HEMATOLOGIC MALIGNANCIES PART 1 LYMPHOMA Flashcards
Hematopoiesis – Review
- Normal hematopoiesis consists of multiple steps of cellular development
- Stem cells initially differentiate to form 2 distinct stem cell pools; myeloid and lymphoid.
- They then undergo further differentiation, proliferation, and maturation, to form the mature blood
cells seen in the peripheral circulation.
Lymphomas encompass
a group of
lymphoproliferative
malignant diseases that
originate from T-cells,
B-cells, or NK cells in
the lymphatic system.
Lymphoma, in lymphoid lineage in the lymphoid tissue
Lymphoma
Lymphomas are a heterogenous group of lymphoproliferative disorders originating in
lymphocytes and/or lymphatic tissues
Hodgkin Lymphoma (HL)
Malignancy of the Reed-Sternberg cell
Non-Hodgkin’s Lymphoma (NHL)
All other lymphomas
More than 40 different subtypes of NHL
Can be B-Cell, T-Cell, NK-Cell
`
Arises in the lymphatic system
Lymph nodes
Extralymphatic organ tissue (Lymphoid tissue in solid organs)
mucosal associated lymphoid tissue (MALT)
Usualyl start off in lymph node but sometimes in other palces like breast, brain, GI
Non-Hodgkin Lymphoma:
risk factors
Non-Hodgkin Lymphoma
(90%)
B-Cell Lymphoma
(85%)
–> diffuse large B cell lymphoma most common 30%
T-Cell Lymphoma
(15%)
NK/T Cell Lymphoma
(very rare)
Risk factors: weakened immune system, autoimmune disease, previous cancer treatment, family
history (first degree relative), certain infections (eg. HIV or EBV (mono) and “Burkitt” lymphoma,
H.pylori and “MALT” lymphoma)
Hodgkin Lymphoma (HL) risk factors
10%
Risk factors: prolonged EBV infection (“mono”), family history (particularly, sibling of same sex), HIV
infection (risk of HL is10X higher in HIV than non-HIV infected people)
B-Cell Lymphoma
AHS Lymphoma Guidelines Version 8 , December 2014
Canadian Cancer Society – Non-Hodgkin Lymphoma
http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/?region=on
Clinical Presentation:
Indolent B cell (e.g. Follicular Lymphoma)
Slow growing lymphadenopathy, hepatomegaly, splenomegaly or cytopenias
Long history of symptoms that wax and wane
Aggressive/Very Aggressive B cell (e.g. DLBCL, Burkitt, Advanced
Hodgkin)
Rapidly growing mass(es) (lymphadenopathy)
“B” symptoms
fevers, night sweats, weight loss
Diagnosis and Pathology
An excisional lymph node biopsy of preferably the largest regionally involved lymph node
For extranodal lymphoma, a sizable biopsy from the organ of origin can be done.
A fine-needle biopsy is inadequate for initial diagnosis of lymphoma
Examination of lymph node by pathologist
Phenotyping - Several markers of interest but the one of highest importance for pharmacists is arguably CD20
(B-cells).
Gene Rearrangements (see below)
Epstein Barr Virus (EBV) studies by in situ hybridization to detect “EBV encoded small nuclear RNA” (EBER)
at the single cell level (i.e. in the cancer cells). Especially for immunocompromised (eg. solid organ
transplant or HIV/AIDS)
Gene Rearrangements associated with
poorer prognosis (prognostic biomarkers)
C-MYC and (BCL2 or BCL 6) =
“Double Hit Lymphoma”
C-MYC and BCL2 and BCL6 = “Triple Hit
Lymphoma”
How many bad markers does the pt have?
Worse prognosis, more aggressive
Work up and diagnosis
Imaging – CT scan or CT/PET scan (preferred)
Assess for Higher Risk Factors (IPI score)
ECOG performance score 2-4
Age > 60 y/o
High LDH
More than one extranodal sites
High LDL is crude marker that there may be a lot of tumors in body
Laboratory tests – examples: CBC with differential, serum chemistries, LDH
Testing for concerning co-morbidities, complications, or infections that can complicate treatment:
HIV test
Additional immunosuppression and many drug interactions between HIV therapies and cancer therapies
Hepatitis B
Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody (anti-HBs), Hepatitis B Core Antibody
(total anti-HBc)
Pregnancy test (if child-bearing potential)
Echocardiogram or MUGA to assess heart function and establish baseline (if requiring an anthracycline)
Pulmonary function tests to assess lung function and establish baseline (if requiring bleomycin)
Hep B - if we use some of the drugs for lymphoma, could have reactivation of hep B, serious infection risk\
Hep C
Treatment of DLBCL
DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
Rituximab IVPB once DAY 1 of each cycle
Cyclophosphamide IVPB once DAY 1 of each cycle
Doxorubicin (Hydroxydaunorubicin) IV direct once DAY 1 of each cycle
Vincristine (Oncovin) IVPB once DAY 1 of each cycle
Prednisone 100 mg PO daily X 5 days DAY 1-5 of each cycle
R-CHOP is given every 21 days (cyclically) for 3-6 cycles depending on disease and patient factors
Goal is cure
Appropriate supportive care
RCHOP
antinauseants with chemotherapy
infection prevention
Example: HBsAg negative/anti-HBc positive and are going to be treated with B-cell depleting
therapy (e.g. rituximab) require Hep B prophylaxis with entecavir or tenofovir and close monitoring
(HBV DNA testing q6-12 months and ALT q3months)
prophylaxis for tumour lysis syndrome (will talk about with leukemia)
Therapy may also include
Radiation
Autologous stem cell transplant (examples: “double hit” or “triple hit” or relapsed disease or
treatment refractory disease)
Cyclophosphamide
MOA
AE and counselling tips
MOA – Alkylating Agent (Nitrogen Mustard type)
Binds to DNA and leads to cross-linking of strands of DNA and RNA and inhibition of protein synthesis.
Myelosuppression
* neutropenia, thrombocytopenia
infection prevention
tips from febrile neutropenia lecture
Hemorrhagic cystitis
* injury to the urothelium by acrolein (metabolite)
good hydration and void frequently
seek medical attention if blood in urine
Nausea/Vomiting
* MEC if single agent, HEC if combined with anthracycline
provide excellent education on antinausents and consider providing a
written schedule
Alopecia
* hair loss
remember, although this is temporary, this one can be stigmatizing and
traumatic
Fertility suppression
* Many factors contribute to degree and gonadal suppression
and potential for ovarian failure
important to discuss BEFORE treatment starts for those of child
bearing/fertilizing potential
Doxorubicin (Hydroxydaunorubicin)
MOA
MOA – Anthracycline
Inhibition of Topoisomerase II prevents religation of DNA during
replication
Damages DNA and cell membranes by producing free radicals
Drug Interactions:
CYP 3A4 and CYP 2D6 Substrate
Example Fluconazole (2D6 inhibitor) could increase risk of toxicities
Example: Carbamazepine (3A4 inducer) could decrease efficacy and
compromise chance of cure
Antioxidants??? - Reduce free radicals!!
Doxorubicin Side Effects
Cardiotoxicity
* Late onset – reduced LVEF or symptomatic CHF
* Early onset - presents from acute transient ECG changes to worrisome arrhythmia
* Baseline echocardiogram or MUGA required. LVEF should be ≥ 50% to use doxorubicin in RCHOP
* LATE onset cardiotoxicity is more common, is highly related to cumulative dose, can occur months to years later, and is irreversible
* anthracycline induced cardiotoxicity may present as reduced LVEF or symptomatic CHF
* EARLY cardiotoxicity is less frequent, NOT dose-related, usually transient occuring during or immediately after administration
Myelosuppression
* neutropenia, thrombocytopenia
* infection prevention
* tips from febrile neutropenia lecture
Nausea/Vomiting
* MEC if single agent, HEC if combined with
cyclophosphamide (AC)
* provide excellent education on antinausents and consider providing a written schedule
Alopecia * remember, although this is temporary, this one can be stigmatizing and traumatic
Red discoloration of urine
* Occasionally can also discolor other body fluids
* Warn patients that their urine may be red/pink/orange after administration as it can be
alarming.
Vincristine (Oncovin)
MOA – Vinca Alkaloid (Periwinkle Plant)
Binds to tubulin (protein on spindle)and prevents mitosis
For IV administration only
Fatal if given intrathecally
Side Effects
Neurotoxicity
Peripheral neuropathy
Autonomic Neuropathy
Constipation – many patients require stool softeners and laxatives prophylactically
Drug Interactions:
CYP 3A4 Substrate
Example – Azole antifungals may increase vincristine toxicity
Long term peripheral neruopathy
Fumbling with buttoning up shirt
Prednisone
Remember 100 mg po daily X 5 days is a large dose of corticosteroid
Monitoring / side effect management issues
Blood glucose
Close monitoring for diabetic patients required
Mood changes
Patient/family education
Insomnia
Some patients may require pharmacotherapy for sleep promotion on prednisone days (e.g. Zopiclone) Can’t sleep well
GERD
Take with food
Consider ulcer prophylaxis with PPI/H2 antagonist for prednisone days
Why Rituximab?
Groupe d’Etude des Lymphomes de l’Adulte (GELA) studies
patients with newly diagnosed DLBCL between 60-80 years of age were randomized to CHOP or CHOP + Rituximab for 8 cycles\
Complete Remission rates:
CHOP 68%
R-CHOP 76% (p = 0.005)
2 year follow up *
Overall Survival IMPROVED- CHOP 57% vs CHOP + R 70% (p = 0.007)
5 year follow up **
Overall Survival IMPROVED - CHOP 45% vs CHOP + R 58% (p = 0.007)
10 year follow up ***
Overall Survival IMPROVED - CHOP 27.6% vs R-CHOP 43.5% (p = 0.007)
Prognosis changed
Really improves survival
Rituximab MOA
3 proposed mechansims
Monoclonal Antibody for CD20
* Most B cells (malignant and non-malignant) are CD 20
positive
* Rituximab destroys B-cells\
Death Star = malignant B cell
“the force” = rituximab
Chimeric (human and mouse) antibody
directed against the B-cell antigen CD20
CD20 is a cell surface antigen
expressed on the surface of both
normal and malignant B cells
There are 3 proposed mechanisms of
action
1. Effector cells (NK, T cells or
macrophages), recognize and kill Ab
labeled B cells
2. Once Ab is attached, complement is
activated, leading to holes in the cell
membrane and cell lysis
Maloney et al. NEJM 2012 3. Ab binding leads to direct cell death
Risk of fever and alleric reaction
Block entire histamine pathway
Can cause hypotension, so hold ACE inhibitor
Rituximab AE
Infusion reactions
Fever, chills/rigors
Hypotension
Symptoms decrease after 1st infusion
Premedication
Acetaminophen 650 mg po 1 hour pre rituximab
Diphenhydramine 50 po/IV 1 hour pre rituximab OR Loratidine 10 mg po daily X 2 days
Hydrocortisone 100 mg IV 1 hour pre-rituximab (optional)
Ranitidine 50 mg IV or 150 mg PO OR Famotidine 20 mg po 1 hour pre rituximab (optional/recommended)
Consider holding antihypertensives 12 hours prior
Typically done for at least the first cycle
Risk of fever and alleric reaction
Block entire histamine pathway
Can cause hypotension, so hold ACE inhibitor
Rituximab INTRAVENOUS
Severe reactions resulting in death have occurred
severe bronchospasm, dyspnea, angioedema
management is to discontinue the rituximab infusion and institute supportive care
oxygen, IV fluids, bronchodilators, anti-histamines and steroids
Rituximab IV dose for DLBCL is 375 mg/m2
NOTE a 500 mg/m2 dose is sometimes used for other indications such as chronic lymphocytic
leukemia (CLL)
First dose should always be given IV. If patient failed to completely receive the
entire first dose, the second dose should also be IV.
If react stop infusion and give supportive care
Hopefully can rechallenge
Rituximab SUBCUTANEOUSLY
Requirements
Subcutaneous Rituximab CANNOT be used for a patients first dose
Avoid irreversible full dose administration when infusion reaction is highest
Can be used in subsequent doses once a patient has received one FULL rituximab IV infusion dose
(even if they had an infusion reaction during the dose).
If patient could not complete a FULL dose, then the next dose must be given IV again
Benefits:
Quicker preparation time in pharmacy
Shorter administration time (nursing and chair time)
Less drug wastage
Dosing
FIXED FLAT DOSE OF 1400 mg
Premedications still required
ERROR PREVENTION IS OF UTMOST IMPORTANCE!!!!
Fixed flat dose for subq
Based on BSA when IV
Subq is never the first dose, if they do react it is all in the body
Do IV frist to make sure it’s ok
Still need pre-meds for subq
Hodgkin Lymphoma
Because it has such a high cure rate, and patients might be quite young,
long term toxicities are a very important consideration; especially for
patients with early stage disease.
Ages 15-30 and 55 and older
Very Curable (>80% of patients)
Usually distinguished by presence of Reed Sternberg cells
Factors which reduce the risk of cure are
(“unfavourable risk”)
Stage IV, ≥3 extranodal sites
Age ≥45 years old
Male gender
Albumin < 40
High white blood cell count (WBC ≥ 15)
Lymphocytopenia (lymphocytes <8% or <
0.6)
Hg < 105
Factors which reduce ability to tolerate
intense chemo are:
Age ≥ 60 years old
ECOG > 2
HIV positivity
Treatment of Hodgkin Lymphoma
Esc-BEACOPP q21 days for 6 cycles
NOTE – more intense and more toxic
Higher risk of long term infertility
ABVD q 28 days for 6 cycles
NOTE – with ABVD, patients receive chemotherapy
every 2 weeks!!
NOTE: Patients may switch from one to the other based on a PET scan after cycle 2
Lot of risk factors, lets do Esc-BEACOP and scan them
It they’re doing good, we can do ABVD
Or the other way around
Bleomycin (the “B” in ABVD or escBEACOPP)
MOA – causes DNA strand scission through formation of an intermediate metal complex
Side Effects
Dermatologic effects
Rash on pressure areas and skin creases
Hyperpigmentation
Mucositis and stomatitis
Respiratory effects
Pneumonitis and pulmonary fibrosis
Caution in patients with existing respiratory disease – all patients will have pulmonary function tests prior to initiating treatment
Pulmonary tests and/or chest X-ray may be done periodically to assess lungs through treatment
Loss of appetite
Big one is pulm fibrosis
Vinblastine (the “V” in ABVD)
MOA – Vinca Alkaloid (Periwinkle Plant)
Binds to tubulin (protein on spindle)and prevents mitosis
For IV administration only
Fatal if given intrathecally
Side Effects:
Neurotoxicity (<1%) is much less than vincristine
Can still be constipating
Myelosuppression (>10%) is much higher than vincristine
Drug Interactions:
CYP 3A4 Substrate
Example – Azole antifungals may increase vincristine toxicity
Dacarbazine (the “D” in ABVD)
MOA
Prodrug for methyltriazenoimidazole carboxamide (MTIC)
MTIC cytotoxicity is thought to be due to methylcarbonum ions that attach
nucleopyilic groups in DNA
Side Effects:
nausea and/or vomiting (HEC)
anorexia in > 90%
leukopenia and thrombocytopenia
Procarbazine (the first “P” in esc BEACOPP)
Alkalating Agent
MOA not clearly defined, possibly free radical damage
Monoamine Oxidase Inhibiting Activity (MAOI)
Avoid high tyramine content food/drink
AVOID ALCOHOL - can cause a disulfiram like reaction (flushing, headache, palpitations, hypertension)
NO DELI MEATS
Avoid sympathomimetic drugs (pseudoephedrine)
Adverse Effects:
Infertility
Ovarian failure, azoospermia
Bone marrow suppression
Secondary malignancies
PO for 7 days
lymphoma staging
stage 1: single lymph node region/ one extralymphatic organ
2: 2 or more lymph node regions on sade side of diaphragm
3: on both sigde of diagram
4: diffuse involvement
see slide
