Faculty convened for a virtual OncLive Scientific Interchange and Workshop to interpret emerging trial data and treatment strategies for systemic mastocytosis.
As treatment strategies for systemic mastocytosis evolve, considerations for patient quality of life (QOL) and symptom management should be a key factor in the equation, experts shared during a a recent OncLive® Scientific Interchange and Workshop.1
"A lot of [the management of systemic mastocytosis] becomes a question about symptom impact rather than symptom burden," said Raajit Rampal, MD, PhD, said regarding emerging data and evolving strategies in systemic mastocytosis.1
That distinction anchored faculty discussion of indolent systemic mastocytosis, even as they debated how far disease modification can be stretched in a population with near-normal life expectancy. The panel also reviewed newly reported data before turning briefly to advanced systemic mastocytosis, where faculty agreed prognosis is dictated less by mast cell burden than by the associated hematologic neoplasm.
Rampal is a director at both the Center for Hematologic Malignancies and Myeloproliferative Neoplasms (MPNs) Program at Memorial Sloan Kettering Cancer Center in New York, New York.
The workshop was moderated by Tracy I. George, MD, chief scientific officer, president of the Innovation Business Unit, and medical director of Hematopathology at ARUP Laboratories, as well as a professor of pathology at the University of Utah School of Medicine in Salt Lake City.
Other workshop faculty included:
Faculty split on validated symptom assessment tools for systemic mastocytosis. Radia utilizes symptom scores like the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF), compared with Giannetti and Reiter, who favor clinician assessment coupled with reports from patients.
However, Radia concurred with the two, pointing out the limitations of symptom scores. “We have some objective markers that are validated, but they do miss a lot of the domains,” Radia said. “It's about getting a truer picture…the conversation with the patient is really important.”
Akin explained that such symptom forms can miss high-consequence events.
“Anaphylaxis and osteoporosis are not [accounted for in symptom assessment forms], but they might actually reduce the patient quality of life the most,” Akin explained, then highlighted the Mastocytosis Control Test as a validated compromise.
The discussion pivoted to specific symptoms and which can require more focused management approaches. The experts highlighted symptoms such as fatigue, cognitive symptoms, gastrointestinal symptoms, and bone pain.
“The challenging bit from [symptoms like cognitive symptoms and bone pain], which are the most challenging ones, is that they're multifactorial,” Radia added. “We have to think of better ways of making [the term of brain fog] deconstructed so it's meaningful medically, as well as to the patient. For the very few patients who get severe bone pain, that's really difficult.”
In the phase 2 PIONEER study (NCT03731260), patients received up to 5 years of avapritinib (Ayvakit) at once-daily doses of 25 mg or placebo. Data from the trial showed that patients who received avapritinib for 1 year (n = 173) reported a –30.96% mean change in Mastocytosis Quality of Life Questionnaire (MC-QOL) score, in addition to a mean change of -35.41% at 4 years (n = 79).2
Moreover, at 4 years, 51.9% of patients reported a reduction in how often their ability to attend school or work is limited by systemic mastocytosis and 58.2% reported a reduction in how often their interpersonal relationships are limited.3 Patients who received avapritinib also demonstrated a 50% or more tryptase reduction rate of 54%, with 68% of patients experiencing at least a 50% KIT D816V variant allele frequency reduction (P <.001 for both).2
Multiple workshop faculty noted how improvements in symptom burden and QOL, even for one symptom, can make a significant difference for patients.
“Things [like QOL] are important for our patients. Sometimes even a little bit of symptom improvement can lead to significant QOL improvement for individual patients,” Vacchani said. “Even a 25% or 30% decrease of bowel movements per day for some of these patients could mean [more freedom] to go to concerts, work, and grocery shopping. That can mean a lot for our patients, [and these data] definitely do resonate with me.”
Additionally, other faculty underscored how, while promising, symptom score improvement data should not solely inform treatment decision-making.
“At the end of the day, what we're really trying to do is improve the QOL, and that's very dependent on [a patient’s] most bothersome symptom,” Giannetti said. “All [of these trial end points] are important, but I'm not sure that I would single out any as being the most globally important assessment.”
In the phase 2 SUMMIT trial (NCT05186753), patients (n = 119) who received once-daily 100 mg doses of bezuclastinib (CGT0486) experienced 24-week mean change in total symptom score (TSS) of –24.32 points (95% CI, –27.56 to –21.08) vs –15.41 points (95% CI, –19.57 to –11.24) with placebo (P < .001).4
Moreover, 95.4% of patients achieved at least a 50% tryptase reduction, and 85.7% of patients experienced at least a 50% KIT D816V VAF reduction at 24 weeks.
Since PIONEER and SUMMIT evaluated avapritinib and bevaclastinib, respectively, vs placebo, experts cautioned against making cross-trial comparisons between the two agents in the absence of prospective head-to-head data. Importantly, they noted that the two studies utilized different methods for evaluating patient-reported outcomes: PIONEER featured the ISM-SAF, while SUMMIT used the Mastocytosis Symptom Severity Daily Diary. (MS2D2).
“These are different symptom assessment tools done differently. It's not just a different tool, but [theses] are also checked differently,” Vachhani explained. “If you just compare the absolute amount of symptom decrease that happened in the avapritinib arm of PIONEER vs the bezuclastinib arm of SUMMIT, it would give you one answer, but if you try to attempt a more apples-to-apples comparison by adjusting for what the baseline symptom scores were on each of the arms, then it looks actually very identical. On the other hand, the biomarker improvements are definitely more with bezuclastinib at 100 mg.”
Other faculty members discussed each data set in terms of symptoms and QOL for patients with advanced systemic mastocytosis.
“The non-penetrance into the central nervous system [with bezuclastinib] is an important differentiating factor, especially for patients on higher doses of avapritinib for advanced systemic mastocytosis,” Tashi highlighted. “[These patients can] get these so-called brain fogs, maybe because of the treatment. I have quite a few of [these patients where] it may be beneficial to use bezuclastinib instead.”
Regarding a potential FDA approval of bezuclastinib for indolent systemic mastocytosis, faculty members weighed in on potential use cases for the drug. In March 2026,
“One niche for bezuclastinib could be in those who have cognitive changes on [treatment with] avapritinib. I have a handful [of patients] who are unwilling to do avapritinib because they have some vascular hemangiomas that have a very low but quantifiable risk [above] the general population for bleeding,” Giannetti added. “Patients like that are appropriately concerned about avapritinib; that potentially would be a really nice niche for bezuclastinib.”
Beyond QOL considerations, the toxicity profiled of the two agents could also serve as a basis for treatment considerations.
“It [also may involve] looking at the safety profiles. [For] patients who have liver involvement, maybe you might be a bit more cautious if you've got to choose between [avapritinib and bezuclastinib],” Radia explained “If you have your hands tied to whether you can escalate a dose of avapritinib and your patients lose their response, you can be safe in the knowledge that if you move them over to bezuclastinib, they [should] still have a response.”
Workshop faculty highlighted the specific challenges of each patient as essential when approaching advanced systemic mastocytosis treatment for patients who progress from indolent systemic mastocytosis.
“[How to approach treatment] depends on what the problem is that we're dealing with. In patients with organ dysfunction, that's one thing, but in a patient with, for example, a concurrent chronic myelomonocytic leukemia [CMML], organ dysfunction may be the first thing we deal with, but then we have to think about the broader and longer-term perspective of what's going to happen in the bone marrow,” Rampal said. “We see so many of these cases where patients get better on TKIs from the perspective of a mast cell disease, only to eventually have the CMML blossom and become the real driving problem for the patient. The perspective has to inform where the starting point is, meaning that these patients might need a stem cell transplant.”
