Evaluating AYVAKIT in patients with systemic mastocytosis with an associated hematological neoplasm (SM-AHN)

WHO Criteria1,2
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The World Health Organization (WHO) Diagnostic Criteria

Diagnosis of SM requires the presence of 1 major criterion and ≥1 minor criterion, or ≥3 minor criteria

Major criterion
  • Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s)
Minor criteria
  • Atypical mast cell morphology, including spindle shape or immature morphology, present in >25% of all mast cells on bone marrow smears or in other extracutaneous organ(s)*
  • Mast cells aberrantly express 1 or more of the following antigens: CD2, CD25, CD30
  • KIT p. D816V mutation or other activating KIT mutation† detected in peripheral blood, bone marrow, or other extracutaneous organ(s)
  • Baseline serum tryptase concentration of >20 ng/mL in the absence of an associated myeloid neoplasm; in the case of a known HɑT, the tryptase level could be adjusted‡

For an Advanced SM diagnosis, criteria for one of the Advanced SM subtypes must be met

AGGRESSIVE SM (ASM)
  • SM criteria fulfilled
  • ≥1 C-finding
  • C-findings:
    • Cytopenia(s) (1 or more found)
      • Absolute neutrophil count <1 x 109/L
      • Hemoglobin <10 g/dL
      • Platelet count <100 x 109/L
    • Hepatopathy: Ascites and elevated liver enzymes§ ± hepatomegaly or cirrhotic liver ± portal hypertension
    • Spleen: Palpable splenomegaly with hypersplenism ± weight loss ± hypoalbumenia
    • GI tract: Malabsorption with hypoalbumenia ± weight loss
    • Bone: Large-sized osteolysis (≥20 mm) ± pathological fracture ± bone pain
SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED HEMATOLOGIC NEOPLASM (SM-AHN)
  • SM criteria fulfilled
  • Also meets criteria for AHN as a distinct entity per the WHO classification
MAST CELL LEUKEMIA (MCL)
  • SM criteria fulfilled
  • ≥20% mast cells in bone marrow aspirate smears

*Well-differentiated round cell morphology may be seen in a small subset of cases; mast cells in such cases are usually positive for CD30 and negative for CD2 and CD25.

†Any type of KIT mutation counts as a minor SM criterion when published solid evidence for its transforming behavior is available. An overview of potentially activating KIT mutations is provided in the supplementary material of Valent et al (2021).

‡A possible mode for adjustment has been proposed by Valent et al (2021): the basal tryptase level may be divided by 1 plus the number of extra copies of the α-tryptase gene. For example, if the tryptase level is 30 ng/mL and 2 extra copies of the α-tryptase gene are found in a patient with HαT, the HαT-corrected tryptase level is 10 ng/mL (30/3=10), thereby not meeting the level of a minor systemic mastocytosis criterion.

§Alkaline phosphatase levels are typically elevated in patients with Advanced SM and SM-induced liver damage. In some of these patients, only elevated liver enzymes are found, without (clinically relevant) ascites.


HɑT=hereditary alpha-tryptasemia.

The following hypothetical profiles are examples of patient types who may have a diagnosis of SM-AHN and are fictionalized through review of the published literature, clinical guidelines, clinical studies, and Prescribing Information for avapritinib. The information presented here does not represent medical advice for any individual patient; Blueprint Medicines does not directly or indirectly practice medicine.

Review of this material does not substitute for review of the AYVAKIT Prescribing Information, diagnostic criteria, clinical practice guidelines, and other reference literature about the diagnosis of Advanced SM. Healthcare providers should make all treatment decisions based on the individual patient circumstances and their clinical judgment.

It is the healthcare provider's discretion to assess which disease component (ie, SM or AHN) warrants immediate treatment.3
Hypothetical patient profile of a 59 year old female with suspected SM-AHN (MPN-ET)

OLGA
59-year-old
 female

Hypothetical patient profile of a 64 year old male diagnosed with SM-AHN (CMML-0)

JAMES
64-year-old
 male

Hypothetical patient profile of a 72 year old male with suspected SM-AHN (very low-risk MDS)

MARIO
72-year-old
 male

Hypothetical patients.
Individual results may vary.
icon olga
BaselineAYVAKIT Treatment
Meet Olga
59-year-old female with suspected SM-AHN (MPN-ET)4
Hypothetical patient. Individual results may vary.
PATIENT HISTORY AND PRESENTATION
  • MPN-ET diagnosis previously confirmed per WHO diagnostic criteria
  • Olga returned to her doctor reporting pain throughout the body, discomfort in the abdominal area, unexpected weight loss, and chest pain along with dry cough5
  • Ongoing symptoms prompted Olga to request time off from work and cancel a vacation in order to work with her healthcare team to find the source of her health issues
CLINICAL WORKUP
  • Clinical workup showed elevated serum tryptase, low hemoglobin, and normal platelet count6,7
    • Due to elevated serum tryptase along with gastrointestinal symptoms, a full myeloid mutation profile was requested, including KIT D816V5,8
    • Myleoid mutation profile detected JAK2 but not KIT D816V, so a high-sensitivity KIT D816V test was conducted, which confirmed a KIT D816V mutation
  • Physical examination and imaging confirmed marked splenomegaly, pleural effusion requiring use of diuretics, and osteoporosis associated with bone pain8
KIT=KIT proto-oncogene, receptor tyrosine kinase; SM-AHN (MPN-ET)=systemic mastocytosis with an associated clonal hematological myeloproliferative neoplasm-essential thrombocythemia; WHO=World Health Organization.
Findings at Baseline6-12
Serum tryptase176 ng/mL
Hemoglobin8.2 g/dL
Platelet count450 x 109/L
Myeloid mutation profileDetection of JAK2
KIT status and methodKIT D816V+ confirmed by high-sensitivity (<1% limit of detection) ddPCR in peripheral blood
Bone marrow biopsy
  • 16 mast cell aggregates with spindled forms (60%)
  • Mast cells in bone marrow express CD25
Physical examination/imaging
  • Splenomegaly
  • Pleural effusion
  • Osteoporosis
Olga was diagnosed with SM-AHN and was prescribed AYVAKIT for Advanced SM.

Please see WHO criteria for more information about diagnosis.8,12
Results With AYVAKIT Treatment4
AYVAKIT efficacy results in the clinical studies were based on an ORR under the modified IWG response criteria for Advanced SM. These studies were not powered to demonstrate a response on each of the individual AHN components or data points included above. This information is hypothetical and individual results may vary.
  • Olga was started on AYVAKIT 200 mg once daily. Per dosing guidelines, platelets were monitored every 2 weeks for the first 8 weeks
  • As treatment continued, Olga told her care team that she noted her bone pain subsided and her lower abdominal pain was reduced
  • Olga experienced headaches and dizziness after 3 months of treatment
  • Olga continued on 200 mg of AYVAKIT once daily
Clinical Findings After 12 Weeks4,13
TreatmentAYVAKIT 200 mg once daily
Serum tryptase79.2 ng/mL
Hemoglobin12.4 g/dL
Platelet count180 x 109/L
Continued treatment
  • 60% reduction in neoplastic mast cells in bone marrow biopsy
  • 30% reduction in splenomegaly volume
Adverse events experienced during AYVAKIT treatment and dose modifications
  • Grade 1 neutrophil count decrease and Grade 1 decrease in lymphocytes
  • Grade 1 headaches
  • Grade 1 dizziness
  • No dose modifications were made
Duration of treatmentRemains on treatment for >1 year at 200 mg
AHN=associated hematological neoplasm; IWG=International Working Group; ORR=overall response rate.
icon james
BaselineAYVAKIT Treatment
Meet James
64-year-old male diagnosed with SM-AHN (CMML-0)4
Hypothetical patient. Individual results may vary.
PATIENT HISTORY AND PRESENTATION
  • CMML-0 diagnosis previously confirmed per WHO diagnostic criteria
  • James was under periodic observation to monitor disease progression and emergence of clinically significant symptoms5
  • James returned to his doctor, presenting with fatigue, hypersensitivity to pollen, and long-standing maculo-papular skin rashes that resulted in pruritus6
  • Symptoms did not improve, and James was now experiencing weight loss in addition to continuing fatigue6
  • James reported that his fatigue limits the time he can spend with his grandchildren
CLINICAL WORKUP
  • Clinical workup showed enlarged spleen, abnormal levels of serum tryptase, low hemoglobin, and low platelet count. In addition, high-sensitivity PCR assay in peripheral blood confirmed KIT D816V7-9
  • Bone marrow biopsy confirmed the presence of spindle-shaped neoplastic mast cell aggregates10
KIT=KIT proto-oncogene, receptor tyrosine kinase; PCR=polymerase chain reaction; SM-AHN (CMML-0)=systemic mastocytosis with associated clonal hematological chronic myelomonocytic leukemia–subtype 0; WHO=World Health Organization.
Findings at Baseline7-12
Serum tryptase209 ng/mL
Hemoglobin10.2 g/dL
Platelet count 135 x 109/L
Peripheral blood blast count1% peripheral blasts
Absolute monocyte count10% persistent >3 months
Myeloid mutation profileDetection of KIT D816V, SRSF2, TET2
KIT status and methodKIT D816V+ confirmed by high-sensitivity (<1% limit of detection) ddPCR in peripheral blood
Bone marrow biopsy
  • Mast cells in the bone marrow express CD25
  • Mast cells in aggregates of ≥15 mast cells/cluster; 30%-35% of mast cells appearing spindle-shaped; bone marrow blast at 4%
Physical examination/imaging
  • Palpable splenomegaly >5 cm below left costal margin with hypersplenism
  • Hepatomegaly with mild ascites
James was diagnosed with SM-AHN and was prescribed AYVAKIT for Advanced SM.

Please see WHO criteria for more information about diagnosis.7,10
Results With AYVAKIT Treatment4
AYVAKIT efficacy results in the clinical studies were based on an ORR under the modified IWG response criteria for Advanced SM. These studies were not powered to demonstrate a response on each of the individual AHN components or data points included above. This information is hypothetical and individual results may vary.
  • James was started on AYVAKIT 200 mg once daily. Per dosing guidelines, platelets were monitored every 2 weeks for the first 8 weeks
  • James returned with facial edema, and reported feeling confused and lost
    • Per AYVAKIT dosing guidelines, dose was interrupted for 8 weeks and treatment was resumed at 100 mg
  • After 1 year of treatment, James continued to be maintained on therapy at 100 mg daily and was tolerating it well
Clinical Findings After 12 Weeks4,13
TreatmentAYVAKIT 200 mg once daily
Serum tryptase83.6 ng/mL
Platelet count185 x 109/L
Continued treatment
  • Bone marrow biopsy showed 60% reduction in neoplastic mast cell aggregates
  • No palpation of spleen ≥5 cm below the ribs, radiological examination showed a decrease in spleen and liver volume
Adverse events experienced during AYVAKIT treatment and dose modifications
  • Grade 1 facial edema
  • Grade 2 cognitive effect (confusion and feeling lost)
  • Dose reduced to 100 mg once daily
Duration of treatmentRemains on treatment for >1 year at 100 mg
AHN=associated hematological neoplasm; IWG=International Working Group; ORR=overall response rate.
icon mario
BaselineAYVAKIT Treatment
Meet Mario
72-year-old male with suspected SM-AHN (very low-risk MDS)4,5
Hypothetical patient. Individual results may vary.
PATIENT HISTORY AND PRESENTATION
  • Mario visited his doctor with complaints of extreme tiredness that caused significant impact on his daily activities6
  • Mario is experiencing weight loss and reports that extended periods of diarrhea prevent him from spending time outside of his home6
CLINICAL WORKUP
  • Clinical workup detected enlarged spleen, low hemoglobin, and low platelet count7,8
  • Due to abnormal CBC, a myeloid mutation test was requested7
  • Bone marrow biopsy showed spindle-shaped mast cell aggregates9
CBC=complete blood count; ICH=intracranial hemorrhage; KIT=KIT proto-oncogene, receptor tyrosine kinase; SM-AHN (very low-risk MDS)=systemic mastocytosis with associated clonal–very low-risk hematological myelodysplastic syndrome; WHO=World Health Organization.
Findings at Baseline7-12
Serum
 tryptase		256 ng/mL
Hemoglobin8.8 g/dL
Platelet
 count		75 x 109/L
Absolute
 neutrophil
 count		1.4 x 109/L
Myeloid mutation profileDetection
 of SF3B1
KIT status
 and method		KIT D816V+ confirmed by high-sensitivity (<1% limit of detection) ddPCR in peripheral blood
Bone marrow
 biopsy
  • >50% of mast cells are spindle-shaped in mast cell infiltrates
  • CD117 and CD25 detected in mast cells
Physical examination/
imaging		Palpable splenomegaly with hypersplenism
Other
 remarkable
 findings
  • Hypoalbuminemia with albumin at 2 g/dL
  • Thrombocytopenia
Mario was diagnosed with SM-AHN and was prescribed AYVAKIT for Advanced SM.
Please see WHO criteria for more information about diagnosis.7,9
Results With AYVAKIT Treatment4
AYVAKIT efficacy results in the clinical studies were based on an ORR under the modified IWG response criteria for Advanced SM. These studies were not powered to demonstrate a response on each of the individual AHN components or data points included above. This information is hypothetical and individual results may vary.
  • Mario was started on AYVAKIT 200 mg once daily. Per dosing guidelines, platelets were monitored every 2 weeks for the first 8 weeks
  • Mario started to experience grade 1 periorbital edema and Grade 1 fatigue, diarrhea, and nausea
    • Platelet counts reduced to 48 x 109/L
      • Dose was interrupted for 8 weeks until platelet count >50 x 109/L
      • Treatment resumed at 100 mg once daily with continued platelet monitoring
  • After 1 year of treatment, Mario continued to be maintained on therapy at 100 mg daily and continues to be monitored for adverse reactions
Clinical Findings After 12 Weeks4,13
TreatmentAYVAKIT 200 mg once daily
Serum tryptase18 ng/mL
Hemoglobin9.3 g/dL
Platelet count90 x 109/L
Absolute neutrophil count2.0 x 109/L
Bone marrow biopsyNo presence of mast cell infiltrates in the bone marrow
Physical examination and other remarkable findings
  • No palpation of splenomegaly
  • Albumin at 3.8 g/dL
Adverse events experienced during AYVAKIT treatment and dose modifications
  • Grade 2 diarrhea
  • Grade 1 neutropenia
  • Dose reduced to 100 mg once daily
Duration of treatmentRemains on treatment for >1 year at 100 mg
AHN=associated hematological neoplasm; IWG=International Working Group; ORR=overall response rate.
 
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References: 1. WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited April 24, 2024]. (WHO Classification of Tumours Series, 5th ed.; vol. 11). https://tumourclassification.iarc.who.int/chapters/63 2. Vaes M et al. Targeted Treatment Options in Mastocytosis. Front Med. Published online July 20, 2017. doi:10.3389/fmed.2017.00110 3. Pardanani A. Am J Hematol. 2023;98(7):1097-1116.