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Midostaurin: A Promising New Option for Patients With Advanced Systemic Mastocytosis

December 30, 2021

Advanced systemic mastocytosis (SM) is a rare myeloproliferative neoplasm associated with poor prognosis and a lack of effective treatment options. The oral, multitarget protein kinase inhibitor midostaurin is known to inhibit KIT D816V, a mutation present in about 90 percent of patients with SM.

In a multicenter, open-label, phase II study published in The New England Journal of Medicine, researchers evaluated the efficacy, safety, and patient-reported outcomes of twice-daily midostaurin 100 mg in patients with advanced SM, finding that the drug led to an overall response rate (ORR) of 60 percent, and similar response rates regardless of disease subtype, KIT mutation status, or exposure to previous therapy.

"Midostaurin showed clinical activity in the most advanced form of SM, mast cell leukemia, with eight of the 16 patients with this highly fatal variant of SM responding," Jason Gotlib, MD, MS, first author of the study, told ASH Clinical News. "Historically, the survival of these patients typically has been less than six months. In our study, the median duration of response had not yet been reached for patients with aggressive SM."

Dr. Gotlib, from the Hematology Division at the Stanford University School of Medicine – Stanford Cancer Institute in Stanford, California, and authors enrolled patients with aggressive SM, SM with an associated hematologic neoplasm, or mast-cell leukemia (according to the World Health organization criteria) into the study. Patients were excluded if they had received ≥3 prior treatments for mastocytosis or had a cardiac ejection fraction <50 percent.

Between January 2009 and July 2012, 116 patients were enrolled from 29 sites, with 89 patients eligible for efficacy analysis:

  • 16 with aggressive SM
  • 57 with SM with an associated hematologic neoplasm
  • 16 with mast-cell leukemia

The remaining 27 patients were not eligible for efficacy analysis due to the absence of measurable C-findings.

Patients received twice-daily midostaurin 100 mg for six four-week treatment cycles; dose reductions to 50 mg twice daily or interruptions of ≤21 days were allowed if toxic effects occurred. Patients continued treatment until disease progression, death, unacceptable toxic effects, or withdrawal.

Patient-reported outcomes (assessed via the Memorial Symptom Assessment Scale) and quality of life (assessed via the Medical Outcomes Study 12-Item Short-Form Health Survey) were collected at baseline, every cycle during the first 12 cycles, and every three cycles thereafter. Imaging and central evaluations of bone marrow specimen and KIT D816V mutations were performed at baseline, at the end of cycles three or six (or both), every six cycles thereafter, and at the end of treatment.

The median treatment duration was 11.4 months (range = 0.3-51.5 months), and the median follow-up was 26 months (range = 12-54 months).

The ORR was 60 percent (95% CI 49-70%), and 45 percent of the patients had a major response (defined as complete resolution of at least one type of mastocytosis-related organ damage). Responses were observed in all patient subgroups, the authors reported, and "response rates were similar regardless of the subtype of advanced SM, KIT mutation status, or exposure to previous therapy." (See TABLE for response rates.)

The median overall survival (OS; a secondary endpoint) was 28.7 months (95% CI 18.1-not estimated) in the primary efficacy population and 33.9 months (95% CI 20.3-45.5) in the intention-to-treat population (ITT; all 116 patients who received midostaurin, including those who could not be evaluated for response).

The following median OS rates were observed in each patient subgroup:

  • aggressive SM: not reached (95% CI 28.7-not estimated)
  • SM with an associated hematologic neoplasm: 20.7 months (95% CI 16-44.4)
  • mast-cell leukemia: 94 months (95% CI 7.5-not estimated)

The median progression-free survival (PFS; a secondary endpoint) was 14.1 months in the entire primary population; however, PFS was longer among patients with aggressive disease (28.7 months) compared with those with an associated hematologic neoplasm (11 months) or mast-cell leukemia (11.3 months).

In addition, the researchers observed a reversal of organ damage among patients with all types of C-findings. Forty percent of patients (n=8/20) who were dependent on red cell transfusions at baseline became transfusion-independent, as did patients (n=4/4) who were dependent on platelet transfusion.

Of the 72 patients who were evaluated for bone marrow response, 57 percent (n=41) experienced a ≥50 percent decrease in bone marrow mast-cell burden, and 33 percent of patients (n=24) maintained this improvement for at least two consecutive biopsies. "This [>50% reduction] was an independent marker of longer overall survival (along with having a response) in a multivariate analysis (hazard ratio = 0.33; p=0.01)."

"The median best percentage decreases in mast cells in the bone marrow and serum tryptase levels (a blood marker of mast cell disease burden) were 59 percent and 58 percent, respectively," Dr. Gotlib told ASH Clinical News. Furthermore, "decreases in bone marrow mast cell burden or serum tryptase level were observed in 78 percent of patients."

Patient-reported symptoms and safety were assessed in the total ITT population. The most commonly reported baseline patient-reported symptoms were lack of energy (86%), feeling of drowsiness (72%), and difficulty sleeping (60%). Thirty of the 32 patient-reported symptoms decreased in frequency with midostaurin treatment; however, symptoms of nausea and vomiting, known treatment-related adverse events (AEs), did not decrease.

The most common non-hematologic AEs were nausea (79%), vomiting (66%), and diarrhea (54%), and the authors noted that these symptoms "were usually responsive to anti-emetics and administration of midostaurin with meals." The most frequent grade 3/4 non-hematologic AEs were fatigue (9%) and diarrhea (8%). New or worsening grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 24 percent, 41 percent, and 29 percent of patients, respectively, mostly among those with pre-existing cytopenias.

Sixty-five patients had dose reductions (56%), mostly due to AEs (n=48), though the dose was able to be re-escalated in 32 percent of patients (n=21).

Eighty-four patients (72%) discontinued treatment, while 28 percent (n=32) were still receiving treatment and 48 patients were still alive at data cutoff. Discontinuation was most frequently related to disease progression (33%) and AEs (22%). The median OS after discontinuation was 6.8 months (95% CI 3.1-11.8). Seventeen patients died during the course of treatment or within 28 days of discontinuing treatment due to progression of mastocytosis (n=8), cardiac arrest (n=2), multi-organ failure (n=2), sepsis (n=2), pneumonia (n=1), unspecified cardiac disorder (n=1), and congestive heart failure (n=1). Thirteen patients (11%) developed secondary acute myeloid leukemia.

"In addition to reducing splenomegaly, midostaurin was associated with clinically significant benefits with respect to patient-reported symptoms and quality of life," the authors wrote, "that may be related to combined inhibitory effects on the proliferation of neoplastic mast cells and mediator release."

"The clinical benefit of midostaurin in patients with advanced SM represents a large unmet therapeutic need," Dr. Gotlib concluded. "[The study] also validates the principle that inhibition of KIT D816V, a major driver of disease pathogenesis, is a viable therapeutic strategy in SM."

The study's findings are limited by its single-group design and lack of a comparator arm. The authors also noted that the study was designed by the drug's manufacturer – Novartis Pharmaceuticals – and a steering committee. The sponsor collected and analyzed the data in conjunctions with the authors, who had full access to the data.

The authors noted that future studies are needed to evaluate midostaurin in combination with other drugs and in the peri-transplant setting in patients with advanced SM.


Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530-41.

TABLE. Best Overall Response to Midostaurin
Variable Any subtype of advanced symptomatic mastocytosis(n=89) Aggressive systemic mastocytosis (n=16) Systemic mastocytosis with an associated hematologic neoplasm(n=57) Mast-cell leukemia (n=16)
Major or partial response as best overall response
Number of patients with response 53 12 33 8
Overall response rate 60(95% CI 49-70) 75(95% CI 48-93) 58(95% CI 44-71) 50(95% CI 25-75)
Duration of response
Median number of months 24.1(95% CI 10.8-not evaluable) Not reached(95% CI 24.1-not evaluable) 12.7(95% CI 7.4-31.4) Not reached(95% CI 3.6-not evaluable)
Best overall response
Major response 40(45%) 10(62%) 23(40%) 7(44%)
0 0 0 0
19(21%) 6(38%) 9(16%) 4(25%)
    Pure clinical
15(17%) 4(25%) 9(16%) 2(12%)
    Unspecified 6(7%) 0 5(9%) 1(6%)
Partial response (PR) 13(15%) 2(12%) 10(18%) 1(6%)
    Good PR 11(12%) 1(6%) 10(18%) 0
    Minor PR 2(2%) 1(6%) 0 1(6%)
Stable disease 11(12%) 1(6%) 7(12%) 3(19%)
Progressive disease 10(11%) 1(6%) 6(11%) 3(19%)
Not evaluable for response 15(17%) 2(12%) 11(19%) 2(12%)


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