Midostaurin therapy for indolent and smoldering systemic mastocytosis: Retrospective review of Mayo Clinic experience
Authors: Faiqa Farrukh, Naseema Gangat, Mithun V. Shah, Mark R. Litzow, Michelle A. Elliott, Kebede Begna, Christopher C. Hook, Ayalew Tefferi, Animesh Pardanani
Journal: American Journal of Hematology (2022)

Patients with systemic mastocytosis (SM) can have a high symptom burden due to the release of mast cell (MC) mediators, including fatigue, musculoskeletal pain, flushing, pruritus, urticaria, abdominal cramping/pain, diarrhea, nausea, vomiting, anaphylaxis, headache, etc. Midostaurin is a multitargeted kinase inhibitor with activity against the KITD816V mutation, that has been approved by the Food & Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) based on data from two open label phase II studies.1, 2 In the D2201 study (NCT00782067) in advanced SM, in addition to an overall response rate of 69% (modified Valent criteria) and 17% (International Working Group [IWG] criteria), significant improvements were observed in health-related quality-of-life measures and investigator-adjudicated MC mediator-related symptoms.3 Based on these data, midostaurin was studied in an open-label, non-randomized, single-center, phase II study (NCT01920204) of 20 indolent SM (ISM) patients with severe MC activation symptoms that were refractory to antihistamine medications.4 After 12 weeks of treatment, a median 35% (range 16%–56%, p < .01) reduction in symptom severity was observed, as per the Mastocytosis symptom assessment form (MSAF). There was also a median 29% (range 16%–47%, p < .001) improvement in disease-specific quality-of-life as measured by the Mastocytosis quality-of-life questionnaire (MQLQ). This was associated with a reduction in serum tryptase level (36–15.5 μg/L, p < .001), reduction in bone marrow MC% in 50% of evaluable patients (median 7.5% to 4%), improvement in 80% of patients with urticaria pigmentosa (UP)/skin symptoms, with 40% reduction in median Scoring Mastocytosis (SCORMA) index. In the current study, we reviewed our institutional experience with midostaurin treatment of ISM and smoldering SM (SSM) patients in routine clinical practice. After approval by the Mayo Clinic institutional review board, consecutive ISM/SSM patients were recruited from the institutional SM database, filtered by documentation of midostaurin treatment by the patient's local or Mayo provider. Conventional criteria were used for SM diagnosis and disease subclassification. Response assessment of MC mediator-related symptoms and skin involvement was adapted from previously described criteria.5 Complete response (CR), major response (MR), partial response (PR), and no response (NR) described complete resolution, > 50% resolution, 10–50% resolution, and < 10% resolution of MC symptoms and/or skin lesions, respectively, based on descriptions in treating physician/provider notes, and adjudicated by careful review of the electronic medical record by the first and/or last author. Serial monitoring of serum tryptase level and bone marrow biopsies were performed at the treating physician/provider's discretion. Adverse event grading was as per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Date of the last follow-up was updated through August 2021. Thirteen patients (median age 50 years, females 77%), of whom 11 had ISM and 2 SSM were recruited (Table S1). Of these, 9 patients (69%) had cutaneous MC involvement, 11 of 12 evaluable patients (92%) had detectable KITD816V mutation, and 10 of 11 evaluable patients (91%) had elevated serum tryptase level at baseline. All patients had MC mediator level symptoms, the most frequent being diarrhea in 77%, pruritus/flushing in 54%, nausea/vomiting in 46%, and abdominal pain/cramping, fatigue, musculoskeletal pain, and weight loss (38% each). The predominant indication for midostaurin treatment was MC symptoms in 10 patients (77%), MC skin lesions in 1 patient (8%), and a combination of both factors in 2 patients (15%). All patients had inadequate symptom control with antihistamine drugs at baseline. In addition, five patients had previously received cromolyn sodium and one patient each had received imatinib and 2-chlorodeoxyadenosine treatment; prior use of cladribine was for 6 months and that of imatinib 19 months. The median midostaurin starting dose was 200 mg daily (range 50-200 mg) (Table 1). The median treatment duration was 14 months (range 4–36). Complete response, major response, and partial response rates for MC-mediator symptoms and MC-skin lesions were 8%/23%/31% and 22%/11%/11%, respectively. The post-treatment serum tryptase level decreased in nine patients (82%), with normalization of tryptase level in three patients (27%; institutional normal tryptase level was <11.5 mg/dL). The median decrease in tryptase level was 48% (range 30–91) and the median duration to maximum tryptase level decrease was 5 months (range 1–16). A follow-up bone marrow biopsy was obtained in five patients at a median 6 months post-treatment—one patient had complete resolution of MC infiltrates, three patients had decreased MC burden and one patient had no change in MC burden. In a retrospective comparison, response rates appeared broadly similar to Cladribine therapy.6 (Table S2). n evaluated = 12 5 (1–16) n evaluated = 12 6 (4–25) n evaluated = 5 6 (3–16) n evaluated = 12 9 (75) Treatment was discontinued in six patients (46%) due to complete response (n = 1), adverse effects (n = 1), no-response (n = 2) and adverse effects-suboptimal response (n = 2). Of 12 patients where data was available, midostaurin was dose reduced in 9 patients (75%); dose reductions were due to side effects, mostly worsening GI symptoms (nausea, vomiting, diarrhea, belching, dysgeusia), fatigue, and insomnia. Dose reduction did not lead to loss of response in any previously responding patient, including the patient with CR where midostaurin was discontinued with the intention to resume in case of increase in tryptase level above 20 mg/dL; the tryptase level in this patient remained stable and symptoms did not recur after drug discontinuation. Most GI side effects were most were grade 1/2 in severity—two patients developed grade 3 vomiting and one patient grade 3 diarrhea. The three patients without dose reduction started treatment at 50, 100, and 200 mg daily. The median dose at last follow-up was 100 mg daily (range 50–200 mg). There were no documented instances of significant QTc prolongation, pancreatitis or persistent cytopenias. All patients were alive at last follow-up. The current study, which had a longer treatment duration than the previously published prospective study,4 confirms that midostaurin treatment has clinical benefit in ISM/SSM patients; 62% and 44% had improvement in MC-related mediator symptoms and MC skin lesions, respectively. Clinical responses to midostaurin were associated with significant reductions in serum tryptase levels and possibly, a decrease in bone marrow MC burden, although small patient numbers and a lack of central histopathology review precludes any definite conclusions with regards to the latter. The tolerability of midostaurin was limited by a high incidence of gastrointestinal adverse effects, which led to frequent dose reduction (nine patients) and/or treatment discontinuation (five patients); these observations raise questions regarding the drug's utility in a patient population needing long-term treatment for a relatively indolent disease. Limitations of the current study include its retrospective design, use of nonuniform midostaurin doses, and lack of use of validated patient-reported outcome forms to assess treatment-associated changes in patient symptoms and quality-of-life. Dr. Animesh Pardanani is a part of Adelphi Values, Advisory Board (participation is NOT currently active). None of the other authors have any competing financial interests. Faiqa Farrukh: abstracted data from clinical charts, analyzed the data, wrote the first draft of manuscript, approved the final draft of the manuscript. Naseema Gangat: contributed patients, approved the final draft of the manuscript. Mithun V. Shah: contributed patients, approved the final draft of the manuscript. Mark L. Litzow: contributed patients, approved the final draft of the manuscript. Michelle A. Elliott: contributed patients, approved the final draft of the manuscript. Kebede Begna: contributed patients, approved the final draft of the manuscript. Ayalew Tefferi: proposed project concept, contributed patients, wrote the first draft of manuscript, approved the final draft of the manuscript. Animesh Pardanani: analyzed the data, contributed patients, wrote the first draft of manuscript, approved the final draft of the manuscript. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Table S1 Baseline clinical and demographic characteristics of 13 patients with indolent/smoldering mastocytosis prior to initiation of midostaurin treatment, stratified by the presence or absence of mast cell skin lesions Table S2 Clinical characteristics and response to treatment of 33 patients with indolent/smoldering mastocytosis treated with either cladribine (n = 20) or midostaurin (n = 13) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.