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Redefining the diagnostic criteria for bone marrow mastocytosis

Nov 18, 2021
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Mastocytosis, a hematopoietic neoplasm defined by the expansion and build-up of neoplastic mast cells (MCs) across many organ systems, can be divided into many subcategories that are reflective of the patient outcome. These categories include indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), referred to as non-advanced systemic mastocytosis (SM) variants, while SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), MC leukemia (MCL), and MC sarcoma are classified as advanced SM. Currently, the World Health Organization (WHO) classifies bone marrow mastocytosis (BMM) as a transient variant of ISM, characterized by bone marrow involvement and the absence of skin lesions. However, diagnostic criteria for BMM have been stagnant and additional ones have not been proposed. Therefore, Roberta Zanotti et al.1 investigated the adverse prognostic factors of WHO-classified patients with BMM from the European Competence Network on Mastocytosis (ECNM) registry and compared characteristics and outcomes of BMM based on the defined risk factors and typical ISM with skin lesions (ISMtyp). The aim of the study1 was to define BMM as a distinct SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels.

Methods

  • The ECNM registry comprises data from patients with different classifications of mastocytosis in 25 European centers and one center in the US
  • Data entered from 1,567 patients into the ECNM registry, until April 2018, were included in the analysis Table 1
  • Two patients were excluded from this analysis because they were diagnosed with intestinal involvement and lacked a bone marrow (BM) evaluation

Results

Prevalence of WHO-based BMM among all ISM patients

  • ISMtyp based on WHO criteria and the presence of skin lesions were diagnosed in 75.1% of all patients with ISM
  • The remaining 24.9% of patients were classified as WHO-based BMM
  • The median time between the onset of symptoms and diagnosis of SM was 2 years (range, 0.1–36.6 years) for BMM and 8.3 years (range, 0.1–64.8 years) for ISMtyp
  • The median time between SM diagnosis and analysis in this study was 4.4 years (range, 0.2–21.9) in BMM and 4.8 years (range, 0.1–33.4) in ISMtyp

Comparison of patient characteristics between WHO-based BMM and ISMtyp

Patients with WHO-based BMM

  • Were statistically significantly older at diagnosis compared to ISMtyp patients, with a median age of BMM at 52.2 years vs ISMtyp at 45.4 years (p < 0.001)
  • Consisted of mainly male patients, with a male/female ratio of 1.48/0.61 (BMM/ISMtyp; p < 0.001)
  • Had lower tryptase levels and lower burden of neoplastic mast cells, and commonly had allergic reactions, primarily triggered by Hymenoptera

There was no difference in the performance status at diagnosis between the two groups. Significantly lower levels of alkaline phosphatase (aPhos) (p < 0.001), greater hemoglobin (Hb) measurements (p < 0.001), higher lactate dehydrogenase (LDH) levels (p < 0.001), and lower basal serum tryptase (sT) levels (p < 0.001), were observed in patients with WHO-based BMM compared to patients with ISMtyp (Table 1).

Table 1. Characteristics of patients with BMM and ISMtyp*

Characteristic

WHO-based BMM
(N = 390)

ISMtyp
(N = 1,175)

p value

Males, number (%)

233 (59.7)

443 (37.7)

<0.001

Age, years, median (range)

52.2 (19–83)

45.4 (18–82)

<0.001

Performance status according to WHO ≥2, number (%)

11 (2.9)

28 (2.4)

0.708

Tryptase, ng/mL, median (range)

23.9 (2.1–366)

34.2 (1–885)

<0.001

Hemoglobin, g/dL, median (range)

14.5 (7.1–19.9)

14.0 (8.6–18.2)

<0.001

LDH, U/L, median (range)

175 (102–511)

162 (77–821)

<0.001

aPhos, U/L, median (range)

68 (19–150)

74 (20–317)

<0.001

Major diagnostic criteria, %

73.4

89.9

<0.001

Exon 816 KIT mutation, %

85.9

85.1

0.789

CD25 expression by flow or IHC, %

97.0

95.3

0.856

CD2 expression by flow or IHC, %

85.8

78.5

0.011

MC infiltration in BM by IHC (%), median (range)

5 (0.5–50)

10 (0–60)

<0.001

Karyotype abnormal, %

3.8

3.3

0.736

Organomegaly, %

5.1

8.9

0.020

              Splenomegaly

2.9

4.3

0.831

              Hepatomegaly

2.4

5.6

0.128

              Lymphadenopathy

2.7

1.8

0.510

Dysmyelopoiesis, %

0.8

1.9

0.233

Non-advanced IPSM, %

              Low risk

64.9

69.4

              Intermediate 1 risk

31.6

26.5

0.209

              Intermediate 2 risk

3.5

4.1

aPhos, alkaline phosphatase; BM, bone marrow; BMM, bone marrow mastocytosis; IHC, immunohistochemistry; IPSM, International prognostic scoring system for mastocytosis; ISM, indolent systemic mastocytosis; ISMtyp, typical indolent systemic mastocytosis; LDH, lactate dehydrogenase; MC, mast cell; WHO, World Health Organization.
*Adapted from Zanotti et al.1
The number of patients with available data on related parameter varies (except median age and male sex), and percentages are calculated based on these numbers.
Bonferroni correction (adjusted level α = 0.05/23 = 0.0021). Statistically significant p < 0.05 values are in bold.

  • In WHO-based BMM patients, the presence of one B-Finding and tryptase level ≥125 ng/mL were confirmed risk factors for progression in multivariate analyses
  • Data about the presence of B-Findings were available in 338 patients with WHO-based BMM and 1,059 patients with ISMtyp. The presence of a single B-Finding was observed in 6.5% of patients in WHO-based BMM and in 10.9% of patients with ISMtyp (p = 0.007)
  • A lower BM MC infiltration grade (p < 0.001), and reduced major diagnostic SM criterion on BM biopsy sections (p < 0.001) was documented in patients with WHO-based BMM compared to patients with ISMtyp
  • No differences in frequency of the KIT D816V mutation (a common SM activating gene), expression of CD25 and CD2 in BM MC, and abnormal karyotypes were seen

In terms of mediator-related symptoms, hypersensitivity reactions (77.4% vs 34.1%; p < 0.001) and Grade 3–4 constitutional and/or cardiovascular symptoms (45.9% vs 26.5%; p < 0.001) were more common in the WHO-based BMM group than ISMtyp group.

Overall survival (OS) and progression-free survival (PFS) of patients with ISMtyp and WHO-based BMM

  • Follow-up data were available in 77.0% of patients with WHO-based BMM (n = 300) and in 73.1% of patients with ISMtyp (n = 859)
  • A total of 2% of patients from the WHO-based BMM group and 4.3% from the ISMtyp group progressed to a higher-grade variant of SM
    • No disease progression to SSM was observed in the WHO-defined BMM group while 1.4% of patients with ISMtyp progressed to SSM.
    • Progression to SM-AHN was observed in both groups.
  • The estimated 10-year PFS of BMM and typical ISM was 95.9% and 92.6%, respectively, and the median time to progression was not reached in both groups
  • The estimated 10-year OS of patients with BMM and ISMtyp was 96.9% and 93.1%, respectively
  • The median OS was not reached for the WHO-based BMM patients and was 28.4 years (95% CI, 24.2–32.6) for patients with ISMtyp (p = 0.185)

Prognostic variables affecting PFS and OS in the WHO-defined BMM group are also investigated in univariate and multivariate analyses (Table 2).

Table 2. Effect of the prognostic variable in univariate analyses on PFS and OS of 300 patients with WHO-defined BMM*

Prognostic variables

Risk population

PFS
(p value)

OS
(p value)

Male sex

0.986

0.351

Age, years

≥60

0.430

0.001

Performance status WHO

≥2

0.481

0.002

Tryptase (ng/mL)

≥125

0.001

0.002

Hemoglobin (g/dL)

<11

n.d.

n.d.

Platelets (× 109/L)

<100

0.932

0.951

Leukocytes (× 109/L)

≥16

n.d.

n.d.

Monocytes (× 109/L)

≥1.0

0.011

0.746

Eosinophils (× 109/L)

≥0.5

0.603

0.694

Alkaline phosphatase (U/L)

≥100

0.260

0.001

Presence of one B-Finding

<0.001

0.013

BMM, bone marrow mastocytosis; n.d., not done; OS, overall survival; PFS, progression-free survival; WHO, World Health Organization.
*Adapted from Zanotti et al.1

  • Monocytosis (>1.0 × 109/L), presence of one B-Finding, and an sT level ≥125 ng/mL had a significant impact on PFS in univariate analysis, but only the presence of one B-Finding and an sT level ≥125 ng/mL were confirmed as independent prognostic variables in multivariate analyses.
  • Older age, WHO performance status >1, an sT level ≥125 ng/mL, and the presence of one B-Finding were found to be risk factors for worse OS; however, the multivariate analyses did not show any significant independencies
  • Following on the data from the multivariate analyses on PFS, patients with WHO-based BMM were divided into two groups: low-risk BMM defined by no B-Finding and a basal sT level < 125 ng/mL (n = 274), and high-risk BMM defined by either one B-Finding and/or an sT level ≥ 125 ng/mL (n = 26)
    • BMM patients without any of these risk factors had a greater better PFS (p < 0.05) and better OS (p < 0.05) than other ISM patients
  • Patients with low-risk BMM had a significantly better PFS (p = 0.013) and significantly better OS (p = 0.010) compared to patients with either ISMtyp or high-risk BMM
  • The estimated 10- and 20-year PFS was 96.7% and 96.7% for patients with low-risk BMM, and 92.4% and 85.7% for patients with ISM or high-risk BMM, respectively
  • The estimated 10- and 20-year OS was 98.8% for patients with low-risk BMM and 93.1% and 70.7% for patients with ISM or high-risk BMM, respectively

A total of 43 patients died; six from the patients with BMM, and 37 from the patients with ISMtyp (Table 3).

Table 3. Cause of death in patients with ISMtyp and WHO-based BMM*

Cause of death, n (%)

ISMtyp

WHO-defined BMM

Total deaths

37 (4.3)

6 (2.0)

Mastocytosis

10 (1.2)

1 (0.3)

Other neoplasia

8 (0.9)

3 (1.0)

Cardiovascular disease

8 (0.9)

0 (0.0)

Unknown

9 (1.0)

1 (0.3)

Other

2 (0.2)

1 (0.3)

BMM, bone marrow mastocytosis; ISMtyp, typical indolent systemic mastocytosis; WHO, World Health Organization.
*Adapted from
Zanotti et al.1

Conclusion

In summary, the authors suggest that the study findings support the proposal to reform true BMM as low-risk BMM based on ISM criteria, the absence of skin lesions, the absence of B-Findings, and tryptase levels <125 ng/mL, and to combine high-risk BMM cases with ISMtyp. This would indicate that there are ISM patients who do not present with skin lesions but have one B-Finding, and/or an sT level ≥125 ng/mL, and/or clear histologic evidence of multiorgan involvement. Although this analysis is based on a large dataset, further confirmatory studies are needed.

  1. Zanotti R, Bonifacio M, Lucchini G, et al. Refined diagnostic criteria for bone marrow mastocytosis: A proposal of the European Competence Network on Mastocytosis. Leukemia. 2021. DOI: 1038/s41375-021-01406-y

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