Leukaemias

Leukemias

Heterogeneous clonal hematopoietic progenitor and/or stem cell malignancy in which immature or mature hematopoietic cells proliferate and accumulate in the bone marrow, blood, and/or other tissues

Which 2 pathways from blood stem cell form what blood cell types

What type of cells are formed by granulocytopoeisis

By what process are platelets formed

Name them

Most common leukaemia type

AML = 90% of all acute leukemias in adults

(estimated 20,240 new cases and 11,400 deaths expected in the United States in 2021)

By what fold does risk increase for AML between 20 & 65 yrs

10 fold increase in risk

AML medial diagnosis age

68 years

How does survival compare for AML for children vs patients aged 45 vs 60+

Children 5-year survival = 70%.

45% 5-year survival for patients aged 45

<10% for those older than 60 years

Most common risk factor for AML

The most common recognized risk factor is previous exposure to radiation or chemotherapeutics which result in therapy-related AML (t-AML) and account for ~10% to 20% of all AML cases

Name 2 environmental exposures that can → AML

Environmental exposures linked to the development of t-AML include benzene and ionizing radiation

Latency period for AML after exposure

5 to 10-year latency period

Name the 3 primary mutations that transform normal HSC (haematopoietic stem cells) → pre-leukaemia HSC → Leukaemia stem cells

Primary mutations = DNMT3A, TET2, IDH1/2

Name the 4 secondary mutations that transform pre-leukaemia HSC → Leukaemia stem cells

Secondary mutation s= FLT3ITD, JAK2, NMP1, NRAS

AML symptoms

Pallor

Bone pain

Fever

Fatigue

Hepatosplenomegaly

Bruising & bleeding

How does a blood film of AML look

5 tests for AML

Diagnosis with BMAT

Flow Cytometry

Cytogenetics

FISH

Molecular analysis

7 classes of AML

What % blasts in the blood or bone marrow indicates acute leukaemia

20%

Do you need 20% blasts to diagnose leukaemia

No - Most AML-defining genetic abnormalities can establish AML without reaching the 20% blast threshold

Name 2 types of AML that require >20% blasts for diagnosis

BCR-ABL

CEBPA

Treatment for young, fit patients with AML

DA 3 + 10: (Daunorubicin x 3d) + (Cytarabine x 10 d)

FLAG-Ida: Fludarabine + Cytarabine + G-CSF + Idarubicin

Complete remission (CR) rate for AML treatment (DA 3 + 10 & FLAG-Ida)

70%

CR rate in AML with unfavourable chromosomal abnormalities / adverse cytogenetics

47%

CR rate in therapy related AML

51%

CR rate in secondary AML

39%

What 3 drugs are used in Older/Less fit AML patients to Maximise survival/Maintain Quality of Life

Azacitidine

Decitabine

Low-Dose Cytarabine

CR rate in Older/Less fit AML patients

30%

Median overall survival length for Older/Less fit AML patients

12 months

Mutation in APML

Acute promyelocytic leukemia is characterized by a balanced reciprocal translocation resulting in the fusion of the PML gene on chromosome 15 with the RARA gene on chromosome 17.

Hypergranular / Typical APL (M3) makes up what % of cases

60-70%

How does Hypergranular / Typical APL (M3) present on an FBC

Low WBCs

How does Hypergranular / Typical APL (M3) present on a blood film

Abnormal promyelocytes with numerous red to purple cytoplasmic granules that are typically darker and larger than normal neutrophil granules.

Identifiable faggot/matchstick cells with numerous Auer rods.

How does Hypogranular / Microgranular APL (M3v) present on a blood film

. Leukocytosis.

. Numerous abnormal promyelocytes readily identified on a peripheral blood smear.

. Irregular nucleus and granulations sparser and finer compared with the hypergranular form.

. Faggot cells with multiple Auer rods less commonly seen.

What’s the problem in APML

Coagulopathy causing early deaths with CNS and GI bleeds

Treatment for APML

ATRA (all trans retinoic acid)

What causes APL differentiation syndrome

Risk with APML is dependent on what

WCC at presentation

Drug Tx for APML

ATRA + ATO ± anthracycline

How else is APML treated

Management of differentiation

syndrome and coagulopathy

Pathogenesis of APL

How does retinoic acid work on APL

Most common leukemia in children

Acute lymphoblastic leukemia (ALL)

Prevalence of ALL in children & adults

ALL = 23% of all paediatric cancer diagnoses and 76% of leukemias among children <15 years of age)

20% of adult acute leukemias.

2 subtypes of ALL

B lymphoblastic

T lymphoblastic

How is ALL diagnosed & other tests

Diagnosis with BMAT

Flow Cytometry

Cytogenetics

FISH

Molecular analysis

How does treatment differ for fit vs unfit pts with ALL

What is DFS

Disease free survival

Are transfusions used in ALL

Yes - Support Hb and platelets

Tx for mucositis in ALL

Mucositis in ALL (acute lymphoblastic leukaemia) = inflammation and ulceration of the mucous membranes, particularly in the mouth and gastrointestinal tract, often caused by chemotherapy

A pump might be used for fluids & meds.

Parenteral nutrition might be used

How is TLS treated in ALL

Tumor Lysis Syndrome (life-threatening oncological emergency - massive number of leukaemia cells die very quickly) is treated with Fluids, rasburicase & allopurinol

What is sarcopenia

A loss of skeletal muscle mass and strength (can happen with long periods in bed)

What is the most prevalent lymphoid malignancy in North America and Europe

CLL

CLL is less common among what ethnicities

African & Asian

CLL median age at diagnosis

72

Is there a difference in prevalence between men & women in CLL

Yes - Men:Women = 2:1

Name a precursor condition that can progress to CLL.

Monoclonal B-cell lymphocytosis (MBL)

Sx of CLL

Asymptomatic- incidental finding in FBC

Anemia

Thrombocytopenia

Lymphadenopathy

Splenomegaly

Fatigue

Night sweats

Weight loss

Fever

How is CLL staged

RAI BINET

Grey = features that make it that stage

Green = Low/Intermediate/High

Name1 investigation that is sufficient to establish a diagnosis of CLL?

PB immunophenotyping

Which immunophenotype is characteristic of CLL

Lymphocytes CD5, CD19 CD20 CD23 +

Name 3 other investigations that can be done for CLL

Lymph node biopsy

Bone marrow biopsy

CT neck thorax abdomen pelvis

What is the purpose of the CLL-IPI?

Prognostic assessment and risk stratification

What is the range of CLL-IPI

0-10 points

What goes into calculating the CLL-IPI score

Age

Clinical stage

17p13 deletion and/or

TP53 mutation

IGHV mutation status

B2M level (mg/L)

What value for each of these gives what CLL-IPI score:

• Age

• Clinical stage

• 17p13 deletion and/or

• TP53 mutation

• IGHV mutation status

• B2M level (mg/L)

What is considered low, intermediate, high and very high risk using the CLL-IPI score

Low-risk patients (score 0-1), 93.2%

Intermediate risk (score 2-3), 79.3%

High risk (score 4-6), 63.3%

Very high risk (score 7-10), 23.3%

These are all possible features of CLL

True/False Most patients never receive chemo for CLL

True - Majority of patients will never need treatment

What 3 things would need to be considered in the Tx of CLL

(- Mutated IGHV: More favourable prognosis; generally slower disease progression.

- Unmutated IGHV: Less favourable prognosis; generally faster progression.

- TP53 mutation / del(17p): High-risk disease. If treatment is indicated, targeted therapy is preferred over conventional chemoimmunotherapy.

- Comorbidities and quality of life: Influence which treatment is chosen and whether its benefits outweigh its risks.)

Mutation associated with CML

BCR-ABL1 fusion gene, which is usually derived from a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22) (q34;q11), resulting in a derivative chromosome known as the Philadelphia (Ph) chromosome

CML accounts for what % of adult leukemia cases

15% to 20%

What is the worldwide annual incidence of CML per 100,000

1-2 cases per 100,000

Is there a gender predominance in CML

male-to-female ratio, 1.3:1 (male slight predominance)

CML median age of diagnosis in EU vs US

EU: 60 and 65 years

US 65 - 74

CML is what % of leukaemias in children

2% of all leukemias in children <15 years of age

9% of all leukemias in adolescents 15 to 19 years of age

Signs & symptoms of CML

Asymptomatic- incidental finding in FBC

Anaemia

Hepatomegaly

Thrombocytopenia/thrombocytosis

Splenomegaly

Fatigue

Night sweats

Weight loss

Fever

2 phases of CML

Chronic phase

Blast phase

In the scoring of CML what does the social score take into account & what is considered low/intermediate/high risk

In the scoring of CML what does the hasford score take into account & what is considered low/intermediate/high risk

In the scoring of CML what does the EUTOS score take into account & what is considered low/high risk

In the scoring of CML what does the ELTS score take into account & what is considered low/intermediate/high risk

How is CML diagnosed

BMAT

4 other investigations for CML

Flow Cytometry (blast phase)

Cytogenetics

FISH

RT-PCR

Drug treatment options for CML

TKIs

1st gen Imatinib

2nd gen Dasatinib

• Nilotinib

• Bosutinib

3rd gen Ponatinib

Supportive tests & treatment options for CML

Baseline echocardiogram, ECG

Control of BP

How is CML treatment monitored

BCR-ABL transcripts: Measure how much leukaemia-associated BCR-ABL mRNA is present in the blood

BCR-ABL mRNA levels aim for 3, 6, 12 months

- 3 months: Aim for ≤10%.

- 6 months: Aim for ≤1%.

- 12 months: Aim for ≤0.1% — this is Major Molecular Response

What is the difference in BCR-ABL mRNA levels in a molecular response (MR) of 4 vs 4.5

MR4: BCR-ABL has decreased by at least 10,000-fold (4-log reduction).

MR4.5: BCR-ABL has decreased by at least ~32,000-fold (4.5-log reduction)

Tempo = fast/slow

Diagnosis = PM/BM

Survival = variable/good/excellent