1. Acute Lymphoblastic Leukemia Maggie Davis Hovda 5/26/2009

2. Definition Neoplastic disease which results from a mutation in a single lymphoid progenitor cell at one of several discrete stages of development B Cell or T Cell

4. Epidemiology Most common childhood acute leukemia, ~80% Incidence in adults ~20% Bimodal distribution of occurrence:  Peak at age 2-5  Second increased incidence after age 50

5. Pathogenesis Acquired Genetic Change in Chromosome  Change in number, ie ploidy  Change in structure Translocations (most common) Inversions Deletions Point mutations Amplifications Changes in normal means of cell differentiation, proliferation, and survival

6. Mechanisms of Leukemia Induction 1 – Activation of a proto- oncogene OR creation of a fusion gene with oncogenic properties - Ph Chromosome t(9;22) 2 – Loss or inactivation of ≥ 1 tumor suppressor gene - p53 (p16 mutation)

7. Etiology Unknown ? Genetic Predisposition  Increased incidence amongst monozygotic and dizygotic twins Down Syndrome Disorder with chromosomal fragility:  Fanconi’s anemia  Bloom Syndrome  Ataxia-Telangiectasia ? Infections  HTLV1 in T cell leukemia/lymphoma  EBV in mature B cell ALL  HIV in lymphoproliferative DO

8. Presentation Nonspecific Symptoms  Fatigue/decreased energy  Fever  Easy bruising  Bleeding  Dyspnea  Dizziness  Infection Joint, extremity pains CNS involvement

9. Clinical Presentation Physical Exam  Pallor  Ecchymoses  Petechiae  LAD  Hepatosplenomegaly Lab Abnormalities  anemia  wbc vary 0.1 (20-40%) - >100 k (10-16%)  Platelets – usually ↓  ↑ LD, uric acid  CXR: eval for thymic mass  CSF to eval for involvement

10. Diagnosis Morphologic  French American British Classification L1: small uniform blasts (pediatric ALL) L2: larger, more variable sized blasts (adult ALL) L3: uniform cells with basophilic and sometimes vacuolated cytoplasm (mature B cell ALL)

11. Immunophenotyping From: Jabbour, E. et al. Adult Acute Lymphoblastic Leukemia. Mayo Clinic Proc. 2005;80(11):1517-1527

13. Cytogenetic Abnormalities From: Jabbour, E. et al. Adult Acute Lymphoblastic Leukemia. Mayo Clinic Proc. 2005;80(11):1517-1527

14. Classification of ALL Immunologic Subtype % of casesFAB SubtypeCytogenetic Abnormalities Pre-B ALL75L1, L2t(9;22), t(4;11), t(1;19) T cell ALL20L1, L214q11 or 7q34 B cell ALL5L3t(8;14), t(8;22), t(2;8) From: Harrison’s Principles of Internal Medicine, 16th ed. 2005. Chapter 97, Malignancies of lymphoid cells.

15. Differential Diagnosis ITP Aplastic Anemia Infectious mononucleosis Rheumatoid Arthritis Rheumatic Fever Collagen Vascular Disease

16. Treatment 1 – Remission Induction 2 – Intensification (Consolidation) Therapy 3 – Maintenance Therapy 4 – CNS Prophylaxis 5 – Allogeneic Stem Cell Transplant

17. Treatment Remission Induction  Goals: restore normal hematopoiesis, induce a complete remission rapidly in order to prevent resistance to drugs  Standard induction regimen 4 or 5 drugs: vincristine, prednisone, anthracycline, L- asparaginase, +/- cyclophosphamide Intensification  High doses of multiple agents not used during induction or re-administration of the induction regimen

18. Treatment Maintenance Therapy  Daily po 6MP, weekly MTX, monthly pulses of vincristine and prednisone for 2-3 yrs CNS Prophylaxis  Given during induction and intensification  Intrathecal: MTX, Cytarabine, corticosteroids  Systemic: high dose mtx, cytarabine, L-asparaginase  +/- Cranial Irradiation

19. Treatment Stem Cell Transplant  Done during first CR  Indications: Ph Chromosome t(4;11) mutation Poor initial response to induction therapy Other  Adolescents benefit significantly from pediatric ALL regimens vs. adult regimens

20. Relapse & Prognosis Relapse  Most occur during treatment or within the first 2 years  Bone Marrow is the most common site  Poor prognostic factors in patients previously treated: Relapse on therapy Short initial remission after intense therapy T-cell immunophenotype Ph Chromosome Circulating blasts High leukocyte count at relapse

21. Prognosis Overall better in children than in adults In adults, worse outcomes with:  Increasing age, >60  Increased wbc count at presentation

22. Sources Jabbour, E. et al. Adult Acute Lymphoblastic Leukemia. Mayo Clinic Proc. 2005;80(11):1517-1527 Xavier, T. Chemotherapy of acute leukemia in adults. Expert Opin. Pharmacother. (2009) 10(2):221-237 Williams Hematology, 6 th ed. 2001. Chapter 97, Acute Lymphoblastic Leukemia. Harrison’s Principles of Internal Medicine, 16 th ed. 2005. Chapter 97, Malignancies of lymphoid cells.