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Chapter 72 Mast Cells and Mastocytosis 1183

IFN-α are sometimes used to control mediator symptoms, especially days every 4–8 weeks at a dose of 0.10–0.13 mg/kg over 2 h IV.
when these symptoms are refractory to conventional antimediator- Among 9 evaluable patients (1 discontinued because of toxicoderma),
type drugs. In addition, low-dose IFN-α has been suggested for ISM the drug elicited improvement in symptoms, and a decrease (often
patients with drug-resistant osteoporosis. Otherwise, however, these rapid) in urticaria pigmentosa lesions, MC burden, serum tryptase
agents are not recommended for use in ISM or SSM. In patients with levels, and urine metabolites of MC activation.
25
rapidly progressive ASM or MCL, more intensive therapy is usually In the Mayo Clinic experience, cladribine was administered for
2
recommended, whereas cladribine alone or IFN-α alone are insuffi- 5 days at a dose of 5 mg/m /day (or 0.13–0.17 mg/kg/day) for 5 days
cient to control rapid disease expansion or transformation in SM. IV. A median of 3 cycles (range, 1–9) was administered. The overall
response rate was 12 of 22 (55%), consisting of 1 CR, 7 MR, and 4
PR. Responses were observed in 5 of 9 ISM, 1 of 2 ASM, and 6 of
Interferon-α 11 SM-AHN patients. Improvement in mediator symptoms, organo-
megaly, C-findings (e.g., ascites, anemia), and markers of MC burden
IFN-α has been used as monotherapy or in combination with and/or activation (e.g., serum tryptase level and MC-derived urine
corticosteroids, mostly in patients with ASM with slow progression metabolites) were observed. The median response duration was 11
or mono-organ involvement. For example, the drug works effectively months, and inferior outcomes were predicted by leukocytosis,
in patients with ASM with liver involvement and ascites. Prednisone monocytosis, and circulating immature myeloid cells, the latter
or prednisolone 0.5–1 mg/kg is initiated with IFN-α (or as a lead-in remaining significant in a multivariate analysis.
dose for several days prior) in order to improve its efficacy and toler- The long-term French experience with cladribine in both indolent
26
ability, and tapered over 2–3 months if feasible. In some patients with (n = 36) and advanced (n = 32) SM patients was recently published.
severe and persistent mediator symptoms or organ damage that is Cladribine was administered as an infusion or subcutaneously at a
particularly responsive to corticosteroids, a longer term maintenance dose of 0.14 mg/kg, for 1–5 days, every 4–12 weeks. A median of
dose (e.g., ≤10 mg daily) may be required. IFN-α dosing has been 3.7 courses was administered (range, 1–9). The overall response rate
variable between studies and an optimal dose has not been identified. was 72%, split between 92% and 50% for indolent and advanced
Starting doses have ranged from 1 million units (MU)/day to 3 MU disease, respectively. Among patients with advanced SM, the respec-
three times weekly, with median total weekly maintenance doses in tive CR, MR, and PR rates were 0%, 37.5%, and 12.5%. Significant
the range of 15–30 MU. Because of the (low) risk of anaphylactic decreases in serum tryptase levels was only observed in ISM patients,
reactions, consideration should be given to hospitalization of patients and changes in BM MC burden were only evaluated in nine patients,
during the first days of treatment, if possible. precluding a substantive conclusion regarding this endpoint. Median
In the Mayo experience with IFN-α (with or without predni- durations of response were 3.71 (range, 0.1–8) and 2.47 (range,
25
sone), 21 of 40 evaluable patients responded (53%); response rates 0.5–8.6) years for indolent and advanced SM, respectively. Lympho-
by subgroup were: six of 10 ISM, six of 10 ASM, and nine of 20 penia (82%), neutropenia (47%), and opportunistic infections (13%)
SM-AHN. The 21 responses consisted of one complete remission were the most common grade 3/4 adverse events. Although cladribine
(CR), six major responses (MRs), and 14 partial responses (PRs). The has activity in selected patients with SM, its use in subjects with
median duration of response (DOR) was 12 months (range, 1–67) indolent disease (even those with refractory mediator symptoms)
with no statistical difference between responders and nonresponders needs to be approached very cautiously because of the potential for
regarding use of prednisone or the median weekly dose of IFN-α. substantial high-grade toxicities in these individuals who otherwise
However, the absence of mediator-related symptoms was associated exhibit similar survival to age-matched controls.
with a significantly lower response rate.
In the French experience with 20 SM patients (four ISM and 16
ASM), IFN-α-2b was initiated at 1 MU daily and progressively Tyrosine Kinase Inhibitors
2
increased as tolerated up to 5 MU/m daily. Among the 13 patients
treated for at least 6 months (mean daily dose: 3.2 MU daily), all had Dasatinib
partial or complete resolution of systemic or cutaneous disease mani-
festations and/or MC mediator levels, but no significant reduction in Multikinase inhibitors with activity against KIT have been evaluated
BM MC burden. The lack of a substantive effect on tumor load and in patients with advanced SM. Dasatinib is a dual SRC/ABL kinase
rapid relapse in four responding patients after drug withdrawal sug- inhibitor that is used as front-line treatment of chronic myelogenous
gests that IFN-α exerts a cytostatic effect on MCs. leukemia, or as second- or third-line therapy for patients with intoler-
Responses to IFN-α primarily include amelioration of MC ance to, or resistance to imatinib (or nilotinib). Dasatinib exerts rela-
mediator symptoms and associated laboratory markers of MC activa- tively weak inhibition of KIT D816V and has a short half-life. A case
tion such as levels of histamine or its metabolites. Single cases and series and a phase II trial of dasatinib (140 mg total daily dose)
small case series, in addition to the aggregate data from the aforemen- revealed limited activity in SM. In the phase II trial of 33 patients
tioned larger trials, indicate variable potential to ameliorate skin (ISM, n = 18; ASM, n = 9; SM-AHN), 11 (33%) responded. Two
lesions, osteoporosis, and C findings such as cytopenias, hepato/ complete responses were recorded in patients who were negative for
splenomegaly with liver dysfunction and/or ascites, and weight loss. the KIT D816V mutation, including a patient with JAK2 V617F-
Toxicities associated with IFN-α such as flu-like symptoms, myelo- positive SM-PMF and a patient with SM-CEL. The other 9 responses
suppression, transaminitis, hypothyroidism, depression, and bone provided symptomatic benefit only, without clinically significant
pain are not uncommon, and result in a moderate proportion of reductions in either BM MC burden or serum tryptase levels. In the
patients requiring dose-reduction or drug discontinuation. context of the CML experience, (which may also pertain to the
treatment of SM), side effects of dasatinib have included pleural and
pericardial effusions, cytopenias, an increased risk of bleeding, as well
Cladribine as immunosuppression.

Cladribine has been used off-label across a spectrum of SM subtypes.
In 2013 cladribine received orphan designation (not marketing Imatinib
authorization) for the treatment of SM in Europe. Following an
initial report indicating that cladribine could elicit improvement of Imatinib is currently the only US Food and Drug Administration–
mediator symptoms, urticaria pigmentosa lesions, and reduction of approved drug for SM and is indicated for adult patients with ASM
MC burden and the serum tryptase level, Kluin-Nelemans and col- without the KIT D816V mutation or with unknown KIT mutational
leagues published a series of 10 patients, including 3 with ISM, 1 status. The general utility of imatinib in SM is therefore limited given
SSM, 3 SM-AHN, and 3 ASM. Cladribine was administered for 5 the high prevalence of the KIT D816V mutation, and the increasing