Haematological malignancies

1. Dr Anindya Mukherjee Senior Resident Dept of Radiotherapy PGIMER, Chandigarh

2.  Brief overview of the haematological system  Leukaemias.  Lymphomas.  Myelodysplastic Syndromes.  Plasma Cell disorders.

4.  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

5.  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

6. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML)

7. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML) By onset and progression

8. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML) By cell type

9. Classification of leukaemia ALL/CLLAML/CML

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

12. Risk factors •Acquired -Cytotoxic chemotherapy -Haematological e.g. myelodysplasia (AML) •Inherited -DNA repair defects, immune defects -Other e.g. Down syndrome

13. 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).

14. •Imaging -CXR, CT (pneumonia, mediastinal mass, lytic bone lesions) •BM biopsy -Flow cytometry, cytogenetics and immunohistochemistry ->20% blasts

15. 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.

16. Pathophysiology Formation of fusion genes  dysregulation of proto-oncogene e.g. TEL-AML1 (25%). 85% are derived from B-cell precursors.

17. 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

18. Small basophilic blasts with few granules Hand mirror cells

19. 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

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

21. 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)

22. Auer rods, oddly shaped, increased N:C

23. Treatment of acute leukaemia Supportive: Problem Anaemia Thrombocytopenia DIC Infection Tumour lysis syndrome CNS prophylaxis Treatment Packed RBCs Platelets (if <10) FFP, cyroprecipitate Antibiotics, reverse barrier nursing Allopurinol/rasburicase Intrathecal chemo e.g. methotrexate, cytarabine

24. 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.

25.  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

26. Prognosis of acute leukaemia 5 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 leukaemia 5 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

28. RISK FACTORS: •Acquired -Radiation (CML) -Immunodeficiency e.g. HIV/AIDS, post-transplant -Pesticides •Inherited -Family history (CLL, now known as SLL)

29. 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

30. 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.

31. 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

33. 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

34. 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.

35. Diagnosis: -LAP and /or Splenomegaly -B lymphocytes in Peripheral Blood not exceeding 5 X 109 /L

36. 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

39. Definitive management of SLL/CLL CLL •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’

40. Other: •Monoclonals •Surgery -Splenectomy for splenomegaly or pancytopenia •Radiotherapy -Pallative for bulky LN or splenomegaly

41. 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

43.  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

48. Lymphoma

49. What’s the difference between leukaemia and lymphoma?

52. Hodgkin’s lymphoma Originates 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

53. 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

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

55. 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

56. 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

57. •Lymph node USS and excision biopsy Important to see the architecture of the LN!

59. Ann-Arbour staging Automatic stage IV if extranodal involvement. Systemic symptoms = B, extranodal = E, >10cm = X, splenic involvement = S

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

61. 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

63. 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

64. 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

65. Pathogenesis

66. 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

67. 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

68. 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

69. Prognosis of lymphoma 5 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

70.  Multiple Myeloma.  MGUS.  Smouldering Myeloma.

71.  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

73.  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)

74.  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)

75. 1. Production of a single monoclonal antibody (paraprotein)  ‘M’ band in γglobulin region on serum/ urine electrophoresis 2.Increased clonal plasma cells in the bone marrow  >10% monoclonal plasma cells on bone marrow biopsy 3. Evidence of organ damage (‘CRAB HAI’)

77.  h  Consolidation- no consensus.  Maintenance- Bort/Thalix/Cyclo phos – no consensus.  RELAPSE/REFRACTORY Borte+ Dexa - M.C regime used.

78.  Renal disease  rehydration – 3L/day  Bone disease  Bisphosphonates  Radiotherapy to bony lesions  Corticosteroids  Anaemia  Transfusion/ EPO  Hyperviscosity  Plasmapheresis  Infection  Broad spectrum Abx and antifungals

79.  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)

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