Leukemia Flashcards
leukemia
definition
Leukemia is a malignancy of the blood
Increased production and proliferation of abnormal leukocytes and leukocyte precursors in the bone marrow and in circulating blood
lines of leukemia
- Myelogenous leukemias arise from the granulocyte
(neutrophils, eosinophils, basophils and monocytes), erythrocytes and platelets.
Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML) - Lymphocytic leukemias involve the lymphocyte lineage
T and B lymphocytes.
Acute Lymphocytic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL)
leukemia
patho
Uncontrolled/dysfunctional multiplication of one or more types of leukocytes, resulting in the presence of undifferentiated, immature, nonfunctional cells in the bone marrow.
Malignant transformation occurs at different levels of cell differentiation
Acute leukemias
High proportion of immature and nonfunctional cells
Blast cells
Chronic leukemias
Higher proportion of mature cells
Some of these cells have reduced function
Acute vs chronic leukemia
Acute leukemias
High proportion of immature and nonfunctional cells
Blast cells
Chronic leukemias
Higher proportion of mature cells
Some of these cells have reduced function
Sub-types of Leukemia
chronic leukemias tend to have leukocytosis (increase in leukocytes)
Chronic Lymphocytic Leukemia (CLL)
General
aka small lymphocytic lymphoma (SLL)
CLL/SLL is considered one disease with different manifestations
CLL = disease primarily manifesting in the blood
SLL = disease involvement primarily nodal
- Characterized by the progressive accumulation of a population of small mature B lymphoctyes
Most common form of adult leukemia
Median age of diagnosis is 70
CLL has a strong familial predisposition
No definitive causative factors are associated with CLL
CLL/SLL
Clinical manifestations & Physical Examination
Asymptomatic (with incidental findings on a CBC)
Fatigue
Dyspnea on exertion
Increased incidence of infections
Lymphadenopathy
Splenomegaly
“B” symptoms – Fevers, night sweats, weight loss
Appetite loss
Unusual bruising/bleeding
CLL/SLL
Workup/Diagnosis
CBC with differential
Leukocytosis
Lymphocytosis (high)
Anemia
Thrombocytopenia
Peripheral smear – “smudge cells” - classic for CLL
Hypogammaglobulinemia
Flow cytometry immunophenotyping
Increased number of circulating lymphocytes that are monoclonal B cells expressing CD5 antigen
Cytogenetic studies (FISH, etc.)
Lymph node biopsy
CT scans
+/- bone marrow biopsy
CLL
CLL
factors to consider for Tx
May develop
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Initiation of therapy dependent on several factors
Lymphocyte doubling time- looking at CBCs to see how fast WBC count doubles.
Disease stage
Age
Comorbidities
Symptoms
ACFatigue
Symptomatic lymphadenopathy
Therapy goal in most patients is palliation
CLL
Tx
Early stage
Observation
Targeted biologics- not chemo
Anti-CD20 agent (Rituximab{Rituxan}, Obinutuzumab{Gazyva}) + one of the following:
Tyrosine kinase inhibitor:
Ibrutinib (Imbruvica)
BCL-2 targeted agent:
Venetoclax (Venclexta)
Curative therapy (allogeneic transplant) is reserved for younger patients with aggressive symptomatic disease
Ibrutinib (Imbruvica)
general
BTK Inhibitor
Inhibits Bruton tyrosine kinase leading to inhibition of malignant B cell proliferation
Dosing: 420mg PO daily
Caution with CYP3A inhibitors
Ibrutinib (Imbruvica)
Side effects
Side effects:
Lymphocytosis (increases by 2-3x before it goes down)
HTN
Cardiac arrhythmias
Rash
Infections
Bleeding risk in conjunction with Warfarin (Coumadin)
Venetoclax (Venclexta)
general
BCL-2 Inhibitor
Inhibits B-cell lymphoma 2 protein leading to restoration of apoptosis
Dosing: 400mg PO daily (slow titration to max dosing)
Venetoclax (Venclexta)
side effects
Side Effects:
Tumor lysis syndrome
May need hospitalization for first cycle
Neutropenia
Infection
Tumor Lysis Syndrome
general and clin man
Risk in hematologic and rapidly proliferating solid tumor malignancies
Caused by rapid release of cellular contents
With impaired breakdown:
Hyperuricemia
Acute kidney injury
Hyperkalemia
Hyperphosphatemia
Clinical manifestations
Nausea/vomiting
Seizures
Arrhythmias
Death
tumor lysis syndrome
tx
Prevention
Baseline uric acid level
Allopurinol 100mg PO daily-TID starting before chemotherapy initiation
Inhibits xanthine oxidase (prevents conversion to uric acid)
Rasburicase IV weight dosing IV x 7 days
Converts uric acid to allantoin, inactive metabolite easily renally excreted
Avoid with G6PD deficiency
Aggressive IV hydration
Chronic Myeloid Leukemia (CML)
general
Malignancy driven by the BCR-ABL-1 gene product (active tyrosine kinase)
Translocation between the long arms of chromosomes 9 and 22
Philadelphia Chromosome (Ph)
15% of all cases of leukemia
Median age at diagnosis is 55yrs
No familial associations
Usually a primary leukemia
CML
Clin man
Typically asymptomatic with incidental findings on a CBC
Fatigue, malaise
Weight loss
Early satiety
LUQ pain
Bone pain
Night sweats
Thrombotic or vasoocculsive events
Splenomegaly (20-70%)
CML
phases
90% of patients present in the indolent or chronic phase
Chronic phase
Accelerated phase
Blastic phase
CML
signs of turning into acute (AML)
Signs of transformation to AML
Leukocytosis resistant to therapy
Increasing anemia
Increasing blasts
Constitutional symptoms
CML
Dx
CBC with differential
Leukocytosis (10-500) :
Left shift with many neutrophils
Bands
Myelocytes
Blasts
Elevated basophils
Thrombocytosis
Anemia in 1/3 of patients
CMP
Uric acid
Bone marrow biopsy with cytogenetic analysis
FISH testing (identifies % of Ph chromosome)
PCR for BCR-ABL gene
CML
Tx
Response to treatment is gauged by quantitative PCR levels
Tyrosine Kinase Inhibitor (TKI) therapy
Imatinib (Gleevec) 1st drug
30% reach major molecular response in 1 yr
Nilotinib (Tasigna)
71% MMR in 1 yr
Allogeneic transplant if fails TKI or in accelerated/blast phase
Leukopheresis
Symptoms from hyperleukocytosis
Total leukemia blood cell count greater than 50 x 109/L (50,000/microL) or 100 x 109/L (100,000/microL)
Symptoms of decreased tissue perfusion
Medical emergency!
Side effects of TKIs
Drug rashes
QTc prolongation
Edema
Cytopenias
Diarrhea
Acute Lymphocytic Leukemia (ALL)
general
Malignancy defined by the proliferation and accumulation of clonal blast cells (B- or T- lymphocyte progenitor) in the marrow
Most common in children
Median age at diagnosis: 15
57.2% < 20 at age of diagnosis
26.8% of cases are ≥45 at age of diagnosis
11% diagnosed at age ≥ 65yrs
75%-80% of acute leukemias in children
Risk factors:
Age >70
Exposure to chemo or radiation therapy
Genetic disorders
Down’s syndrome
rare = neurofibromatosis, Klinefelter, Fanconi, etc.
**Philadelphia chromosome and BCR-ABL1 fusion*
ALL
clin man
Presentation can be highly variable
Approx 50% patients present with fever
Fatigue and lethargy
> 25% of patients (esp. young children) may have a limp from bone pain or arthralgia
Arthralgia and bone pain less severe in adults
Occasionally, life-threatening infection or bleeding
Lymphoblasts can accumulate in various extramedullary sites
Meninges, testes, thymus, liver, spleen, and lymph nodes
ALL
Labs/ Dx
CBC with differential,
Anemia, neutropenia, and thrombocytopenia common (All cell lines will be down)
Blasts
(90% of patients have circulating blasts at diagnosis)
CMP
LDH
Correlates with tumor burden
Uric acid, phosphorus, calcium, (tumor lysis syndrome), coagulation studies
Bone marrow biopsy (>20% lymphoblasts)
Lumbar puncture
Leukemic blasts can be identified in as many as 33% of pediatric patients and approx. 5% of adult patients at diagnosis of ALL
most of these patients lack neurologic symptoms
Echocardiogram
Cardiac risks from chemotherapy
ALL
Chemo phases
Treatment consists of three standard phases:
Induction
Consolidation
Maintenance
ALL
Tx
Needs CNS-directed therapy
In adult ALL, long-term disease-free survival rates:
35 to 50% with chemotherapy alone
45 to 60% with allogeneic transplantation
Most relapses typically occur during treatment or within the first 2 years after completion
CAR-T therapy is improving survival
ALL
CAR-T therapy
- Chimeric antigen receptor T cells
- A newer immunotherapy for relapsed refractory ALL in age <25yrs, also some types of lymphomas (in adults)
- Patient’s own T cells are removed and genetically modified to express a receptor programmed to fight against specific cells (in this case those that express CD19, present on the B cell precursor in ALL)
- T cells are infected using a virus carrying a specific CAR
- The modified T cells are then infused back into the patient
- Response rates up to 90%
Unfortunately, frequent relapses
Acute Myeloid Leukemia (AML)
epidemiology and eti
Malignancy characterized by infiltration of bone marrow, blood, and other tissues by proliferative, clonal, undifferentiated cells (myeloid origin)
Incidence increases with age
Median age at diagnosis: 65
Risk factors:
Benzene exposure
Smoking
Exposure to petroleum products, paint, embalming fluids, ethylene dioxide, herbicides, pesticides
Certain genetic syndromes
Prior chemotherapy
Underlying bone marrow disorder
AML
Clin Man
Fatigue, weakness
Anorexia
Weight loss
Fever (10%)
Easy bleeding/bruising (5%)
Occasionally bone pain
Splenomegaly,
Hepatomegaly
Lymphadenopathy
Sternal tenderness
AML
Workup/Dx
CBC with differential
Anemia
Thrombocytopenia
Mild leukocytosis or leukopenia
CMP, LDH, uric acid, phosphorus, coagulation studies
Peripheral smear
Auer rods on the peripheral smear
Bone marrow biopsy (20% blasts)
Flow cytometry
Cytogenetic analyses (karyotype +/- FISH), Molecular analyses, HLA typing
These studies are essential because of the prognostic value specific mutations hold
+/- brain imaging
+/- Lumbar puncture
Echocardiogram
Subtypes of AML
Acute Promyelocytic Leukemia (APL)
Subtype of AML that must be quickly recognized and promptly treated
Disseminated Intravascular Coagulation
Significant GI bleeding, intrapulmonary hemorrhage, ICH
Treatment can rapidly reduce DIC complications
ATRA (all-trans retinoic acid) + ATO (arsenic trioxide)
Without treatment, APL has median survival of < 1month
With modern therapy, APL is associated with the highest cure rates
AML
Tx and complications
Treatment consists of
Induction chemotherapy (to induce remission)
Consolidation
Transplant or some form of maintenance therapy
Chemotherapy treatment has similar complications/risks as in ALL
