1. Adult acute lymphocytic leukemia Adult acute lymphocytic leukemia Jaya V.Juturi MD 5/5/2004

2. JM 35 year old Hispanic male patient 2 week history of generalized malaise and pallor One week history of easy bruisability No relevant medical or surgical history No high risk behavior, non-smoker, has 8 siblings.

3. JM No fevers, gum bleeding, chills, Five pound weight loss over a week to 10 days Ecchymoses and oral thrush Otherwise exam normal, no lymphadenopathy, hepatosplenomegaly WBC 6.1, Hgb 3.2, Plts 4000

9. Acute Lymphocytic Leukemia Incidence is about 3000-4000 cases a year 2/3 of these occur in children 80% of children are cured 35-40% adults with ALL survive 2 years

10. Acute Lymphocytic Leukemia Only 30% adults cured Biology of the disease appears to be different Intensive chemotherapy and CNS prophylaxis contribute to most cures! Accurate diagnosis is crucial and an experienced hematopathologist should always be involved

11. Pui, C.-H. et al. N Engl J Med 1998;339:605-615 Kaplan-Meier Analyses of Event-free Survival (Top Panel) and Overall Survival (Bottom Panel) in 2255 Children with ALL in 13 Consecutive Studies Conducted at St

12. Morphology VS Immunophenotype ALL can develop from any lymphoid cell blocked from maturation Most sensitive B-cell marker is CD 19, CD 7 for T-cell lineage, CD- 13 or CD 33 for myeloid cells Cytoplasmic CD 79a for B-cells, CD3 for T-cells and myelo peroxidase fro myeloid cells TdT elevated in most ALL Accurate diagnosis in 99% cases with the above described methods

13. Morphology VS Immunophenotype Aberrant myeloid antigen expression can be seen in about a third of the adults with ALL 20% AML cases may have an elevated TdT ALL B-cell lineage 80% T-cell lineage 10-15% FAB classification

14. Cellular classification (FAB) L-1 mature appearing lymphoblasts L-2 pleomorphic lymphoblasts L-3 is most B-cell ALL 95% of all acute lymphocytic leukemias except B-cell type have and elevated TdT expression (terminal deoxynucleotidyl transferase expression)

15. Pui, C.-H. et al. N Engl J Med 2004;350:1535-1548 Transformation of Hematopoietic Cells in the Pathogenesis of ALL

16. Risk assessment Adults Hyperleukocytosis at presentation Adverse cytogenetic profile CNS or Testicular involvement at presentation Pre-T cell leukemia and resistance to chemotherapy Delayed early response to chemotherapy

17. Pui, C.-H. et al. N Engl J Med 1998;339:605-615 Estimated Frequencies of Specific Genotypes among Children and Adults with ALL

18. Pui, C.-H. et al. N Engl J Med 2004;350:1535-1548 Kaplan-Meier Analysis of Event-free Survival According to the Subtype of Leukemia in 467 Children with ALL Who Were Enrolled in Three Consecutive Treatment Protocols at St

19. Pui, C.-H. et al. N Engl J Med 1998;339:605-615 Proposed Risk-Classification System for ALL According to Immunophenotype and Genotype, Age, Leukocyte Count, Early Response to Treatment, and Presence or Absence of Extramedullary Disease (in B-Cell-Precursor Disease)

20. Supportive/clinical care At least 50% patients with Acute lymphocytic leukemia present with fever. Often secondary to cytokines TNF, IL-1 and IL-6 But in about a third this fever is secondary to an infection Monitor for hyperuricemia, hyperkalemia and hyperphosphatemia in all patients----Tumor lysis syndrome

21. Supportive/clinical care Intravenous hydration. Allopurinol, cytoreduction ?Leukapheresis, hyperviscosity Psychosocial support Indwelling catheters Transfusion support

22. Treatment Well designed clinical trials and multi-drug regimens have contributed to the cure rate Fractionated high dose cytoxan, high dose methotrexate and cytarabine form the core of most regimens given in an intense two to eight month fashion Most regimens also routinely include dexamethasone, vincristine, as well as asparaginase in children and anthracycline in an adult

23. Treatment Induction of complete remission occurs in 97-99% of children and 75-80% of the adults Cranial prophylaxis or treatment is a must for all patients Most induction treatments are followed by maintainance therapy long term The role of consolidation in adults is not clear

24. Treatment Granulocyte colony stimulating factors hasten neutropenic recovery and thereby reduce complications of chemotherapy They do not appear to improve or affect response to chemotherapy Maintainance often lasts 2-3 years 6-mercaptopurine and methotrexate are the most commonly used drugs 6-mercaptopurine and methotrexate are the most commonly used drugs

25. CNS prophylaxis CNS can be a potential sanctuary for leukemic cells Presymptomatic therapy directed towards the CNS usually with intrathecal chemotherapy and systemic chemotherapy… CNS relapse less than 2% with such therapy Role of cranial irradiation not clear anymore…risk of neurotoxicity and can occasionally cause brain tumors ? Role in high risk patients…T-cell ALL or presentation with hyperleukocytosis

26. Pui, C.-H. et al. N Engl J Med 1998;339:605-615 Treatment Strategies Associated with Improved Outcomes in Clinical Studies of ALL

27. Allogeneic stem cell transplant Indicated for patients who do not have a response to initial induction treatment and for those who relapse and go into a second remission Transplantation during the first remission remains controversial MLL gene abnormalities and BCR-ABL translocations given their unfavorable prognosis are often treated with an allogeneic transplant HLA matched sibling transplant is ideal, but for those who lack suitable family donors a matched unrelated transplant is reasonable Umbilical cord blood transplants are feasible in children and may not require the same degree of histocompatibility

28. JM Treated with Hyper CVAD/MTX-Ara-c regimen and CNS prophylaxis Residual leukemia at the end of the first two cycles… Primary refractory disease is being allo-transplanted in the near future 8 siblings being typed and HLA matching in process

29. Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia … Journal of Clinical Oncology, Vol 18, Issue 3, 2000: 547 204 adult ALL patients Median age 40 yrs T-cell disease in 17%. Leukocytosis in 26%, Leukocytosis in 26%, Philadelphia chromosome–positive disease in 16% Philadelphia chromosome–positive disease in 16% A mediastinal mass in 7%. A mediastinal mass in 7%.

30. Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia … Journal of Clinical Oncology, Vol 18, Issue 3, 2000: 547 Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).

31. Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia … Journal of Clinical Oncology, Vol 18, Issue 3, 2000: 547 91%achieved complete remission (CR) and 6% died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%).

32. Survival based on Ph + status