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Chapter 29 Inherited Bone Marrow Failure Syndromes 389

In general, the best scenario for a curative HSCT is when the establishment of a prognosis for these patients in the years ahead.
procedure is performed before developing MDS/AML using a Because apoptosis is a central mechanism of neutropenia in these
matched-related donor and when the patient is in good physical patients, future studies will determine whether the term maturation
condition. In a small series of six transplanted patients for MDS or arrest should be replaced by accelerated apoptosis as a descriptive term
AML, two with MDS who underwent the procedure without being for the BM findings. It appears that cellular models involving trans-
given induction chemotherapy survived, but four with AML given fection of the mutant genes into human myeloid cell lines provide
induction chemotherapy had significantly more morbidity and died evidence of how neutropenia occurs. Potentially, these models can
posttransplant, raising questions about conditioning strategies for also be used to examine new approaches to preventing apoptosis and
these patients. Two other cases with AML from Japan were published serve to provide clues to new and more effective therapies. Consider-
in 2013. In both cases HSCT without prior AML-type chemotherapy able data now confirm the effectiveness of G-CSF in the treatment
was successfully applied. of various forms of K/SCN. However, the inconvenient administra-
The discovery of an isolated BM clonal cytogenetic abnormality tion, potential long-term effects, and lack of response in 10% of
without other evidence of MDS or AML in patients with congenital patients require the development of alternative therapies. Gene
neutropenia raises management issues. One option is to perform therapy is still to be developed.
HSCT if there is a matched donor as soon as feasible. This has gener-
ally been recommended for patients with −7, 7q−, or +21. The a
priori argument is that the chance for cure is higher when the patient Cyclic Neutropenia
is well and has a low burden of malignant cells. The problem with
this decision centers on not knowing the tempo of progression from Cyclic neutropenia is an autosomal dominant disorder characterized
cytogenetic evolution to clear-cut MDS or AML. Thus there may not by a regular, repetitive reduction in peripheral blood neutrophils for
be a need to rush to transplant in all patients. Instead, one recom- 3 to 4 days every 19 to 23 days. Between nadirs, the patients have
mendation is to lower the G-CSF to the lowest dose that maintains normal or nearly normal neutrophil counts. Patients usually present
9
neutrophil counts greater than 0.5 × 10 /L and to monitor the patient in infancy or childhood and have a less severe infectious course
regularly with blood counts and by serial BM testing. compared with those with K/SCN. However, life-threatening infec-
Opinions also vary about the best way to manage patients with tions have been reported. A proportion of patients need treatment.
other genetic changes such as G-CSF-R or RAS mutations but without Daily administration of G-CSF typically improves symptoms in most
clonal BM cytogenetic abnormalities or morphologic evidence of patients.
transformation. In one patient with an isolated G-CSF receptor Cyclic neutropenia is caused by heterozygous mutations in the
mutation, an HSCT was performed to eliminate the risk of leukemic ELANE (ELA2) gene that encodes neutrophil elastase. The mutations
conversion. Debate about this approach continues, and watchful usually occur at the active site of neutrophil elastase without disrupt-
waiting is an acceptable option. ing the enzymatic substrate cleavage by the active site. The mutations
Therapeutic options for newly diagnosed patients with K/SCN seem to disturb a predicted transmembrane domain, leading to exces-
must be constantly reevaluated. It is largely accepted that G-CSF sive granular accumulation of elastase and defective membrane
induces robust neutrophilic responses and eliminates infections localization of the enzyme. The myeloid precursors are characterized
almost completely in more than 90% of K/SCN patients. Therefore by cyclic increases in apoptosis. However, the precise molecular
it should be the first treatment choice. HSCT has been regarded as mechanism for the cycling hematopoiesis has not been defined. It is
“salvage” therapy for patients who either acquire evidence of malig- also not clear why the same mutations in ELANE are associated with
nant myeloid transformation or fail to respond to G-CSF altogether. both cyclic and K/SCN phenotypes.
For KS patients transplanted with a fully matched donor before
transforming to MDS/AML and in stable health, the chance for cure
is at least 85%, possibly higher. The SCNIR data support this esti- Myelokathexis and WHIM Syndrome
mate. Not only is the neutropenia fully corrected by HSCT, but the
risk of MDS/AML is also eliminated. The onerous burden of daily Myelokathexis is a rare autosomal dominant disorder with recurrent
subcutaneous injections is removed, the financial expense is relieved, bacterial infections caused by a reduced number and function of
and the side effects of G-CSF are prevented. Clearly, an 85% cure neutrophils. Neutropenia is typically moderate to severe. Degenera-
rate stacks up favorably against the high cumulative incidence of tive changes in the granulocytes are characteristic and include pyknotic
incurable MDS/AML over time, particularly in patients who require nuclear lobes, fine chromatin filaments, and hypersegmentation. The
large doses of G-CSF. HSCT is a reasonable option as front-line BM is usually hypercellular with granulocytic hyperplasia. The
therapy for selected higher risk patients instead of G-CSF, and the pathophysiology of myelokathexis has been attributed to a defective
option should be discussed fairly and sensibly with newly diagnosed release of BM cells into the peripheral blood. Neutrophil precursors
patients and families. are characterized by decreased expression of BCL-X and accelerated
apoptosis. G-CSF ameliorates the neutropenia and leads to clinical
Bisphosphonates for Osteoporosis improvement during episodes of bacterial infection.
In 50% of K/SCN patients on G-CSF, bone density measurements WHIM syndrome refers to the association of myelokathexis with
show varying degrees of osteopenia and osteoporosis. It is unclear other features (warts, hypogammaglobulinemia, infections, and
whether the osteopenia in SCN is caused by G-CSF or the underlying myelokathexis). Most cases are caused by mutations in the chemokine
disease or a combination of both. Most of the cases with osteopenia receptor gene CXCR4 but dysfunction of GRK3, a negative regula-
are subclinical and asymptomatic, but some patients complain of tor of CXCR4, has also been implicated. The mutations result in
bone pain and have fractures. Evidence shows that bisphosphonates enhanced chemotactic response of neutrophils in response to the
are an effective treatment for the majority of these cases. CXCR4 ligand CXCL12 (stroma-derived factor 1) and pathologic
retention of neutrophils in the BM. Patients with wild type CXCR4
Future Directions might have other genetic defects that lead to an enhanced interac-
The list of K/SCN genes is by no means complete, and further studies tion between CXCR4 and CXCL12 and an enhanced chemotactic
are necessary to discover novel genes. It is also not clear if there is an response, such as reduced inhibition of CXCL12-promoted inter-
association between specific mutations and the risk of evolution to nalization, and desensitization of CXCR4 by G protein–coupled
MDS and acute leukemia, but studies are ongoing to try to answer receptor (GPCR) kinase-3 caused by decreased transcription of the
this clinical question. At present, diagnosis of cyclic and congenital GPCR kinase-3. G-CSF induces a prompt increase in neutrophil
neutropenia still depends primarily on observations of serial blood numbers and gamma globulin levels may also increase. Twice-daily
cell counts, but it is expected that mutational analysis of the ELANE injections of plerixafor (CXCR4 antagonist) in three patients were
gene will become a routine part of making the diagnosis and the associated with an increase in neutrophil counts, fewer infections