2nd part of haem (-CLL)

Acute lymphoblastic leaukaemia facts and types

• most common childhood malignancy

• relapse leasing cause of death

• risk genes

• 2 types : B-ALL and T-ALL

B-ALL vs T-ALL (3)

• B-ALL more common (85-90%) vs T-ALL (10 - 15%)

• T-ALL more aggressive w high wbc, mediastinal mass and cns involvement

• B-ALL increased risk from philadelphia chr, bcr::abl1 t(9;22), kmt2a rearraged

• T-ALL usually notch 1/fbxw7 pathway or pten/ras mutation

ALL clinical presentation

1. Bone Marrow failure : Anaemia, neutropaenia, pancytopaenia

2. extramedullary infiltration : hepatosplenomegaly, lymphadenopathy, CNS involvement (esp t-all)

Diagnosis of ALL(5)

bone marrow aspiration and trephine biopsy to check

• morphology : blast percentage

• immunophenotyping : cd 19, cd 10, cd3

• cytogenetics and molecular: karyotype, fish for fusion gene testing

Measurable residual disease by flow cytometry or molecular testing for prognosis

ALL tretament (3)

• chemotherapy + mtx

• blinatumomab / cart cell therapy

• stem cell transplant

Acute myeloid therapy facts

• less often (15%) but need more intensive therapy

• often relapse

• usually due to kmt2a rearrangement (11q23) but alsonpm1 mutation and flt3-itd

AML diagnosis and prognosis

• cytogenetics

• wbc

• french american british classification

• flow cytometric mrd for prognosis (even intermediate risk should be considered high)

AML possible treatment

• anthracycline (cardiotoxic) + cytarabine

• targeted rherapies : fly3 inhibitors, cd33 antibody -drug conjugate

Infabt All

• More aggresive w more wbc, extramdeullary disease vs children

• 75% carry kmt2a rearrangement (fuse with other)

• tx w blinatumomab + chemo

Down syndrome associated leukaemia + steps (4)

• children w trisomy 21 increased leakaemia, x30 or up to x500

3 step

1. trisomy 21 in fetal liver haematopoietic stem cells

2. acquired gata 1 mutation → tl-ds

3. additional oncogenic effects

• self limiting but need close monitoring

• sensitive to cytabrine → treatment toxicity

Clinical practice safety measures

• FHx : early onset leukaemia, generations affected, bm failure

• HSCT donor selection : dont use sibling w same germline mutation as donor

• treatment avoidance : avoid alkylating agents, chemo , radiotherapy

• genetic counselling

Myeloid neoplasm types (3)

• myeloproliferative neoplasms : increased terminally differentiated myeloid cells

• myelodysplastic neoplasms : maturation defect assoc w cytopaenias

• Acute myeloid leukaemias : maturation defect + increased proliferation →accumulate immature myeloid cells

MPN subtypes (4)

• CML : BCR-ABL

• Polycythaemia Vera

• Essential thrombocytopaenia

• primary myelofibrosis

Gain of function clonal mutation in MPNs

• Tyr Kinase : BCR-ABL1 / JAK2

• Cytokine receptors : MPL

• Chaperone, Ca2+ binding : CALR (calreticulin)

jak2 and CALR

• Jak2 : JAKSTAT pathway for functional haematopoiesis in response to cytokines

• CALR: act as chaperone of folding proteins, mutations in CALR cause activation of mutant megakaryocytes

Polycythaemia vera what and clinical features (4)

• increase Hct and Hb and RBC mass → sludging

• Hyperviscosity blood cause impaired o2 delivery, causing

headache, dizziness, vertigo, tinnitus, visual disturbances

• HTN, erythromelalgia (periodic flare ups)

• aquagenic pruritis (worsens after mass due to histamine release)

• plethora, ruddy cyanosis

Polycythaemia vera complications

• thrombosis affecting:-

1. Arterial : MI, ischaemic stroke, TIA

2. Venous : DVT, bowel infarction (portal and mesenteric vein )

3. microvascular : neurological sx, erythromyalgia causing ischaemic necrosis

• Bleeding : high turnover causing hyperuricasmia (+ 2. gout)

Diagnosis of polycythaemia vera (4)

• increased HB/Hct (>16/16.5)

• jak2 mutation

• BM biopsy : hypercelullarity for age, panymyelosis, subnormal epo level

• Peripheral blood smear : erythrocytosis, thrombocytsosis

PV treatment (5)

• Phlebotomy to reduce hct, low dose ASA

if high risk of thrombosis / increase myeloproliferation

• cytireductive therapy : hydroxyurea, interferon a

• jak2 inhibitors : ruxolitinib

• anagrelide if extreme thrombosis

• splenectomy if splenomegaly pain

Essential thrombocytopaenia what + clinical features (5)

• sustained megakaryocyte proliferation → Chronic thrombocytosis → acquired VWD

• Many Asx, but may cause

1. Neurological sx : headache, tia, paresthesia

2. thrombosis : PE, erthromelalgia, etc

3. Bleeding : gi,skin,etc

4. in pregnancy : spontaneous abortion, iu growth retardation

5. hepatosplenomegaly

Diagnosis of essential thrombocytopaenia (3+)

• thrombocytosis

• jak2, calr lr mpl mutations

• bm biopsy : megakaryocyte lineage w increased enlarged mature megakaryocyte + platelet clumps of varied platelet size and shape

Essential thrombocytopaenia treatment

• low risk et : low dose aspirin

• high risk et : aspirin + cytoreductive therapy (hydroxyurea → anagrelide → ruxolitinib

Primary myelofibrosis what and dx (5+)

• increased marrow fibrosis and extramedullary haematopoiesis

• megakaryocyte proliferation and atypia ± fibrosis (early or late)

• JAK2, CALR, MPL mutation

• ± anaemia, leukocytosis, increased ldh

• ± splenomegaly

• leukoerythroblastosis for late

nb bm lften inaspirable (dry tap)

primary myelofibrosis clinical features (5) + tx

• Asx, but if have

1. Extramedullary haematopoiesis

2. splenomegaly ± hepatomehaly

3. portal htn : ascites, varices, epper gi bleed

4. portal vein thrombosis

5. leukoerythroblastic rxn

• no specific tx byt hsc / ruxolitinib maybe considered

When to suspect myedysplastic neoplasm (4)

• unexplained monocytosis

• macrocytosis ± anaemia

• cellular dysplasia in blood film

• cytopaenia in adults

MDS what

• clonal hsc disordee w 2 different mechanism for producing cytopaenia

1. imcreased apoptosis of precursor cells

2. abnormal proliferation of abnormal stem cells

• causing ineffective haematopoiesis ± megaloblatic maturation

nb transformation to aml common

Morphological sign of dysplasia in mds

• dyserythropoiesis :megaloblastic changes + ring sideroblast (nucleated rb. w iron granule in perinucleus)

• dysgranulopoiesis : Auer rods + pseudo pelger -heut neutrophils (aviator glasses nuclei)

• dysmegakaryopoiesis : micromegakatyocyte + pawn ball megalaryocyte

MDS symptoms

• anaemia : macrocytic

• neutropaenia : infections

• thrombocytopaenia : bleeding

MDS aetiology

• idiopathic

• previous chemo : topoisomerase ii, alkylating agents

• ionising radiation

• chemical exposure

• cigarette

What is bcl2

• bcl inhibits apoptosis

• bcl2 overexpression results in prolonged cell survival in cancers

• bcl2 follicle centre cell, c-myc in burkitts lymphom

Lymphoma clinical festures (4)

• lymphadenopathy

• splenomegaly

• bone marrow involvement (pancytopaenia, lymphocytosis)

• systemetic systems (fever, weight loss, night sweats)

dx lymphoma

• physical exam

• imaging : ct, mri, us

• biopsy : tissue, ln

• aspiration of bm

• PCR

• immunophenotyping and molecular : flow cytometry

Hodgkins disease

• diseases characterised by reed sternberg cells (neoplastic b cells)

• surrounded by many reactive cells : b&t, lymphocytes, plasma cells

• immunophenotype : cd30+ & ebv +ve

Classical hodgkins lymphoma

• nodular sclerosing w reed sternberg cells

• staging using ann arbor system

1. single nodal

2. 2 or more in same side

3. both sides

4. disseminated

a. Asx, B w fever, weight loss, night sweats

follicular lymphoma

• non hodgkins lymphoma

• CD20+VE & BCL2 +ve [t14;18]

• dx by bone marrow biopsy

• follicular pattern : b follicle centre cells

Diffuse large b cell lymphoma

• single mass, v aggressive

• evolve from low grade

• may progress to high grade lymphomas → richters syndrome

burkitts lymphoma

• ya

• usually extranidal : jaw, abdomen, gonads

• c-myc, ebv

Mucosal lymphomas (maltomas)

• low grade b cell lymphoma, localised

• tx active surveillance, chemo, immuno, rt

Biological behavious NHL

• low grade : follicular, sll, marginal

• high grade : dlbcl

hodgkins vs nhl (3)

• localised vs systemic

• nodal vs extranidal

• rarely invloves bm vs bm

monoclonal gammopathy of undetermined significance

• most common plasma cell neoplasm

• presence of monoclonal immunoglobulin in plasma and/or urine

• Asx but serum protein <g/dl and bm neoplastic cells <10%

• have 1 (non igm)- 1.5% (igm) to myeloma / lymphoma respectively

nb cek serum protein by electrophoresis gel

Monoclonal gammopathy of renal significance

• any bcell/plasma cell clonal disorder that produces nephrotoxic monoclonal ig

• directly or indirectly cause kidney damage

• majority are glomerular disorders

Multiple myeloma

• blood cancer of b cells, almost all from mgus

• end organ characterised by CRAB

• Calcium excess, Renal insufficiency, Anaemia, Bone lesions

sx Multiple myeloma (5)

• hypercalcaemia

• bence jones protein

• cast nephropathy (myeloma kidney + tamm horsfall protein)

• also suppressed humoral immunity

• punched out (pepper pot skull) in calvarium

multiple myeloma dx (4)

• bone marrow aspiration / biopsy

• serum / urine electrophoresis

• serum / urine flc assay

• fbc

Plasma cell myeloma tx (4)

• protease inhibitor

• immunomodulators

• chemo

• asct

smouldering myeloma

• Asxm M protein >3g/dl

• bm plasma b/ 10-60

• no end organ damage

solitary plasmacytoma

• single lesion of bone or st (osseous or extrao

• no bm involvement

• clonal plasma cells upon biopsy

amyloidoses and physical pro[erties

• large group of disorders in which misfolding of extracelullar protein into b sheet, insoluble aggregates

• cause tissue deposits and organ dysfunction

• 7-10 nm which is seen w congo red dye

primary (al) amyloidosis

• most common, acquired due to plasma cell dyscaria

• sx : nephrotic syndrome, chf, racoon eyes, popeyes sign, nail dystrophy, macroglossia

• dx : biopsy w congo red stain, presence of monoclonal light chains, check for deposits

• tx : liver transplamt, crispr, MaB, interfere fibril formn