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Home , Acute monocytic leukemia, Acute myeloid leukemia, Monocytic leukemia

Common Presentations of AML • vague history of chronic progressive lethargy Acute myeloid and related myeloid : • 1/3 of patients with acute leukemia will be acutely ill with significant skin, soft tissue, or respiratory WHO 2008 brings us closer to . understanding clinical behavior No conflicts of interest to disclose • Petechiae with or without bleeding may be present

• 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 is generally low but severe is uncommon • Approximately 9,000 new cases yr in US

• The peripheral white 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) • is frequently observed-- 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 , 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 • chemical exposure to , 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 for AML patients? • LkLeukem ia cause dbid by prior c hemo therapy Clinical understanding of disease goes only so far • Poor initial response to 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

French‐American British (FAB) French‐American British (FAB) Classification for AML Classification for AML

% of adult % of adult FAB 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 M5 Acute 10% Average M5 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… 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 that are abnormally silenced? same is doomed to fail. Cytogenetics

Figure from Baylin and Schuebel, Nature 2007

2 Prognostic value of single mutations for Major cytogenetic subgroups of AML and associated gene subsets of AML (partial list) mutations

Gene 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 ) 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 (pending eval of EF) • Consolidation chemotherapy – A third drug, , may be added too – pt in complete 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 and (consolidation) therapy is required or patients will have transfusion dependence universally relapse • Repeat 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 suggest benefit for transplant, but debate rages… • Cornellison et al, Blood, 2007 •Koreth at al, JAMA, 2009

5 Outcomes in AML patients over 60 years of age based on karyotype at diagnosis…POOR In treating older AML patients with

127/635 standard therapy, the combination of low efficacy and high toxicity is Cytogenetics 5 year OS

CBF 19% not terribly appealing …

Fewer than 5 aberrations; 7.5% no rare aberration, not CBF >5 aberrations or rare 0 aberrations Can subsets be identified that will do better than others with intensive therapy?

Farag, et al, Blood 2006 (CALGB)

Treating the “older” AML patient

•Who should be treated “intensively”? Subsets who are likely to do better than most… –Core binding factor (CBF) AML Myelodysplastic syndromes – Those with NPM1 gene mutations (()MDS)

•Consider alternative (experimental) therapy if: – Comorbid disease –Age >70 – Borderline functional status – Cytogenetic adverse risk

MDS: Characteristics MDS: Clinical Overlap/Associations •Clonal bone marrow disorders usually with hypercellular marrow, low counts, and cell function abnormalities – “ineffective erythropoiesis”, resources being used but the final PNH product is essentially non‐functional MDS

AA AML • Natural history is highly variable –Typical presentation is older patient with and anemia, often patients are treated inappropriately for iron deficiency initially PRCA LGL –Can progress to AML, often fatal even if it does not due to high risk of MPD infection over time

•No cure except for allogeneic transplantation, but most patients are elderly and not candidates

6 Myeloid Neoplasms: major subgroups and features at diagnosis

Disease BM Cellularity % Marrow Blasts Maturation Morphology Blood Counts Organomegaly

MPN Usually Normal or slightly Present , Effective Variable; one or Common increased, increased; <10% in erythroid precursors more myeloid often normal in chronic phase relatively normal, lineage usually ET megakaryocytes initially I thought this was supposed to abnormal increased Myeloid/lymphoid Increased Normal or slightly Present Relatively normal Effective Eosinophilia Common Neoplasms with increased; <20% in (≥1.5x109/L) eosinophilia and chronic phase abnormalities of be a talk about WHO 2008! PDGFRA, PDGFRB, OR FGFR1 MDS Increased, Normal or increased; Present Dysplasia in one or Ineffective Cytopenia(s) Uncommon occasionally <20% more myeloid normocellular lineage or hypocellular MDS/MPN Increased Normal or slightly Present Usually one or more May vary among Variable, WBC Common increased; <20% lineages dysplastic; lineages usually JMML often has increased minimal dysplasia AML Usually Increased >20%, Varies, May or may not be Ineffective or WBC variable, Uncommon increased except in some cases usually associated with effective usually with specific minimal dysplasia in one or anaemia and cytogenetic more lineages thrombocy- abnormalities or in topenia some cases of erythroleukaemia MPN, myeloproliferative neoplasms, MDS, myelodysplastic syndromes; MDS/MPN, myelodysplastic/myeloproliferative neoplasma; AML, acute myeloid leukaemia; ET, essential thronbocythaemia; JMML, juvenile myelomonocytic leukaemia; WBC, white blood cells.

Myeloproliferative Neoplasms Significant changes in the diagnosis and (MPN) classification of MPN • The nomenclature has been changed from "myeloproliferative disorders" (MPDs) to "myeloproliferative neoplasms" (MPNs). •Chronic myelogenous leukaemia, BCR-ABL positive (CML) • Diagnostic algorithms for PV, ET, and PMF have substantially changed to include information regarding JAK2 V617F and •Chronic neutrophilic leukaemia (CNL) similar activating mutations. Additional clinical, laboratory, and •Polyyycythaemia vera ( PV) histologic parameters have been included to allow diagnosis and sub cl assifi cati on regardl ess of wh eth er JAK2 V617F or a • (PMF) similar mutation is or is not present. •Essential thrombocythaemia (ET) • The platelet count threshold for the diagnosis of ET has been •Chronic eosinophilic leukaemia, NOS (CEL, NOS) lowered from 600 x 109/L to 450 x 109/L. • • Some cases previously meeting the criteria for chronic •Myeloproliferative , unclassifiable (MPN, eosinophilic leukemia (CEL) may be categorized in a new U) subgroup, "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1."

• Systemic mastocytosis has been included in the MPN category.

Significant changes in the diagnosis Myelodysplastic Syndromes and classification of MDS •Refractory cytopenia with unilineage dysplasis (RCUD) • Patients with refractory cytopenia(s) suspected to – Refractory anaemia (RA) have MDS, but who lack diagnostic morphologic – Refractory neutropenia (RN) features may be considered to have presumptive – Refractory thrombocytopenia (RT) evidence of MDS if they have specific MDS-related •Refractoryyg() anaemia with ring sideroblasts (RARS) cytogenetic abnormalities. •Refractory cytopenia with multilineage dysplasia (RCMD) •Refractory anaemia with excess blasts (RAEB) • An over-arching category of MDS, refractory cytopenia with unilineage dysplasia, has been added •Myelodysplastic syndrome with isolated del(5q) to incorporate patients who exhibit unilineage •Myelodysplastic syndrome, unclassifiable (MDS,U) dysplasia associated with refractory anemia •Childhood myelodysplastic syndrome (unilineage erythroid dysplasia), refractory – Provisional entity: Refractory cytopenia of childhood neutropenia (unilineage dysgranulopoiesis), or (RCC) refractory thrombocytopenia (unilineage dysmegakaryocytopoiesis), and who have fewer than 1% blasts in the blood and fewer than 5% in the bone marrow.

7 Acute Myeloid Leukaemia Related Significant changes in the diagnosis Myeloid Neoplasms and classification of MDS

• The category of refractory cytopenia with multilineage dysplasia is Acute myeloid leukaemia with recurrent genetic abnormalities no longer subdivided according to whether 15% or more of the AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 erythroid precursors are ring sideroblasts (RS), that is, the former category of RCMD-RS is now incorporated in RCMD. AML with inv(16)(P13.1q22) or t(16;16)(p13.1;q22); CBFB- MYH11 • Patients with 2% to 4% blasts in the blood and less than 5% blasts AML with t(15;17)(q22;q12);PML-RARA ithbin the bone marrow sh ould ldbdi be diagnosed as h avi ng RAEB -1if1 if AML with t(9;11)(p22;q23);MLLT3-MLL other clinical and laboratory findings of MDS are present. AML with t(6;9)(p23;q34); DEK-NUP214 • A provisional entity, refractory cytopenia of childhood (RCC), has AML with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1 been added to include children with cytopenia(s) with less than AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 2% blasts in the peripheral blood and less than 5% in the bone marrow and evidence of dysplasia in 2 or more lineages. For Provisional entity: AML with mutated NPM1 children with 2% to 19% blasts in the blood and/or 5% to 19% in Provisional entity: AML with mutated CEBPA the bone marrow, the MDS subclassification should be made using the same criteria used for adults. Acute myeloid leukaemia with myelodysplasis-related changes

Therapy-related myeloid neoplasms

Acute Myeloid Leukaemia Related Myeloid Neoplasms

Acute myeloid leukaemia, not otherwise specified AML with minimal differentiation AML without maturation AML with maturation Major Changes in AML Acute myelomonocytic leukaemia Acute monoblastic/monocytic leukaemia categgyory Acute erythroid leukaemias Pure erythroid leukaemia Erythroleukaemia, erythroid/myeloid Acute megakaryoblastic leukaemia Acute basophilic leukaemia Acute panmyelosis with myelofibrosis Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis Myeloid leukaemia associated with Down syndrome Blastic plasmacytoid dendritic cell neoplasms

AML with recurrent genetic AML with recurrent genetic abnormalities abnormalities

• As in the previous edition, AML with t(8;21)(q22;q22), • The former category, AML with 11q23 (MLL) abnormalities has inv(16)(p13.1q22) or t(16;16)(p13.1;q22), and APL with been redefined to focus on AML with t(9;11)(p22;q23); MLLT3- t(15;17)(q22;q12) are considered as acute leukemia regardless MLL. Translocations of MLL other than that involving MLLT3 of blast count in the PB or BM, but in contrast to the previous should be specified in the diagnosis. Other abnormalities of MLL, edition, for AML with t(9;11)(p22;q23) or other 11q23 such as partial tandem duplication of MLL should not be placed in abnormalities, as well as for all other subgroups (except the this category. rare instance of some cases of erythroleukemia) blasts of 20% or more of white blood cells in PB or of all nucleated BM cells • Three new cytogenetically defined entities are added: (1) AML with is required for the diagnosis of AML. t(6;9)(p23;q34); DEK-NUP214, (2) AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1; and (3) AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1. • In APL with t(15;17)(q22;q12); PML-RARA, variant RARA translocations with other partner genes are recognized • Two provisional entities are added: AML with mutated NPM1 and separately; not all have typical APL features and some have all- AML with mutated CEBPA. Although not included as a distinct or trans retinoic acid (ATRA) resistance. provisional entity, examination for mutations of FLT3 is strongly recommended in all cases of cytogenetically normal AML.

8 AML with myelodysplasia-related changes Therapy-related myeloid neoplasms

• Cases are no longer subcategorized • The name was changed and expanded from "AML with multilineage dysplasia" to "AML with as "alkylating agent related" or myyypelodysplasia-related changes." "topoisomerase II-inhibitor related."

• Cases of AML are assigned to this category if (1) they have a history of MDS or MDS/MPN and have evolved to AML, (2) they have a myelodysplasia- related cytogenetic abnormality, or (3) at least 50% of cells in 2 or more myeloid lineages are dysplastic.

Myeloid proliferations related to Down AML, Not Otherwise Specified syndrome • Some cases previously assigned to the subcategory of AML, NOS as acute erythroid leukemia or acute • This new category incorporates transient megakaryoblastic leukemia may be reclassified as abnormal myelopoiesis as well as MDS AML with myelodysplasia-related changes. and AML that is Down syndrome–related. MDS an d AML rel at ed t o D own synd rome • Cases previously categorized as AML, NOS, acute are biologically identical and thus are megakaryoblastic leukemia should be placed in the considered together as " appropriate genetic category if they are associated with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1, associated with Down syndrome." or AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1. Down syndrome–related cases are excluded from this category as well.

Blastic plasmacytic dendritic cell Myelodysplastic/Myeloproliferative neoplasm Neoplasms (MDS/MPN)

• This is a new category that includes most cases •Chronic myelomonocytic leukaemia (CMML) previously classified as blastic NK-cell lymphoma/leukemia or agranular CD4+ CD56+ •Atypical chronic myeloid leukaemia, BCR-ABL 1 negative (aCML) hematodermic neopp;lasm; it is derived from a precursor of plasmacytoid dendritic cells. •Juvenile myelomonocytic leukaemia (JMML)

•Myelodysplastic/Myeloproliferative neoplasm, unclassifiable (MDS/MPN,U)

•Provisional entity: Refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T)

9 Conclusions Significant changes in the diagnosis and classification of MDS/MPN • Never before have we had such powerful tools to deepen our understanding of AML and MDS

• Some cases of CMML with eosinophilia are relocated to the category "Myeloid/lymphoid neoplasms with eosinophilia • No patient group has truly “favorable” risk with the and PDGFRB rearrangement." possible exception of APL

• The category atypical CML has been renamed atypical CML, BCR-ABL1–negative to emphasize that it is not merely a • Heterogeneity of disease highlights the need to deepen variant of CML, BCR-ABL1–positive. our molecular understanding of pathogenesis to develop • RARS-T remains as a "provisional entity" classified as effective new treatments MDS/MPN, unclassifiable, RARS-T. The criteria have been – And to find the patients who should OR should not receive a modified to include refractory anemia, dyserythropoiesis in particular therapy the bone marrow with ring sideroblasts accounting for 15% or more of erythroid precursors, and megakaryocytes with features resembling those in PMF or ET; the platelet • One fits all is easier. But we’ve tried that for 30+ years-- threshold is lowered to 450 x 109/L. its just not very effective…the future is molecular biology

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