Hematologic Agents - ImiDs // Proteosome Inhibitors // BCR/ABL TKIs

The 5 classes of Hematologic Oncologic agents that are pertinent for the exam

1. Immunomodulators (IMiDs)

2. Proteosome Inhibitors

3. BCR/ABL TKIs

4. Anti-CD20s antibodies

5. Anti-CD30s antibodies

Immunomodulators (IMiDs) Agents

• Lenalidomide

Common uses

• Multiple Myeloma

• Lymphoma

• MDS

Immunomodulators (IMiDs) (Lenalidomide) MOA

• Multimodal!!!

  • Induces Apoptosis

  • Inhibits Angiogenesis

  • Inhibits Adherence of myeloma cells to bone marrow stromal cells

  • Inhibits Cytokine release

  • Augments immune host cells against myeloma cells

“4 A’s and cytokine release”

Immunomodulators (IMiDs) (lenalidomide) Common toxicities and RBS

Common (FEDR)

• Fatigue

• Edema

• Dyspnea

• Rash

RBS

• Thromboembolism

  • Combination induction myeloma therapy: risk-adapted VTE prophylaxis

    • Aspirin OR LMWH (enoxaparin 40mg daily)/warfarin (goal INR 2-3)

• Fetal Toxicity!!!****

  • Requires REMS: prescriber, patient, pharmacy registration

  • No more than 4 week supply at one time

  • Think of the Thalidomide Disaster!!!!

other RBS

• Myelosuppression

• CNS toxicity (drowsy)

• Constipation, Skin rash, Neuropathy

What is the SAVED score in relation to IMids (lenalidomide) ?

• Looks at Risk factors for VTE in patients taking IMiDs

  • Surgery within 90 days

  • Asian race

  • VTE history

  • Age >80 years

  • Dexamethasone dose

High risk = >2 points —> Give enoxaparin, Warfarin, or Dalteparin

Low Risk = <2 points —→ No intervention, just ASA 81-325 mg

Proteosome Inhibitors Agents

• Bortezomib

Common uses

• Multiple Myeloma

• Amyloidosis

• Lymphoma

• Waldenstrom’s macroglobulinemia

Proteasome Inhibitors (Bortezomib) MOA

• Proteasomes normally destroy proteins marked for degradation

  • When that protein (IkB) is degraded by proteasome, a NF-kB cell is “liberated” and causes cancer cell growth, angiogenesis, cell adhesion to tumor microenvironment

• Bortezomib inhibits Proteasome activity —→ inhibits NF-kB cell liberation —→ inhibits cell growth, angiogenesis, etc

Proteasome Inhibitors (Bortezomib) common toxicities / RBS

Common

• Myelosuppression

• Peripheral Neuropathy

  • Giving once weekly SQ reduces risk of severe Neuropathy

• Fatigue, Rash

RBS

• Herpes Zoster reactivation —→ give PPX Acyclovir 200 mg

• Hepatotoxicity

• DO NOT ADMIN INTRATHECALLY

BCR/ABL TKIs Agents

• Imatinib (Gleevec)

Common uses

• PhChr positive CML and ALL

• PDGFR positive MDS/MPD and hypereosinophilia

• c-Kit positive mastocytosis, melanoma, GIST

BCR/ABL TKIs (Imatinib/Gleevec) MOA

• BCR/ABL is the oncogene produced by the Philadelphia chromosome: [t(9;22)]

  • PDGFR & c-Kit are also tyrosine kinases which may be overexpressed in cancers or other diseases

• Imatinib competes with ATP —→ impaired transfer of phosphate to its substrate —→ inhibits cell proliferation and causes apoptosis

BCR/ABL TKIs (Imatinib/Gleevec) Class-wide toxicities

• Fluid retention/Edema

  • incidence 86% —> higher risk with higher doses and older age (pleural effusions, pericardial effusions, pulm edema, ascites)

  • Caution in patients prone to fluid accumulation (Heart failure)

• Bone Marrow/Myelosuppression

  • Grade 3/4, neutropenia 64%, Thrombocytopenia 63%, anemia 53%

• GI toxicity (73%), hemorrhage (50%), CV events (1-10%)

Important points about Imatinib and the entire class of BCR-ABL TKIs

• Take Imatinib with FOOD

• Entire class agents have DDIs with substrates for CYP3A4 (Example, BZDs, Statins… many more)

• PPIs and H2RAs can reduce AUC