Targeted Therapy in Hematology

Question 1

Understand the principles of “Magic Bullet” a.k.a targeted therapy

Answer 1

use drugs/interventions that target more unique properties of the malignancies

Question 2

Pathophysiology, diagnosis and treatment of chronic myeloid leukemia (CML)

Answer 2

Pathophysiology
* t(9;22) - BCR/ABL protein (Philadelphia chromosome)
* Constitutively active tyrosine kinase
* Around 50% of adults are p190; everyone else is p210
Diagnosis
* Identify the Philadelphia chromosome (via karyotyping) - 95%
* If negative, may still have the BCR/ABL protein (identified by PCR, 2.5%)
Treatment
* Imatinib - tyrosine kinase inhibitor…occupies the ATP binding pocket of the ABL kinase domain
* This prevents substrate phosphorylation and signaling
* A lack of signaling inhibits proliferation and survival

Question 3

imatinib

Answer 3

tyrosine kinase inhibitor - blocks ATP binding domain

Question 4

Ruxolitinib

Answer 4

JAK stat inhibitoruses: primary myelofibrosis

Question 5

Ibrutinib

Answer 5

BTK inhibitor - Bruton’s Tyrosine Kinase

• Forms covalent bond with Cys-481 in BTK
• Blocks NF-kB
• Lymphocyte counts goes up at first, and then declines In B cell disorders
• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Waldenstrom’s macroglobulinemia

Question 6

Idelalisib

Answer 6

PI3K inhibitor
* In B cell disorders
* Orally available
Approved for:
* relapsed chronic lymphocytic leukemia (CLL),
* relapsed follicular B-cell non-Hodgkins lymphoma (FL),
* relapsed small lymphocytic lymphoma (SLL)

Question 7

Vismodegib

Answer 7

Inhibits hedgehog pathwayUse: Basal cell carcinoma that has metastasized or relapsed after treatment with surgery or for patients who are not candidates for surgery or radiation

Question 8

Vemurafenib

Answer 8

BRAF inhibitionuse for V600E BRAF mutated melanoma

Question 9

Bortezomib

Answer 9

Multiple myelomaPrevents degradation of intracellular proteins by reversibly inhibiting the 26S proteasomeAffects multiple signaling cascades within all cells

Question 10

Nilotinib/dasatinib

Answer 10

Tyrosine kinase inhibitors that are similar ot imatinib but work better for Philadelphia positive ALL