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Basics of AML • the Hematocrit Is Generally Low but Severe Anemia Is Uncommon • Approximately 9,000 New Cases Yr in US

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Basics of AML • the Hematocrit Is Generally Low but Severe Anemia Is Uncommon • Approximately 9,000 New Cases Yr in US Common Presentations of AML • vague history of chronic progressive lethargy Acute myeloid leukemia and related myeloid neoplasms: • 1/3 of patients with acute leukemia will be acutely ill with significant skin, soft tissue, or respiratory WHO 2008 brings us closer to infection. understanding clinical behavior No conflicts of interest to disclose • Petechiae with or without bleeding may be present • Leukemias with a monocytic component may Steven Devine, MD have gingival hypertrophy from leukemia infiltration/ extramedullary involvement (of The Ohio State University CNS, gums, skin, other) Lab Findings in AML Basics of AML • The hematocrit is generally low but severe anemia is uncommon • Approximately 9,000 new cases yr in US • The peripheral white blood cell count may be increased, decreased, or normal. • Incidence of AML rises with advancing age – Approximately 35% of all AML patients will have ANC < 1,000/uL; circulating blast cells may be absent 15% of the time • The median age is 65 • Disseminated intravascular coagulation (DIC) is common, it is nearly universal in acute promyelocytic leukemia – Most children with leukemia have ALL (not AML) • Thrombocytopenia is frequently observed-- platelet counts <20,000/uL are common, often leads to bruising or bleeding (gums, petechiae) • AML is about 80% of adult acute leukemias But usually we don’t know why… Outcomes for AML patients are poor, few older patients (those age>60) survive 5 years • An increased incidence of AML is associated with certain congenital conditions like Down syndrome, Bloom's syndrome, Fanconi's anemia Outcomes for younger AML patients For older patients (>60 years) • Patients with acquired diseases such as myelodysplastic syndromes, myeloproliferative disorders, and other pre-leukemic states may progress to AML • A variety of environmental factors, both work/treatment- related may cause the disease • exposure to ionizing radiation • chemical exposure to benzene, and possibly Farag, et al, Blood 2006 (CALGB) hydrocarbons Byrd, et al, Blood 2002 (CALGB) • treatment with alkylating agents, topoisomerase inhibitors 1 • Older age (>60) Outcomes worse if: • High WBC (over 20,000/uL) How can we improve outcomes • Prior hematologic disorder like myelodysplastic syndrome for AML patients? • LkLeukem ia cause dbid by prior c hemo therapy Clinical understanding of disease goes only so far • Poor initial response to chemotherapy How can we begin to tell that one AML is • Poor performance status different from another (in terms of likelihood that our treatment will work)? • ADVERSE RISK CYTOGENETICS French‐American British (FAB) French‐American British (FAB) Classification for AML Classification for AML % of adult % of adult FAB Prognosis compared to FAB Prognosis compared to Name AML Name AML subtype average for AML subtype average for AML patients patients Undifferentiated acute myeloblastic Undifferentiated acute myeloblastic M0 5% Worse M0 5% Worse leukemia leukemia Acute myeloblastic leukemia with Acute myeloblastic leukemia with M1 15% Average M1 15% Average miiinima l maturation miiinima l maturation Acute myeloblastic leukemia with Acute myeloblastic leukemia with M2 25% Better M2 25% Better maturation maturation M3 Acute promyelocytic leukemia 10% Best M3 Acute promyelocytic leukemia 10% Best M4 Acute myelomonocytic leukemia 20% Average M4 Acute myelomonocytic leukemia Morphology20% Averagedoes Acute myelomonocytic leukemia with Acute myelomonocytic leukemia with M4 eos 5% Better M4 eos not5% tell you whoBetter will eosinophilia eosinophilia M5 Acute monocytic leukemia 10% Average M5 Acute monocytic leukemia get10% cured andAverage who M6 Acute erythroid leukemia 5% Worse M6 Acute erythroid leukemia will5% not Worse M7 Acute megakaryoblastic leukemia 5% Worse M7 Acute megakaryoblastic leukemia 5% Worse How we understand risk in Molecular diagnostics—what AML is finally changing… mutations are relevant to outcome The only way to make a leap forward in and (hopefully) treatment selection? improving outcomes in AML… The human genome project comes to AML …understand the molecular biology of the disease(s). …understand the reality that each AML case is unique. Treating all cases the The epigenome and AML‐‐‐role of normal genes that are abnormally silenced? same is doomed to fail. Cytogenetics Figure from Baylin and Schuebel, Nature 2007 2 Prognostic value of single gene mutations for Major cytogenetic subgroups of AML and associated gene subsets of AML (partial list) mutations Gene Mutation Prognostic Impact NPM1 Favorable in absence of Flt3 ITD Flt3 ITD Unfavorable Flt3 TKD CtControvers ilial CEBPA Favorable MLL PTD Unfavorable Ras Neutral WT‐1 Controversial Runx1 Unfavorable Dohner, K. et al. Haematologica 2008;93:976‐982 Note: APL excluded Cytogenetic/Molecular If you were the patient, what would Risk Stratification for 2010 Known as “core‐ binding factor” sound better? Risk group Subsets AML Favorable t(8;21)(q22;q22); RUNX1‐RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB‐MYH11 “History tells us that you are likely to do poorly Mutated NPM1 without FLT3‐ITD (normal karyotype) with conventional treatment, but its all we have Mutated CEBPA (normal karyotype) so let’s give it a try anyway.” Intermediate‐I All other combinations of FLT3 and NPM1 Intermediate‐II t(9;11)(p22;q23); MLLT3‐MLL Cytogenetic abnormalities not classified as favorable or adverse “History tells us that you are likely to do poorly Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1‐EVI1 with conventional treatment, so we have altered t(6;9)(p23;q34); DEK‐NUP214 t(v;11)(v;q23); MLL rearranged your treatment plan to mitigate this risk and ‐5 or del(5q); ‐7; abnl(17p); complex karyotype; monosomal karyotype improve your chances.” Adapted from Dohner et al, Blood 2010 Quick terminology for AML Treatment/Induction • Supportive care as discussed • Induction chemotherapy • 7+3 – patient with leukemia about to be treated – 7 days of Ara-c by continuous infusion – 3 days of an anthracycline (pending eval of EF) • Consolidation chemotherapy – A third drug, etoposide, may be added too – pt in complete remission at last testing, no • Inpatient care for induction usually required evidence of disease (patient has already • Remission occurs in 60-80% of patients gone home, and this is planned at the follow up visit) 3 More terminology Typical course of AML induction • Complete response (CR): • ANC >1000, Plt >100, RBC independence • In house about a month • maturation of all hematopoietic cell lines • less than 5% blasts • Older patients fare far worse in terms of response as well as treatment-related • No other signs or symptoms of disease morbidity/mortality • Leukemic burden 1012 reduced to 109, additional • Most patients develop febrile neutropenia and (consolidation) therapy is required or patients will have transfusion dependence universally relapse • Repeat Bone Marrow at count recovery Consolidaton 5 years without relapse after • Varying opinions in required number of consolidations or “cycles” needed, but we do know it high dose Ara-C is required as without it nearly all patients relapse #pts 5 yr • Typically first consolidation occurs 2-3 weeks after survival count recovery from induction Inv 16 57 79% t(8,21) • Subsets of patient do far better Normal 140 40% – when High Dose Ara-c (HiDAC) is given Cytog Adverse • Allogeneic transplantation may be employed for 88 21% Cytog those with the high risk of relapse, even in first remission; and after relapse Bloomfield, et al. 1998 How do we integrate the prognostic/ predictive information in AML? What should we do with high risk Single‐gene Gene profiles marker miRNA profiles AML patients? Individualized Treatment Cytogenetics Age, clinical factors Genome sequencing? 4 How can we use prognostic Use of cytogenetics to select therapy information more effectively in 2010? Patients with “core‐binding factor” (CBF) fusion genes Use cytogenetics and molecular risk to guide have better survival when choices for therapy they receive repeated cycles of high dose cytosine arabinosid e (ara‐c) after they achieve remission. – Chemotherapy This is called consolidation –Role of allogeneic stem cell transplantation for therapy. patients in first complete remission (CR1) –We need better therapies targeting unique molecular aberrations for each patient! Bloomfield, et al. 1998, depicted are all patients, but That’s why they are in the benefit to higher dose was due to CBF patients “favorable” risk group AlloHCT for AML Patients <60 years Role of transplantation in CR1 • Allogeneic hematopoietic cell transplant • Adverse risk cytogenetics (AlloHSCT) is the single most effective therapy –Most agree allograft appropriate consolidation at least currently available for the prevention of up to 55‐60 years of age. (Those >60 years require relapse novel transplantation techniques in order to survive the process) •But, AlloHCT is still risky and many treating physicians remain reluctant to recommend in CR1 until mortality rates can be substantially lowered AlloHCT for AML Patients <60 years AlloHCT for AML Patients <60 years in CR1 in CR1 • Adverse risk cytogenetics • Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least –Most agree allograft appropriate consolidation at least up to 55‐60 years of age up to 55‐60 years of age • Favorable risk cyygtogenetics (CBF pp)atients) • Favorable risk cytogenetics –No role for transplant –No role for transplant • Intermediate risk cytogenetics –This is where it gets complicated – Recent meta‐analyses
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