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The advancement of precision cancer treatment has enabled more and more patients to use precise and efficient new treatment methods
.
For example, the clinical research of the highly selective KIT/PDGFRA inhibitor Avapritinib (Avapritinib) has made a leap forward in the treatment of advanced systemic mastocytosis (AdvSM)
.
The diagnosis and treatment of a disease has entered a new era, and many things need to keep pace with the times
.
As the mystery of AdvSM is gradually unveiled, the various tests carried out on patients must comply with the requirements of precise targeted therapy.
It is not limited to the previous "classic projects" such as KIT D816V mutations and serum trypsin
.
More comprehensive and complete genetic testing can not only help doctors better use the new treatment option of avatinib, but also play an important role in accurately analyzing the prognosis of patients in combination with the latest evaluation models in recent years
.
"Precision treatment, testing first" should also become the motto of AdvSM diagnosis and treatment
.
The use of various precise detection methods to guide clinical diagnosis and treatment of KIT D816V mutation is only part of the characteristics of this disease.
When medical textbooks describe many diseases, they often frankly admit that "the pathogenesis of this disease is unknown.
" Systemic mastocytosis belongs to this.
Class of diseases
.
Even the iconic KIT D816V mutation, which has a positive mutation rate of 80%, has not been fully understood by scientists and doctors
.
KIT D816V mutation is an important diagnostic criterion for systemic mastocytosis, and it is also the main target of targeted drugs such as Avatinib and Midostaurin, but its specific mechanism has not yet been elucidated.
.
And there are a number of research data showing that the scope of KIT D816V mutation is not limited to mast cells
.
For example, in the hematological tumors (ie SM-AHN) often associated with AdvSM patients, the patient’s hematopoietic stem cells, progenitor cells, and even neutrophils, monocytes and eosinophils may be detected with KIT D816V mutations[ 1]
.
The earlier the KIT D816V mutation occurs, the deeper and wider the impact on the blood system may be [2]
.
At the signal pathway level, the KIT D816V mutation may activate a series of downstream pathways such as PI3K, STAT3/5, RAS, JAK2, and promote the abnormal clonal proliferation, survival and invasion of mast cells
.
Other studies have shown that the KIT D816V mutation may cause mast cells to continuously release a large amount of interleukin-6 (IL-6), leading to a cytokine storm [3]
.
SM is a multi-mutation disease (picture source: Blood) However, systemic mastocytosis is actually a "multi-mutation disease".
In addition to the iconic KIT D816V mutation, about 90% of AdvSM patients may also be detected A variety of somatic mutations, including SRSF2, ASXL1, RUNX1 and DNMT3A mutations (S/A/R/D), have been confirmed to be related to the poor prognosis of patients [4-5]
.
The latest version of the US NCCN clinical practice guidelines recommends that for patients with suspected systemic mastocytosis, in addition to the detection of KIT D816V mutations, at least three somatic mutations of S/A/R should be detected in the diagnosis, and the second generation should be considered when necessary.
Sequencing (NGS) provides important information for evaluating the prognosis of patients
.
Another "classic item" for the detection of systemic mastocytosis is serum trypsin, which is also one of the disease diagnostic criteria, but the proportion of clinical tests is not high, and it specifically evaluates the level of tryptase and the prognosis of patients.
There are few studies on the relationship [6], and it is expected that more professionals will pay attention to tryptase detection in the future, so as to improve the diagnosis rate of systemic mastocytosis and achieve new progress in diagnosis
.
However, to accurately assess the prognosis of patients with systemic mastocytosis, detection of KIT D816V mutations, serum tryptase and somatic mutations may not be enough
.
With the gradual deepening of medical understanding of this disease, new prognostic evaluation models are constantly emerging
.
Perfect the various examinations, and really use the prognostic model.
First review a knowledge point: systemic mastocytosis is divided into indolence (ISM), smoking type (SSM), aggressive (ASM), and associated hematological tumors (SM- AHN) and mast cell leukemia (MCL) five subtypes, of which the latter three are included in the advanced stage (AdvSM) category
.
From the names of these subtypes, we can see the difference between the clinical characteristics of the disease and the patient's prognosis
.
Due to the low incidence of systemic mastocytosis, survival analysis is also relatively small
.
Past data show that the life expectancy of ISM patients is not much different from that of healthy people of the same age.
Only a very small number of patients are at risk of disease progression or even malignant transformation [7-8]; the median overall survival (OS) of SSM patients is about 120 months.
Patients with ISM are significantly shorter [9]
.
The overall prognosis of AdvSM patients is indeed very bad before the approval of drugs such as Avatinib and Midostaurin that target the KIT D816V mutation
.
An analysis in 2009 showed that the median OS of ASM patients was about 41 months, the median OS of SM-AHN patients was 24 months, and the median OS of MCL patients was only 2-4 months [7]
.
Differences in life expectancy between SM patients of each subtype and healthy people of the same age (picture source: Blood) Compare the data in the Avatinib EXPLORER study.
The median OS of all AdvSM patients is 46.
9 months.
MCL patients with the worst prognosis before (13 cases) The 3-year survival rate reached 76%, and the 3-year survival rate of SM-AHN patients was also 62%.
It can be seen how important precision targeted therapy is for AdvSM patients [9]
.
However, when judging the prognosis of systemic mastocytosis, in addition to the subtype of the patient’s disease, doctors often need to combine the somatic gene mutations mentioned above, as well as laboratory test indicators such as tryptase, hemoglobin, and platelets.
, To conduct a comprehensive analysis
.
Foreign scholars have proposed a number of prognostic models for systemic mastocytosis.
The included indicators are different, and the accuracy of prediction is also different
.
Among them, the global mastocytosis prognostic score (GPSM) system, initially proposed by Spanish scholars in 2020 and perfected and verified in 2021, has high practical value
.
This model is divided into two sets of evaluation systems for progression-free survival (GPSM-PFS) and overall survival (GPSM-OS).
It uses the laboratory test indicators of more than 400 patients and the four somatic cells of S/A/R/D.
For mutation status, the scoring system as shown in the table below has been formulated.
The specific indicators and Cut-off values included are: Although the current GPSM system GPSM-PFS/OS score is not included in the KIT D816V mutation status (also does not include the mutation allele score/ VAF), but verification in more than 850 patients shows that its predictive value for patients with PFS and OS is relatively good in the existing scoring models, and bone marrow biopsy is not necessary information, and it is more convenient to use [10]
.
However, the current WHO diagnostic criteria for systemic mastocytosis has not yet included items such as alkaline phosphatase, β2-microglobulin, and S/A/R/D somatic mutations
.
To make good use of GPSM-PFS/OS and other models in clinical practice, adequate communication between doctors and patients is required, and relevant examinations are perfected as much as possible
.
A journey of a thousand miles begins with accurate detection and guidance of precise treatment with one step.
This is an inevitable trend in the development of cancer treatment.
However, there are not many treatments for systemic mastocytosis, and it is difficult to achieve diagnosis and treatment guided by detection
.
For example, in the NCCN clinical practice guidelines, there is only one such recommendation-patients with negative KIT D816V mutations can choose imatinib
.
For KIT D816V mutation-positive AdvSM patients, both Avatinib and Midostaurin are recommended as the preferred regimen (Preferred Regimen), but it is not yet possible to further clarify which patients can benefit significantly from the treatment, which requires follow-up Research to analyze
.
As for ISM/SSM patients with relatively good prognosis but impaired quality of life due to various symptoms, whether new targeted therapies such as avatinib can change the disease process and bring long-term benefits also requires clinical research and long-term benefits.
Follow-up to confirm, but from the preliminary results of early clinical studies, the prospects are very promising
.
The journey of a thousand miles begins with a single step.
Learning the diagnosis and treatment of systemic mastocytosis is not too late.
It can even be said that in this rapidly changing tumor species, everyone starts from scratch
.
If you learn more, you can go a step further, reduce missed diagnosis and misdiagnosis, and make good use of existing treatments
.
References: 1.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al.
KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA ) in a series of 113 patients[J].
Blood, 2006, 108(7): 2366-2372.
2.
Martelli M, Monaldi C, De Santis S, et al.
Recent advances in the molecular biology of systemic mastocytosis: implications for diagnosis , prognosis, and therapy[J].
International Journal of Molecular Sciences, 2020, 21(11): 3987.
3.
Tobío A, Bandara G, Morris DA, et al.
Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production [J].
Haematologica, 2020, 105(1): 124-135.
4.
Jawhar M, Schwaab J, Schnittger S, et al.
Additional mutations in SRSF2,ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis[J].
Leukemia, 2016, 30(1): 136-143.
5.
Muñoz-González JI, Alvarez-Twose I, Jara-Acevedo M , et al.
Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis[J].
Blood, The Journal of the American Society of Hematology, 2019, 134(5): 456-468.
6.
Matito A, Morgado JM, Alvarez-Twose I, et al.
Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome[J].
PLoS One, 2013, 8(10): e76116.
7.
Lim KH, Tefferi A, Lasho TL, et al.
Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors[J].
Blood, 2009, 113(23): 5727-5736.
8.
Escribano L, Álvarez-Twose I, Sánchez-Muñoz L, et al.
Prognosis in adult indolent systemic mastocytosis:a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients[J].
Journal of Allergy and Clinical Immunology, 2009, 124(3): 514-521.
9.
Gotlib J, Radia DH, George TI, et al .
Pure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I, Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoPure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I , Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoPure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I , Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoAuthor of this articleTan ShuoAuthor of this articleTan Shuo
.
For example, the clinical research of the highly selective KIT/PDGFRA inhibitor Avapritinib (Avapritinib) has made a leap forward in the treatment of advanced systemic mastocytosis (AdvSM)
.
The diagnosis and treatment of a disease has entered a new era, and many things need to keep pace with the times
.
As the mystery of AdvSM is gradually unveiled, the various tests carried out on patients must comply with the requirements of precise targeted therapy.
It is not limited to the previous "classic projects" such as KIT D816V mutations and serum trypsin
.
More comprehensive and complete genetic testing can not only help doctors better use the new treatment option of avatinib, but also play an important role in accurately analyzing the prognosis of patients in combination with the latest evaluation models in recent years
.
"Precision treatment, testing first" should also become the motto of AdvSM diagnosis and treatment
.
The use of various precise detection methods to guide clinical diagnosis and treatment of KIT D816V mutation is only part of the characteristics of this disease.
When medical textbooks describe many diseases, they often frankly admit that "the pathogenesis of this disease is unknown.
" Systemic mastocytosis belongs to this.
Class of diseases
.
Even the iconic KIT D816V mutation, which has a positive mutation rate of 80%, has not been fully understood by scientists and doctors
.
KIT D816V mutation is an important diagnostic criterion for systemic mastocytosis, and it is also the main target of targeted drugs such as Avatinib and Midostaurin, but its specific mechanism has not yet been elucidated.
.
And there are a number of research data showing that the scope of KIT D816V mutation is not limited to mast cells
.
For example, in the hematological tumors (ie SM-AHN) often associated with AdvSM patients, the patient’s hematopoietic stem cells, progenitor cells, and even neutrophils, monocytes and eosinophils may be detected with KIT D816V mutations[ 1]
.
The earlier the KIT D816V mutation occurs, the deeper and wider the impact on the blood system may be [2]
.
At the signal pathway level, the KIT D816V mutation may activate a series of downstream pathways such as PI3K, STAT3/5, RAS, JAK2, and promote the abnormal clonal proliferation, survival and invasion of mast cells
.
Other studies have shown that the KIT D816V mutation may cause mast cells to continuously release a large amount of interleukin-6 (IL-6), leading to a cytokine storm [3]
.
SM is a multi-mutation disease (picture source: Blood) However, systemic mastocytosis is actually a "multi-mutation disease".
In addition to the iconic KIT D816V mutation, about 90% of AdvSM patients may also be detected A variety of somatic mutations, including SRSF2, ASXL1, RUNX1 and DNMT3A mutations (S/A/R/D), have been confirmed to be related to the poor prognosis of patients [4-5]
.
The latest version of the US NCCN clinical practice guidelines recommends that for patients with suspected systemic mastocytosis, in addition to the detection of KIT D816V mutations, at least three somatic mutations of S/A/R should be detected in the diagnosis, and the second generation should be considered when necessary.
Sequencing (NGS) provides important information for evaluating the prognosis of patients
.
Another "classic item" for the detection of systemic mastocytosis is serum trypsin, which is also one of the disease diagnostic criteria, but the proportion of clinical tests is not high, and it specifically evaluates the level of tryptase and the prognosis of patients.
There are few studies on the relationship [6], and it is expected that more professionals will pay attention to tryptase detection in the future, so as to improve the diagnosis rate of systemic mastocytosis and achieve new progress in diagnosis
.
However, to accurately assess the prognosis of patients with systemic mastocytosis, detection of KIT D816V mutations, serum tryptase and somatic mutations may not be enough
.
With the gradual deepening of medical understanding of this disease, new prognostic evaluation models are constantly emerging
.
Perfect the various examinations, and really use the prognostic model.
First review a knowledge point: systemic mastocytosis is divided into indolence (ISM), smoking type (SSM), aggressive (ASM), and associated hematological tumors (SM- AHN) and mast cell leukemia (MCL) five subtypes, of which the latter three are included in the advanced stage (AdvSM) category
.
From the names of these subtypes, we can see the difference between the clinical characteristics of the disease and the patient's prognosis
.
Due to the low incidence of systemic mastocytosis, survival analysis is also relatively small
.
Past data show that the life expectancy of ISM patients is not much different from that of healthy people of the same age.
Only a very small number of patients are at risk of disease progression or even malignant transformation [7-8]; the median overall survival (OS) of SSM patients is about 120 months.
Patients with ISM are significantly shorter [9]
.
The overall prognosis of AdvSM patients is indeed very bad before the approval of drugs such as Avatinib and Midostaurin that target the KIT D816V mutation
.
An analysis in 2009 showed that the median OS of ASM patients was about 41 months, the median OS of SM-AHN patients was 24 months, and the median OS of MCL patients was only 2-4 months [7]
.
Differences in life expectancy between SM patients of each subtype and healthy people of the same age (picture source: Blood) Compare the data in the Avatinib EXPLORER study.
The median OS of all AdvSM patients is 46.
9 months.
MCL patients with the worst prognosis before (13 cases) The 3-year survival rate reached 76%, and the 3-year survival rate of SM-AHN patients was also 62%.
It can be seen how important precision targeted therapy is for AdvSM patients [9]
.
However, when judging the prognosis of systemic mastocytosis, in addition to the subtype of the patient’s disease, doctors often need to combine the somatic gene mutations mentioned above, as well as laboratory test indicators such as tryptase, hemoglobin, and platelets.
, To conduct a comprehensive analysis
.
Foreign scholars have proposed a number of prognostic models for systemic mastocytosis.
The included indicators are different, and the accuracy of prediction is also different
.
Among them, the global mastocytosis prognostic score (GPSM) system, initially proposed by Spanish scholars in 2020 and perfected and verified in 2021, has high practical value
.
This model is divided into two sets of evaluation systems for progression-free survival (GPSM-PFS) and overall survival (GPSM-OS).
It uses the laboratory test indicators of more than 400 patients and the four somatic cells of S/A/R/D.
For mutation status, the scoring system as shown in the table below has been formulated.
The specific indicators and Cut-off values included are: Although the current GPSM system GPSM-PFS/OS score is not included in the KIT D816V mutation status (also does not include the mutation allele score/ VAF), but verification in more than 850 patients shows that its predictive value for patients with PFS and OS is relatively good in the existing scoring models, and bone marrow biopsy is not necessary information, and it is more convenient to use [10]
.
However, the current WHO diagnostic criteria for systemic mastocytosis has not yet included items such as alkaline phosphatase, β2-microglobulin, and S/A/R/D somatic mutations
.
To make good use of GPSM-PFS/OS and other models in clinical practice, adequate communication between doctors and patients is required, and relevant examinations are perfected as much as possible
.
A journey of a thousand miles begins with accurate detection and guidance of precise treatment with one step.
This is an inevitable trend in the development of cancer treatment.
However, there are not many treatments for systemic mastocytosis, and it is difficult to achieve diagnosis and treatment guided by detection
.
For example, in the NCCN clinical practice guidelines, there is only one such recommendation-patients with negative KIT D816V mutations can choose imatinib
.
For KIT D816V mutation-positive AdvSM patients, both Avatinib and Midostaurin are recommended as the preferred regimen (Preferred Regimen), but it is not yet possible to further clarify which patients can benefit significantly from the treatment, which requires follow-up Research to analyze
.
As for ISM/SSM patients with relatively good prognosis but impaired quality of life due to various symptoms, whether new targeted therapies such as avatinib can change the disease process and bring long-term benefits also requires clinical research and long-term benefits.
Follow-up to confirm, but from the preliminary results of early clinical studies, the prospects are very promising
.
The journey of a thousand miles begins with a single step.
Learning the diagnosis and treatment of systemic mastocytosis is not too late.
It can even be said that in this rapidly changing tumor species, everyone starts from scratch
.
If you learn more, you can go a step further, reduce missed diagnosis and misdiagnosis, and make good use of existing treatments
.
References: 1.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al.
KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA ) in a series of 113 patients[J].
Blood, 2006, 108(7): 2366-2372.
2.
Martelli M, Monaldi C, De Santis S, et al.
Recent advances in the molecular biology of systemic mastocytosis: implications for diagnosis , prognosis, and therapy[J].
International Journal of Molecular Sciences, 2020, 21(11): 3987.
3.
Tobío A, Bandara G, Morris DA, et al.
Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production [J].
Haematologica, 2020, 105(1): 124-135.
4.
Jawhar M, Schwaab J, Schnittger S, et al.
Additional mutations in SRSF2,ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis[J].
Leukemia, 2016, 30(1): 136-143.
5.
Muñoz-González JI, Alvarez-Twose I, Jara-Acevedo M , et al.
Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis[J].
Blood, The Journal of the American Society of Hematology, 2019, 134(5): 456-468.
6.
Matito A, Morgado JM, Alvarez-Twose I, et al.
Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome[J].
PLoS One, 2013, 8(10): e76116.
7.
Lim KH, Tefferi A, Lasho TL, et al.
Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors[J].
Blood, 2009, 113(23): 5727-5736.
8.
Escribano L, Álvarez-Twose I, Sánchez-Muñoz L, et al.
Prognosis in adult indolent systemic mastocytosis:a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients[J].
Journal of Allergy and Clinical Immunology, 2009, 124(3): 514-521.
9.
Gotlib J, Radia DH, George TI, et al .
Pure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I, Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoPure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I , Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoPure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
10.
Muñoz-González JI, Álvarez-Twose I , Jara-Acevedo M, et al.
Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study[J].
The Lancet Haematology, 2021, 8(3): e194-e204.
The author of this articleTan ShuoAuthor of this articleTan ShuoAuthor of this articleTan Shuo
