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Professor of Medicine
Department of Medicine
Harvard Medical School
Chief of the Division of Leukemia
Department of Medical Oncology
Division of Hematologic Malignancies
Dana‐Farber Cancer Institute
Daniel J. DeAngelo, MD, PhD, has disclosed that he has received funds for research support from AbbVie, Blueprint, GlycoMimetics, and Novartis and consulting fees from AbbVie, Agios, Amgen, Autolus, Blueprint, Forty Seven, GlycoMimetics, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda.
Systemic mastocytosis (SM) is a rare condition that is challenging to diagnose. Making a diagnosis of SM requires meeting a subset of major and minor pathologic findings as defined by the WHO. The major finding is the presence of mast cell aggregates in bone marrow (BM) and/or other extracutaneous organs, and the minor findings are atypical/spindle-shaped mast cell morphology, CD25-positive mast cells, an activating KIT D816V mutation, and elevated tryptase. Patients are considered to have advanced systemic mastocytosis (AdvSM) when they develop organ dysfunction, at which point they have a limited life expectancy and meet the indications for therapy.
In this commentary, I provide a brief overview of current treatment options and review the most clinically important studies on AdvSM from the 2021 American Society of Hematology (ASH) annual meeting.
Available Treatment Options for AdvSM
The FDA has approved 2 therapies for AdvSM, with both being indicated for treatment of adults who have AdvSM, including aggressive SM, SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia. The first is midostaurin, a multikinase inhibitor with activity against KIT D816V, and the second is avapritinib, a tyrosine kinase inhibitor that more selectively targets KIT D816V. Other therapies used in practice include cladribine, a nonspecific nucleoside analogue, and occasionally interferon.
Patients also require supportive care to mitigate mast cell activation symptoms such as anaphylaxis and gastrointestinal toxicity. These supportive approaches incorporate H1 or H2 antihistamines, leukotriene antagonists, mast cell stabilizers such as cromolyn, and even corticosteroids.
ASH 2021 Highlights in AdvSM
Assessing Response and Characteristics of Nonresponders in Pivotal Avapritinib Trials
ASH 2021 featured 2 important analyses of the pivotal trials that led to FDA approval of avapritinib for AdvSM. The first analysis characterized the effects of avapritinib on BM and hematologic parameters in the phase II PATHFINDER trial. George and colleagues reported a rapid reduction in BM mast cell burden as early as 8 weeks after initiating avapritinib. More than 95% of patients achieved a reduction in BM mast cell burden, with almost 84% experiencing a reduction ≥50%. Other markers indicated improvement in BM morphology, including decreases in immature or spindle-shaped mast cells, a decrease in the proportion of CD25-positive and CD30‑positive mast cells, and decreased fibrosis in BM biopsies. These findings demonstrate that avapritinib induces very rapid and deep morphologic remissions in BM.
Deininger and colleagues analyzed molecular markers of disease progression in the phase I EXPLORER trial. Only 14 patients (20%) had clinical progression on avapritinib, and in most cases, progression was only within the associated hematologic neoplasm (AHN) rather than the mast cell component. Both responders and those experiencing progression exhibited a complicated pattern of comutations that were not associated with KIT. These data indicate that patients with SM‑AHN may need combination therapy comprising a targeted KIT inhibitor plus another nonselective therapy to treat the AHN (eg, a DNA methyltransferase inhibitor such as azacitidine or decitabine).
Real-World Efficacy of Cladribine
Cladribine is associated with profound reductions in mast cell burden but few complete remissions. Tefferi and colleagues analyzed the real-world efficacy of cladribine therapy in 42 consecutive cases with SM, including 22 with AdvSM, treated at the Mayo Clinic. The overall response rate was 77% in the patients with AdvSM. Most responses were decreases in the BM mast cell burden and not complete remissions, which are defined by International Working Group classification as a return of normal hematopoiesis and resolution of the C-findings. Nevertheless, cladribine remains an effective option for patients who do not tolerate or who progress on targeted therapy.
Performance of MARS in UK Cohort
Prognostic scoring systems to help guide management decisions for patients with AdvSM are under development, including the mutation-adjusted risk score (MARS) prognostic scoring system that was developed by Reiter and colleagues using data from US, German, and European patients with AdvSM. MARS is calculated using 5 parameters (age, anemia, thrombocytopenia, presence of 1 high-risk mutation, and presence of ≥2 high-risk mutations) and is independent of WHO classification. At ASH 2021, Sriskandarajah and colleagues reported that MARS performed well in a real-world cohort of 55 patients with AdvSM in the UK. The reported 10-year overall survival rate was 87% in the low-risk group, 35% in the intermediate-risk group, and 30% in the high-risk group. These consistent results for OS based on the MARS prognostic risk groups argue that we should approach patients with AdvSM in a similar manner to the approach we take with patients with myelodysplastic syndromes and myeloproliferative neoplasms. Indeed, MARS may be able to better identify which patients have advanced disease and need therapy.
Organ Dysfunction by AdvSM Subtypes
Liver dysfunction is an important yet frequently overlooked complication of AdvSM. Using data from a Stanford registry, Liang and colleagues analyzed the pattern of organ dysfunction at initial presentation across all AdvSM subtypes. Of note, liver-related organ damage occurred more frequently in patients with SM-AHN and mast cell leukemia as opposed to aggressive SM.
Approximately 5% of the general population has hereditary α-tryptasemia (HαT), a condition characterized by elevated serum tryptase and mast cell activation symptoms caused by an increased copy number of TPSAB1. At ASH 2021, Vanderwert and colleagues reported that HαT occurred in 65.9% of a cohort with mast cell activation symptoms without a concurrent SM diagnosis and in 9.3% of patients with SM. Individuals with SM and HαT do not achieve normalized serum tryptase even with targeted therapy, and it is important to be aware of the higher prevalence of HαT in these populations.
Phase II Trial of Novel KIT D816V Inhibitor Bezuclastinib (CGT9486)
Finally, I want to highlight a trial that just opened recently. Gotlib and colleagues reported on a multicenter phase II trial evaluating the activity, pharmacology, and safety of bezuclastinib in patients with AdvSM (NCT04996875). Bezuclastinib is an investigational tyrosine kinase inhibitor that is highly selective for the KIT D816V alteration and has pharmacologic properties different from approved agents (eg, limited central nervous system penetration).
How will these new data in AdvSM from ASH 2021 affect your practice? Please answer the polling question and join the conversation by posting a comment in the discussion section.