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976 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 63: Basophils, Mast Cells, and Related Disorders 977

Bisphosphonates reported in only one study, which used non–T-cell-depleted blood SCT
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Osteoporosis in patients with mastocytosis may be unrecognized and in a patient with an associated myeloproliferative neoplasm. The
thus undertreated, especially in patients with milder forms of disease. It value of allogeneic SCT in mastocytosis may result from the immuno-
is thus important to utilize dual-energy x-ray absorptiometry (DEXA) therapeutic effects of the donor marrow rather than the myeloablative
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scanning in the evaluation of those with mastocytosis. Recommended conditioning regimen. One study using nonmyeloablative blood SCT
approaches for the treatment of osteoporosis include calcium supple- for treatment of advanced systemic mastocytosis in three patients with
mentation, consideration of estrogen replacement in postmenopausal advanced mastocytosis reported no effect on mastocytosis progression
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women, and use of bisphosphonates. 204 despite the induction of a graft-versus-mast-cell response. Perhaps
performing targeted therapy directed at the mast cell compartment
Nonsteroidal Antiinflammatory Agents before transplantation would improve outcome.
Nonsteroidal antiinflammatory agents have been useful in some patients
whose primary manifestations are recurrent episodes of flushing, syn- Tyrosine Kinase Inhibitors
cope, or both. 202,204 It should be noted that these agents may exacerbate The availability of low-molecular-weight inhibitors of tyrosine kinases
ulcer disease. Patients with a history of aspirin sensitivity should not be suggested the mutated KIT tyrosine kinases in mastocytosis as a thera-
placed on this therapy unless they first undergo desensitization. peutic target. Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland)
currently is the only such drug available. It has a specific inhibition
Glucocorticoids; Methoxypsoralen profile that includes ABL1, KIT, and PDGFR (platelet-derived growth
Cutaneous lesions have been treated with either glucocorticoids or factor receptor) tyrosine kinases. 217,218 Although the drug inhibits
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8-methoxypsoralen plus ultraviolet A (PUVA), largely to reduce wild-type KIT and KIT bearing juxtamembrane-activating mutations
209
pruritus or for cosmetic improvement. No evidence indicates such similar to those found in gastrointestinal stromal tumors, it does not
approaches alter the progression of systemic disease. Relapses 3 to 6 inhibit KIT bearing the codon 816 mutations associated with most
months after cessation of PUVA therapy are common. Patients may common forms of systemic mastocytosis. 219,220 This finding is attributed
experience a decrease in the intensity of lesions after exposure to nat- to a conformational change in KIT bearing the codon 816 mutation,
ural sunlight. Repeated or extensive application of glucocorticoids may which interferes with the association of the drug with the ATP-binding
result in cutaneous atrophy or adrenocortical suppression. 208 domains of the receptor. Consistent with these observations, imatinib
Systemic glucocorticoids are used to decrease significant malab- mesylate showed a strong in vitro cytotoxic effect on mast cells bearing
sorption and ascites in patients with advanced disease. In adults, oral wild-type KIT. Mast cells bearing a codon 816 mutation isolated from
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221
prednisone (40 to 60 mg/day) usually results in decreased symptoms marrow of patients with mastocytosis were fairly resistant to the drug.
over a 2- to 3-week period. After initial improvement, steroids usually These studies suggest imatinib mesylate is unlikely to be an effective
can be tapered to an alternate-day regimen. However, with time, the therapy for patients who carry codon 816 mutations. However, the drug
ascites frequently recurs. Such patients reportedly can benefit from a appears to be of value when there is an imatinib-sensitive mutation or
portacaval shunt. in KIT816-unmutated patients. For example, a patient with an unusual
form of systemic mastocytosis associated with a KIT mutation (Phe-
Interferon-α Cladribine 522Cys) affecting the transmembrane region of the receptor responded
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Patients with more advanced categories of systemic mastocytosis may to treatment with imatinib. Accordingly, a careful mutational analy-
be candidates for approaches directed at reducing the mast cell bur- sis of a sample enriched for lesional mast cells appears to be essential
den. None of these approaches has resulted in cure of the disease. For in patients with mastocytosis before contemplating imatinib therapy.
severe disease, some limited success has been reported for interferon Other tyrosine kinase inhibitors that decrease the activity of KIT with
α (IFN-α) and it is often considered to be a first-line drug of choice codon 816 mutations including midostaurin (PKC412) and dasatinib
along with cladribine. 204,211,212 It is presumed to act by restricting the pro- are in clinical trials. 222,223 Studies to date suggest that midostaurin may
liferation of hematopoietic progenitor cells. Studies with IFN-α, often produce significant decreases in mast cell burden in some patients. 222
in combination with glucocorticoids, have reported variable success, Some patients with a variant of chronic eosinophilic leukemia
with unchanged or modest reductions in marrow infiltration with mast (clonal hypereosinophilic syndrome) and FIPIL1-PDGFRA fusions
cells, and in tryptase levels. Many patients do report symptomatic ben- exhibit elevated serum tryptase levels, increased numbers of mast cells
efits. Resolutions of ascites and increased bone remineralization also in the marrow, some of which can appear atypical and spindle shaped,
have been reported. Use of IFN-α is often limited by side effects such tissue fibrosis, and, like other patients who have the FIPIL1-PDGFRA
as fever, fatigue, and cytopenias. Its use is not routinely recommended fusion gene, are responsive to imatinib mesylate. 224,225 Such cases are
for patients with indolent systemic disease, unless there is concomitant classified within the World Health Organization category of myeloid
severe osteoporosis. and lymphoid neoplasms with eosinophilia and abnormalities of PDG-
Cladribine (2-chlorodeoxyadenosine), a nucleoside analogue, does FRA, PDGFRB, or FGFR1.
not require cells in active cell cycle to exert its cytotoxic activity and may
be beneficial in slowly progressing neoplastic processes. The drug has Monoclonal Mast Cell Activation Syndrome
myelosuppressive and immunosuppressive properties and thus cannot Monoclonal mast cell activation syndrome (MMAS) is a term adopted
be recommended for patients with indolent disease. 204 by a consensus conference to be applied to patients who are found to
have one or two minor diagnostic criteria for mastocytosis but lack
226
Hematopoietic Stem Cell Transplantation the full diagnostic criteria for systemic disease. Patients with such
Allogeneic stem cell transplantation (SCT) has been employed as a findings have been identified within groups of patients diagnosed with
treatment option for patients with advanced categories of mastocytosis idiopathic anaphylaxis and patients with anaphylaxis to stinging insects.
associated with poor survival. SCT has been used to treat a hemato- It is possible that these studies are identifying patients with a progres-
logic disorder associated with mastocytosis in relatively few cases. 213–216 sive clonal mast cell disorder that may one day meet the diagnostic
Although these studies reported favorable responses of the associated criteria for systemic mastocytosis. For now, such patients are treated
hematologic disorders, complete remission of the mast cell disease was symptomatically and for anaphylaxis. Followup at yearly intervals is

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