. GOURDIN, F. REYES, J.L. LEJONC, J. BRETON-GoRIUS, P. MANNONI,
B. DREYFUS: The Cellular Distribution of Erythrocyte and Normoblast
Al and A Antigens in Normal and Preleukemic States. An Immunoelectron
Microscopy Study ........................ 221
H. ROCHANT, H. TONTHAT, A. HENRI, M. TITEUX, B. DREYFUS: Abnormal
Distribution of Erythrocytes Al Antigens in Preleukemia as Demonstrated
by an Immunofluorescence Technique . . . . . . . . . . . . . . . .·237
Discussion of papers by SALMON, GOURDIN et al. and ROCHANT et al. . . 249
A.c. HOLLINSlrnAD: Cell Membrane Antigens Associated with Human Adult
Acute Leukemia 257
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
SECTION III: PATHOPHYSIOLOGY
E.P. CRONKITE, L.E. FEINENDEGEN: Notions about Human Stem Cells 269
Discussion . . . . . . . . . . .'. . . . . . . . . . . . . . . . . 279
A. BASERGA: Preleukemic States in the Light of the Leukemia Cytokinetics 285
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
M. LIEBERMAN, H.S. KAPLAN: The Role of Lymphoid and Haematopoietic
Target Cells in Viral Lymphomagenesis of C57BLjKa Mice. I. Susceptibility
to Viral Replication . . . . . . . . . . . . . . . . . . . . . . . . 291
H.S. KAPLAN, M. LIEBERMAN: The Role of Lymphoid and Haematopoietic
Target Cells in Viral Lymphomagenesis of C57BLjKa Mice. II. Neoplastic
Transformation of Bone Marrow-Derived Cells in the Thymic Microenvi-
ronment . . . . . . . . . . . . . . . . . . 301
Discussion of papers by LIEBERMAN and KAPLAN. . . . . . . 310
R.D. BARR, S. PERRY: Oncogenesis in Human Acute Leukemia 319
Discussion . . . . . . . . . . . . . . . . . . . . . . . 325
E. PEDRINIS, A. ZIMMERMANN, M. BERTSCHMANN, M.W. HESS, H. COTTIER:
Problems Relating to Immunoselection of Leukemias 329
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
SECTION IV: GENERAL DISCUSSION
I. Is Preleukemic States an Adequate Designation? 347
II. Should Hemopoietic Dysplas,ias be Treated? 353
III. A Registry for Hemopoietic Dysplasias . . . . 357
Preleukemic States
Jean BERNARD*
I
Preleukemic states may be prototypes, forerunners or incomplete manifestations
of leukemia, or unrelated diseases bearing superficial resemblances to leukemia.
By definition, a preleukemia does not allow the diagnosis of acute leukemia
and yet develops into leukemia. However, in our present state of ignorance,
we cannot predict the leukemic outcome. Hence, if we are to diagnose preleuke
mia other than retrospectively, we will inevitably include in the diagnosis other
entities which dot not develop into leukemia, but resemble the preleukemic
states morphologicany and clinically. It is this uncertainty of prospective diag
nosis which has caused the great interest in the subject.
The preleukemic states proper, i.e. those that will develop into leukemias
can conceptually be of 2 types: early subclinical stages of leukemia and clinical
states which are merely conducive to the development of leukemia. It is not
clear how these 2 states can be distinguished from each other or from those
only apparently preleukemic states that do not carry with them the eventual
leukemic outcome.
It become crucial to define the onset of leukemia. It is almost trivial to
note that the diagnosis requires not only the presence on an increased number
of mature and immature cells in the peripheral blood, but alteration of the
hemopoietic tissues which must be widespread and significant in the individual
sites. The difficulty arises when one attempts to define how many different
areas of hemopoietic tissues must be involved to distinguish pre1eukemia from
leukemia. What must the rate of cell division be to characterize the onset
of leukemia? There is not set of criteria that can claim general acceptance.
Meanwhile, we must continue our semantic efforts to define leukemia and
preleukemia and related conditions such as dyserythropoiesis and refractory
anemia. Perhaps these terms can be eliminated as irrational. Perhaps we need
to consider new terms such as the recently proposed term "stem cell disorder".
At any rate, to explore the limits of our knowledge and our nomenclature
should be one of the objects of the symposium.
Two tasks confront us. First, how to distinguish the different types of preleuk
emia from each other and from similar conditions which do not lead to leukemia,
and from the onset of early leukemia. Secondly, how to exploit these forerunners
or models of leukemia to get to the bottom of questions of etiology and patho
genesis of leukemia.
* Clinique des Maladies du Sang, Hopital Saint Louis, 2, Place du Fournier, F-75010 Paris, France
Reprint requests to: Professor Jean Bernard
6 J. Bernard
II
Three types of leukemic states seem to offer possible approaches to the problem
of etiology and pathogenesis: first, the leukemias of known origin which include
viral leukemias of animals and leukemias due to radiation and chemotherapy
in both experimental animals and man; secondly, certain types of leukemia
of unknown origin; and thirdly, the quasi-preleukemic states of prolonged remis
sion and apparent cure in childhood leukemia which suddenly relapse.
Viral leukemia of animals has been the subject of numerous sophisticated
studies, but they have not yet answered the following important questions.
Is leukemia under these given conditions inevitable? If not, what special features
separate those conditions that develop into leukemia from those that do not?
Is spontaneous regression possible after cellular lesions have appeared? If so,
is it possible to promote this reversibility to prevent progression by timely
intervention and by what sort .of intervention?
A quite different set of questions arises in leukemia induced in man and
experimentat animals by irradiation and chemicals. Two additional factors require
attention: variability and duration. The development of leukemia in this instance
is certainly not inevitable. For example, a population subject to a given dose
of radiation or of a chemical agent can be divided into several groups. One
with persistance of normal health; a second which develops immediately an
obvious leukemia; a third with appearance of various non-leukemic blood dis
orders; and a fourth in which a succession of non-leukemic episodes is followed
by overt leukemia. Observation of the last two groups over many years may
perhaps answer some of our questions. For instance, will a leukopenia or neutro
philic leukocytosis inevitably progress to leukemia? Can certain apparently leu
kemic states characterized by the presence of a few blasts regress? Can these
anomalies be recognized and corrected? Modern methods of the study of cells
in different environments have perhaps not been exploited sufficiently. It would
be useful to examine the role played by a preceding illness, whether it be
a non-malignant condition such as polyarthritis or a malignant one such as
Hodgkin's disease in which radiation or chemotherapy triggers the appearance
of leukemia.
Experimental work has shown that under certain conditions radiation may
cause liberation of latent leukemogenic viruses in mice. Similar discoveries have
been made in relation to various chemical agents. Perhaps by use of this model,
in which the inducer is known, one could define exactly the earliest moment
at which precise markers of viral expression, such as new sequences of RNA
in antigenic proteins can be recognized. In addition, the study of these markers
during the development of the syndrome could define the physiopathologic
mechanisms of the hematologic and clinical events more precisely.
Concerning the leukemias of unknown etiology, the study of spontaneous pre
leukemia is relevant. It has gone through two stages. The initial phase consisted
of simplistic and poorly organized descriptions of all the symptoms preceding
the time before leukemia can be diagnosed, a second phase brought more precise
distinction of syndromes such as the acute aplasia in children, and the" oligo blas
tic" disorders of adults. It is high time that a third phase of detailed analysis
Definition of the Preleukemic States 7
of these disease states began. We need to compare the appearance of "blasts"
which appear to be leukemic, yet regress and turn out not to be leukemic,
as observed in Down's disease, with a small number of similar immature cells
which appear to be non-leukemic, yet progress and turn out to leukemic after
all.
Concerning remissions in childhood leukemia, these have become more and
more prolonged recently and actual cures have been obtained. Their number
is still small. In the great majority of cases, the "complete" remissions of pro
longed duration are in fact incomplete and may be comparable to some of
the preleukemic states. The study of these complete remissions has, in the past,
been concerned with survival only. We may now begin to ask, can the eventual
relapse be predicted? Can appropriate treatment prevent it? Such studies may
profit from consideration of the" true" preleukemic states and in turn strengthen
our knowledge of these states. Of particular interest are the prolonged remissions
of 4 or 5 years duration which suddenly relapse. Have there been regular divi
sions of leukemic cells during the entire duration of remission? Or have truly
quiescent cells suddenly been reawakened and how? It has recently been
postulated minute sub-populations exist which may include these quiescent cells.
Are we dealing with reactivation of a dormant virus or possibly even reinfection
from an exogenous one?
The solution, or at least a suitable start toward solving these questions
could shed new light on the preleukemic states. Conceivably, such studies could
eventually lead to prevention and permit early and rational therapy of the leuke
mias themselves.
SECTION I
CLINICAL AND HEMATOLOGICAL DATA
The Preleukemic Syndrome: Clinical and Laboratory
Features, Natural Course, and Management
James W. LINMAN and Grover C. BAGBY, Jr.
ABSTRACT. The clinical and laboratory features of the early stages in the
evolution of acute nonlymphocytic leukemia are reviewed. Based on a retrospective
analysis of 34 patients who died with an acute myelomonoblastic leukemia, the" pre
leukemic syndrome" has been s~own to display a clinical picture sufficiently specific
to permit its recognition prospectively (i.e., before the development of overt leuke
mia). The results to date of a variety of prospective studies are reviewed, and
the approach(es) to the management of these cases is considered.
KEY WORD: Preleukemia
INTRODUCTION
Our interest in the early phases of evolving leukemia (i.e., the preleukemic
syndrome) was intensified several years ago as the result of a retrospective
study designed to evaluate the lack of morphologic homogeneity in the acute
nonlymphocytic leukemias. The results of this project have been described
elsewhere [1]; in brief, 132 cases of acute nonlymphocytic leukemia were analy
zed, and each patient displayed morphologic evidence of involvement by more
than one cell line. At the time of diagnosis of overt leukemia, there were
leukemic changes in all marrow cell lines (erythrocytic, granulocytic, megakaryo
cytic, and monocytic) in 83 of these cases (63%); in 38 (29%) three lines were
affected, and in 11 cases (8%) two cell lines appeared to be involved. It was
concluded from these observations that acute nonlymphocytic leukemia(s) was
basically a marrow stem cell disease and that most (if not all) of the acute
nonlymphocytic leukemias were variants of one disease. We have used as a
label for the leukemic phase of this myeloproliferative disorder "myelomonocy
tic leukemia" (" myelo-" to indicate that all myeloid - that is, marrow elements
are involved, and "mono-" to emphasize the prominent monocytoid features).
Because of the striking variability in courses among these 132 cases, it seemed
inappropriate to attempt further subdivision into "acute" and "chronic" types.
An alternative designation that is acquiring more and more appeal is "nonlym-
Division of Hematology and Medical Oncology, and the Osgood Memorial Center for Leukemia
Research, University of Oregon Health Sciences Center, Portland, Oregon
Requests for reprints to: James W. Linman, M.D., Head, Division of Hematology and Medical
Oncology, University of Oregon Health Sciences Center, 3181 S.W. Sam Jackson Park Road,
Portland, Oregon 97201, U.S.A.
12 J.W. Linman and G.C. Bagby, Jr.
phocytic leukemia" with "acute nonlymphocytic leukemia" being reserved for
those patients who are clearly in the blastic phase of their disease. Attempts
to apply strict morphologic criteria to the classification of the leukemias supports
the suggestion that most leukemias can be divided into four groups (acute lym
phocytic, chronic lymphocytic, chronic granulocytic, and nonlymphocytic) [2];
the first three types have easily recognizable clinical pictures, whereas the non
lymphocytic leukemias are characterized by variability in findings and natural
courses. We currently believe that the nonlymphocytic leukemias reflect a single
polyphasic disorder and that the various labels that have been used in the
past most likely represent stages in the evolution of the disease and/or differing
host responses (e.g., erythroleukemia, DiGuglielmo's syndrome, monocytic leu
kemia, granulocytic leukemia, and megakaryocytic leukemia).
In addition to clarifying the clinical manifestations of overt nonlymphocytic
leukemia(s), the retrospective study described above was responsible for an
additional study that has sh~d light on the clinical and laboratory features
of the evolutionary stages in the disease prior to the development of the classical
cytologic and histologic features of acute leukemia (i.e., a marrow packed with
blast cells). Contrary to the widely held opinion that "preleukemia" can be
diagnosed only retrospectively (i.e., after the onset of blast cell leukemia), our
observations point to a rather monotonous hematologic syndrome that does
permit prospective recognition.
CLINICAL AND LABORATORY FEATURES
1. Retrospective Studies
Among our 132 cases of acute nonlymphocytic leukemia, the majority (52%)
gave a history of a poorly defined hematologic disorder of variable duration
that preceded the onset of leukemia; in 41 cases (31 %) a preleukemic phase
could be documented; in 34 cases (26%) clinical and laboratory data, including
blood smears and marrow specimens, were available. Retrospective analysis
of these cases yielded diagnostic criteria that have since withstood prospective
testing. Details of this project have been published [3, 4]; however, these observa
tions will be summarized here, for they form the basis of our Prospective
studies now in progress.
Most of these 34 patients were men (30) with a median age of 58 and
a range of 16 to 80 years (68% were 50 years of age or older when their
hematologic disease began). Symptoms and physical findings lacked specificity
and were ordinarily attributable to too few blood cells, that is, anemia (weakness
and pallor), thrombocytopenia (a hemorrhagic diathesis), and/or neutropenia
(increased susceptibility to infections). Splenomegaly was present in less than
20%.
In contrast to the nondescript nature of the symptoms and physical findings,
the hematologic manifestations proved to be remarkably constant and straight
forward. Peripheral blood cytopenias dominated the picture with pancytopenia
being commonest (Table 1). Abnormalities in red cell morphology were conspic-
