Haematological Malignancies Flashcards

Question

How PMF treated?

Answer 1

Aspirin Hydroxycarbamide Interferon-a Ruxolitinib if JAK2 positive Candidates for stem cell transplant

Answer 2

Transplant Pegylated interferon-α (IFN-α) Corticosteroids. Hydroxyurea Cyclophosphamide, Imatinib: for those with FIP1L1-PDGFR alpha fusion tyrosine kinase translocations

Answer 3

Transplant Pegylated interferon-α (IFN-α) Hydroxyurea Transplant JAK2 inhibitors currently user clinical tial for treatment of CNL.

Answer 4

No longer considered an MPN Accumulation of mast cells Aggressive disease that requires rapid treatment

Answer 5

Mast cell cytoreductive therapy to ameliorate disease-related organ dysfunction. Midostaurin: small-molecule inhibitors that target mutant-KIT

Answer 6

The Dynamic International Prognostic Scoring System (DIPSS) Plus uses the following eight risk factors. (Such scoring dictates NICE funding) Age older than 65 Constitutional symptoms  Hemoglobin lower than 10 g/dL White blood cell count greater than 25 x109 /L Peripheral blood blasts greater than 1 percent Platelet count less than 100 x109 /L Transfusion need Unfavorable karyotype The risk groups based on these eight risk factors are: Low-risk - Patients with no risk factors  Intermediate 1 risk (INT-1) - Patients with one risk factor  Intermediate 2 risk (INT-2) - Patients with two or three risk factors  High-risk - Patients with four or more factors

Answer 7

MF: 10-20% PV: 7.9–17% ET: 8.1% for ET Progression to myelofibrosis (MF) over a period of 20 years occurs in 26% of PV and 19.9% of ET.  

Answer 8

All new patients should be referred to the MDT for confirmation of diagnosis, prognosis and management plan, taking into account their performance status, needs and co-morbidities

Answer 9

WHO myeloid neoplasms BJH 2021

Answer 10

Sub classification of MPN Characterisation of BCR-ABL1 Leads to overproliferation of mature white blood cells- granulocytes These granulocytes are abnormal and build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anaemia, or easy bleeding may occur.

Answer 11

Chronic myeloid leukaemia (CML) accounts for approximately 15% of adult leukemias. Median age of 57

Answer 12

The advent of tyrosine kinase inhibitor (TKI) therapy has transformed CML from a fatal disease into a chronic disease for the majority of patients. With the introduction of TKI therapy in 2001, the 8-year survival is now 87% and continues to improve. The life expectancy of a newly diagnosed patient with Philadelphia chromosome-positive (Ph+), BCR-ABL1+ CML in chronic phase (CP) is now very close to that of age matched individuals in the general population

Answer 13

There is evidence regarding one of the causes of CML being acute radiation exposure as it has been observed at a high incidence in atomic bomb survivor.

Answer 14

Newly diagnosed cases can be asymptomatic and discovered as part of a routine medical examination. Common findings at presentation: splenomegaly, fatigue, malaise, weight loss, night sweats, and anemia. Splenomegaly is the most common finding on physical exam and is present in over half of the patients.

Answer 15

Chronic phase - Increased WBC >10 - Leukocytosis and/or basophillia - BCR-ABL1 - <10% blasts Accelerated phase - increased WBC >25 - Platelets <100 - <20% blasts - BCR-ABL1 and other abnormalities Blast crisis - increased WBC >25 - >20% blasts - BCR-ABL1 and other abnormalities

Answer 16

BCR-ABL1 - 95% of cases due to t(9;21)(q34.1;q11.2) - 5% of cases are cryptic or complex rearrangements Results in the Philadelphia chromosome on der 22

Answer 17

p210: In CML, the breakpoint cluster region is almost always in the major BCR (M-bcr), forming an abnormal fusion protein, e13a2/e14a2 p230: Rarely, the breakpoint occurs in the μ-BCR region, between exons 17-20. This encodes for a larger fusion protein p190: Ph-positive acute B-ALL, and occasionally in AML, but rarely in CML - e1a2, poor repsonse4 to imatinib

Answer 18

Promotes cell proliferation and blocks apoptosis. The hybrid protein has constitutive activated tyrosine kinase activity. Activates downstream pathways including RAS/MAPK, PIK3/AKT, JAK/STAT The 3BP1 (binding protein) binds normal ABL1 on the SH3 domain, which prevents SH1 activation. For BCR/ABL1, the N-terminal exon of BCR binds to SH2, hiding SH3, which therefore cannot be bound to 3BP1, and thus activating SH1

Answer 19

+Ph +8 i(17q) -7 -5 3q26 abnormalities (MECOM) Increased risk of transformation to blast phase

Answer 20

FISH- rapid detection, detects cryptic rearrangements G-banding on bone marrow: identify Ph and additional chromosomal abnormalities (ACAs) RT-PCR on blood: determine transcript type RQ-PCR:

Answer 21

FISH- 3 days G banding and RT-PCR- 14 days

Answer 22

Measurable residual disease (MRD) can show response to treatment, predict relapse and suggest when it is suitable for treatment change or treatment free remission Happens 3 monthly until MMR achieved and then 6 monthly

Answer 23

RQ-PCR- BSH and ELN guidelines recommend this technology Extracted RNA is converted to cDNA using reverse transcriptase- 2 separate reactions for BCR-ABL1 and ABL1 Uses Taqman technology. Fluorescently labelled probe for BCR-ABL1 and ABL1 and probe contains quencher molecule which prevents the fluorescence The ROI is amplified by taq polymerase which digests the probe releasing the quencher. This releases the fluoresence Each round of amplification therefore increases the fluorescence which is measured. The ct value is the amplification round it takes for the fluorescence to cross a specific threshold. This is then compared to a standard curve to find an absolute number of copies of BCR-ABL1. This is then normalised to ABL1 to produce a ratio Standardised to international scale

Answer 24

A lab specific coversion factor given that is used on the final BCR-ABL1:ABL1 ratio during MRD monitoring with RQ-PCR This improves comparability between labs and allows for specific thresholds for MRD e.g. MMR, MR4

Answer 25

>35%- continuing disease <35%- residual diseae <1% CCyR (complete cytogenetic response) <0.1% MMR (major molecular repsonse) <0.01% MR4 MR4.5 MR5 10,000 copies of ABL1 transcripts are also required to ensure sensitivity of analysis

Answer 26

Optimal - 3 months <10% - 6 months <1% - 12 months <0.1% - >12 months <0.01% If milestones are not met then they should consider changing treatment to a second or third generation TKI

Answer 27

Poor tolerance- had to discontinue Primary resistance- never responded to imatinib Secondary resistance- acquired resistance variants in ABL1 TKD or clonal progression

Answer 28

BSH and ELN guidelines state that ABL1 kinase domain testing should be varied out to look for resistance variants The specific variant may suggest a specific TKI should be used Often tested with nested RT-PCR to enrich for ABL1 KD, followed by sanger

Answer 29

These TKIs compete with ATP for the binding site of BCR::ABL1, thus rendering its phosphorylation ability inactive.

Answer 30

Nilotinib Bosutinib Dasatinib Ponatinib- sensitive to all common AKD variants including T315L

Answer 31

If patients have a deep molecular response (MR4 or more) for over 12 months, patients can stop treatment This requires an increased in MRD monitoring to monthly for the first 12 months

Answer 32

Myelodysplatic syndrome/neoplasm Heterogeneous group characterised by clonal expansion of myeloid cells with impaired differentiation Results in dysplasia in one or more myeloid lineages- leading to anaemia, neutropenia and/or thrombocytopenia

Answer 33

The incidence of MDS in the UK is 3.72/100 000 population/year; predominantly a disease of the elderly (median age at diagnosis 75.7 years) The annual incidence is 1-2 per million children, with 10-25% presenting with increased blasts

Answer 34

Exposure to cytotoxic agents (alkylating), PARP inhibitors or radiotherapy for an unrelated neoplasm (formally categorised as MN-pCT). Therapy-related myeloid neoplasms account for 10-20% of all cases of MDS/AML/MDS/MPN with a strong association with TP53 mutations. Exposure to benzene (smoking), agricultural chemicals and solvents (19) Germline predisposition

Answer 35

Cytopenias Anaemia: fatigue, dizziness Neutropenia: increased infections Thrombocytopenia: bleeding/bruising Can overlap with MPN and risk of transformation to AML

Answer 36

Persistent cytopenias: <10g/dL Hb, <100 x 109/L platelet count, <1.8 x 109/L absolute neutrophil count BM Morphology: dysplasia in 10% of cells, 5-19% blasts, ringed sideroblasts Flow: Increase in CD34+, CD15, CD16, CD14 and CD56 Genetics: detection of MDS related abnormality

Answer 37

MDS with defining genetic abnormalities - MDS with isolated 5q del - MDS with SF3B1 - MDS with bi-allelic TP53 del MDS morphologically defined - MDS low blasts - MDS hypoblastic - MDS-IB1 (10% blasts) - MDS-IB2 (20% blasts)

Answer 38

International prognostic scoring system - uses karyotype/ cytogenetically visible abnormalities to put patients into prognostic groups

Answer 39

Very good: -Y, del11q Good: normal, del5q, del21p, del20q Intermediate: del7q, +8, i(17q) Poor: -7, inv(3), complex (3 abnormalities) Very poor: Complex >3

Answer 40

Can only be used at diagnosis Can't be used for secondary MDS Does not take into account sequence variants

Answer 41

Updated prognostic scoring system that uses haematologic, cytogenetics and molecular genetics Six categories with different prognoses and an online tool Can be used for primary and secondary MDS

Answer 42

Found in 50% of patients Del5q- favourable Monosomy 7 or del7q- poor prognosis, associated with alkylating agents Del20q and del12p- favourable 3q abnormalities- MECOM rearrangements -Y - non specific to MDS

Answer 43

Found in a range of genes TP53- adverse ASXL1- adverse SF3B1- favourable TET2, RUNX1, DNMT3A, EZH2

Answer 44

MDS can be caused by germline mutation (autosomal recessive and X-linked recessive) found in Fanconi anaemia (FA genes), severe congenital neutropenia (ELANE), Shwachman-Diamond syndrome (SBDS), Diamond-Blackfan anaemia (RPS genes) and telomere biology disorders (TERT, TERC). Germline mutations can also occur in RUNX1, ETV6 and DDX41

Answer 45

Cytogenetics - G banding and SNP arrays used - At WMRGL, SNP arrays used for all confirmed MDS cases (higher resolution and can detect CN-LOH) and G banding used for high risk cases (detects balanced translocations) Molecular - Myeloid gene panel

Answer 46

Age-related Clonal Haematopoiesis of Indeterminate Potential (CHIP) Patient with CHIP has a better survival rate compared to MDS, and lower risk of progression to AML, but still have a risk of progression to a haematological neoplasm compared to individuals without mutations Non -defining abnormalities e.g. DNMT3A, TET2, ASXL1

Answer 47

Clonal Cytopenias of Undetermined Significance (CCUS), where dysplasia has not been found, therefore cannot be classified as MDS. One or more unexplained cytopenias persistent for 4 months or longer, presence of one or more somatic mutations with VAF ≥2% Can be non-malignant causes such as B12, folate deficiency

Answer 48

Karyotype on follow-up BM biopsies can detect clonal evolution where there was a cytogenetic marker at diagnosis or can use specific FISH probes, however, limited sensitivity. Can use NGS data to monitor variant allele frequencies (VAF’s) and monitor emerge of sub-clones. High-risk mutations (TP53, FLT3) should be assessed with every BM biopsy.

Answer 49

Only curative treatment- stem cell transplant for high risk patients Supportive therapy: transfusions, iron-chelating agents, anti-biotics Chemotherapy: Azacytidine considered to be non-intensive, is a hypomethylating agent Cytarabine- intensive Targeted therapies: - Lenalidomide available specifically for del5q patients, immunomodulation therapy acting on cytokine signalling pathways - IDH inhibitors: Ivosidenib Immunotherapy - durvalumab (anti-PD-L1) in combination with aza- low risk MDS

Answer 50

Median overall survival for MDS patients is 5 years Patients with a high-risk karyotype (involving 3 or more unrelated abnormalities or chromosome 7 abnormality) had a median survival of four months Around 30% of MDS patients progress to AML (21).

Answer 51

BSH WHO IPSS-R/IPSS-M

Answer 52

Heterogeneous neoplasms The accumulation of immature myeloid precursor cells which have derived from the unregulated proliferation of a single abnormal progenitor

Answer 53

Bone marrow becomes overcrowded with blasts leading to bone marrow failure - Anaemia (fatigue) - Neutropenia (Infections) - Thrombocytopenia (bruising/bleeding) Can be fatal in weeks/months if untreated Can lead to organ infiltration including spleen, liver, CNS, bones, chloroma

Answer 54

AML is relatively rare but is the most common acute leukemia in adults. The incidence is approximately 4 per 100,000 people per year. Incidence increases with age

Answer 55

Risk factors may include cigarette smoking, past chemotherapy or radiation treatment/exposure

Answer 56

Bone marrow - >20% blasts - Complete blood count Flow - CD13, CD33, CD34, CD117, HLA-DR - Identify leukemia associated immunophenotype (LAIP) for MRD monitoring by flow Biochemistry - Myelo-peroxidase (MPO): an enzyme which is present in the primary granules of myeloid cells is an unequivocal marker of myeloid lineage Genetic abnormlaities - t(8:21) (q22;q22);RUNX1::RUNX1T1 - Inv(16) (p13.1q22) or t(16;16) (p.13.1;q22);CBFB::MYH11 - t(15;17)(q24.1;q21.2) ; PML-RARA - t(9;11)(p22;q23); MLLT3:: KMT2A - FLT3 - NPM1

Answer 57

WHO 2022 - Genetics and morphology FAB - Morphology based ICC 2022 - Diagnosis and prognosis

Answer 58

WHO 2017= 20% blasts OR presence of AML defining genetic abnormalities (t15:17 and t8:21, inv16), irrespective of blast percentage. WHO 2022= regards blast cut-offs as largely arbitrary and does not require any blast threshold for the diagnosis of AML with defining genetic abnormalities (with the exception of AML with BCR::ABL fusion and with CEBPA mutation, which requires 20% blasts). Newly recognized entities included AML with: KMT2A-r/ MECOM-r / NUP98 rearrangement Abandoned entity: AML with mutated RUNX1 was mainly reclassified as AML-MR

Answer 59

Acute myeloid leukemias with defined genetic abnormalities Acute myeloid leukemias defined by differentiation

Answer 60

APL with t(15;17)(q24.1;q21.2)/PML::RARA AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 AML with inv(16)(p13.1q22)/CBFB::MYH11 AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A AML with t(6;9)(p22.3;q34.1)/DEK::NUP214 AML with t(1;22)(p13.3;q13.1); RBM1::MRTFA AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 AML with mutated NPM1 AML with mutated CEBPA AML with KM2TA rearrangements AML with NUP98 rearrangements AML with MECOM rearrangements AML associated with MDS AML with other defined genetic abnormalities

Answer 61

FAB (French-American-British) . The 1976 FAB classification relied essentially on blast morphology. Divided into 8 subgroups M0-M7 M0: Undifferentiated AML M1: AML with minimal maturation M2: AML with maturation M3: Acute promyelocytic leukemia (APL) M4: Acute myelomonocytic leukemia M5: Acute monocytic leukemia M6: Acute erythroid leukemia M7: Acute megakaryocytic leukemia

Answer 62

ICC provides a hierarchical classification of AML, based on genetic determinants with clinical and prognostic relevance. The ICC stratifies AML into five molecular subgroups: (i) AML with recurrent genetic abnormalities (both gene rearrangements and gene mutations) (ii) AML with mutated TP53 (iii) AML with myelodysplasia (MDS)-related gene mutations (a new category with 10%–19% blasts in the bone marrow or peripheral blood, in recognition of the similarities in biology and prognosis between these patients and those with ≥20% blasts) (iv) AML with MDS-related cytogenetic abnormalities (v) AML, not otherwise specified (NOS)

Answer 63

Recurrent genetic abnormalities - ICC and WHO have similar recommendations - t(9:11) MLLT3::KTM2A is separate from other KMT2A mutations in ICC - Mutated CEPBA vs. Bzip CEBPA- WHO 2022 allows any biallelic mutation (not only in-frame bZIP derangements) as well as monoallelic bZIP mutations for the diagnosis of AML with CEBPA mutation) Blast cut-off for AML - Both acknowledge the blurring boundary between MDS and AML - WHO-regards blasts cut-off as arbitrary; any blast % with recurrent genetic abnormalities - ICC- at least 10% blast threshold for recurrent genetic abnormalities (to support a differential diagnosis with MDS) - ICC recognise MDS with 10-19% blasts as being MDS/AML but WHO keep MRS with 10-19% blasts as MDS-IB2 TP53 mutation - Both acknowledge MDS with bi-mutated TP53 as distinct poor prognosis entity - Unlike the ICC, the WHO does not recognize TP53 mutations as genetic classifiers and does not consider AML with TP53 mutations as a separate diagnostic category

Answer 64

Classification (WHO, FAB, ICC) Prognosis (ELN) Treatment stratification MRD monitoring Demonstrate clonality and disease progression

Answer 65

ELN 2022 - Genetics at initial diagnosis - Split into favourable, intermediate and adverse

Answer 66

Favourable: - RUNX1:RUNX1T1 - CBFB:MYH11 - NPM1 without FLT3-ITD - CEBPA Intermediate: - NPM1 with FLT3-ITD - wt NPM1 with FLT3-ITD - MLLT3::KMT2A Adverse: - BCR::ABL1 - DEK::NUP214 - MECOM - TP53 - KAT6A::CREBBP - ASXL1, BCOR, EZH2, SF3B1

Answer 67

Class I - Variants that give a proliferative e.g. BCR-ABL1, FLT3, KIT Class II - Variants that block haematopoeitic differentiation - PML-RARA, CBFB-MYH11, RUNX1::RUNX1T1, KMT2A Both required for AML

Answer 68

Acute promyelocytic leukaemia 5-10% of AML diagnoses Associated with PML-RARA translocation Morphologically see promyeloblasts and auer rods APL is treated with combinations including all trans retinoic acid (ATRA) and arsenic trioxide (ATO), with or without additional chemotherapy and has excellent prognosis as compared to other non-APL AML subtypes

Answer 69

RARA regulates myeloid differentiation PML forms nueclar bodies which inhibit apoptosis PML-RARA inhibits apoptosis and differentiation

Answer 70

Core binding factor - hematopoietic transcription factors characterized by heterodimers of two units (CBFA consisting of RUNX1 etc and CBFB) RUNX1:RUNX1T1 - RUNX1 regulates differentiation and RUNX1T1 is a transcriptional repressor CBFB-MYH11 - Tethers the CBF complex including RUNX1 outside of the nucleus, repressing differentiation

Answer 71

Induction - Myeloblative treatment to obtain remission - 3+7 regime (cytarabine and daunorubicin) - targeted therapies Consolidation - Deepen remission to eliminate any AML cells to prevent relapse Maintenance - maintain remission Cure: stem cell transplant

Answer 72

ATRA-ATO: PML::RARA- forces differentiation as it is a more potent analogue of RA which forced binding Venetoclax: BCL2 inhibitor, increased response with NPM1 Midostaurin: FLT3 inhibitor Ivosidenib/Enasidenib: IDH inhibitor CBF AML: favourable risk with Gemtuzumab Ozogamicin AML with MDS changes: CPX-351

Answer 73

Flow cytometry -LAIP Leukaemia associated immunophenotype- clonal markers identified at diagnosis - DfN (different-from-normal) approach- aberrant surface antigen expression patterns not present in normal bone marrow are identified at follow-up

Answer 74

RQ-PCR - if MRD marker identified: PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 - Monitored at diagnosis, post 2 cycles, and then every three months for 24 months ddPCR and NGS can also be considered according to ELN

Answer 75

50-80% achieve complete remission after treament. ~50% who achieve CR develop recurrent AML. Patients who have not responded (are resistant) to treatment and patients who have relapsed generally have a poor prognosis. Survival rates for AML are lowest for all cancers (15% survive after 5years). Younger age groups have better prognosis. <40yrs 60% survive 5yrs+ / >70yrs 5% survive 5yrs+

Answer 76

AML may be a curable disease in young and older fit patients. It becomes harder to treat with age; fewer patients are cured as age advances and therapeutic complications are increasingly common. All patients should be treated with therapy adjusted to performance status and AML risk stratification.

Answer 77

G banding: Detect large rearrangements to aid classification FISH: PML-RARA, KMT2A, NUP98, CBF Fragment analysis: Rapid FLT3-ITD and NPM1 insertion detection NGS: Detection of prognostic and recurrent AML abnormalities e,g, FLT3-TKD, TP53, ASXL1, CEBPA

Answer 78

FLT3 - in frame ITD varying in size - determines an intermediate prognosis - can be used for MRD monitoring - treatment with midostaurin NPM1 - 4bp insertion- frameshift - Good prognosis - WHO classification - MRD marker - Good response to venetoclax

Answer 79

ELN WHO ICC FAB ESMO

Answer 80

Chronic lymphocytic leukaemia Pathological accumulation of small mature lymphocytes Small lymphocytic lymphoma is the same disease but is found mainly in lymph nodes rather than blood and bone marrow

Answer 81

CLL/SLL is the most common leukaemia in the Western world populations with an age-adjusted annual incidence of 4.9 per 100,000

Answer 82

Although the overwhelming majority of CLLs occur sporadically there is clear evidence of an inherited predisposition to this disease in 10-15% of the cases. First-degree family members of patients with CLL have an increased risk of developing CLL as well as various types of B cell NHL.

Answer 83

Most CLL patients are asymptomatic (diagnosed incidentally) but some may present with fatigue, increased infections (T cell suppression) autoimmune haemolytic anaemia, infections, splenomegaly, lymphadenopathy or extra-nodal infiltrates. Ranges from a near-normal life expectancy to rapidly progressing disease and early death

Answer 84

>5000 per ul monoclonal B lymphocytes in the blood Flow: Matutes score- CD5+, CD19+, CD20+ CD23+, CD43+, CD10- Morphology: small mature lymphocytes with dense nuclei filling almost all the cytoplasm. Smudge cells- artefacts from fragile cells and characteristic

Answer 85

Most CLL patients do not receive treatment, instead watch and wait When disease progresses and treatment is required, genetics is used to look at prognosis and treatment markers

Answer 86

IGHV TP53 ATM Trisomy 12 del13q

Answer 87

IGHV-mutated (IGHV-M) – associated with good prognosis as cells are more mature IGHV-unmutated (IGHV-UM) – associated with poor prognosis as cells more immature when disease started

Answer 88

NGS Lymphotrack assay - IGHV VDJ domain sequenced - if <98% homology to germline then it is considered mutated - if >98% to germline than unmutated

Answer 89

IGHV unmutated- poor prognosis Chromosome alterations - Del(17p) - TP53 - poor, reduced response to chemo-immunotherapy - Del(11q) - ATM- poor - Del (13q)- favourable - Trisomy 12- intermediate SNVs: TP53, BIRC3- poor NOTCH1, SF3B1- intermediate

Answer 90

Resistance to ibruitinib treatment

Answer 91

Prognostic scoring system that uses age, stage, IGHV status, TP53 status Gives a risk for %5 year survival

Answer 92

Includes deletions and SNVs - detected by FISH and/or NGS TP53 abnormalities are associated with worse disease outcomes due to resistance to chemoimmunotherapy Often biallellic loss

Answer 93

MRD in CLL is not routinely used in practice but is recommended for trials RQ-PCR for IGHV can be done - done at diagnosis, after 6 cycles, end of therapy and then every 3 months

Answer 94

Watch and wait - not treated until considered active disease ESMO define active disease as - evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopaenia - progressive lymphadenopathy - hepatosplenomegaly and/ or splenomegaly - constitutional symptoms - symptomatic or functional extra nodal involvement

Answer 95

ESMO guidelines (dependant upon IGHV and TP53 status) Chemo-immunotherapy - Ibrutiinib (BTK inhibitor) - venetoclax (BCL2 inhibitor)

Answer 96

Approximately 6% of patients will relapse within six to 12 months and another 14% will do so within two years.

Answer 97

Hairy cell leukaemia (HCL) is a rare lymphoid leukaemia and gets its name from the chracteristic short, thin projections that look like hair on its cells. classical (cHCL) and variant (vHCL). CHCL and vHCL differ in therapeutic response and prognosis.

Answer 98

BRAFV600E mutations in ∼100% of cHCLs, ∼30% of vHCLs harbour activating mutations in MAP2K

Answer 99

Treatment with small-molecule inhibitors of active BRAF – eg vemurafenib or dabrafenib

Answer 100

Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L clonal B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL).

Answer 101

Rare aggressive mature B cell neoplasm that represents less than ~1% of all leukaemia Characterized by the presence of large lymphoid cells (prolymphocytes) accounting for at least 55% of total circulating cells in the peripheral blood Prolymphocytes are defined as large cells with clumped chromatin, a large single prominent vesicular nucleolus and abundant cytoplasm

Answer 102

Aberrations in MYC and TP53 portend worst prognosis Poor prognosis in general; the degree of treatment response is dictated by anaemia, degree of lymphocytosis and molecular prognostic markers

Answer 103

Chemotherapy - in the absence of 17p deletion or TP53 mutation, rituximab in association to FC (fludarabine, cyclophosphamide) or bendamustine is the recommended first line therapy - For TP53 mutated, treatment with alemtuzumab or more recently ibrutinib are used

Answer 104

ERIC ESMO WHO

Answer 105

Disease is caused by genetic lesions in B and T progenitor cells resulting in clonal expansion of immature progenitor B and T cells

Answer 106

Accumulation of immature blast cells at the expense of blood cells in the bone marrow and also in the peripheral blood as well as in extramedullary sites (lymph nodes, testes, central nervous system (CNS) and spleen).

Answer 107

Accumulation of progenitor T cells. Always involves bone marrow and nearly always peripheral blood. T-LBL frequently shows bulky mediastinal (thymic) involvement, although any lymph node or extranodal site may be involved including the skin, tonsils, liver, spleen, CNS, and testes.

Answer 108

The B-ALL estimated annual incidence worldwide is 1-4.75 cases per 100,000 population 85% of ALL in children 75% of ALL in adults

Answer 109

T-ALL accounts for about 15% of childhood ALL cases; it is more common in adolescents than in younger children, and more common in males than in females. T-ALL accounts for approximately 25% of cases of adult ALL and 15% of children

Answer 110

Previous treatments with chemotherapy Genetic predisposition - Down syndrome (20-fold increased risk) - Fanconi Anaemia - LFS Weakened immunity/Infections: - HTLV-1 mainly associated with T-cell ALL - HIV - Treatments after an organ transplant

Answer 111

B-ALL commonly presents with bone marrow failure - thrombocytopenia (easy bleeding or bruising) - anaemia (fatigue, dyspnoea) - neutropenia (infections). The leukocyte count can be variable. Lymphadenopathy and hepatosplenomegaly, bone pain, fever, weight loss, night sweats

Answer 112

T-ALL typically presents with a high leukocyte count, and often a concurrent large mediastinal or other tissue mass- can grow rapidly and present as a respiratory emergency Pleural and/or pericardial effusions are also reported. 

Answer 113

Flow: >20% B-lymphoblasts. CD19, CD20, CD22, CD79a, CD10 (common ALL antigen), TdT Genetic testing do determine classification

Answer 114

Flow: >20% T-lymphoblasts. CD3, CD7, CD2, CD5, CD1a, TdT. Genetic testing do determine classification - FISH - SNP arrays

Answer 115

B-ALL with Recurrent Genetic Abnormalities: - B-ALL with t(9;22)(q34.1;q11.2); BCR-ABL1 - B-ALL with t(v;11q23.3); KMT2A rearranged - B-ALL with t(12;21)(p13.2;q22.1); ETV6-RUNX1 - B-ALL with hyperdiploidy - B-ALL with hypodiploidy - B-ALL with t(5;14)(q31.1;q32.3); IGH-IL3 - B-ALL with t(1;19)(q23;p13.3); TCF3-PBX1 - B-ALL with iAMP21 (intrachromosomal amplification of chromosome 21) - B-ALL with BCR-ABL1-like (Ph-like) - B-ALL with other genetic abnormalities - B-ALL, Not Otherwise Specified (NOS)

Answer 116

T-ALL with Recurrent Genetic Abnormalities: - T-ALL, Not Otherwise Specified (NOS) - T-ALL with recurrent genetic abnormalities (e.g., rearrangements of TLX1, TLX3, and TAL1 genes).

Answer 117

B-ALL with hyperploidy - >50 chromosomes - Present in up to 30% childhood B-ALL - Favourable B-ALL with hypoploidy - 24-43 chromosomes - 1% of childhood and 10% of adults - Unfavourable - Associated with TP53 and/or RB1 Can be detected by G-banding, FISH, arrays and flow cytometry

Answer 118

WHO classification Associated with IKZF1 deletions 2-5% in children and >25% in adults Unfavorable outcome but some may respond to imatinib. Usually e1a2 which responds worse than CML transcripts Can be used for MRD monitoring

Answer 119

More than 90 different partners including AF4, MLLT3 Accounts for 70-85% in adolescents ALL, 2% in childhood and adult Unfavorable prognosis Presents with high WCC and CNS involvement

Answer 120

Most commonly TCF3::PBX1- intermediate prognosis TCF3::HLF- poor prognosis Rare in adult, 5% in children

Answer 121

Rare Associated with IKZF1 deletion, marked eosinophillia Intermediate prognosis

Answer 122

Favorable prognosis 25% of childhood cases, <3% of adults

Answer 123

Defined by >5 copies of RUNX1 with >3 o more copies of a single abnormal chromosome 21 1-2% Unfavourable

Answer 124

ABL class fusions e.g. ABL1, ABL2, PDGFRA, PDGFRB or JAK/STAT abnormalities Frequency increases with age 10-15% children, 20-25% adults Unfavourable

Answer 125

NOTCH1 pathway (60% of cases) Rearrangements involving T cell receptor (TCR) genes Kinase signalling pathway (JAK/STAT, RAS/MAPK, PI3K/AKT, ABL1) Epigenetic deregulation Ribosomal dysfunction Altered expression of oncogenes miRNAs or long-noncoding RNA

Answer 126

Subgroup of T-cell ALL - Children- intermediate prognosis Adults- very poor prognosis

Answer 127

M91 (lots of entries) Including - Karyotype - Structural variants by NGS, FISH, RT-PCR - WGS

Answer 128

Very urgent diagnostic: BCR::ABL1 by FISH - 3 calendar days Urgent upfront treatment determining: FISH and karyotype - 7 calendar days; SNP array 14 days Urgent monitoring: ALL concerns re relapse – FISH and karyotype - 7 calendar days Routine monitoring: FISH and ddPCR – 14 calendar days Non urgent for prognostication/stratification where not required pre-treatment: karyotype or SNP array – 21 calendar days

Answer 129

Most commonly by SNP arrays Also use G banding and FISH G banding can be difficult due to rapid apoptosis- often need dir dir cultures which do not have many metaphases

Answer 130

The ALLTogether trial is a significant international clinical study focused on treating ALL in patients below 30. It puts patients into genetic risk groups which determines which treatment patients get The Primary Objective of ALLTogether is to: - improve survival and quality of survival with ALL by a number of interventions - de-intensification of therapy - experimental intensification

Answer 131

Array, NGS - Hyper and hypodiploidy- - iAMP21 - CNVs FISH, G-banding, NGS, RT-PCR - Fusions

Answer 132

Good risk - ETV6-RUNX1 - Hyperdiploidy Intermediate - TCF3-PBX1 - B-other Poor risk - KMT2A rearranged - BCR-ABL1 - iAMP21 - Hypodiploidy - TCF3-HLF

Answer 133

Alltogether trial (for patients <30 years) to classify into risk groups -- Looks at deletons in 8 key genes: ETV6, PAX5, BTG1, CDKN2A/CDKN2B, PAR1, IKZF1,RB1 and EBF1 - CNA-Good risk with no evidence high risk genetics will be used along with MRD to classify patients into the IR-Low (intermediate risk low) group and will receive different treatment to high risk patients - The classifer does not apply to older adults or T-ALL

Answer 134

Patients with good risk genetics can tolerate higher MRD levels during treatment and still have good outcomes compared to patients with poor risk genetics and the same MRD level. Treatment is stratified according to various risk categories including genetic risk and MRD levels.

Answer 135

ALL treatment has significant toxicity, therefore it is desirable to administer the least intensive treatment that will still cure disease. MRD monitoring is crucial for treatment stratification into different intensities (treatment arms). The relationship between genetic risk groups and MRD levels means that patients can be stratified into the appropriate treatment arm

Answer 136

Fusions - BCR-ABL1 - ETV6-RUNX1 - KMT2A Monitoring of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements. - Ig/TCR MRD uses surrogate markers i.e. the rearrangements are not disease causative, they just happen to be present in ALL cells.

Answer 137

Immunoglobulins are produced by B-cells and may be membrane bound as part of the B-cell receptor complex, or secreted as antibodies by plasma cells. Formed from 2 heavy chains (encoded by the IgH genes) and 2 light chains (encoded by IgK or IgL genes) Immunoglobulins are a component of the acquired immune system and have a constant region (formed by C gene segments) joined to a hypervariable antigen binding domain formed by joining of the V (variable), D (diversity) and J (joining) gene segments (heavy chain) or V-J joining (light chain). Somatic recombination of these regions to produce variable region. D-J joining in IgH always occurs before V segment joining. In ALL cells are immature and do not express functional immunoglobulins, therefore partial (incomplete) D-J rearrangements frequently occur

Answer 138

T-cells can be either have an αβ TCR (~90-95% of blood T-cells) or a γδ TCR (5-10% of blood T-cells, more abundant in epithelia). Generation of TCR diversity occurs in the thymus and T-cells are more abundant in blood (10-25% of nucleated cells) than B-cells (3-10% nucleated cells). TCRα is not generally used in MRD as very complex locus

Answer 139

Healthy individuals will be polyclonal for Ig/TCR gene rearrangements- millions of different rearrangements with no single one predominating Clonal expansions of cells carrying particular Ig/TCR rearrangements can occur in response to infection or as a consequence of ALL leukaemogenesis (as ALL is a clonal expansion of immature lymphocytes). We can perform a screening PCR across the V(D)J region which will pick up dominant clones in Ig and TCR genes. This clone will therefore be associated with the leukaemia cells and can be used as a biomarker and monitored using RQ-PCR As B-ALL and T-ALL cells are immature, can see cross lineage rearrangements (e.g. IGH D-J rearrangements in T-ALL, TCRG, TCRD and TCRB rearrangements in B-ALL)

Answer 140

Treatment typically takes place in 3 phases: Induction, Consolidation and Maintenance. and is often dependent upon risk group Induction (remission induction) – 1 month – hyper-CVAD - Cyclophosphamide - Vincristine - Anthracycline drug such as doxorubicin (Adriamycin) or daunorubicin - Dexamethasone or prednisone - If BCR-ABL1 +- Imatinib Consolidation (intensification) – a few months - If the leukaemia goes into remission, the next phase often consists of another fairly short course of chemo, using many of the same drugs that were used for induction therapy. Stem cell transplant can be suggested to patients with poor prognostic factors. Maintenance – two years - After consolidation, the patient is generally put on a maintenance chemotherapy program of low dose of methotrexate and 6-mercaptopurine (6-MP). In some cases, this may be combined with other drugs such as vincristine and prednisone.

Answer 141

Targeted therapies for T-ALL - Venetoclax (anti Bcl2) - Navitoclax (Bcl-xL) Targeted therapy for B-ALL - Imatinib for BCR-ABL1 + - Immunotherapies: Rituximab (anti CD20), Ofatumumab (anti-CD20), Blinatumomab (CAR-T)

Answer 142

Stem cell transplantation (autologous or allogeneic) is usually reserved for ALL in first remission that has a higher risk of relapse (e.g. BCR-ABL1, KMT2A), and for patients who have already relapsed and achieved a second remission. In preparation for stem cell transplantation, patients with ALL are usually given very high doses of chemotherapy or total body irradiation (TBI), called myeloablative conditioning. Reduced-intensity conditioning and nonmyeloablative conditioning are less intensive treatments that can prepare the bone marrow for transplantation and are being studied in older patients and others who are not candidates for myeloablative treatment.

Answer 143

There is increasing evidence that adult ALL cells are more resistant to chemotherapy and have a higher MRD after therapy compared to children. Older ALL patients can have lower rates of complete remission and more treatment-related toxicities due to decreased drug tolerance (such as asparaginase), resistance to treatment agents (corticosteroids, L-asparaginase, cytarabine, daunorubicin, vincristine) and alterations in drug metabolism. The Cancer and Leukaemia Group B (CALGB) study demonstrated that the administration of L-asparaginase is well tolerated by adult patients and that patients with T-cell ALL had a better prognosis compared to those with pre-B-cell AL In adults, MRD evaluation has only recently been incorporated into treatment algorithm. Using the MRD response can accurately select patients for HSCT, thus sparing adult patients with negative MRD from transplant-related toxicities

Answer 144

WHO NCCN ESMO ALLTogether trial

Answer 145

Tumours of the lymphoid tissue which may spread and infiltrate the bone marrow Can affect B and T cells Presentation: - Enlarged lymph nodes, masses, splenomegaly, anaemia, thrombocytopenia, lethargy - B symptoms include fever, weight loss, night sweats

Answer 146

Early B cell factor 1 (EBF1), E2A, and PAX5 are the three main transcription factors for early B cell development. The production of a functional and unique BCR through V(D)J recombination is the central process for the generation of a mature B cell.

Answer 147

Classified using clincial features, morphology, immunophenotype and genetics First split into - Hodgkins lymphoma: characterised by the presence of reed-sternberg cells which are large abnormal lymphocytes in a background of reactive cells - Non-hodgkins lymphoma: split into B cell, T cell and NK cell lymphomas Classified using WHO 2022 (updated from 2016) and ICC 2022 guidelines which are based on the REAL 1994 guidelines

Answer 148

Chromosomal translocations involving one of the Ig loci and a proto-oncogene. These translocations happen as by-products during the processes of V(D) J recombination, SHM, and class switching. The DNA strand breaks occurring in each of these processes bear an inherent risk of generating translocations. The translocation of a proto-oncogene into an Ig locus in B cell lymphomas deregulates the oncogene expression through the associated Ig enhancers, which are highly active in the B cells. B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival- BCR signalling important

Answer 149

Mature (small) B cell neoplasms - CLL/SLL - Hairy Cell Leukaemia - Marginal Zone Lymphoma - Follicular Lymphoma (including pediatric) - Mantle Cell Lymphoma - Lymphoplasmacytic Lymphoma Large B cell neoplasms (morphologically appear DLBCL, BL or HGBL) - Diffuse Large B cell Lymphoma NOS - High Grade B cell Lymphoma NOS - High grade B cell lymphoma-11q - Diffuse large B-cell lymphoma/ high grade B-cell lymphoma with MYC and BCL2 rearrangements - Large B-cell lymphoma with IRF4 rearrangement - Burkitt Lymphoma

Answer 150

Low-grade, indolent disease (chronic) with good prognosis 2nd most common NHL (20-30% of cases) Morphology: Predominantly small centrocytes with few centroblasts. Immunophenotype: CD10+, BCL6+, BCL2+. Molecular Abnormalities: t(14;18)(q32;q21) IGH::BCL2

Answer 151

Median age 15-18 and more common in males (10:1). Excellent prognosis and a conservative watch‐and‐wait approach is recommended. Morphology: Follicular growth, has a blastoid morphology with highly proliferative follicle centres Does not have BCL2, BCL6, IRF4 or Ig rearrangements. Does have MAP2K variants

Answer 152

GI Follicular lymphoma - Duodenal-type FL - Multiple polyps - Good prognosis Testicular Follicular lymphoma - Increased frequency in children - Lack BCL2 translocation - Good prognosis - Can be treated with surgery alone Diffuse-Appearing Follicular Lymphoma - Often large localised inguinal masses - Largely diffuse pattern - Low grade morphology - Lack BCL2 rearrangement - Have 1p36 deletion (not specific, can be seen in conventional FL)

Answer 153

Low grade but aggressive, often has bone marrow involvement 3-10% of NHL cases Prognosis is poor (2-5 years) Morphology: Small to medium-sized lymphoid cells with monomorphic appearance. Immunophenotype: CD5+, Cyclin D1+, CD19+, CD20+. IHC: overexpression of Cyclin D1 Molecular Abnormalities: t(11;14)(q13;q32) translocation involving IGH::CCND1.

Answer 154

Mantle Cell Lymphoma International Prognostic Index - morphology (blastoid/pleomorphic variant), immunophenotype, proliferative index (labeling of Ki67) and presence of TP53 deletions/mutations since the occurrence of one or more of these variables associated with a poor prognosis - TP53 mutations associated with resistance to chemotherapy

Answer 155

BTK inhibitors Venetoclax CD-19 directed CAR-T

Answer 156

Subtypes: Extranodal (MALT)- most common, Nodal, and Splenic. MALT is associated with chronic infections Morphology: Small B cells with marginal zone growth pattern. Immunophenotype: CD20+, CD79a+; usually CD5-, CD10-. Molecular Abnormalities: t(11;18)(q21;q21) BITC3::MALT1 associated with extra nodal. No recurrent assisted with nodal or splenic

Answer 157

Small B cell lymphoma, also called Waldenström macroglobulinemia (WM) when monoclonal IgM is present 1-2% of NHL Morphology: Bone marrow involvement by small lymphocytes, plasmacytoid lymphocytes, and plasma cells. Infiltration can be interstitial, nodular, or diffuse. Immunophenotype: CD19+, CD20+, CD38+, CD138+. CD5-, CD10-, CD23-, and Cyclin D1-, which helps differentiate LPL from other small B-cell lymphomas. Molecular: MYD88 L265P mutation is present in over 90% of cases. Also has some IgH rearrangements

Answer 158

Non-Hodgkin lymphomas (NHL) are the seventh most common type of cancer in the US, accounting for 4.3% of all newly diagnosed cancers. In 2021, the incidence rate of NHL in the US was estimated at 19.6 cases per 100,000 per year, 4.68 of which were DLBCL Incidence of different subtypes vary Usually affects those in 7th or 8th decade

Answer 159

Age Transformation from indolent condition e.g. CLL or follicular lymphoma Immundeficiency e.g, HIV or immunosuppressant treatment Chemicals such as pesticides

Answer 160

Highly agrressive and most common NHL (30-50%) Usually occurs in adults Can be further classified into WHO classifications e.g. DLBCL NOS, DLBCL/HGBL with MYC/BCL2

Answer 161

Can be de novo or develop from another entity e.g. CLL (richter transformation) or Follicular lymphoma CLL poor prognosis, candidate for stem cell transplant Follicular better prognosis

Answer 162

Presents with a rapidly enlarging tumour mass at a single or multiple nodal/extranodal sites. Some common sites for extranodal presentation include gastro-intestinal tract, bones, testes, spleen. CNS DLBCL: cognitive dysfunction and psychomotor slowing, headaches, and blurred vision/floaters Primary mediastinal (thymic) DLBCL (PMBL): mediastinal mass that may affect respiratory or cardiac systems, Primary cutaneous DLBCL – leg type (PCLBCL): red rapidly growing tumours on one or both of the lower legs

Answer 163

DLBCL can be classified by the cell of origin (when in B cell development did the lymphoma arise): Germinal Center B-cell-like (GCB) DLBCL - Cells were in a stage of active proliferation and somatic hypermutation. - Improved prognosis and respond better to R-CHOP regime - Often involves BCL2 rearrangements Activated B-cell-like (ABC) DLBCL - Cells were in are in a stage of differentiation towards plasma cells. - Poor prognosis and resistance to R-CHOP - Assocviated with activation of the NG-kB pathway which restricts apoptosis - Looking at targeted therapies

Answer 164

The Hans algorithm uses 3 markers to distinguish GC from non-GC subtypes: CD10, BCL6 & IRF4/MUM1. EzH2 SNVs or CNVs also used (included in test directory)- GC type

Answer 165

BCL2 BCL6 MYC (double or triple hit- not longer classified like this in WHO 2022)

Answer 166

Anti-apoptotic oncogene. Translocation t(14;18)(q32;q21), which juxtaposes the BCL2 gene with the immunoglobulin heavy chain (IGHV) gene enhancer (14q32), resulting in deregulated expression of BCL2. This translocation is more frequent in GC DLBCL (30 – 40%) than in ABC DLBCL, although it is more commonly duplicated or amplified in the latter.

Answer 167

BCL6 is a transcriptional repressor in cell cycle control, proliferation and differentiation, apoptosis, and DNA damage response. IGH::BCL6 t(3;14)(q27;q32) BCL6 translocation, leading to a loss of gene regulation, is found in up to 35% of DLBCL cases, and is believed to contribute to malignant transformation in germinal center-derived B cells (GCB).

Answer 168

C-MYC acts as a transcriptional regulator involved largely with cell cycle progression (from G1 to S phase) and the inhibition of terminal differentiation. Rearrangement of the C-MYC with IgH gene, or lambda (λ) and kappa (κ) light chain genes subsequently caused upregulation of gene expression, leading to resistance to apopotosis triggers. Such translocations are observed in 7-15% of de novo DLBCL and 8% of post-transformation DLBCL. Note that other translocations partners can be involved.

Answer 169

Biopsy Morphology: partial architecture effacement, with a diffuse proliferation of medium or large lymphoid cells. Immunophenotype: high Ki-67 proliferation index and expression of pan-B cells markers (CD19, CD20, CD79a & PAX5) Molecular: MYC, BCL2 and BCL6 FISH can also be used to aid diagnosis

Answer 170

Prognosis is determined using IPI. This usually includes 5 factors: - Age: ≤ or > 60 years - LDH: ≤ or > upper limit of normal range - Performance Status (ECOG) 0/1 or > 1 - Ann Arbor Stage: I/II (one or more sites, but same side of diaphragm) or III/IV (sites on both sides of the diaphragm and/or involvement of extra-lymphatic sites such as liver or bone marrow) - Number of extranodal sites 0/1 or > 1 This scoring system puts in risk groups and gives a 5 year survival COO classification and presence of double/triple hit also influence prognosis

Answer 171

Currently, monitoring is performed by imaging (CT/PET scan) after end of treatment. As risk of relapse is higher within the first 2 years, patients are monitored every 6 to 12 months during the first 5 years following end of treatment. ctDNA being monitored as part of clinical trials

Answer 172

R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. This regimen is generally given every three weeks for six cycles. This may be complemented by radiotherapy.

Answer 173

Relapse is relatively common, and usually occurs between 1 and 3 years after end-of treatment (~30%).

Answer 174

Second line therapy include immunochemotherapy, usually in combination with rituximab (anti-CD20) and bendmustine (alkylating agent). CAR-T (trials)

Answer 175

High grade, highly aggressive disease Rare in developed countries; more common in endemic areas (e.g., Africa). Associated with Epstein Barr virus (EBV) and HIV Previously subtyped as endemic, immunodeficiency-related, and sporadic but now classified as EBV+ and EBV- by WHO 2022

Answer 176

Patients often present with a rapidly growing mass, elevated lactate dehydrogenase (LDH), and increased uric acid levels because of the tumour’s rapid doubling time The primary site of sporadic BL is typically the abdomen

Answer 177

Morphology: increased apoptosis resulting in starry sky appearance due to macrophages containing cellular debris, monotomous cells with round nuclei Immunophenotype: CD10+, BCL6+, MYC+. Molecular: MYC translocations - most commonly t(8;14)(q24;q32) MYC::IGH. IGL and IGK are less common partners

Answer 178

The prognosis for adults is usually poorer than children, especially if they have bone marrow involvement (adults approx 50%, children as high as 90% survival).

Answer 179

BL and DLBCL can be indistinguishable and have different prognoses and different treatment regimes The WHO 2022 also now classifies these lymphomas based on molecular abnormalities

Answer 180

BCL6 is very variable and is not required for classification in WHO 2022. New category is DLBCL/High grade B lymphoma Triple hit - MYC, BCL2, BCL6 - Can be just MYC and BCL2 (+/- BCL6) - DLBCL/High grade B lymphoma Double Hit - MYC and BCL2 (DLBCL/High grade B lymphoma) - MYC and BCL6 (High grade B cell lymphoma NOS) - BCL2 and BCL6 (Diffuse large B cell lymphoma, NOS)

Answer 181

FISH - MYC, BCL2, BCL6 rearrangements - on FFPE and/or bone marrow or if involved If specifically Burkitt's then IGH::MYC Can also use IHC- less specific and does not confirm fusion partner

Answer 182

Previously known as Burkitt-like lymphoma with 11q Morphology is similar to burkitt lymphoma but without MYC rearrangement Characteristic chromosome 11q gain or loss Immunophenotype: CD10+, BCL6+, BCL2-

Answer 183

Clonality - Ig rearrangements to help diagnose IGH, MYC, BCL2 and BCL6 rearrangments - FISH, help classify EZH2 - NGS for SNVs and CNVs - help determine COO BTK, PLAG2 - NGS for SNVs - Resistance to BTK treatment MYD88 - Subtyping and poor prognosis

Answer 184

There are 36 recognised distinct T-cell and NK-cell subtypes. Within the WHO22 Edition, these subtypes are grouped together on the basis of site of presentation, the T-cell of origin or shared morphologic and immunophenotypical features. Divided into peripheral T-cell lymphomas - Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL-NOS) - Anaplastic Large Cell Lymphoma (ALCL) Cutaneous T-cell lymphomas - Mycosis fungoides and Sezary Syndrome 10-15% of NHLs

Answer 185

Enlarged lymph nodes, weight loss, night sweats, fever, itchy skin Patches of dry skin and red rash, mushroom-like tumours

Answer 186

Histology and IHC (pan T-cell marker CD3, CD5; and lineage specific – CD4, CD8, CD2, CD7) Clonality - TCR loci rearrangements using PCR or NGS to confirm clonal population - clonal T cells can be reactive so is not definitive

Answer 187

Most common T-cell lymphoma in children Morphology - Large cells with abundant cytoplasm and horseshoe shaped nuclei, CD30+ Consists of ALK positive - 10-15% - Most commonly ALK::NPM1 in 80% of cases - treatment with ALK TKIs And ALK negative - Rarer and seen in adults - DUSP22 rearrangements in 20-30%- better prognosis - TP63 rearrangements- chemorefractory

Answer 188

Epigenetic regulators (TET2, DNMT3A, IDH2) TCR signalling and activation and PIK3/protein kinase B pathways

Answer 189

STAT3 and STAT5B

Answer 190

Inversions and translocations involving the TCL1 family of genes Abnormalities in chromosome 8 and ATM is frequently disrupted. Up to 75% of patients harbour mutations in STAT5B, JAK1, JAK3. Complex karyotype (70%) poor prognosis.

Answer 191

Once clonality has been associated with the lymphoma, T-cell clonality – TCR gene rearrangement can be used to monitor and evaluate recurrence; detecting and assessing any residual disease.

Answer 192

Combination chemotherapy as initial treatment, CHOP, CHOEP, EPOCH Autologous stem cell transplants can also be considered as consolidation therapy.

Answer 193

Topical chemotherapy for cutaneous lymphomas + systemic if high grade - Small molecule inhibitors – JAK/STAT, SYK and P13K inhibitors - TKIs – crizotinib - Immunomodulatory – Lenalidomide - CAR-T - Monoclonal antibodies - Alemtuzmab

Answer 194

Most PTCL subtypes are associated with poor outcomes with conventional chemotherapy and consideration for clinical trial and HSCT should be given. Good outcomes for paediatric cases with ALCL

Answer 195

Multiple myeloma (MM) is a malignancy of terminally differentiated (post GC B cell) plasma cells (PC) and is the second most common haematological malignancy after non-Hodgkin lymphoma Characterised by the secretion of a monoclonal immunoglobulin protein (also known as M protein or monoclonal protein), which is produced by the abnormal PCs. The malignant PCs are primarily resident in the bone marrow (BM), but they can also be seen in the peripheral blood and other extramedullary sites, such as soft tissue and organs

Answer 196

Monoclonal Ig protein in the serum or urine CRAB Hypercalcaemia Renal insufficiency, Anaemia, and/or Bone disease with lytic lesions

Answer 197

Characterised by the infiltration of clonal PCs into the bone marrow (<10% clonal BM PCs) and the secretion of monoclonal protein (M-protein <30g/L). MGUS is completely asymptomatic and precedes the development of multiple myeloma. 20% of MGUS will develop in MM

Answer 198

Intervening stage between MGUS and MM

Answer 199

Rare and aggressive form of leukemia and plasma cell dyscrasia- can develop from MM PCL can be divided into primary PCL (PCL) and secondary PCL (sPCL) following previously diagnosed multiple myeloma (MM); the latter typically occurring at a late and advanced stage of MM. PCL is defined by at least 20% circulating plasma cells and a total plasma cell count in peripheral blood of at least 2 × 109/L.

Answer 200

PET/CT Blood and urine test - M protein (diagnostic marker in 97%). With evolving disease and de-differentiation of myeloma cells, M protein may decrease - Detect Ig heavy and light chains by serum protein electrophoresis Bone marrow - Morphology >10% - Flow CD138+, CD38-, CD45-, light chain restirction

Answer 201

MM is highly heterogeneous with some patients progressing rapidly, while others surviving more than 10 years. This clinical diversity is mainly driven by genetic changes. These alterations are important prognostic factors and can be divided into primary, disease-initiating abnormalities and secondary events, related to further progression of the disease.

Answer 202

Primary abnormalities occur early when the normal plasma cell transitions to a clonal, premalignant stage Most secondary abnormalities occur later in the disease course with malignant transformation or during progression of the malignancy.

Answer 203

Trisomies of odd number chromosomes (not 1, 13, 21)/ hyperdiploidy- 42% IgH translocation (30%) - CCND1 - FGFR3 - MAF - CCND3 IGH and trisomy Monosomy 14 Subgroups do not overlap- all mutually exclusive

Answer 204

Monosomy 13/del(13q) Del 17p/ Monosomy 17 del 1p (CDKN2C) Gain of 1q

Answer 205

Multi-target NGS panel - small variant (KRAS, NRAS, BRAF, TP53, DIS3, FAM46C, IRF4) IGH-FGFR3, IDH-CCND3, IGH-CCND1, IGH-MAF, IGH-MAFB, IGH rearrangement FISH FISH Hyperdiploidy copy number FISH del(1p), gain(1q), del(17p) TP53 copy number FISH

Answer 206

MACS for CD18+ positive cells - sort cells to only have plasma cells as there can be as little as 2% in bone marrow due to patchy disease

Answer 207

Prognostic scoring for MM Integrates the presence of high-risk cytogenetic abnormalities [t(4;14), t(14;16), and del17p determined by interphase FISH and serum lactate dehydrogenase (LDH) levels i

Answer 208

Adverse IGH translocations: t(4;14) + t(14;16) + t(14;20) (~15% of patients) 1q gain (usually assessed by the number of copies of the CKS1B gene at 1q21) TP53 loss (17p13 deletion). The presence of a biallelic inactivation (i.e. by an additional mutation) of TP53 may particularly shorten overall survival, but at present TP53 mutation rarely requested in routine testing 1p32.3 (CDKN2C) loss, but the association of CDKN2C loss and poor outcome is confined to patients in receipt of intensive treatment/bone marrow transplantation

Answer 209

FISH - most common and recommended by R-ISS - Limited to specific targets SNP arrays - Select LOH and multiple abnormalities - requires 15-20% more plasma cells - Can't detect balanced translocations RQ-PCR - identify IGH translocations NGS - Being developed to detect structural, CNVs and SNVs

Answer 210

Absence of serum and urine M-protein, absence of any soft tissue plasmacytomas and <5% PC in the BM MRD by flow cytometry to detect malignant PC and discriminate aberrantly expressed cell surface markers Imaging with PET/CT RQ-PCR of IGH rearrangements but is not widely available

Answer 211

VRD regime Patients initially receive a combination of a proteasome inhibitor (usually bortezomib) and an immunomodulatory agent (commonly lenalidomide) along with dexamethasone. Autologous and allogenic stem cell transplant ASCT is still the most common standard of care

Answer 212

Almost all patients who initially respond to treatment will eventually relapse. Triplet therapy, Bi-specific and CAR-T cell are common types of regimes used for relapsed patients.

Answer 213

NICE guidelines International Myeloma Working group Best practise BMJ

Answer 214

Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias Can be acquired or inherited Can lead to progression to MDS/AML Aplastic anaemia is the most common form

Answer 215

Aplastic anaemia is a rare and heterogeneous disorder. It is defined as pancytopenia with a hypocellular bone marrow (BM) in the absence of an abnormal infiltrate or marrow fibrosis.

Answer 216

The incidence is 2–3 per million per year in Europe, but higher in East Asia.

Answer 217

Radiation and chemotherapy Exposure to toxic chemicals such as pesticides Drugs to treat rheumatoid arthritis and some antibiotics Autoimmune disorders Viral: hepatitis, EBV and HIV. Pregnancy (rarely)

Answer 218

Anaemia and thrombocytopenia. Serious infection occasionaly Peaks at 10-25 years and again at 60

Answer 219

Diagnosis of exclusion so requires testing for testing for other etiology 1. Exclude other causes of pancytopenia and hypocellular bone marrow e.g. MDS, lymphoma, B12/folate deficiency 2. Exclude inherited failure syndrome 3. Screen for underlying cause 4. Document coexisting abnormal cytogenetic cones Take BM aspirate and blood - full blood count (PB haemoglobin concentration (Hb) <100 g/L, and/or PB platelet count <50 × 109/L and/or PB neutrophil count <1.5 × 109/L. - reticulocyte count (young ref blood cells) - hypocellular bone marrow - Rule out viral infections and autoimmune diseases

Answer 220

Camitta criteria Severe AA - Marrow cellularity <25% - PB neutrophil count <0.5 x109/L - BP platelet count <20 x109/L Very severe AA - <0.2 x 109/L Non-severe AA - Not fulfilling above criteria

Answer 221

Dysregulated immune system (viral infection is the major driver of aAA) leading to autoreactive T cell destruction of hematopoietic stem and progenitor cells (HSPC) An antigen is presented to a cytotoxic T cell (CD8+-CTL) via a Class 1 HLA molecule, and autoreactive T cells are activated then begin to expand. T cells release cytokines including TNF-α and INF-γ, which have direct apoptotic effects on the HPSC, ultimately resulting in bone marrow failure

Answer 222

Cytogenetic aberrations have been described in 5-15% of adult patients with severe aplastic anemia (SAA), and these patients were generally younger than patients with normal karyotype: LOH6p Trisomy 8 7q deletion Monosomy 7 Trisomy 6 13q deletion Increases risk of leukaemic transformation

Answer 223

BCOR BCORL1 DNMT3A PIGA ASXL1 ASXL1, DNMT3A and RUNX1 are associated with cloncal evolution and increased risk of transformation to MDS/AML and show poorer response to immunosuppressive therapy

Answer 224

Blood transfusions Many patients do not undergo treatment but if become dependent on transfusions or have other symptoms: - Immunosuppressive therapy (ATG with CSA)- suppresses T cells - Eltrombopag (TPO receptor agonist) - stimulates more platelets - Haematopoietic stem cell transplantation (HSCT)

Answer 225

Five-year survival is >75% for patients who undergo bone marrow transplant from a suitable donor Approximately 10% of patients with AA will later develop MDS or AML, and as many as 25% will develop PNH

Answer 226

BSH guidelines SNP arrays for copy number testing - important to help distinguish between AA and MDS- doesn't exclude

Answer 227

Bone marrow failure syndrome clinically characterized by acquired hemolytic anemia and thrombosis. Cells have mutation in PIGA gene. PIGA-mutated cells have defective cell surface expression of GPI)- anchored proteins including CD55 and CD59, making them vulnerable to complement mediated hemolysis.

Answer 228

Pure red cell aplasia (PRCA) is a rare disorder that designates anaemia secondary to failure of erythropoiesis. PRCA is characterized by an isolated normocytic anaemia with severe reticulocytopenia in the peripheral blood, and defined by absence or near absence of erythroid precursors in the bone marrow (erythroid hypoplasia).

Answer 229

There are no specific signs or symptoms associated with PRCA The most common presentation is the same as that of anaemia. Generalized fatigue, decreased exercise tolerance, palpitations, and in extreme cases, presyncope or syncope

Answer 230

Diamond - Blackfan anaemia

Answer 231

Primary PRCA may be an autoimmune disorder resulting from an IgG inhibitor of erythropoiesis or it may be a clonal disorder most closely resembling MDS. The frequency of leukemic transformation in primary PRCA is less than 1%. Secondary PRCA describes cases of PRCA associated with a wide array of autoimmune/ inflammatory, infectious, or neoplastic disorders In many cases the underlying mechanism is immunologic but generally not mediated by an antibody.

Answer 232

Parvovirus B19 infection - member of the erythroviruses - Very common virus - The virus invades and destroys red cell progenitors, and the aplasia is terminated when neutralizing antibodies develop - If immunocompromised, leads to a persistent infection that is toxic to the erythroid progenitor cells and leads to chronic red cell aplasi

Answer 233

Drug-induced PRCA represents an acute and generally reversible form of isolated erythroid aplasia.At least 50 drugs and chemicals have been associated with PRCA - Diphenylhydantoin - Rifampicin - rhEPO - Azathioprine - Isoniazid

Answer 234

Blood count - reticulocytes <1% Bone marrow - absence of erythroblasts Cytogenetics -abnormal may suggest MDS Parvovirus - B19 parovirus testing

Answer 235

Treatment of B19 parvovirus-associated PRCA Intravenous immunoglobulin (IVIG), which contains a large amount of anti–HPV-B19 IgG, is the treatment of choice for HPV-B19 PRCA. Treatment of drugs induced PRCA Recovery of erythropoiesis usually occurs shortly after discontinuation of the offending medication

Answer 236

Rare, life-threatening conditions characterized by overstimulation of the immune system (lymphocytes and macrophages) leading to systemic inflammation, hypercytokinemia and multi-organ failure. Caused by EBV infection Can also be familial

Answer 237

HLH is characterized by fever, hepatosplenomegaly, bicytopenia or pancytopenia, hemophagocytosis in the BM and lymphoid tissues, liver dysfunction and central nervous system (CNS) symptoms. Clinical manifestations of HLH are mainly a result of tissue infiltration by T cells and macrophages and the accompanying excessive cytokine storm.

Answer 238

Autosomal recessive disease caused by mutations in PRF, UNC12D, STX11, STXBP2

Answer 239

Associated with viral, bacterial infections, malignancy and autoimmune diseases

Answer 240

Receiving hematopoietic stem cells to replace ablated malignant cells This is often the only cure for haem malignancies Can be allogenic or autologous

Answer 241

Less intensive chemotherapy regime where not all host bone marrow is ablated prior to transplant- good for patients who cannot withstand intense chemo This reduces graft vs host disease (GvHD) and increases graft vs leukaemia (GvL) GvL is mediated by T cell which attacks leukaemia cells so patients can have T cell top ups

Answer 242

PBSC collected by Apheresis . Donor given G-CSF for 4-5 days prior to donation to mobilise stem cell Advantages - Easier and safer for the donor (Apheresis) - More rapid and efficient engraftment achieved (due to increased mature T-cell component which facilitates engraftment) - increased graft versus tumour affect Disadvantages - Chronic graft versus host disease is more of a problem

Answer 243

Preferred in children due to the reduced long term GvHD Children usually have myeloablative BMT (less risk of relapse (T-cell GvL effect less important)) Children tolerate infectious complications where immune reconstitution is delayed

Answer 244

HLA class I molecules display peptides that result from the degradation of cytosolic proteins to the cell surface where they can be recognized by the CD8+T cells

Answer 245

HLA class II molecules display peptides that result from the degradation of endocytosed proteins to the cell surface where they can be recognized by the CD4+ T cells

Answer 246

HLA matching - Human leukocyte antigens (HLA) are genes in major histocompatibility complexes (MHC) that help code for proteins that differentiate between self and non-self CMV status - Preference is to transplant CMV positive graft to CMV positive recipient and CMV negative graft to CMV negative recipient Blood type - A, B, O - Delayed erythrocyte engraftment and pure red cell aplasia Gender - increased risk of GvHD Age - T cell decrease quality

Answer 247

HLA Matched sibling/ unrelated matched - 7/8 (ideally 8) HLA required for Haplo donor - 4/8 from a first degree relative who shares at least one full haplotype with the recipient (one of the two high density HLA antigens match) Umbilical cord blood - HLA matching less stringent (due to low immunogenicity of the CB T-cells) - 4/6 of HLA A, B and DRB1 is sufficient

Answer 248

Looks at i) Risk of Non-BMT related mortality (dependent on the patients health and co-morbidities) Vs ii) Risk of disease relapse The HCT-CI scores co-morbidities (0-3) to assist the decision of whether to transplant or not Examples include: 1) Arrythmia (1) 2) Diabetes (1) 3) Moderate/severe renal (2) 4) Moderate pulmonary (2) 5) Prior malignancy (3) 6) Heart valve disease (3)

Answer 249

Mix of host and donor cell types after a stem cell transplant, can be monitored by microsatellite analysis to determine graft effect If the % chimerism decreases it may suggest the graft is failing Also measure the % of T cells- mediate GvL effect- can be given a top up of T cells

Answer 250

Amplification of 16 short tandem repeat (STR) using semi-quantitative multiplex PCR DNA to generate a genetic profile for the pre-transplant patient and donor Preliminary assessment of STRs unique to the Donor and patient is carried out in an initial analysis The informative alleles are subsequently used to quantify the cells present in the post-HSCT sample Sensitivity around 1%

Answer 251

T-cell inhibition - Cyclosporin and methotrexate primarily used as effective prophylaxis of acute GvHD (less effective in controling chronic GvHD) T-cell depletion - Positive selection of CD34+ cells is the most common method Essential in 2nd donor transplants as GvHD Post-transplantation cyclophosphamide (PTCy) in Haplo HSCT - PTCyis often used to prevent GVHD, especially in patients who have undergone haplo-identical transplantation - PTCy effectively eradicates allo-reactive T cells after haplo-identical stem cell infusion, but hematopoietic stem cells are spared

Answer 252

Activated T cells have been associated with reduced capacity for GVHD after adoptive transfer. Several different approaches using either anti-CD3/CD28 or anti-CD3 and IL-2 with interferon-γ termed cytokine induced killer (CIK) cells have resulted in expansion of T cells with antitumor properties yet have limited GVHD capacity. After expansion, CIK cells have antitumor capabilities primarily through NKG2D-mediated mechanisms, as well as other cytolytic functional receptor ligand interactions.

Answer 253

CAR-T cells are the subject of intense investigation as a strategy of a bridge to transplant or instead of transplantation. These cells have been used in a small number of patients from bone marrow donors and shown to have limited capacity for GVHD induction but exert an antitumor effect.

Haematological Malignancies Flashcards

(278 cards)