Leukemia Flashcards
Acute Leukemia
- Group of hematologic malignancies
- Characterized by proliferation of immature hematopoietic elements (blasts) and maturation arrest
- Leukemia initiating cell has self-renewal properties (leukemia stem cell)
- Can be myeloid, lymphoid, or (rarely) biphenotypic
Leukemogenic
Events
- DNA damage ⇒ ionizing radiation, chemicals, chemotherapeutic agents
- Inherited factors ⇒ possibly through loss of tumor suppression genes, Down syndrome
- Virus infections ⇒ HTLV-I associated w/ adult T-cell leukemia/lymphoma
- Abnormal immune response to infection ⇒ ETV6/RUNX1 in childhood ALL (acute lymphoblastic leukemia)
Differentiation Block
Cells are no longer able to develop beyond the blast stage.
Proliferation Advantage
- FLT3 = fms-like tyrosine kinase 3
- Mutations ⇒ ligand independent autophosphorylation of the receptor
- Results in constitutive activation
- Present in about 30% of newly diagnosed cases of AML
Acute Leukemia
Pathophysiology
- ↑ Blasts in blood and bone marrow
- Replacement of normal hematopoietic elements ⇒ neutropenia, anemia, and thrombocytopenia
-
Malignant blasts can infiltrate extramedullary organs
- Brain and testes ⇒ common in ALL
- Skin and gums ⇒ common in AML
- Hyperleukocytosis ⇒ presence of many myeloblasts causing obstruction of small arterioles in brain, eye, lung
Acute Leukemia
WHO Classification
-
By definition:
- Blasts > 20% of the bone marrow or peripheral WBC differential count
-
Two main categories:
- Acute Myeloid Leukemia
- Acute Lymphoblastic Leukemia
- Morphology is not always reliable to distinguish myeloid from lymphoid
Myeloblasts
Morphology
- Auer rod ⇒ abnormal azurophilic granules that have formed crystals
- Indicates myeloid differentiation & AML
Acute Leukemia
Immunohistochemical Evaluation
ALL “PAS”
AML is a MES
Acute Leukemia
Immunophenotyping
Based on flow cytometry:
Acute Myeloid Leukemia (AML)
Overview
- Arises from myeloblastic stem cells
- 1% of all cancers
- Median age 68
- Can arise de novo
- Can arise secondary to chemotherapy or another bone marrow disorder
Acute Myeloid Leukemia (AML)
FAB Classification
Based on morphology:
Know M3, M4, M5
Acute Myeloid Leukemia (AML)
WHO Classification
Based on recurrent genetic abnormalities, etiologies, and morphology:
Acute Myeloid Leukemia (AML)
Presenting Symptoms
- Infections (low neutrophils)
- PNA
- Cellulitis
- Usu. not URI’s
- Bleeding (low platelets)
- Fatigue (low Hb)
Acute Myeloid Leukemia (AML)
Initial Work-up
-
Physical exam:
- Unlike ALL, there is generally no lymphadenopathy or organ involvement
-
Labs:
- CBC w/ diff; peripheral smear; coags; type and cross;
- Uric acid, Ca, PO4, Cr, K
- Flow cytometry (peripheral blood vs bone marrow)
- Bone marrow biopsy
Acute Myeloid Leukemia (AML)
Diagnostic Evaluation
-
Morphology
- Abnormal hypercellular bone marrow
-
Cytochemical staining
- PAS ⊖
- ⊕ for MPO, SBB, Nonspecific esterase
-
Immunophenotype
- Flow cytometry: Myeloid antigens
- ⊕ for CD34, CD13, CD33, and CD117
- Flow cytometry: Myeloid antigens
- Cytogenetics
- Molecular studies
Acute Myeloid Leukemia (AML)
Prognosis
- Two factors determine prognosis:
-
Age
- Younger = better
- Prognosis for pts > 60 years old remains poor
-
Cytogenetic abnormalities
- t(15;17) ⇒ Acute Promyelocytic Leukemia (APL) ⇒ very good prognosis
- t(8;21) / t(16;16) / inv(16) ⇒ Core Binding Factor AML ⇒ good prognosis
- No abnormalities ⇒ intermediate prognosis
- del(7) / 11q23 (KMT2A) / multiple abnormalities ⇒ poor prognosis
Acute Promyelocytic Leukemia (APL)
Characteristics
- Associated w/ t(15;17) translocation
- Highly curable
- Often presents w/ DIC (but also can present w/ thrombosis)
-
Treated w/ chemotherapy fee regimens
- All trans-retinoic acid (ATRA) and Arsenic trioxide (ATO)
Monocytic Leukemias
Characteristics
- Often present w/ leukocytosis as opposed to leukopenia
- Risk for leukostasis ⇒ symptomatic hyperleukocytosis
- (typically blasts > 50K)
- Hypoxic respiratory failure
- Stroke
- Tissue infiltration
- Gingival hyperplasia
- Leukemia cutis
- CNS involvement
Risk-Adapted Treatment
Principles
-
Pts w/ best prognosis receive least intense treatment
- ↓ Risk of treatment induced mortality
- Ex. APL [t(15;17)] ⇒ Chemotherapy-free utilizing all trans retinoic acid and arsenic trioxide
-
Pts w/ worst prognosis receive most intense treatment
- ↓ Reduce relapse risk
- Intermediate/Poor risk ⇒ Induction chemotherapy and consolidation transplant
- Ex. CBF leukemia ⇒ Induction and consolidation chemotherapy
Multi-Agent Chemotherapy
Adverse Effects
- Mucositis
- Alopecia
- Pancytopenia ⇒ infection risk
- In children ⇒ growth retardation
- In young adults ⇒ amenorrhea in women, infertility in men and women
Acute Lymphoblastic Leukemia (ALL)
Characteristics
- Most common childhood malignancy
- Peak age of 2-4 years in industrialized countries
- More common in Hispanics and Caucasians than African Americans
- Slightly more common in males than female
Acute Lymphoblastic Leukemia (ALL)
FAB Classification
Based on morphology.
Acute Lymphoblastic Leukemia (ALL)
WHO Classification
Genetic/molecular based system.
B-cell Acute Lymphoblastic Leukemia (B-ALL)
Translocations
Fusions w/ chimeric protein expression:
- t(9;22) → BCR-ABL
- t(12;21) → ETV-6-RUNX1
- 11q23 → KMT2A (MLL)
T-cell Acute Lymphoblastic Leukemia (T-ALL)
Translocations
Juxtaposition of a proto-oncogene to TCR ⇒ over-expression of a normally silent gene
t(1;14) → BCL9-IGH
Lymphoblastic Lymphoma (LBL)
Overview
- Morphologically and immunophenotypically indistinguishable from ALL
-
Distinction is based on:
- Site of disease
-
Amount of bone marrow involvement
- 20% lymphoblasts in the bone marrow ⇒ ALL
- < 20% lymphoblasts in the bone marrow w/ extramedullary manifestations ⇒ LBL
- Management is similar for both
ALL vs LBL
Acute Lymphoblastic Leukemia (ALL)
Clinical Presentation
- Fever, pallor, fatigue
- Organomegaly (30-50 % w/ HSM)
- Adenopathy
- Bone pain, limp, arthritis (40 %)
- Headache, cranial nerve palsy
- Prolonged “viral illness”
- Bruising, petechiae, bleeding
Acute Lymphoblastic Leukemia (ALL)
Initial Work-up
-
Physical exam:
-
Head to toe, w/ emphasis on testes, CNS, lymphadenopathy, organomegaly
- Testicles and CNS are termed sanctuary sites
- Difficult for chemotherapy to reach
-
Head to toe, w/ emphasis on testes, CNS, lymphadenopathy, organomegaly
-
Labs:
- CBC w/ diff; peripheral smear; coags; type and cross;
- Uric acid, Ca, PO4, Cr, K
- Flow cytometry (peripheral blood vs bone marrow)
- Bone marrow biopsy
Acute Lymphoblastic Leukemia (ALL)
Diagnostic Evaluation
- Morphology
-
Cytochemical staining
- ⊕ PAS
- ⊖ MPO, SBB, Nonspecific esterase
- Immunophenotype
- Flow cytometry: B-cell or T-cell antigens
-
Cytogenetics
- Ig and TCR gene rearrangement studies
Acute Lymphoblastic Leukemia (ALL)
Peripheral Blood Evaluation
- Immature blasts are lymphocyte-like
- Minimal cytoplasm
- Nucleoli present
- Larger than RBCs
Acute Lymphoblastic Leukemia (ALL)
Bone Marrow Examination
Marrow almost completely replaced by abnormal cells
Acute Lymphoblastic Leukemia (ALL)
Immunophenotypic Markers
Acute Lymphoblastic Leukemia (ALL)
Prognostic Features
-
CNS disease (20%)
- Higher risk of relpase
-
Early response to therapy
-
Morphologic: Rapid early responders do better
- Obtaining remission by day 14, with ⊖ MRD by day 28
-
Measurable residual disease (MDR)
- Measurement of very low levels (1 in 1000) of leukemic cells by PCR
- High MRD at the end of induction ⇒ higher risk of relapse
-
Morphologic: Rapid early responders do better
Acute Lymphoblastic Leukemia (ALL)
Treatment Overview
Children ⇒ > 95% achieve remission and 80% are cured
Adults ⇒ 65-85 %achieve remission w/ cure rates of 35-40%
-
What made the difference?
- Development of complex chemotherapeutic regimens
- Improvements in supportive care
- Recognition of CNS as sanctuary site
- Risk adaptive therapy
- Bone Marrow Transplant for highest risk pts
Acute Lymphoblastic Leukemia (ALL)
Treatment in Children
- Induction (3 or 4 drug): 95% will achieve remission
- Consolidation
- Interim maintenance
- Delayed intensification
- Maintenance (to complete 2 years of therapy for girls, 3 years of therapy for boys)
-
High-risk ⇒ allogeneic transplant
- Refractory disease
- MRD positive
- Poor-risk
Acute Lymphoblastic Leukemia (ALL)
Treatment in Adults
-
Induction (Hyper CVAD, pediatric regimen, etc)
- Vincristine, Steroids, Cytoxan and Anthracycline
-
Consolidation
- High dose Cytarabine, Cytoxan, Methotrexate, Asparaginase
- SCT may be used
-
Maintenance (2-3 years)
- 6-MP, Methotrexate, monthly steroids, and Vincristine
- CNS Prophylaxis
- High-risk ⇒ allogeneic transplant
Myeloproliferative Neoplasms
- Group of (mostly) clonal hematologic disorders
- Characterized by accumulation of mature cells
- Accumulation can involve one or more cell lines
- No age, sex or race predilection
- Rare disorders w/ collective annual incidence of 5/100,000
Chronic Myeloid Leukemia (CML)
Overview
- Most common in middle-aged adults
-
Clinical signs and symptoms include:
- Leukocytosis w/ left-shift (often in asymptomatic individuals)
- Basophilia
- Elevated LDH and uric acid
- Splenomegaly
Chronic Myeloid Leukemia (CML)
Diagnosis
Dx can be confirmed by demonstration of the t(9;22) by:
- Karyotyping
- Fluorescent In-Situ Hybridization (FISH)
- BCR-ABL mRNA by PCR
Although dx of CML requires demonstration of t(9;22), not all diseases w/ t(9;22) are CML.
Chronic Myeloid Leukemia (CML)
Clinical Course
t(9;22) is both sufficient and required to develop CM
Disease goes through three phases:
-
Chronic phase ⇒ ↑ WBC w/ left shift
- Typically remains stable for 3-4 years (up to 10 years)
- Pts generally have no or minimal sx
- W/o treatment median survival is 5-7 years
- Disease inevitably will progress to accelerated phase and blast crisis
-
Accelerated phase ⇒ Additional cytogenetic abnormalities, uncontrollable WBC, ↑ basophilia
- Median survival w/o treatment is 12-18 months
- Blast phase (acute leukemia)
Chronic Myeloid Leukemia (CML)
Blood Smear
Numerous different types of granulocytes at different stages of maturation
Chronic Myeloid Leukemia (CML)
Therapeutic Options
Allogeneic stem cell transplantation
- Only tx modality w/ curative potential
- Cure rates vary
- 80%+ for young (<40 years) pts w/ an HLA-identical sibling donor
- 40% for elderly pts undergoing a matched-unrelated donor transplant
- Cure rates are much worse for pts transplanted in accelerated phase (40%) or blast crisis (20%)
- Somewhat worse for pts transplanted > 1 year after diagnosis
Imatinib mesylate
(Gleevac)
- Novel therapeutic options for CML (“targeted therapy”)
-
Tyrosine kinase inhibitor
- Occupies ATP binding site in BCR-ABL oncoprotein ⇒ ⊗ of BCR-ABL tyrosine kinase activity
- Side effects are minimal
-
Treatment-of-choice for most pts w/ CML in chronic phase
- 65% of pts in chronic phase will achieve a sustained (> 7 years) complete cytogenetic response w/ imatinib
- No Ph chromosome on cytogenetic exam
- 30-40% of pts will not have e/o BCR-ABL transcript by PCR
- BCR-ABL fusion gene presence can still be demonstrated in isolated ‘stem’ cells
- 65% of pts in chronic phase will achieve a sustained (> 7 years) complete cytogenetic response w/ imatinib
Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia (SLL/CLL)
Overview
- Lymphoma / leukemia composed of small clonal B-cells
- M > F, Age > 50 yrs
- Considered low grade, but incurable
-
SLL and CLL are morphologically, phenotypically, and genotypically indistinguishable
- Differ only in degree of peripheral blood lymphocytosis
- 5K WBCs regardless of lymphadenopathy ⇒ CLL
- < 5K WBCs ⇒ SLL
- Differ only in degree of peripheral blood lymphocytosis
- SLL is 7% of NHL
- CLL is the most common leukemia in western world
CLL
Presentation
-
Mostly asymptomatic
- Often identified on routine blood work w/ isolated lymphocytic leukocytosis
- ± Recurrent respiratory infections due to hypogammaglobulinemia
- ± Immunologic issues such as hemolytic anemia or immune thrombocytopenic purpura
CLL
Diagnosis
-
Peripheral blood flow cytometry
- ⊕ for CD19, CD20, CD23
- ⊖ CD10
- CD5 usually ⊕
- Bone marrow biopsy is not required
CLL
Prognosis
Prognostic studies include:
-
FISH
- del(13q) = good
- del(17p) = bad
-
IGHV mutation (immunoglobulin heavy chain variable region)
- Presence is favorable
- Absence is unfavorable
-
Next-generation sequencing (NGS)
- TP53 mutation is unfavorable
CLL
Management
- Unless presence of sx from compressive LNs or splenomegaly or severe cytopenias then observation is preferred
-
Treatment, if required, is dependent on risk-stratification and age:
- Chemoimmunotherapy
- Fludarabine, cyclophosphamide, rituximab (FCR)
- Bendamustine, rituximab (BR)
- BTK Inhibitors
- Ibrutinib
- Acalabrutinib
- Chemoimmunotherapy
Chronic Lymphocytic Leukemia (CLL)
Peripheral Blood Smear
Numerous mature lymphocytes
About the size of RBCs
Hairy Cell Leukemia
Overview
- Considered a chronic B-cell lymphoproliferative disorder
- Initially described as leukemic reticuloendotheliosis
- Bone marrow infiltration by atypical lymphocyte w/ “hairy” projections
- Characterized by splenomegaly, pancytopenia
- 4:1 male to female ratio
- Usu. 40-60 y/o
Hairy Cell Leukemia
Clinical Presentation
Typical presenting symptoms:
-
Pancytopenia w/ infection, bleeding, etc
- Can see a monocytopenia
- Splenomegaly, usually massive
Hairy Cell Leukemia
Diagnosis
-
Bone marrow biopsy
- Bone marrow infiltration by atypical lymphocyte w/ “hairy” projections and indistinct cytoplasmic border
- Stains w/ TRAP = tartrate resistant acid phosphatase ⊕
-
Immunophenotype:
- ⊕ for CD103, CD11c, CD25, CD22
- ⊖ for CD5, CD10, CD23
-
Molecular
- BRAF mutation
Hairy Cell Leukemia
Management
- Goal is long-term remission
- Generally not considered curable w/ standard therapies
- Therapy consists of chemotherapy ± immunotherapy
- Nucleoside analogs – cladribine, pentostatin
- Anti CD20 MoAb – Rituximab
- Salvage targets
- Vemurafenib (BRAF inhibitor)
