Page 466 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 29 Inherited Bone Marrow Failure Syndromes 387

literature, there were 128 cases of congenital neutropenia reported altered stem and progenitor cells in congenital neutropenia. G-CSF
and three cases of AML up to 1989 (the first year that G-CSF was may rescue malignant clones that would otherwise be destined for
available for general use), leading to a crude estimated risk of leukemia apoptosis. The clinical interplay between G-CSF and the receptor
of 2%. Nevertheless, because most patients with congenital neutro- mutation was underscored in the report of a patient with congenital
penia died at a young age from bacterial sepsis or pneumonia in the neutropenia on G-CSF who developed a receptor mutation and
precytokine era, the true risk of patients with congenital neutropenia AML. When G-CSF was stopped, the blast count in blood and
developing MDS/AML was not clearly defined. Specific mutations in BM fell to undetectable levels on two occasions without giving
(i.e., G214R or C151Y) were associated in one study with a high risk chemotherapy, although the mutant receptor was persistently detect-
for evolution to AML. able during the remissions. A similar patient has been observed in
G-CSF therapy completely changed clinical outcomes of K/SCN. Toronto (Y. Dror, unpublished data).
Before G-CSF, the median duration of survival was about 3 years; An axiom of oncogenesis is that rapidly dividing cells are more
the current median age is more than 40 years. The number of docu- susceptible to mutational events. Because therapeutic G-CSF provides
mented cases of MDS/AML has dramatically increased since 1989, a powerful proliferative signal for BM cells, it is a reasonable hypoth-
which likely reflects the natural history of the disease that is now esis that congenital neutropenia BM progenitors acquire new muta-
allowed to manifest by prolonging life. However, whether G-CSF tions. From the evidence cited herein, acquisition of a G-CSF receptor
increases this risk or hastens the appearance of leukemia is still mutation in the face of therapeutic G-CSF in congenital neutropenia
debatable. can provide the hyperresponsive replicative scenario that can relent-
The risk of MDS/AML is higher in patients requiring higher doses lessly evolve into MDS/AML. Is recombinant human G-CSF a car-
of G-CSF. According to SCNIR data, less responsive patients, defined cinogen? This would seem highly unlikely. As a physiologic regulator
9
as those having ANCs of less than 2.1 × 10 /L on G-CSF doses of hematopoiesis, it would be unexpected for G-CSF to break
greater than 8 µg/kg/day had a cumulative incidence of MDS/AML molecular bonds and cause DNA damage even when used in thera-
of 34% after 15 years; more responsive patients, defined as having peutic dosages.
9
ANCs of greater than 2.1 × 10 /L on G-CSF doses lower than 8 µg/ In one patient with K/SCN who progressed to MDS/L, clonal
kg/day had a cumulative incidence of 15%. The data were interpreted evolution was assessed by exome sequencing of whole marrow cells.
as indicating that a poor response to G-CSF defines an “at-risk” A pro-proliferative, differentiation-defective GCSFR mutation was
population and predicts an adverse outcome. The data do not neces- found, that persisted and acquired secondary mutations. The fre-
sarily support a cause-and-effect relationship between development quency of RUNX1 mutations was high in a cohort of K/SCN patients
of MDS/AML and G-CSF therapy. The results may only mean that who developed MDS/L. Mutations in RUNX1 and GCSFR cooperate
patients requiring higher G-CSF therapy have a more severe clinical to promote clonal expansion.
and hematologic phenotype. A report from the French Severe Chronic
Neutropenia Study Group confirmed that increased exposure to
G-CSF with respect to dose and duration in congenital neutropenia Differential Diagnosis
patients was associated with a heightened risk of MDS/AML, but
they do not speculate on the mechanism. The commonest cause of isolated neutropenia in very young children
Conversion to MDS/AML in K/SCN patients is associated with is viral-induced BM suppression. An antecedent history of good
cellular genetic abnormalities that provide insight into the pathobiol- health, the occurrence of a viral illness, and the transient nature of
ogy of the transformation and may be useful in identifying patients the neutropenia distinguish this disorder from K/SCN.
who are at high risk. Several cellular and genetic changes have been Autoimmune neutropenia of infancy is recognized as a fairly
found in the BM of patients with K/SCN who received G-CSF. specific syndrome of early childhood. Low neutrophil numbers are
Whether these changes are coupled to G-CSF therapy is unknown. often discovered during the course of routine investigation for a
Remarkably, the abnormalities have predictable, similar characteristics benign febrile illness. The illness abates, but the neutropenia persists,
in most patients and underscore a fairly specific multistep pathogen- sometimes for months and occasionally for years. A BM biopsy is
esis in the evolution into MDS/AML. At varying time points after normocellular, and an aspirate shows active granulopoiesis up to the
starting G-CSF therapy, about half of the congenital neutropenia band stage; neutrophils may be normally represented, reduced or
patients who transform acquire the same activating RAS oncogene absent. The neutropenia is caused by increased peripheral destruction
mutation, namely a GGT (glycine) to GAT (aspartic acid) substitu- and the diagnosis can be supported by demonstrating specific anti-
tion at codon 12. More than 90% of patients who transform also granulocyte antibodies on neutrophils. The prognosis is good, the
show an acquired cytogenetic clonal alteration in BM cells, usually neutropenia is self-limited albeit protracted, and patients seldom
−7 or 7q− but also +21 or +8. Complex cytogenetics (e.g., −7 and develop serious bacterial infections as a result of it. Other infrequent
+21) have also been identified. More than 80% of patients develop acquired causes of severe, isolated neutropenia in this age group
one or more GCSFR point mutations. These GCSFR mutations are include BM suppression from a drug or toxin and neutrophil seques-
nonsense mutations that result in the truncation of the C-terminal tration as part of a hypersplenism syndrome.
cytoplasmic region, a subdomain that is crucial for G-CSF–induced Of the IBMFSs, SDS can also manifest as isolated neutropenia
maturation. The acquired mutation is directly operative in the con- but can be identified because of growth failure, the malabsorption
version to MDS/AML. In murine models, the mutation results in component caused by pancreatic insufficiency, fatty changes in the
impaired ligand internalization, defective receptor downmodulation, pancreas seen on CT scanning or ultrasonography, and characteristic
and enhanced growth signaling that produces an exaggerated hyper- skeletal abnormalities. Glycogen storage disease type 1b (GSD-1b)
proliferative effect in response to G-CSF. This also confers resistance and Barth syndrome are also in the differential diagnosis. Neutro-
to apoptosis and enhances cell survival that favors clonal expansion penia can also be a prominent part of antibody deficiency syndromes
in vivo. The detection of GCSFR mutations places patients at high and cellular immunodeficiency disorders (Table 29.8); investiga-
risk for malignant conversion, but the time course from detection of tion of chronic neutropenia of childhood should include an immu-
mutations to overt MDS/AML varies considerably and may take noglobulin electrophoresis, T-cell proliferative studies, and
years. quantitation of T-cell subsets and NK cell activity. Cyclic neutrope-
Although patients requiring higher doses of G-CSF to attain nia is distinguished by predictable symptomatology, especially mouth
safe neutrophil levels are at a higher risk of developing MDS/AML, sores about every 3 weeks (19–23 days), often associated with chronic
there is no definitive evidence that G-CSF directly causes malignant gingivitis. A complete blood count two or three times a week for
transformation. G-CSF may simply be an “innocent bystander” that 4 to 8 weeks demonstrates the diagnostic oscillation pattern with a
corrects the neutropenia, prolongs patient survival, and allows time cyclic nadir. Other unclassified inherited neutropenia syndromes
for the malignant predisposition to declare itself. Alternatively, G-CSF with vertical transmission or in siblings have been described. The
may accelerate the propensity for MDS/AML in the genetically neutropenia in such cases are typically mild to moderate. When severe