Interpretation of the 2021v3 NCCN Guidelines for Systemic Mastocytosis, Avatinib Becomes the First Choice

Introduction Mastocytosis is a heterogeneous group of diseases caused by the clonal proliferation of abnormal mast cells and aggregation in the skin or multiple organ systems.
In the 2017 revised World Health Organization (WHO) classification, mastocytosis is classified as It is classified as a separate disease type and is divided into 3 major categories according to pathological features, location of disease and clinical manifestations: cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma (MCS)
.

SM can be divided into five subtypes, namely indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with other clonal hematological diseases (SM-AHN), and mast cell leukemia.
(MCL), of which the latter three are referred to as late SM
.

SM is the most common mastocytosis in adults and is characterized by mast cell (MC) infiltration of one or more extracutaneous organs (with or without cutaneous involvement), with variable clinical manifestations and poor patient prognosis, especially patients with advanced SM
.

In 2021, NCCN has released three editions of the guidelines, and has made several updates to its SM diagnosis and treatment.
Yimaitong was honored to invite Prof.
Xiao Zhijian from the Institute of Hematology, Chinese Academy of Medical Sciences to conduct SM diagnosis and advanced SM treatment in the latest edition of the NCCN guidelines.
read
.

Professor Xiao Zhijian Deputy Director of the Institute of Hematology, Chinese Academy of Medical Sciences, Director of Myelodysplastic Syndrome (MDS) Diagnosis and Treatment Center Member of the Hematology and Oncology Branch Member of the Experimental Hematology Professional Committee of the Chinese Society of Surgeons Deputy Director of the State Key Laboratory of Experimental Hematology Deputy Editor-in-Chief of the Journal of Leukemia and Lymphoma Published more than 300 papers in international and domestic core journals, including in Blood, Leukemia and other journals Published more than 40 papers included in SCI.
Diagnosis and prognostic staging of SM Primary criteria: MC multifocal dense infiltration (≥15 MC aggregates) detected in bone marrow and/or other extracutaneous organ sections Spindle-shaped or atypical morphology in >25% of infiltrating MCs in biopsy sections of external organs, or immature or atypical in >25% of MCs in bone marrow aspirate smears
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The KIT D816V mutation is detected in bone marrow, blood, or other extracutaneous organs
.

MCs in bone marrow, blood, or other extracutaneous organs express CD25 with or without CD2 expression in addition to normal MC markers
.

Persistent increase in serum total tryptase >20 ng/mL (this parameter is not valid in the presence of an associated myeloid tumor)
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The 2017 revised WHO diagnostic criteria include 1 major diagnostic criterion and 4 minor diagnostic criteria.
When there are major criteria and ≥1 minor criteria, or ≥3 minor criteria, SM can be diagnosed
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Clinically suspected patients with SM need to be comprehensively evaluated, and specific diagnosis should be made according to the diagnostic criteria to distinguish CM, SM, monoclonal mast cell activation syndrome (MMAS) or other causes of mast cell activation.
The diagnostic process is shown in Figure 1
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Figure 1.
Diagnostic algorithm for mastocytosis.
SM is further divided into 5 distinct subtypes based on MC burden, degree of organ involvement, and organ damage associated with SM (ie, B symptoms and C symptoms) (Figure 2)
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Fig.
2 SM subtype diagnostic process Class B symptoms: suggest a high MC burden and have involved multiple hematopoietic lineages, with no evidence of organ damage
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High MC burden (shown on bone marrow biopsy): MC infiltration >30% (focal dense aggregates) and serum total tryptase >200 ng/mL
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Dysplasia of the non-mast cell lineage or myeloproliferation but not meeting the definitive diagnostic criteria for an associated hematological neoplasm with normal blood counts or only mild abnormalities
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Liver, spleen, and lymph nodes were enlarged, but there was no organ dysfunction
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Category C symptoms: suggestive of MC infiltration leading to organ damage (confirmed by biopsy if possible)
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Bone marrow dysfunction caused by tumorous MC infiltration, manifested as ≥1 cytopenia; absolute neutrophil count <1.
0×109L, hemoglobin <100g/L, and/or platelet count <100×109/L
.

Hepatomegaly with hepatic impairment, ascites and/or portal hypertension
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Bone involvement with large lytic lesions (≥2cm) and/or pathological fractures (except for pathological fractures caused by osteoporosis)
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Splenomegaly with hypersplenism
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Malabsorption and weight loss due to gastrointestinal MC infiltration
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The prognosis of SM patients is affected by various factors such as SM subtype, age, blood counts, and cytogenetic characteristics.
The MARS, MAPS, IPSM, and GPSM scoring systems can be used for prognostic stratification
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Treatment of advanced SM The treatment of advanced SM mainly includes cytoreductive therapy and allogeneic hematopoietic stem cell transplantation (HSCT)
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In the NCCN guidelines, cytoreductive regimens are divided into three categories: preferred regimens, other recommended regimens, and regimens useful in some cases, and all patients are recommended to be referred to a specialized mastocytosis center for diagnosis and treatment
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For SM-AHN patients whose ASM and SM components need to be treated as soon as possible, the preferred treatment options are avatinib, clinical trials or midostaurin; cladribine or peginterferon alfa-2a ± prednisone can be As an alternative recommended regimen; imatinib is only recommended for patients with ASM who are KIT D816V mutation-negative or unknown, well-differentiated SM (WDSM), or eosinophilic with the FIP1L1-PDGFRA fusion gene
.

For patients with MCL±AHN, the preferred treatment options are still avatinib, clinical trials, or midostaurin; cladribine can be used as other recommended options
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Allogeneic HSCT has been evaluated in patients with advanced SM, and results are significantly influenced by SM subtype and type of conditioning regimen: reduced-intensity conditioning regimens have lower survival than myeloablative conditioning regimens; MCL patients have the shortest survival
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If patients with ASM and MCL respond adequately to initial cytoreductive therapy, evaluation for allogeneic HCT should be considered
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In patients with SM-AHN, allogeneic HCT should be considered as part of initial therapy when the AHN component requires HCT; if the SM component presents with advanced SM (adequate response to cytoreductive therapy) or progresses during treatment For advanced SM, allogeneic HSCT should also be considered
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Figure 3 Recommendations for advanced SM treatment Professor Xiao Zhijian commented that SM is a rare disease.
Excessive proliferation and activation of abnormal mast cells can lead to extensive damage to multiple organ systems in the body of patients with SM.
Its clinical manifestations are highly heterogeneous, requiring a multidisciplinary team (MDT ) to participate in the diagnosis and treatment together
.

At present, the difficulty in the diagnosis and treatment of SM in China lies in the difficulty of identification.
SM patients are often treated in different departments, and the misdiagnosis rate is extremely high.
Therefore, for recurrent unexplained allergic reactions, edema, osteoporosis, gastrointestinal ulcers or chronic abdominal cramps , to be highly suspicious of the existence of SM
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SM-related evaluation should be performed in adult patients with suspected clinical symptoms, elevated serum tryptase levels, or biopsy-proven cutaneous mastocytosis (MIS) related to release of mast cell mediators or allergic reactions [1]
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In clinical patients suspected of SM, molecular detection of KIT D816V should be carried out using highly sensitive detection methods (such as ASO-qPCR or ddPCR)
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In SM patients, >90% of patients have KIT D816V mutation.
Therefore, for suspected SM patients, collecting bone marrow or tissue samples for KIT D816V detection should be listed as a routine diagnostic screening test [1]
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Compared with indolent SM, advanced SM is more aggressive, progresses rapidly, and has a poorer prognosis.
Its overall survival (OS) varies from months to years, with a median OS of ≤3.
5 years [2], and should be become the focus of clinical attention
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In recent years, the identification of the KITD816V mutation and the emergence of new targeted therapies have significantly improved the diagnosis and treatment of SM
.

In particular, avatinib, the first KIT D816V selective inhibitor clinically validated in SM
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In two studies of avatinib in patients with advanced SM (EXPLORER study and PATHFINDER study), patients achieved an overall response rate (ORR) of 75%, avatinib significantly reduced mast cell burden, induced sustained remission, and The depth of remission deepened over time and was well tolerated by patients.
Common (≥25%) adverse events (any grade, ≥3) were peripheral edema (50%, 3%), periorbital edema (48%, 3 %), thrombocytopenia (45%, 16%), and anemia (32%, 16%), and only 3 (5%) patients discontinued due to treatment-related adverse events [2,3]
.

The EXPLORER study showed that the median OS of avatinib in patients with advanced SM was 46.
9 months, which greatly improved patient survival [4]
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Based on these two studies, in June 2021, the FDA has approved avatinib for the treatment of advanced SM, including ASM, SM-AHN and MCL [5], and the subsequently updated 2021 v3 NCCN SM guidelines will include avatinib Listed as the preferred recommended regimen, and a new section on the management of toxicity for avatinib was added (Figure 4)
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In addition, co-administration of avatinib with strong and moderate CYP3A inhibitors increases the concentration of avatinib and should be avoided in clinical practice.
If co-administration of avatinib with moderate CYP3A inhibitors cannot be avoided, Avatinib dose should be adjusted [1]
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Figure 4 Avatinib toxicity management Before the advent of avatinib, there was no KIT D816V mutation-selective inhibitor, and the multikinase inhibitor midostaurin was approved for the treatment of advanced SM with an ORR of 28%, although it can be delayed SM progresses, but has little effect on the organ damage associated with SM, and the survival rate of patients is still low [6]
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Avatinib is the first effective selective inhibitor of KIT D816V, its emergence significantly improved the survival of patients with advanced SM and brought a milestone progress for the treatment of advanced SM
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References: [1] NCCN.
The NCCN guidelines for Systemic Mastocytosis (version 3.
2021) [EB/OL].
[2022-03-21].
[2] DeAngelo, DJ, Radia, DH, George, TI et al.
Safety and Efficacy of avapritinib in advanced systemicmastocytosis: the phase 1 EXPLORER trial[J].
Nat Med.
2021;27(12):2183-2191.
[3].
Gotlib,J.
, Reiter, A.
, Radia, DH et al.
Efficacy and safety of avapritinib inadvanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDERtrial[J].
Nat Med.
2021;27(12):2192-2199.
[4] Gotlib J, Radia DH, George TI, etal.
Pure pathologic response is associated with improved overall survival inpatients with advanced systemic mastocytosis receiving avapritinib in the phaseI EXPLORER study[J].
Blood, 2020, 136(Suppl 1): 37-38.
[5] USFood and Drug Administration.
FDAapproves avapritinib for advanced systemic mastocytosis[EB/OL].
https:// Gotlib J, et al.
Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis[J].
N Engl J Med.
2016;374(26):2530-2541.
NPM-CN-HEMA-060-20230328 Editor: Mia typesetting: Wenting stamps "read the original text", we will make progress together