For:
Advanced Systemic Mastocytosis*
Important Safety Information:

CONTRAINDICATIONS
Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioed…

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Indication: RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Disease Information

What to Look Out for

Symptomology of mastocytosis1,2

Mastocytosis symptoms Mastocytosis symptoms
  • Skin-related symptoms include itching (pruritus), flushing (usually triggered by temperature changes, fever, exercise, and friction), hives (urticaria), and swelling (angioedema)2
  • Constitutional symptoms include fatigue, chills, sweats, anaphylaxis, osteopenia/osteoporosis, bone pain, back pain, joint pains (arthralgia), muscle pains (myalgia), and weakness1
  • Gastrointestinal symptoms include nausea, vomiting, abdominal pain, and diarrhea2
  • Organ-related symptoms include cytopenias, hepatomegaly, ascites, lymphadenopathy, malabsorption or protein-losing enteropathy with weight loss, osteolysis with pathologic fracture, splenomegaly, and hypersplenism1

Symptoms related to mast-cell mediator release

  • Clinical presentation of SM is dependent on the location and severity of mast cell infiltration2,3
  • Clinical suspicion of mastocytosis should start with the presence of varied signs and symptoms that relate to mast-cell mediator release and/or after recognition of the characteristic skin lesions4

Maculopapular cutaneous mastocytosis in patients with adulthood-onset mastocytosis5

Advanced systemic mastocytosis symptom presentation Advanced systemic mastocytosis symptom presentation

(A) Characteristic small brown monomorphic lesions often start to develop on the thigh; (B-E) lesions spread over several years to the trunk and extremities; (F) confluence of lesions may be associated with advanced SM categories.
Displayed with permission from Elsevier.


Who Is at Risk

A rare and often misdiagnosed/underdiagnosed disease3

  • Advanced systemic mastocytosis (SM)* is a rare group of myeloid neoplasms, with an estimated worldwide prevalence ranging from 1 per 20,000 to 40,000 people6,7
  • Patients with advanced SM can be difficult to identify and often cycle between health care professionals without reaching a definitive diagnosis for 2 to 10+ years4,8-10

*Aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL) are collectively referred to as advanced SM.

Prompt identification of advanced SM can make a critical difference4

  • It is important to monitor patients with hematologic neoplasms for signs and symptoms that may point toward SM-AHN4
  • Patients who may have undiagnosed SM-AHN include those with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), chronic myelomonocytic leukemia (CMML), non-Hodgkin lymphoma (NHL), or myeloma4
  • Many patients will present with heterogeneous symptoms. It is crucial to identify advanced SM as soon as it is suspected to help your patients minimize severe implications and provide them with effective treatment options as soon as possible3,4

How to Diagnose

Advanced SM can only be verified by histological and/or molecular findings on biopsy material other than skin4

  • Advanced SM should be suspected, regardless of skin manifestations, in patients with severe and/or unexplained recurrent anaphylaxis, unexplained hematologic abnormalities, unexplained osteoporosis and, most importantly, an elevated baseline serum tryptase level4

 

Key steps in advanced systemic mastocytosis diagnosis

Serum tryptase levels

  • Determine serum tryptase levels (>20 ng/mL)1,4,11
    • In many patients with advanced SM, serum tryptase concentration exceeds 20 ng/mL, and the level correlates with total burden of mast cells and their activation

Bone marrow biopsy

  • Perform bone marrow biopsy1,4,11
    • As bone marrow is almost always involved, the histopathologic evaluation of bone marrow biopsy specimens for mast cell infiltration is crucial to establish the diagnosis of advanced SM

Organ damage

  • Evaluate for organ damage, including4,11,12
    • Laboratory/medical evaluations for cytopenias, abnormal liver function, and malabsorption (hypoalbuminemia), as well as documentation of weight loss
    • Additional testing such as CT scan to check for further evidence of organ damage, including ascites or portal hypertension, and X-rays to evaluate for large osteolytic lesions and/or pathologic fractures

KIT D816V mutation

  • Test for KIT D816V (including allelic burden)1,13
    • The KIT D816V mutation is the most common mutation, occurring in ~90% of patients with SM


How to Determine Subtype

Key diagnostic feature of each subtype of advanced systemic mastocytosis1

Diagnostic features of advanced systemic mastocytosis subtypes Diagnostic features of advanced systemic mastocytosis subtypes
  • Aggressive systemic mastocytosis (ASM) is characterized by at least one C-finding (see below)1
  • Systemic mastocytosis with associated hematologic neoplasm (SM-AHN) is typically a myeloid disease such as an overlap myelodysplastic–myeloproliferative disorder and often reflects multilineage involvement of KIT D816V6
  • Mast cell leukemia (MCL) is defined by a bone marrow aspirate with at least 20% mast cells1

Definition and measurement of C-findings

Clinical findings related to organ damage from infiltrating mast cells are referred to as C-findings and can include1,3,4,6:

  • Cytopenias
    • Bone marrow dysfunction manifested by one or more cytopenia(s) (ANC <1.0 x 109/L, hemoglobin <10 g/dL, or platelets <100 x 109/L), but no obvious non–mast cell hematopoietic malignancy
  • Liver-function abnormalities
    • Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
  • Spleen impairment
    • Palpable splenomegaly with hypersplenism
  • Weight loss
    • Malabsorption with hypoalbuminemia and weight loss due to gastrointestinal mast cell infiltrates
  • Osteolytic bone lesions
    • Skeletal involvement with large osteolytic lesions and/or pathologic fractures

ANC, absolute neutrophil count; CT, computed tomography.

 

References:
  1. Pardanani A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. Am J Hematol. 2016;91(11):1146-1159.
  2. Arock M, Akin C, Hermine O, Valent P. Current treatment options in patients with mastocytosis: status in 2015 and future perspectives. Eur J Haematol. 2015;94(6):474-490.
  3. Broesby-Olsen S, Dybedal I, Gülen T, et al. Multidisciplinary management of mastocytosis: Nordic Expert Group Consensus. Acta Derm Venereol. 2016;96(5):602-612.
  4. Gülen T, Hägglund H, Dahlén B, Nilsson G. Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease. J Intern Med. 2016;279(3):211-228.
  5. Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35-45.
  6. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541. 
  7. Systemic mastocytosis. Orphanet website. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2467. Updated November 2008. Accessed June 11, 2018.
  8. Wang SA, Hutchinson L, Tang G, et al. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chromosomal abnormalities in SM and AHNMD components. Am J Hematol. 2013;88(3):219-224.
  9. Horny HP, Sotlar K, Valent P. Differential diagnoses of systemic mastocytosis in routinely processed bone marrow biopsy specimens: a review. Pathobiology. 2010;77(4):169-180.
  10. Sev’er A, Sibbald RG, D’Arville C. Thousand faces of mastocytosis: mistaken medical diagnoses, patient suffering & gender implications. Women’s Health & Urban Life. 2009;8(2):84-112.
  11. Data on file. Study no. PKC412D2201. Novartis Pharmaceuticals Corp; 2016.
  12. Valent P, Akin C, Sperr WR, et al. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol. 2003;122(5):695-717.
  13. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366-2372.

 

INDICATION for RYDAPT® (midostaurin) capsules.

Systemic Mastocytosis
RYDAPT is indicated for the treatment of adult patients with aggressive systemic  mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

IMPORTANT SAFETY INFORMATION for RYDAPT® (midostaurin) capsules

CONTRAINDICATIONS
  • Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema
WARNINGS AND PRECAUTIONS
Embryofetal Toxicity
  • Do not use during pregnancy. Midostaurin caused severe embryofetal abnormalities and death in animal studies 
  • Verify pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT
  • Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose
  • Males taking RYDAPT should use effective contraception with females of reproductive potential and pregnant women and for at least 4 months after the last dose
  • Pregnancy exposure registry to monitor pregnancy outcomes: Females who may have been exposed to RYDAPT during pregnancy, directly or through a male partner receiving RYDAPT, should contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://psi.novartis.com
Pulmonary Toxicity
  • Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy
  • Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology
ADDITIONAL CONSIDERATIONS
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants from RYDAPT, advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the last dose
Infertility
  • Based on findings in animals, RYDAPT may impair fertility in females and males of reproductive potential. It is unknown whether these effects on fertility are reversible
Drug Interactions
  • Strong CYP3A4 Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and may reduce efficacy
  • Strong CYP3A4 Inhibitors: Coadministration with strong CYP3A4 inhibitors may increase midostaurin concentrations and may increase the risk of toxicity. Monitor patients for increased risk of adverse reactions, especially during the first week of RYDAPT use in each chemotherapy cycle and the first week of consecutive RYDAPT administration. Consider alternative therapies that do not strongly inhibit CYP3A4 activity 
ADVERSE REACTIONS
Aggressive Systemic Mastocytosis (SM), SM With Associated Hematological Neoplasm, Mast Cell Leukemia
  • Most common adverse reactions (≥20%) excluding lab terms were nausea (82%), vomiting (68%), diarrhea (54%), edema (40%), musculoskeletal pain (35%), abdominal pain (34%), fatigue (34%), upper respiratory tract infection (30%), constipation (29%), pyrexia (27%), headache (26%), and dyspnea (23%)
  • Grade ≥3 adverse reactions (≥5%) excluding lab terms were fatigue (9%), sepsis (9%), gastrointestinal hemorrhage (9%), pneumonia (8%), diarrhea (8%), febrile neutropenia (7%), edema (7%), dyspnea (7%), nausea (6%), vomiting (6%), abdominal pain (6%), and renal insufficiency (5%)
  • Most common (≥10%) nonhematologic grade ≥3 lab abnormalities were hyperglycemia (nonfasting) (18%), lipase increase (18%), and hyperuricemia (11%)
  • Most common (≥20%) hematologic grade ≥3 lab abnormalities were thrombocytopenia (27%), neutropenia (22%), anemia (38%) and lymphopenia (27%)

Please see full Prescribing Information for RYDAPT® (midostaurin) capsules.

*Aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL) are collectively referred to as advanced systemic mastocytosis (SM).