Onco Exam 3 (copy)

SLIDE 484 OUT OF 495

What percent of newly diagnosed cases of lukemia are CLL

~7% of newly diagnosed cases

What is the average age of diagnosis for CLL

Average age of diagnosis is 71

What deems CLL incurable?

Incurable without HSCT – bone marrow transplant

What is the etiology of CLL

Etiology unknown
Not linked to radiation, chemicals, or prior chemotherapy

What are the risk factors for CLL

Male gender (2:1)
Caucasian
Advanced age
Family history

Compare and contrast between CLL and SLL

SLL \= Small Lymphoblastic Lymphoma
Different manifestations of the same disease
CLL abnormal lymphocytes predominate in blood, bone marrow and lymphoid tissue
SLL abnormal lymphocytes rarely found in blood

What are the two staging systems for CLL and what different measures do they use?

Rai Staging System
Binet Staging System

Both use hgb, plt, and enlarged lymph nodes.

What are the poor prognostic factors for CLL

CD38+ (≥30%)
ZAP70+ (≥20%)
Unmutated IgVH (≤2% mutation)
Del 11q
Del 17p
Complex Karytoype

What prognostic factors indicate a poor response to fludarabine in CLL?

CD38+
ZAP70+

What is a positive prognostic factor in CLL

Del 13q

What is the diagnostic criteria for CLL

Presence of at least 5000 clonal B-cells/µL in the peripheral blood by flow cytometry
--FISH to detect cytogenetic abnormalities: Deletion 13q, Deletion 11q, Deletion 17p
--Molecular analysis for IGHV mutation status

What is the clinical presentation of CLL

Splenomegaly (54%)
Hepatomegaly (14%)
Lymphadenopathy (87%)
Fever, fatigue, weight loss

What are some laboratory findings that indicate CLL

Lymphocytosis Monoclonal population of \>
5,000/mm3 lymphocytes
Anemia/ Thrombocytopenia

What do you do during early disease for CLL

Observation for early-stage disease

What are the preferred regimens for CLL w/o Del(17p)/TP53 mutation and
Age ≥ 65 or Age < 65 with Comorbidities (CrCl

Ibrutinib (category 1)
Acalabrutinib ± obinutuzumab (category 1)
Venetoclax + obinutuzumab (category 1)

What are the preferred regimens for CLL w/o Del(17p)/TP53 mutation and Age < 65 Without Significant Comorbidities

Ibrutinib (category 1)
Acalabrutinib ± obinutuzumab (category 1)

What is a second line regimen for CLL w/o Del(17p)/TP53 mutation and Age < 65 Without Significant Comorbidities

FCR (fludarabine, cyclophosphamide, and rituximab) preferred if IGHV-mutated

What are the preferred therapies for patients with relapsed or refractory CLL w/o Del(17p)/TP53 mutation

Acalabrutinib (category 1)
Ibrutinib (category 1)
Venetoclax + rituximab (category 1)

What is the preferred regimen for CLL with Del(17p)/TP53 mutation

Ibrutinib
Acalabrutinib ± obinutuzmab
Venetoclax + Obinutuzumab

What is the preferred regimen for relapsed or refractory CLL with Del(17p)/TP53 mutation

Acalabrutinib (category 1)
Ibrutinib (category 1)
Venetoclax + rituximab (category 1)

What treatment is preferred for young patients with no comorbidities, who can tolerate intense therapy, and who have IGHV-mutated

FCR (fludarabine, cyclophosphamide, and rituximab)

What is a Richter’s Transformation

Histologic transformation from CLL to more aggressive lymphoma, such as DLBCL or HL
Exceedingly poor outcomes

What are features that are associated with risk of developing Richter’s transformation

Unmutated IGHV
del(17p) and complex karyotypes (≥ 3 abnormalities)

What is the relation between the immunogenicity and how foreign an antibody is?

The more different a monocolonal antibody is, the more that it is likely to have an allergic reaction

What type of monoclonal antibody is Rituximab

Chimeric

What type of monoclonal antibody is Obinutuzumab

Humanized

What type of monoclonal antibody is Alemtuzumab

Humanized

What type of monoclonal antibody is Ofatumumab

Human

What is the MOA of Obinutuzumab (Gazyva)

Anti-CD20

How do you administer Ofatumumab

Acetaminophen, antihistamine, and steroid 30-60 minutes prior

ADRs of Ofatumumab

Hep B reactivation (BBW) - Must screen before initiation
Progressive multifocal leukoencephalopathy (BBW) - Observe for neurodeficits
Myelosuppression
Infusion reactions
TLS (tumor lysis syndrome)
Arthralgia/Myalgia

Why do we start with a low dose of Obinutuzumab

to see if they will have a reaction before we start on the actual dosing regimen

Pentostatin (Nipent) MOA

Purine antimetabolite that inhibits adenosine deaminase

Pentostatin (Nipent) dosing adjustments

CrCl 46 to 60 mL/minute: Administer 70% of dose.
CrCl 31 to 45 mL/minute: Administer 60% of dose.
CrCl

Pentostatin (Nipent) ADRs

Experienced physician (BBW)
CNS toxicity (BBW) - 1-11%
Hepatotoxicity (BBW) - 2-19% have elevated transaminases
Pulmonary toxicity (BBW)
Renal toxicity (BBW) - 3-10% have increase Scr
Myelosuppression
Rash (26-43%)
Low emetic potential

Ibrutinib (Imbruvica) MOA

Inhibits BTK, an integral component of the B-cell receptor and cytokine signaling pathway

Ibrutinib (Imbruvica)PK

Metabolism: CYP3A4 (major)

Ibrutinib (Imbruvica) Dose adjustments

Child-Pugh A: low
Child-Pugh B: lower
Child-Pugh C: Avoid

Ibrutinib (Imbruvica) drug interactions

Moderate CYP3A4 inhibitors: 280 mg PO once daily
Strong CYP33A4 inhibitors: Avoid

Ibrutinib (Imbruvica) ADRs

Cardiac
\--- Arrhythmias in 6-9% (baseline EKG)
\--- Heart failure
\--- Hypertension (monitor BP)
\--- Stroke/MI
Diarrhea (36-59%)
Myelosuppression
\--- Lymphocytosis in first few weeks, resolves after 3-4 months
Bleeding (40% of patients)
Progressive multifocal encephalopathy
TLS
Secondary malignancy

Acalabrutinib (Calquence) MOA

2nd generation BTK inhibitor

Acalabrutinib (Calquence) PK

Metabolism: CYP3A4 (major), PGP

Acalabrutinib (Calquence) Drug interactions

Avoid with PPI
Separate 2 hours from H2RA or antacids
Strong CYP3A4 inhibitors: Avoid
Moderate CYP3A4 inhibitors: 100 mg once daily
Strong CYP3A4 inducers: 200 mg q12h

Acalabrutinib (Calquence) ADRs

Cardiac
\--- Arrhythmias in 2% (baseline EKG)
\--- Heart failure
\--- Hypertension grade 3 or worse in 3% (monitor BP)
\--- Stroke/MI
Diarrhea (31%)
Headache (resolves over 1-2 months)
Myelosuppression
Lymphocytosis in first few weeks, resolves after 3-4 months
Bleeding
Progressive multifocal encephalopathy
TLS
Secondary malignancy

Venetoclax (Venclexta) MOA

Inhibits anti-apoptotic protein BCL-2

Venetoclax (Venclexta) drug interactions

Contraindicated with strong CYP3A4 inhibitors

Venetoclax (Venclexta) Dosing

Week 1: 20 mg once daily
Week 2: 50 mg once daily
Week 3: 100 mg once daily
Week 4: 200 mg once daily
Week 5: 400 mg once daily

Venetoclax (Venclexta)ADRs

TLS

What do you give for prophylaxis treatment with Venetoclax (Venclexta) for low, medium and high tumour burden

Low – oral hydration, and allopurinol
Medium – oral hydration (consider IV hydration), allopurinol
High – oral and IV hydration, allopuronol or febuxostat, and maybe rasburicase

Idelalisib (Zydelig) MOA

PI3K inhibitor, inhibits the B-cell receptor signaling pathway

Idelalisib (Zydelig) PK

Metabolism: CYP3A4 (major), PGP

Idelalisib (Zydelig) dose adjustment

ALT/AST \>3-5x ULN or bilirubin \>1.5-3x ULN: Continue current dose; monitor LFTs at least weekly until ALT/AST and/or bilirubin ≤1x ULN
ALT/AST \>5-20x ULN or bilirubin \>3-10x ULN: Hold therapy. Monitor LFTs at least weekly until ALT/AST and/or bilirubin ≤1x ULN, then reinitiate therapy at 100 mg twice daily
ALT/AST \>20x ULN or bilirubin \>10x ULN: Discontinue

Idelalisib (Zydelig) ADRs

Hepatotoxicity (BBW)
\--- Severe hepatotoxicity in 18%
Severe diarrhea/colitis (BBW)
\--- 47% have any grade diarrhea
Pneumonitis (BBW)
\--- 4% of patients
Infection (BBW)
\--- 21% of patients
Intestinal perforation (BBW)
\---

Lenalidomide (Revlimid) MOA

Decrease TNF alpha
Decrease osteoclast survival
Decreases VEGF and decreases angiogenesis
Cell cycle arrest
Increased expression of tumour suppressor genes such as p21
Increases T cell co-stimulation

What are the IMID therapies (immuno modulatory drugs)

thalidomide, lenalidomide, pomalidomide

What are the three BBWs with the immune modulatory drugs (thalidomide, lenalidomide, pomalidomide)

1) VTE, 2) Hematologic toxicity, 3) Embryo-Fetal toxicity
All have REMS program

What is the median age of Hodgkin Lymphoma

39

What is the median age of non -Hodgkin Lymphoma

66

Describe the key differences between Hodgkin Lymphoma and non Hodgkin lymphomas

Hodgkin Lymphoma
\--- pediatric
\--- Often diagnosed at early stage
\--- Presence of Reed-Sternberg cells (mature B cells, two nuclei) by microscopy
\--- Homogenous disease
\--- 5-year OS \> 86%

Non-Hodgkin Lymphoma
\--- Older age
\--- Often diagnosed late stage
\--- Absence of reed-Sternberg cells and can affect B or T cells
\--- Heterogeneous disease
\--- 5-year OS ~70%

What percent of the cells effected in NHL are B cells

85-90% B-cell lymphomas

What is the most aggressive form of NHL

Burkitt's Lymphoma

What are some aggressive NHLs

Diffuse Large B-Cell Lymphoma (DLBCL)
Mantle Cell Lymphoma (MCL)
Peripheral T-Cell Lymphoma

How does diffuse large B cell lymphoma present

Enlarged lymph nodes
B symptoms:
--Fever
--Night sweats
--Weight loss
Fatigue

What are the factors taken into account for the IPI to evaluate Diffuse Large B-Cell Lymphoma

age
LDH (lactate dehydrogenase)
Ann arbor stage
Extranodal disease
Performance status

What are the risk factors for Diffuse Large B-Cell Lymphoma

Older age
Men (slightly increased risk)
Chemical exposure (benzene or chemotherapy)
Viral infection
\--- EBV
\--- HIV, HTLV-1, HHV-8
Immune deficiency
\--- Solid organ transplant
Autoimmune disorders
\--- Rheumatoid arthritis
\--- SLE
Obesity/Diet

What cytogenetic markers should you test for in Diffuse Large B-Cell Lymphoma

MYC rearrangements
BCL2 and/or BCL6 rearrangements
Double-hit lymphoma
Triple-hit lymphoma
Burkitt’s Lymphoma

What is the difference between a Double-hit lymphoma, Triple-hit lymphoma, and a Burkitt’s Lymphoma

Double-hit lymphoma - MYC rearrangement + BCL2 or BCL6 rearrangement

Triple-hit lymphoma - MYC rearrangements + BCL2 + BCL6 rearrangements

Burkitt’s Lymphoma - MYC rearrangements as the sole cytogenetic abnormality
Often present with extranodal involvement

What are the drugs in R-CHOP therapy

Rituximab (Rituxan)
Cyclophosphamide (Cytoxan)
Doxorubicin (Adriamycin) (Hydroxydaunorubicin)
Vincristine (Oncovin)
Prednisone 100

All drugs day 1, prednisone continues from day 1 - 5
Repeat cycle every 21 days

What is the preferred treatment for Non-bulky DLBCL

R-CHOP x 3 cycles + RT (category 1)

What is the preferred treatment for Stage III-IV DLBCL

Clinical trial
R-CHOP x 6 cycles (category 1)

After 2-4 cycles, restage to assess response
If responding, continue for a total of 6 cycles
If not responding, change treatment

When do DLBCL patients receive CNS Prophylaxis and what drug is used for the prophylaxis

Intrathecal methotrexate and/or cytarabine for 4-8 doses

What do you do for DLBCL relapse?

Clinical Trial
ICE or R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide)
CAR-T (Axicabtagene ciloleucel/Tisagenlecleucel/Lisocabtagene Maraleucel)

Describe ICE or R-ICE therapy

Rituximab Day 0 (only if CD20+)
Ifosfamide Day 2
Carboplatin Day 2
Etoposide Day 1, 2, and 3

What are the approved CAR-T therapies

Axicabtagene ciloleucel/ Tisagenlecleucel/ Lisocabtagene Maraleucel)

What are the first line options for Double-Hit/Triple-Hit/Burkitt’s Lymphoma

Clinical trial recommended
DA-R-EPOCH
R-HyperCVAD (previously covered during ALL)
R-CODOX-M/R-IVAC

What is DA-R-EPOCH (Dose adjusted - R-EPOCH)

Rituximab Day 1
Etoposide, doxorubicin, vincristine, All three mixed together and given IV continuous infusion Day 1-4
Prednisone Day 1-5
Cyclophosphamide - Day 5
(750 mg/m2/day if baseline CD4 is \> 200
375 mg/m2/day if baseline CD4 is 50-200
Baseline CD4 counts

What is the cyclophosphamide dosing in DA-R-EPOCH

750 mg/m2/day if baseline CD4 is \> 200
375 mg/m2/day if baseline CD4 is 50-200
Baseline CD4 counts

When is the R-CODOX-M/R-IVAC regimen used

Double-Hit/Triple-Hit/Burkitt’s Lymphoma

What are the factors to determine response criteria for NHL

physical exam
Lymph node, and lymph node masses
Bone marrow

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)

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 is the only treatment effective for treating peripheral neuropathy caused by vincristine?

Duloxetine (Cymbalta)

How is cyclophosphamide metabolized?

It is a prodrug activated by mixed hepatic oxidase enzymes

What are the adverse effects associated with cyclophosphamide?

Hemorrhagic cystitis SIADH; Myelosuppression; rash/SJS; alopecia; moderate to high emetic potential

What causes hemorrhagic cystitis in cyclophosphamide usage?

Acrolein metabolite is a direct bladder irritant

How is hemorrhagic cystitis prevented in patients using cyclophosphamide?

MESNA (directly binds + inactivated metabolite); IV hydration

What CYPs is doxorubicin a major substrate of?

CYP2D6 and 3A4

How are anthracyclines metabolized?

Primarily hepatic

What is the drug class of doxorubicin

Anthracyclines

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 phases is vincristine specific for?

M and S phases

How is vincristine metabolized?

CYP3A4

What are the BBWs for vincristine?

Extravasation ONLY IV ADMIN