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Home , Acute monocytic leukemia, Acute myeloid leukemia

Acute myeloid and related myelidloid neoplasms: WHO 2008 brings us closer to understanding clinical behavior No conflicts of interest to disclose

Steven Devine, MD The Ohio Sta te UiUnivers ity Common Presentations of AML • vague history of chronic progressive lethargy

• 1/3 of patients with acute leukemia will be acutely ill with significant skin, soft tissue, or respiratory .

• Petechiae with or without bleedinggy may be present

• Leu kem ias w ith a monocy tic componen t may have gingival hypertrophy from leukemia infiltration/ extramedullary involvement (of CNS, gums, skin, other) Lab Findings in AML • The is generally low but severe is uncommon

• The peripheral white cell count may be increased, decreased, or normal. – Approximately 35% of all AML patients will have ANC < 1,000/uL; circulating blast cells may be absent 15% of the time

• Disseminated intravascular coagulation (DIC) is common, it is nearly universal in acute promyelocytic leukemia

• is frequently observed-- counts <20,000/uL are common, often leads to bruising or blee ding (gums, pe tec hiae ) Basics of AML • Approximately 9,000 new cases yr in US

• Incidence of AML rises with advancinggg age

• The median age is 65 – Most children with leukemia have ALL (not AML)

• AML is about 80% of adult acute But usuallyyy we don’t know why…

• An increased incidence of AML is associated with certain conggyyenital conditions like , Bloom's syndrome, Fanconi's anemia

• 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 hydrocarbons • treatment with alkylating agents, topoisomerase inhibitors Outcomes for AML patients are poor, few older patients (h(those age>60) survive 5 years

Outcomes for younger AML patients For older patients (>60 years)

Farag, et al, Blood 2006 (CALGB) Byrd, et al, Blood 2002 (CALGB) • Older age (>60) Outcomes worse if:

• High WBC (over 20 , 000/uL)

• Prior hematologic disorder like

• Leukemia caused by prior

• Poor initial response to chemotherapy

• Poor performance status

• ADVERSE RISK How can we improve outcomes for AML patients?

Clinical understanding of disease goes only so far

How can we begin to tell that one AML is different from another (in terms of likelihood that our treatment will work)? French‐American British (FAB) Clflassification for AML

% of adult FAB compared to Name AML subtype average for AML patients Undifferentiated acute myeloblastic M0 5% Worse leukemia Acute myeloblastic leukemia with M1 15% Average minimal maturation Acute myeloblastic leukemia with M2 25% Better maturation M3 Acute promyelocytic leukemia 10% Best M4 Acute myelomonocytic leukemia 20% Average Acute myelomonocytic leukemia with M4 eos 5% Better M5 Acute 10% Average M6 Acute erythroid leukemia 5% Worse

M7 Acute megakaryoblastic leukemia 5% Worse French‐American British (FAB) Clflassification for AML

% of adult FAB Prognosis compared to Name AML subtype average for AML patients Undifferentiated acute myeloblastic M0 5% Worse leukemia Acute myeloblastic leukemia with M1 15% Average minimal maturation Acute myeloblastic leukemia with M2 25% Better maturation M3 Acute promyelocytic leukemia 10% Best M4 Acute myelomonocytic leukemia Morphology20% Averagedoes Acute myelomonocytic leukemia with M4 eos not5% tell you whoBetter will eosinophilia M5 get10% cured andAverage who M6 Acute erythroid leukemia will5% not Worse M7 Acute megakaryoblastic leukemia 5% Worse The only way to make a leap ffdorward in improving outcomes in AML…

…understand the molecular biology of the disease(s).

…understand the reality that each AML case is unique. TTtireating all cases the same is doomed to fail. How we understand risk in Molecular diagnostics—what AML is finally changgging… are relevant to outcome and (hopefully) treatment selection?

The human genome ppjroject comes to AML

The epigenome and AML‐‐‐role of normal that are abnormally silenced? Cytogenetics

Figure from Baylin and Schuebel, Nature 2007 Prognostic value of single mutations for subsets of AML (partial list)

Gene MMttiutation PtiPrognostic IItmpact NPM1 Favorable in absence of Flt3 ITD Flt3 ITD Unfav orable Flt3 TKD Controversial CEBPA FblFavorable MLL PTD Unfavorable Ras Neutral WT‐1Controversial Runx1 Unfavorable Major cytogenetic subgroups of AML and associated gene mutations

Dohner, K. et al. Haematologica 2008;93:976‐982 Note: APL excluded Cytogenetic/Molecular Ris k SifiiStratification for 2010 Known as “core‐ binding factor” 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 Mutated NPM1 wittouthout FLT3‐ITD ((onorm al kayotype)aryotype) Mutated CEBPA (normal )

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

Adverse inv(()(qq3)(q21q26.2 ) or t(3 ;3)(q 21 ;q26.2 ); RPN1‐EVI1 t(6;9)(p23;q34); DEK‐NUP214 t(v;11)(v;q23); MLL rearranged ‐5 or del(5q); ‐7; abnl(17p); complex karyyp;yotype; monosomal karyypyotype

Adapted from Dohner et al, Blood 2010 If you were the patient, what would sound better?

“History tells us that you are likely to do poorly with conventional treatment, but its all we have so let’s give it a try anyway.”

“History tells us that you are likely to do poorly with conv entio n al treatme nt, so we haaeve aaeedltered your treatment plan to mitigate this risk and improve your chances.” Quick terminology for AML

• Induction chemotherapy – patient with leukemia about to be treated

• Consolidation chemotherapy – pt in complete at last testing, no evidence of disease (patient has already gone home, and this is planned at the follow upp) visit) Treatment/Induction

• Supportive care as discussed • 7+3 – 7 days of Ara-c by continuous infusion – 3 days of an (pending eval of EF) – A third drug, eto poside , ma y be added too • Inpatient care for induction usually required • Remission occurs in 60-80% of patients More terminology

• Complete response (CR): • ANC >1000, Plt >100, RBC independence • maturation of all hematopoietic cell lines • less than 5% blasts • No other signs or symptoms of disease

• Leukemic burden 1012 reduced to 109, additional (consolidation) therapy is required or patients will universally relapse Typical course of AML induction

• In house about a month

• Older pa tien ts fare f ar worse i n t erms of response as well as treatment-related morbidity/mortality

• Most patients develop febrile and have transfusion dependence

•Repeat B on e M arr ow at count r ecov er y Consolidaton • Varying opinions in required number of consolidations or “cycles” needed, but we do know it is required as without it nearly all patients relapse

• Typically first consolidation occurs 2-3 weeks after count recovery from induction

• Subsets of patient do far better – when High Dose Ara-c (HiDAC) is given

• Allogeneic transplantation may be employed for those with the higgp,h risk of relapse, even in first remission; and after relapse 5 years without relapse after high dose Ara-C #pts 5 yr survival Inv 16 57 79% t(8,21) Normal 140 40% Cytog Adverse 88 21% Cytog

Bloomfield, et al. 1998 What should we do with high risk AML patients? How do we integrate the prognostic/ predictive information in AML?

Single‐gene Gene profiles marker miRNA profiles Individualized Treatment Cytogenetics Age, clinical factors

Genome sequencing? How can we use prognostic information more effectively in 2010? Use cytogenetics and molecular risk to guide choices for therapy

– Chhhemotherapy –Role of allogeneic stem cell transplantation for patien ts in firs t compltlete remiiission (CR1) –We need better therapies targeting unique molecular aberrations for each patient! Use of cytogenetics to select therapy

Patients with “core‐binding factor” (CBF) fusion genes have better survival when they receive repeated cycles of high dose cytosine arabinoside (ara‐c) after they achieve remission.

This is called consolidation therapy.

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 Role of transplantation

• Allogeneic hematopoietic cell transplant (AlloHSCT) is the single most effective therapy currently available for the prevention of relapse

•But, AlloHCT is still risky and many treating physicians remain reluctant to recommend in CR1 until mortality rates can be substantially low ered AlloHCT for AML Patients <60 years in CR1 • Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to 55‐60 years of age. (Those >60 years require novel transplantation techniques in order to survive the pp)rocess) AlloHCT for AML Patients <60 years in CR1 • Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to 55‐60 years of age •Favorable risk cytogenetics – No role for transplant AlloHCT for AML Patients <60 years in CR1 • Adverse risk cytogenetics –Most agree allograft appropriate consolidation at least up to 55‐60 years of age •Favorable risk cytogenetics (CBF patients) –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 Outcomes in AML patients over 60 years of age bdbased on karyotype at diagnosi s…POOR

127/635

Cytogenetics 5 year OS

CBF 19%

Fewer than 5 aberrations; 7.5% no rare aberration, not CBF >5 aberrations or rare 0 aberrations

Farag, et al, Blood 2006 (CALGB) In tttireating older AML patien ts with standard therapy, the combination of low efficacy and high toxicity is not terribly appealing …

Can subsets be identified that will do bttbetter than others with intensive therapy? Treating the “older” AML patient

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

• Consider alternative (experimental) therapy if: – Comorbid disease –Age >70 – Borderline functional status – Cytogenetic adverse risk Myelodysplastic syndromes (MDS) MDS: Characteristics •Clonal disorders usually with hypercellular marrow, low counts, and cell function abnormalities – “ineffective erythropoiesis”, resources being used but the final product is essentially non‐functional

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

•No cure except for allogeneic transplantation, but most patients are elderly and not candidates MDS: Clinical Overlap/Associations

PNH MDS

AA AML

PRCA LGL MPD I thought this was supposed to be a talk about WHO 2008! Myeloid Neoplasms: major subgroups and features at diagnosis

Disease BM Cellularity % Marrow Blasts Maturation Morphology Blood Counts Organomegaly

MPN UllUsually NllihtlNormal or slightly PtPresent GltGranulocytes, Effecti ve ViblVariable; one or Common increased, increased; <10% in erythroid precursors more myeloid often normal in chronic phase relatively normal, lineage usually ET megakaryocytes initially abnormal increased Myeloid/lymphoid Increased Normal or slightly Present Relatively normal Effective Eosinophilia Common Neoplasms with increased; <20% in (≥15x101.5x109/L) eosinophilia and chronic phase abnormalities of PDGFRA, PDGFRB, OR FGFR1 MDS Incr eased, Norm al or in cr eased; Presen t Dyspl asi a in on e or Ineeecteffective Cytopeni a(s) UUconcomm on 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 (MPN)

•Chronic myelogenous leukaemia, BCR-ABL positive (CML) •Chronic neutrophilic leukaemia (CNL) •Polycythaemia vera (PV) • (PMF) •Essential thrombocythaemia (ET) •Chronic eosinophilic leukaemia, NOS (CEL, NOS) • •Myeloproliferative neoplasm, unclassifiable (MPN, U) Significant changes in the diagnosis and classifi cati on of MPN

• The nomenclature has been changed from "myeloproliferative disorders" (MPDs) to "myeloproliferative neoplasms" (MPNs).

• Diagnostic algorithms for PV, ET, and PMF have substantially changed to include information regarding JAK2 V617F and simil ar acti vati ng mut ati ons. Additi onal cli ni cal , l ab orat ory, and histologic parameters have been included to allow diagnosis and subclassification regardless of whether JAK2 V617F or a similar is or is not present.

• The platelet count threshold for the diagnosis of ET has been lowered from 600 x 109/L to 450 x 109/L.

• Some cases previously meeting the criteria for chronic eosinophilic leukemia (CEL) may be categorized in a new subgroup, "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1."

• Systemic mastocytosis has been included in the MPN category. MldMyelodyspl ltiSdastic Syndromes •Refractory cytopenia with unilineage dysplasis (RCUD)

– Refractory anaemia (RA) – Refractory neutropenia (RN) – Refractory thrombocytopenia (RT) •Refractory anaemia with ring sideroblasts (RARS) •Refractory cytopenia with multilineage dysplasia (RCMD) •Re frac tory anaemi a w ith excess bl as ts (RAEB) •Myelodysplastic syndrome with isolated del(5q) •Myelodysplastic syndrome, unclassifiable (MDS,U) •Childhood myelodysplastic syndrome – Provisional entity: Refractory cytopenia of childhood (RCC) Significant changes in the diagnosis and classiffSfication of MDS

• PtitPatients with ref ract ory cyt openi i()a(s) suspect tdted to have MDS, but who lack diagnostic morphologic features may be considered to have presumptive evidence of MDS if they have specific MDS -related cytogenetic abnormalities.

• An over-arching category of MDS , refractory cytopenia with unilineage dysplasia, has been added to incorporate patients who exhibit unilineage dyypsplasia associated with refractor y anemia (unilineage erythroid dysplasia), refractory neutropenia (unilineage dysgranulopoiesis), or refractory thrombocytopenia (unilineage dysmegakaryocytopoiesis), and who have fewer than 1% blasts in the blood and fewer than 5% in the bone marrow. Significant changes in the diagnosis and classification of MDS

• The category of refractory cytopenia with multilineage dysplasia is no longer subdivided according to whether 15% or more of the erythroid precursors are ring sideroblasts (RS), that is, the former category of RCMD-RS is now incorporated in RCMD.

• Patients with 2% to 4% blasts in the blood and less than 5% blasts in the bone marrow should be diagnosed as having RAEB-1 if other clinical and laboratory findings of MDS are present.

• A provisional entity, refractory cytopenia of childhood (RCC), has been added to include children with cytopenia(s) with less than 2% blasts in the peripheral blood and less than 5% in the bone marrow and evidence of dysplasia in 2 or more lineages. For children with 2% to 19% blasts in the blood and/or 5% to 19% in the bone marrow, the MDS subclassification should be made using the same criteria used for adults. Acute Myeloid Leukaemia Related Myeloid Neoplasms

Acute myeloid leukaemia with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(P13.1q22) or t(16;16)(p13.1;q22); CBFB- MYH11 AML with t(15;17)(q22;q12);PML-RARA AML with t(9;11)(p22;q23);MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 Provisional entity: AML with mutated NPM1 Provisional entity: AML with mutated CEBPA

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 Acute myelomonocytic leukaemia Acute monoblastic/monocytic leukaemia Acute erythroid leukaemias Pure erythroid leukaemia Erythroleukaemia, erythroid/myeloid Acute megakaryoblastic leukaemia Acute basophilic leukaemia Acute ppyanmyelosis with m yelofibrosis Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis Myyyeloid leukaemia associated with Down syndrome Blastic plasmacytoid dendritic cell neoplasms Major Changes in AML category AML with recurrent genetic abnormalities

• As in the previous edition, AML with t(8;21)(q22;q22), inv(16)(p13.1q22) or t(16;16)(p13.1;q22), and APL with t(15;17)(q22;q12) are considered as acute leukemia regardless of blast count in the PB or BM, but in contrast to the previous edition, for AML with t(9;11)(p22;q23) or other 11q23 abnormalities, as well as for all other subgroups (except the rare instance of some cases of erythroleukemia) blasts of 20% or more of white blood cells in PB or of all nucleated BM cells is required for the diagnosis of AML .

• In APL with t(15;17)(q22;q12); PML-RARA, variant RARA translocations with other partner genes are recognized separatelllhilAPLfdhllly; not all have typical APL features and some have all- trans retinoic acid (ATRA) resistance. AML with recurrent genetic abnormalities

• The former category, AML with 11q23 (MLL) abnormalities has been redefined to focus on AML with t(9;11)(p22;q23); MLLT3- MLL. Translocations of MLL other than that involving MLLT3 should be specified in the diagnosis. Other abnormalities of MLL, suchtiltddlitifh as partial tandem duplication of MLL shldtblhould not be placed di in this category.

• Three new cytogenetically defined entities are added: (1) AML with 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.

• Two provisional entities are added: AML with mutated NPM1 and AML with mutated CEBPA. Although not included as a distinct or provisional entity, examination for mutations of FLT3 is strongly recommended in all cases of cytogenetically normal AML. AML with myelodysplasia-related changes

• The name was changed and expanded from "AML with multilineage dysplasia" to "AML with myelodysplasia-related changes."

• CfAMidhiif(1)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. Therapy-related myeloid neoplasms

• Cases are no longer subcategorized as "alkyygglating agent related" or "topoisomerase II-inhibitor related." AML, Not Otherwise Specified

• Some cases previously assigned to the subcategory of AML, NOS as acute erythroid leukemia or acute megakaryoblastic leukemia may be reclassified as AML with myelodysplasia-related changes.

• CiltidAMLNOStCases previously categorized as AML, NOS, acute megakaryoblastic leukemia should be placed in the appropriate genetic category if they are associated with inv(3)(q21q26 .2) or t(3;3)(q21;q26 .2); RPN1-EVI1, or AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1. Down syndrome–related cases are excluded from this categgyory as well. Myeloid proliferations related to Down syndrome

• This new category incorporates transient abnormal myelopoiesis as well as MDS and AML that is Down syndrome–related. MDS and AML related to Down syndrome are biologically identical and thus are considered together as " associated with Down syndrome." Blastic plasmacytic dendritic cell neoplasm

• This is a new category that includes most cases previously classified as blastic NK-cell lymphoma/leukemia or agranular CD4+ CD56+ hematodermic neoplasm; it is derived from a precursor of plasmacytoid dendritic cells. Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

•Chronic myelomonocytic leukaemia (CMML)

•Atypical chronic myeloid leukaemia, BCR-ABL 1 negative (aCML)

•Juvenile myelomonocytic leukaemia (JMML)

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

•Provisional entity: Refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) Significant changes in the diagnosis and classification of MDS/MPN

• Some cases of CMML with eosinophilia are relocated to the category "Myeloid/lymphoid neoplasms with eosinophilia and PDGFRB rearrangement."

• The category atypical CML has been renamed atypical CML, BCR-ABL1–negative to emphasize that it is not merely a variant of CML, BCR-ABL1–positive.

• RARS-T remains as a "provisional entity" classified as MDS/MPN, unclassifiable, RARS-T. The criteria have been modifffied to include refractory anemia, dyserythropoiesis in 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 thresh old is lowere d to 450 x 109 /L. Conclusions

• Never before have we had such powerful tools to deeppgen our understanding of AML and MDS

• No patient group has truly “favorable” risk with the possible exception of APL

• Heterogeneity of disease highlights the need to deepen our molecular understanding of pathogenesis to develop effective new treatments – And to find the patients who should OR should not receive a particular therapy

• One fits all is easier. But we’ve tried that for 30+ years-- its just not very effective…the future is molecular biology