Isolated Bone Marrow Mastocytosis may be Associated with Reduced Overall Survival

  

    

    
SMcm 

      N: 155 (%)
    
IBMM 

      N: 38 (%)
    
p-value
  
  

    
Cutaneous    symptoms 
    
115 (74.2)
    
17 (44.7)
    
0.0004
  
  

    
Flush 
    
72 (46.5)
    
11 (29)
    
0.05
  
  

    
Pruritus 
    
64 (41.3)
    
9 (23.7)
    
0.04
  
  

    
Darier’s sign 
    
75 (48.4)
    
1 (2.6)
    
<0.01
  
  

    
Superficial urticaria
    
2 (1.3)
    
4 (10.5)
    
<0.01
  
  

    
Angioedema 
    
5 (3.2)
    
8 (21.0)
    
<0.01
  
  

    
Gastro-intestinal    symptoms
    
84 (54.2)
    
20 (52.6)
    
0.83
  
  

    
Diarrhea 
    
70 (45.2)
    
16 (42.1)
    
0.73
  
  

    
Abdominal cramping
    
70 (45.2)
    
11 (29.0)
    
0.06
  
  

    
Nausea 
    
15 (9.7)
    
7 (18.4)
    
0.12
  
  

    
Cardiovascular    symptoms 
    
49 (31.6)
    
18 (47.4)
    
0.06
  
  

    
Syncope 
    
21 (13.6)
    
7 (18.4)
    
0.44
  
  

    
Hypotension 
    
24 (15.5)
    
7 (18.4)
    
0.65
  
  

    
All    shock 
    
26 (16.7)
    
14 (36.8)
    
0.006
  
  

    
Mixed shock 
    
4 (2.5)
    
1 (2.6)
    
0.98
  
  

    
Idiopathic shock 
    
18 (11.8)
    
9 (23.7)
    
0.05
  
  

    
Hymenoptera shock 
    
10 (6.5)
    
5 (13.2)
    
0.16
  
  

    
Allergic shock 
    
12 (7.7)
    
6 (15.8)
    
0.12
  
  

    
Urinary    symptoms
    
23 (14.8)
    
2 (5.3)
    
0.12
  
  

    
Respiratory    symptoms 
    
14 (9)
    
7 (18.4)
    
0.09
  
  

    
Cough 
    
2 (1.3)
    
0 (0)
    
0.48
  
  

    
Dyspnea 
    
12 (7.7)
    
7 (18.4)
    
0.04
  
  

    
Depression 
    
16 (10.3)
    
2 (5.3)
    
0.3
  
  

    
Headache 
    
32 (20.7)
    
3 (7.9)
    
0.07
  

Table 1: Mast cell mediator-related symptoms in two populations.

We included 193 adult patients with SM. We diagnosed 38 patients with IBMM (19.6%). The duration of follow-up was 300 months (IQR: 24-128). Regarding the overall survival, there were six deaths in the IBMM group (15.7%) and none in SMcm population (p<0.01) (Figure 1). Among these patients, four deaths were related to the mastocytosis associated haematological disorder and the latter two were due to lung cancer and septic shock. The sex ratio was similar in both groups with 44.5% of male in SMcm population and 44.7% in IBMM group. IBMM patients were significantly older than SMcm patients (56 years (IQR: 42.5-61.8) versus 46 years (IQR: 35- 56.8) (p = 0.02). The average of the delay of diagnosis between first manifestations and diagnosis was significant different between two groups: 3 months (IQR: 1-5.5) in IBMM population versus 5 months (IQR: 1-10.3) in SMcm group (p=0.001).

Regarding mast cells mediator-related symptoms (mcms), superficial spontaneous urticaria (10.5% vs. 1.3%, p=0.03) and angioedema (21% vs. 3.2%, p<0.01) were more frequent in IBMM as compared to SMcm patients. Similarly, anaphylactic shock, was more frequent in IBBM than SMcm patients (36.8% vs. 16.7 %, p = 0.006), especially idiopathic anaphylactic shock subtypes (23.7% vs. 11.6%, p = 0.05). In IBMM group the dyspnea was also more frequent (18.4% vs. 9%, p=0.04) than in SMcm group. By contrast, SMcm patients exhibited a higher frequency of other symptoms related to skin mast cells than IBMM patients flush (46.5% vs. 28.9%, p = 0.05), and pruritus (41.3% vs. 23.7%, p = 0.04).

Regarding others mcms, there was no significant difference between the two groups (Table 1). There was no significant difference between the two populations concerning WHO criteria of SM, biological parameters, frequency of other neoplastic hematologic disease (myelodysplastic syndrome, polycythemia, leukemia, lymphoma…) and bone marrow features, including bone fracture (data not shown).

The IPSM was statistically significant more important in the IBBM group vs SMcm group (mean: 0.8 vs. -0.6, p<0.001).

To our knowledge, this is the first study showing a significant difference in terms of overall survival in IBMM vs SMcm patients. Indeed more of observed deaths in IBMM patients were related to a haematological neoplasm associated with mastocytosis. The IPSM score validated the data found in our cohort.

Moreover, we show that 19.6% of our adult cohort with SM presented IBBM. These patients showed higher prevalence of cutaneous symptoms such as superficial urticarial, angioedema and, anaphylactic shock especially idiopathic ones. These results underscores the importance of screening this population for the diagnostic criteria defined by the WHO in order to optimize their care, especially in case of idiopathic anaphylactic shock.

The frequency of IBBM patients varies between 10.5 to 54.7% according to the literature data [9-13]. Alvarez-Twose I et al., [11] showed a frequency of 29.6 % cases of IBMM (48 cases of out 162 all SM) in the Spanish population. Lim et al., found a frequency of 10.5% patients with IBMM (36 of out 342 all SM) in American population [9]. Zanotti R et al. [12] showed a frequency of IBMM of 54.7% (46 of out 84 patients) among indolent SM Italian patients. This frequency is probably overestimated because authors selected patients who presented unexplained/recurrent anaphylaxis or severe allergic reactions to hymenoptera stings with persistent elevated serum tryptase level. More recently, European Competence Network on Mastocytosis [13] showed a prevalence of 23.7% of IBMM among all mastocytosis patients without advanced SM.

What emerges from the literature and in our study is the prevalence of anaphylaxis and/or severe anaphylaxis like as anaphylactic shock in IBMM patients. In fact, in the series of Lim et al., 78% of them had history of anaphylactic reactions. In the series of Zanotti et al., 95.6% of IBMM had anaphylaxis, whose 91.3% after hymenopter sting. In our cohort, the frequency of anaphylactic shocks was also higher in IBBM than SMcm patients. That might explain the delay of diagnosis between first manifestations and diagnosis least important in IBBM than SMcm patients. Therefore, IBMM patients seem distinct from other SM patients in terms of anaphylactic shock’s risk [14,15]. A quickly diagnostic could also allow us to ensure them optimal care. For example, patients with anaphylactic shock to hymenoptera venom should be considered for life-long venom immunotherapy [15,16], and the patients with idiopathic anaphylactic shock may also be effectively treated with omalizumab [17].

Our study indicates that IBMM is associated with a higher frequency of life-threatening symptoms and reduced survival. Collaborative longitudinal studies are needed to better evaluate these patients and improve quality of care.

References

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