Abstract

Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow–derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.

Introduction

Mastocytosis is a heterogeneous disorder characterized by the abnormal growth and accumulation of morphologically and immunophenotypically abnormal mast cells (MCs) in one or more organs. The clinical presentation of mastocytosis is diverse, and many patients do not fit the classical description—namely, a variably long history of urticaria pigmentosa (UP), followed by the insidious onset of flushing, cramping abdominal pain, diarrhea, bone pain, and hepatosplenomegaly.1-4  Unlike pediatric cases, most adults with UP-like skin lesions have systemic disease (ie, systemic mastocytosis [SM]) at presentation, a condition generally confirmed by a bone marrow (BM) biopsy.5  MCs are derived from CD34+/KIT+ pluripotent hematopoietic cells in the bone marrow6 ; its neoplastic counterparts are morphologically atypical (spindled shape, hypogranular cytoplasm, nuclear atypia),7,8  and express abnormal cell surface markers (CD25 and/or CD2).9,10  Most, if not all, adult mastocytosis patients carry gain-of-function KIT receptor mutations, most commonly D816V in the tyrosine kinase domain.11,12 

The natural history of SM, ranging from indolent forms spanning years to more aggressive subtypes that rapidly progress to leukemia, complicates decision making regarding the choice of therapeutic modalities and timing of intervention. In 1988, Mayo Clinic investigators proposed a classification wherein SM patients were grouped into the following subtypes: (1) indolent SM (ISM); (2) SM with associated hematologic disorders (SM-AHD); (3) aggressive SM (ASM); and (4) mast cell leukemia (MCL), based on distinct clinicopathologic features.2  In 2001, the World Health Organization (WHO) formalized this classification and further refined it by incorporating recent advances in SM, including identification of KITD816V, aberrant expression of cell surface markers on neoplastic MCs, and elevated tryptase level in serum.13  Although the WHO proposal represents a major advance in identifying clinically distinct SM subgroups based on defined criteria and, consequently, has been widely adopted in clinical practice, it has hitherto not been validated in a large cohort of SM patients.

The aim of the current study was (1) to describe the clinical and laboratory features at presentation in a large cohort of SM patients; (2) to describe the risk of leukemic transformation and estimate mortality of SM patients within the context of the current WHO classification; (3) to estimate life expectancy relative to age- and sex-matched controls as a basis for clinical decision making; (4) to evaluate prognostic relevance of the WHO subclassification of SM, and to identify additional clinical, laboratory, and/or bone marrow histologic features that have prognostic value; and (5) to evaluate the prevalence and prognostic relevance of KITD816V and JAK2V617F mutations in this cohort.

Methods

Patients

The current study was approved by the Mayo Clinic Institutional Review Board. All patients provided informed authorization for use of their medical records for research purposes, and research was carried out in accordance with the principles of the Declaration of Helsinki. Prospective SM patients 18 years of age or older were identified by querying institutional electronic databases from January 1976 to October 2007. The flagged medical charts were thoroughly reviewed; study inclusion patients were required to have BM pathology reviewed at our institution and presence of SM confirmed. Clinical and laboratory features at diagnosis, survival data, and progression to leukemia were documented, and SM was subclassified according to the 2001 WHO proposal.14 

Bone marrow studies

BM aspirates and trephine sections were reviewed by one of us (C.-Y.L.). All patients satisfied the 2001 WHO criteria for the diagnosis of SM. Special immunohistochemical stains were used to identify MC in biopsy material, including tryptase (n = 228; 67%) and KIT (n = 123; 36%). The other stains used were Giemsa, toluidine blue, chloroacetate esterase, aminocaproate esterase, and acridine orange. Pathognomonic MC infiltrates were confirmed and overall BM cellularity and MC burden were recorded for each case. The percentage BM involvement by MC was based on review of trephine specimens. The pattern of MC infiltration, percentage of BM blasts in aspirate smears, and degree of eosinophilic infiltration were also recorded. CD2 and/or CD25 expression on BM MCs was studied by immunohistochemistry and/or flow cytometry in a subset of cases (n = 84; 25%), as previously described.10  Cytogenetic analysis was performed at diagnosis and the karyotype was classified using the International System for Cytogenetic Nomenclature Criteria.

Molecular studies

Mutation analysis was performed in DNA derived from archived cytogenetic pellets obtained at the time of BM biopsy. KITD816V was evaluated using an allele-specific oligonucleotide polymerase chain reaction assay with fragment analysis performed on an ABI 3130xl genetic analyzer (Applied Bioscience, Foster City, CA). Briefly, polymerase chain reaction (PCR) was used to amplify a fragment containing the mutation site in 2 separate tubes: one containing a reverse primer complementary to the unmutated sequence and the other containing a reverse primer complementary to the mutated sequence. Each reverse primer was labeled with a fluorescent tag and both tubes contained an identical, nonlabeled forward primer. Both primer sets amplified a 200-bp fragment that differed only at the mutation site. Samples negative for mutation lacked an amplified fragment in the mutated reaction tube, whereas positive samples showed amplified fragments in both the unmutated and mutated tubes. The test is sensitive to 0.01% as determined by dilution of DNA from a positive cell line (HMC-1, containing homozygous mutation) in DNA from a negative cell line (HL-60). The primer sequences were as follows: forward primer: 5′-AATATAAGCAACACTATAGT-3′; reverse primer unmutated: 5′-FAM-ATTAGAATCATTCTTGATGA-3′; reverse primer mutated: 5′-HEX-ATTAGAATCATTCTTGATGT-3′. PCRs were performed in a total volume of 25 μL using approximately 50 ng DNA, 20 pmol each primer, 5 nmol dNTPs, 1.75 units AmpliTaq-Gold, and standard PCR buffer (1.5 mM MgCl2, 10 mM Tris-HCl, pH 8.3, 50 mM KCl). JAK2V617F analysis was performed as previously described.15 

Statistical analyses

Actuarial probability of survival and leukemia-free survival were estimated using the Kaplan-Meier product limit method. Overall survival was defined as the time between diagnosis and death (as a result of all causes) or end of follow-up (censored observations). Leukemia-free survival was calculated from diagnosis to progression to acute leukemia/MCL or end of follow-up. Comparison between Kaplan-Meier curves was carried out by the log-rank test. Univariate and multivariate analyses were performed by Cox proportional hazards regression model. Expected survival curves were calculated using Hakulinen cohort method and were matched by age and sex to the US population for the appropriate time period based on diagnosis date.16-18  The Fisher exact test or χ2 test for 2 × 2 contingency tables and Wilcoxon rank-sum test or Kruskal-Wallis test were used to test for differences in proportions of nominal variables and medians of continuous variables, respectively. Correlation between 2 continuous variables was determined with the nonparametric Spearman rank-order correlation coefficient. Statistical analyses of the data were carried out using the StatView software package (SAS version 9.1; SAS Institute, Cary, NC).

Results

Clinical and laboratory features

The demographic, clinical, and laboratory features of the 342 study patients are summarized in Tables 1 and 2 and compared between WHO SM subgroups in Table 3. One hundred fifty-nine patients (46%) had ISM; 138 (40%), SM-AHNMD; 41 (12%), ASM; and 4 (1%), MCL. One patient each with SM-AHNMD and MCL presented with a histologically confirmed focal mast cell sarcoma-like lesion (iliac bone and chest wall, respectively). A greaterproportion of SM-AHNMD patients were male compared with ISM and ASM (P < .001). ISM patients were younger (P < .001) and exhibited a longer duration of symptoms before diagnosis (P < .001) compared with the other WHO subgroups. ISM patients also exhibited a higher prevalence of UP-like skin lesions (P < .001), cutaneous symptoms (P < .001), MC mediator-related symptoms (P < .001), anaphylactoid reactions (P < .001), and gastrointestinal symptoms (P = .05). In contrast, patients with ASM and SM-AHNMD exhibited a greater frequency of constitutional symptoms (P < .001), hepatosplenomegaly (P < .001), and lymphadenopathy (P = .005).

Table 1

Demographic and clinical characteristics at referral of 342 patients with SM

CharacteristicNo. of patients (%)Median (range)
Total no. of SM patients 342  
    ISM 159 (46)  
        Isolated bone marrow mastocytosis 36 (23)  
        Smoldering systemic mastocytosis 22 (14)  
    ASM 41 (12)  
    SM-AHNMD 138 (40)  
    MCL 4 (1)  
Male 188 (55)  
Age, y  57 (19-87) 
Time from appearance of symptoms to diagnosis of SM, mo  33 (0-516) 
Follow-up, mo   
    From onset of symptoms  69 (1.6-741.1) 
    From diagnosis of SM  20.7 (0-417.1) 
Clinical findings   
    Urticaria pigmentosa 140 (41)  
    Cutaneous symptoms* 182 (53)  
    Constitutional symptoms 142 (42)  
    Mediator-related symptoms 160 (47)  
    Idiopathic and/or recurrent anaphylactoid reaction 57 (17)  
    Musculoskeletal symptoms§ 107 (31)  
    Gastrointestinal symptoms 221 (65)  
Hepatosplenomegaly   
    Hepatomegaly, n = 342 92 (27)  
    Splenomegaly, n = 335 123 (37)  
    Both hepatomegaly and splenomegaly, n = 335 72 (21)  
Lymphadenopathy 73 (21)  
Leukemic transformation (AML or MCL) 21 (6)  
CharacteristicNo. of patients (%)Median (range)
Total no. of SM patients 342  
    ISM 159 (46)  
        Isolated bone marrow mastocytosis 36 (23)  
        Smoldering systemic mastocytosis 22 (14)  
    ASM 41 (12)  
    SM-AHNMD 138 (40)  
    MCL 4 (1)  
Male 188 (55)  
Age, y  57 (19-87) 
Time from appearance of symptoms to diagnosis of SM, mo  33 (0-516) 
Follow-up, mo   
    From onset of symptoms  69 (1.6-741.1) 
    From diagnosis of SM  20.7 (0-417.1) 
Clinical findings   
    Urticaria pigmentosa 140 (41)  
    Cutaneous symptoms* 182 (53)  
    Constitutional symptoms 142 (42)  
    Mediator-related symptoms 160 (47)  
    Idiopathic and/or recurrent anaphylactoid reaction 57 (17)  
    Musculoskeletal symptoms§ 107 (31)  
    Gastrointestinal symptoms 221 (65)  
Hepatosplenomegaly   
    Hepatomegaly, n = 342 92 (27)  
    Splenomegaly, n = 335 123 (37)  
    Both hepatomegaly and splenomegaly, n = 335 72 (21)  
Lymphadenopathy 73 (21)  
Leukemic transformation (AML or MCL) 21 (6)  

ISM indicates indolent systemic mastocytosis (SM); ASM, aggressive SM; SM-AHNMD, SM with associated clonal hematologic non–mast cell lineage disease; MCL, mast cell leukemia; AML, acute myeloid leukemia; and No., number.

*

Includes pruritus, flushing, urticaria, and angioedema.

Includes weight loss, fever, chills, and night sweats.

Includes headache, dizziness/lightheadedness, syncope/presyncope, hypotension, anaphylaxis, palpitation/tachycardia, bronchoconstriction/wheezing, and peptic ulcer disease.

§

Includes bone pain, arthralgias, and myalgias.

Includes nausea/vomiting, dyspepsia, dysphagia, diarrhea, constipation, abdominal pain/cramping, bloating/flatulence, early satiety, heartburn, gastrointestinal tract bleeding, malabsorption, and steatorrhea.

Either palpable or detected by imaging studies.

Table 2

Laboratory findings at referral of 342 patients with SM

LaboratoryNo. of patients (%)Median (range)
Hemoglobin, g/L 341 (99) 128 (51-174) 
    Hb < 100 64 (19) 90 (51-99) 
White blood cell count, ×109/L 340 (99) 7.6 (1.2-87.2) 
    WBC > 10 109 (32) 15.4 (10.1-87.2) 
    WBC 4-10 198 (58) 6.6 (4.1-10) 
Absolute neutrophil count, ×109/L 333 (97) 4.3 (0.2-42.5) 
Absolute monocyte count, ×109/L 333 (97) 0.4 (0-81) 
Absolute lymphocyte count, ×109/L 333 (97) 1.9 (0-15.8) 
Absolute eosinophil count, ×109/L 332 (97) 0.2 (0-38.4) 
    AEC 1.5 or more 49 (15) 3.8 (1.5-38.4) 
Platelet count, ×109/L 334 (98) 212 (2-1625) 
    PLT > 100 269 (81) 248 (101-1625) 
    PLT 50-100 39 (12) 73 (54-97) 
    PLT < 50 26 (8) 28 (2-46) 
Albumin, 35-50 g/L 265 (77) 39 (20-51) 
    Albumin < 35 51 (19) 31 (20-34) 
Total protein, 63-79 g/L 265 (77) 72 (47-94) 
    TP WNL 210 (79) 72 (63-79) 
Serum alkaline phosphatase, 45-115 U/L 318 (93) 181 (19-3680) 
    SAP > UNL 127 (40) 395 (111-3680) 
Aspartate aminotransferase, 8-48 U/L 320 (94) 18 (1-194) 
    AST > UNL 37 (12) 46 (32-194) 
Alanine aminotransferase, 7-55 U/L 99 (29) 20 (4-222) 
    ALT > UNL 10 (10) 82 (47-222) 
Total bilirubin, 1.71-17.1 μM 292 (85) 12 (1.71-133.4) 
    T bili > UNL 65 (22) 25.7 (18.8-133.4) 
Lactate dehydrogenase, 122-222 U/L 164 (48) 150.5 (11-926) 
    LDH > UNL 28 (17) 324.5 (213-926) 
Ferritin, 20-300 μg/L 105 (31) 215.9 (6-17 980) 
    Ferritin > UNL 47 (45) 658 (207-17 980) 
Serum tryptase, < 11.5 ng/mL 160 (47) 63.6 (3.7-2000) 
    Tryptase 11.5 or more 154 (96) 66.6 (11.9-2000) 
    Tryptase 200 or more 33 (21) 303 (200-2000) 
Urine histamine, < 35 μg/g Cr/24h 58 (17) 62.3 (12-985.6) 
    U histamine 35 or more 41 (71) 107.6 (36.7-985.6) 
Urine N-methylhistamine, 30-200 μg/g Cr 64 (19) 354.5 (5-5447) 
    U M-histamine > UNL 52 (81) 508.5 (98-5447) 
Urine beta prostaglandin F2α, 1000 ng or less/24 h 99 (29) 2215 (119-21 608) 
    U PGF2α > UNL 74 (75) 3262 (1132-21 608) 
LaboratoryNo. of patients (%)Median (range)
Hemoglobin, g/L 341 (99) 128 (51-174) 
    Hb < 100 64 (19) 90 (51-99) 
White blood cell count, ×109/L 340 (99) 7.6 (1.2-87.2) 
    WBC > 10 109 (32) 15.4 (10.1-87.2) 
    WBC 4-10 198 (58) 6.6 (4.1-10) 
Absolute neutrophil count, ×109/L 333 (97) 4.3 (0.2-42.5) 
Absolute monocyte count, ×109/L 333 (97) 0.4 (0-81) 
Absolute lymphocyte count, ×109/L 333 (97) 1.9 (0-15.8) 
Absolute eosinophil count, ×109/L 332 (97) 0.2 (0-38.4) 
    AEC 1.5 or more 49 (15) 3.8 (1.5-38.4) 
Platelet count, ×109/L 334 (98) 212 (2-1625) 
    PLT > 100 269 (81) 248 (101-1625) 
    PLT 50-100 39 (12) 73 (54-97) 
    PLT < 50 26 (8) 28 (2-46) 
Albumin, 35-50 g/L 265 (77) 39 (20-51) 
    Albumin < 35 51 (19) 31 (20-34) 
Total protein, 63-79 g/L 265 (77) 72 (47-94) 
    TP WNL 210 (79) 72 (63-79) 
Serum alkaline phosphatase, 45-115 U/L 318 (93) 181 (19-3680) 
    SAP > UNL 127 (40) 395 (111-3680) 
Aspartate aminotransferase, 8-48 U/L 320 (94) 18 (1-194) 
    AST > UNL 37 (12) 46 (32-194) 
Alanine aminotransferase, 7-55 U/L 99 (29) 20 (4-222) 
    ALT > UNL 10 (10) 82 (47-222) 
Total bilirubin, 1.71-17.1 μM 292 (85) 12 (1.71-133.4) 
    T bili > UNL 65 (22) 25.7 (18.8-133.4) 
Lactate dehydrogenase, 122-222 U/L 164 (48) 150.5 (11-926) 
    LDH > UNL 28 (17) 324.5 (213-926) 
Ferritin, 20-300 μg/L 105 (31) 215.9 (6-17 980) 
    Ferritin > UNL 47 (45) 658 (207-17 980) 
Serum tryptase, < 11.5 ng/mL 160 (47) 63.6 (3.7-2000) 
    Tryptase 11.5 or more 154 (96) 66.6 (11.9-2000) 
    Tryptase 200 or more 33 (21) 303 (200-2000) 
Urine histamine, < 35 μg/g Cr/24h 58 (17) 62.3 (12-985.6) 
    U histamine 35 or more 41 (71) 107.6 (36.7-985.6) 
Urine N-methylhistamine, 30-200 μg/g Cr 64 (19) 354.5 (5-5447) 
    U M-histamine > UNL 52 (81) 508.5 (98-5447) 
Urine beta prostaglandin F2α, 1000 ng or less/24 h 99 (29) 2215 (119-21 608) 
    U PGF2α > UNL 74 (75) 3262 (1132-21 608) 

g indicates grams; dL, deciliter; L, liter; UNL upper normal limit; WNL, within normal limits; U, units; μg, micrograms; mg, milligrams; ng, nanograms; Cr, creatinine; and No., number.

Table 3

Comparison of demographic, clinical, and laboratory characteristics between SM subgroups

CharacteristicNo. (%) of patientsMedian (range)ISMASMSM-AHNMDP for ISM vs ASMP for ASM vs AHNMDP for ISM vs AHNMDOverall P
Total no. of SM 342  159 (46) 41 (12) 138 (40)     
Demographic characteristics          
    Male 188 (55)  69 (43) 19 (46) 97 (70) NS .005 < .001 < .001 
    Age, y  57 (19-87) 49 (19-84) 65 (32-85) 65 (20-87) < .001 NS < .001 < .001 
    Time from symptoms to SM diagnosis, mo  33 (0-516) 72 (0-516) 18 (0.7-372) 15.1 (0.6-360) < .001 NS < .001 < .001 
Clinical characteristics          
    Urticaria pigmentosa 140 (41)  100 (63) 15 (37) 25 (18) .002 .01 < .001 < .001 
    Cutaneous symptoms* 182 (53)  119 (75) 20 (49) 42 (30) .001 .03 < .001 < .001 
    Constitutional symptoms 142 (42)  30 (19) 24 (59) 85 (62) < .001 NS < .001 < .001 
    Mediator-related symptoms 160 (47)  110 (69) 9 (22) 39 (28) < .001 NS < .001 < .001 
    Idiopathic and/or recurrent anaphylactoid reaction 57 (17)  53 (33) 2 (5) 2 (1) < .001 NS < .001 < .001 
    Musculoskeletal symptoms§ 107 (31)  48 (30) 17 (41) 41 (30) NS NS NS .3 
    Gastrointestinal symptoms 221 (65)  113 (71) 26 (63) 79 (57) NS NS .01 .05 
    Hepatomegaly 92 (27)  22 (14) 16 (39) 53 (38) < .001 NS < .001 < .001 
    Splenomegaly, N = 335 123 (37)  26 (17) 18 (44) 76 (57) < .001 NS < .001 < .001 
    Both hepatomegaly and splenomegaly, N = 335 72 (21)  15 (10) 13 (32) 43 (32) < .001 NS < .001 < .001 
    Lymphadenopathy 73 (21)  22 (14) 11 (27) 40 (29) .05 NS .001 .005 
B-findings 168 (49)  53 (33) 22 (54) 90 (65) .02 NS < .001 < .001 
    BM MC > 30% or serum tryptase > 200 ng/mL 60 (18)  23 (14) 9 (22) 26 (19) NS NS NS .4 
    Hypercellular BM or dysmyelopoiesis, without cytopenias 20 (6)  13 (8) 6 (15) n/a NS n/a n/a n/a 
    Hepatosplenomegaly and/or LNP without functional impairment 144 (42)  41 (26) 18 (44) 83 (60) .02 NS < .001 < .001 
C-findings 80 (23)  n/a 41 (100) 36 (26) n/a < .001 n/a n/a 
    BM dysfunction with cytopenia(s)# 17 (5)  n/a 13 (32) n/a n/a n/a n/a n/a 
    Hepatomegaly with functional impairment 31 (9)  n/a 11 (27) 20 (14) n/a NS n/a n/a 
    Splenomegaly with hypersplenism 27 (8)  n/a 9 (22) 16 (12) n/a NS n/a n/a 
    Osteolysis/pathological fractures 23 (7)  n/a 18 (44) 5 (4) n/a < .001 n/a n/a 
    Malabsorption with weight loss 3 (1)  n/a 2 (5) 1 (1) n/a NS n/a n/a 
    Leukemic transformation, AML or MCL 21 (6)  1 (< 1) 2 (5) 18 (13) NS NS < .001 < .001 
Laboratory characteristics          
    Hemoglobin, g/L 341 (99) 128 (51-174) 139 (81-167) 113 (51-165) 109 (64-174) < .001 NS < .001 < .001 
        Hb < normal 155 (45) 105 (51-134) 28 (18) 24 (59) 99 (72) < .001 NS < .001 < .001 
        Hb < 100 64 (19) 90 (51-99) 4 (3) 10 (24) 48 (35) < .001 NS < .001 < .001 
White blood cell count, ×109/L 340 (99) 7.6 (1.2-87.2) 6.6 (1.6-19.3) 8.2 (1.7-37.1) 10.2 (1.2-87.2) .01 NS < .001 < .001 
        WBC > 10 109 (32) 15.4 (10.1-87.2) 22 (14) 17 (41) 70 (51) < .001 NS < .001 < .001 
        WBC 4-10 198 (58) 6.6 (4.1-10) 124 (79) 21 (51) 50 (36) < .001 NS < .001 < .001 
ANC, ×109/L 333 (97) 4.3 (0.2-42.5) 4.2 (0.6-12.4) 4.2 (0.9-17.8) 4.8 (0.2-42.5) NS NS NS .3 
    ANC < 1.0 15 (5) 0.7 (0.2-1) 2 (1) 2 (5) 11 (8) NS NS .005 .02 
AMC, ×109/L 333 (97) 0.4 (0-81) 0.3 (0-81) 0.5 (0-5.2) 0.7 (0-11.2) .003 NS < .001 < .001 
ALC, ×109/L 333 (97) 1.9 (0-15.8) 1.9 (0.1-7.6) 1.9 (0.5-7.4) 1.7 (0.3-15.8) NS NS NS .5 
AEC, ×109/L 332 (97) 0.2 (0-38.4) 0.1 (0-2.1) 0.2 (0-9.2) 0.4 (0-38.4) .02 NS < .001 < .001 
    AEC 1.5 or more 49 (15) 3.8 (1.5-38.4) 2 (1) 10 (25) 37 (28) < .001 NS < .001 < .001 
Platelet count, ×109/L 334 (98) 212 (2-1625) 260 (39-570) 179 (20-561) 129 (2-1625) .001 NS < .001 < .001 
    PLT < 150 101 (30) 79 (2-149) 6 (4) 16 (39) 76 (55) < .001 NS < .001 < .001 
    PLT < 100 65 (19) 58 (2-97) 2 (1) 11 (27) 50 (37) < .001 NS < .001 < .001 
Albumin, 35-50 g/L 265 (77) 39 (20-51) 41 (30-51) 38 (20-48) 38 (20-49) < .001 NS < .001 < .001 
    Albumin < 35 51 (19) 31 (20-34) 10 (9) 10 (26) 29 (27) .005 NS .001 .001 
Total protein, 63-79 g/L 265 (77) 72 (47-94) 73 (60-89) 73 (55-85) 70 (47-94) NS NS .007 .03 
    WNL 210 (79) 72 (63-79) 101 (87) 28 (76) 78 (72) NS NS .006 .02 
SAP, 45-115 U/L 318 (93) 181 (19-3680) 142.5 (43-1957) 269.5 (33-3375) 206.5 (19-3680) < .001 NS < .001 < .001 
    SAP > UNL 127 (40) 395 (111-3680) 36 (25) 24 (60) 65 (50) < .001 NS < .001 < .001 
AST, 8-48 U/L 320 (94) 18 (1-194) 19 (1-194) 17 (6-93) 18 (5-185) NS NS NS 
    AST > UNL 37 (12) 46 (32-194) 10 (7) 5 (13) 22 (17) NS NS .008 .03 
ALT, 7-55 U/L 99 (29) 20 (4-222) 19.5 (6-117) 15 (4-122) 21.5 (7-222) NS NS NS .3 
    ALT > UNL 10 (10) 82 (47-222) 4 (7) 1 (9) 5 (16) NS NS NS .4 
Total bilirubin, 1.7-17.1 μM/L 292 (85) 12 (1.7-133.4) 10.3 (1.7-68.4) 12 (3.4-88.9) 13.7 (3.4-133.4) NS NS < .001 < .001 
    T bili > UNL 65 (22) 25.7 (18.8-133.4) 13 (11) 10 (28) 42 (32) .01 NS < .001 < .001 
LDH, 122-222 U/L 164 (48) 150.5 (11-926) 127 (11-283) 146 (97-390) 170.5 (46-926) NS NS < .001 < .001 
    LDH > UNL 28 (17) 324.5 (213-926) 2 (4) 1 (9) 25 (25) NS NS .001 .002 
Ferritin, 20-300 μg/L 105 (31) 215.9 (6-17 980) 81 (7-384) 332.5 (37-2244) 328 (6-17 980) .002 NS < .001 < .001 
    > UNL 47 (45) 658 (207-17 980) 5 (18) 7 (58) 34 (54) .02 NS .001 .004 
Serum tryptase, < 11.5 ng/mL 160 (47) 63.6 (3.7-2000) 53.6 (11.4-1410) 145 (10-2000) 75.4 (3.7-1360) .02 NS NS .03 
    Tryptase 11.5 or less 154 (96) 66.6 (11.9-2000) 89 (99) 14 (93) 49 (92) NS NS NS .08 
    Tryptase 200 or more 33 (21) 303 (200-2000) 11 (12) 6 (40) 15 (28) .007 NS .02 .009 
Urine histamine, < 35 μg/g Cr/24 h 58 (17) 62.3 (12-985.6) 49 (17-985.6) 210.1 (105-409) 85.6 (12-843) .01 NS NS .05 
    U histamine 35 or more 41 (71) 107.6 (36.7-985.6) 21 (62) 4 (100) 15 (79) NS NS NS .2 
Urine N-methylhistamine, 30-200 μg/g Cr 64 (19) 354.5 (5-5447) 335 (33-4156) 445 (37-775) 1332.5 (5-5447) NS NS NS .4 
    U M-histamine > UNL 52 (81) 508.5 (98-5447) 41 (80) 6 (86) 5 (83) NS NS NS .9 
Urine beta PGF2α, 1000 ng or less/24 h 99 (29) 2215 (119-21 608) 1880 (119-13 100) 1952 (184-21 608) 4083 (572-18 680) NS NS .007 .03 
    U PGF2α > UNL 74 (75) 3262 (1132-21 608) 50 (69) 9 (82) 14 (93) NS NS NS .1 
CharacteristicNo. (%) of patientsMedian (range)ISMASMSM-AHNMDP for ISM vs ASMP for ASM vs AHNMDP for ISM vs AHNMDOverall P
Total no. of SM 342  159 (46) 41 (12) 138 (40)     
Demographic characteristics          
    Male 188 (55)  69 (43) 19 (46) 97 (70) NS .005 < .001 < .001 
    Age, y  57 (19-87) 49 (19-84) 65 (32-85) 65 (20-87) < .001 NS < .001 < .001 
    Time from symptoms to SM diagnosis, mo  33 (0-516) 72 (0-516) 18 (0.7-372) 15.1 (0.6-360) < .001 NS < .001 < .001 
Clinical characteristics          
    Urticaria pigmentosa 140 (41)  100 (63) 15 (37) 25 (18) .002 .01 < .001 < .001 
    Cutaneous symptoms* 182 (53)  119 (75) 20 (49) 42 (30) .001 .03 < .001 < .001 
    Constitutional symptoms 142 (42)  30 (19) 24 (59) 85 (62) < .001 NS < .001 < .001 
    Mediator-related symptoms 160 (47)  110 (69) 9 (22) 39 (28) < .001 NS < .001 < .001 
    Idiopathic and/or recurrent anaphylactoid reaction 57 (17)  53 (33) 2 (5) 2 (1) < .001 NS < .001 < .001 
    Musculoskeletal symptoms§ 107 (31)  48 (30) 17 (41) 41 (30) NS NS NS .3 
    Gastrointestinal symptoms 221 (65)  113 (71) 26 (63) 79 (57) NS NS .01 .05 
    Hepatomegaly 92 (27)  22 (14) 16 (39) 53 (38) < .001 NS < .001 < .001 
    Splenomegaly, N = 335 123 (37)  26 (17) 18 (44) 76 (57) < .001 NS < .001 < .001 
    Both hepatomegaly and splenomegaly, N = 335 72 (21)  15 (10) 13 (32) 43 (32) < .001 NS < .001 < .001 
    Lymphadenopathy 73 (21)  22 (14) 11 (27) 40 (29) .05 NS .001 .005 
B-findings 168 (49)  53 (33) 22 (54) 90 (65) .02 NS < .001 < .001 
    BM MC > 30% or serum tryptase > 200 ng/mL 60 (18)  23 (14) 9 (22) 26 (19) NS NS NS .4 
    Hypercellular BM or dysmyelopoiesis, without cytopenias 20 (6)  13 (8) 6 (15) n/a NS n/a n/a n/a 
    Hepatosplenomegaly and/or LNP without functional impairment 144 (42)  41 (26) 18 (44) 83 (60) .02 NS < .001 < .001 
C-findings 80 (23)  n/a 41 (100) 36 (26) n/a < .001 n/a n/a 
    BM dysfunction with cytopenia(s)# 17 (5)  n/a 13 (32) n/a n/a n/a n/a n/a 
    Hepatomegaly with functional impairment 31 (9)  n/a 11 (27) 20 (14) n/a NS n/a n/a 
    Splenomegaly with hypersplenism 27 (8)  n/a 9 (22) 16 (12) n/a NS n/a n/a 
    Osteolysis/pathological fractures 23 (7)  n/a 18 (44) 5 (4) n/a < .001 n/a n/a 
    Malabsorption with weight loss 3 (1)  n/a 2 (5) 1 (1) n/a NS n/a n/a 
    Leukemic transformation, AML or MCL 21 (6)  1 (< 1) 2 (5) 18 (13) NS NS < .001 < .001 
Laboratory characteristics          
    Hemoglobin, g/L 341 (99) 128 (51-174) 139 (81-167) 113 (51-165) 109 (64-174) < .001 NS < .001 < .001 
        Hb < normal 155 (45) 105 (51-134) 28 (18) 24 (59) 99 (72) < .001 NS < .001 < .001 
        Hb < 100 64 (19) 90 (51-99) 4 (3) 10 (24) 48 (35) < .001 NS < .001 < .001 
White blood cell count, ×109/L 340 (99) 7.6 (1.2-87.2) 6.6 (1.6-19.3) 8.2 (1.7-37.1) 10.2 (1.2-87.2) .01 NS < .001 < .001 
        WBC > 10 109 (32) 15.4 (10.1-87.2) 22 (14) 17 (41) 70 (51) < .001 NS < .001 < .001 
        WBC 4-10 198 (58) 6.6 (4.1-10) 124 (79) 21 (51) 50 (36) < .001 NS < .001 < .001 
ANC, ×109/L 333 (97) 4.3 (0.2-42.5) 4.2 (0.6-12.4) 4.2 (0.9-17.8) 4.8 (0.2-42.5) NS NS NS .3 
    ANC < 1.0 15 (5) 0.7 (0.2-1) 2 (1) 2 (5) 11 (8) NS NS .005 .02 
AMC, ×109/L 333 (97) 0.4 (0-81) 0.3 (0-81) 0.5 (0-5.2) 0.7 (0-11.2) .003 NS < .001 < .001 
ALC, ×109/L 333 (97) 1.9 (0-15.8) 1.9 (0.1-7.6) 1.9 (0.5-7.4) 1.7 (0.3-15.8) NS NS NS .5 
AEC, ×109/L 332 (97) 0.2 (0-38.4) 0.1 (0-2.1) 0.2 (0-9.2) 0.4 (0-38.4) .02 NS < .001 < .001 
    AEC 1.5 or more 49 (15) 3.8 (1.5-38.4) 2 (1) 10 (25) 37 (28) < .001 NS < .001 < .001 
Platelet count, ×109/L 334 (98) 212 (2-1625) 260 (39-570) 179 (20-561) 129 (2-1625) .001 NS < .001 < .001 
    PLT < 150 101 (30) 79 (2-149) 6 (4) 16 (39) 76 (55) < .001 NS < .001 < .001 
    PLT < 100 65 (19) 58 (2-97) 2 (1) 11 (27) 50 (37) < .001 NS < .001 < .001 
Albumin, 35-50 g/L 265 (77) 39 (20-51) 41 (30-51) 38 (20-48) 38 (20-49) < .001 NS < .001 < .001 
    Albumin < 35 51 (19) 31 (20-34) 10 (9) 10 (26) 29 (27) .005 NS .001 .001 
Total protein, 63-79 g/L 265 (77) 72 (47-94) 73 (60-89) 73 (55-85) 70 (47-94) NS NS .007 .03 
    WNL 210 (79) 72 (63-79) 101 (87) 28 (76) 78 (72) NS NS .006 .02 
SAP, 45-115 U/L 318 (93) 181 (19-3680) 142.5 (43-1957) 269.5 (33-3375) 206.5 (19-3680) < .001 NS < .001 < .001 
    SAP > UNL 127 (40) 395 (111-3680) 36 (25) 24 (60) 65 (50) < .001 NS < .001 < .001 
AST, 8-48 U/L 320 (94) 18 (1-194) 19 (1-194) 17 (6-93) 18 (5-185) NS NS NS 
    AST > UNL 37 (12) 46 (32-194) 10 (7) 5 (13) 22 (17) NS NS .008 .03 
ALT, 7-55 U/L 99 (29) 20 (4-222) 19.5 (6-117) 15 (4-122) 21.5 (7-222) NS NS NS .3 
    ALT > UNL 10 (10) 82 (47-222) 4 (7) 1 (9) 5 (16) NS NS NS .4 
Total bilirubin, 1.7-17.1 μM/L 292 (85) 12 (1.7-133.4) 10.3 (1.7-68.4) 12 (3.4-88.9) 13.7 (3.4-133.4) NS NS < .001 < .001 
    T bili > UNL 65 (22) 25.7 (18.8-133.4) 13 (11) 10 (28) 42 (32) .01 NS < .001 < .001 
LDH, 122-222 U/L 164 (48) 150.5 (11-926) 127 (11-283) 146 (97-390) 170.5 (46-926) NS NS < .001 < .001 
    LDH > UNL 28 (17) 324.5 (213-926) 2 (4) 1 (9) 25 (25) NS NS .001 .002 
Ferritin, 20-300 μg/L 105 (31) 215.9 (6-17 980) 81 (7-384) 332.5 (37-2244) 328 (6-17 980) .002 NS < .001 < .001 
    > UNL 47 (45) 658 (207-17 980) 5 (18) 7 (58) 34 (54) .02 NS .001 .004 
Serum tryptase, < 11.5 ng/mL 160 (47) 63.6 (3.7-2000) 53.6 (11.4-1410) 145 (10-2000) 75.4 (3.7-1360) .02 NS NS .03 
    Tryptase 11.5 or less 154 (96) 66.6 (11.9-2000) 89 (99) 14 (93) 49 (92) NS NS NS .08 
    Tryptase 200 or more 33 (21) 303 (200-2000) 11 (12) 6 (40) 15 (28) .007 NS .02 .009 
Urine histamine, < 35 μg/g Cr/24 h 58 (17) 62.3 (12-985.6) 49 (17-985.6) 210.1 (105-409) 85.6 (12-843) .01 NS NS .05 
    U histamine 35 or more 41 (71) 107.6 (36.7-985.6) 21 (62) 4 (100) 15 (79) NS NS NS .2 
Urine N-methylhistamine, 30-200 μg/g Cr 64 (19) 354.5 (5-5447) 335 (33-4156) 445 (37-775) 1332.5 (5-5447) NS NS NS .4 
    U M-histamine > UNL 52 (81) 508.5 (98-5447) 41 (80) 6 (86) 5 (83) NS NS NS .9 
Urine beta PGF2α, 1000 ng or less/24 h 99 (29) 2215 (119-21 608) 1880 (119-13 100) 1952 (184-21 608) 4083 (572-18 680) NS NS .007 .03 
    U PGF2α > UNL 74 (75) 3262 (1132-21 608) 50 (69) 9 (82) 14 (93) NS NS NS .1 

ISM indicates indolent systemic mastocytosis (SM); ASM, aggressive SM; SM-AHNMD, SM with associated clonal hematologic non–mast cell lineage disease; MCL, mast cell leukemia; AML, acute myeloid leukemia; No., number; BM, bone marrow; ANC, absolute neutrophil count; AMC, absolute monocyte count; ALC, absolute lymphocyte count; AEC, absolute eosinophil count; LNP, lymphadenopathy; SAP, serum alkaline phosphatase; AST, aspartate transaminase; ALT, alanine transaminase; LDH, lactate dehydrogenase; PG prostaglandin; g, grams; dL, deciliter; L, liter; UNL upper normal limit; WNL, within normal limits; U, units; μg, micrograms; mg, milligrams; ng, nanograms; Cr, creatinine; NS, not significant; and n/a, not applicable.

*, †, ‡, §, ‖, and ¶, please see Table 1 legend.

#

Absolute neutrophil count < 1.0 ×109/L; hemoglobin < 100 g/L; or platelet count < 100 ×109/L.

Approximately one-third and one-quarter of SM-AHNMD and ASM patients, respectively, had significant anemia (Hgb < 100 g/L [10 g/dL]) and thrombocytopenia (platelets < 100 × 109/L), and 51% of SM-AHNMD patients exhibited leukocytosis (P < .001). Fifty-six (16%) patients exhibited prominent eosinophilia (absolute eosinophil count > 1.5 × 109/L [1500/μL]): 31% and 22% with SM-AHNMD and ASM, respectively, versus 3% with ISM (P < .001). Relatively few ISM patients exhibited increased levels of serum uric acid (3%), lactate dehydrogenase (4%), bilirubin (11%), or ferritin (18%); or hypoalbuminemia (9%)—in contrast, a 2- to 3-fold greater proportion of SM-AHNMD and ASM patients displayed these laboratory abnormalities (P ≤ .004). Serum tryptase (normal < 11.5 ng/mL) was measured in 160 patients (47%), and virtually all (96%) had an elevated level (median 64 ng/mL; range 4 to 2000 ng/mL). A greater proportion of ASM and SM-AHNMD patients exhibited a serum tryptase level 200 ng/mL or higher compared with ISM patients (P = .009).

Bone marrow histology

Bone marrow histopathologic findings are described in Table 4. The median BM cellularity for the ISM, ASM, SM-AHNMD, and MCL subgroups was 50% (range 20%-100%), 75%, (30%-100%) 90%, (30%-100%), and 88%, (80%-95%), respectively (P < .001). The median BM MC percentage for the whole group of patients was 10% (range 1%-90%) and was significantly (P = .003) higher in MCL (median, 75%; range, 60%-90%) compared with ASM (median, 13%; range, 1%-70%), SM-AHNMD (median, 11%; range, 1%-70%), or ISM (median, 10%; range, 1%-90%). All 27 patients with BM blasts 5% or more were diagnosed with SM-AHNMD (9 had refractory anemia with excess blasts-2 [RAEB-2]; 7, chronic myelomonocytic leukemia-1 [CMML-1]; 4, myeloproliferative neoplasm (MPN)-unclassifiable; 2, RAEB-1; 2, AML-M2; 1, CMML-2; 1, chronic eosinophilic leukemia; and 1, essential thrombocythemia).

Table 4

Bone marrow histopathologic findings at referral of 342 patients with SM

Bone marrow characteristicsNo (%) of patientsMedian (range)ISMASMSM-AHNMDP
BM cellularity corrected for age, N = 327  70 (20-100) 50 (20-100) 75 (30-100) 90 (30-100) < .001 
    High 200 (61)  49 (32) 24 (67) 123 (91)  
    Normal 108 (33)  88 (58) 9 (25) 11 (8)  
    Low 19 (6)  15 (10) 3 (8) 1 (1)  
BM % MC, N = 299  10 (1-90) 10 (1-90) 13 (1-70) 11 (1-70) .2 
    BM MC < 10 109 (36)  58 (41) 9 (26) 42 (35) .1 
    BM MC 10-30 151 (51)  68 (48) 17 (50) 66 (55)  
    BM MC > 30 39 (13)  15 (11) 8 (24) 12 (10)  
BM MC nuclear morphology, N = 259      .002 
    Oval 191 (74)  87 (78) 21 (66) 82 (73)  
    Elongated 48 (19)  24 (22) 7 (22) 17 (15)  
    Indented/lobulated 16 (6)  3 (9) 10 (9)  
    Round 4 (2)  1 (3) 3 (3)  
BM MC granularity, N = 243       
    Normal to > 50% 164 (67)  86 (82) 16 (50) 61 (60) < .001 
BM % blast, N = 342      < .001 
    BM blast < 5 315 (92)  159 (100) 41 (100) 111 (80)  
    BM blast 5-10 16 (5)  16 (12)  
    BM blast > 10 11 (3)  11 (8)  
BM eosinophil infiltration grade, N = 257      < .001 
    Absent 27 (11)  8 (7) 5 (16) 11 (10)  
    Minimal to moderate 207 (81)  99 (91) 25 (78) 82 (73)  
    Intense 23 (9)  2 (2) 2 (6) 19 (17)  
BM fibrosis grade, N = 122       
    2+ or more 44 (36)  5 (14) 8 (47) 31 (46) .004 
BM MC immunophenotype (flow cytometry), N = 70       
    CD2 positivity 38 (54)  27 (66) 4 (50) 7 (33) .05 
    CD25 positivity 65 (93)  39 (95) 8 (100) 18 (86) .4 
BM MC immunophenotype (immunohistochemistry)       
    CD2 positivity, N = 18 3 (17)  2 (15) n/a 1 (20) n/a 
    CD25 positivity, N = 23 23 (100)  15 (100) n/a 8 (100) n/a 
Bone marrow characteristicsNo (%) of patientsMedian (range)ISMASMSM-AHNMDP
BM cellularity corrected for age, N = 327  70 (20-100) 50 (20-100) 75 (30-100) 90 (30-100) < .001 
    High 200 (61)  49 (32) 24 (67) 123 (91)  
    Normal 108 (33)  88 (58) 9 (25) 11 (8)  
    Low 19 (6)  15 (10) 3 (8) 1 (1)  
BM % MC, N = 299  10 (1-90) 10 (1-90) 13 (1-70) 11 (1-70) .2 
    BM MC < 10 109 (36)  58 (41) 9 (26) 42 (35) .1 
    BM MC 10-30 151 (51)  68 (48) 17 (50) 66 (55)  
    BM MC > 30 39 (13)  15 (11) 8 (24) 12 (10)  
BM MC nuclear morphology, N = 259      .002 
    Oval 191 (74)  87 (78) 21 (66) 82 (73)  
    Elongated 48 (19)  24 (22) 7 (22) 17 (15)  
    Indented/lobulated 16 (6)  3 (9) 10 (9)  
    Round 4 (2)  1 (3) 3 (3)  
BM MC granularity, N = 243       
    Normal to > 50% 164 (67)  86 (82) 16 (50) 61 (60) < .001 
BM % blast, N = 342      < .001 
    BM blast < 5 315 (92)  159 (100) 41 (100) 111 (80)  
    BM blast 5-10 16 (5)  16 (12)  
    BM blast > 10 11 (3)  11 (8)  
BM eosinophil infiltration grade, N = 257      < .001 
    Absent 27 (11)  8 (7) 5 (16) 11 (10)  
    Minimal to moderate 207 (81)  99 (91) 25 (78) 82 (73)  
    Intense 23 (9)  2 (2) 2 (6) 19 (17)  
BM fibrosis grade, N = 122       
    2+ or more 44 (36)  5 (14) 8 (47) 31 (46) .004 
BM MC immunophenotype (flow cytometry), N = 70       
    CD2 positivity 38 (54)  27 (66) 4 (50) 7 (33) .05 
    CD25 positivity 65 (93)  39 (95) 8 (100) 18 (86) .4 
BM MC immunophenotype (immunohistochemistry)       
    CD2 positivity, N = 18 3 (17)  2 (15) n/a 1 (20) n/a 
    CD25 positivity, N = 23 23 (100)  15 (100) n/a 8 (100) n/a 

ISM indicates indolent systemic mastocytosis (SM); ASM, aggressive SM; SM-AHNMD, SM with associated clonal hematologic non–mast cell lineage disease; %, percentage; BM, bone marrow; MC, mast cell; No., number; and n/a, not accessed or not applicable.

Cytogenetic and molecular studies

Cytogenetic data were available for 186 (54%) patients, 37 of whom (20%) had chromosomal aberrations (excluding 5 patients with sole deletion of chromosome Y). Recurrent chromosomal abnormalities included trisomy 8, monosomy 7, del(13q), del(5q), trisomy 10, del(20q), trisomy 6, trisomy 19, and trisomy X. Abnormal karyotype was more frequently detected in SM-AHNMD (31%) and ASM (20%), as opposed to ISM (5%; P < .001). All 7 patients with more than one chromosomal abnormality had SM-AHNMD. Fifty-six patients displayed prominent eosinophilia; 52% of 23 patients screened for FIP1L1-PDGFRA and 62% of 34 patients screened for KITD816V carried the mutation. Eight patients with eosinophilia were screened for FIP1L1-PDGFRA and KITD816V: there were no instances of concomitant presence of these mutations. Archived bone marrow was available in 165 (48%) patients for KITD816V and JAK2V617F analysis. By allele-specific PCR, KITD816V mutation was detected in 113 patients (68%): ISM, 78%; ASM, 82%; and SM-AHNMD, 60% (P = .03). The sole MCL leukemia patient who was tested did not harbor this mutation. JAK2V617F mutation was detected (mutant allele burden > 1%) in 6 patients (4%); all had SM-AHNMD, including 4 with non-MC lineage myeloproliferative neoplasm. Five (83%) of the 6 patients harbored KITD816V and JAK2V617F mutations concomitantly.

Survival studies and leukemic transformation

After a median follow-up of 20.7 months (range = 0-417 months), 153 (45%) deaths were recorded (26 ISM, 25 ASM, 99 SM-AHNMD, 3 MCL). The median survival of the cohort was 63 months, which is inferior compared with the age- and sex-matched US population (Figure 1A). Survival in patients with ISM (median, 198 months) was superior (P < .001) to that of patients with ASM (median, 41 months), SM-AHNMD (median, 24 months), or MCL (median, 2 months) and not significantly different from that of the control population (Figure 1B). Information regarding the cause of death was available for 13 (50%) of the 26 ISM patients: disease progression to ASM (n = 3), development of solid tumors (n = 3), comorbid cardiovascular conditions (n = 3), complications from massive MC mediator release (n = 2), acute myeloid leukemia (n = 1), and infection (n = 1). Among 21 (6%) cases of leukemic transformation in the overall cohort (18 with AML and 3 MCL), 18 (86%) occurred in the setting of SM-AHNMD; 2, ASM; and 1, ISM (P < .001; Table 3).

Figure 1

Survival of systemic mastocytosis patients. (A) The observed Kaplan-Meier survival for systemic mastocytosis patients (red) compared with the expected age- and sex-matched US population's survival (blue). (B) The observed Kaplan-Meier survival for systemic mastocytosis patients classified by disease type ISM (red), ASM (green), AHNMD (yellow), and MCL (purple) compared with the expected age- and sex-matched US population's survival (blue) for the entire cohort.

Figure 1

Survival of systemic mastocytosis patients. (A) The observed Kaplan-Meier survival for systemic mastocytosis patients (red) compared with the expected age- and sex-matched US population's survival (blue). (B) The observed Kaplan-Meier survival for systemic mastocytosis patients classified by disease type ISM (red), ASM (green), AHNMD (yellow), and MCL (purple) compared with the expected age- and sex-matched US population's survival (blue) for the entire cohort.

Prognostic factors

In addition to specific diagnosis based on the WHO proposal, other demographic, clinical, and laboratory variables were examined for their prognostic relevance (Table 5). In this regard, the pitfalls of considering multiple variables must be kept in mind and certain variables (eg, splenomegaly, hypoalbuminemia; identified by § in Table 5) represent B- or C-findings and are therefore already accounted for in the WHO classification. Multivariable analysis showed a significant and independent association between inferior survival and WHO subtype (P < .001), advanced age (P < .001), history of weight loss (P = .01), anemia (P = .007), thrombocytopenia (P < .001), hypoalbuminemia (P < .001), and excess BM blasts (> 5%; P = .004).

Table 5

Unfavorable prognostic factors in SM by univariate analysis

Prognostic factorNo. of patientsNo. of deathsMedian survival, moP, log-rank test
Age, y     
    Younger than 65 222 64 163 < .001 
    65 or older 120 89 24  
Sex     
    Female 154 60 136 .001 
    Male 188 93 45  
WHO variant     
    ISM 159 26 198 < .001 
    ASM 41 25 41  
    SM-AHNMD 138 99 24  
    MCL  
Symptoms and signs     
    Urticaria pigmentosa     
        No 202 113 34 < .001 
        Yes 140 40 163  
    Cutaneous symptoms*     
        No 160 95 34 < .001 
        Yes 182 58 146  
    Constitutional symptoms     
        No 200 57 145 < .001 
        Yes 142 96 20  
    Mediator-related symptoms     
        No 182 103 41 < .001 
        Yes 160 50 146  
    Weight loss     
        No 224 67 136 < .001 
        Yes 118 86 17  
    Splenomegaly§     
        No 212 60 156 < .001 
        Yes 123 88 25  
    Hepatomegaly§     
        No 250 87 96 < .001 
        Yes 92 66 30  
    Lymphadenopathy§     
        No 269 109 82 .005 
        Yes 73 44 38  
Laboratory findings     
    Anemia     
        No 186 45 165 < .001 
        Yes 155 108 20  
    Thrombocytopenia     
        No 233 70 136 < .001 
        Yes 101 78 15  
    Leukocytosis     
        No 231 82 136 < .001 
        Yes 109 71 25  
    Absolute eosinophil count 1.5 × 109/L or more     
        No 283 115 75 < .001 
        Yes 49 34 18  
    PB immature myeloid cells     
        No 244 79 136 < .001 
        Yes 89 71 13  
    Ferritin level > 300 μg/L     
        No 58 25 66 < .001 
        Yes 47 36 17  
    SAP > UNL     
        No 191 66 119 < .001 
        Yes 127 81 24  
    AST > UNL     
        No 283 123 69 .004 
        Yes 37 22 24  
    Hypoalbuminemia§     
        No 215 98 82 < .001 
        Yes 50 34 12  
    LDH > UNL     
        No 136 60 57 .008 
        Yes 28 20 20  
    Total bilirubin > 18.8 μM/L     
        No 237 101 82 < .001 
        Yes 55 41 15  
    Serum tryptase level > 200 ng/mL     
        No 127 20 136 < .001 
        Yes 33 19 30  
Bone marrow findings     
    BM cellularity§     
        Low 19 NR < .001 
        Normal 108 13 295  
        High§ 200 128 30  
    BM MC 30% or more§     
        No 235 82 96 < .001 
        Yes 64 45 30  
    BM blasts 5% or more     
        No 315 131 72 < .001 
        Yes 27 22 11  
    BM fibrosis grade 2+ or more     
        No 78 41 61 < .001 
        Yes 44 32 18  
    Karyotype     
        Normal 144 68 53 .002 
        Abnormal 42 33 13  
Prognostic factorNo. of patientsNo. of deathsMedian survival, moP, log-rank test
Age, y     
    Younger than 65 222 64 163 < .001 
    65 or older 120 89 24  
Sex     
    Female 154 60 136 .001 
    Male 188 93 45  
WHO variant     
    ISM 159 26 198 < .001 
    ASM 41 25 41  
    SM-AHNMD 138 99 24  
    MCL  
Symptoms and signs     
    Urticaria pigmentosa     
        No 202 113 34 < .001 
        Yes 140 40 163  
    Cutaneous symptoms*     
        No 160 95 34 < .001 
        Yes 182 58 146  
    Constitutional symptoms     
        No 200 57 145 < .001 
        Yes 142 96 20  
    Mediator-related symptoms     
        No 182 103 41 < .001 
        Yes 160 50 146  
    Weight loss     
        No 224 67 136 < .001 
        Yes 118 86 17  
    Splenomegaly§     
        No 212 60 156 < .001 
        Yes 123 88 25  
    Hepatomegaly§     
        No 250 87 96 < .001 
        Yes 92 66 30  
    Lymphadenopathy§     
        No 269 109 82 .005 
        Yes 73 44 38  
Laboratory findings     
    Anemia     
        No 186 45 165 < .001 
        Yes 155 108 20  
    Thrombocytopenia     
        No 233 70 136 < .001 
        Yes 101 78 15  
    Leukocytosis     
        No 231 82 136 < .001 
        Yes 109 71 25  
    Absolute eosinophil count 1.5 × 109/L or more     
        No 283 115 75 < .001 
        Yes 49 34 18  
    PB immature myeloid cells     
        No 244 79 136 < .001 
        Yes 89 71 13  
    Ferritin level > 300 μg/L     
        No 58 25 66 < .001 
        Yes 47 36 17  
    SAP > UNL     
        No 191 66 119 < .001 
        Yes 127 81 24  
    AST > UNL     
        No 283 123 69 .004 
        Yes 37 22 24  
    Hypoalbuminemia§     
        No 215 98 82 < .001 
        Yes 50 34 12  
    LDH > UNL     
        No 136 60 57 .008 
        Yes 28 20 20  
    Total bilirubin > 18.8 μM/L     
        No 237 101 82 < .001 
        Yes 55 41 15  
    Serum tryptase level > 200 ng/mL     
        No 127 20 136 < .001 
        Yes 33 19 30  
Bone marrow findings     
    BM cellularity§     
        Low 19 NR < .001 
        Normal 108 13 295  
        High§ 200 128 30  
    BM MC 30% or more§     
        No 235 82 96 < .001 
        Yes 64 45 30  
    BM blasts 5% or more     
        No 315 131 72 < .001 
        Yes 27 22 11  
    BM fibrosis grade 2+ or more     
        No 78 41 61 < .001 
        Yes 44 32 18  
    Karyotype     
        Normal 144 68 53 .002 
        Abnormal 42 33 13  

No. indicates number; ISM indicates indolent systemic mastocytosis (SM); ASM, aggressive SM; SM-AHNMD, SM with associated clonal hematologic non–mast cell lineage disease; MCL, mast cell leukemia; dL, deciliter; L, liter; UNL upper normal limit; μg, micrograms; mg, milligrams; ng, nanograms; AST, aspartate transaminase; SAP, serum alkaline phosphatase; LDH, lactate dehydrogenase; BM, bone marrow; MC, mast cell; and NR, not reached.

*

Includes pruritus, flushing, urticaria, and angioedema.

Includes weight loss, fever, chills, and night sweats.

Includes headache, dizziness/lightheadedness, syncope/presyncope, hypotension, anaphylaxis, palpitation/tachycardia, bronchoconstriction/wheezing, and peptic ulcer disease.

§

Represent B- or C-findings per the 2001 WHO classification of SM.

Discussion

To our knowledge, the current study is the largest SM series reported in the literature. The clinical findings pertain to an adult SM population with bone marrow histology–confirmed disease that was seen at a tertiary care center. Consequently, extrapolation to an SM population identified primarily on the basis of UP-like skin lesions, or one that includes pediatric patients, may not be valid.

Consistent with previous studies, the current cohort had a slight male preponderance; the relatively long duration between onset of symptoms and diagnosis is consistent with absence of UP-like skin lesions in a majority of patients, and also to the referral nature of our practice. The life expectancy of SM patients was shorter relative to age- and sex-matched controls. As initially observed by Travis et al,2  survival decreased rapidly after diagnosis: to 60% at 3 years, with a subsequent slower decline to 50% at 5 years. Beyond 5 years, the slope of the survival curve was similar to that of the control population. This observation confirms that the excess deaths in SM patients occur within the first 3 (and up to 5) years after diagnosis.

The current study validates the prognostic relevance of the WHO classification for SM. Patients with ISM have a significantly better prognosis in terms of overall survival and leukemia-free survival compared with ASM and SM-AHNMD patients. Furthermore, the life expectancy of ISM patients was not significantly different from the age- and sex-matched US population for the appropriate time period based on the diagnosis date. Furthermore, leukemic transformation rarely occurs in ISM patients. In contrast, the median survival of SM-AHNMD and ASM patients was 2 and 3.5 years, respectively; MCL patients, not surprisingly, had the poorest prognosis with median survival of 2 months. These data are clinically relevant and serve as a basis for guiding therapeutic decisions in SM patients. It supports the view that, in general, therapy for ISM ought to be symptom directed and potentially immunosuppressive and leukemogenic therapies are best avoided in these patients given the relatively good prognosis and normal life expectancy.19,20  For patients with ASM or MCL, or the rare ISM patient with recurrent severe anaphylaxis or syncope not responding to conventional approaches, the goal of therapy is to reduce the systemic MC burden. Published data suggest that interferon-alpha and 2-chlorodeoxyadenosine (2-CdA) have significant inhibitory activity against the malignant MC clone, however both agents are plagued by problems, namely, poor tolerability and uncertainty regarding optimal dose/duration of therapy (IFN-α), or potential mutagenic effects, myelosuppression, and immunosuppression (2-CdA).21,22  Imatinib is relatively ineffective in KITD816V-positive SM,23  however may have activity in the rare SM case with other KIT mutations (eg, KITF522C),24  or in patients with eosinophilia and MC proliferation who harbor the FIP1L1-PDGFRA mutation.25-27  Preliminary data suggest that dasatinib has limited therapeutic activity in SM28,29 ; however, its role in combination with chemotherapeutic agents is under active investigation.30,31 

In the WHO proposal, “B-” and “C-”findings serve as surrogate markers for a high MC burden, and impaired organ function resulting therefrom, respectively, and are used to classify SM patients. Given that B- and C-findings have been defined somewhat arbitrarily (for instance, is Hgb < 100 g/L [10 g/dL] as prognostically relevant as Hgb < 80 g/L [8 g/dL], or Hgb < normal? Similarly, is presence of pathologic fracture as prognostically relevant as hypoalbuminemia?), we conducted a multivariate analysis to identify those variables that may have prognostic relevance within the context of the WHO subgroups. Among the demographic variables, advanced age (≥ 65 years) was independently associated with shorter survival. Anemia and thrombocytopenia were also independently associated with shorter survival; notably, the threshold for identifying poor risk patients was lower than the corresponding C-findings (defined as hemoglobin < 100 g/L [10 g/dL] and platelet count < 100 × 109/L). Weight loss and hypoalbuminemia were also independently associated with shorter survival regardless of whether this resulted from malabsorption. Among the histologic variables, only excess BM blasts (> 5%) was independently associated with shorter survival. It has been reported that the percentage of MCs in BM smears may distinguish between clinical variants of SM32 ; this aspect was not examined in our study because MCs were quantified only in trephine biopsy specimens.

In the current analysis, prevalence of KITD816V using a sensitive (0.01%) assay was broadly consistent with published data,11  considering our use of DNA from unfractionated BM cells. Detection of KITD816V was not significant in the survival analysis; however, the mutation was significantly associated with presence of C-findings (83% vs 64%; P = .03) and higher BM MC burden (median, 13% vs 10%; P = .01). JAK2V617F was infrequently detected in SM patients and appeared to be restricted to SM-AHNMD, where it frequently coexisted with KITD816V. In contrast, none of the FIP1L1-PDGFRA–positive patients in our cohort harbored KITD816V, an observation that is consistent with the complete clinical and histologic responses seen with imatinib therapy in these patients.

In summary, we have described the clinical, laboratory, and BM histologic features at presentation in a large cohort of adult SM patients. Survival of this cohort is shorter relative to an age- and sex-matched control population. When patients are classified into WHO subgroups, there are significant differences in disease characteristics. ISM patients have a normal life expectancy and leukemic transformation is rarely seen in these patients; in contrast, the other SM subgroups have a significantly poorer prognosis. We have validated the prognostic relevance of the WHO proposal for SM, and have identified additional risk factors (advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts) that are significantly associated with shorter survival.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Acknowledgments

We acknowledge the contribution of Diane Grill in the Biostatistics Division, Mayo Clinic, for generating the survival curves.

Authorship

Contribution: K.-H.L. collected and analyzed the data and wrote the paper; A.T. designed the study, analyzed the data, and wrote the paper; T.L.L. and C.F. performed the molecular analysis; M.P. and J.H.B. collected and analyzed the data; R.F.M. performed the KIT mutation analysis; C.-Y.L. performed the bone marrow histology analysis; and A.P. designed the study, analyzed the data, and wrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: A. Pardanani, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: pardanani.animesh@mayo.edu.

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