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MED-341: Acute Leukaemia

MED-341: Acute Leukaemia. Professor Abdulkareem Almomen, MD, FRCPC (March 2011). Acute Leukaemia: main subtypes. Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Biphenotypic Acute Leukemia (BAL): My + Ly. Proliferation + differentiation block / maturation arrest.

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MED-341: Acute Leukaemia

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  1. MED-341: Acute Leukaemia Professor Abdulkareem Almomen, MD, FRCPC (March 2011)

  2. Acute Leukaemia: main subtypes • Acute Myeloid Leukemia (AML) • Acute Lymphoblastic Leukemia (ALL) • Biphenotypic Acute Leukemia (BAL): My + Ly

  3. Proliferation + differentiation block / maturation arrest AML: definition / concept • Clonal expansion of myeloid blasts in blood marrow (BM), peripheral blood (PB) or other tissue • Minimum threshold of blast cells for defining AML (BM): • >20% blasts

  4. Maturation arrest

  5. Maturation arrest

  6. Normal Bone Marrow: Cell Heterogeneity

  7. BM in AML: Monomorphous Cell Appearance

  8. AML5a AML4-eos

  9. AML: epidemiology • Incidence: 2 - 3 pts /100.000 inhab - year • Overall: 1.2% (US) • Lineal increase with age: <35: < 1 /100.000 inhab - year >65: >10 /100.000 inhab - year • Median age: 60 - 70 year-old • Not apparent increase during last years

  10. AML: clinical presentation • Bone marrow failure • Anemia • Neutropenia • Thrombocytopenia • Extramedullary involvement (skin, gums, CNS, other) • Proliferative symptoms • Coagulopathy • Leukostasis • Metabolic disorders (tumor lysis syndrome)

  11. AML: skin infiltration (granulocytic sarcoma)

  12. AML: gums (gingival) infiltration

  13. Acute Myeloid Leukemia (AML)

  14. AML - diagnosis: • Cytology • PB • BM (BM aspirate ± BM biopsy) • Cytochemistry • MPO (myeloperoxidase) & Sudan Black B (SBB) – Myeloid origin • Non-specific esterase (NSE): -naphthyl acetate (ANA), -naphthyl butyrate (ANB) – Monocytic origin • Inmunophenotype • Hematopoietic precursors: CD34, HLA-DR, CD45 • My Ag: CD13, CD33, CD15, MPO, CD117 • Megakaryoblastic Ag: CD41, CD61 • Cytogenetics • Molecular biology • Fusion transcripts (RT-PCR): PML/RAR-, AML1/ETO, CBF-/MYH11, MLL/..., BCR/ABL, DEK/CAN) • New mutations with prognostic impact: flt-3-ITD, CEBPalfa, NPM, …

  15. AML – Auer rod

  16. MPO Naphtol-As-D-acetate esterase -naphthyl acetate esterase AML : Cytochemistry

  17. CD14 PE 104 104 100 100 101 101 102 103 102 103 100 103 101 102 104 100 101 102 103 104 104 100 101 102 103 104 100 101 102 103 CD123 FITC CD2 FITC CD34 FITC NG2 PE CD56 PE AML : Flow cytometry

  18. AML: Cytogenetics

  19. FISH: PML/RARA fusion signal bcr1bcr3 RT-PCR PML/RAR-alpha Acute Promyelocytic Leukemia (APL, M3) Anti-PGM3 pattern staining

  20. FAB classification for AML: lineage/differentiation- based • Minimally differentiated (M0) • AML w/o maturation (M1) • AML with maturation (M2) • Promyelocytic (M3) • Myelomonocytic (M4) • Monoblastic (M5a) • Monocytic (M5b) • Erythroleukemia (M6) • Acute megakaryoblastic (M7) Granulocytic diff Monocytic diff

  21. WHO classification (AML): towards molecularly-based categories I. AML with recurring genetic abnormalities • AML with t(8;21)(q22;q22) & (AML1/ETO) rearrangement • AML with abn BM eosinophils & inv(16)(p13q22)/t(16;16)(p13;q11) - CBF/MYH11 rearrangement • Acute promyelocytic leukemia associated to t(15;17)(q22;q11-12) & PML/RAR- rearr • AML with 11q23 (MLL) abn II. AML with multilineage dysplasia III. Therapy-related AML IV. AML not otherwise categorized WHO, 2001

  22. AML: main cytogenetic abnormalities • Favorable:t(15;17), t(8;21), inv(16) • Intermediate risk:normal karyotype • Unfavorable:abn 5 (del/-5), abn 7 (del/-7), inv(3q)/t(3;3), complex karyotype (≥5 abn), abn 11q, t(6;9), del(17p)

  23. Anthacycline + Ara-C /… Induccion CT Refractory Salvage therapy Post-remission tx CR~75% Intensification CT Ara-C HD-based Relapse CT AlloSCT AutoSCT Long-term OS~35-40% (<60) AML (non-APL): standard approach

  24. Acute Lymphoblastic Leukemia (ALL)

  25. ALL: definition • Clonal expansion of lymphoid (precursor lymphoid cells) in blood marrow (BM), peripheral blood (PB) or other tissue

  26. ALL: main subtypes • B-cell ALL / precursor B lymphoblastic leukemia • T-cell ALL / precursor T lymphoblastic leukemia

  27. ALL: epidemiology • Incidence: 2/100.000 (inhab-year) • 3/4 in children • B-ALL: • 80-85% • Predominance in children • 10% presenting without BM involvement (B-cell lymphoblastic lymphoma) • T-ALL: • 15% of children ALL • 25% of adult ALL • Predominance in adolescent / young male pts • Frequent presentation with exclusive extramedullary involvement (T-cell lymphoblastic lymphoma)

  28. ALL: characteristic clinical features • Extramedullary involvement • CNS • Mediastinal (T-ALL) • Other (lymph node, testicular, ...) • B symptoms • Bone marrow failure • Metabolic disorder

  29. T-ALL: mediastinal involvement

  30. ALL – FAB1 subtype

  31. ALL – FAB2 subtype

  32. B-ALL: immunological classification Common B-lineage antigens: HLA-DR, CD19, CD79a,CD22 • Pro-B (B-cell progenitor, B-I): Tdt+, CD10(-), cytIg(-), CD20(-) • Common (early pre-B, B-II): TdT(+), CD10(+),cytIg(-) • Pre-B (B-III): Tdt(+), cytIg(+) • Mature B-ALL (B-IV):Tdt(-), sIg+, CD20(+)

  33. T-ALL: immunological classification T-ALL/Common Ag: Tdt, CD3cyt, CD7 • Early T-ALL: CD1(-),CD2(-),CD3s(-), CD5(-),CD4(-), CD8(-) • Thymic T-ALL: CD1a(+),CD2(+),CD5(+) • Mature T-ALL: CD1a(-), CD2(+),CD5(+),CD3s(+)

  34. ALL: main cytogenetic abnormalities • Favorable: t(12;21), • Intermediate risk: normal karyotype, t(1;19) • Unfavorable: t(9;22), 11q23 abn [t(4;11) & other], hypoploid

  35. Antr. / VCR / PDN L-ASA, ARA-C, CFM CR:  83% Consolidation CT AlloSCT AutoSCT ALL: current therapeutic approach Induction Post-remission CT (reinduction & maintenance) Surv*:  80% (children)  35% (adults)

  36. Bcr-Abl Substrate P ATP P P P Y = Tyrosine P = Phosphate Imatinib: molecular-targeted therapy for Ph-positive ALL Abl: a highly overexpressed tyrosine kinase protein in CML & Ph-pos ALL Goldman et al, Lancet 2000

  37. Imatinib: blocks abl function by interfering with ATP binding Bcr-Abl Substrate P ATP P P P Y = Tyrosine P = Phosphate Imatinib: molecular-targeted therapy for Ph-positive ALL Bcr-Abl Goldman et al, Lancet 2000

  38. Outcome • Response criteria • Complete response • Cytogenetics response • Molecular response • Failure: primary refractory, relapse • …

  39. Definition of CR NCI criteria (Cheson et al, 1999) • <5% blasts in BM • Absence of extramedullary leukemia • Recovery of PB counts (ANC >1 & platelet >100x109/L) • Minimum 4-week duration

  40. Response assessment: types (degree) of response CR (morphologic assessment)<5% of BM blast cells Low sensitivity Universally applicable Cytogenetic CRAbsence of abnormal metaphases Low sensitivity Only in cases with cytogenetic abn (i.e., Ph-pos) Molecular response Clearance of molecular marker (bcr/abl, PML/RAR, AML1/ETO,...) Only in AL with known molecular marker High sensitivity (1 x 10-5)

  41. Morphologic assessment of response Non-CR CR

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