Congenital and Acquired Bone Marrow Failure

268 Pages·2017·11.47 MB·English

by  Mahmoud Aljurf

CONGENITAL
AND ACQUIRED
BONE MARROW
FAILURE
Edited by
M.D. Aljurf
Adult Hematology and Bone Marrow Transplantation
Oncology Center, King Faisal Specialist Hospital
and Research Center, Riyadh, Saudi Arabia
E. GluckMAn
Eurocord, Saint Louis Hospital, Paris, France
c. Dufour
Hematology Unit
G. Gaslini Children’s Hospital, Genova, Italy
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List of Contributors
S.O. Ahmed Adult Hematology and Bone Marrow S. Elmahdi Department of Pediatrics, Graduate
Transplantation, Oncology Center, King Faisal School of Medicine, Nagoya University, Nagoya,
Specialist Hospital and Research Center, Riyadh, Japan
Saudi Arabia
P. Farruggia Pediatric Hematology and Oncology
G. Aldawsari Adult Hematology and Bone Marrow Unit, A.R.N.A.S. Ospedale Civico, Palermo, Italy
Transplantation, Oncology Center, King Faisal
F. Fioredda Hematology Unit, G. Gaslini Children’s
Specialist Hospital and Research Center, Riyadh,
Hospital; Unità di Ematologia Istituto Giannina
Saudi Arabia
Gaslini, Genova, Italy
M.D. Aljurf Adult Hematology and Bone Marrow
S. Gandhi Department of Haematological Medicine,
Transplantation, Oncology Center, King Faisal
King’s College Hospital/King’s College London,
Specialist Hospital and Research Center, Riyadh,
London, United Kingdom
Saudi Arabia
S. Giraudier Hematology Laboratory, Henri–
H. Alzahrani Adult Hematology and Bone Marrow
Mondor Hospital, Paris–Est–Creteil University,
Transplantation, Oncology Center, King Faisal
Paris, France
Specialist Hospital and Research Center, Riyadh,
Saudi Arabia E. Gluckman Eurocord, Hospital Saint-Louis, Paris,
France
M. Ayas Pediatric Hematology–Oncology and Stem
Cell Transplantation, King Faisal Specialist Hospital F. Grimaldi Hematology, Department of Clinical
and Research Center, Riyadh, Saudi Arabia Medicine and Surgery, Federico II University,
Naples, Italy
A. Bacigalupo Istituto di Ematologia, Policlinico
Universitario A. Gemelli, Universita’ Cattolica del B. Höchsmann Institute of Transfusion Medicine,
Sacro Cuore, Roma, Italy University of Ulm; Institute of Clinical Transfusion
Medicine and Immunogenetics, German Red Cross
F. Ciceri Hematology and BMT Unit, IRCCS San
Blood Transfusion Service Baden–Württemberg–
Raffaele Scientific Institute; University Vita-
Hessia, and University Hospital Ulm, Ulm,
Salute San Raffaele, IRCCS San Raffaele Scientific
Germany
Institute, Milano, Italy
K. Hosokawa National Institutes of Health, National
J.N. Cooper National Institutes of Health, National
Heart, Lung, and Blood Institute, Bethesda, MD,
Heart, Lung, and Blood Institute, Bethesda, MD,
United States
United States
S. Kojima Department of Pediatrics, Graduate
J.H. Dalle Hematology–Immunology Pediatric
School of Medicine, Nagoya University, Nagoya,
Department, Robert–Debre Hospital, Paris,
Japan
France
T. Leblanc Hematology–Immunology Pediatric
C. Dufour Hematology Unit, G. Gaslini Children’s
Department, Robert–Debre Hospital, Paris, France
Hospital; Unità di Ematologia Istituto Giannina
Gaslini, Genova, Italy
ix
x List of Contributors
J.C.W. Marsh Department of Haematological P. Scheinberg Oncology Center, Hospital São José
Medicine, King’s College Hospital/King’s College National Institutes of Health, National Heart, Lung,
London, London, United Kingdom and Blood Institute, Bethesda, MD, United States
D. Meyran Hematology–Immunology Pediatric H. Schrezenmeier Institute of Transfusion
Department, Robert–Debre Hospital, Paris, France Medicine, University of Ulm; Institute of Clinical
Transfusion Medicine and Immunogenetics,
M. Miano Hematology Unit, G. Gaslini Children’s
German Red Cross Blood Transfusion Service
Hospital; Unità di Ematologia Istituto Giannina
Baden–Württemberg–Hessia, and University
Gaslini, Genova, Italy
Hospital Ulm, Ulm, Germany
G.J. Mufti Department of Haematological
S. Sica Istituto di Ematologia, Policlinico
Medicine, King’s College Hospital/King’s College
Universitario A. Gemelli, Universita’ Cattolica del
London, London, United Kingdom
Sacro Cuore, Roma, Italy
J.R. Passweg Division of Hematology, University
M.T.L. Stanghellini Hematology and BMT Unit,
Hospital Basel, Basel, Switzerland
IRCCS San Raffaele Scientific Institute, Milano,
R. Peffault de Latour BMT Unit, French Reference Italy
Center for Aplastic Anemia and PNH, Saint-Louis
A. Tichelli Hematology, University Hospital of
Hospital, Paris, France
Basel, Basel, Switzerland
A.M. Risitano Hematology, Department of Clinical
M.T. Van Lint Divisione di Ematologia e Trapianto
Medicine and Surgery, Federico II University,
di Midollo Osseo, IRCCS AOU San Martino IST,
Naples, Italy
Genova, Italy
A. Rovó Hematology, University Hospital of Bern,
A.J. Warren Cambridge Institute for Medical
Bern, Switzerland
Research; The Department of Haematology,
A. Ruggeri Eurocord, Hospital Saint-Louis; University of Cambridge; Wellcome Trust–Medical
Hematology Department, Hospital Saint Antoine, Research Council Stem Cell Institute, University of
Paris, France Cambridge, Cambridge, United Kingdom
S. Samarasinghe Department of Haematology, N.S. Young National Institutes of Health, National
Great Hormond Street Hospital, London, United Heart, Lung, and Blood Institute, Bethesda, MD,
Kingdom United States
Introduction
From the first descriptions by Ehrlich over a haploidentical and cord blood transplants, and
century ago to where we are today, the under- in supportive care of hematopoietic stem cell
standing of the pathogenesis and biology and transplantation have lead not only to the expan-
of the diseases that are encompassed under sion of the potential donor pool, but also to re-
the umbrella of the “bone marrow failure syn- markable improvements in the outcome of he-
dromes” have witnessed tremendous progress. matopoietic stem cell transplantation for bone
This has been coupled with significant improve- marrow failure from related and unrelated stem
ments in the clinical care and outcomes of both cell sources with excellent rates of cure, par-
congenital and acquired forms of bone marrow ticularly in the younger patients, when a fully
failure. matched unrelated donor is used.
When considering acquired bone marrow Telomere shortening and telomeropathies
failure, in the last 4 decades, aplastic anemia have been increasingly recognized as contrib-
has progressed from a disease that was almost uting factors for bone marrow failure and stem
universally fatal to one in which the majority cell exhaustion in acquired states and causative
of patients can now expect to be cured and lead factors for the increasing number of entities of
normal lives. We have gained noteworthy in- congenital bone marrow failure.
sights in understanding the immune mechanism Several new treatment modalities have
of hematopoietic stem cell destruction, stem cell emerged during the last decade, most notable
niche, and T-cell dysregulation. This knowledge of which is the introduction of thrombopoietin
has placed immunosuppressive therapy at the mimetic agents. Possible interventions to rescue
center stage in the treatment of aplastic anemia, telomere length are being actively investigated.
and has facilitated the initiation of clinical trials Given the exciting progress in the field, this
for the use of new potential therapies to treat ac- book is a timely educational initiative produced
quired aplastic anemia. jointly by the Working Party of Severe Aplas-
Substantial progress in the knowledge about tic Anemia of the European Society for Blood
the role of somatic mutations and their relation and Marrow Transplantation and the European
to clonal hematopoiesis in acquired bone mar- School of Haematology.
row failure has been facilitated by the use of the The contents are a collection of up-to-date
next generation sequencing technologies, and contributions from world-renowned experts in
has allowed us to understand their relationship the field of congenital and acquired bone mar-
with myelodysplastic syndromes, paroxysmal row failure. The chapters in this book provide
nocturnal hemoglobinuria, and the risk of dis- extensive coverage for all aspects of congenital
ease progression. and acquired bone marrow failure, including bi-
Advances in HLA-typing technology, prog- ology, pathology, and treatments involving he-
ress in the field of alternate donor availability, matopoietic stem cell transplantation.
xi
xii IntroductIon
We hope this book will be an important re- With the endorsement of the European Soci-
source for scientists, clinicians, nurses, and all ety for Blood and Marrow Transplantation and
other health-related professionals involved in the European School of Haematology
research and patient care with the bone marrow
failure syndromes. Mahmoud Aljurf, Eliane Gluckman, Carlo Dufour
C H A P T E R
1
Epidemiology of Acquired Bone
Marrow Failure
F. Grimaldi*, S. Gandhi**, A.M. Risitano*
*Hematology, Department of Clinical Medicine and Surgery, Federico II University,
Naples, Italy; **Department of Haematological Medicine, King’s College Hospital/
King’s College London, London, United Kingdom
INTRODUCTION studies to gather data on the epidemiology of
AA. Based on the two epidemiological studies
Paul Ehrlich in 1888 gave the first seminal carried out in Europe and Asia that used the
description of aplastic anemia (AA) in a preg- same methodology, the incidence of the disease
nant woman, where the normal hemopoietic is two- to threefold higher in Asia than in the
tissue was replaced by a fatty marrow and West [2–12]. This variability in incidence rates
empty spaces, the “hypocellular” marrow that may reflect differences in exposure to environ-
resulted in pancytopenia. Idiopathic AA is mental factors including viruses, drugs and
a rare form of acquired bone marrow failure, chemicals, genetic background, diagnostic cri-
where improved supportive care, early insti- teria, and study designs.
tution of immunosuppressive treatment, and In the following sections, a short review of
hematopoietic stem cell transplantation have studies performed and available in literature, in-
led to better treatment outcomes [1]. Several cluding case series and reports to determine the
retrospective studies from Europe, United epidemiology and demographics of AA across
States, South America, and Asia suggest that different centers of the world is presented. Dis-
the incidence is 0.6–6.1 cases per million popu- cussion is restricted to acquired cases of AA, and
lation. In addition, the incidence of AA shows hence the inherited bone marrow failure syn-
geographical variability, with lower rates re- dromes, the inevitable cases of marrow aplasia
ported in Europe, North America, and Brazil that follow intentional chemoirradiation treat-
and higher rates in Asia. However, the rarity of ments and cytopenias of nutritional deficiencies
disease means there have been few prospective or other causes have been excluded.
Congenital and Acquired Bone Marrow Failure 1
http://dx.doi.org/10.1016/B978-0-12-804152-9.00001-4 Copyright © 2017 Elsevier Inc. All rights reserved.
2 1. EpIdEMIology oF ACquIrEd BonE MArrow FAIlurE
INCIDENCE OF AA IN DIFFERENT South Asia, in this study were found to have an
GEOGRAPHICAL REGIONS incidence even higher than their counterparts
AND RACE from East Asia, at 7.3 per million [13]. This study
suggested that Asian children have an increased
The annual incidence of AA varies from 0.6 incidence of AA, possibly as a result of a genetic
to 6 per million populations per annum across predisposition. Indeed, in a hospital based case
centers in different continents. Most findings control study from Lucknow (India), the annual
are from retrospective studies, and even retro- incidence of childhood AA was determined to be
spective reviews of death registries. However, 6.8 per million [14].
this incidence masks the variability that is seen Benzene has been found to be toxic to the
across continents and different ethnic groups; hemopoietic progenitor cells. In large collab-
for example, reports from the Barcelona group orative studies between the National Cancer
(2008), which was a detailed prospective study Institute and American and Chinese institutions
by Montané et al. [2] had an incidence of 2.34 per [15], hematologic susceptibility to benzene has
million population. This incidence rate is simi- been correlated to nucleotide polymorphism
lar to the 2.0 per million reported by the Inter- in key drug metabolic patways [16]. Thus, he-
national Agranulocytosis and Aplastic Anemia matotoxicity from exposure to benzene may be
Study (IAAAS) [3], which was conducted in Eu- particularly evident among genetically suscep-
rope and Israel from 1980 to 1984, and to rates re- tible populations, and it is plausible that the
ported in smaller national studies in Europe that increased incidence of AA seen in Asia may be
included United Kingdom [4], France [5], Scan- related not only to increased exposure but also
dinavia [6], and in South Americas and Brazil [7]. to key polymorphism in genes regulating the
The incidence was accurately determined to be 4 metabolism and cytokine expression.
cases per million population in Bangkok [8], but Similarly, although AA incidence reported
based on prospective studies, it may actually be in a multicenter Latin American study remains
closer to 5.6 cases per million population in the very low at 1.6 per million; this study corrobo-
rural areas of Thailand (Khonkaen region) [9]. rated the association between risk of exposure to
In the prospective Chinese Epidemiologic Study benzene, chloramphenicol, and also azithromy-
Group of Leukemia and Aplastic Anemia survey, cin and predisposition to AA in this area [17,18].
7.4 per million was reported as a national inci-
dence, which clearly is much on the higher side,
but may have been overestimated, as stringent AGE AND GENDER RELATED
criteria for the diagnosis of AA, as bone marrow DEMOGRAPHICS OF AA
study, were not strictly applied [10]. Increased
incidence in Eastern countries may be related to In nearly all modern studies of AA, the sex
environmental factors, such as increased expo- ratio has been close to 1:1, which is unusual for
sure to toxic chemicals and pesticides on agricul- immune-mediated diseases [2,19]. An exception
tural farms, practiced in the Far East and South to this has been a study from the Sabah prov-
Asia. However, the incidence of AA in children ince in Malaysia [12], where an unusually high
of immigrants from the East Asia in a pediat- male to female ratio was noted at 3:4. Similarly
ric population from the ages 0 to 14 years, in a a male preponderance was also noted in stud-
study from British Columbia (Canada) was sig- ies from Thailand [9], India [20], and Pakistan
nificantly higher at 6.9 per million, as compared [21]. This may reflect the underreporting of cases
to children of white/mixed ethnic descent at 1.7 of AA among females and access to adequate
per million [11]. Children of immigrants from healthcare services in Asia. However, it remains
AA And AssoCIAtIon wIth toxIns/drugs 3
unclear why a female preponderance is not seen tries and Europe, where recently an incidence of
in a quintessential autoimmune disorder, such as 5.4%, stable across the years, has been reported
AA among studies in Europe and United States. in a large registry study from EBMT [25].
In all the largest studies available, including a Cases of AA associated with HAV, HBV, HGV,
series of 300 patients reported by Clinical Center parvovirus B19 [26–29], Epstein–Barr virus
at NIH by Young et al. [22], the Barcelona report (EBV) [30], transfusion-transmitted virus (TTV)
[2] and epidemiologic study from Thailand [9], [31] or echovirus [32] infections have been re-
2 patient age peaks of incidence are constantly ported. In a German–Austrian study of 213 pe-
observed, one among young adults and the sec- diatric cases aged 17 years or less of AA, 80% of
ond in the elderly. This characteristic biphasic cases were idiopathic, 9% followed posthepatitis
distribution shows two peaks, one from 10 to AA, 7% were following viral infections, and 4%
25 years and the second above 60 years. Within were associated with drugs/toxins [33].
the younger age group, a small peak in the in- Parvovirus B19 is the causative agent for fifth
cidence is observed in childhood, probably due disease, usually in the immunocompetent host.
to overlap with inherited marrow-failure syn- However, transient aplastic crises have been re-
dromes featured by a less penetrating pheno- ported in chronic hemolytic anemias, such as
type, where classical physicalanomalies of the sickle cell disease owing to reticulocytopenia,
inherited marrow-failure syndromes are not ob- and cases of severe AA have also been reported
vious. On the other hand, the second incidence in normal individuals during an acute episode
peak of AA seen above 60 years may reflect the of infection [34]. The actual incidence of acute
smaller pool of hematopoietic stem cell reserve parvovirus B19 infection at presentation in AA
left, with age-related telomeric attrition and its is not known, but in single case series of 27 pa-
capacity to maintain normal hemopoiesis, in the tients with AA from India, parvovirus B19 IgM
face of an immune insult against the hematopoi- and viral DNA was detected in nearly 40% of the
etic precursor cells [23]. cases [35]. This maybe an important etiological
factor, especially in immunocompromised host
or patients with chronic hemolytic anemias.
POSTHEPATITIS AA AND AA Very recently retrospective observations
OCCURRING AFTER VIRAL about eight AA cases occurring during HIV in-
INFECTIONS fection have been reported [36]. Even if AA ap-
pears to be a late rare complication in HIV pa-
Posthepatitis AA is a stereotypical syndrome, tients, report from Pagliuca et al. [36] highlights
where pancytopenia often presents 2–3 months that immunosuppressive therapy is a feasible
after an acute attack of seronegative severe but strategy in AA patients and that better outcome
self-limited liver inflammation. This distinct is observed in patients eligible to transplant,
variant has been commonly seen in 5–10% of while death for infection remain the principle
“classical” AA cases, typically occurring in ado- cause of mortality in undertreated patients.
lescent boys and young men [24]. Severe imbal-
ance of the T-cell immune system as seen with
“classical” AA, human leukocyte antigen (HLA) AA AND ASSOCIATION WITH
association, and effective response to immuno- TOXINS/DRUGS
suppressive therapy strongly suggest an im-
mune-mediated mechanism. As for other form There is no discernible difference in the de-
of AA, higher incidence is noted in East Asia mographics or clinical behavior, including re-
(4–10%), when compared to the Western coun- sponse to immunosuppressive therapy, between
4 1. EpIdEMIology oF ACquIrEd BonE MArrow FAIlurE
patients classified as having “drug or toxin in- clined to the point that it has not been reported
duced” versus “idiopathic” AA [37]. as significant risk factor in any recent systematic
Benzene is the most widely studied and im- epidemiologic study of AA in Western countries.
plicated amongst toxins causing AA. The rela- Even in Thailand where the need for such effec-
tionship was initially brought to light by a case tive and inexpensive antibiotic is substantial, and
where a series of workers exposed through their usage is reported 100 times greater than in the
specific occupations [15] and has since been West, association with AA is infrequent, prob-
detected in some, but not all population-based ably due to lower-doses prescription [9].
case-control studies. An association has been In the IAAAS study [3] approximately 25%
seen in some case-control studies but even when of the identified AA cases were related to
present, the proportion of cases that can be at- drug use. Major drug associations were with
tributed to this chemical has been small. Studies gold salt (relative risk, RR of 29), antithyroid
on American workers earlier in this century sug- drugs (RR of 11), and nonsteroidal antiinflam-
gested that the risk of AA was about 3% in men matory agents (RR of 8.2 for Indomethacin).
exposed to concentration higher than 300 ppm, Similarly in 235 patients with AA prospec-
and in the more recent IAAAS study [3], benzene tively followed by the Barcelona group [2],
was accounted for about 1–3% of AA recorded 67 cases (28.5%) had a history of exposure to
cases. Similarly in Thailand population, benzene drugs or toxic agents that have been associated
carried a relative risk of 3.5 but accounted for an with AA, sometime in the preceding 6 months.
etiologic fraction of only 1% [9]. Forty nine (20.8%) cases had been exposed to
Pesticides have been associated with AA in a the following drugs (Table 1.1). In addition, 21
large number of medical records. In the Indian (8.9%) cases had been exposed to toxic agents:
cohort of pediatric AA, although significantly insecticides (n = 8), benzene (n = 6), and other
higher blood levels of organochlorine com- solvents (n = 10).
pounds were detected suggesting an associa-
tion, they were not entirely supported by statis- TABLE 1.1 Exposures to drugs reported to be
tical methods [14]. Anecdotal case reports of AA Associated with Aplastic Anemia in the
following use and pesticides, such as dichloro- 2–6 Months prior to hospital Admission
Among 235 Cases (Montané et al. [2])
diethyly-trichlorthane (DDT), chlordane or lin-
dane, or following exposure to organic solvents, Drug N (%)
such as toluene and other molecules resembling
Allopurinol 9 (3.8)
benzene, or containing benzene ring, again point
merely to an association. Unfortunately, system- Indomethacin 9 (3.8)
atic population case-control studies correlating Gold salts 9 (3.8)
level and duration of exposure of these identi- Sulfonamides 9 (3.8)
fied toxins and AA onset are lacking.
Carbamazepine 5 (2.1)
Initially suggested by accumulation of case re-
Ticlopidine 4 (1.7)
ports, specific drug associations have been estab-
Chloramphenicol 3 (1.2)
lished in different population based study and
have changed across time, mainly due to chang- Oxyphenbutazone 3 (1.2)
es in drugs diffusion and utilization. Chloram- Phenylbutazone 3 (1.2)
phenicol, for example, that gained notoriety for Penicillamine 3 (1.2)
its prominent association with AA in the 1950s
Clopidogrel 2 (0.8)
and for decades was considered the common-
Methimazole 2 (0.8)
est cause of the disease, has progressively de-