Acute Lymphoblastic Leukemia

ALL

1. ACUTE LYMPHOBLASTIC LEUKEMIA By Dr. Ayush Garg

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

3. Commonest form of malignancy in childhood. Majority are children of 2-10 yrs Peak incidence at 4 – 5 yrs of age. Acute onset with short history of duration. 85% are B cell 15% are T cell 5 times more frequent in childhood than AML epidemiology

4. 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

5. 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

6. Blast cells ALL is characterized by presence of immature cells – blast cells of >20% in the -blood picture -bone marrow examination Features of blast cells - very high N:C ratio - large cells with large nuclei - absence of cytoplasmic granules - presence of round or convoluted nuclei

7. Normal marrow Entire marrow replaced by blast Marrow showing blasts

8. FAB CLASSIFICATION OF ALL Cyt o l o gic Features L1 L2 L3 Cell Size Small Cells P r edom i n a t e , H omo Genous L a r g e , he t e r ogeno u s In Size Large Homogenous Cytoplasm Scanty Va r ia b l e ,of t en Moderately Abundant M o de r a t e l y Abundant Nucleoli Small One Or More, often Large One Or Mo r e, p rom i nent Nuclear Shape Homogenous Variable, He t e r ogeno us Stippled, Hom o g e nous Nuclear Shape Regular Irregular Clefts Regular Cyt.Basophilia Variable Variable Intensely Basophilic Cyt.Vacuolation Variable Variable Prominent

9. I m m uno l o g i c Subtype % Of Cases FAB Subtype Cytogenetic Abnor m a l it e s Pre B ALL 75 L1,L2 t(9;22),t(4;11) t(1;19) T cell ALL 20 L1,L2 14q11 Or 7q34 Mature Bcell All( burkitt Leukemia ) 5 L3 t(8;14) Classification of ALL(WHO)

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

11. T Cell ALL(L1)

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

13. 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

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

15. T Cell ALL(CD3 Positive)

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

17. Symptoms Percentage Fatigue 92 Bone Or Joint Pain 79 Fever 71 Weight Loss 66 Abnormal Masses 62 Purpura 51 Other Haemorrhage 27 Infection 17

18. Physical findings Physical findings Percentage Splenomegaly 86 Lymphadenopathy 76 Hepatomegaly 74 Sternal Tenderness 69 Purpura 50 Fundic Changes 14

19. 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

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

21. Confirmatory Bone marrow aspiration/biopsy

22. Criteria for diagnosis Bone marrow or peripheral smear showing Aleast 30% blast(FAB) Atleast 20%blast (WHO) MPO N egative , TDT positive is hallmark of L ymphoblast , however in L3 TDT is negative

23. Investigation s Cytogenetics. Flow cytometry. LDH,Serum uric acid Coagulation profile LFT,RFT Chest xray,CT chest Blood culture Baseline Echo,ECG

24. 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

25. 6-MP, 6-mercaptopurine; BMT, bone marrow transplant; CNS, central nervous system; MTX , methotrexate. GAP-POMP (GAP refers to the schedule of mercaptopurine administration given on 14 days of each 21-day cycle, thus a 7-day GAP) repeats a 3-week cycle until 2 years of continuous complete remission: vincristine, prednisone, mercaptopurine , methotrexate; high-dose cycle; vincristine, mercaptopurine , high-dose intravenous and intrathecal methotrexate.

26. 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

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

28. 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 M ethotrexate 12mg IT days 1,8,15,22

29. 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.

30. Induction 2 Induction2 drugs Dose and schedule Cyclophosphamide 650mg/m2 i.v days 1 and 15 Cytosine arabinoside 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

31. 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

32. 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

33. 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.

34. CNS prophylaxis In most regimens, CNS prophylaxis for patients at lower risk is achieved with systemic and intrathecal chemotherapy without cranial irradiation. Children with high-risk features are at an increased risk of CNS relapse and, historically, have received prophylactic cranial irradiation. These features include a presenting WBC count of 50,000/ μL or greater; those with WBC counts over 100,000/ μL are at particularly high risk of CNS relapse. Additional high-risk features that are indications on some treatment protocols for cranial irradiation are T-cell phenotype, Ph chromosome–positive ALL, and the presence of t(4;11). Infants younger than age 12 months with 11q23 abnormalities are at high risk of CNS relapse but because of their young age are usually treated without cranial irradiation , using intensified systemic and intrathecal chemotherapy to treat the CNS.

35. Historically, the standard dose for high-risk ALL cranial prophylaxis had been 1800 cGy ; however, published trials from the Berlin-Frankfurt-Munster group used 1200 cGy in patients with CNS-1 disease with good results. The standard dose for prophylactic cranial irradiation in those patients with high-risk disease still treated with irradiation is now 1200 cGy . Patients with an isolated CNS relapse occurring 18 months or more after initial diagnosis have an event-free survival of approximately 80 % when treated with intensive systemic chemotherapy and cranial or craniospinal irradiation. A dose of 1800 cGy to the cranial field has been shown to be effective in such patients.

36. Technique of brain rt The technique for cranial irradiation must ensure coverage of the cranial meninges as well as other areas of potential access to the CNS such as - the cribriform plate, - the posterior retina and posterior globe of the eye, - the exit regions of cranial nerves III, IV, V, and VI, and - the inferior extent of the temporal meninges . The field extends to the C1-C2 interspace unless a clinical field arrangement is used, in which case the field would be brought to the C2-C3 interspace.

37. To ensure adequate dose to the meninges, the entire calvaria is covered and the energy should be 4 MV or 6 MV photons. Custom blocks are used to shield normal tissues. Parallel opposed lateral fields are used. Immobilization is critical to ensure precise treatment and reproducibility and use of immobilization devices is recommended when possible. Sedation may be required for younger patients who are unable to fully cooperate.

38. CRANIAL IRRADIATION TECHNIQUE Every field should be treated in every sessions Daily Single Dose Is 1.5 G y . This is administered in 5 sessions per week until the total dose has been applied Angulation of the beam (3-5 deg posterior),half beam- to avoid opthalmological complications Fields-lateral parallel opposed cranial fields,postero -anterior spinal fields

39. CRANIAL IRRADIATION dosage CHILDREN LESS THAN ONE YEAR- NO IRRADIATION ONE TO TWO YEARS- 12 GY MORE THAN 2 YEARS- 18 GY ADULTS 24-30Gy ALL IC BFM 2002

40. CR ANIAL PROP HY L A X IS - A L L ALL-BFM 83 - 12 G y of preventive CRT was as effective as 18 G y OF HIGH- SRG ALL-BFM 90 - Reducton Of Long Term Morbidity In PRED-GR patients by limiting radiation dose - 12 G y to MR-ALL AND HR ALL -86 TO 90 - I n critical groups incidence of CNS relapse was less than 5 %. Especially With HD-MTX and MTX - IT incidence was less than 3 % . ALL-BFM-90 - 12 G y instead of 18 G y provided equally efficient CNS prophylaxis in high risk groups had PGR A LL-B F M 9 5

41. CRANIAL PROPHYLAXIS-ADULTS Central Nervous System Recurrence Rate in Adult Acute Lymphoblastic Leukemia- Cancer May 15, 2010 PROTOCOL CNS R E L A P S E PROPHYLAXIS HYPERCVAD 4% NO RT BFM 1% 18GY AUG BFM 1% 18GY CALGB 11% 24GY

42. NEURAXIS IRRADIATION I N DICA T IO N S - O V ERT C N S L E U K EM I A I N A D U L T S : U n s u i t a b l e for chemotherapy, isolated CNS relapse . DOSAGE- TO THE CRANIUM -24 TO 30 G y . TO THE SPINE-15 to 18G y . 1.5 TO 1.8 G y / # The Role of Craniospinal Irradiation in Adults with a Central Nervous System Recurrence of Leukemia - Cancer 2004;100:2176–80.

43. 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.

44. Refractory ALL

45. 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

46. Newer drugs Monoclonal antibodies Rituximab(cd20), Epratuzumab (CD22), Alemtuzumab (CD52), Gemtuzumab (CD33) A ntimetabolites Clofarabine , Nelarabine Tyrosine k inase inhibitor Imatinib , Nilotinib , Dasatinib Vornistat , Sirolimus , Everolimus , Oblimersen ,

47. 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.

48. R el a p s e 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

49. Thank you