MPNs Flashcards
Side effects common to all TKis
Cytopenias, rash, arthralgias, N/V/D, edema
Specific side effects of Dasatanib
Pleural effusion, pulmonary artery hypertension
Specific side effects of Nilotinib
Black box warning QTc prolongation and sudden death, pancreatitis, arterial occlusion events (CVD, PVD, at higher doses), hyperlipidemia, hyperglycemia, hyperbilirubinemia,
Liver toxicity, cytopenias, rash, fatigue, myalgias.
Specific side effects of Imatinib
cardiac failure, fluids retention, liver toxicity, rash, diarrhea.
Specific side effects of Bosutinib
diarrhea, fetal harm,transaminitis, no black box warning
Specific side effects of Ponatinib
Arterial occlusion + venous thrombosis/hepatotoxicity, HTN, cardiac arrhythmia and hemorrhage.
- pan-BCR-ABL1 TKI inhibitor with activity against CML with T315I mutation and in those with resistance to multiple TKI inhibitors
Treatments for Anemia in myelofibrosis
- ESAs (if EPO<500)
- Androgens (ex. danazol)
- Corticosteroids (if there is a hemolytic component)
- Immunomodulatory Drugs (thalidomide, lenalidomide)
- Transfusions
- Ruxolitinib (helpful for splenomegaly, symptoms and potentially survival but will likely worsen anemia so likely not in a patient with Hb ~70)
Name 8 causes of increased thrombotic risk in ET
- Jak2
- CVD RFs (smoking, HTN, DM2)
- Age >60
- WBC >11
- Hg <120
- Prior thrombosis
- Male
- BM fibrosis
Others: Pregnancy Known thrombophilia Other cancers OCP/HRT
Optimal Hct for PV patients?
As per Cyto-PV NEJM 2013:
All (both Male and female) < 0.45
If they ask for more specifics, then comment on:
Female < 0.42
Pregnant < 0.36
Mutations seen in atypical CML
SETBP1, CSF3R, ASXL1
Compare CAL-R in ET/PMF to JAK2-V617F
CAL-R- tends to be younger, higher platelet count, less thrombosis. Better survival and less anemia in PMF.
Triple negative has worst prognosis.
Benefits of Jakavi as seen in COMFORT-1, COMFORT-2.
Primary end point: Reduction in spleen size by >/= 35% by 24 weeks (COMFORT-1) or 48 weeks (COMFORT-2).
Decreased splenomegaly
Decreased MF associated symptoms
Improved quality of life
May increase OS (seen in COMFORT1 (vs. placebo) at 3 and 5 year follow up analyses, but not in COMFORT2 (vs. best available therapy).
What are two non-therapy related hemostatic laboratory abnormalities in MPNs?
o Acquired vWD
o Acquired APC resistance
o Platelet functional defects
3 causes of congenital polycythemia
- AD polycythemia aka EPOR mutations
- Chuvash polycythemia (affects VHL gene causes increased EPO)
- High affinity hemoglobin
- Low 2,3 -BPG
- Congenital methemoglobinemia
- HIF2A (EPAS1 mutation)
- Proline Hydroxylase (EGLN1 mutation)
4 gene rearrangements seen in eosinophilic disorders and their treatments.
- FIP1L1-PDGFRA (low dose imantinib)
- FIP1L1-PDGFRB (low dose imantinib)
- FGFR1 (bad prognosis, chemo/transplant)
- PCM1-JAK2 (ruxolitinib)
What is Mepolizumab and what diseases is it used in?
Monoclonal Ab directed against IL-5, a growth factor important for eosinophil maturation and activation.
- beneficial in glucocorticoid-sensitive HES, including idiopathic HES, lymphocytic variants of HES (L-HES), and HES/eosinophilic granulomatosis with polyangiitis (EGPA) overlap
PDGFRA-alpha blocker that is used in systemic mastocytosis and GIST tumors?
Avapritinib
5 high molecular risk genes in the MIPSS score of PMF?
- IDH1
- IDH2
- EZH2
- ASXL1
- SRSF2
Treatment options for symptomatic, non-transplant eligible PMF include Ruxolitinib, HU or ______. The latter of which can cause what severe and potentially fatal complication?
Fedratinib
- effective for reducing splenomegaly and other PMF-related symptoms,
- associated with Wernicke-like encephalopathy
- serum thiamine level should be repleted before beginning fedratinib, and levels should be checked periodically during treatment.
Fedratinib should not be given to patients with severe liver impairment, taking strong or moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors.
WHO criteria of PV.
Need 3 major or 2M and 1m:
Major:
- Hg >165 (male) or >160 (female), or Hct >0.49 (male) or >0.48 female, or inc RBC mass (>25% above ULN)
- Jak2 V617F or Exon 12
- BMBx w/ hypercellularity for age, w/ trlineage growth (panmyelosis) inc prominent erythroid, granulocytic and megakaryotic proliferation w/ pleomorphic, mature megakaryocytes.
Minor:
1. Abnormal serum epo
WHO criteria of ET.
Need 4M or first 3 major and 1m
Major:
1) plt count >/=450
2) Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.
3) Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
4) Presence of JAK2, CALR, or MPL mutation
Minor
1.Presence of a clonal marker or absence of evidence for reactive thrombocytosis
WHO criteria of PMF
Need 3 major criteria, and at least 1 minor criterion
Major
- Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
- Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms
- Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal marker,* or absence of reactive myelofibrosis
Minor
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
1. Anemia not attributed to a comorbid condition
2. Leukocytosis ≥11 × 109/L
3. Palpable splenomegaly
4. LDH increased to above upper normal limit of institutional reference range
5. Leukoerythroblastosis
What is atypical CML?
- MDS/MPN overlap syndrome, characterized by absence of t(9;22).
- Presents in elderly with elevated neutrophil count but low plt and/or Hg
- BMbx- increased cellularity with no increased blasts. Also see dysplasia in , megakaryocytes and erythroids.
- Prognosis is poor.
Common mutations:
SETBP1, CSF3R, trisomy 8, ischromosome 17q.
WHO Criteria of CNL?
- WBCs ≥25 x 109/L with >80% segs/bands and <10% immature precursor cells
- Hypercellular marrow with <5% nucleated cells being myeloblasts
- Normal neutrophil maturation with granulocytic dysplasia
- No reactive causes of neutrophilia
- No other chronic myeloid neoplasm
