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Therapy for Advanced SM
Selecting Therapy for Patients With Advanced Systemic Mastocytosis

Released: April 21, 2022

Expiration: April 20, 2023

Prithviraj Bose
Prithviraj Bose, MD
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Selecting Therapy for Patients With Advanced Systemic Mastocytosis
Systemic mastocytosis (SM) is a rare mast cell proliferation disorder with variable outcomes—where patients with indolent disease can have a near-normal lifespan, yet those with advanced disease may live only several years after diagnosis. Despite its rarity, multiple therapies are available to manage advanced SM (AdvSM). In this commentary, I review key data on AdvSM, its treatment options, and how to select therapy for individuals with this condition.

SM Subtypes
The entities aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) generally comprise AdvSM, although there are some nuances. For example, a C finding (organ damage from the infiltrating mast cells) is required only for a diagnosis of ASM, whereas MCL—defined by the presence of ≥20% mast cells on bone marrow aspirate smears—can sometimes be chronic, ie, lacking C findings. SM-AHN is the most common subtype of AdvSM but represents a heterogenous group in which the SM component can be indolent, smoldering, or aggressive. Outcomes may be determined by either the SM or the AHN component, making it important to decide which entity deserves attention first.

Compared with patients with indolent and smoldering SM, those with AdvSM have considerably shorter survival: In a 2019 study from the European Competence Network on Mastocytosis (ECNM), median overall survival (OS) times for ASM, SM-AHN, and MCL were 5.7, 2.9, and 1.9 years, respectively. Fortunately, AdvSM is rare; a 2020 German study estimated the incidence and prevalence of AdvSM to be “at least” 0.8 and 5.2 per million, based on locally diagnosed cases in an area of 2.5 million inhabitants.

Treatment Options
Conventional cytoreductive therapies for SM include interferon and cladribine. Interferon, with or without glucocorticoids, was found to have a rate of “major” response (defined as complete resolution of ≥1 C findings) in ASM of approximately 21% by Valent criteria. The cytotoxic chemotherapeutic agent cladribine yielded a response rate by the same criteria of 50% in 32 patients with AdvSM, with 37.5% being major responses and 12.5% partial responses. The median duration of response (DoR) with cladribine was 2.47 years for ASM and 4.77 years for SM-AHN. A recent report from the Mayo Clinic on cladribine in 22 patients with AdvSM found an overall response rate (ORR) of 77% (45% major responses) and a median DoR of 10 months.

Three therapies are approved by the FDA for AdvSM. The first, imatinib, lacks efficacy against the most common KIT D816V mutant and is, therefore, not an option for most patients. The other 2 approved therapies are midostaurin, a multikinase inhibitor, and avapritinib, a highly potent and selective inhibitor of KIT D816V, the driver mutation found in 90% to 95% of patients with SM.

In the pivotal phase II study of midostaurin in AdvSM, the ORR by modified Valent criteria in 89 evaluable patients was 60%, 45% being major responses. The median DoR was 24.1 months, median progression-free survival (PFS) 14.1 months, and median OS 28.7 months. The presence of SRSF2/ASXL1/RUNX1 mutations and a decrease in KIT D816V variant allele frequency (VAF) of <25% predicted for inferior OS on midostaurin.

Gastrointestinal toxicity is a particular problem with midostaurin; routine antiemetic and antidiarrheal prophylaxis should be considered for patients receiving this agent. The prescribing information does contain a warning for pulmonary toxicity (eg, interstitial lung disease and pneumonitis). The starting dose in AdvSM is 100 mg twice daily with food.

In the phase I and II trials of avapritinib, the ORR across 85 evaluable patients with AdvSM was 75% using the modified International Working Group for Myeloproliferative Neoplasm Research and Treatment–ECNM criteria. When these same criteria were applied post hoc to the midostaurin pivotal trial, the ORR was 28%, and the rate of complete response (CR) and partial response (ie, not counting “clinical improvement”) was 17%. Returning to avapritinib, the rate of CR plus CR with partial hematologic recovery (CRh) was 36% in the phase I trial and 19% in a preplanned interim analysis of the phase II trial. CR/CRh is rare with midostaurin. Responses to avapritinib were rapid and deepened over time, with a median time to response of 2 months in both trials and a median time to CR/CRh of 5.6-9 months. In the phase I trial, the median DoR was 38 months, and median OS had not been reached after a median follow-up of 23 months.

Although the ORRs and CR/CRh rates were numerically higher in midostaurin-naive patients, survival was not substantially different between midostaurin-naive and midostaurin-exposed patients. Consistent and profound reductions were observed in bone marrow mast cells, serum tryptase, spleen volume, and KIT D816V VAF. Interestingly, marked decreases in monocyte and eosinophil counts were observed in patients with SM-AHN where the AHN was chronic myelomonocytic and eosinophilic leukemia, respectively. This is consistent with KIT D816V being present in multiple lineages, as has been shown.

Periorbital and peripheral edema are very common with avapritinib. Cognitive impairment, mostly low grade and dose dependent, may be seen. Intracranial hemorrhage is a particular concern in patients with a baseline platelet count below 50 x 109/L; avapritinib is not approved in this setting. The starting dose in AdvSM is 200 mg daily on an empty stomach.

Selecting Therapy
Because SM-AHN is the most common subtype of AdvSM, deciding whether treatment of the SM or the AHN component is more urgent is a fundamental step in choosing therapy. Attribution of organ damage to the mast cell component or to the AHN can be a challenge. Of the 2 FDA-approved KIT inhibitors, avapritinib is the more potent and selective, which appears to translate to greater efficacy in terms of both response rates and survival. Risk factors for toxicity, such as severe thrombocytopenia, baseline cognitive impairment, and/or gastrointestinal symptoms, also may help in selecting between avapritinib and midostaurin.

Imatinib can be very useful in the rare cases lacking KIT D816V, which must be looked for using a highly sensitive assay such as droplet digital or allele-specific oligonucleotide polymerase chain reaction. Though nonspecific, cladribine remains a useful agent in situations where rapid debulking is desired, although responses to avapritinib are rapid, as well.

Treatment options are available for patients progressing on KIT inhibitors. Avapritinib retains efficacy in patients previously treated with midostaurin, but data are not yet available on the efficacy of midostaurin in those previously treated with avapritinib. Bezuclastinib is a new small-molecule inhibitor of mutant KIT that exhibits limited penetration of the blood–brain barrier. This agent is being studied in the APEX trial in patients with AdvSM (NCT04996875); prior midostaurin and/or avapritinib are permitted. BLU-263 is a similar agent with activity against KIT D816V and is under investigation in the phase II/III HARBOR trial (NCT04910685). Outside of clinical trials, cladribine remains an important option for patients whose disease progresses on KIT inhibitors. 

To learn more about the latest developments in AdvSM, please read this commentary from Daniel J. DeAngelo, MD, PhD.

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Which of the following best describes when you are most likely to recommend clinical trials over current FDA-approved KIT inhibitors for your patients with AdvSM?
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