Dr Anindya MukherjeeSenior Resident

Dept of RadiotherapyPGIMER, Chandigarh

Brief overview of the haematological system

Leukaemias. Lymphomas. Myelodysplastic Syndromes. Plasma Cell disorders.

Patients present with pancytopaenia Symptoms of anaemia Infections Bleeding NB AML M3 presents with DIC!

Diagnosis to death 6-12 weeks if untreated Chemosensitive Best initial test is blood smear

Blast cells present WBC can be low, normal or high

Patients present more insidiously Less likely to present with pancytopaenia Diagnosis to death 6-12 years if

untreated Less chemosensitive Best initial test is full blood count

WCC always high DLC check is crucial.

‘Smudge’ cells in CLL on smear

Classification of leukaemia

•Acute lymphoblastic leukaemia (ALL)

•Chronic lymphoblastic leukaemia (CLL)

•Acute myeloid leukaemia (AML)

•Chronic myeloid leukaemia (CML)

Classification of leukaemia

•Acute lymphoblastic leukaemia (ALL)

•Chronic lymphoblastic leukaemia (CLL)

•Acute myeloid leukaemia (AML)

•Chronic myeloid leukaemia (CML)

By onset and progression

Classification of leukaemia

•Acute lymphoblastic leukaemia (ALL)

•Chronic lymphoblastic leukaemia (CLL)

•Acute myeloid leukaemia (AML)

•Chronic myeloid leukaemia (CML)

By cell type

Classification of leukaemia

ALL/CLLAML/CML

Proliferation of progenitor cells in the bone marrow results in replacement of normal haematopoeitic cells and bone marrow failure.

Risk factors

•Acquired-Cytotoxic chemotherapy-Haematological e.g. myelodysplasia (AML)

•Inherited-DNA repair defects, immune defects -Other e.g. Down syndrome

Investigations in leukaemia

•History and examination

•Bloods-Peripheral blood tests (anaemia, thrombocytopenia, hyperleukocytosis, neutropenia)-PBS(blasts, dysplastic neutrophils (2º AML))-U&Es (hyperuricaemia)-LDH-Clotting screen -LFTs, BUN/ creatinine ratio -Septic screen (if infection suspected).

•Imaging-CXR, CT (pneumonia, mediastinal mass, lytic bone lesions)

•BM biopsy-Flow cytometry, cytogenetics and immunohistochemistry->20% blasts

Also known as ‘lymphocytic’.

Epidemiology

•Incidence = 1/50,000. Slight male predominance.•Commonest type of childhood leukaemia (70%)•Peak age 2-5 years, but later increase >50.

Pathophysiology

Formation of fusion genes dysregulation of proto-oncogene e.g. TEL-AML1 (25%).

85% are derived from B-cell precursors.

Findings specific for ALL•Examination

-Lymphadenopathy-Splenomegaly (10-20% presentation)-CNS signs- more likely

•Bloods-Anaemia- usually severe, signs present-WBCs- variable, usually neutropenia-Smear- smallish basophilic blasts, few granules, hand-mirror cells-Clotting- 10% ALL presents with DIC

•Imaging-Mediastinal mass in some T cell ALL

Small basophilic blasts with few granules

Hand mirror cells

Also known as ‘myelogenous’.

Epidemiology

•Incidence = 3.7/100,000. Slight male predominance.•Commonest type of adult leukaemia (90%)•Can occur at any age but median is 70 years

Pathophysiology

Two classes of mutations may be required, similar to ALL:

Findings specific for AML•Examination

-Lymphadenopathy unusual-Leukaemia cutis (10%), chloroma (rare)

•Bloods-Anaemia- usually severe, signs present-WBCs- variable, usually neutropenia-Smear- Auer rods in large hypergranular myeloblasts-Hypokalaemia in monocytic leukaemia-Clotting- DIC commoner in acute promyelocytic leukaemia (M3)

Auer rods, oddly shaped, increased N:C

Treatment of acute leukaemiaSupportive:

ProblemAnaemiaThrombocytopeniaDICInfection

Tumour lysis syndromeCNS prophylaxis

TreatmentPacked RBCsPlatelets (if <10)FFP, cyroprecipitateAntibiotics, reverse barrier nursingAllopurinol/rasburicase

Intrathecal chemo e.g. methotrexate, cytarabine

NonPML AML:

•Induction 4-6wks(anthra+cytarabine)•Consolidation( no consensus)•Poor G.C pts- BSC/Pall care +/- azacytidine / decitabine / hydroxyurea,etc.•CNS radiotherapy•BM transplantation(ASCT)-for intermediate and adverse risk AML( not good risk AML)

PML:• (ATRA) +/- ATO during induction f/b 1-2 cy anthracyclines as consolidation.

Identify lineage- B cell or T cell. Differentiate Ph+ and Ph- ALL Complete cytogenetics assay to identify high/intermediate and

low risk karyotypes. Rx( ex- BFM protocol) > Prephase- pred/dexa + 1st TIT for CNS prophylaxis. Avoids

TLS plus provides prognostic information. >Induction( to achieve CR/mRD 6-16 weeks after chemo):

Usually Induction I and II phases VCR/Anthra/cyclophos/L-ASPARGINASE>Post remission consolidation- HD Mtx/HD cytarabine +/- L-

asparginase>Maintenance- daily 6-MCP+ weekly MTx.CNS prophylaxis- TIT(Cyt/Mtx/Dexa)+ IV HD MTx/Cyt

Prognosis of acute leukaemia5 year survival rates

•ALL -Children- 75%-Adults- 40%-Worse if <1 or >60, high WBC, >4w to remission

•AML-30-50%-Better if BM Tx, children, worse if >60

Prognosis of acute leukaemia5 year survival rates

•ALL -Children- 75%-Adults- 40%-Worse if <1 or >60, high WBC, >4w to remission

•AML-30-50%-Better if BM Tx, children, worse if >60

RISK FACTORS:

•Acquired-Radiation (CML)-Immunodeficiency e.g. HIV/AIDS, post-transplant-Pesticides

•Inherited-Family history (CLL, now known as SLL)

Stepped-up production of granulocytes and their precursors and failed apoptosis leads to insidious progression towards a blast crisis.

Epidemiology

•Incidence= 0.6-2/100,000•Can occur at any age but rare in children. Peak incidence at 40-60 •Less common than AML, CLL

Pathophysiology

95% involve t(9;22)(q34;q11) translocation, resulting in the Philadelphia chromosome. This forms a fusion gene- BCR-ABL1 with constitutively active tyrosine kinase activity.

Findings specific for CML

Usually asymptomatic!•Examination

-Splenomegaly- may be only feature at latent phase, massive later on

•Bloods-Anaemia- mild, worsens with progression-WBCs- extremely high-Smear- leukocytosis with granulocyte left-shift

DEFINITIVE MANAGEMNT OF CML

•Imatinib/Dasatinib/Nilotinib-Tyrosine kinase inhibitor, targets BCR-ABL1. Greatly increases 5 year survival compared to older drug therapies-Initial treatment, continued indefinitely if optimal response.

•ASCT in failure to two/three TKIs

98% develop from B cells.

Epidemiology

•Incidence = 4.2/100,000. Slight male predominance.•Most common form of leukaemia in the West•Usually >55, median age 72, rare <40.

Diagnosis:

-LAP and /or Splenomegaly

-B lymphocytes in Peripheral Blood not exceeding 5 X 109/L

Findings specific for CLL

Usually asymptomatic!• Examination

-Lymphadenopathy/splenomegaly present in late disease.

• Bloods-WBCs- extremely high-Smear- lymphocytosis with ‘smudge/

soccerball cells’• Other

-Richter’s syndrome-Prolymphocytic transformation

Definitive management of SLL/CLLCLL•Watchful waiting with regular monitoring(Rai 0,I,II stages without active disease).•FludaCytaRituxi/ B-cell receptor inhibitor( for Rai0,I,II with active disease or Rai III and IV).•ASCT in patients responding to BCR inhibitor( eg-rituximab/idelalisib/ibrutinib)•For p53 del/mutation- BCRi better than FCR.•Chemotherapy. Indications:

-Severe systemic symptoms-Progressive splenomegaly/lymphadenopathy-Increased WBC/reduced ‘doubling time’

Other:•Monoclonals•Surgery

-Splenectomy for splenomegaly or pancytopenia

•Radiotherapy-Pallative for bulky LN or splenomegaly

Prognosis of chronic leukaemiaPrognosis of chronic leukaemia•CLL

-Rai Staging:-Low risk(Rai 0) > 10 yrs.-Intermediate Risk(Rai I and II) > 8 yrs.-High Risk( Rai III and IV) > 6.5 yrs or lesser.

•CML-Overall 5 year survival with imatinib now 89% (or more?)

BM transplant is the only curative therapy

Clonal haematopoetic stem cell disorders in elderly characterised by ineffective haematopoiesis leading to blood cytopenias and by progression to acute myeloid leukaemia (AML) in one third of cases.

Inherited predisposition, eg Down’s , fanconi; sometimes acquired secondary to CT/RT.

Diagnosis: Peripheral blood counts, Bone marrow trephine Biopsy( for cytogenetics), LDH, ferritin, transferrin saturation , EPO

Lymphoma

What’s the difference between leukaemia and lymphoma?

Hodgkin’s lymphomaOriginates from B cells in the germinal centres of lymphoid tissue and is characterised by orderly spread from one LN group to another.

Epidemiology

•Incidence = 2.2/100,000, 30% of all lymphoma•Bimodal distribution with peaks at 15-30 and >50 years•Slight male predominance

Risk factors

•Acquired-HIV/AIDS- increases with CD4 count-Previous non-Hodgkin’s lymphoma-Autoimmune conditions

•Inherited-Immune defects-Family history of H/non-H lymphoma, CLL

Pathogenesis

Some proliferation of malignant Reed-Sternberg cells (probably of B cell lineage) and abnormal mononucleocytes.

Presentation

•Painless non-tender rubbery enlarged LN-Cervical involvement in 60-70%, axillary in 10-15%, inguinal in 6-12%-May increase/decrease in size spontaneously-May become ‘matted’ and non-mobile-Contiguous progression to nearby groups-Alcohol-induced pain

•Systemic symptoms-Especially fever (30%), may be cyclic-And severe pruritis (25%)

•Other-Early satiety due to splenomegaly

Investigations•FBC

-Exclude leukaemia, mononucleosis•ESR/CRP•LFTs•U&Es•CXR

-Lymphadenopathy, mediastinal expansion•CT

-Thorax, abdomen for staging•BM biopsy•Other

-HIV, Monospot, LDH, thoracentesis, PET, LP, MRI

•Lymph node USS and excision biopsy

Important to see the architecture of the LN!

Ann-Arbour staging

Automatic stage IV if extranodal involvement. Systemic symptoms = B, extranodal = E, >10cm = X, splenic involvement = S

Treatment

Supportive•Fertility•Cardiac function•Respiratory function•Tumour lysis syndrome•Others, as indicated (see leukaemias slide)

Treatment

Definitive•IA/IIA

-Radiotherapy alone- affected nodal areas-IFRT/ISRT= 20-30Gy.-Chemo with radiotherapy of affected nodes

•IB/IIB/III/IV-Chemo- ABVD/BEACOPP

•BM transplant-If still progressive despite chemo or after induction of remission after relapse

Non-Hodgkin’s lymphoma• A heterogeneous group of lymphoid tumours,

mostly of B cell origin. Characterised by irregular pattern of spread and common extranodal disease, they vary in their aggressiveness.

• Epidemiology Incidence = 17/100,000 Median age is >50 Diffuse large B cell and follicular lymphoma commonest

Risk factors

•Acquired-Infection e.g. EBV (Burkitt’s, sinonasal), HTLV-1 (T cell), HCV, HHV8 (Kaposi’s), H. pylori (gastric MALT)-Previous chemotherapy/Hodgkin’s-Autoimmune disorders e.g. Sjogren’s, Hashimoto’s-Immunodeficiency e.g. post-transplant, HIV/AIDS

•Inherited

Pathogenesis

Presentation•Painless non-tender rubbery enlarged LN

-Non-contiguous progression•Systemic symptoms

-Commoner in high-grade•Rash

-Cutaneous involvement e.g. mycosis fungoides, anaplastic large-cell etc.

•Abdominal pain, early satiety -Splenomegaly but unusual as rarely massive-Hepatomegaly

•Mass-Testicular-GI, symptoms of obstruction

•Shortness of breath, pleuritic chest pain, SVC syndrome-Mediastinal mass in high grade

•Neurological-Primary CNS lymphoma, commoner in immunosuppressed

Investigations•FBC

-Anaemia, thrombocytopenia, neutropenia-Thrombocytosis, lymphocytosis may occur

•ESR/CRP•LFTs•U&Es

-Obstructive nephropathy, hypercalcaemia•Serology

-HIV, HTLV-1, HCV•Imaging

-CXR-Intrathoracic lymphadenopathy, mediastinal expansion-CT-Thorax, abdomen for staging-Bone scan-PET-MRI- Brain, cord-USS- Scrotum

•BM biopsy-Should always be carried out

Treatment•Low grade

-Localised (rare)- radiotherapy, surgery-Disseminated- watch and wait or chemo when symptomatic/organ dysfunction-Gastric MALT- associated with H pylori, antibiotic therapy curative in 90%

•High grade-Aggressive chemo e.g. R- CHOP( 2/3 wkly)- Assess response usually after 6 cy followed by IFRT / ISRT= 30-36Gy-Allogenic stem cell transplantation-CNS prophylaxis in very high grade e.g. Burkitt’s

Prognosis of lymphoma5 year survival rates•Hodgkin’s- highly curable

-I/II- 90%-IV- 65%-Long-term sequelae of treatment

•Non-Hodgkin’s- vary widely (see IPI)-Overall 63%-Indolent follicular lymphoma I/II- 91% but may not be curable-DLBLC- curable with aggressive chemo

Multiple Myeloma. MGUS. Smouldering Myeloma.

Presdisposing factors Radiation Benzene Pesticides

Epidemiology 4 per 100,000 per year Median age 66 years

Pathophysiology Post germinal centre B cell proliferation

Monoclonal antibody

Hypercalcaemia(>11.5 mg/dl) Renal impairment( CrCL< 40ml/min) Anaemia( < 10g/dl absolute or > 2 g/dl

below LLN) Bone disease ( lytic/punched out)

Hyperviscosity Amyloidosis (AL) Infection (recurrent)

PBS and film ESR Urine dipstick 24 hour urine collection(Free Light chain assay) U&Es Urate Albumin, calcium, phosphate, ALP Serum and urinary electrophoresis Serum Ig X-ray (BM Biopsy –diagnostic rather than screening)

1. Production of a single monoclonal antibody (paraprotein) ‘M’ band in γglobulin region on serum/ urine

electrophoresis2.Increased clonal plasma cells in the bone

marrow >10% monoclonal plasma cells on bone

marrow biopsy3. Evidence of organ damage (‘CRAB HAI’)

h

Consolidation- no consensus.

Maintenance- Bort/Thalix/Cyclophos – no consensus.

RELAPSE/REFRACTORY

Borte+ Dexa - M.C regime

used.

Renal disease rehydration – 3L/day

Bone disease Bisphosphonates Radiotherapy to bony lesions Corticosteroids

Anaemia Transfusion/ EPO

Hyperviscosity Plasmapheresis

Infection Broad spectrum Abx and antifungals

MGUS: Often discovered

incidentally in elderly Characterised by:

Serum monoclonal proteins< 3g/dL

<10% plasma cells in bone marrow

Absence of en-organ damage(CRAB spectrum)

Smouldering MM: Serum monoclonal

protein> 3g/dL. Presence of end-

organ damage( CRAB spectrum)