Flashcards in HAEM - Acute & chronic leukaemia Deck (44)
From what do leukaemias arise from?
Stem cell & progenitor cell populations (e.g. multipotential progenitor, common lymphoiad progenitor, common myeloid progenitor, megakaryocyte erythrocyte progenitor)
List (4) examples of lymphoid mature cells
List (8) examples of myeloid mature cells
Cancer that starts in blood forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the blood stream
Circulating malignant cells of hematopoietic origin in the blood or bone marrow
Etiology of Leukemias
Unknown in majority
Etiological factors include:
–Previous cytotoxic therapy
–Exposure to ionizing radiation
–Chemical exposure e.g. benzene
–Infections e.g. adult T cell leukemia lymphoma and HTLV-1
–Genetics e.g. trisomy 21 (Down Syndrome) and high risk AML
–Rare familial syndromes e.g. fanconi’s anaemia 52% develop AML or MDS by age 50
(4) Clinical Presentation of Acute Leukemia
–Anemia: Lethargy, dyspnoea, pallor, presyncope
–Neutropenia: Fevers / rigors, infections
–Thrombocytopenia: Bruising, bleeding
–B symptoms: Fevers, sweats, weight loss
–Less commonly: lymphadenopathy, hepatosplenomegaly, symtpoms of hyperleucocytosis
Which leukaemia can occasionally have a mediastinal mass?
Acute lymphocytic leukaemia -> SVC obstruction -> red face, dyspnoea, cough
(5) Key Investigations in Acute Leukemia
•Full blood count and film
•Bone marrow biopsy
Aim of these tests is to determine the type of leukaemia, the prognosis and how best to monitor response to therapy
What (2) do you expect to see on blood film of AML?
Cytopaenia due to suppression of normal haematopoiesis
Blasts (large nucleus, little cytoplasm. Nucleus looks immature; big nucleoli)
Monomorphic. (looks pretty identical)
What % of infiltration by malignant cells is classified as acute leukaemia?
>20% blasts of nucleated cells
What is Auer rod pathognomic for?
What markers of immunophenotyping do you look for in AML?
- myelodi markers
- immature markers
e.g. CD34, CD33, CD11
What markers of immunophenotyping do you look for in ALL?
- immature T&B cell markers -> determine subtype of ALL
Discuss cytogenetics in AML
It determines the prognosis
- Good risk: t(8;21), inv 16, t(15;17) -> can be cured with standard chemotherapy
- Intermediate risk: (70% pts): mostly normal cytogenetics
- Poor risk: monosomy 7, multiple complex abnormalities, chromosome 3 abnormalities -> must have transplant to have a chance of cure
Discuss molecular testing in AML & its relationship to prognosis
especially important for intermediate risk group by cytogenetics (majority) to help better predict prognosis
molecular testings are more sensitive than cytogenetics (cytogenetics needs a lot of cells)
- FLT3 internal tandem duplication: poor prognosis
- nucleophosmin (NPM1) & CEBPA: good prognosis
How (4) do you monitor response to therapy in acute leukaemia after chemotherapy?
1. Marrow aspirate and trephine:
- less than 5% = morphological remission
- CG remission = disappearance of any previous abnormalities
3. Flow cytometry
- Remission = no detection of cells with aberrant phenotype
4. Molecular studies
- Remission = no detectable transcript if a quantifiable translocation eg AML1-ETO in t(8;21 ); serial zero levels c/w remission and likely cure but rising levels may impend relapse
What are the principles of treatment in AML?
- determine appropriate treatment according to age, condition, prognosis
- palliative for elderly & poor prognosis
- induction chemotherapy for fit pts (cytarabine & anthracycline)
- determine response after marrow recovery
- if good response, consolidation cycles (x2 in AML) with marrows after each cycle to check disease status
- determine need of allogeneic transplant based on age (usually eligible if younger than 60yo) & prognostic features
Differences in ALL therapy to the general principles of acute leukaemia
- maintenance therapy after consolidation without transplant
- multiple drugs used. Important L-asparaginase
- higher rate of CNS relapse -> intrathecal chemotherapy as prophylaxis
Discuss acute promyelocytic leukaemia (APML)
- compared to AML
- coagulation studies
- the M3 subtype of acute myelogenous leukemia (AML)
- abnormal accumulation of immature granulocytes called promyelocytes
- good prognosis
- Px: bruising, bleeding
- coagulation studies: DIC with low fibrinogen due ot release of procoagulants from malignant promyelocytes
Describe APML morphology under microscope
characteristic faggot cells containing many Auer rods
Ix of APML (acute promyelocytic leukaemia)
- Cytogenetics: t(15;17)
- PML-RAR alpha fusion
Discuss cytogenetics of acute lymphoblastic leukaemia
A key determinant of prognosis
–Poor prognosis cytogenetics include t(4;11)
–Good prognosis: children with hyperdiploidy
Principles of treatment of ALL in older patients
- steroids, vincristine
Eligibility of allogeneic transplant in ALL
less than 50yo (c.f. 60yo in AML) + moderate-good prognostic features
If not receiving an allograft; maintenance chemotherapy for 2 years
(3) stages of CML
- chronic (majority; often asymptomatic+ incidental finding)
Some may have symptoms from splenomegaly & feel vaguely unwell
What Px would you have in untreated CML?
High WCC, anaemia
What would you see in CML blood film?
Hyperleukocytosis with ALL stages of myeloid development in the peripheral blood
(4) Ix of CML & what do you expect to see
•FBE: leukocytosis with spectrum of early myeloid cells, basophils, eosinophilia
–increased numbers of blasts in more advanced cases
•Cytogenetics: Pathognomic finding is the Philadelphia chromosome t(9;22)
•Molecular: BCR-ABL fusion gene
What is the cytogenetic pathognomic finding of CML?
Philadelphia chromosome t(9;22) -> BCR-ABL fusion
What is the key molecular abnormality of CML?
BCR-ABL fusion gene
Mx of CML
Standard therapy: tyrosine kinase inhibitors (Imatinib)
- selective killing of CML cells -> remission
- no longer need for allograft
- in most no major toxicity
If resistant to Imatinib due to mutation of binding sites -> use second generation tyrosine kinase inhibitors
- e.g. dasatinib
How does Imatinib work in CML?
Imatinib blocks ATP binding of BCR-ABL protein -> reduces signalling that drives cell proliferation
How do you monitor response to therapy in CML?
Monitoring the amount of the abnormal bcr-abl transcript in the peripheral blood each 3 mths by PCR
a rise in bcr-abl% may signify resistance to therapy, most often due to a mutation in the binding site of imatinib to abl
Describe chronic lymphocytic leukaemia
•By far the commonest leukaemia in adults
•May be an asymptomatic finding on blood film
Affects B cell lymphocytes -> grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells.
CLL is a stage of small lymphocytic lymphoma (SLL), a type of B-cell lymphoma, which presents primarily in the lymph nodes
(2) initial Ix of CLL & what you expect to see
•Morphology (blood and bone marrow)
–small mature lymphocytosis with smear cells
–cytopenias due to autoimmune phenomenon or marrow infiltration
–B lymphocytes co-expressing CD5 ( they don’t normally! ) and CD19, CD23
What do you expect to see in blood film of CLL?
Small mature lymphocytosis, smear cells & thrombocytopaenia
How do you monitor response to therapy in CLL?
CT scans - by observing size of lymph nodes before and after
Do all CLL patients need treatment?
Criteria for need for treatment is based on symptoms (regardless of level of WCC), cytopenia, bulky glands or spleen
Deletion of 17p (c.f. deletion of 13q for indolent course) & TP53 mutation are associated with more aggressive course.
- Bone marrow biopsy & cytogenetics also often not necessary; may do in younger pts for prognosis
- CT scans: not useful in asymptomatic
- chemo in asymptomatic no benefits
What gives the diagnosis in CLL?
Discuss prognosis of CLL
- factor for good prognosis
- factor for poor prognosis
Many patients esp those with minimally raised WCC -> prolonged survival even w/o treatment
Loss of p53 -> terminal phase more rapidly
Mx of CLL
Early stage disease & asymptomatic:
- expectant Mx only
- no benefit from therapy
- monoclonal antibodies for relapsed disease
Only curative option: allograft but majority are ineligible
FBE results of APML (acute promyelocytic leukaemia)
cytopaenia, increased APTT/INR
Can also see characteristic faggot cells containing many Auer rods in blood film
Mx of APML
- correct coagulopathy with paltelets, cryoprecipitate & fibrinogen as needed. If not fixed -> people can die due to procoagulation
- all trans retinoic acid (ATRA) to induce promylocyte differentiation
Can be cured with arsenic + ATRA upfront WITHOUT chemotherapy. Hence most curable now.