Final Flashcards

1
Q

What is Hodgkin Lymphoma (HL) characterized by? How do HL symptoms present? What is the best way to diagnose?

A

Reed-Sternberg cells

B symptoms:
- Fever (38º C)
- Drenching sweats (esp. at night)
- Unintentional weight loss of greater than 10% in less than 6 months

Diagnosis:
- Excisional biopsy (take the whole lymph node out

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2
Q

How do you treat early stage, advanced stage, relapsed disease, and mainthenance therapy for Hodgkin Lymphoma?

A

Goal: CURE

Early stage:
- Radiation
- ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine)
SEs: pulmonary toxicity

Advanced stage:
- ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine)
- or AAVD (Doxorubicin, Brentuximab vendotin, Vinblastine, Dacarbazine)
SEs: peripheral neuropathy

Relapsed:
- High dose chemo, then autologous stem cell transplant

Maintenance:
- Brentuximab vedotin after stem cell transplant if high risk

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3
Q

How do patients with Non-Hodgkin Lymphoma (NHL) present? How should you diagnose NHL?

A

Presentation depends on tumor location:
- B-cell: lymph nodes, spleen, bone marrow
- T-cell: extra nodal sites (skin and lungs)

  • Lymphadenopathy (can lead to organ dysfunction)
  • B symptoms
  • Extranodal involvement
  • Primary CNS lymphoma

Diagnosis: Excisional biopsy

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4
Q

What are the differences between HL and NHL based on # of nodes, spread, Mesenteric nodes/Waldeyer ring, and extranodal presentation?

A

Hodgkin:
- single group of nodes
- orderly spread
- mesenteric nodes and Wadeyer ring are rarely involved
- extranodal presentation is rare

Non-Hodgkin Lymphoma:
- multiple peripheral nodes
- noncontinuous spread
- mesenteric nodes and Waldeyer ring are commonly involved
- extranodal presentation is common

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5
Q

How do we treat Diffuse Large B-Cell Lymphoma (DLBCL)? What do we test in NHL patients due to viral reactivation?

A

R-CHOP (Rituximab (anti-CD20), Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
SEs: neutropenia

Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb).
- Treat with entecavir 0.5mg daily

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6
Q

What are the 4 aspects of Multiple Myeloma presentation?

A

C: Calcium (hypercalcemia)
R: Renal dysfunction
A: Anemia
B: Bone lesions or fractures

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7
Q

What is the pathophysiology behind Chromic Myeloid Leukemia (CML)? How do these patients present? How should we diagnose?

A

Unregulated myeloid proliferation leads to excess mature neutrophil production. The philadelphia chromosome (BCR-Abl) is involved, which causes a constitutively active tyrosine kinase, which increases proliferation of the CML clone.

Presentation:
- Incidental finding during routine exam or CBC
- Leukocytosis (sticky blood)

Diagnosis:
- Bone marrow biopsy

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8
Q

What is our goal of treatment for CML and how do we treat it? What is the molecular response we are looking for?

A

Goal: Eradicate leukemic clone with minimal toxicity. The only way to cure is an allogenic hematopoietic stem cell transplant (HSCT)

Treatment: Tyrosine Kinase Inhibitors (TKIs)
- Imatinib (nausea)
- Dasatinib (fluid retention/pleural effusion)
- Nilotinib (QTc interval prolongation and metabolic syndrome)
- Bosutinib (Diarrhea) - Last line
- Ponatinib (ischemic reactions, vascular occlusion, hypertension)
for all of these, watch for CYP3A4 reactions (antifungals need dose reduction

Response:
- Gold standard is ≤ 0.01% BCR-ACL

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9
Q

What is the pathophysiology behind Chronic Lymphoid Leukemia (CLL)? How do you diagnose CLL?

A

Monoclonal B lymphocyte transformation undergoes clonal expansion, which leads to lymphocyte accumulation.

Diagnosis:
- Bone marrow biopsy

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10
Q

When do we treat CLL? How we treat CLL? What is important to know about venetoclax?

A

We treat when there are symptoms. We do NOT treat a number.

Treatment:
1. BTK inhibitors: acalabrutinib +/- obinutuzumab (anti-CD20), venetoclax + obinutuzumab, zanubrutinib
*watch out for transient lymphocytosis. It does NOT signify disease progression & resolves by week 12.

Venetroclax: SO MANY DRUG INTERACTIONS!! CYP3A4 and p-GP. Also SEVERE toxicities (tumor lysis syndrome)

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11
Q

What is the pathophysiology behind Acute Myeloid Leukemia (AML)? How do these patients present? How do we diagnose?

A

A single leukemic cell expands & mutates, then proliferates, which results in monoclonal population of leukemic cells. This throws off the balance between proliferation and differentiation.

Presentation:
- Signs of pancytopenia: anemia, neutropenia, thrombocytopenia
- Bone pain from hyperactive bone marrow
- Gum hypertrophy

Diagnosis:
- Bone marrow biopsy showing greater than 20% basts

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12
Q

How do we treat AML?

A

NO CURE

Induction (goal is remission)
- Intensive: cytarabine + idarubicin OR daunorubicin (7+3)

Consolidation (goal is to prevent relapse)
- Favorable: high dose cytarabine (watch out for neurotoxicities and chemical conjunctivitis)
- Unfavorable: stem cell transplant

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13
Q

What is the pathophysiology of Acute Lymphoblastic Leukemia? How do these patients present? How do you diagnose?

A

Like AML, a single leukemic cell expands & mutates, then proliferates, which results in monoclonal population of leukemic cells. This throws off the balance between proliferation and differentiation. Occasionally, philadephia chromosome can be associated (worse outcomes). In this case, add a TKI to the multi-agent chemotherapy.

These patients present similarly to AML.
- Signs of pancytopenia: anemia, neutropenia, thrombocytopenia
*One important difference is that ALL can hide in the brain.

Diagnosis: Bone marrow biopsy

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14
Q

How do you treat ALL?

A

Induction (goal -> remission)

Consolidation (goal -> eradicate residual disease)
- Hyper CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone)
all pts need CNS phophylaxis/treatment (intrathecal chemo)

Maintenance (goal -> prevent relapse): for 2-3 years
- 6-MP, methotrexate, prednisone, vincristine

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15
Q

What happens in these phases of the cell cycle: G1, S, G2, Mitosis

What phase is the CDK4/6 checkpoint and the R point?

A

G1 - gathering building blocks for DNA replication
- CDK4/6 check point (check if we have the building blocks, if there’s DNA damage, and if there’s a signal to proceed through the cell cycle)
- Restriction point (point of no return)

S - synthesis. DNA is replicated here

G2 - assembling machinery for mitosis

Mitosis - chromosomes are segregated and split into two cells

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16
Q

Which phase of the cell cycle do all antimetabolites target? What is their dose-limiting toxicity?

A

Antimetabolites target S phase. They inhibit synthesis through blocking the production of one or more building block (ex. nucleotides)

Myelosuppression is the dose limiting side effect

17
Q

Which two pyrimidine analogs interfere with pyrimidine nucleotide synthesis? Which two inhibit DNA polymerase?

A

Pyrimidine nucleotide synthesis: (uridine analogs)
- 5-FU: converted to FdUMP to mimic dUMP, which inhibits thymidine synthesis (Leucovorin can inc. activity)
- Capecitabine: prodrug of 5-FU that is a little more specific to tumor cells

Inhibit DNA polymerase: (cytosine analogs)
- Cytarabine (Ara-C): Competitively inhibits DNA polymerase. It is especially toxic in the CNS, since the CNS doesn’t have cytidine deaminase, which metabolizes cytarabine (Tetrahydrouradine inhibits cytidine deaminase, which increases efficacy)
- Gemcitabine: Same MOA as cytaracine, but has more potency

18
Q

What antimetabolite blocks the synthesis of purine nucleotides? Which enzymes activate and inactivate this medication? What med increases the conc. of the medication?

A

6-MP: inhibits enzymes in de novo purine biosynthesis
- HGPRT activates 6-MP
- TPMT inactivates 6-MP
- Allopurinol increases the conc. of 6-MP

19
Q

What medication is an antifolate and how does it work? What medication acts as a “rescue” for it?

A

Methotrexate - Mimics DHFR, which inhibits folate production. Folate is an essential cofactor needed for many enzymatic reactions.
- Leucovorin is the rescue, since it acts as a folate.

20
Q

How do alkylating agents work? What cell cycle are they specific to, if any? What 2 drugs do we use and what are their dose-limiting toxicities?

A

Alkylating agents generate electrophilic intermediates that react with nucleophilic groups on DNA/proteins. In this reaction, an alkyl is added. Most commonly, thiols are the reactive group the alkylating agent react with.
- These are not cell-cycle specific, but may favor G1/S
- As a class, these cause secondary malignancies, myelosuppression, and N/V

Cyclophosphamide: prodrug that requires hydroxylation by CYP450, then conversion to PM in the tumor cell. Dose limiting toxicity is hemorrhagic cystitis, but we can use Mesna to mitigate this

Mitomycin C: Can cross-link. Myelosuppression is dose-limiting.

21
Q

How do platinum drugs work? What cell cycle are they specific to? What is the most common agent we use and what is its dose-limiting toxicity?

A

Platinum drugs are covalent cross-linkers, but they do not add an alkyl group to the compound.
- These are not cell-cycle specific, but they may favor G1/S

Cisplatin: requires conversion to its aquo form, then it produces intrastrand links. It’s dose-limiting toxicity is nephrotoxicity

22
Q

How do Topo 1 inhibitors work? What cell cycle do they target? Which agent do we use?

A

Topo 1 inhibitors bind to topo 1 and DNA which ends up messing up the DNA.
- These are specific to S phase, since that’s where transcription is happening.

Irinotecan - Converted to its active metabolite SN-38, which is then metabolized by UGT1A1 to be inactive

23
Q

What are the 3 different Topo 2 inhibitor mechanisms that we use? What cell cycle are they each specific to and what toxicities should we be worried about?

A
  1. Doxorubicin (anthracycline): intercalates DNA, causes free-radical damage, and inhibits topo II.
    - non-cell cycle specific, but leans toward G2/M
    - dose limiting side effect is cardiotoxicity
    - can use Dexrazoxane to mitigate cardiotoxicity, since it detoxifies free radicals
  2. Etoposide: inhibits religation of double stranded DNA breaks
    - specific to G2
  3. Bleomycin: intercalates and causes free radicals
    - specific to G2/M phase
    - pulmonary toxicity is dose-limiting
24
Q

What are the 2 classes of microtubule inhibitors that we have and how do they work? Which cell-cycle are they specific to and what mechanism of resistance are we cautious of? What 2 agents are in each class and what toxicities should we be worried about?

A

Both specific to M phase. Worried about pgp for both!!

  1. Vinka alkaloids - microtubule destabilizers (prevent assembly)
    - Vincristine: neurotoxicity
    - Eribulin: lower rate of neurotoxicity
  2. Taxanes - microtubule stabilizers (prevent depolymerization)
    - Paclitaxel: myelosuppression (neurotoxicity is reversible)
    - Ixabepilone (epothiolones): good toxicity. Neurotoxicity is reversibe. also not a good pgp substrate
25
Q
A