Leukemias Definition 1) Acute a) 20% or more blasts in the BM and/or the circulation blood b) duration of 3 months (or less)

d b) duration of 3 months (or less) Two types of cells 1) myeloid- so get AML and CML 2) lymphoid- so get CML and ALL Depends on which is getting proliferated- a) if less blasts, chronic b) if more blasts, acute Classified by age < 15 yrs- ALL 15-35 AML 40-60 CML and AML (MC) >60 CLL (MC overall and after 60) Diff myeloblasts and lympoblasts? N/C ratio and nucleus is much bigger in lymphoblasts myeloblasts have more granules and more cyto and less nucleus as less space (N/C ratio is lower) and N/C is higher in lymbhoblasts b) lymphoblasts irregularly shaped c) myeloblasts has MPO positive Risk Factors overall 1) radiation- could be accidental or therapeutic (therapeutic has become a big cause of leukemia) WHO created new groups of AML and created therapy linked leukemia other form of therapy linked leukemia are medication- a) alkylating agents b) topoisomerase inhibitors c) chloramphenicol 2) chromosomal abnormalities- Downs syndrome 3) chemical exposure 4) Myeloproliferative diseases- CML, polycythemia vera, refractory anemia, ringed sinderoblastic anemia 5) Myelodysplastic syndrome 6) immunodeficiency syndromes7) viral and bacterial infections AML Proliferative disorder and maturation arrest of myeloid series cells within the BM Do not see mature forms; most are myeloblasts Since proliferating like crazy, suppress other cell lineages and everything else goes down get anemia (normocytic normochromic anemia, granulocytopenia etc.) Causes 1) chromosomal abnormalitiesa) Klinefelters b) Fanconi

c) Kostmann syndrome- GCF genes are not stimulated d) Downs 2) radiation- therapeutic and accidental exposure 3) medicationa) alkylating agents (cause 4-6 yrs following therapy and usually a myeloproliferativ disorder first and then leukemia) b) topoisomerase inhibitors (1-3 yrs following therapy and this causes leukemia first) c) chlormaphneicol 4) Chemicals a) benzene b) pesticides c) embalming fluid Classification WHO- i) therapeutic linked ii) myeloproliferative diseases and myelodysplastic syndrome iii) chromosomal iv) others FAB- only based on morphological characteristics 1) M0- undifferentiated no markers and can only find by flow cytometry CD13, CD33 2) M1- myeloblast without maturation 3)M2-myeloblasts with maturation a) t (8, 21)- better prognosis b) MC AML c) auer rods slender 4) M3-hypergranular promyelocytic leukemia a) granularity is very high and highest of all subtypes b) DIC is freq linked to it c) auer rods d) t (15,17) PML- 15; RAR-a- 17 i) they make a fusion gene called PML- RARa and this blocks cell differentiation high doses of retinoic acid or tretinoin or vit A will unblock this 5) M4- myelomonocytic a) M4 Eo- inversion of chromosome 16 (Eo= eosinophils) 6) M5- monocytic a) gum and skin infiltration and organ infiltration like liver and spleen i) swollen gums ii) skin infiltration leukemia cutis MCC is hairy cell leukemia > AML > ALL can lead to distortion of facial features and causes leonine facies (distorted features and also in leprosy) 7) M6- erythroleukemia 8) M7- megakaryocytic CD 41, 61 Clinical Presentation 1) bleeding- easy bruising, epistaxis***- nose bleed, eccymoses- bleeding under the skin

a) also internal bleeding in resp and cns b) oozing blood from sites like IV sites 2) fatigues- anemic 3) weakness- exertion first and then all the time 4) infections- granulocytopenia- chicken pox (rash), CMV, viral infections mainly 5) weight loss 6) fever w/ or w/out infection 7) bone pain- all the proliferation leads to bone stretching 8) M5- gum hypertrophy, swollen gums, bleeding gums, 9) M3- DIC Physical examination 1) changes in skin 2) resp and cns changes 3) excess cells clump to a tumour chloroma (stain green) and can form in breast, mediastinum and put pressure on the area Investigations 1) >20% blasts 2) MPO pos cells 3) dec amount of other cells- thrombocytopenia, granulocytopenia 4) translocation studies Treatment Two stages: 1) remission induction a) goal to achieve complete remission designated as CR i) Neutrophils >1000 ii) platelets > 100,000 Should be there for at least 4 weeks iii) no blasts in circulation iv) <5% blasts in BM b) two drugs are usedi) cytarabine- give IV continuous for 7 days 7, 3 regime ii) daunorubicin- give on day 1, 2 and 3 After one cycle of i) and ii) if complete remission, go to post remission phase and if did not achieve remission- i) repeat for 5, 2 days or ii) try diff agents- cyclosporine, arsenic etc- this one is recommended as if it did not work first time, will not work second time maybe iii) etoposide 2) post remission a) Goal- to clear up the remaining leukemic cells b) give cytarabine alone- if no donor Toxicity i) cerebellar toxicity ii) pulmonary toxicity

c) stem cell transplant- if donor available If M3, add tretinoin along with this- DOC for M3 Danourubicin + tretinoin can get retinoic acid syndrome- dyspnea, chest pain, pleural effusion excessive treatment leads to sticking of leukemic cells in these areas CML Increased proliferation of all the stages mainly mature cells and excess of mature cellshighest number of WBCs very few blast cells Mature cells are more in number but survive longer and this long survival is represented as a low LAP score (leukocyte alkaline phosphatase- enzyme released in leukocytes) if survive longer, the enzymes go lower with age high LAP- leukemoid reaction! Pathogenesis: Translocation (9,22) Bcr- abl fusion gene (this is 100% specific to CML******* not t 9, 22); Philadelphia chromosome- after fusion of chr 22 BCR (breakpoint cluster region)- chr 22; ABL- chr 9 (reverse translocation as 9 attached to 22) philadephia chr as it happened in Philadelphia makes p210 increases tyrosinase kinase activity mitotic activity goes up and more and more cells are forming = reduces apoptosis = more cells and longer surviving cells 9, 22 also in ALL Clinical presentation 1) insidious onset as chronic and will take a long time 2) high cell turnover a) fever without infection b) excessive sweating c) tumour lysis syndrome- gout- add allopurinol- as lots of uric acid formation d) weight loss 3) bone tenderness a) check in sternum and will hurt bad 4) splenomegaly a) compresses stomach- early satiety 5) thrombocytopenia- bleeding, eccymoses 6) chloroma is rare 7) leukostasis due to tons of cells- clump and prevent flow- leads to thrombus formation a) blindness- clotting of retinal vessels b) priapism- sustained and painful- coagulation of penile BVs 8) lymph nodes can be enlarged Diagnosis 1) BM biopsy- few blasts, high cell count 2) nucleated RBCs 3) anemia, granulocytopenia

4) CML is the only leukemia with a potential for thrombocytosis****** everywhere else thrombocytopenia but not all CML will have this! a) thrombocytosis is MC though! Complications 1) Accelerated phase a) increased in blasts b) never goes beyond 20% (10-20%) c) comes 2-3 post diagnosis with an inc in blast cells, splenomegaly, anemia (cannot be explained by bleeding), prominent basophilia***** (>20%) inc histamine and pruritis, diarrhea etc. d) will not respond well to the treatment e) survival after this is 1-2 years 2) Blast crisis- very bad prognosis a) increased in blast cells b) blasts go beyond 20%- CML becomes AML c) Pelger Ruet Anomaly- hypersegmented neutrophils d) survival after is 4-6 months e) smoking increases the risk of CML patients going to this Treatment 1) Imatinib mesylate- Gleevac wonder drug and has changed the prognosis of CML dramatically cure is high and can work for accelerated and blast crisis apoptosis of cells of t 9, 22 signal transduction inhibitor can work for all age groups 2) newer version of imatinib- nesatinib 3) ifn-a 4) busulfan 5) stem cell transplant- younger the patient the better; if diagnose within 1 year of onset and got donor, best prognosis why not called BM transplant? Stem cell source is not only from BM anymore; can be from circulation or umbilical cord; a) autologous- if cancer is controlled, promote stem cell growth and put in BM i) advantages- no rejection as from own body ii) disadvantages- might be some cancer activity and you put in bm b) allogenic- take from a diff person that is HLA matched (should be 100%; only one loci diff allowed) i) advantages- no relapse of cancer ii) disadvantages- rejection 6) splenectomy- if worried about pressure symptoms or thrombocytopenia 7) leukophoresis- take granulocytes and leukocytes out of the blood ALL

Acute leukemia decided by a) less than 3 months b) lymphoblasts instead of myeloblasts c) blasts >20 % Causes 1) viruses****- EBV (burkitts, hodgkins, post- organ transplant lymphoma), HTLV-1 (adult T cell), Hep C (plasmocytic lymphomas) , HIV (large diffuse lymohomas), H. pylori (small cell lymphoma) 2) medication 3) immunodeficiency Clinical Presentation 1) weight loss 2) fatigue 3) weakness 4) anemia 5) CNS and testicle infiltration*************- specific to ALL a) testicular- unilateral, painless enlargement of the testis- Right testicle is higher than left testicle and IVC pulls the right testicle higher up b) CNS- focal neurological deficit, epilepsy, coma, nuchal rigidity 6) lymphadenopathy*************** (CLL and ALL) more prominent in ALL than AML Labs 1) more lymphoblasts than myeloblasts Treatment 3 phases 1) remission and induction a) vincristine b) predisone c) l-asparaginase Look to see if significant drop in blasts and if no blasts, remission! 2) consolidation (CNS prophylaxis) think of ALL a) mtx + 6-MP mtx is given intrathecally in the subarachnoid space 3) maintenance a) daily low dose/ weekly dose of cytarabine/ mtx/ cyclophosphamide 4) stem cell transplant is good too CLL MC Leukemia and very slow growing and that is why in the >60 yrs Can be aggressive: 1) richters syndrome- when CLL converts to diffuse large cell lymphomas Causes Similar to CML Clinical Presentation

1) lymph nodes everywhere MC lymph node disorders- non hodgkins > plasma cells > CLL > hodgkins All other ones the same as CML 2) no thrombosis***** Diagnosis 1) look for lymph cells Treatment 1) cytarabine (or fludarabine) + rituximab + cyclophosphamide 2) localized lymph node therapy is one of the options Adult T cell Linked with HTLV-1 Flower nuclei Bone- osteoporosis like condition (unique), hypercalcemia Hairy Cell Leukemia Cytoplasmic projections TRAPP pos Hugh spleen and can come to the right side Increased infection with M. avium No lymphadenopathy MCC of leukemia cutis Treatment 1) Cladribine