Onco Exam One - Yaccabucci

What does a “Grade One” adverse effect mean?

Mild, no intervention necessary

What does a “Grade Two” adverse effect mean?

Moderate, non-invasive intervention indicated

What does a “Grade Three” adverse effect mean?

Severe, hospitalization indicated

What does a “Grade Four” adverse effect mean?

Life-threatening, urgent intervention indicated

What does a “Grade Five” adverse effect mean?

Death

What is the TNM model for staging of cancer?

T = tumor size (0-4)

N = Nodal involvement (0-3)

M = Metastatic (organ to organ) disease (0-1)

How does cancer spread/what are the stages of spread?

Stage 1-3 (pre-metastatic)

\-Normal cells initially, then one abnormal cell appears, then it multiplies until angiogenesis (development of new blood vessels to the abnormal cells) occurs at which point it is malignant or invasive cancer

Stage 4 (metastatic)

\- Local breakdown of the tumor/cancer occurs allowing for it to spread through the blood vessel to a new location where a secondary tumor forms

What is RECIST?

Response Evaluation Criteria in Solid Tumors

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Methodology to evaluate activity and efficacy of cancer therapeutics in solid tumors

According to the RECIST criteria, what is considered a complete response?

Disappearance of all target lesions

According to the RECIST criteria, what is considered a partial response?

At least 30% decrease in the sum of diameters of target lesions from baseline

According to the RECIST criteria, what is considered an objective response?

OR = CR + PR ; sum of patients who has any degree of positive response

What is a key function of neutrophils?

Protection against infection

What do B cells ultimately become?

Plasma cells that produce immunoglobulin (antibody) specific for an antigen

Where is leukemia isolated to?

Peripheral blood and bone marrow

Where is lymphoma isolated?

Lymph nodes

What is the origin of luekemia?

Myeloid or lymphoid

What is the origin of lymphoma?

Always lymphoid

What are the key differences between acute and chronic leukemia?

Acute - rapid onset, symptomatic, rapidly fatal if untreated, primarily immature blast cells, leukocytosis or leukopenia

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Chronic - slowly progressive, mostly asymptomatic (diagnosed on routine labs), may survive years without treatment, immature and mature cells, typically leukocytosis

What is the most common form of acute leukemia among adults?

Acute myeloid leukemia

What are the risk factors for acute myeloid leukemia?

Older age; prior chemotherapy (alkylating agents, topo II inhibitors, antimetabolites); ionizing radiation exposure; benzene exposure; cigarette smoking; antecedent blood disorders (MDS, aplastic anemia, myelofibrosis; hereditary chromosomal abnormalities (Down’s, Blooms, Klieninfelter’s)

How does a patient with AML present?

Fatigue and dyspnea (due to anemia)

Infection (neutropenia)

Bleeding (thrombocytopenia, coagulopathy)

Confused (CNS involvement, leukostasis)

What are thrombocytopenia, anemia, and neutropenia caused by in AML?

Overcrowding (“clogged pipe”)

What are laboratory findings for AML?

1/3 pancytopenia, 1/3 WBC WNL, 1/3 leukocytosis

Anemia, thrombocytopenia, neutropenia

Spontaneous tumor lysis syndrome (release intracellular contents)

Disseminated intravascular coagulopathy (increased risk bleeding and clotting at same time)

What is leukocytosis and how does it present?

Oncologic emergency - hyper-viscosity syndrome (“blood slugging”)

Stupor; SOB; vision changes; stroke; respiratory failure; cardiac ischemia; renal failure; renal hemmorhage

How do you manage leukocytosis?

Hydroxyurea - antimetabolite used for cytoreduction

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Leukapheresis

What is the world health definition of AML?

At least 20% myeloid blasts isolated on bone marrow biopsy or peripheral blood

What is the cytogenetic definition of AML?

Detection of cytogenetic abnormalities known to indicate AML such as t(8;21), t(15;17), t(16:16), inv(16)

What molecular mutations are associated with AML?

FLT3, IDH1, IDH2, TP53

What is the role of the FLT3 gene?

It encodes a receptor tyrosine kinase that regulates hematopoiesis

What does a FLT3 internal tandem duplication indicate in AML and when is it considered high?

It is a poor prognostic factor of AML and if the ratio is over 0.5 then it is considered high

What cytogenetic markers are high risk in AML?

Del 5q, -5

Del 7q, -7

11q23

t(9,22)

What molecular marker is considered high risk in AML?

FLT3-ITD mutation

What is a favorable genetic abnormality in AML?

Mutated NPM1 without FLT3-ITD or with FLT3-ITD

What are poor/adverse genetic abnormalities in AML?

t(v;11q23.3)

\-5 or del(5q)

Wild type NPM1 and FLT3-ITD

What are other factors outside of genetic abnormalities that indicate poor prognosis?

Increasing age; secondary or treatment-related AML, High WBC at diagnosis (>100,000), relapsed AML

What is the 7+3 regimen for patients 60 years and younger?

Cytarabine 100-200 mg/m2 IV daily continuous infusion for 7 days + daunorubicin 60-90 mg/m2 IV over 1-2 hours for three days

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Idarubacin 12 mg/m2 may be used instead of daunorubicin

What is the 7+3 regimen for patients over 60 years old?

Cytarabine 100-200 mg/m2 IV daily continuous infusion for 7 days + daunorubicin 60 mg/m2 IV over 1-2 hours for 3 days

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Idarubicin 12 mg/m2 or mitoxantrone may be used instead of daunorubicin

Is the 7+3 regimen concurrently given?

Yes

What is induction therapy for adults under 60 years old if they have favorable risk cytogenetics and no mutations?

7+3

What is induction therapy for adults under 60 years old if they have favorable risk cytogenetics and are CD33 positive?

7+3 with gentuzumab ozogamicin

What is induction therapy for adults under 60 years old if they have intermediate or poor risk cytogenetics with no mutation?

7+3

What is induction therapy for adults under 60 years old if they have intermediate or poor risk cytogenetics with a FLT3 mutation?

7+3 with midostaurin

What is intensive induction therapy for adults 60 and older with favorable risk cytogenetics and no mutations?

7+3

What is intensive induction therapy for adults 60 and older with favorable risk cytogenetics that are CD33 positive?

7+3 with gemtuzumab ozogamicin

What are the different intensive induction therapy options for adults 60 and older with intermediate and poor risk cytogenetics?

7+3;

7+3 with gemtuzumab ozogamicin if CD33-positive;

Liposomal cytarabine and daunarubicin if therapy related or MDS-related AML;

7+3 with midostaurin if FLT3 mutation

What are the options for intensive induction therapy for 75+ year olds with intermediate and poor risk cytogenetics?

Venetoclax and hypomethylating agent OR low dose cytarabine

What are the treatment options for adults 60 and older who are NOT candidates for intensive induction therapy and do not have actionable mutations?

Hypomethylating agent alone;

Gemtuzumab ozogamicin alone for CD33 positive;

Low dose cytarabine alone

What are the treatment options in elderly (75+) patients who are not candidates for intensive induction therapy but who do not have actionable mutations?

Venetoclax and hypomethylating agent OR low dose cytarabine which is preferred

What characteristics prevent candidacy for intensive induction therapy in those 60+ years old?

Significant renal or hepatic dysfunction

What are the treatment options for adults 60 and older who are not candidates for intensive induction therapy and that have an IDH1 mutation?

Ivosidenib and Azacitidine (preferred) OR ivosidenib monotherapy

What is the treatment option for adults 60 and older who are not candidates for intensive induction therapy that have an IDH2 mutation?

Enasidenib

What are the treatment options for adults 60 and older who are not candidates for intensive induction therapy and have a FLT3 mutation?

A hypomethylating agent and sorafenib OR venetoclax and hypomethylating agent or low-dose cytarabine

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NO MIDOSTAURIN since it is only approved in use with 7+3 regimen

What is the criteria for complete response after induction?

Patient is independent of transfusions, ANC normal, PLT normal, no evidence of extramedullary disease, blasts

What does consolidation therapy depend on?

The patients response and the induction treatment used

What is HiDAC therapy?

High-dose ARA-C (High-dose Cytarabine)

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Cytarabine 1.5 to 3 g/m2 q12 hours on days 1, 3, 5

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Give every 28 days for 3-4 cycles

If a patient received 7+3 induction therapy for AML, what is their consolidation therapy regimen going to be?

HiDAC (High-dose cytarabine)

If a patient’s induction regimen for AML contained a drug with a targetable mutation (CD33, FLT-3), what will that patients consolidation therapy look like?

Continuation of that drug (Gemtuzumab for CD33, Midostaurin for FLT3) plus HiDAC

If a patient received liposomal daunorubicin and cytarabine for induction therapy for AML, what will their consolidation therapy look like?

They will continue liposomal daunorubicin and cytarabine

What is considered a late relapse of AML and what is the treatment for it?

Over 12 months after induction; if relapse then repeat initial induction regimen

How is cytarabine excreted?

\~80-90% renal → don’t use in renal dysfunction

How is cytarabine metabolized?

Haptic (non CYP)

What are the adverse effects of low dose cytarabine?

Myelosuppression; cytarabine rash; fever; n/v (low emetic risk)

What are the adverse effects of HiDAC?

Same as low dose cytarabine, in addition to: Moderate emetic risk; neurotoxicity; conjunctivitis; mucositis

How does neurotoxicity manifest for patients on cytarabine?

Cerebellar syndrome → ataxia, nystagmus, dysarthria

How often do patients on cytarabine require “neuro checks”?

Every 4-6 hours (frequent!!!)

What must be given to prevent conjunctivitis in patients taking cytarabine?

Steroid eye drops

What anthracyclines are used for AML?

Daunorubicin, doxorubicin, and idarubicin

How are anthracyclines metabolized?

Primarily hepatic

What CYPs is doxorubicin a major substrate of?

CYP2D6 and 3A4

What is the dose adjustment for anthracyclines in renal impairment?

If Scr >3 mg/dl → 50% of dose

What is the dose adjustment for anthracyclines in hepatic impairment?

Bilirubin 1.2 to 3 → 75% dose;

Bilirubin 3.1 to 5 → 50% dose;

Bilirubin >5 → avoid use

What are the black box warnings associated with anthracyclines?

Extravasation, myelosuppression, cardiomyopathy, hepatic impairment, renal impairment

How is extravasation caused by anthracyclines managed?

Apply a cold pack and evaluate for antidote use - DMO 1-2 mL applied q 6 hours for 7-14 days or dexrazoxane (Totect)

How can anthracycline cardiotoxicity present?

Short term - arrhythmia’s;

Long term (decades) - congestive HF

What are the risk factors for anthracycline cardiotoxicity?

Cumulative dose (#1 risk factor); female gender; hypertension; baseline LV dysfunction; African America; Over 65 yo or under 18 yo; renal failure; concomitant exposure to radiation or other cardiotoxic medications

What is the indication for liposomal duanorubicin and cytarabine?

Secondary AML

What are the additional adverse effects of the liposomal duanorubicin and cytarabine combination product?

Myelosuppression is longer; copper toxicity (Wilson’s disease); purple secretions

What class is decitabine?

Hypomethylating agent

What is the mechanism of action of decitabine?

After phosphorylation it is incorporated into DNA and inhibits DNA methyltransferase, causing hypomethylation and cell death

How is decitabine metabolized/excreted?

Cytadine deaminase

When do you hold decitabine treatment?

Hold if Scr is 2+ or if ALT/T bili is 2+ during treatment

What are the adverse effects of decitabine?

Myelosuppression, arthralgias/myalgias, hepatotoxicity, hyperglycemia, nephrotoxicity; LOW emetic potential

What is the class of Azacitidine?

Hypomethylating agent

What is the mechanism of action of azacitidine?

After phosphorylation, it is incorporated into DNA and inhibits DNA methyltranseferase, causing hypomethylation and cell death

How is azacitidine metabolized?

Hepatically via hydrolysis

How is azacitidine excreted?

50-85% in urine

For how many days is decitabine taken?

For 5 days every 28 days

For how many days is azacitidine taken?

For 7 days every 28 days

In what patient population must you provide caution in terms of dosing for Azacitidine?

In patients with renal impairment

What are the adverse effects of azacitidine?

Myelosuppression, hepatotoxicity, arthralgias/myalgias, nephrotoxicity, injection site reactions (polysorbate 80), MODERATE emetic potential

What is the mechanism of action of gemtuzumab oxogomicin?

It’s a CD33 directed mAb-drug conjugate that is internalized and releases a calcicheamicin derivate that causes DNA strand breaks and induces apoptosis

Essentially an alkylating agent

What is the metabolism of gemtuzumab ozogomicin?

Non-cyp

What must you premedicate with before taking gemtuzumab ozogomicin?

Acetaminophen and diphenhydramine 1 hour prior to infusion

What BBW is associated with gemtuzumab ozogomicin?

Hepatotoxicity including veno-occlusive disease (VOD)W

What are the adverse effects associated with gemtuzumab ozogomicin?

Hepatotoxicity; Myelosuppression (up to 42 days post dose); TLS (tumor lysis syndrome; cytoreduce to WBC < 30,000 before treatment); QT prolongation; infusion reactions; MODERATE emetic potential

Do you ever rechallenge if a patient develops VOD while on gemtuzumab ozogomicin?

NO

Explain what happens in VOD (veno-occlusive disease)?

Small blood vessels leading into the liver become obstructed due to endothelial damage following chemotherapy

What are the risk factors of developing VOD while on gemtuzumab ozogomicin?

Dose of gemtuzumab;

Baseline hepatic impairment;

Patients receiving HSCT (hematopoetic stem cell transplant) after treatment with gemtuzumab

What are the signs/symptoms/lab abnormalities associated with VOD?

Weight gain, ascites, jaundice, hepatomegaly, elevation in bilirubin/transaminase

How do you manage VOD caused by gemtuzumab ozogomicin?

Discontinue the therapy permanently; consider defibrotide (breaks clots up; bleed risk)