Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the proliferation of immature lymphocytes. It most commonly affects children aged 2-6 years and has a peak incidence in adults at around 35 years of age. The disease involves replacement of normal bone marrow by leukemic blasts. Treatment involves chemotherapy with regimens depending on risk stratification including induction, consolidation, CNS prophylaxis and maintenance phases. Prognosis depends on factors like age, white blood cell count, genetics and response to initial treatment.

1. ACUTE LYMPHOBLASTIC LEUKEMIA PROF.S.TITO’S UNIT M5 DR.M.ARIVUMANI

2. Acute lymphoblastic leuKemia is malignant disease of marrow in which early lymphoid precursors proliferate and replace the normal haematop oietic cells

3. Normal marrow

4. Entire marrow replaced by blast

5. Marrow showing blasts

6. Relative frequencies of lymphoid malignancies NHL(62.4%)

7. Epidemiology pea K incidence in 2 to 6 years more in boys than girls. median age in adults-35years Etiology less studied environmental and genetic factors

8. Chromosomal abnormalities in ALL ABNORMALITIES ADULTS(%) CHILDREN(%) Normal karyotype 16-34 9 hypodiploidy 4-9 1 hyperdiploidy 2-9 25 t (9;22) 11-30 4 t (4;11) 3-7 6 t (10;14) 4-6 4 t (8;14) 4 2 t ( 1;19) 3 5 9p abnormality 5-16 7-13 6q abnormality 2-6 4-6 12p abnormality 4-5 22

9. Factors predisposing ALL GENETIC ENVRONMENTAL Downs,turner, klinefelter Ionising radiation Fanconi,diamond blackfan Drugs NF Type1 alkylating agents Ataxia telengiectasia nitrosourea SCID epipodophyllotoxin PNH benzene exposure Li-fraumeni syndrome advanced maternal age Blooms syndrome paternal smoking

10. FAB CLASSIFICATION OF ALL CYTOLOGIC FEATURES L1 L2 L3 Cell size Small cells predominate,homogenous Large,heterogenous in size Large homogenous cytoplasm Scanty Variable,often moderately abundant Moderately abundant nucleoli Small One or more,often large One or more,prominent Nuclear shape Homogenous Variable, heterogenous Stippled, homogenous Nuclear shape Regular Irregular clefts regular Cyt.basophilia variable variable Intensely basophilic Cyt.vacuolation variable variable prominent

11. Classification of ALL(WHO) Immunologic subtype % of cases FAB subtype Cytogenetic abnormalites Pre B ALL 75 L1,L2 t(9;22),t(4;11)t(1;19) Tcell ALL 20 L1,L2 14q11 or 7q34 Mature Bcell ALL(burkitt leukemia) 5 L3 t(8;14)

12. Pre B ALL(L1) Small blasts wth thin rim of cytoplasm

13. T Cell ALL(L1)

14. T Cell ALL (L2) Irregular clefts of nucleus

15. Burkitt leukemia-Mature B Cell ALL(L3)-vacuolations

16. CNS Leu k emia (csf showing blasts)

17. B Cell ALL (85%) type tdt CALLA Surface Ig Early pro B ALL positive negative negative Pre Bcell ALL positive positive negative Mature B ALL negative positive positive

18. T Cell ALL(15%) Early subtype CD3 -, CD4-,CD8- or CD3-,CD4+,CD8+. Later subtype CD3+ with CD4+ or CD8+

19. T Cell ALL(CD3 Positive)

20. CLINICAL FEATURES Due to infiltration of marrow SYMPTOMS Due to decreased production of normal marrow elements

21. Symptoms symptoms percentage fatigue 92 Bone or joint pain 79 fever 71 Weight loss 66 Abnormal masses 62 purpura 51 Other haemorrhage 27 infection 17

22. Physical findings Physical findings percentage splenomegaly 86 lymphadenopathy 76 hepatomegaly 74 Sternal tenderness 69 purpura 50 Fundic changes 14

23. Investigations CBC-Anemia,thrombocytopenia,leucopenia or leucocytosis. Peripheral smear study-circulating blast can be seen.

24. Confirmatory Bone marrow aspiration/biopsy

25. Bone marrow biopsy(gross specimen)

26. Criteria for diagnosis Bone marrow or peripheral smear showing Aleast 30% blast(FAB) Atleast 20%blast (WHO) MPO Negative,tdt positive is hallmar k of Lymphoblast,however in L3 tdt is negative

27. Investigation (cont) Cytogenetics. Flow cytometry.

28. Investigation (cont) LDH,Serum uric acid Coagulation profile LFT,RFT Chest xray,CT chest Blood culture Baseline Echo,ECG

29. Treatment Pre Chemotherapy supportive care Chemotherapy Preinduction Remission induction-phase 1 & 2 Reinduction CNS preventive therapy consolidation Maintenance therapy Allogenic stem cell transplantation Newer drugs Supportive care Treatment of relapse Effects of treatment

30. Supportive care Treat metabolic complications hyperuricemia-hydration,rasburicase hyperphosphatemia-po4 binders hypocalcemia-Ca supplements Hyperleuc k ocytosis-leu k opharesis Infection control-broad spectrum antibiotics Hematologic support

31. Preinduction Prednisolone 1mg/ k g p.ofor 5 days Rechec k blast after 5 days, if blast count dropped-good response.

32. Treatment of ALL Induction 1 cycle chemotherapy Dose and schedule Induction Prednisolone or 1mg/kg p.o days 1-28 days vincristine 1.5mg/m2 i.v weekly one dose x 4 weeks doxorubicin 30mg/m2 i.v weekly one dose x 4 weeks L-Asparginase 1,00,000 u/m2(total dose) in divided doses of 10,000 u daily for 10 days CNS Preventive therapy methotrexate 12mg IT days 1,8,15,22

33. Reassess After 4 wee k s of phase 1 induction assess marrow for remission. If there is remission taper prednisolone and after 1 wee k of restart phase2 induction, If there is no remission give 2 more wee k ly doses of vincristine and doxo and then assess, if still no remission go for alternate regimen.

34. Induction 2 Induction2 drugs Dose and schedule Cyclophosphamide Cytosine arabinoside 650mg/m2 i.v days 1 and 15 75mg/m2 i.v x 4 days a weeks for 4 week i.e day 1-4,8-11,15-18,22-25 methotrexate 12mg/m2 IT days 1,8,15,22 Cranial radiation 200 cGy x 9days

35. Reinduction Reinduction drug Dose and schedule vincristine 1.5 mg/m2 i.v weekly one dose on day 1 and 8 doxorubicin 30mg/m2 i.v. weekly one dose on day 1 and 8 prednisolone 1mg/kg p.o daily for 14 days

36. consolidation consoldation drugs Dose and schedule cyclophosphamide 750/m2 .i.v days 1 and 15 Cytosine arabinoside 75mg/m2 doses days 1-4 and 15-18

37. Maintenance phase duration- upto 2 years maintenance drug Dose and schedule 1 st month methotrexate 12.5mg i.t on day 1 vincristine 1.4mg/m2 .v day 1 prednisolone 1mg/kg p.o daily day 1-7 6 mercaptopurine 60mg/m2 p.o. daily for next 3 weeks methotrexate 15mg/m2 p.o. once a week for 3 weeks. 2 nd month 6 MCP and T.Methotxerate for 4 weeks.

38. Follow up If the patient completes chemotherapy for 2 years without relapse-stop chemo and follow up. No relapse within 5 years-can be declared as cured.

39. Refractory ALL

40. Allogenic stem cell transpantation Usually done in second remission. Can be done in first remission in high ris k patients WBC>25000 philadelphia chromosome positive poor initial response to remission induction

41. Newer drugs Monoclonal antibodies rituximab(CD20),epratuzumab(CD22) alemtuzumab(CD52),gemtuzumab(CD33) Antimetabolites clofarabine,nelarabine Tyrosine k inase inhibitor imatinib,nilotinib,dasatinib Vornistat,sirolimus,everolimus,oblimersen,

42. Late effects of treatment Cranial irradiation-cognitive and intellectual impairment,cns neoplaysms Chemotherapeutic drugs-secondary AML Endorine dysfunctions-short stature,obesity,growth retardation Anthracycline-cardiotoxicity Steroid-avascular necrosis of bone.

43. Relapse Reappearance of blast at any site in the body after initial remisson during chemotherapy or after comleting chemo. Marrow relapse-poor outcome Hyper CVAD regimen allogenic BM transplant CNS relapse -Triple IT –alternate days till csf clears,then twice wee k ly 6 doses.then one dose every wee k 6 doses. - cranial irradiation Testicular relapse -chemotherapy plus b/l testicular radiation

44. Cns relapse

45. Prognostic factors in ALL Determinants Favourable unfavourable WBC Counts <10,000 >2,00,000 Age 2-10 years <1yr,>10yr Gender female male Ethnicity white blac Node,liver,splenomegaly absent massive Testicular enlargement absent present CNS involvement absent Csf blast and pleocytosis FAB Type L1 L2 Cytogenetics T(12;21)(TEL-AML1) Trsomies 4,10,17 t(9;22)(bcr-abl) t(4;11)(MLL-AF4) Ploidy hyperdipoidy hypodiploidy Time to remission <14days >28days

46. References. 1.Harrison’s principles of internal medicine 17 th edition 2.Williams hematology 8 th edition 3.Wintrobe’s clinical hematology 4.Nelson textboo K of paediatrics 5.ash.hematologylibrary.com/image ban k.

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