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Expert Perspectives on Incorporating Targeted Therapies Into Multidisciplinary Management of Advanced Systemic Mastocytosis
  • CME
  • CE

Prithviraj Bose, MD
person default
Ilene A. Galinsky, NP
Caitlin R. Rausch, PharmD
Released: April 12, 2022

Management of Advanced SM

Treatment Goals

Prithviraj Bose, MD:
The goals of treatment in patients with advanced SM are to control and prevent triggering of symptoms and to reduce mast cell burden (cytoreduction), thereby preventing further organ damage and prolonging survival.13 Cytoreductive therapies have included cladribine, peginterferon α-2a with or without prednisone, and allogeneic HSCT. More recently, the multikinase inhibitor midostaurin and the selective inhibitor avapritinib have become preferred approaches for cytoreduction. We will first review the efficacy and safety data on these 2 targeted agents.


Prithviraj Bose, MD:
Midostaurin is a multikinase inhibitor with broad activity against both KIT D816V and wild-type KIT.13 The FDA approved midostaurin for the treatment of adults with aggressive SM, SM-AHN, or MCL in 2017, based on the results of a phase II trial, which we will review next.14,15

Registrational Phase II Trial of Midostaurin in Patients With ASM, SM-AHN, or MCL

Prithviraj Bose, MD:
The efficacy and safety of midostaurin in advanced SM was evaluated in an international, open-label, single-arm phase II trial.15 Patients were eligible if they had ASM, SM-AHN, or MCL, had received <3 prior treatments for mastocytosis, and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-3. Participants received midostaurin 100 mg orally twice daily in 4-week cycles until progressive disease (PD), death, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response in the first six 4-week cycles maintained for ≥8 weeks, as adjudicated by the steering committee per modified Valent and Cheson criteria. The intention-to-treat (ITT) population comprised 116 patients and the primary efficacy population comprised 89 patients. The ITT population included both patients who were eligible—the primary efficacy population—and those who were ineligible, defined as patients who could not undergo a response evaluation because they lacked measurable C-findings or had C-findings deemed unrelated to SM.

Phase II Trial of Midostaurin in AdvSM: Response in Primary Efficacy Population (Primary Endpoint)

Prithviraj Bose, MD:
The overall response rate (ORR) was 60% by Valent and Cheson criteria, including 45% with a major response and 15% with a partial response (PR).15 The median duration of response was 24.1 months.

It is critical to point out that the criteria for response adopted in this trial are different from the more recent trials evaluating avapritinib in advanced SM. The PATHFINDER and EXPLORER trials of avapritinib used the modified International Working Group (IWG) criteria, and observed ORRs of 75%, as we will discuss soon in more detail.16,17 By comparison, the European Medicines Agency and the FDA performed post hoc analyses of the midostaurin data using the modified IWG criteria and reported lower ORRs of 28% and 17%, respectively.18 This illustrates how the response criteria used can make a huge difference in the reported outcomes.

Phase II Trial of Midostaurin in AdvSM: Clinicopathologic Measures of Response

Prithviraj Bose, MD:
Among 72 evaluable patients, 57% achieved a decrease in BM mast cell burden of ≥50%.15 Fifty-three of 89 patients (60%) had ≥50% decrease in serum tryptase, and 30 of 39 (77%) patients with splenomegaly at baseline had any reduction in spleen volume.

Phase II Trial of Midostaurin in AdvSM: Overall Survival

Prithviraj Bose, MD:
After a median follow-up of 26 months, median overall survival (OS) was 33.9 months in the ITT population and 28.7 months in the primary efficacy population.15 The OS rates were quite similar between the populations, with 46% in each population alive at Year 3.

Phase II Trial of Midostaurin in AdvSM: Safety

Prithviraj Bose, MD:
The most common nonhematologic adverse events (AEs) seen with midostaurin were GI toxicities: nausea (79%), vomiting (66%), and diarrhea (54%).15 Most of these GI toxicities were low grade. Grade 3/4 anemia occurred in 41%, thrombocytopenia in 29%, and neutropenia in 24%. There were midostaurin dose reductions in 56% of patients and 72% discontinued treatment, with the most common reasons being PD (in 33% of patients) and AEs (22%). We will discuss the management of midostaurin toxicities in more detail later.


Prithviraj Bose, MD:
Avapritinib is a tyrosine kinase inhibitor with selective activity against KIT D816V as well as PDGFRA, PDGFRA mutants, and KIT exon 11, 11/17, and 17 mutants.18,19 As I mentioned earlier, the FDA approved avapritinib for advanced SM based on positive results from the EXPLORER and PATHFINDER trials.16,17 An important limitation is that avapritinib is not recommended for patients with advanced SM and a platelet count <50 x109/L.

Phase I EXPLORER Trial of Avapritinib in Patients With AdvSM

Prithviraj Bose, MD:
EXPLORER was an international, open-label, dose-escalation and -expansion phase I trial of avapritinib in patients with advanced SM and an ECOG PS of 0-3; the trial was later amended to require a platelet count ≥50 x 109/L.17 Patients in the dose-escalation part of the study received avapritinib at doses from 30 to 400 mg/day orally in 28-day cycles. Those in the dose-expansion part received doses starting at 200 or 300 mg/day orally. The primary endpoints were maximum tolerated dose, the recommended dose for a phase II study , and safety.

EXPLORER: Best Confirmed Response per mIWG-MRT-ECNM Response Criteria

Prithviraj Bose, MD:
The ORR (CR + CRh + PR + clinical improvement [CI]) among 53 evaluable patients was 75%, including 36% with complete remission (CR) or complete remission with partial recovery of peripheral blood counts (CRh), 34% with PR, and 6% with CI.17 The ORR varied some by prior treatment use, although patient numbers are small and differences were not subject to statistical analysis. Of those who had received prior treatment, 69% achieved a response vs 86% of those with no prior treatment. The ORRs were 59% and 83% in those with vs without prior midostaurin, respectively.

Interestingly, an analysis of the EXPLORER trial presented at American Society of Hematology (ASH) 2021 reported that in those with SM-AHN, progression mostly occurred in the non‑mast cell component while the SM component stayed in remission.20 A separate analysis also presented at ASH 2021 found that after approximately 6 cycles of avapritinib, the immunophenotype and mast cell morphology in the BM mostly returned to normal.21

EXPLORER: Overall Survival

Prithviraj Bose, MD:
After a median follow-up of 23 months, median OS was not reached (95% CI: 47 to not estimable).17

Registrational Phase II PATHFINDER Trial of Avapritinib in Patients With AdvSM

Prithviraj Bose, MD:
The PATHFINDER trial was an international, open-label phase II trial of avapritinib conducted in patients with advanced SM.16 Eligible patients had at least 1 evaluable baseline C finding or MCL subtype, a platelet count ≥50 x 109/L, serum tryptase ≥20 ng/mL, and an ECOG PS of 0-3. Participants received avapritinib at 200 mg/day in 28-day cycles until PD, intolerance, withdrawal, or death. The primary endpoint was ORR per IWG criteria.

PATHFINDER: Best Confirmed Response per mIWG-MRT-ECNM Response Criteria

Prithviraj Bose, MD:
The ORR was 75%, including 19% with CR/CRh, 31% with PR, 25% with CI, and 13% with SD.16 Among patients with prior treatment exposure, the ORR was 74% vs 78% in those without prior therapy. The ORR was 82% among those with prior midostaurin vs 67% with no prior midostaurin.

PATHFINDER: Clinicopathologic Measures of Response

Prithviraj Bose, MD:
A ≥50% reduction in BM mast cells was observed in 88% of patients, and 60% eliminated BM mast cell aggregates.16 The serum tryptase level decreased ≥50% in 93% of patients, and KIT D816V VAF decreased ≥50% in the peripheral blood of 60% of patients.


Prithviraj Bose, MD:
Grade ≥3 AEs were reported in 52% of patients receiving avapritinib.16 The most common nonhematologic AEs were periorbital edema (45%) and peripheral edema (42%), which were both predominantly low grade. Diarrhea, nausea, and vomiting occurred in 8% to 11% of patients, again mostly low grade. Turning to the hematologic AEs, grade ≥3 neutropenia occurred in 23% of patients, thrombocytopenia in 15%, anemia in 8%, and leukopenia in 5%.

Cognitive events occurred in 11% of patients, none of whom experienced a high-grade cognitive event. One patient experienced a grade 4 subdural hematoma. This individual began treatment despite worsening thrombocytopenia (a platelet count of 33 x 109/L). Indeed, avapritinib is not recommended in patients with platelet counts <50 x 109/L.19 Dose reductions occurred in 68% of patients, most frequently due to neutropenia (19%) and thrombocytopenia (18%). AEs led to treatment discontinuation in 10% of patients.

We will later discuss management of these toxicities, along with an illustrative case study.

Other Therapies

Prithviraj Bose, MD:
Other therapies used in the treatment of patients with advanced SM include cladribine, imatinib, interferon, and allogeneic HSCT. Of these, imatinib is approved by the FDA for use in patients with ASM who are negative for KIT D816V or have unknown KIT mutational status.22 Imatinib is also active against eosinophilia-associated myeloid neoplasms with FIPL1-PDGFRA fusion.7 The safety profile for imatinib includes severe edema, cytopenias, congestive heart failure, hepatotoxicity, GI perforations, bullous dermatologic reactions, and hypothyroidism.22 Patients on imatinib should also have their renal function monitored.

An ORR of 50% to 77% using the Valent criteria has been reported with the use of cladribine in patients with advanced SM.10,23,29 This agent is associated with some toxicity, as illustrated by retrospective analyses of cladribine use in patients with indolent and advanced SM, which reported high-grade lymphopenia (in 27% to 82%), neutropenia (27% to 47%), thrombocytopenia (27%), and opportunistic infections (13%).

Peginterferon α-2a with or without prednisone can be considered for patients with slow disease progression who have no need for rapid cytoreduction.7,10 Among patients with advanced SM, interferon-α with or without prednisone was associated with an ORR of 45% to 60%. This agent has a well-known safety profile characterized by fatigue, depression, and thrombocytopenia.

Finally, allogeneic HSCT may be considered for patients with ASM and MCL if they have achieved a response to initial cytoreductive therapy, and for those with SM-AHN when the AHN requires HSCT and/or if SM is advancing or advanced.7 An ORR of 70% has been reported in a retrospective analysis of allogeneic HSCT in 57 patients with advanced SM, with a 3-year OS rate of 57%.1 Allogeneic HSCT complications included a 1-year treatment-related mortality rate of 20%; grades 2-4 chronic graft-vs-host disease (GVHD) occurred in 23% and acute GVHD in 40%, with 2 patients dying from acute GVHD complications.

Guidance on Cytoreductive Therapies for Advanced SM

Prithviraj Bose, MD:
To summarize, the National Comprehensive Cancer Network guidelines on mastocytosis recommend avapritinib, midostaurin, or a clinical trial as a preferred strategy.7 Cladribine is an “other recommended regimen” and may be considered when rapid debulking is required in patients with ASM or SM-AHN. Peginterferon α-2a, with or without prednisone, is another option for ASM and SM-AHN, and it may be considered in patients with slow disease progression. Imatinib may also be useful in patients with negative or unknown KIT D816V status, well-differentiated SM, or if eosinophilia is present and the patient is positive for FIP1L1-PDGFRA.

Select Ongoing Research in SM

Prithviraj Bose, MD:
There are several areas of active research in patients with SM. For example, avapritinib is under investigation in patients with indolent SM in the double-blind, phase II PIONEER trial (NCT03731260). An early analysis of this trial presented at ASH 2020 reported that avapritinib was associated with a significant decrease in total symptom score vs placebo (P = .001).24

Bezuclastinib is an investigational tyrosine kinase inhibitor with selective activity against mutant KIT in a preclinical study.25 A distinguishing feature of this agent is that its penetration of the blood–brain barrier is limited, giving the potential for fewer intracranial bleeds and less cognitive impairment. Bezuclastinib is under clinical investigation in both advanced SM (APEX; NCT04996875) and nonadvanced SM (SUMMIT; NCT05186753), and we await those data.

BLU‑263 is another investigational, next-generation KIT inhibitor with activity against KIT D816V and minimal CNS penetration.26 This agent is being evaluated in the randomized, double-blind phase II/III HARBOR trial in patients with indolent SM (NCT04910685). Again, we will wait to see the data on this new agent.

Please take a moment to answer the following repeated question before continuing with the activity.

Case 1: Treatment and Outcome

Prithviraj Bose, MD:
We will return to our first case study, which featured a 75‑year‑old man diagnosed with SM-AHN positive for KIT D816V as well as mutational abnormalities in SRSF2, TET2, and CUX1. A diagnosis of SM-AHN had been made based on his BM and molecular results.

Ilene A. Galinsky, NP:
The patient was enrolled on a clinical trial evaluating avapritinib. He started at a dose of 100 mg/day, and after 2 months, the percentage of mast cells in his BM went from >40% to 10% to 15%. After 1 year, his BM showed rare mast cells, indicating that he was in complete remission. He experienced no AEs on avapritinib and tolerated treatment very well.

Unfortunately, after 2 years, when he returned for a regular visit, he had 2% peripheral blasts and was pancytopenic. His BM at this time showed >20% blasts, compatible with AML. Interestingly, no mast cell disease was seen in BM. He received several cycles of azacitidine and venetoclax, but unfortunately he died as a consequence of the AML.

Prithviraj Bose, MD:
SM-AHN is the most common subtype of advanced SM, and it presents 2 problems to be managed—the mast cell component and the nonmast cell component. Long‑term follow-up from the EXPLORER trial of avapritinib in advanced SM suggests that progression often involves the nonmast cell component with the SM remaining in remission, as you describe in this case.20 It is possible that the KIT mutation, which drives the SM, may also, in part, drive the AHN—perhaps explaining some of the responses observed in the AHN component in the PATHFINDER trial.16 The KIT D816V mutation has been shown to be present in multiple lineages, not just the mast cell lineage.1

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