Hematologic Malignancies Leukemias Flashcards
Chronic Myeloid Leukemia (CML) - Epidemiology
In 2024 estimated 9,280 new cases of CML
Median age of diagnosis: __
More common in ___ (2.5 vs. 1.5)
5-year relative survival: 70%
66
men
CML – Pathophysiology
Unregulated myeloid proliferation = excess mature neutrophil production
oncogenic protein resulting in the pathogenesis of CML = ___ chromosome
- ___ active tyrosine kinase
- Increased proliferation of the CML clone
- Decreased apoptosis
- philadelphia
- Constitutively
CML – Philadelphia chromosome
Breaks in chromosome 9 & 22 = translocate to form BCR-ABL fusion gene
- ___ active oncogene
Constitutively
CML – Risk Factors
- No genetic component identified
- ___ radiation
- Atomic ___ survivors
- Ionizing
- bomb
CML – Presentation
Incidental finding during routine examination or CBC
- Fatigue, Sweating, Bone pain, Weight loss
___ : medical emergency
- As high as 1,000,000 cells/mm3
◦ Risk of leukostasis
leukocytosis
CML – Treatment
No treatment, fatal within 5 years
Goals: eradicate leukemic clone with minimal toxicity
◦ Only to cure way is ___ hematopoietic stem cell transplant (HSCT)
Tyrosine kinase inhibitors (TKIs)
◦ Dramatically changed clinical course
◦ Disease control for many years = treat as a chronic disease
allogenic
CML
2nd Generation TKIs (3)
- all are approved in first line setting
- faster and deeper response
Dasatnib, Nilotinib, Bosutinib
No overall survival advantage when compare to imatinib
CML – Resistance
- BCR-ABL gene amplification/ overexpression
- Mutations in the kinase domain
- Secondary genetic alterations
T315I super resistance gene
CML - Asciminib
newest TKI
- Can be used in ___ resistant CML, but study yet to be published on outcome
- Different dosing for CML CP with and without T315I
◦ 40 mg PO BID
◦ 200 mg PO BID
T315I
TKI DISCONTINUATION CRITERIA
- No history of AP or BP
- On TKI therapy for at least __ years
- Quantifiable BCR-ABL = BCR-ABL < 0.01%(deep molecular response)
- Stable deep molecular response for > __ years
3
2
MONITORING AFTER DISCONTINUATION
- Quantifiable ___
- Patient must remain in major molecular response (MMR, BCR-ABL < 0.1%
- Loss of MMR = restart TKI within ___ weeks
PCR
4 weeks
CML – Summary
Translocation between the long arms of chromosomes 9 and 22
- BCR-ABL fusion oncogene (aka Philadelphia chromosome)
Three phases: ___ , ___ , ___
TKIs have revolutionized the treatment and prognosis of CML
- Selection based on patient factors and resistance testing
chronic, accelerated, blast crisis
Chronic Lymphoid Leukemia (CLL)
Can convert to an
aggressive lymphoma:
___ transformation
Richter’s
CLL – Risk Factors
median diagnosis age: ___
old, white, male
70
CLL – Cytogenetics
Del(11q) is associated with extensive lymphadenopathy, disease progression
and shorter median survival
◦ May respond well to fludarabine + alkylating agent
Del( ___ ) is associated with the worst outcomes
◦ Reflects the loss of the key tumor suppressor ___ gene
◦ Short treatment free intervals, poor response to chemotherapy, and short median survival‐
- 17p
- TP53
CLL – Treatment
Treatment reserved for:
◦ Stage III or IV disease
◦ Clinical symptoms
◦ End organ dysfunction
- Disease treatment selection is stratified based on cytogenetics and age
- First line option for all: ___ inhibitors as single agent or chemoimmunotherapy
BTK
We do NOT
treat a number!
CLL – Venetoclax
Inhibits BCL-2 resulting in release of BIM and PUMA
◦ BCL-2 is a ___ protein
◦ BIM and PUMA are ___ proteins
- pro-survival
- pro-apoptotic
CLL – Venetoclax & Drug
Interactions!
CYP ___ and ___
CYP3A4, P-gp
CLL – Relapse or Refractory Disease
Goal of treatment is to ___ symptoms
◦ Current therapies do not cure disease
◦ Patient will ___ after treatment
Management of relapse depends on:
◦ Age and performance status
◦ Previous therapy
◦ Response and duration of response to therapy
◦ Time from last therapy
palliate
relapse
CLL – Lymphocytosis or Tumor
Flare
Transient increase in absolute lymphocyte count
◦ Associated with ___ , ___ , and ___
Peaks early in treatment course
◦ Resolves by week 12
Does not signify disease progression
acalabrutinib, ibrutinib, zanubrtuinib
CLL – Summary
Patients with early stage (asymptomatic) disease may only require observation
del( ___ ) is associated with worse prognosis
1st line treatment with
◦ Zanubrutinib/acalabrutinib +/- obinutuzumab (or rituximab) indefinitely
◦ Venetoclax + obinutuzumab x 1 year
Transient ___ may occur with BTK inhibitors
- 17p
- lymphocytosis
AML – Epidemiology
More common in men than women
Median age at diagnosis: __
5-year relative survival
rate: 31.9%
- Highest leukemic deaths in aged 75-84
- 69
AML – Pathophysiology
- Arise from single leukemic cell = expands & acquires additional mutations = proliferation
resulting in monoclonal population of leukemic cells - Failure to maintain balance between ____ and ___
- Defect in the pluripotent stem cell or a myeloid precursor stem cell
- Leukemic cells have growth advantage = crowd out normal cells
proliferation, differentiation
AML – Risk Factors
Secondary AML
- From other disease (i.e. myelodysplastic syndrome)
* Treatment related
* ___ agents
* ___inhibitors
Primary AML
* Genetic predisposition
* Environmental carcinogens
- alkylating
- Topoisomerase II
AML – Presentation
Signs of pancytopenia
- ___ : fatigue, pallor, palpitations
- ___ : infections
- ___: gingival bleeding, ecchymosis, epistaxis
___ pain
___ hypertrophy
- anemia
- neutropenia
- thrombocytopenia
- bone
- gum
AML – Diagnosis
Bone marrow biopsy: greater than ___ % blasts
20%
AML – FLT3 Mutations
Mutations in the fms-related tyrosine kinase 3 gene (FLT3) are present in 30% of adults with newly diagnosed AML
Cause a factor-independent growth of leukemia cells
Associated with ___ overall prognosis
◦ More aggressive disease
◦ Lower chance of complete remission
◦ Higher rate of relapse
___ can target this mutation: midostaurin, quizartinib, gilteritinib (2nd line only)
worse
TKI
AML – Treatment
induction
Goal: remission
Consolidation
Goal: prevent relapse
Intensive Induction eligible (7+3)
- Continuous infusion cytarabine + anthracycline
- FLAG-ida +/- gemtuxumab ozogamicin (CD33 + disease)
- Venetoclax + hypo-methylating agent
Intensive induction ineligible
- Venetoclax + hypo-methylating agent
- Hypo-methylating agents; lower dose chemotherapy
Supportive Care
Blood products, prophylactic anti-infectives, hydroxyurea
* Goal: Symptomatic management
Intensive Chemotherapy
(7+3)
- cytarabine, idarubicin/daunorubicin
AML – Acute Promyelocytic Leukemia (APL)
t(15;17) = PML:RARA
- All trans retinoic acid (ATRA)
- Restores normal maturation/differentiation pathway
- Arsenic trioxide (ATO)
Differentiation Syndrome:
* High risk patients can get
prophylaxis with steroids.
Hydroxyurea for treatment
* Signs and sympoms
AML – Summary
Diagnosis based on bone marrow biopsy
Treatment divided into induction and consolidation
◦ Induction: induce a complete remission
◦ Consolidation: eradicate residual disease & maintain remission
Low intensity therapy may be an option in those not fit for intense induction chemotherapy
ALL – Epidemiology
Median age at diagnosis: ___
◦ Most common in ___ , adolescents and young adults aged
15-39 years old
More common in Hispanics and Whites
5-year relative survival rate: 72%
◦ Older age = poorer prognosis
Acute Lymphocytic Leukemia — Cancer Stat Facts
17
children
ALL - presentation
pancytopenia
ine pain
gum hypertrophy
lympadenopathy
abdominal masses
painless testicular enlargement
ALL – Diagnosis
Bone marrow biopsy with greater than or equal to ___ % blasts
Classified by:
◦ Type of lymphocyte
◦ Degree of differentiation
20
ALL – Philadelphia Positive Disease
___ added to multi-agent chemotherapy
TKI
ALL can hide in sanctuary sites
brain and testes
Most protocols include intrathecal chemotherapy!
Ph positive: ___ + vincristine + prednisone
Ph negative:weekly ___ + daily 6MP + monthly vincristine (POMP)
TKI
methotrexate
ALL – HyperCVAD
HyperCVAD
◦ Hyper-fractionated cyclophosphamide
◦ Vincristine
◦ Doxorubicin (Adriamycin)
◦ Dexamethasone
Methotrexate (high-dose) and cytarabine
Intrathecal cytarabine and intrathecal
methotrexate with each cycle
ALL - Blinatumomab
Bispecific T-cell engager
◦ Fragment of antibody that binds CD19 and CD3
Toxicities very different than standard antineoplastics
◦ Cytokine release syndrome (CRS)
◦ Immune effector cell-associated neurotoxicity syndrome (ICANS)
Asparaginase
Enzyme that breaks down asparagine (an essential amino acid)
Utilized in many multiagent chemotherapy regimens, but only done in specialized centers and patients are
closely monitored for infusion allergic reactions
3 formulations in clinical use:
◦ PEG
◦ Calaspargase pegol-mknl (Cal-PEG) (1-21 years old)
◦ Erwinia
Unique toxicities:
◦ Hypersensitivity
◦ Anaphylaxis
◦ Pancreatitis
◦ Hemorrhage
◦ Thromboembolism
◦ Hyperglycemia
◦ Hypertriglyceridemia
◦ Hepatotoxicity
ALL – Relapse/Refractory
Disease
Treatment options:
◦ Consider changing BCR-ABL inhibitor
◦ Clofarabine
◦ Nelarabine (T-cell ALL)
◦ Vincristine sulfate liposomal
◦ Blinatumomab (if not used first line)
◦ Inotuzumab ozogamicin (if not used first line)
◦ CAR-T cell therapy = tisagenlecleucel or brexucabtagene autoleucel
◦ Allogenic stem cell transplant if patients get in to 2nd remission
ALL – Summary
Risk stratification plays a large role in overall prognosis
Treatment regimens are comprised of an anthracycline, steroid, vincristine, ± pegaspargase
◦ Dose adjusted HyperCVAD or ECOG1910 are 2 protocols used frequently
Maintenance therapy plays a large role in treatment
BCR-ABL is important in therapy selection and overall prognosis. If positive add TKI to treatment
