ABSTRACT
The current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO‐HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM‐AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO‐defined mast cell leukemia (MCL; N = 13), which included mast cells with both “mature” and “immature” morphology. The ICC‐defined subcategories were mostly similar with the exception that SM‐AHN was replaced by SM associated with another myeloid neoplasm (SM‐AMN; N = 235) and WHO‐defined MCL was replaced by ICC‐defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO‐defined MCL (median 1.8 years) vs. SM‐AHN (median 2.3 years; p = 0.3) but significantly different between ICC‐defined MCL (median 0.08 years) vs. SM‐AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC‐defined SM‐AMN and SM associated with lymphoid neoplasm (SM‐ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter‐independent prognostic contributions of both ICC‐defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO‐HAEM5‐defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO‐HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.
Keywords: advanced, aggressive, indolent, leukemia, smoldering
Overall survival data among 910 Mayo Clinic patients with systemic mastocytosis stratified by the International Consensus Classification (ICC) and the Mayo Alliance Prognostic Scoring System (MAPS).
1. Introduction
Mast cells (MCs) originate from hematopoietic stem cells through successive differentiation from common myeloid, granulocyte‐monocyte, and basophil‐mast cell progenitors [1]. MCs in humans reside in the bone marrow (BM) and other tissues, including the spleen, lung, and gastrointestinal mucosae. Mastocytosis refers to a neoplastic proliferation of morphologically and immunophenotypically abnormal MCs with accumulation in one or more organ systems, which almost always include the BM in adults. Mastocytosis is broadly categorized into systemic mastocytosis (SM) [2], cutaneous mastocytosis (CM) [3], and mast cell sarcoma [4]. SM is, in turn, classified into multiple subtypes by the International Consensus (ICC) [5] and World Health Organization (WHO) [6] classification systems. Both the ICC (2025) [7] and WHO‐HAEM5 (2024) [6] are revisions of the immediately preceding revised 4th edition of the WHO classification of hematopoietic tumors (WHO‐HAEM4R; 2016) [8].
SM is broadly classified into advanced (SM‐Adv) and non‐advanced (SM‐non‐Adv) variants, while subcategories of each are listed differently under the ICC [5, 7] versus WHO [6, 8] classification systems [9]. The ICC‐recognized subcategories of SM‐non‐Adv include indolent (ISM) and smoldering (SSM) SM, while the corresponding list according to WHO‐HAEM5 includes ISM, SSM, and a third subcategory labeled as bone marrow mastocytosis (BMM). Subclassification of SM‐Adv is also different between the ICC and WHO‐HAEM5: (i) mast cell leukemia (MCL), according to both the ICC and WHO‐HAEM5, is defined by the presence of ≥ 20% mast cells in the BM aspirate smear; however, the ICC but not WHO‐HAEM5 requires, in addition, “immature” mast cell cytomorphology (e.g., promastocytes, metachromatic blasts, multinucleated/highly pleomorphic MCs), (ii) SM with an associated hematological neoplasm (SM‐AHN), encompassing both myeloid and lymphoid neoplasms, per WHO‐HAEM5, or SM with associated myeloid neoplasm (SM‐AMN), per ICC, (iii) aggressive SM (ASM) is similarly defined by the ICC and WHO‐HAEM and requires the presence of MC‐associated organopathy.
We have recently reported on the prognostic relevance of distinguishing “MCL‐immature” (ICC‐defined MCL) from “MCL‐mature” (WHO‐defined MCL) [10, 11]. These observations were commensurate with a Mayo Clinic report from 2009 that showed a dismal outcome in patients with MCL‐immature while life expectancy in those with ISM/SSM was comparable to that of the general population [12]. Also in the recent past, we published on 329 Mayo Clinic patients with SM‐Adv and showed significant differences in survival between patients with ICC‐defined MCL‐mature and MCL‐immature and SM‐AMN and SM‐ALN [13]. The particular study also considered the Mayo Alliance Prognostic System (MAPS) for SM [14], in order to examine independent prognostic contributions. The MAPS clinical model includes (i) age > 60 years, (ii) anemia (hemoglobin level below the lower limit of normal, adjusted for sex), (iii) thrombocytopenia (platelet count < 150 × 109/L), (iv) elevated serum alkaline phosphatase (ALP) level (above the upper limit of normal), and (v) advanced versus non‐advanced SM. The main objective of the current study was to utilize a large Mayo Clinic series of patients with SM (N = 910), in order to examine the prognostic relevance of the ICC versus WHO‐HAEM5 classification of SM, as well as that of the MAPS, in context with each other.
2. Methods
This study was conducted in accordance with the approval granted by the institutional review board (IRB). Patient data were retrospectively reviewed through the Mayo Clinic hematopathology and institutional electronic database, with the dataset recently updated in November 2024. The current study included SM cases diagnosed from 1968 to 2024, covering five decades. Diagnoses of systemic mastocytosis and its morphological subcategories were confirmed through clinical evaluations, and patients were required to have BM pathology reviewed at the Mayo Clinic. Diagnostic criteria were according to WHO‐HAEM4R; 2016 [8]. Additionally, we used current ICC [5] and WHO‐HAEM5 [8] in order to re‐categorize patient groups for comparative analysis; in the process, WHO‐defined MCL was subclassified into ICC‐defined MCL (immature cytomorphology) and WHO‐defined MCL (with mature or immature cytomorphology) with the latter being assigned to ASM or ISM/SMM, as dictated by the presence or absence of C findings. Next‐generation sequencing was performed in a subset of the study population, following previously described methodologies [15].
Statistical analyses were conducted on clinical and laboratory data collected at the time of the initial diagnosis. Overall survival was defined as the duration from diagnosis to death (from of all causes) or the end of follow‐up (censored observations). The probability of survival was estimated using the Kaplan–Meier product limit method, and univariate and multivariate analyses were performed by the Cox proportional hazards regression model. All statistical calculations, including survival analysis and risk factor determination, were conducted using JMP Pro version 18.0.2 (SAS Institute, Cary, NC, USA).
3. Results
A total of 910 patients with SM (median age 56 years, range 12–89; males 50%) were seen at the Mayo Clinic from 1968 to 2024 and confirmed to meet the WHO‐HAEM4R diagnostic criteria for SM (Tables 1 and 2) [8]. WHO‐HAEM5‐defined subcategories included ISM/SSM (n = 518; 57%), ASM (n = 106; 12%), SM‐AHN (n = 273; 30%), and MCL (n = 13; 1%) [16]. Recategorization of study patients according to the ICC included ISM/SSM (n = 552; 61%), ASM (n = 115; 12%), SM‐AMN (n = 235; 26%), and MCL (n = 8; 1%) [5]. Considering all study patients, median (range) values were 13.2 g/dL (5.1–18.4) for hemoglobin, 7 × 109/L (0.3–73.4) for leukocyte count, 232 × 109/L (2–1625) for platelet count, 4 g/dL (2–5.2) for serum albumin, and 106 U/L (19–3680) for serum alkaline phosphatase (ALP). BM MC percentage, among 656 evaluable cases, was < 5% in 10% of patients, 5%–10% in 53%, 11%–50% in 30%, and > 50% in 7%. Serum tryptase level was available in 664 patients and showed values of < 20 ng/mL in 21% of patients, 20–200 ng/mL in 68%, and > 200 ng/mL in 11%. Palpable hepatomegaly and splenomegaly were seen in 15% and 25% of patients, respectively. NGS information was available in 240 patients, with the most frequent mutations encountered being KITD816V (81%), TET2 (39%), ASXL1 (17%), CBL (14%), DNMT3A 11%, SRSF2 10%, SF3B1 9%, TP53 (8%), IDH2 (5%), RUNX1 (5%), IDH1 (3%), EZH2 (3%), and NRAS (2%). Cytogenetic information was available in 574 cases and showed abnormal karyotype in 13% (Tables 1 and 2). Median follow‐up was 3.9 years (range 0–43.3); during this period, 345 (38%) deaths and 35 (4%) leukemic transformations were documented.
TABLE 1.
Clinical and laboratory findings of 910 patients with systemic mastocytosis (SM), stratified by the types of SM according to the WHO classification: Indolent systemic mastocytosis/smoldering systemic mastocytosis (ISM/SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM‐AHN), and mast cell leukemia (MCL).
| Variables | All patients (N = 910) | ISM/SSM (N = 518) | ASM (N = 106) | SM‐AHN (N = 273) | MCL (N = 13) | p |
|---|---|---|---|---|---|---|
| Demographic | ||||||
| Age, median (range) | 56 (12–89) | 49 (12–88) | 63 (25–86) | 67 (18–89) | 67 (41–83) | < 0.01 |
| Age > 60, n (%) | 389 (43) | 123 (24) | 65 (61) | 193 (71) | 8 (62) | < 0.01 |
| Males, n (%) | 453 (50) | 217 (42) | 50 (47) | 180 (66) | 6 (46) | < 0.01 |
| Laboratory and mast cells biochemical markers | ||||||
| Hemoglobin g/dL, median (range), N evaluable = 865 | 13.2 (5.1–18.4) | 14 (7.5–18.1) | 12.1 (5.1–17) | 11 (5.2–18.4) | 9.6 (7.2–12) | < 0.01 |
| WBC × 109/L, median (range), N evaluable = 858 | 7 (0.3–73.4) | 6.6 (1.6–56) | 7 (2–37.1) | 8 (0–73) | 8 (3.5–28.2) | < 0.01 |
| Platelet × 109/L, median (range), N evaluable = 859 | 232 (2–1625) | 257 (30–664) | 197 (19–570) | 146 (2–1625) | 132 (25–633) | < 0.01 |
| Bone marrow mast cells, n (%), N evaluable = 656 | < 0.01 | |||||
| Less than 5% | 64 (10) | 49 (12) | 2 (3) | 13 (7) | 0 (0) | |
| 5%–10% | 348 (53) | 240 (59) | 28 (38) | 80 (46) | 0 (0) | |
| 11%–50% | 197 (30) | 101 (25) | 25 (34) | 71 (41) | 0 (0) | |
| More than 50% | 47 (7) | 17 (4) | 19 (25) | 10 (6) | 1 (100) | |
| Serum tryptase ng/mL, n (%), N evaluable = 664 | < 0.01 | |||||
| Less than 20 | 142 (21) | 109 (26) | 6 (8) | 26 (16) | 1 (8) | |
| 20–200 | 451 (68) | 284 (69) | 54 (69) | 111 (69) | 2 (17) | |
| More than 200 | 71 (11) | 19 (5) | 18 (23) | 25 (15) | 9 (75) | |
| Serum albumin g/dL, median (range), N evaluable = 513 | 4 (2–5.2) | 4.2 (2–5.2) | 3.8 (2–5.2) | 3.8 (2–4.9) | 3.9 (3.9–3.9) | < 0.01 |
| Serum albumin < 3.5 g/dL, n (%), N evaluable = 513 | 98 (19) | 22 (9) | 20 (28) | 56 (30) | 0 (0) | < 0.01 |
| Serum ALP U/L, median (range), N evaluable = 761 | 106 (19–3680) | 86 (26–1957) | 203 (33–2004) | 154 (19–3680) | 159 (57–1423) | < 0.01 |
| Serum ALP > UNL, n (%), N evaluable = 761 | 342 (45) | 118 (29) | 71 (70) | 146 (61) | 7 (70) | < 0.01 |
| Anemia and organomegaly | ||||||
| Hepatomegaly, n (%), N evaluable = 801 | 124 (15) | 30 (6) | 29 (34) | 64 (27) | 1 (100) | < 0.01 |
| Splenomegaly, n (%), N evaluable = 784 | 198 (25) | 44 (10) | 41 (48) | 112 (47) | 1 (100) | < 0.01 |
| Anemia sex adjusted, n (%), N evaluable = 865 | 305 (35) | 54 (11) | 52 (50) | 187 (70) | 12 (92) | < 0.01 |
| Mutations and karyotypes | ||||||
| KIT (D816V) mutation, n (%), N evaluable = 406 | 328 (81) | 149 (82) | 50 (83) | 121 (79) | 8 (73) | 0.8 |
| Adverse mutations, n (%), N evaluable = 240 | 123 (51) | 19 (24) | 15 (43) | 89 (75) | 0 (0) | < 0.01 |
| Other mutations, n (%), N evaluable = 240 | ||||||
| ASXL1 mut | 40 (17) | 2 (3) | 6 (17) | 32 (27) | 0 (0) | < 0.01 |
| RUNX1 mut | 12 (5) | 1 (1) | 0 (0) | 11 (9) | 0 (0) | 0.2 |
| NRAS mut | 5 (2) | 0 (0) | 0 (0) | 5 (4) | 0 (0) | 0.01 |
| TET2 mut | 67 (39) | 6 (13) | 10 (32) | 51 (54) | 0 (0) | 0.5 |
| CBL mut | 22 (14) | 1 (2) | 2 (7) | 19 (23) | 0 (0) | 0.6 |
| DNMT3A mut | 17 (11) | 6 (13) | 2 (7) | 9 (11) | 0 (0) | 0.7 |
| SRSF2 mut | 23 (10) | 0 (0) | 6 (17) | 17 (14) | 0 (0) | 0.2 |
| SF3B1 mut | 14 (9) | 2 (4) | 1 (4) | 11 (13) | 0 (0) | 0.9 |
| TP53 mut | 12 (8) | 4 (9) | 1 (3) | 7 (9) | 0 (0) | 0.8 |
| IDH2 mut | 8 (5) | 2 (4) | 1 (3) | 5 (6) | 0 (0) | 0.03 |
| IDH1 mut | 4 (3) | 1 (2) | 1 (3) | 2 (2) | 0 (0) | 0.2 |
| EZH2 mut | 4 (3) | 0 (0) | 1 (3) | 3 (4) | 0 (0) | 0.6 |
| Abnormal karyotype, n (%), N evaluable = 574 | 73 (13) | 12 (4) | 5 (8) | 55 (25) | 1 (9) | < 0.01 |
| Follow‐up and prognosis | ||||||
| Median follow‐up in years (range) | 3.9 (0–43.3) | 7.2 (0–43.3) | 3.6 (0–33.8) | 1.72 (0–32.2) | 1.2 (0.01–15.2) | < 0.01 |
| Leukemic transformations, n (%) | 35 (4) | 12 (2) | 5 (5) | 18 (7) | 0 (0) | < 0.01 |
| Deaths, n (%) | 345 (38) | 85 (16) | 61 (58) | 191 (70) | 8 (62) | < 0.01 |
Note: Bold font denotes values that were significant.
Abbreviations: APL, alkaline phosphatase; UNL, upper normal limit.
TABLE 2.
Clinical and laboratory findings of 910 patients with systemic mastocytosis (SM), stratified by the types of SM according to the ICC classification: Indolent systemic mastocytosis/smoldering systemic mastocytosis (ISM/SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated myeloid neoplasm (SM‐AMN), and mast cell leukemia (MCL).
| Variables | All patients (N = 910) | ISM/SSM (N = 552) | ASM (N = 115) | SM‐AMN (N = 235) | MCL (N = 8) | p |
|---|---|---|---|---|---|---|
| Demographic | ||||||
| Age, median (range) | 56 (12–89) | 50 (12–88) | 63 (18–86) | 68 (20–89) | 67 (41–74) | < 0.01 |
| Age > 60, n (%) | 389 (43) | 144 (26) | 71 (62) | 169 (72) | 5 (63) | < 0.01 |
| Males, n (%) | 453 (50) | 237 (43) | 57 (50) | 155 (66) | 4 (50) | < 0.01 |
| Laboratory and mast cells biochemical markers | ||||||
| Hemoglobin g/dL, median (range), N evaluable = 865 | 13.2 (5.1–18.4) | 13.9 (7.5–18.1) | 11.8 (5.1–17) | 10.7 (5.2–18.4) | 9.7 (7.7–11.9) | < 0.01 |
| WBC × 109/L, median (range), N evaluable = 858 | 7 (0.3–73.4) | 6.6 (1.6–55.7) | 6.7 (1.7–37.1) | 8.4 (0.3–73.4) | 9 (3.8–28.2) | < 0.01 |
| Platelet × 109/L, median (range), N evaluable = 859 | 232 (2–1625) | 253 (30–664) | 196 (19–570) | 125.5 (2–1625) | 93 (25–218) | < 0.01 |
| Bone marrow mast cells, n (%), N evaluable = 656 | < 0.01 | |||||
| Less than 5% | 64 (10) | 55 (13) | 3 (4) | 6 (4) | 0 (0) | |
| 5%–10% | 348 (53) | 256 (59) | 29 (37) | 63 (44) | 0 (0) | |
| 11%–50% | 197 (30) | 105 (24) | 28 (35) | 64 (45) | 0 (0) | |
| More than 50% | 47 (7) | 17 (4) | 19 (24) | 10 (7) | 1 (100) | |
| Serum tryptase ng/mL, n (%), N evaluable = 664 | < 0.01 | |||||
| Less than 20 | 142 (21) | 117 (27) | 7 (8) | 17 (12) | 1 (12.5) | |
| 20–200 | 451 (68) | 297 (69) | 58 (68) | 95 (69) | 1 (12.5) | |
| More than 200 | 71 (11) | 19 (4) | 20 (24) | 26 (19) | 6 (75) | |
| Serum albumin g/dL, median (range), N evaluable = 513 | 4 (2–5.2) | 4.2 (2–5.2) | 3.7 (2–5.2) | 3.8 (2–4.9) | 3.9 (3.9–3.9) | < 0.01 |
| Serum albumin < 3.5 g/dL, n (%), N evaluable = 513 | 98 (19) | 28 (10) | 24 (31) | 46 (30) | 0 (0) | < 0.01 |
| Serum ALP U/L, median (range), N evaluable = 761 | 106 (19–3680) | 87 (26–1957) | 191 (33–2004) | 169 (19–3680) | 171 (88–1423) | < 0.01 |
| Serum ALP > UNL, n (%) N evaluable = 761 | 342 (45) | 129 (29) | 74 (68) | 135 (65) | 4 (80) | < 0.01 |
| Anemia and organomegaly | ||||||
| Hepatomegaly, n (%), N evaluable = 801 | 124 (15) | 31 (6) | 31 (34) | 61 (30) | 1 (100) | < 0.01 |
| Splenomegaly, n (%), N evaluable = 784 | 198 (25) | 47 (10) | 44 (49) | 106 (53) | 1 (100) | < 0.01 |
| Anemia sex adjusted, n (%), N evaluable = 865 | 305 (35) | 66 (13) | 60 (53) | 172 (75) | 7 (88) | < 0.01 |
| Mutations and karyotype | ||||||
| KIT (D816V) mutation, n (%), N evaluable = 406 | 328 (81) | 158 (80) | 53 (82) | 114 (83) | 3 (50) | 0.3 |
| Adverse mutations, n (%), N evaluable = 240 | 123 (51) | 22 (24) | 16 (41) | 85 (81) | 0 (0) | < 0.01 |
| Other mutations, n (%), N evaluable = 240 | ||||||
| ASXL1 mut | 40 (17) | 3 (3) | 6 (15) | 31 (29) | 0 (0) | < 0.01 |
| RUNX1 mut | 12 (5) | 1 (1) | 0 (0) | 11 (10) | 0 (0) | 0.3 |
| NRAS mut | 5 (2) | 0 (0) | 0 (0) | 5 (5) | 0 (0) | 0.01 |
| TET2 mut | 67 (39) | 8 (15) | 10 (30) | 49 (56) | 0 (0) | 0.8 |
| CBL mut | 22 (14) | 1 (2) | 2 (7) | 19 (25) | 0 (0) | 0.8 |
| DNMT3A mut | 17 (11) | 7 (14) | 3 (9) | 7 (9) | 0 (0) | 0.7 |
| SRSF2 mut | 23 (10) | 1 (1) | 7 (18) | 15 (14) | 0 (0) | 0.1 |
| SF3B1 mut | 14 (9) | 2 (4) | 1 (3) | 11 (14) | 0 (0) | 0.7 |
| TP53 mut | 12 (8) | 5 (10) | 1 (3) | 6 (8) | 0 (0) | 0.8 |
| IDH2 mut | 8 (5) | 2 (4) | 1 (3) | 5 (6) | 0 (0) | 0.02 |
| IDH1 mut | 4 (3) | 1 (2) | 2 (7) | 1 (1) | 0 (0) | 0.2 |
| EZH2 mut | 4 (3) | 0 (0) | 1 (3) | 3 (4) | 0 (0) | 0.6 |
| Abnormal karyotype, n (%), N evaluable = 574 | 73 (13) | 13 (4) | 7 (10) | 52 (27) | 1 (14) | < 0.01 |
| Follow‐up and prognosis | ||||||
| Median follow‐up in years (range) | 3.9 (0–43.3) | 7.1 (0–43.3) | 3.4 (0–33.8) | 1.56 (0–32.2) | 0.07 (0.01–1.78) | < 0.01 |
| Leukemic transformations, n (%) | 35 (4) | 13 (2) | 6 (5) | 16 (7) | 0 (0) | < 0.01 |
| Deaths, n (%) | 345 (38) | 96 (17) | 69 (60) | 174 (74) | 6 (75) | < 0.01 |
Note: Bold font denotes values that were significant.
Abbreviations: APL, alkaline phosphatase; UNL, upper normal limit.
In comparing clinical and laboratory characteristics across morphologic subgroups, it is important to note differences in class definitions between WHO‐HAEM5 and ICC; for example, the ICC definition of MCL applied only to patients with immature mast cell cytomorphology (MCL‐immature, n = 8) while the WHO classification of MCL included cases with mature mast cell cytomorphology (MCL‐mature, n = 5). Similarly, while WHO‐defined SM‐AHN encompassed both myeloid and lymphoid neoplasms (n = 273), the ICC definition of SM‐AMN was limited to myeloid neoplasms only (n = 235). Accordingly, Tables 1 and 2 outline inter‐group differences for WHO‐HAEM5 and ICC, separately.
Age and sex distributions were significantly different among WHO‐HAEM5 and ICC morphologic subgroups: median age in years (male sex %) were 49 (42%) for ISM/SSM, 63 (47%) for ASM, 67 (66%) for SM‐AHN, 68 (66%) for SM‐AMN, 67 (46%) for WHO‐defined MCL, and 67 (50%) for ICC‐defined MCL (p < 0.01; Tables 1 and 2). Significant differences were also apparent between WHO‐HAEM5 (Table 1) and ICC (Table 2) subcategories involving a number of other clinical parameters including mutation profiles and karyotype, with the exception of KIT mutational frequency that was similar across the WHO‐HAEM5 subcategories (range 73%–83%; p = 0.8) and ICC subcategories (50%–83%; p = 0.3), although frequency was numerically lower in ICC‐defined MCL (50%; Tables 1 and 2). By contrast, adverse mutations (e.g., ASXL1, RUNX1, NRAS) were more likely to occur with ICC‐defined SM‐AMN (81%) or ASM (41%) versus ICC‐defined MCL (0%) or ISM/SSM (24%). Abnormal karyotype was also more likely to be seen with ICC‐defined SM‐AMN (27%) versus ICC‐defined MCL (14%) versus ASM (10%) versus ISM/SSM (4%).
Tables 1 and 2 separately illustrate clinical and laboratory characteristics of patients by WHO‐HAEM5 and ICC classifications, respectively. A higher proportion of patients aged over 60 years was seen with SM‐AHN (71%), SM‐AMN (72%), ASM (61%/62%), WHO‐defined MCL (62%), ICC‐defined MCL (63%) versus ISM/SSM (24%/26%) categories (p < 0.01). The corresponding male sex representations were 66%, 66%, 47%/50%, 46%, 50%, versus 50%/50%. Anemia, defined as a hemoglobin level below the lower limit of the sex‐adjusted reference range, was more prevalent with SM‐AHN (70%), SM‐AMN (75%), WHO‐defined MCL (92%), and ICC‐defined MCL (88%) versus ISM/SMM (11%/13%) or ASM (50%/53%; p < 0.01). Serum alkaline phosphatase (ALP) levels above the upper limit of the institutional reference range were recorded in 45% of patients, more frequently in ASM (70%/68%), SM‐AHN (61%), SM‐AMN (65%), WHO‐defined MCL (70%) and ICC‐defined MCL (80%). Markedly elevated serum tryptase levels (> 200 ng/mL) were seen in 11% of all patients and significantly more in WHO‐defined MCL (75%), ICC‐defined MCL (75%) versus SM‐AHN (15%), SM‐AMN (19%), ASM (23%/24%), or ISM/SSM (5%/4%). Palpable hepatomegaly and splenomegaly were more likely to be seen with SM‐Adv, in general (p < 0.01). Abnormal karyotype was more likely to be seen with SM‐AHN (25%; p < 0.01) and SM‐AMN (27%; p < 0.01). Previously recognized adverse mutations were more likely to be seen with SM‐AMN (81%) and SM‐AHN (75%) versus ICC‐defined MCL (0%), WHO‐defined MCL (0%), ASM 41%, ASM (43%) or ISM/SSM (24%).
3.1. Survival Analysis
Figure 1 depicts survival data stratified by WHO‐HAEM5 (Figure 1a) and ICC (Figure 1b). In both instances, patients with ISM/SSM displayed significantly longer survival at a median of 24.3 years, and survival in ASM (median 5.8–6 years) was longer than that of SM‐AHN (median 2.3 years) and SM‐AMN (median 2 years) (p < 0.01 in all instances). Overall survival was the shortest with ICC‐defined MCL (median 0.08 years) followed by WHO‐defined MCL (median 1.8 years), SM‐AHN (median 2.3 years), SM‐AMN (median 2 years), and ASM (median 5.8–6 years). Under WHO‐HAEM5 classification, the difference in survival between WHO‐defined MCL and SM‐AHN was not significant (p = 0.2) but that between ICC‐defined MCL (0.08 years) was significantly different than that of SM‐AMN (median 2 years; p < 0.01). Furthermore, as depicted in Figure S1, survival was similar between SM‐AMN (median 2 years) and ICC‐defined MCL‐mature (median 2.7 years; p = 0.1), ICC‐defined MCL‐mature and ASM (median 6 years; p = 0.8), and ASM and ICC‐defined SM‐ALN (median 8.1 years; p = 0.07).
FIGURE 1.
Overall survival in 910 Mayo Clinic patients with systemic mastocytosis (SM), stratified by (a) world health organization (WHO) classification system, (b) the international consensus classification (ICC). [Color figure can be viewed at wileyonlinelibrary.com]
Table 3 outlines clinical and laboratory parameters found to adversely affect overall survival in univariate and multivariable analysis. The latter, limited to the analysis of clinical variables, identified the following to be independently adverse: SM‐Adv (p < 0.01; HR 6.9; 95% CI: 5.4–8.8), anemia (p < 0.01; HR 6.4; 95%: CI 5.1–8.1), platelet count < 150 × 109/L (p < 0.01; HR 6.2; 95% CI: 4.9–7.7), age > 60 years (p < 0.01; HR 4.8; 95% CI: 3.8–6.1), serum ALP level > upper limit of normal (p < 0.01; HR 3.4; 95% CI: 2.7–4.4), and serum tryptase ≥ 125 μg/L (p < 0.01; HR 4.2; 95% CI: 3.1–5.5). Mutations‐wise, ASXL1 (p < 0.01; HR 4.5; CI: 2.9–7.1), RUNX1 (p = 0.03; HR 2.1; CI: 1.0–4.4), and NRAS (p = < 0.01; HR 7.8; CI: 2.8–21.7) were associated with inferior survival in univariate analysis; in multivariate analysis adjusted for Mayo alliance prognostic factors, ASXL1 (p < 0.01), NRAS (p = 0.04), and SRSF2 (p = 0.03) mutations were independently significant. Notably, SRSF2 (p = 0.9; HR 0.9; CI: 0.4–2.0) did not show a significant impact on survival in univariate analysis. Taken together, these findings confirm the validity of the MAPS (Figure 2) as a robust clinical risk model and also identify ASXL1, NRAS, and SRSF2 mutations and serum tryptase level with additional prognostic contribution. As depicted in Figure 2, the absence of any one of 5 MAPS risk factors is associated with a median survival that is not reached and a 5‐year survival rate of 99%, while median survivals (5‐year rates) were 24.3 years (91%), 11.7 years (71%), 5.7 years (50%), 2.5 years (24%) and 0.7 year (4%) in the presence of one, 2, 3, 4, or 5 risk factors, respectively.
TABLE 3.
Multivariate analysis of (i) clinical variables, and (ii) clinical and molecular variables for overall survival among 910 patients with systemic mastocytosis (SM): risk variables examined were mostly those included in formal prognostic scores for SM.
| Variables | Overall survival | |
|---|---|---|
| Clinical variables | Univariate | Multivariate |
| Advanced systemic mastocytosis | < 0.01 (HR 6.9; 95% CI: 5.4–8.8) | < 0.01 |
| Anemia sex adjusted | < 0.01 (HR 6.4; 95% CI: 5.1–8.1) | < 0.01 |
| Hemoglobin < 10 g/dL | < 0.01 (HR 4.7; 95% CI: 3.7–6.0) | 0.1 |
| Platelet count < 150 × 109/L | < 0.01 (HR 6.2; 95% CI: 4.9–7.7) | < 0.01 |
| Platelet count ≤ 100 × 109/L | < 0.01 (HR 5.0; 95% CI 3.9–6.4) | 0.6 |
| Age > 60 years | < 0.01 (HR 4.8; 95% CI: 3.8–6.1) | < 0.01 |
| Serum ALP > UNLIU/L | < 0.01 (HR 3.4; 95% CI: 2.7–4.4) | < 0.01 |
| Serum ALP ≥ 140 IU/L | < 0.01 (HR 3.5; 95% CI: 2.8–4.4) | 0.2 |
| Serum tryptase ≥ 125 μ/L | < 0.01 (HR 4.2; 95% CI: 3.1–5.5) | < 0.01 |
| Clinical and molecular | Univariate | Multivariate |
| ASXL1 mut | < 0.01 (HR 4.5; CI: 2.9–7.1) | < 0.01 |
| RUNX1 mut | 0.03 (HR 2.1; CI: 1.0–4.4) | 0.8 |
| NRAS mut | < 0.01 (HR 7.8; CI: 2.8–21.7) | 0.04 |
| SRSF2 mut | 0.9 (HR 0.9; CI: 0.4–2.0) | 0.03 |
Note: Bold font denotes values that were significant.
Abbreviations: APL, alkaline phosphatase; UNL, upper normal limit.
FIGURE 2.
Overall survival in 910 Mayo Clinic patients with systemic mastocytosis (SM), stratified by the Mayo alliance prognostic scoring system (MAPS) (risk factors: (i) advanced vs. non‐advanced SM, (ii) age > 60 years, (iii) platelets < 150 × 109/L, (iv) hemoglobin below sex‐adjusted lower limit of normal, (v) alkaline phosphatase above upper limit of normal). [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3a,b illustrate overall survival data based on the MAPS molecular [14] and the mutation‐adjusted risk score (MARS) [17] risk models. Risk variables in the former include SM‐Adv versus ISM/SSM, age > 60 years, platelet counts < 150 × 109/L, serum ALP level > the upper limit of normal, and presence of any one of three adverse mutations (ASXL1, RUNX1, and NRAS). Risk variables in the MARS model include presence of any one of three adverse mutations (SRSF2, ASXL1, RUNX1), platelet count of < 100 × 109/L, hemoglobin levels < 10 g/dL, and age > 60 years. With both molecular models, the survival distinctions across groups were not as evident as they were for the clinical MAPS model [14].
FIGURE 3.
Overall survival in 910 Mayo Clinic patients with systemic mastocytosis (SM), stratified by (a) Mayo alliance prognostic scoring system (MAPS) molecular risk model (risk factors: (i) advanced vs. non‐advanced SM, (ii) age > 60 years, (iii) platelets < 150 × 109/L, (iv) alkaline phosphatase above upper limit of normal), (v) adverse mutations (i.e., ASXL1, RUNX1, and NRAS) (b) Mutation‐adjusted risk score (MARS) (risk factors: (i) age > 60 years, (ii) platelets < 100 × 109/L, (iii) hemoglobin less than 10 g/dL, (iv) adverse mutations (i.e., SRSF2, ASXL1, RUNX1)). [Color figure can be viewed at wileyonlinelibrary.com]
Finally, all‐inclusive multivariable analysis was performed including the MAPS risk factors with either the WHO‐HAEM5 or ICC morphologic subclassification. In both instances, the MAPS risk categories retained significant differences between each other (p < 0.01 in all instances). By contrast, survival data were not significantly different between the WHO‐HAEM5 MCL versus SM‐AHN (p = 0.6) or MCL versus ASM (p = 0.16) morphologic subcategories; by contrast, in a similar multivariable analysis that included MAPS risk factors and the ICC‐defined subcategories, differences in survival remained apparent across all MAPS risk categories (p < 0.01 in all instances) as well as across all ICC‐defined morphologic subcategories (p < 0.03 in all instances), without any exception (Figure S2).
4. Discussion
The current study is notable as the largest single institutional study of SM cases (N = 910) described to date. It is to be recalled that we undertook a similar exercise with 342 patients with SM seen at the Mayo Clinic between 1976 and 2007, which was reported in 2009 and showed the near‐normal life expectancy in patients with ISM/SSM (median 198 months) while prognosis was significantly worse in patients with SM‐Adv, especially in those with ICC‐defined MCL (median 2 months) and WHO‐defined SM‐AHN (median 24 months), as opposed to ASM (median 41 months) [12]. The corresponding median survivals (approximate) obtained in the current study of 910 patients with SM were 291 months in ISM/SSM, 0.9 month for ICC‐defined MCL, 21.6 months for WHO‐defined MCL, 24 months for ICC‐defined SM‐AMN, 27.6 months for WHO‐defined SM‐AHN, and 72 months for ASM (Figure 1).
It is evident from the current study that estimates of survival prediction in MCL might be more accurate for ICC‐defined cases, as was elaborated by two recent reports [10, 11]. Another important observation concerns the distinction between WHO‐defined SM‐AHN and ICC‐defined SM‐AMN. The former includes both lymphoid and myeloid neoplasms as part of the “AHN” component while the latter is restricted to myeloid neoplasms. As was depicted in Figure S1, a significant difference in survival was apparent between ICC‐defined SM‐AMN (median 2 years) and SM‐ALN (median 8.1 years) as well as between ICC‐defined (immature) MCL (median 0.08 years) and WHO‐defined MCL restricted to cases with “mature” MC cytomorphology (median 1.8 years). Figure S1 also suggests similar survival data between SM‐ALN and ASM and between MCL‐mature and ASM. Taken together, these observations validate the prognostic integrity of the ICC, as opposed to WHO‐HAEM5, and expose deficiencies in practical relevance when combining MCL‐mature with MCL‐immature in a common category of WHO‐defined MCL as well as SM‐AMN with SM‐ALN in a common category of WHO‐defined SM‐AHN. Furthermore, there is preliminary evidence to support further delineation of SM‐AMN into specific subcategories, such as SM‐AML, SM‐CMML, SM‐MDS, and SM‐MPN [13].
Another main objective of the current study was to validate the prognostic performance of MAPS [14], in the context of ICC‐defined morphologic classification. According to the MAPS prognostic model [14], median survival in SM was directly and proportionally correlated with the number of five established risk factors: (i) age > 60 years, (ii) anemia (hemoglobin level below the lower limit of normal, adjusted for sex), (iii) thrombocytopenia (platelet count < 150 × 109/L), (iv) elevated serum alkaline phosphatase (ALP) level (above the upper limit of normal), and (v) advanced versus non‐advanced SM; the corresponding median survivals in the particular cohort (N = 543) were “not reached,” “not reached,” 148, 56, 27, and 9 months, in the presence of 0, 1, 2, 3, 4 or 5 risk factors, respectively, and showing significant differences within groups [14]. The corresponding median survivals observed in the current study (N = 754) were eerily similar at “not reached,” 291, 140, 68, 30, and 8.4 months, and also showing significant differences within groups (Figure 2). In the original MAPS report [14], 150 patients were evaluable for NGS‐derived mutations and three mutations were found to be inter‐independently detrimental to overall survival: NRAS, RUNX1, and ASXL1, and were accordingly labeled as “adverse (NRA)” and shown to confer prognostic contribution independent of the MAPS clinical risk factors, allowing for the development of an accompanying clinical‐molecular hybrid model that included adverse mutations, SM‐Adv, thrombocytopenia, increased ALP, and age > 60 years [14]. In the current study, NGS‐derived mutation information was available in 240 patients and univariate analysis showed significant survival impact for ASXL1, NRAS, and RUNX1, but not SRSF2 mutations; however, when adjusted for the MAPS clinical risk factors, RUNX1 lost its significance whereas SRSF2 became significant, suggesting prognostic interaction between these mutations.
Most importantly, using the current patient cohort that is evaluable for both morphology and MAPS clinical risk factors (N = 754), the substitution of “advanced versus non‐advanced SM” by ICC‐defined SM subcategories strengthened the prognostic contribution of morphology without compromising the prognostic contribution from the other MAPS risk factors and sustaining significant differences in survival across ICC morphologic and MAPS risk categories (Figure S2). A similar analysis using WHO‐defined morphologic categories disclosed the absence of significant differences in survival between WHO‐defined MCL and ASM and between WHO‐defined MCL and SM‐AHN (Figure S2). The addition of mutational information into the multivariable model that included ICC‐defined SM categories and MAPS risk factors resulted in ousting of anemia as an independent risk factor, as was the case in the original MAPS study [14]. Taken together, these observations suggest the possibility of revising the clinical and the hybrid clinical‐molecular MAPS risk models for SM by integrating the ICC‐defined morphologic subcategories.
One additional finding from the current study was the apparent prognostic relevance of serum tryptase level ≥ 125 μg/L (N evaluable = 664; p < 0.01; HR 4.2, 3.1–5.5) that was sustained in multivariable analysis that included all five MAPS risk variables as well as ICC‐defined morphologic categories of SM. The particular observation warrants further research and raises the prospect of including serum tryptase level to MAPS, as it has previously been done in the global prognostic score for SM (GPSM) [18] and the International Prognostic Scoring Systems for advanced and non‐advanced SM (IPSM) [19]. Of note, serum tryptase level is currently not included in other risk models including MAPS [14] and the mutation‐adjusted Risk Score for Advanced Systemic Mastocytosis (MARS) [17]. Regardless, it is our contention that the integration of a more refined morphologic classification of SM, such as the ICC, might influence the prognostic contribution of other clinical or molecular risk factors. It is therefore important to include the ICC of SM in future clinical models.
There are several limitations to the current study given its retrospective nature as well as long enrollment period. These include changes in diagnostic methodologies and therapeutic modalities over time. We also acknowledge the relatively small number of cases with ICC‐defined MCL as well as ICC‐defined SM associated with lymphoid neoplasms, which makes it difficult to be definitive in our observations. However, although new modalities of treatment have been introduced recently, we do not believe that there is controlled evidence to suggest their impact on survival and accordingly influence the interpretation of our data.
Author Contributions
A.T., A.P., and F.A. designed the study, collected data, performed statistical analysis, and wrote the paper. A.T. and A.P. also provided patient care. N.G., M.S.P., J.H.B., T.P., and C.Y.A.Y. provided patient care. K.K.R., D.C., A.O., and D.A.A. provided hematopathology expertise. M.K. helped with data collection. All authors have reviewed and approved the manuscript.
Disclosure
The authors have nothing to report.
Ethics Statement
The study was approved by the institutional review board.
Conflicts of Interest
N.G.: Advisory Board for DISC medicine and Agios. The other authors declare no conflicts of interest.
Supporting information
Figure S1. Survival data among 910 Mayo Clinic patients with systemic mastocytosis (SM), stratified by international consensus classification (ICC) with substratification of MCL into MCL‐mature and MCL‐immature and SM‐AHN into SM‐AMN and SM‐ALN.
Figure S2. Multivariable analysis including ICC morphologic subcategories and MAPS risk factors (A) and multivariable analysis including WHO morphologic subcategories and MAPS risk factors (B).
Aperna F., Abdelmagid M. G., Kumar M., et al., “Systemic Mastocytosis in 910 Patients: Prognostic Contribution of the International Consensus Classification in the Context of the Mayo Alliance Prognostic System,” American Journal of Hematology 100, no. 9 (2025): 1566–1576, 10.1002/ajh.27764.
Data Availability Statement
By email request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Survival data among 910 Mayo Clinic patients with systemic mastocytosis (SM), stratified by international consensus classification (ICC) with substratification of MCL into MCL‐mature and MCL‐immature and SM‐AHN into SM‐AMN and SM‐ALN.
Figure S2. Multivariable analysis including ICC morphologic subcategories and MAPS risk factors (A) and multivariable analysis including WHO morphologic subcategories and MAPS risk factors (B).
Data Availability Statement
By email request to the corresponding author.