Haem IV Flashcards
Anaemia
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
Which of the following is used in HL?
FOLFOX
FOLFIRI
FOLFIRINOX
ABVD
R-CHOP
Which of the following is used in HL?
FOLFOX
FOLFIRI
FOLFIRINOX
ABVD
R-CHOP
A 55 yr old is having chemotherapy for her NHL.
Days after treatment, she notices blood in her urine.
Which treatment is most likely to have caused this?
Doxorubicin
Vincristine
Cyclophosphomide
Cisplatin
Bleomcyin
A 55 yr old is having chemotherapy for her NHL.
Days after treatment, she notices blood in her urine.
Which treatment is most likely to have caused this?
Doxorubicin
Vincristine
Cyclophosphomide - causes haemorrhagic cystitis
Cisplatin
Bleomcyin
What are the common genetic alterations seen in CLL?
- most common genetic change is the deletion in chromosome 13
- TP53 mutation
- Trisomy 12: presence of an extra 12th chromosome
- Overexpression of BCL2 proto-oncogene: suppresses programmed cell death (i.e. increases cell survival)
Describe the natural history of CLL
- An initial inciting event or abnormal reaction to an antigen stimulus leads to genetic alterations that allow the formation of a clone of B lymphocytes
- This is a premalignant disorder, which is referred to as monoclonal B cell lymphocytosis (MBL).
- Overtime, further genetic mutations and bone marrow microenvironment changes promote the progression to CLL. This transformation from MBL to CLL occurs at a rate of 1% per year.
- A proportion of patients who develop CLL may remain asymptomatic for many years. However, others may get rapidly progressive disease with complications associated with the defective immune function including cytopaenias and hypogammaglobulinaemia (i.e. low antibody levels).
The symptomatic stage of CLL is characterised by progressive lymphadenopathy, which includes splenomegaly and hepatomegaly, that occurs due to the accumulation of incompetent lymphocytes.
The hallmark feature of CLL is [] due to the infiltration of []
The hallmark feature of CLL is lymphadenopathy due to the infiltration of malignant B lymphocytes.
- symmetrically enlarged lymph nodes in the neck, armpits or groin which is seen in more than 80% of patients at the time of diagnosis
What are the features associated with complications of CLL?
Autoimmune haemolytic anaemia: pallor, dyspnoea, weakness, dizziness
Immune thrombocytopaenia: petechiae, bruising, mucosal bleeding
Hypogammaglobulinaemia: recurrent infections (organ specific)
What would indicate that CLL may be active in a patient? [3]
The onset of the classic “B symptoms” is a sign that the CLL may be active. The symptoms include:
* Frequent, severe night sweats
* Unexplained weight loss >10% of body weight in the previous 6 months
* High fever in the absence of any infections (>38°C)
Describe how you would investigate for CLL [4]
FBC:
- Presence of excess lymphocytes on full blood count that are found to be clonal
PBS:
- indicated to confirm lymphocytosis
- presence of smudge cells artefacts from lymphocytes damaged during the slide preparation because of the fragile nature of these cells.
Immunophenotyping:
- shows the characteristic clonal B lymphocytes expressing CD5 and CD23 antigens.
- detect deletion of TP53 gene
Describe the staging criteria for CLL (there are two)
Binet staging - used more in the UK
* Stage A: < 3 lymphoid sites
* Stage B: ≥ 3 lymphoid sites
* Stage C: presence of anaemia ( < 100 g/L) and/or thrombocytopaenia (< 100 x10^9/L)
Rai staging
* Stage 0 (lymphocytosis): 25% at initial diagnosis
* Stage I-II (lymphocytosis + lymphadenopathy + organomegaly): 50% at initial diagnosis
* Stage III-IV (lymphocytosis + anaemia or thrombocytopaenia +/- lymphadenopathy/ organomegaly): 25% at initial diagnosis
Why might you perfom a Direct antiglobulin test (coombs test) with a query CLL patient? [1]
It should be done in all anaemic patients and before commencing therapy to identify autoimmune-related haemolytic anaemias.
What does NICE recomennd for CLL patients who are previously untreated and without TP53 mutations [3]
Fludarabine, cyclophosphamide and rituximab (FCR)
What is the treatment advised by NICE for the first-line treatment of CLL (Binet stage B or C) in patients for whom FCR chemotherapy is not appropriate? [1]
Chemotherapy with bendamustine is advised by NICE as an option for the first-line treatment of CLL (Binet stage B or C) in patients for whom FCR chemotherapy is not appropriate.
For patients with FCR or bendamustine-based therapy unsuitable, what treatment does NICE recommend? [2]
For adults with FCR or bendamustine-based therapy unsuitable, NICE recommends obinutuzumab in combination with chlorambucil as an option.
What is the treatment NICE rec. for patients with TP53 deletion/mutation have a poor prognosis even after first line FCR combined chemotherapy? [1]
Patients with TP53 deletion/mutation have a poor prognosis even after first line FCR combined chemotherapy. In such cases, chemo agents like ibrutinib can be used.
[] is a monoclonal antibody which has also been shown to be effective in TP53 mutations.
Alemtuzumab is a monoclonal antibody which has also been shown to be effective in TP53 mutations.
[] is the dominant clinical feature among the complication in CLL, which should be treated with [].
Auto‐immune cytopenia is the dominant clinical feature among the complication in CLL, which should be treated with corticosteroids.
[] provides the best opportunity of achieving long‐term disease‐free survival for patients with high‐risk CLL, including those with TP53 abnormalities.
Allogeneic stem‐cell transplantation provides the best opportunity of achieving long‐term disease‐free survival for patients with high‐risk CLL, including those with TP53 abnormalities.
It is a potential option in patients who fail chemotherapy and BCR inhibitor therapy or those with TP53 mutations that do not respond to treatment or relapse. In addition, it can also be considered in those with Richter transformation
Describe potential prophylaxis treatment might give patients with CLL? [4]
Vaccination: influenza, pneumococcal (ensure no contraindication with current therapy)
Antibiotics for infections
Consider intravenous immunoglobulin: treatment of secondary hypogammaglobulinaemia (i.e. IgG < 5g/L)
Consider Pneumocystis jirovecii pneumonia (PJP) and herpes zoster prophylaxis: usually in patients on treatment for relapsed CLL
Which chromosome deletion in CLL has bad prognostics? [1]
Chromosome 17 deletion
What is the most common cytogenetic feature seen in ALL?
t(4;11)
t(12;21)
t(9;22)
Hypodiploid karyotype
Hypodiploid karyotype
What is the most common cytogenetic feature seen in ALL?
t(4;11)
t(12;21)
t(9;22)
Hypodiploid karyotype
Hypodiploid karyotype
The most widely accepted classification system of ALL is the WHO classification.
Describe this classification [3]
- B cell lineage (85% of cases)
- T cell lineage (10-15% cases)
- Rare cases of NK cell lineage (<1% of cases)
Describe the typical presentation of ALL related to marrow failure [4]
Recurrent infections: neutropaenia
Thrombocytopenia:
* Petechiae
* Nose bleeds
* Bruising
Anaemia:
* Fatigue
* Breathlessness
* Angina
* Syncope
Describe the typical presentation of ALL related to tissue infiltration [4]
Lymphadenopathy
- Persistent
- Painless
- Firm & Rubbery
Hepatosplenomegaly
- Can present with anorexia, weight loss or abdomen pain
Bone pain
Mediastinal mass (may result in SVCO)
Testicular enlargement
Describe the FBC seen in a patient with ALL [3]
Thrombocytopaenia
Anaemic
WBC: low or high
- Low indicates lymphoblasts present that have not differentiated as recognisable WBC
- High indicates similar enough to WBC to be counted
U&Es; LDH; uric acid high
- Due to metabolic abnormalities
- TLS
T-cell ALL is rarer than the B-cell form. It is said to typically present in which patient population? [1]
Describe two common presenting symptoms [2]
T-cell ALL is rarer than the B-cell form. It is said to typically present in adolescent males with lymphadenopathy or a mediastinal mass.
What investigational tests should you perfom to assess for features of disseminated intravascular coagulation (DIC)? [2]
Coagulation screen and DDIMER
How would you differentiate ALL from AML based off which parts of the body are implicated [2]
ALL has a predisposition for testicular, and CNS involvement
AML has a predisposition to involve skin and gums or other mucous membranes
Confirm AML through the presence of myeloid features and antigens and absence of any lymphoid antigens.
Desribe how the pre-treatment & supportive therapy phase of ALL is performed [4]
For roughly 5-7 daysL
* Corticosteroids with or without another drug
* Hydration
* Allopurinol
* CNS prophylaxis is given intrathecally
This pre-phase helps reduce the risk of TLS
Desribe how the induction chemotherapyphase of ALL is performed [1]
The selection of chemotherapy is dependent on a multitude of factors including age, Philadelphia chromosome status and the presence of CNS disease. Those with CNS disease require intrathecal chemotherapy and prophylactic therapy may be used in those without to reduce the risk of CNS relapse.
Describe the regime usually used for maintenance therapy fr ALL
daily 6-mercaptopurine and weekly methotrexate
though there is considerable variation.
Describe the regime usually used for consolidation therapy fr ALL
the goal is to prevent the growth of leukaemia from any residual cells (known as a minimal residual disease (MRD)) and to prevent the development of drug resistance, by using numerous agents with multiple mechanisms of action.
For those who don’t achieve a complete remission following induction, termed high-risk cases, ESMO guidelines advise allogeneic haematopoietic cell transplantation leads to better outcomes.
Describe 4 complications of ALL [4]
Tumour lysis syndrome:
- significant metabolic disturbances arising from the rapid breakdown of malignant cells, normally after therapy has been initiated. It should be anticipated and when appropriate prophylaxis may be given with close monitoring and HDU/ITU availability if needed.
Neutropenic sepsis:
- characterised by fever and neutrophils < 0.5 (or expected to fall below 0.5). A medical emergency requiring early identification and management.
SVCO:
- patients may present with features of superior vena cava obstruction (e.g. dyspnea, facial swelling, cough) secondary to a mediastinal mass.
Chemotherapy side-effects:
- depends on the therapy and intensity, can be early (e.g. mucositis, nausea and vomiting, hair loss) or late (e.g. cardiomyopathy, secondary malignancies)
Describe the genetic pathophysiology of CML [3]
presence of the BCR-ABL fusion gene:
- results from a reciprocal translocation between chromosomes 9 and 22
- known as the Philadelphia (Ph) chromosome
- BCR-ABL fusion protein drives uncontrolled cell growth and proliferation, leading to CML.
Describe the typical presentation of CML [+]
- Fatigue/lethargy
- Night sweats
- Weight loss
- Splenomegaly
- Generalised lymphadenopathy
- Symptoms and signs of anaemia
- Altered mental state: due to leucostasis
- Signs secondary to hyperviscosity: a cerebrovascular events; priparism; opthalmic complications
How do you diagose CML? [2]
Cytogenetics:
- identification of Ph chromosome (95%)
- Ph chromosome is not identified on cytogenetics in around 5%. In these patients fluorescent in situ hybridisation (FISH)
What findings for CML would you find on a FBC? [3]
Leucocytosis, typically 20-60 * 109 /L
- The differential may demonstrate increased cell numbers from the myeloid lineage of leucocytes.
Thrombocytosis or thrombocytopenia may occur
Anaemia is a common finding, often normochromic and normocytic, but depending on haematinics, other abnormalities e.g. microcytic, hypochromic anaemia of iron deficiency may also be found.
Describe the different phases of CML [3]
1. Chronic phase
- The vast majority (> 85%) present in the chronic phase of disease.
- Clinical features are typically non-specific and include fatigue, weight loss and night sweats
2. Accelerated phase
- abnormal blast cells take up a high proportion (10-20%) of the bone marrow and blood cells.
- In the accelerated phase symptoms and features become more apparent and severe:
- anaemia, thrombocytopenia and immunodeficiency.
- Disease is more difficult to treat and outcomes worse.
3. Blast crisis
- This phase resembles an acute leukaemia with the rapid expansion of blasts
- pancytopenia occurs
- Without treatment survival is typically a few months.
Describe the treatment regime for CML in the:
- Chronic phase
- Advanced phase
- B
Chronic phase: tyrosine kinase inhibitors
- 1st line: imatinib
- dasatinib
- nilotinib
Advanced:
- Ideally all patients should be treated as part of a clinical trial
Blast phase:
- start / switch a tyrosine kinase inhibitor with induction chemotherapy; followed by stem cell transplant
a. Regular monitoring of which parameter is crucial for assessing the response to treatment and detecting relapse in CML?
A. Hemoglobin levels
B. Platelet count
C. BCR-ABL transcript levels
D. Liver function tests
a. Regular monitoring of which parameter is crucial for assessing the response to treatment and detecting relapse in CML?
A. Hemoglobin levels
B. Platelet count
C. BCR-ABL transcript levels
D. Liver function tests
Which fusion of chromosomes are common in CML? [1]
Which other type of leukaemia does this sometimes occur in?
Lecture content
9:22
Can also occur in ALL
What treatment do we give for Philadelphia chromosome - BCR-ABL? [1]
Lecture
Imatinib
Which of the following is most associated with smudge cells
Acute myeloid leukaemia
Acute lymphoblastic leukaemia
Chronic myeloid leukaemia
Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia
The NICE guidelines on suspected cancer (2021) recommend a full blood count within 48 hours for patients with suspected leukaemia.
They recommend children or young people with [] or [] are sent for immediate specialist assessment.
The NICE guidelines on suspected cancer (2021) recommend a full blood count within 48 hours for patients with suspected leukaemia.
They recommend children or young people with petechiae or hepatosplenomegaly are sent for immediate specialist assessment.
Describe the general management prinicples for AML [2]
Treatment is set up in cycles and organised into induction and consolidation (and occasionally maintenance) stages.
Induction:
- 7+3 GO - An induction regime consisting of cytarabine, daunorubicin and gemtuzumab ozogamicin (GO) (combination therapy)
Consolidation:
- IDAC +/- GO - A consolidation regime consisting of intermediate-dose cytarabine (IDAC) +/- gemtuzumab ozogamicin.
allogenic haematopoietic stem cell transplantation
- for patients with unfavourable prognostic factors (unfavourable cytogenetics) or patients who do not achieve remission through chemotherapy
How would you differentiate between AML & ALL? [2]
terminal deoxynucleotidyl transferase (TdT) positive in ALL
No Auer rods in ALL
How would the following change in AML? [5]
- Prothrombin time
- activated partial thromboplastin time (APTT)
- platelet count
- D-dimer concentration
- fibrinogen concentration
How would the following change in AML?
- Prothrombin time: raised
- activated partial thromboplastin time (APTT): raised
- platelet count: reduced
- D-dimer concentration: elevated
- fibrinogen concentration: reduced
AML typically causes cell lysis. What electrolyte abnormalities would occur because of this? [4]
Hyperphosphatemia, hypocalcemia, hyperkalemia, and hyperuricemia
How would you differentiate between AML & CML? [2]
CML is found with Philadelphia chromosome
State and describe one of the main complications of AML [5]
Leukostasis: excessive number of leukaemic cells, causes increased blood viscosity.
The clinical features are:
* Chest pain
* Headache
* Altered mental status
* Priapism
What supportive treatment do you give alongside Haematopoietic cell transplantation (HCT)? [5]
Antibiotic prophylaxis (broad-spectrum IV antibiotics) for febrile neutropenia
Trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis in neutropenic patients.
Immunisations
ondansetron
Transfusions for severe anaemia, thrombocytopenia.
Which cytogenetic abnomarlities in AML have a really poor prognsosis (3% to 10yrs)? [1]
inversion 3
acute promyelocytic leukaemia (AMPL) can have really bad clotting problems.
This arises from a translocation of which chromosomes? [1]
What medication do we give PML-RARA fusion? [1]
From lecture
t(15:17)
PML-RARA fusion: give ATRA
