Cytoreductive therapy in 108 adults with systemic mastocytosis:
Outcome analysis and response prediction during treatment
with interferon-alpha, hydroxyurea, imatinib mesylate or
Ken H. Lim,1,2Animesh Pardanani,1Joseph H. Butterfield,3Chin-Yang Li,4and Ayalew Tefferi1*
Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has
not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO
diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were
evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-a), hydroxyurea
(HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The
corresponding overall (major) response rates, according to recently published consensus criteria, were
53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM,
aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-
AHNMD) were 60%, 60%, 45% for IFN-a, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-
CdA. The absence of mast cell mediator release symptoms in IFN-a-treated patients and presence of circu-
lating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status
did not influence treatment response. Although the major response rates with these four cytoreductive
agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors
2-CdA or IFN-a as first-line current therapy in SM and identifies patients who are likely to respond to such
therapy. Am. J. Hematol. 84:790–794, 2009.
C 2009 Wiley-Liss, Inc.
Mast cell disease (MCD) is a clinically and histologically
heterogenous disorder characterized by tissue infiltration by
morphologically (spindle-shaped) and immunophenotypi-
cally (CD25-positive) abnormal mast cells (MC) . In
infants and children, MCD often presents with skin-only dis-
ease and might undergo spontaneous regression during
puberty [2,3]. In contrast, the disease is systemic (referred
to as systemic mastocytosis) in adult patients and involves
the bone marrow (BM) in virtually all cases, with or without
activating KIT mutation (most commonly D816V) in SM has
confirmed the neoplastic nature of the disease and
provided a potential target for treatment [7–10]. SM has a
varied presentation ranging from indolent forms with limited
morbidity and normal life expectancy to the rapidly fatal
mast cell leukemia (MCL) . This clinical diversity is also
captured in the World Health Organization (WHO) system
for the subclassification SM: indolent SM (ISM; little or no
evidence of organ dysfunction), aggressive SM (ASM; pres-
ence of organ dysfunction), SM associated with another
clonal hematological nonmast cell lineage disease (SM-
AHNMD), and MCL [11,12].
Current therapy in adult systemic mastocytosis (SM)
includes observation alone, topical therapy for cutaneous
disease, symptomatic noncytoreductive therapy and cytore-
ductive therapy . In general, symptomatic skin disease
including urticaria pigmentosa (UP), MC mediator release
symptoms (MCMRS) and organ dysfunction due to direct
MC infiltration are main indications for treatment in SM.
The treatment of MCMRS includes avoidance of triggering
factors, histamine antagonists and cromolyn sodium. The
presence of organ dysfunction indicates an aggressive clini-
cal course in SM and cytoreductive therapy is usually
employed to decrease MC burden. Cytoreductive therapy is
The identification of
also used for the treatment of MCMRS that are refractory
to usual therapy.
Interferon-alpha (IFN-a) with or without prednisone [14–
17], 2-chlorodeoxyadenosine (2-CdA) [18–20], and imatinib
mesylate (IM) [21–23] have been used in SM as cytoreduc-
tive agents. In addition, hydroxyurea (HU) is often utilized
in the setting of SM-AHNMD. However, the individual merits
of these four cytoreductive agents have not been well char-
acterized because of the rarity of SM and the fact that pub-
lished reports are limited to case studies or small series of
patients with short follow-up information. Furthermore,
patient characteristics that predict response have never
been systematically studied. In the current, relatively large
retrospective study from a single institution, we sought to
address some of these issues.
Patients and Methods
Study design and patients
This study was approved by the institutional review board. We first con-
ducted a search, using the institutional computerized database, to iden-
tify adult patients (age 18 years or older) with SM seen at the Mayo Clinic
1Divisions of Hematology, Mayo Clinic, Rochester, Minnesota;
Hematology-Oncology, Mackay Memorial Hospital, and Mackay Medicine,
Nursing and Management College, Taipei, Taiwan;3Division of Allergic Dis-
eases, Mayo Clinic, Rochester, Minnesota;
Mayo Clinic, Rochester, Minnesota
4Divisions of Hematopathology,
Conflict of interest: Nothing to report.
*Correspondence to: Ayalew Tefferi, MD, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905, USA. E-mail: firstname.lastname@example.org
Received for publication 20 August 2009; Revised 2 October 2009; Accepted 5
Am. J. Hematol. 84:790–794, 2009.
Published online 9 October 2009 in Wiley InterScience (www.interscience.
C 2009 Wiley-Liss, Inc.
American Journal of Hematology
during the period from January 1976 through October 2007. The diagno-
sis and classification of SM were based on the 2001 WHO criteria, 
and patients must have had bone marrow (BM) pathology reviewed at
our institution to confirm the diagnosis. SM with associated eosinophilia
was defined by the presence, in the peripheral blood, of >1.5 3 109/L
absolute eosinophil count. For the purposes of the current study, we
selected patients who received at least one cytoreductive drug and modi-
fied the diagnostic criteria according to the revised 2008 WHO document
. In other words, we excluded patients with FIP1L1-PDGFRA muta-
tion. The medical records of all study patients were reviewed and all
cytoreductive therapy was recorded for each patient. Clinical and labora-
tory parameters and BM histopathological characteristics were collected
at the time of referral. The mutational status of KITD816V, JAK2V617F,
FIP1L1-PDGFRA and TET2 was also recorded when available; recent
studies have revealed significant association of TET2 mutations with SM
and other myeloid malignancies [26–28]. The methods used for mutation
analysis were previously published [6,26–30].
Evaluation of treatment response
Response to cytoreductive therapy was assessed by recently pub-
lished consensus criteria with slight modification on the ASM/MCL
response criteria to simplify the definition of major response (Tables I
and II) . Treatment response in SM-AHNMD was also evaluated by
the same response criteria as ASM/MCL, and response criteria for skin
symptoms/lesions and mast cell mediator related symptoms were also
used whenever applicable. In brief, complete response (CR) to treat-
ment comprised complete resolution of all clinical symptoms and signs
lasting for at least one month. A major response (MR) comprised a
more than 50% improvement in symptoms and signs. A partial
response (PR) comprised a 10% to 50% improvement. Overall
response rate (ORR) was defined as the sum of CR, MR and PR. Du-
ration of response and major adverse effects of individual cytoreductive
agent were also recorded.
The association between clinical, laboratory and genetic characteris-
tics and response to individual cytoreductive agent was calculated by
the Fisher’s exact test or Chi-square test for 2 3 2 contingency tables.
The Wilcoxon rank-sum test was used to test for differences in propor-
tions of medians of continuous variables. Multivariate analysis was per-
formed by logistic regression model. Statistical significance was defined
as a two-sided P value less than 0.05. Statistical analyses of the data
were carried out using the StatView software package (SAS Institute,
Inc., Cary, North Carolina, version 9.1).
A total of 342 adult patients fulfilled the 2001 WHO diag-
nostic criteria for SM. The natural history of these patients
was recently published . Among them, 108 patients ful-
filled the 2008 WHO criteria and had received treatment
that included at least one cytoreductive drug as either first-
line (n 5 89) or second-line (n 5 19) therapy. The clinical
and laboratory characteristics, BM histopathologic features
and genetic characteristics at the time of referral of these
108 SM patients are summarized in Table III. IFN-a with or
without prednisone, HU, IM, and 2-CdA were the most fre-
quently used cytoreductive agents and were administered
to 95 of the 108 study patients. The remaining 13 patients
received other cytoreductive drugs including methotrexate
or bortezomib in two patients with ISM, etoposide in 1
patient with MCL, and methotrexate, vincristine, melphalan,
and combination chemotherapy in 10 patients with SM-
AHNMD. None of these latter drugs were effective.
IFN-a with or without prednisone
IFN-a with or without prednisone (20 and 27 patients,
respectively) was given to 11 patients with ISM, 14 ASM,
and 22 SM-AHNMD. The drug was used as first-line
therapy in 31 patients. The dosage of IFN-a ranged from
0.5 million units (MU) per day to 10 MU three times a
week. The median weekly dose of IFN-a was 15 MU per
TABLE I. Response Criteria For Systemic Mastocytosis Used in the Current Study Were Slightly Modified From Recently
Published Consensus Criteria12
Skin lesions/symptoms Mast cell mediator related symptomsASM/MCL
Complete Response (CR)Complete resolutionComplete resolution lasting ?1 year Complete resolution of tissue mast cell
infiltrates and serum tryptase <20
ng/mL and resolution of organomegalya
More than 50% regression of at least one
C-Finding without progression in other
Major response (MR) More than 50% improvement of all skin
lesions/symptoms and/or decrease in
frequency of severe eventsb(from B
to A or from C to B)
10-50% improvement of all skin lesions/
More than 50% improvement in
symptoms and/or decrease in
frequency of severe eventsb(from B
to A or from C to B)
10–50% improvement in symptoms
and/or decrease in frequency of
severe events (less than defined MR)
Less than 10% improvement and no
decrease in frequency of severe
Partial response (PR)
10-50% regression of one or more
C-Findings without progression in other
Less than 10% improvement in C-Findings
No response (NR)Less than 10% improvement of skin
aDefined as one of the major response subcategory in the original proposed criteria.12
bSevere events are those that require immediate therapy and hospitalization; their frequency is assigned ‘‘A’’ if they occur <1 per year; ‘‘B’’ >1 per year but <1 per
month, and ‘‘C’’ >1 per month.
cDefined as good partial response in the original criteria.
TABLE II. Originally Proposed ASM and MCL Response Criteria by B/C-Findings12
Major response: Complete resolution of at least one (one or more)
C-Finding(s) and no progression in other C-Findings
(a) Complete remission 5 with disappearance of mast cell infiltrates in affected organs and
decrease of serum tryptase levels to <20 ng/mL and disappearance of SM-associated
(b) Incomplete remission 5 with decrease in mast cell infiltrates in affected organs and/or
substantial decrease of serum tryptase level and/or visible regression of organomegaly
(c) Pure clinical response 5 without decrease in mast cell infiltrates, without decrease in
tryptase levels, and without regression of organomegaly
(a) Good partial response: >50% regressionb
(b) Minor response: <50% regressionb
(a) Stable disease: C-Finding-parameters show constant range
(b) Progressive disease: one or more C-Finding(s) show progression
Partial response: Incomplete regression of one or more C-Finding(s)a,
without complete regression and without progress
No response: C-Finding(s) persistent or progressive
aWith or without decrease in mast cell infiltrates, serum tryptase levels, and organomegaly.
bNo progression in other C-Findings are documented.
American Journal of Hematology791
week (range 3.5–30 MU per week). In patients receiving
prednisone with IFN-a, the initial dose of prednisone
ranged from 20 mg to 60 mg per day with a slow tapering
over weeksor monthsin
response was evaluable in 40 of the 47 patients receiving
therapy (follow-up information was not available in seven
some patients. Treatment
patients); CR, MR, and PR were achieved in 1, 6, and 14
patients, respectively (ORR 53%, Table IV). ORR in ISM,
ASM, and SM-AHNMD was 60%, 60%, and 45%, respec-
tively (Table V).
Responses in ISM included control of MCMRS, resolution
of UP and/or reduction in BM MC burden. Responses in
ASMincluded control ofMCMRS,
improvement of skeletal disease, improvement in anemia,
and/or reduction in BM MC burden. These responses were
often accompanied by marked reduction in serum and urine
MC-derived metabolites. Substantial decrease of serum
tryptase level (e.g. from >200 ng/mL to 37 ng/mL) could be
seen in patient who achieved MR. Responses in SM-
improvement in anemia or thrombocytopenia, resolution of
ascites, control of leukocytosis and eosinophilia and/or
reduction in BM MC burden. Overall median duration of
response was 12 months (range, 1–67 months). The
response rate in patients treated with IFN-a with or without
prednisone was 47% and 57% (P 5 0.6), respectively. The
median weekly dose of IFN-a for responders and nonres-
ponders in 36 patients (20 and 16, respectively) with avail-
able information was 15 MU per week (range 3.5–30 MU
per week) and 12.8 MU per week (5–30 MU per week, P 5
0.9), respectively. Absence of systemic mediator-related
response to IFN-a; 41% vs. 77% (P 5 0.03), respectively.
Major toxicities included fatigue, depression and thrombo-
HU was given to 1 ASM, 28 SM-AHNMD, and 1 MCL
patients. The drug was used as first-line therapy in 24
patients. The dose of HU ranged from 500 mg every other
day to 2000 mg per day. Treatment response was evaluable
in 26 of the 30 patients receiving therapy (follow-up infor-
mation was not available in one patient and response was
not evaluable in three patients); PR was achieved in 5 SM-
AHNMD patients (ORR 5 19%). Median duration of
response was 31.5 months (range, 5–50 months), and
most responses were related to the AHNMD component—
control of thrombocytosis, leukocytosis and/or hepatosple-
nomegaly. Major toxicity was myelosuppression.
IM was given to eight patients with ISM, four ASM, 14
SM-AHNMD, and one MCL (none were FIP1L1-PDGFRA-
positive). The drug was used as first-line therapy in 12
patients. The median induction dose of IM was 400 mg per
day (range 100–400 mg per day), and the maintenance
dose in responding patients ranged from 200 mg per day to
TABLE III. Clinical, Laboratory, Bone Marrow Histopathologic
and Genetic Characteristics at Time of Referral in 108
Patients with Systemic Mastocytosis
Characteristics No (%) of patientsMedian (range)
Splenomegaly (N 5 106)g
White blood count (3109/L)
Albumin (3.5–5.0 g/dL)
SAP (45–115 U/L)
AST (8–48 U/L)
Serum tryptase (<11.5 ng/mL)
BM cellularity for age (N 5 105)
BM % MC (N 5 97)
BM MC <10
BM MC 10–30
BM MC >30
BM % blast
BM blast <5
BM blast 5–10
BM blast >10
BM eosinophil infiltration grade (N 5 82)
Minimal to moderate
BM fibrosis grade (N 5 45)
KITD816V mutation (N 5 69)
JAK2V617F mutation (N 5 69)
TET2 mutation (N 5 20)
Abbreviation: AST, aspartate aminotransferase; ASM, aggressive SM; BM, bone
marrow; CEL, chronic eosinophilic leukemia; CMML, chronic myelomonocytic leu-
kemia; eos, eosinophilia; ISM, indolent systemic mastocytosis; MC, mast cell;
MCL, mast cell leukemia; MDS, myelodysplastic syndrome; MPN, myeloprolifera-
tive neoplasms; SAP, serum alkaline phosphatase.
aIncludes 2 SM-polycythemia vera, 4 SM-essential thrombocythemia, 2 SM-
myelofibrosis, and 15 SM-unclassified MPN.
bIncludes pruritus, flushing, urticaria, and angioedema.
cIncludes weight loss, fever, chills, and night sweats.
dIncludes headache, dizziness/lightheadedness, syncope/pre-syncope, hypo-
tension, anaphylaxis, palpitation/tachycardia, bronchoconstriction/wheezing, and
peptic ulcer disease.
eIncludes bone pain, arthralgias, and myalgias.
fIncludes nausea/vomiting, dyspepsia, dysphagia, diarrhea, constipation, ab-
dominal pain/cramp, bloating/flatulence, early satiety, heartburn, gastrointestinal
tract bleeding, malabsorption and steatorrhea.
gSpleen size information was unavailable in 2 patients underwent splenectomy
hEither palpable or detected by imaging studies.
TABLE IV. Response Rates to Interferon-Alpha, Hydroxyurea,
Imatinib mesylate or 2-Chlorodeoxyadenosine in 80 Patients
with Systemic Mastocytosis that were Evaluable for Response
No. of evaluable
Abbreviation: CR, complete response; MR, major response; ORR, overall
response rate; PR, partial response.
792American Journal of Hematology
400 mg per day. Treatment response was evaluable in 22
of the 27 patients receiving therapy (follow-up information
was not available in three patients and response was not
evaluable in two patients); four patients responded (2 MR
and 2 PR). ORR in ISM, ASM, and SM-AHNMD was 14%,
50%, and 9%, respectively. Responses included improve-
ment in UP in one ISM patient, some reduction of BM MC
burden in the remaining 3 patients with ASM or SM-
AHNMD. In one patient with ASM who achieved MR, serum
tryptase level decreased from 26.8 ng/mL to normal range
(<11.5 ng/mL). Median duration of response was 19.6
months (range, 9–69 months).
KITD816V mutation status was known in 21 evaluable
patients; the mutation was detected in 18 (86%) patients.
IM treatment responses in KITD816V-positive patients
included 2 MR and 1 PR (ORR 17%, Table V). One PR
was noted in three patients who were KITD816V-negative
(ORR 33%). None of the six patients with SM associated
with eosinophilia responded to IM treatment; all were
KITD816V-positive. Major toxicities included diarrhea and
peripheral edema. Two patients developed interstitial pneu-
monitis; one patient was successfully treated with cortico-
steroids, and the other one had resolution of pulmonary
symptoms after discontinuation of treatment with IM.
2-CdA was administered to 10 ISM, 3 ASM, and 13 SM-
AHNMD patients. The drug was used as first-line therapy in
eight patients. The dosage of 2-CdA was 5 mg/m2per day
or 0.13–0.17 mg/kg per day for 5 days as a 2-hr intrave-
nous (IV) infusion in most patients. The median number of
treatment cycles in 20 patients was 3 (range 1 to 9). Treat-
ment response was evaluable in 22 of the 26 patients
receiving therapy (follow-up information was not available in
four patients); CR, MR and PR were achieved in 1, 7, and
4 patients, respectively (ORR 5 55%). ORR in ISM, ASM,
and SM-AHNMD was 56%, 50%, and 55%, respectively. In
ISM and ASM, responses to 2-CdA included control of
MCMRS, resolution of UP and/or reduction in BM MC bur-
den. Marked decrease of serum tryptase level (e.g. from
98.4 ng/mL to 30.2 ng/mL) occurred in a patient who
achieved MR. In SM-AHNMD, responses included improve-
ment in constitutional symptoms, control of pruritus and
other MCMRS, resolution of ascites, decreases in hepatos-
plenomegaly, improvement in anemia and/or reduction in
BM MC burden. These responses were sometimes associ-
ated with marked decreases in serum or urine levels of
MC-derived metabolites. Median duration of response was
11 months (range, 3–74 months). Presence of leukocytosis
(WBC >10 3 109/L), monocytosis (absolute monocyte
count >0.9 3 109/L) or circulating immature myeloid cells
was significantly associated with inferior response to 2-
CdA; 17% vs. 69% (P 5 0.03); 17% vs. 73% (P 5 0.046)
and 0% vs. 75%, (P 5 0.006), respectively. However, only
the latter remained significant on multivariable analysis.
Major toxicities were myelosuppression and infection.
TET2 and KITD816V mutational status and response
TET2 mutational status was known in 14 of the 80 cases
that were evaluable for response. Three of the five mutated
cases and six of the nine unmutated cases responded for
an ORR of 60% and 67%, respectively (P 5 0.8).
KITD816V mutational status was known in 53 of the 80
cases that were evaluable for response. Twenty-one of the
40 KITD816V-positive cases and 4 of the 13 KITD816V-
negative cases responded for an ORR of 53% and 31%,
respectively (P 5 0.17).
The treatment of SM remains a challenge to clinicians
because of the diversity and complexity of the disease itself
and the lack of a standard and highly effective therapy. In
this study, we retrospectively analyzed the value of 4 major
cytoreductive drugs (IFN-a, HU, IM and 2-CdA) in the treat-
ment of SM among 80 consecutive patients who were
evaluable for response. Among these four drugs, HU was
frequently used in SM-AHNMD and its activity was mostly
related to its well known myelosuppressive effect and the
drug did not exhibit substantial anti-MC effect. Similarly and
as expected, IM had limited activity with an ORR of 18%.
This is consistent with in vitro experiments that showed IM-
resistance by KITD816V [31–33] and discordant with the
results of another study that suggested an ORR of 36% in
KITD816V-positive SM patients . In yet another study of
20 SM patients treated with IM, only one KITD816V-nega-
tive patient responded while six other patients reported
symptomatic improvement .
IFN-a was the most frequently used agent and displayed
moderate activity (ORR 53%) that was similar across differ-
ent SM subtypes. In a previously published phase II study
of 20 patients with SM treated with IFN-a,  ORR (7 par-
tial and 6 minor responses) was 65%; response rates in
ISM and ASM were 50% and 69%, respectively. In the
same study, high daily drug doses (i.e. more than 3 MU/
m2/d) were associated with better response rates. In our
study, response to IFN-a was not influenced by drug dose
or the addition of prednisone. The novel finding from the
current study, in regards to IFN-a therapy in SM, was the
association between favorable response and presence of
MC mediator release symptoms. This observation needs to
be validated in a prospective study that should include lab-
oratory correlative studies to provide mechanistic insight.
Consistent with our previously published observations,
[19,20] the current study showed substantial treatment ac-
tivity for 2-CdA and our results are similar to those from a
prospective, multicenter study reported by Kluin-Nelemans
et al.  In their study, 10 patients with SM were treated
TABLE V. Overall Response Rates to Interferon-Alpha, Hydroxyurea, Imatinib Mesylate or 2-Chlorodeoxyadenosine in Systemic
Mastocytosis (SM) Stratified by SM Subtype
Interferon-alphaHydroxyurea Imatinib mesylate 2-Chlorodeoxyadenosine
Abbreviation: ISM, indolent systemic mastocytosis; ASM, aggressive SM; SM-AHNMD, SM associated with another clonal hematological non-mast cell lineage disease;
MCL, mast cell leukemia.
American Journal of Hematology793
by 2-CdA at a daily dose of 0.1 to 0.13 mg/kg by a 2-hr IV Download full-text
infusion for 5 days up to 6 cycles. All three patients with
ASM responded and the remaining seven patients (4 ISM
and 3 SM-AHNMD) showed improvement of disease symp-
toms and signs. In another study, Lortholary et al. 
reported an impressive 79% ORR in 33 patients treated
with 2-CdA (0.15 mg/kg by a 2-hr IV infusion or subcutane-
ously for 5 days every 4–12 weeks for one to six cycles).
Myelosuppression was the major adverse effect seen in all
three studies. 2-CdA has also been successfully used to
treat a patient with MCL . In the current study, the pres-
ence of leukocytosis, monocytosis or circulating immature
myeloid cells predicted a suboptimal response to 2-CdA.
Taking into consideration the information from the current
study and that of published reports, it is reasonable to con-
clude that 2-CdA and IFN-a constitute the treatments of
choice, at the present time, for first line therapy in SM. Fur-
thermore, the current study provides information that is
useful in selecting patients who are likely to respond to
response remain inadequate and, in regards to treatment
with 2-CdA, optimal dose and treatment schedule have not
been established. The responses seen with IM were under-
whelming and we currently do not recommend its use in
patients with WHO-defined SM. It goes without saying that
novel drugs are needed; however, the experience so far
with targeted therapy using dasatinib or PKC412 has not
met expectations [36,37].
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