Future directions in ISM, including evolving treatment goals, unanswered questions about osteoporosis, anaphylaxis, resistance, curative strategies, and the need to extend advances to pediatric populations.

Future Directions in ISM: Long-term Outcomes, Unanswered Questions, and Pediatric Considerations

The integration of disease-targeted therapies into indolent systemic mastocytosis (ISM) care is shifting treatment goals from symptom palliation alone toward combined objectives of symptom control and disease modification. As clinicians gain comfort with prescribing KIT D816V inhibitors and more patients receive these agents, expectations increasingly encompass reduction of skin lesions, normalization or marked lowering of serum tryptase, and sustained improvement in quality of life. Long-term extension data from PIONEER, with median follow-up approaching 4 years and some patients exceeding 5 years, indicate that the symptomatic and biomarker benefits of avapritinib can be durable, with no new safety signals and a low incidence of serious adverse events over time.

Despite these advances, important knowledge gaps remain. The impact of KIT inhibition on osteoporosis, which affects approximately 30% of patients with systemic mastocytosis, is incompletely understood. Key questions include whether reducing mast cell burden and mediator release can meaningfully alter bone density trajectories and whether tyrosine kinase inhibitors can be used as standalone approaches or must be combined with standard antiosteoporotic agents such as bisphosphonates or monoclonal antibodies. Similarly, the effect of avapritinib on anaphylaxis risk—seen in roughly 40% of patients and often triggered by Hymenoptera venom or other IgE-mediated stimuli—requires dedicated study. Conceptually, lowering mast cell burden should reduce risk, but prospective, controlled data are lacking.

Longer-term considerations also include the potential for resistance, opportunities for curative or treatment-free remission strategies, and extension of targeted approaches to pediatric disease. To date, no clear cases of clinical resistance to avapritinib have been documented in ISM over follow-up periods of up to 5 years, a finding that may reflect the relatively low proliferative rate of mast cells in indolent disease. Future research may explore combination regimens pairing KIT D816V–selective inhibitors with other pathway-directed agents or monoclonal antibodies to achieve deeper clonal eradication or permit intermittent rather than continuous dosing. In this concluding segment of the video series, Akin highlights these unanswered questions and underscores the need to adapt emerging therapies and evidence-based strategies for children with cutaneous and systemic mastocytosis, a population for whom current approvals and data are limited.

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Key Takeaways in Colorectal Cancer Screening

In the final episode, ‘Key Takeaways in Colorectal Cancer Screening,’ the faculty emphasize that while colonoscopy remains the gold standard, noninvasive stool-based tests are appropriate alternatives for average-risk patients who decline invasive screening. They stress that symptomatic or high-risk individuals—including those with family history, genetic syndromes, inflammatory bowel disease, or prior polyps—require diagnostic colonoscopy rather than screening tests. The discussion highlights emerging DNA- and RNA-based technologies as promising tools to expand screening uptake, particularly given workforce limitations in gastroenterology. With the screening age lowered to 45, capacity constraints have prompted ongoing conversations about how best to allocate colonoscopy resources. Ultimately, the segment reinforces the importance of individualized risk assessment, patient education, and shared decision-making to reduce colorectal cancer morbidity and mortality. Thank you for watching this HCP Live Peers &

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Our next episode, ‘Key Takeaways in Colorectal Cancer Screening,’ the expert faculty reinforce that colorectal cancer screening should be individualized based on risk, symptoms, and patient preference, with colonoscopy reserved for high-risk or symptomatic patients and noninvasive options appropriate for average-risk individuals. The discussion emphasizes shared decision-making, appropriate use of emerging technologies, and the importance of increasing screening rates to reduce both mortality and morbidity from colorectal cancer.

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Michael E. Thase, MD, of the University of Pennsylvania

Maintenance Dosing, Safety Shape GH001 Outlook, With Michael E. Thase, MD

In the third part of an interview discussing phase 2b findings of inhaled mebufotenin (GH001) for 

, Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania, emphasized the importance of maintenance strategies, safety considerations, and future research priorities following rapid antidepressant effects observed in the randomized trial.

“Retreatment will be a reality for most people who have a benefit… I’m telling people, I think it’s going to be every 6 weeks in standard of care,” Thase told 

The double-blind phase 2b study of 81 patients demonstrated significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at day 8 with GH001 versus placebo (least squares mean difference, −15.5; 

 < .001), with remission achieved in 57.5% of treated patients and none receiving placebo. However, durability data from the 6-month extension suggested many patients required additional dosing to maintain benefit.

Thase noted that the risk of relapse clustered early after response. The most vulnerable patients began to show symptom worsening within the first month, with a second group relapsing between months 1 and 2. On average, retreatment occurred approximately 6 weeks after the initial treatment, with additional retreatments distributed over the subsequent 4 months. Overall, roughly 90% of patients required ≥ 1 retreatment within 6 months, and individuals who initially responded typically received about 3 retreatments.

He suggested clinicians anticipate intermittent maintenance dosing, potentially every 6 to 8 weeks, while acknowledging variability. Thase also highlighted a potential role for relapse-prevention–oriented psychotherapy during the maintenance phase, hypothesizing that combining circuit “resetting” effects of psychedelics with structured psychotherapy may reduce retreatment frequency and associated costs.

Regarding safety, Thase reported no severe adverse psychoactive experiences among the 81 treated participants. No patients discontinued due to the intensity of effects, though he cautioned that rare “bad trips” may emerge in larger populations. Supportive clinical monitoring during administration may help patients tolerate transient experiences. He also referenced emerging compounds targeting similar serotonergic pathways without hallucinogenic effects.

Looking ahead, Thase identified replication of efficacy as the primary research priority, followed by optimization of long-term dosing strategies. He noted no evidence of dose tolerance in extension data. He concluded by emphasizing caution pending phase 3 trials, particularly those including US sites, stating that “a sufficient level of caution skepticism” remains appropriate while further data are generated.

“This is a project I've been involved with from the beginning, and so it started one day in early 2020, right at the beginning of the pandemic. We couldn't get this done in the US,” Thase said. “[The] next phase will definitely involve US participation…I really want to wait and see…what happens in phase 3 when we get the big US studies [on] how this will look. My final caveat is that there's a lot of work yet to be done.”

 of the interview with Thase on the lack of a placebo response and the clinical advantages of GH001, respectively.

Relevant disclosures for Thase include Otsuka Pharmaceutical, Janssen Scientific Affairs, E.R. Squibb & Sons, Eli Lilly and Company, H. Lundbeck A S, Boehringer Ingelheim International GmbH, and ITI, Inc. (d/b/a Intra-Cellular Therapies, Inc.).

Cubala WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. 

In part 3 of an interview, Michael E. Thase, MD, discusses retreatment timing, safety monitoring, and research priorities following phase 2b GH001 data.

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Use of symptom and quality-of-life tools alongside biomarkers in PIONEER, principles of dose titration from 25 mg to 50 mg, and practical recommendations for longitudinal safety monitoring.

Measuring Response in ISM: PRO Tools, Biomarkers, and Dose Optimization With Avapritinib

Assessment of therapeutic response in indolent systemic mastocytosis (ISM) requires integration of patient-centered outcomes with objective disease markers. In PIONEER, investigators used an ISM-specific symptom assessment form and a mastocytosis quality-of-life questionnaire (eg, MC-QoL) in conjunction with traditional biomarkers. These instruments captured dimensions such as daily functioning, emotional well-being, and the global impact of disease, thereby extending beyond what can be inferred from serum tryptase, bone marrow mast cell percentages, or KIT D816V variant allele frequency. Clinical experience confirms that symptom burden and mast cell burden may be discordant across individuals, underscoring the need to evaluate both domains when gauging treatment success.

Dose flexibility represents another tool for individualizing therapy. During the extension phase of PIONEER, patients who derived suboptimal benefit at 25 mg daily—judged by persistent symptoms or limited biomarker change—were eligible for escalation to 50 mg at the investigator’s discretion and with patient agreement. Early dose-finding work demonstrated that 25‑, 50‑, and 100‑mg doses all produced substantial symptom reductions in a small cohort, without clear dose-limiting toxicities, prompting selection of 25 mg as the minimal effective dose for broader study. Subsequent experience indicated that some patients who did not achieve satisfactory control at 25 mg improved after titration to 50 mg, without emergence of new safety signals.

From a monitoring standpoint, avapritinib is generally well tolerated in ISM, and current product labeling does not mandate intensive laboratory surveillance. Nonetheless, many experts advocate periodic complete blood counts with differential—particularly to follow platelet trends—as part of good clinical practice. Serial measurement of serum tryptase is commonly used to track mast cell burden, and centers with access to KIT D816V allele burden testing may incorporate this as an additional longitudinal marker. In this video portion, Akin outlines a pragmatic approach to long-term follow-up for patients receiving avapritinib, emphasizing judicious laboratory monitoring, reproductive counseling, and ongoing assessment of clinical response and tolerability.

Victoria Johnson joined MJH Life Sciences in 2020 and has written for NeurologyLive, CGTLive, and is now an assistant managing editor for HCPLive and RheumatologyLive. She doesn’t have enough time for her numerous hobbies. You can reach her at vjohnson@mjhlifesciences.com.

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