JC42 (Medicine) - Leukaemia, Bone Marrow Transplant, Immunogenetics Flashcards

Question

Clinical presentation of AML 2 Complications

Answer 1

**General fatigue** **S/S of BM failure:** profound anaemia, thrombocytopaenia, neutropenia **DIC** in promyelocytic vatiant (APML) **Gum hypertrophy/infiltration + skin + CNS involvement** in myelomonocytic and monocytic subtypes **Fever**: infection Complications: **Neutropenic fever**: infection due to neutropenia **Leukostasis**: due to very high blast count \>300 >>> **respiratory symptoms** (SOB, hypoxia), **neurological** (visual changes, headache, dizziness, tinnitus...)

Answer 2

CBC NcNc anaemia and thrombocytopaenia Leukocytosis or leukopenia PBS **Circulating myeloblast ± Auer rods**

Answer 3

Marrow **Hypercellular** with replacement by **myeloid blasts** Cytochemistry **Myeloperoxidase +ve** (dark staining), **Sudan Black B +ve** Immuno- phenotyping Flow cytometry: expression of **CD34, HLA-DR, CD117, CD13, CD33** (varies with AML subtypes) Cytogenetics - t(8;21)(q22;q22) + **RUNX1-RUNX1T1** - inv(16)(p13.1q22) or t(16; 16)(p13.1;q22) + **CBFB-MYH11** - t(15;17)(q24.1;q21.1) + **PML-RARA** (diagnostic of APL) Molecular genetics Eg. FLT3 mutation → predicts prognosis

Answer 4

1 of: → ≥20% blast in peripheral blood or BM aspirate → AML-defining genetic abnormalities - t(8;21)(q22;q22) + RUNX1-RUNX1T1 - inv(16)(p13.1q22) or t(16; 16)(p13.1;q22) + CBFB-MYH11 - t(15;17)(q24.1;q21.1) + PML-RARA (diagnostic of APL) → Myeloid sarcoma PLUS demonstration of myeloid lineage in leukaemic cells

Answer 5

**MDS, MDS/MPN**: blast count may be marginal (i.e. approaching 20%) **ALL**: some ALL cells may co-express myeloid markers or even be mixed phenotype acute leukaemia **Vitamin B12¸folate deficiency**: pancytopenia, mimic erythroleukaemia **CML in blastic crisis**

Answer 6

1. **Induction phase**: intensive therapy aiming for complete remission * **7+3 regimen: 7d cytarabine infusion + 3d IV Daunorubicin** * Add targeted therapy e.g. FLT3 inhibitor Midostaurin for FLT3 mutant 2. **Consolidation phase** * High dose **cytarabine** (IDAC) 3. **Salvage phase:** for refractory or relapse * FLAG-IDA = fludarabine + cytarabine + idarubicin * MEC = mitoxantrone + etoposide + cytarabine * **Allogeneic HSCT**

Answer 7

Acute promyelocytic leukaemia: biologically and clinically distinct variant of AML □ Characterized by **t(15;17)(q24.1;q21.2);PML-RARA** Clinical features: **S/S of BM failure** (profound anaemia, thrombocytopaenia, neutropenia), **DIC-related coagulopathy**: severe bleeding, thrombotic complications

Answer 8

Peripheral blood: **leukopenia** Circulating malignant promyelocytes: → Morphology: **violet granules ± bundles of Auer rods ('faggot cells')** → Immunophenotype: **MPO+, CD13+, CD33+** → Genetics: **t(15;17)(q24.1;q21.2);PML-RARA**

Answer 9

Induction therapy: → **All-trans retinoic acid (ATRA) + arsenic trioxide (ATO)** for low risk or + conventional chemo (cytarabine + daunorubicin) for high risk Supportive care: → Coagulopathy: **platelet + FFP transfusion** → Differentiation syndrome: **dexamethasone** as prophylaxis Consolidation therapy: → ATO + ATRA or Anthracycline + ATRA

Answer 10

□ All-trans retinoic acid (ATRA): induces differentiation and apoptosis of leukemic cells → Usu in combination w/ chemo (anthracycline eg daunorubicin, ± cytarabine) for induction therapy □ Arsenic trioxide (ATO): induces apoptosis of leukemic cells → Can be used in induction, maintenance, and relapsed cases

Answer 11

most common cancer (~25%) in children, most at 2-5y/o RFs: majority idiopathic, genetic factors Types: - precursor lymphocytes of **B, T or NK lineage** :**B-ALL, T-ALL, NK-ALL** - **Lymphoblastic lymphoma (LBL)**when presenting with lymphatic tissue involvement

Answer 12

Constitutional symptoms: fever, weight loss, night sweats **S/S of marrow failure:** anaemia, neutropenia, thrombocytopenia **Hepatosplenomegaly**and **lymphadenopathy** **S/S of organ infiltration:** important → Bone marrow: bone tenderness → CNS: meningism, headache, N/V → Testis: painless testicular enlargement → Mediastinum mass (esp. T-ALL): SVCO, upper airway obstruction

Answer 13

CBC: NcNc anaemia (of variable severity) and thrombocytopaenia WBC: Variable lymphoblasts PBS **Circulating lymphoblast**: Large, heterogenous basophilic cytoplasm (NO granules, vacuolation, Auer rods) Marrow and tissue section **Hypercellular marrow infiltrate with lymphoblasts** Cytochemistry **Myeloperoxidase –ve** (lineage-defining) Phenotyping Flow cytometry: expression of **B, T, NK cell lineage markers**, Terminal deoxynucleotidyl transferase **(TdT) expression** Cytogenetics and Molecular genetics for Prognosis and Classification only (not diagnostic)

Answer 14

presence of **lymphoblasts >20% in peripheral blood, BM or involved tissue** diagnostic morphology and immunophenotype demonstrating** lymphoid lineage**

Answer 15

AML Burkitt Lymphoma Other lymphoproliferative disorders Reactive lymphocytosis

Answer 16

Induction phase: - Combination chemotherapy: **vincristine + steroid + anthracycline** ± rituximab for CD20+ ALL, BCR-ABL1 TKI for Ph+ ALL - **CNS prophylaxis: Methotrexate or cranial irradiation** Consolidation therapy: * Low risk: **Consolidation chemotherapy ± TKI** * Intermediate risk: **Autologous HSCT** * High risk: **Allogeneic HSCT** Maintenance therapy * TKI monotherapy for Ph+ ALL * Maintenance chemotherapy for Ph- ALL: MTX, 6MPO, Vincristine, steroid

Answer 17

Epidemiology: 15-20% of leukaemias in adults RF: exposure to ionizing radiation Pathogenesis: considered a type of MPN, defined by **BCR-ABL1 fusion gene due to Philadelphia chromosome (t(9;22))**

Answer 18

Asymptomatic, non specific Constitutional symptoms: LOW, LOA, night sweats **Anaemia** and platelet dysfunction (usu. **Thrombocytosis**) **Massive splenomegaly**→ early satiety and LUQ pain

Answer 19

**Chronic** phase (3-4y): relatively indolent disease with minimal symptoms **Acceleration** phase (18mo): 10-19% blasts in PBS/BM, basophils ≥20%, PLT \<100 or \>1000, progressive splenomegaly **Blastic** crisis (1-2mo): acute leukaemia-like picture with \>20% blast

Answer 20

CBC - **Bimodal distribution of neutrophil and myelocyte: Basophilia, monocytosis and eosinophilia** - NcNc **anaemia** (45-60%), - PLT normal or **thrombocytosis** PBS: Morphologically normal leukemic cells Marrow - Morphology: **granulocytic hyperplasia, dwarf megakaryocytes with hypolobulated nuclei** - Cytochemistry **Low leukocyte alkaline phosphatase (LAP) score** - Cytogenetics **Ph chromosome t(9;22) on karyotyping (90-95% +ve), BCR-ABL1 fusion gene on FISH**

Answer 21

Leukaemoid reaction to infection (should have ↑LAP score, toxic granulation) Other chronic myeloid neoplasm: MDS, MPN, MDS/MPN 'Atypical CML': so-called BCR-ABL1-negative CML Other Ph-positive malignancies: minority of ALL, AML

Answer 22

Chronic phase:** BCR-ABL TKI inhibitor** → **Imatinib** [1G] for low-risk, **nilotinib/ desatinib **[2G] for high-risk Accelerated phase: induction **TKI + HSCT** Blastic phase: → Lymphoid crisis: treat as Ph+ ALL → Myeloid crisis: induction TKI + HSCT

Answer 23

Pathogenesis: arise from progression from monoclonal B cell lymphocytosis (common in elderly) □ Consist of clonal B cells arrested in some stage between pre-B and mature B cells with arrested apoptotic mechanisms → accumulation in blood and lymphoid tissues Can also originate from relatively mature B lymphocytes → CLL if cytopenia due to BM infiltration → SLL if LN, splenic or other extramedullary involvement

Answer 24

Asymptomatic (\>80%): **absolute lymphocytosis** Non-specific **B symptoms **(5-10%): → Unintentional weight loss → Fever: \>38oC for ≥2w w/o evidence of infection → Drenching night sweats w/o evidence of infection → Extreme fatigue **Generalized lymphadenopathy** (50-90%): esp. cervical, supraclavicular, axillary **Mild hepatomegaly/ splenomegaly/ both** Skin infiltration: esp at face

Answer 25

Immunodeficiency: cell-mediated + humoral immunity impaired due to lymphocyte dysfunction Anaemia: due to AIHA, marrow infiltration or hypersplenism Thrombocytopenia: due to ITP, marrow infiltration or hypersplenism

Answer 26

CBC * **Clonal Lymphocytosis**: >5×109/L B lymphocyte count * Cytopenia for any lineage Ig Tests: * **Hypogammaglobulinaemia **(~25%): usually all three Ig classes *** High LDH and b2-microglobulin** BM exam: * Lymphocyte infiltration, **Richter's transformation to large cell lymphoma**

Answer 27

Infectious causes of lymphocytosis (non-clonal, under 3 months) Other chronic lymphoproliferative diseases: * Prolymphocytic leukaemia * Mantle cell lymphoma * Lymphoplasmacytic lymphoma * Hairy cell leukaemia * Follicular lymphoma

Answer 28

Watchful waiting if asymptomatic or very old - Targeted therapy: **Ibrutinib, Acalabrutinib**: inactivation of BTK protein leading to B cell apoptosis - **Fludarabine-based regimen for young patients** >> Fludarabine, cyclophosphamide, rituximab - **Chlorambucil-based for old patients** >> chlorambucil ± rituximab **HSCT: as salvage therapy** in selected young patients

Answer 29

Neutropenic Fever Septic shock Tumor lysis syndrome Hyperleukocytosis and Leukostasis DIC in APL

Answer 30

**Neutropenia: ANC ≤1×10⁹/L** Fever: pyrexia \>38.3oC Pathogenesis: - **Neutropenia**: caused by malignant infiltration of marrow or Chemotherapy - **Infection of GI, aero-digestive tract, skin **(from catheter) → G+ bacteria: use of indwelling catheters → G- bacilli: commonest, eg. Pseudomonas aeruginosa → Fungal: prolonged neutropenia → Others: viral reactivation (eg. Hep B, HSV), TB

Answer 31

Clinical features: subtle due to diminished inflammatory repsonse □ **Fever**: often the only presenting sign □ **Localizing S/S** to GI, Skin, Respiratory tract Workup: □ Assess localizing S/S for infection, sepsis and shock **Broad septic workup:** blood, sputum, urine culture and sensitivity testing CXR ± other specimens (eg. LP)

Answer 32

**IV Empirical, broad-spectrum Abx** low-risk, i.e. neutropenia ≤7d + no or few other comorbidities - **Ciprofloxacin+ augmentin/ levofloxacin** high-risk, i.e. ANC ≤0.1 for \>7d, shock, pneumonia, newly onset abdominal pain or CNS signs **- 3/4G cephalosporins: Ceftazidime or Cefepime** - **Tazocin** or sulperazon **- Imipenem or meropenem** (+/- Aminoglycoside, Vancomycin, Amphotericin B if needed) No response: **G-CSF** **Buffy coat (WBC) transfusion** Fluid resuscitation, inotropes

Answer 33

lysis of tumors cells from rapidly proliferating (and drug-sensitive) neoplasm Causes: * After cytotoxic chemotherapy * spontaneously (auto-TLS) * High grade neoplasm with high tumor burden Result: **PAN-HIGH except calcium** → HyperK, hyperPO4, hyperuricaemia, High LDH → Metabolic acidosis (lactate) S/S → HypoCa: **confusion, arrhythmia, tetany, seizure, sensory loss (CATS)** → **AKI** (uric acid nephropathy and acute nephrocalcinosis)

Answer 34

Tx: **Aggressive hydration** Correction of hyperK + ECG monitoring **Rasburicase (recombinant urate oxidate)** **allopurinol/febuxostat (xanthine oxidase inhibitor)** **Renal replacement therapy/ Hemodialysis**

Answer 35

□ Hyperleukocytosis: very high WBC □ Leukostasis: very high blast cell count causing stasis in microcirculations, decrease tissue perfusion Cause: leukemias with large, poorly deformable blasts Pathophysiology: □ Blast cells are less deformable than mature cells → plugs in microcirculation □ High metabolic activity with cytokine production → endothelial damage

Answer 36

S/S: □ **Neurology:** headache, dizziness, tinnitus, gait instability, confusion, coma □ **Pulmonary** (~30%): dyspnoea, hypoxia ± diffuse interstitial/alveolar infiltrates on CXR □ CRV thrombosis: **acute blindness** □ **MI, AKI, priapism, acute limb ischaemia, ischaemic bowel** Mx: □ **Urgent Cytoreduction:** **induction chemotherapy, hydroxyurea or leukapheresis** □ **hydration**: to prevent TLS

Answer 37

Haematological malignancies: * AML/ALL/ CML/ CLL * MDS/ MPN * Lymphoma Non-haematological: * Neuroblastoma Non-malignant marrow disorders: * Severe aplastic anemia - Fanconi, Blackfan-Diamond, Wiskott-Aldrich * Congenital BM failure * Severe haemaglobinopathies: Sickle cell anemia, Thal. major * Primary immunodeficiency - SCID * IEM

Answer 38

Disorders that do not primarily involve haemopoietic stem cells:  Multiple myeloma (MM)  Waldenström macrogloblinemia  Lymphoma  Amyloidosis  Testicular germ cell tumour

Answer 39

1. Eradicate leukaemia cells with **high dose chemotherapy and radiotherapy** 2. **Replace diseased BM** with healthy marrow from normal donor 3. **Graft versus Leukaemia effect**

Answer 40

**Human leukocyte antigen (HLA) matching**: Determines risk of graft-versus-host disease in HSCT * **Syngeneic**: from MZ twin → by definition 12/12 matched, no GVHD * **Matched sibling donor (allogeneic):** 6/6 matched (HLA-A, -B, -DR) * **Matched unrelated donors:** 8/8 matched (HLA-A, -B, -C, -DR) * **Mismatched related donors:** \<6/6 matched, * **Single antigen mismatched siblings** (5/6) or **Haploidentical donors** (3/6) unrelated donors from *HK BM Donor Registry pool* Haploidentical donor - from ANY sibling, parent, child ± other relatives ABO incompatibility doesn't matter

Answer 41

Chemo causing Cytopenia: * Hemorrage, Anaemia * Neutropenic infection/ sepsis * mucositis * Veno-occlusive disease (VOD) of liver HSCT: * **Graft rejection (host-versus-graft)** * **Acute graft-versus-host disease (acute GVDH)**

Answer 42

**Cardiovascular disease from cardiotoxic drug** - main death cause From long-term immunosuppression: **Endocrine dysfunction**: T2DM, hypothyroidism, hypogonadism and Infertility, Osteoporosis **Second malignancy:** relapse, PTLD, Post-treatment MDS, Acute leukemia, Solid tumors **Cataracts** from irradiation **Chronic GVHD**

Answer 43

Allogeneic HSCT: * **Donor HSC** (related or unrelated) harvested \> **Conditioning myeloablative therapy** \> **donor HSC infusion** to rescue from marrow aplasia * Graft-versus-leukemia (GvL) effect * Immunosuppression against Graft-versus-host-disease (GVHD) Autologous HSCT: * **Own HSC **harvested and cryopreserved \> Conditioning myeloablative therapy \>** re-infusion of autologous HSC** to rescue from marrow aplasia

Answer 44

**Bone marrow harvest:** * aspirated from posterior iliac crests under regional/general anaesthesia **Peripheral blood progenitor cell (PBPC):** * G-CSF 3 days prior to harvest → mobilize BM HSC into peripheral blood (1000×) * peripheral blood for apheresis to isolate PBPC **Umbilical cord blood (UCB):** * esp for children due to small volume

Answer 45

Indication: Before HSCT Function: High dose Chemotherapy +/- radiotherapy * Eradicate malignancy/ residual leukemia * Immunosuppression for engraftment, prevent graft rejection Drugs: * Cyclophosphamide * Busulfan * Fludarabine Radiation: Total Body Irradiation

Answer 46

## Footnote Location: **major histocompatibility complex (MHC) locus at 6p** Function: peptide-binding to **present antigens to and activates T cells** □ **MHC class I:** includes HLA-A, -B, -C → Expressed on **all nucleated cells** → Binds CD8+ T cells to activate cell-mediated immunity → Generally determines **risk of graft rejection** □ **MHC class II:** includes HLA-DP, -DQ, -DR → Expressed on professional **antigen-presenting cells** → Binds CD4+ T cells to activate humoral immunity → Generally determines **risk of graft-versus-host disease** □ Role in transplantation: → Determines **risk of graft rejection in solid organ transplant** → matching is preferred but can theoretically be overcome by immunosuppressant use → Determines **risk of graft-versus-host disease in HSCT** → matching is critical

Answer 47

Pathogenesis: * donor T cell recognize host cells (HLA) as foreign → graft-vs-host reaction * \>\>\> inflammatory T cell infiltrate with tissue destruction and apoptosis S/S: 1. Skin rash (pruritic/painful erythematous MP rash becoming confluent ± bullous TEN-like lesions) 2. Gastrointestinal symptoms: Diarrhea, Abdominal pain 3. Liver disease: painful hepatomegaly, obstructive jaundice S/S Treatment: * immunosuppression (CNI + MTX/MMF) ± T cell depletion (ATG) * Topical steroids/ Tacrolimus/ Anti-histamines * IV or oral steroid if GI symptoms * Immunosuppressants (MMF, Sirolimus, Etanercept) or steroids

Answer 48

defined as symptoms develop \>100d of HSCT Pathogenesis: * donor T cell recognize host cells (HLA) as foreign → graft-vs-host reaction * → early inflammation with tissue injury progressing to fibrosis without much infiltrate in late stages S/S: * Skin rash (Lichen planus-like, Sclerotic, asso. nail dystrophy, scarring/non-scarring alopecia…) * Mucositis: Ocular, Oral, GI at esophagus and bowels, Genital * Liver: deranged LFT * Lung: Bronchiolitis obliterans * MSS: fasciitis, myositis Treatment: * Local treatment if mild disease only, eg. oral hygiene, topical steroids, endoscopic dilation, O2 * Systemic treatment if moderate/severe disease \>\> Prednisone ± CNI