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

Supporting Patient Identification of Advanced SM Video

Video to Support Patient Identification of Aggressive Systemic Mastocytosis

There are three subtypes of advanced SM: aggressive SM (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).1

Advanced SM is a rare disease, and can potentially be misdiagnosed.2 There are many possible indicators. Patients might report itching, hives, or swelling on their skin.3 Patients may also report nausea, vomiting, abdominal pain, or diarrhea.3 They may also experience fatigue, chills, sweats, anaphylaxis, bone pain, muscle pain, or weakness.4

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+ years.5

What to Look Out for

Symptomology of mastocytosis3,4

Clinical Presentation of Advanced Systemic MastocytosisNot an actual patient

SKIN4

  • pruritus
  • urticaria
  • angioedema

CONSTITUTIONAL3

  • fatigue
  • chills
  • sweats
  • anaphylaxis
  • bone pain
  • myalgia
  • weakness

GASTROINTESTINAL4

  • nausea
  • vomiting
  • abdominal pain
  • diarrhea

ORGAN3

  • hepatomegaly
  • ascites
  • lymphadenopathy
  • splenomegaly
  • hypersplenism

Symptoms are not limited to only those listed.

  • Skin-related symptoms include itching (pruritus), flushing (usually triggered by temperature changes, fever, exercise, and friction), hives (urticaria), and swelling (angioedema)4
  • Constitutional symptoms include fatigue, chills, sweats, anaphylaxis, osteopenia/osteoporosis, bone pain, back pain, joint pains (arthralgia), muscle pains (myalgia), and weakness3
  • Gastrointestinal symptoms include nausea, vomiting, abdominal pain, and diarrhea4
  • Organ-related symptoms include cytopenias, hepatomegaly, ascites, lymphadenopathy, malabsorption or protein-losing enteropathy with weight loss, osteolysis with pathologic fracture, splenomegaly, and hypersplenism3

Symptoms related to mast-cell mediator release

  • Clinical presentation of SM is dependent on the location and severity of mast cell infiltration2,4
  • 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 lesions6

Maculopapular cutaneous mastocytosis in patients with adulthood-onset mastocytosis7

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 disease2

  • 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 people8,9
  • 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+ years5

*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 difference6

  • It is important to monitor patients with hematologic neoplasms for signs and symptoms that may point toward SM-AHN6
  • 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 myeloma6
  • 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 complications and provide them with effective treatment options as soon as possible2,6

How to Diagnose

Advanced SM can only be verified by histological and/or molecular findings on biopsy material other than skin6

  • 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)3,6,11
    • 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 biopsy3,6,11
    • 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, including6,11,13
    • 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)3,14
    • 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 mastocytosis3

Diagnostic features of advanced systemic mastocytosis subtypes
  • Aggressive systemic mastocytosis (ASM) is characterized by at least one C-finding (see below)3
  • 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 D816V8
  • Mast cell leukemia (MCL) is defined by a bone marrow aspirate with at least 20% mast cells3

Definition and measurement of C-findings

Clinical findings related to organ damage from infiltrating mast cells are referred to as C-findings and can include2,3,6,8:

  • 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. 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.
  2. 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.
  3. Pardanani A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. Am J Hematol. 2016;91(11):1146-1159.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Systemic mastocytosis. Orphanet website. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2467. Updated November 2008. Accessed June 11, 2018.
  9. 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.
  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. 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.
  13. 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.
  14. 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
Embryo-Fetal Toxicity
  • Do not use during pregnancy. Midostaurin caused severe embryo-fetal 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://report.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
Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated With Combination Chemotherapy
  • Prolonged (≥44 days) grade 4 neutropenia and thrombocytopenia were reported in 2 pediatric patients with FLT3 mutation-positive AML treated with midostaurin and combination chemotherapy. An azole antifungal (a strong CYP3A4 inhibitor) was coadministered which may increase midostaurin concentrations and risk of toxicity
  • The safety and effectiveness of RYDAPT in pediatric patients have not been established
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 CYP3A Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and may reduce efficacy
  • Strong CYP3A 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 
  • CYP2B6, BCRP, OATP1B1 Substrates: RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate. Coadministration of RYDAPT increased the exposure of a breast cancer resistance protein (BCRP) and organic anion transporter polypeptide (OATP)1B1 substrate. Dose adjustments for coadministered CYP2B6, BCRP, or OATP1B1 substrates may be necessary with RYDAPT
ADVERSE REACTIONS
Aggressive Systemic Mastocytosis (SM), SM With Associated Hematologic Neoplasm, Mast Cell Leukemia
  • Most common adverse reactions (≥20%) excluding laboratory 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 laboratory terms were fatigue (9%), sepsis (9%), gastrointestinal hemorrhage (9%), pneumonia (8%), diarrhea (8%), febrile neutropenia (8%), edema (7%), dyspnea (7%), nausea (6%), vomiting (6%), abdominal pain (6%), and renal insufficiency (5%)
  • Most common (≥10%) nonhematologic grade ≥3 laboratory abnormalities were hyperglycemia (nonfasting) (18%), lipase increase (18%), and hyperuricemia (11%)
  • Most common (≥20%) hematologic grade ≥3 laboratory abnormalities were lymphopenia (42%), anemia (38%), thrombocytopenia (27%), and neutropenia (22%)

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).