ces 2016 02 - acute and chronic myeloid leukemias

CES 2016.02: Acute Myeloid LeukemiaMauricio Lema Medina MD

Definiciones• Linfoma:

– Tumor maligno de tejido linfoides• Leucemia:

– “Sangre blanca” : Neoplasia maligna de la célula madre hematopoyética que causa proliferación de leucocitos •Blastos – formas inmaduras (Aguda)•Células de apariencia más diferenciada (Crónica)•Granulocitos (mieloide) •Linfocitos (linfoide)

Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004

Definiciones• Leucemia aguda:

– Leucemia en donde el elemento celular que prolifera es inmaduro (blastos).

– > 20% de blastos en la médula ósea. • Mieloide

– si exhibe morfología o marcadores de granulocitos o sus precursores

• Linfoide – si exhibe morfología o marcadores de linfocitos o sus

precursores• Bifenotípica

– si exhibe marcadores de ambas estirpes


Definiciones• Leucemia crónica:

– Leucemia en donde el elemento celular que prolifera exhibe diferenciación similar a la normal. •Linfoide

– Si la célula que domina es similar en apariencia y en marcadores a los linfocitos maduros

•Mieloide – Si las celulas que proliferan son similares a los

precursores de los granulocitos


Leucemias


Leucemias Aguda• Acumulación de blastos en la medula ósea


Manifestaciones Clínicas leucemias agudas

• Síntomas debido a:– Falla medular– Infiltración tisular– Leucostasis– Síntomas constitucionales– Otros (CID)

• Duración corta de síntomas


Falla medular• Neutropenia:

– Infecciones y sepsis• Anemia:

– Fatiga, palidez• Trombocitopenia:

– Sangrado


Infiltración de tejidos y órganos

• Bazo, hígado y GL agrandados• Hipertrofia gingival• Dolor óseo• Otros órganos: CNS, piel, testiculo


Leucostasis• Acumulación de blastos en la

microcirculación afectando la microcirculación

• Pulmones: hipoxemia, infiltrados pulmonares

• SNC: stroke• WBC > 50 x 109/L


Síntomas Constitucionales• Fiebre y sudoración (Común)• Pérdida de peso (menos común)


Examen físico• Fiebre• Esplenomegalia• Hematomegalia• Linfadenopatía• Dolor esternal• Sangrado: GI, SNC, cutáneo• Coagulopatía• Infiltración gingival• Infiltración meníngea• Sangrado retiniano


Características de laboratorio

• WBC usualmente elevado pero puede ser normal o bajo

• Blastos en sangre periférica• Anemia normocítica• Trombocitopenia• CID• > 20% de blastos en MO


Médula Ósea en Leucemia Aguda

• Necesaria para el diagnóstico• Útil para determinar el tipo• Útil para el pronóstico


Etiology• Classified by the

cellular appearance of the primary stem cell– Common myeloid

progenitor (CMP)•AML or ANLL

– Common lymphoid progenitor (CLP)•ALL

Myeloblast with Auer rods

http://upload.wikimedia.org/wikipedia/commons/d/d8/Auer_rods.PNG

http://www.pathologystudent.com/?attachment_id=21

Distinción de LMA de LLA• Microscopía de luz

– LMA: Auer, gránulos citoplásmicos– LLA: no Auer rods ni granulos.

• Tinciones especiales (cytochemistry)• Citometría de flujo


LMA


Bastones de Auer en LMA


LLA


TINCIONES INMUNOHISTOQUÍMICA FRECUENTEMENTE UTILIZADAS EN LEUCEMIAS

Nombre de la tinción Tipo de LeucemiaMieloperoxidasa (MPO) Células Mielomonocíticas

Sudán Negro B (SBB) Células Mielomonocíticas

Esterasa de cloroacetato (SE) Células Granulocíticas y sus blastos

Esterasa alpha naftilbutirato (NSE)

Células Monocíticas

PAS en bloques Linfoblastos, eritroblastos

PAS en parches Células Mieloides

TdT La mayoría de los linfoblastos, algunos mieloblastos

Fosfatasa ácida resistente a tartrato

Leucemia de Células Vellosas

Fosfatasa alcalina leucocitaria Baja en leucemia mieloide crónica

Azul de prusia Anemia refractaria con sideroblastos en anilloCreado por: Mauricio Lema Medina - LemaTeachFiles© - 2004

CORRELACIÓN DE LA INMUNOHISTOQUÍMICA Y EL INMUNOFENOTIPO DE LEUCEMIAS AGUDAS

Clasificación del FAB

Inmunohistoquímica Inmunofenotipo

M0 MPO-, SBB-, SE-, NSE- CD13, CD33, HLA DR, icMPO, TdT+/-

M1 MPO+, SBB+, SE+, NSE- CD13, CD33, HLA DR, icMPO

M2 MPO+, SBB+, SE+, NSE- CD13, CD33, HLA DR, icMPO

M3 MPO+, SBB+, SE+, NSE- CD13, CD33, icMPO

M4 MPO+, SBB+, SE+, NSE+ CD13, CD33, HLA DR, icMPO, CD14

M5 MPO+/-, SBB+, SE-, NSE+ CD13, CD33, HLA DR, icMPO, CD14

M6 MPO+, SBB+, PAS+ CD13+/-, CD33+/-, icMPO, Glicoforina

M7 MPO-, SBB+/-, PAS+ CD33, CD41, CD61, icMPO

L1, L2 MPO-, SBB-, PAS+ CD19, CD10+/-, sIg-

L3 MPO-, SBB-, PAS+ CD19, sIg+, Kappa o Lamda

LLA de células T MPO-, SBB-, PAS+ CD3+/-, icCD3+

Abreviaturas: MPO: Mieloperoxidasa, SBB: Sudán negro B, SE: Esterasa específica, NSE: Esterasa no específica, PAS: Periodic Acid-Shiff, ic: Intracelular


M1: AML without maturation• Myeloblast with

Auer rod• High N:C ratio• Fine chromatin• Prominent nuclei

M2: Aml with maturation

All stages of neutrophil maturation>20% myeloblastsAuer rods common

M3: promyelocytic leukemia (faggot cell)

Faggot cells with bundles of Auer rodsGenetic translocation t(15;17)Hypergranulation

M4: Acute myelomonocytic leukemia (AMML)

Monoblasts and promonocytes seenSome neutrophil precursors seenVacuolization often seen

M5: Acute monoblastic leukemia

MonoblastsHemophagocytosisNuclear lobulation

M6: Acute erythroid leukemia

Striking poikHigh number of RBC precursors>20 Myeloblasts

• Peripheral blood– May see micromegakaryoblasts– Megakaryocyte fragments– Cytopenias– Dysplastic segmented neutrophils and

platelets• Bone marrow

– Often get “dry tap” – Fibrosis

M7: Acute Megakaryoblastic Leukemia

Acute myeloid leukemia

AML is a neoplastic disease characterized by infiltration of the blood, bone marrow, and other tissues by proliferation, clonal undifferentiated cells of the hematopoietic system.

Harrisons’s, 19th Ed.

Acute myelogenous leukemia

3.5 por 100.000

Male preponderance

Increases with age (10x more frequent in older than 65)

Hereditary: 21+, Fanconi, Bloom, ATM, Kostman, p53, RunX1, C/EBP alfa

Preleukemic blood conditions: MDS/MPS

1

2

3

4

5

Introduction


Acute Myeloid Leukemia

Radiation

Chemicals: Benzene, a solvent used in the chemical, plastic, rubber, pharmaceutical industries. Petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides

Drugs: Alkylating agents, topo II inhibitors, other anti cancer agents, chloramphenicol, phenyl butazone, chloroquine, methoxypsoralen

1

2

3

Introduction



WHO classification of AML

Morphology, Immunophenotype, Clinical, Cytogenetics and Molecular

More than 20% of myeloid blast in the bone marrow

With recurrent genetic abnormalities: t(8;21)/RUNX1, inv(16), t(16;16), t(15;17)/PML/RARA, 11q (MLL)

AML with myelodysplasia-related changes: post MDS, post MDS/MPD, sin MDS

Therapy-related myeloid neoplasm

123

AML, not otherwise specified (AML with minimal differentiation, AML without maturation, AML with maturation, Acute myelomonocytic leukemia, Acute monoblastic and monocytic leukemia, Acute Erythroid leukemia, Acute Megakaryocytic leukemia, Acuta basophilic leukemia, Acute panmyelosis with myelofibrosis

4

Other:Myeloid sarcomaMyeloid proliferations related to Down syndromeBlastic plasmocytoid dendritic neoplasm

5


Hematopoietic SC

Epigenetic deregulationMutations in DNMT3A, ASXL1, IDH2, and TET2

Preleukemic SC

Further mutations

AML

Döhner H et al. N Engl J Med 2015;373:1136-1152.

Eight Functional Categories of Genes That Are Commonly Mutated in Acute Myeloid Leukemia.


Blasts: CD13+, CD33+ Megakariocytes: CD41+/CD61+ APL

t(15;17) PML/RARA rearrangements

Core Binding Factor (CBF) AML t(8;21)(q22;q22), Inv(16)(p13,1q22),

t(16;16)(p13.1;q22) Fusion product RUNX1-RUNX1T1 CBFB-MYH11

t(15;17) with APL, Inv(16) with abnormal eosinophils, t(8;21) with slender Auer rods, expression of CD19, and increased normal eosinophils , t(9;22), t(11…) with abnormal monocytes

PML/RARA RUNX1-RUNX1T1…t(8:21) CBFB-MYH11… inv(16) or t(16;16) MLLT3-MLL… t(9;11) DEK-NUP214… t(6;9)(p23;q34) FLT3 ITD (prognostic in normal karyotype AML) AML with mutated NPM1 AML with mutated CEBPA

Immuophenotype, genetics, chromosomes and molecular classification


Molecular prognostic markers in AMLGenes Chromosome location Prognostic impactNPM1 mutations 5q Favorable

CEBPA 19q Favorable

FLT3-ITD 13q Adverse

Kit mutation 4q Adverse

FLT3-TKD 13q Adverse

RUNX1 mutations 21q Adverse

WT1 mutations 11p Adverse

ASXL1 mutations 21q Adverse

DNMT3A mutations 2p Adverse

IDH mutations 2q Adverse

MLL-PTD 11q Adverse

TET2-mutations 4q Adverse

BAALC overexpression 8q Adverse

ERG overexpression 21q Adverse

MN1 overexpression 21q Adverse

EVI1 overexpression 3q Adverse

miR155 overexpression 21q Adverse

miR3151 overexpression 8q Adverse

miR181a overexpression 1q Favorable Harrisons’s, 19th Ed.

Döhner H et al. N Engl J Med 2015;373:1136-1152.

Frequency and Clinical Significance of Recurrent Gene Mutations in Adults with AML.


Chromosome findings at diagnosis are the most important independent prognostic factors in AML

Prognostic factors

t(15;16)RUNX1-RUNX1T1t(8;21)Inv(16)

CN-AML

Complex karyotypet(6;9), inv(3), -5, -7, abn(17p)t(v;11)(v;q23)MLL rearranged, RPN1-EVI1Monosomal karyotype

NPM1 mutations (without FLT3 mutations)CEBPA mutations

FLT3 mutations (with or without NPM1 mutation)


Smith ML, et al. Blood Rev. 2011;25:39-51.

Independent Prognostic Variables in AML

MRC/NCRI AML Trials: OS

100

80

40

20

00 1 2

Patie

nts

Aliv

e (%

)

3 4 5 6 7 8 9 10

t(15;17) (n = 330)t(8;21) (n = 247)inv(16)/t(16;16) (n = 154)CEBPα biallelic (n = 47)FLT3-ITD WT/NPM1 mut (n = 248)Other intermediate (n = 471)FLT3-ITD mut/NPM1 WT (n = 100)Other adverse (n = 130)

76%

58%52%51%

26%

11%

Yrs From Entry

60


Adverse prognostic factors- Age- Prolonged cytopenias- Treatment-related AML- Low PS- High blodd leukocyte count- Hyperleukocytosis

- CNS bleeding- Pulmonary leukostasis

Achievemente of CR is associated with a good prognosis- ANC greater than 1000- Platelet greater than 100.000- No circulating blasts- BM blasts less than 5%- Absence of extramedullary

leukemia


Kantarjian H, et al. Cancer. 2010;21:4896-4901.

Survival in AML by Time Period

1.0

0.8

0.6

0.4

0.2

0

Surv

ival

Pro

babi

lity

0 1 2 3 4 5 6 7Yrs

1980-Present Age< 60 ≥ 60

Total19201769

Died12651519

Median, Mos17.5 6.2

5 Yrs, %308

P < .001

8

Acute myeloid leukemia: symptoms

Nearly half have had symptoms for less than 3 months Fatigue (half) Anorexia & weight loss Fever (10%) Abnormal hemostasis: bleeding / bruising (5%) Bone pain Lymphadenopathy Tumor mass of myeloid blasts


Acute myeloid leukemia: signs

Fever Splenomegaly Hepatomegaly Lymphadenopathy Sternal tenderness Infection Hemorrhage

Retinal hemorrhage (15%) GI Bleeding Pulmonary bleeding CNS bleeding

Infiltration of the skin, gingivae, soft tissues, meninges (monoblastic leukemia and those with 11q23 chromosomal abnormalities


Acute myeloid leukemia: hematologic findings

Anemia Normocytic normochromic Reduced reticulocyte count Accelerated RBC destruction Active blood loss

Leukocyte count abnormalities Median leukocyte count at presentation: 15.000 Leukopenia in 25-40% Leukocytosis greater than 100.000 in 25%

Peripheral leukocyte abnormalities Seen in 95%. Primary nonspecific granules Fine, lacy chromatin One or more nucleoli Auer rods

Thrombocytopenia Found in 75% 25% have less than 25.000 Abnormal shapes


Acute myeloid leukemia: pretreatment evaluation

PS

Dentition/Retinal evaluation

BM aspirate / biospsy- Morphology- Cytogenetics (Karyotype)- Flow-cytometry- Molecular studies

Overall functional integrity of:- CV: Echocardiography- Pulmonary- Hepatic- Renal- Viral serology (CMV, HSV-1, varicella-zoster)

AML cytogenetics and molecular markers

Rule-out infection

RBC type and screen

Address anemia and thrombocytopenia- Clotting studies- Consider platelet transfusion if bleeding

About 50% have high serum uric acid- Allopurinol- Hydration

HLA testing for possible allogeneic HSCT

Placement of CVA device

Lumbar puncture if CNS symptoms

Spinal MRI if back pain


Diagnosis AML

CBF AML Low-Risk CN-AML High-Risk AML

Daunorubicin-Cytarabine induction

chemotherapy


chemotherapy


chemotherapy

CR CR CR

High-dose cytarabine Autologous HSCT Allogenic HSCT

No CR/Relapsed No CR/Relapsed No CR/Relapsed

Re-induction, followed by

Allogeneic HSCT

Re-induction, followed by

Allogeneic HSCTPalliative

Relevant Trials of Dose-Intensification in AML

ECOG E1900: daunorubicin 90 mg/m2 x 3 superior to 45 mg/m2 x 3 in pts < 60 yrs[1] - But not in patients with adverse cytogenetics, FLT3-ITD, or aged 50 yrs or older

HOVON: daunorubicin 90 mg/m2 x 3 = 45 mg/m2 x 3 in pts ≥ 60 yrs[2]

- But superior in patients aged 60-65 yrs

ALFA-9801: idarubicin 12 mg/m2 x 3 and x 4 superior to daunorubicin 80 x 3 for CR[3]

- But not for EFS and OS

MRC AML15: more durable CR in patients receiving FLAG-Ida than ADE/DA[4]

- But higher initial toxicity

HOVON: high-dose cytarabine = intermediate-dose cytarabine in induction[5]

- Unknown whether intermediate dose = “standard dose”

1. Fernandez H, et al. N Engl J Med. 2009;361:1249-1259. 2. Löwenberg B, et al. N Engl J Med. 2009;361:1235-1248. 3. Pautas C, et al. J Clin Oncol. 2010;28:808-814. 4. Burnett AK, et al. Leukemia. 2013;27:843-851. 5. Löwenberg B, et al. N Engl J Med. 2011;364:1027-1036.

7+3Cytarabine 100-200 mg/m2, continuous infusion, q24, x7 days Anthracycline: Daunorubicin 90 mg/m2/qd (or idarubicin 12 mg/m2), days 1, 2, 3

High-dose Cytarabine + AnthracyclineCytarabine 2000 mg/m2, q12h, 6 daysAnthracycline: Daunorubicin 60 mg/m2/qd (or idarubicin 12 mg/m2), days 1, 2, 3

Cytarabine Hematologic

Neutropenia Anemia Thrombocytopenia

Mucositis Pulmonary toxicity Irreversible cerebellar toxicity

Anthracyclines Hematologic Mucositis Cardiac


Older than 60 may not tolerate induction classic induction chemotherapy

Daunorubicin 45 mg/m2 Single-agent Clofarabine or Azacytidine

are used FLT3 inhibitors appear promising (quizartinib) Gemtuzumab-ozogamicin useful in CBF

leukemia Gemtuzumab-ozogamicin reduces relapse and

increases survival when combined with chemotherapy in patients (young and all) WITHOUT poor prognostic cytogenetics.

If after induction chemotherapy, leukemic cells are present in the BM, consider 5+2 reinduction (prognosis is poorer, though).

Other considerations about induction chemotherapy


HD-Ara-C2-4 cycles of HiDAC in younger (less than 60) AML patientsCytarabine 3000 mg/m2, q12h, days 1, 3 and 5

Cytarabine Hematologic

Neutropenia Anemia Thrombocytopenia

Mucositis Pulmonary toxicity Irreversible cerebellar toxicity

2-4 cycles of HiDAC in younger (less than 60) AML patientsCytarabine 1000-1500 mg/m2, q12h, days 1, 2, 3

2-4 cycles of HiDAC in younger (less than 60) AML patientsCytarabine 1000-1500 mg/m2, qd, days 1, 2, 3, 4, 5, 6

AML in the elderly

Kantarjian H, et al. Cancer. 2006;106:1090-1098.

AML in Older Adults: Disease and Patient Factors Predict Prognosis

• Adverse prognostic factors– Aged 75 yrs or older– Unfavorable karyotype– Treatment outside LAFR– AHD ≥ 12 mos– ECOG PS > 2– LDH > 600 u/L– Creatinine > 1.3 mg/dL

• Risk group by number of factors

– Low: 0– Intermediate: 0-2– High: ≥ 3

Prop

ortio

n of

Pat

ient

s Su

rviv

ing

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 12 24 36 60 84 9648 72

Mos

Survival SurvivalRisk group Total Dead Median, % at

Mos 5 YrsLow 121 82 18 17Intermediate 558 475 7 8High 301 288 1 1P < .001

Source: With permission from Sekeres MA et al. Blood 2008;112:Abstract 221.

Methyltransferase Inhibitor (MTI) Induced DNA Hypomethylation and Gene Activation

Azacitidine (AZA) and decitabine (DAC) are incorporated into DNA in lieu of cytosine residueInactivates DNA methyltransferase (DMT)Leads to formation of newly synthesized DNA with unmethylated cytosine residuesResults in hypomethylation and transcription of previously quiescent genes

DMT

AZA

A:T

C:G

G:C

C:G

G:Cm

mDMT

DAC

A zDMT

A:T

C:G

G:C

C:G

G:C

5

Azacytidine vs Conventional Care Regimens for WHO-Defined AML: OS

Fenaux P, et al. J Clin Oncol. 2010;28:562-569.

Prop

ortio

n of

Pat

ient

s Su

rviv

ing

1.00.90.80.70.60.50.40.30.20.1

04010 15 20 25 30 35

Mos Since Random Assignment

16.0 mos

16% Conventional care

50%24.5 mos Azacitidine

Patients at Risk, nAzacytidineConventional care

5558

00

4343

2622

156

103

40

10

3836

0

Acute promyelocytic leukemia

Considerations Bleeding Thrombosis Abundant Auer rods

APL t(15;17) PML/RARA rearrangements

Treatment considerations Differentiating agents

ATRA (all trans-retinoic acid) Arsenic trioxide

Anthracycyclines Most patients do not need Allo-HSCT Maintenance chemotherapy

ATRA / 6-MP / Methotrexate Excellent prognosis (85%)

t(15;17), PML/RARA

APL0406 Study of ATRA + ATO or Chemo in Low-/Intermediate-Risk APL: Results

ATRA + ATO was noninferior to ATRA + chemotherapy for 2-yr EFS in patients with low-/ intermediate-risk APL

100% CR with ATO, 95% CR with chemo

Incidence of differentiation syndrome similar between arms

OS: 98.7% with ATRA + ATO vs 91.1% with ATRA + chemo (P = .02)

Lo-Coco F, et al. ASH 2012. Abstract 6.

EFS

0

40

80

100

0

Prob

abili

ty o

f EFS

(%)

12 24 36 48 60Mos From Diagnosis

P = .02 ATRA + ATOATRA + chemo

97.1%

85.6%

20

60

Further reading

• AML, in Harrison’s 19th Ed, Chapter 107 (678-686)• Döhner H et al. N Engl J Med 2015;373:1136-1152.

CES 2016.02: Chronic myeloid leukemiaMauricio Lema Medina MD

Chronic myeloid leukemia (CML)

“CML is a clonal hematopoietic stem cell disorder. The disease is driven by de BCR-ABL1 chimeric gen product, a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation beween the long arms of chromosmes 9 and 22, t(9;22)(q34;q11.2), cytogenetically detected as te Philadephia chromosome (Ph)”

Kantarjian H, Cortes J.



“Presence of BCR-ABL1 abnormality in a patient with a myeloproliferative neoplasm”



Anatomía patológica - Autopsia

Crisis blástica

Fase crónica

CML

Esplenomegalia masiva Sangre blanca

Últimos meses de vida Indistinguible de una leucemia

aguda Fiebre, anemia, sangrado

Supervivencia de 2-4 años Letal en 100%

Pocos años Esplenomegalia masiva Leucocitosis No anemia, no trombocitopenia

Caracterización nosológica

Chronic myeloid leukemia

Incidence and epidemiology- 15% of all cases of leukemia- Median age at diagnosis is 55-65- Only 3% younger than 20- Incidence increases with age- Incidence in the US: 1.5/100.000/yr- Stable incidence in the US- Worlwide incidence estimated at 100.000 cases/yr- Prevalence in the US rising- No familial clustering- Only very-large radiation exposure appear to increase CML

BCR-ABL1Activating autophosphorilation

BCR-ABL1p

Transcription

Apoptosis

Cytoskeletal organization

Degradation of inhibitory proteins

210 kDaltons

BCR-ABL1 variants

BCR-ABL1 normal variant- p210- “Normal” CML

Centromeric BCR-ABL1 variant- p190 - Common in Ph+ ALL- Poorer prognosis in CML

Telomeric BCR-ABL1 variant- P230- AKA micro-BCR-ABL1- More indolent course

Resistant BCR-ABL1 variants- Several- Usually become apparent after TKI therapy- The most significant is the highly TKI-resistant T351I

Further molecular derangements p53, p16, RB, MYC, EV11

Multiple pathway activation

BCR-ABL1

+8, iso-17q and second PhGenomic instability

LeukocytosisSplenomegaly

Proliferation

Chronic phase

Accelerated phase

Blastic crisis

CML: symptoms

In the US, 50-60% of patients are ASYMPTOMATIC when diagnosed (routine lab tests)

In other parts of the world, patients present with high CML burden

Splenomegaly Anemia Abdominal pain Weight loss Fatigue


CML: symptoms


Parameter PrecentageOver 60 yo 18

Female 45

Splenomegaly 30

Hepatomegaly 5

Lymphadenopathy 5

Hb less than 10 15

Platelets greater than 450 35

Plasteles less than 100 5

WBC greater than 50 40

BM blasts greater than 5% 5

BM basophils greater than 5% 15

PB blasts greater than 3% 10

PB basophils greater than 7% 10

Cytogenetic clonal evolution 5

Sokal low-risk 65

Sokal intermediate-risk 25

Sokal High-risk 10

CML: symptoms

Unusual presentation Thrombotic or vasoocclusive events

Priapism Myocardial infarction Venous thrombosis Visual disturbances Dyspnea Pulmonary insufficiency Drowsiness Loss of coordination Confusion Cerebrovascular accidents


CML: symptoms

Unusual presentation Bleeding

Retinal hemorrhages GI Bleed

Accelerated phase Fever Cachexia Severe fatigue Bone and joint aches Bleeding Thrombotic events Infections


Chronic myeloid leukemia: signs

Splenomegaly (20-70%) Hepatomegaly Lymphadenopathy Extramedullary disease (CML transformation) High basophil may cause histamine:

Pruritus, Diarrhea, Flushing and GI ulcers


Chronic myeloid leukemia: hematologic findings

Peripheral blood leukocytes Leukocytosis: 10-500.000 Left-shift

Neutrophils Bands Myelocytes Metamyelocytes Promyelocytes Blasts (less than 5%)

Increased eosinophils Increased basophils

Thrombocytosis Thrombocytemia is rare, and portends a poor outcome

Anemia In 1/3

Low leukocyte alkaline phosphatase High B12 levels, uric acid, LDH and lysozyme An unexplained and sustained leukocytosis should prompt a BM

examination with cytogenetics


neutrófilo

basófilo

metamielocitos

mielocitos


F. Crónica

F. Blástica

Chronic myelogenous leukemia: bone marrow and cytogenetics

Bone marrow Should always be performed at diagnosis Hypercellular Marked myeloid hyperplasia High myeloid to erythroid ratio (15-20:1) BM blasts less than 5% Increased reticulin stain

CytogeneticsDocumentation of t(9;22)(q34;q11.2) in 90%Clonal evolution appears in 10% at diagnosis

Trisomy 8A double pHIsochromosome 1717p deletion20q-

FISH or PCR


Chronic myelogenous leukemia: response criteria

Complete hematologic response (CHR) Normal CBC

Partial cytogenetic response Ph+ metaphases in 35%, or less Equivalent to BCR-ABL1 transcripts by the IS of 10% or less

Complete cytogenetic response (CCyR) Cytogenetic (ie, karyotype) absence of Ph abnormality Equivalent to BCR-ABL1 transcripts by the IS of 1% or less

Major molecular response (MMR) Equivalent to BCR-ABL1 transcripts by the IS of 0.1% or less Greater than a 3-log decrease in the BCR-ABL1 transcript

Complete molecular response (CMR) Equivalent to BCR-ABL1 transcripts by the IS of 0.0032 or less Greater than a 4.5-log decrease in the BCR-ABL1 transcript


Crisis Blastic crisisPB or BM Blasts greater than 30%

Extramedullary involvementMay be myeloid or lymphoid, or other

Accelerated phasePB blasts greater than 15%,

PB blasts + Promyelocytes greater than 30% PB basophils greater than 20%,

Cytogenetic clonal evolutionThrombocytopenia less than 100.000

Chronic phaseLeukocytosis< 5% Blastos

< 15% Basophils< 20% Blasts + Promyelocytes

Platelets > 100.000/mm3

Harrison’s, 19th Ed.

70% OS at 4-yrs

75% OS at 8-yrs


Prognosis for CML patients today are dependent on depth of response to TKI therapy.



Anti-BCR-ABL1 TKI- Imatinib

- First generation- Approved in chronic-, accelerated-, blastic- phase, salvage therapy

- Nilotinib- Second generation (30 times more potent than imatinib)- AE: Hyperglycemia, pancreatitis. LT: diabetes, vasoocclusive.- Approved in chronic-, accelerated-, salvage therapy

- Dasatinib- Second generation (300 times mor potent than imatinib)- Dual SRC-ABL inhibition. - AE: Pleural or pericardial effusions, myelosup.. LT: Pulmonary HTN- Approved in chronic-, accelerated-, blastic- phase, salvage therapy

- Bosutinib- Second generation (50 times mor potent than imatinib)- Dual SRC-ABL inhibition. - AE: Diarrhea- Approved as salvage therapy

- Ponatinib- Third generation. Higher toxicity including HTN, CV events- Active against T351I mutation

Non-TKI protein synthesis inhibitor- Omacetaxine

Chronic myeloid leukemia

Imatinib, dasastinib or nilotinib

Dasastinib, nilotinib, bosutinib orponatinib

First-line

SalvagePonatinib: T351I

TKI AEs Well tolerated SAEs in 5-10% Fluid retention, weight gain, nausea,

diarrhea, skin rashes, periorbital edema, bone or muscle aches, fatigue.

Nilotinib and dasatinib can cause QTc prolongation

Chronic toxicities: renal dysfunction (all, 3%), pulmonary hypertension (dasatinib), arterial hypertension (ponatinib), diabetes and hyperglycemia (nilotinib), vasoocclusive complications (nilotinib, ponatinib)

Theratogenic (3/125).

Allogeneic HSCT is curative in CML

1-year treatment-related mortality of 5-30%

Futher 10-15% die of subtle complications over the years- Chronic GVHD- Second malignancies- Organ dysfunction

Other AEs- Infertility- Cataract formation- Hip necrosis- Chronic immune related complications

Allogeneic HSCT in Chronic myeloid leukemia


Allogeneic HSCT in Chronic myeloid leukemia

CML phase Use of TKI Allo-SCT

Accelerated or blastic Interim therapy to achieve minimal CML burden

As soon a possible (exception: de novo accelerated phase)

Imatinib failure in chronic phase; T351I mutation

Ponatinib to achieve minimal CML burden

Depends on LT follow-up

Imatinib failure on chronic phase; no clonal evolution; no mutations; good initial response

Second-line TKI long-term Third-line after second-line TKI failures

Imatinib failure in chronic phase; clonal evolution or mutations or no cytogenetic response to second-line TKI

Interim therapy to achieve minimal CML burden

Second-line

Olter patients after imatinib failures in chronic phase

Salvage TKIs as longer-term therapy

May forgo Allogeneic SCT in favor of good QoL


Chronic phase CML

Imatinib 400 mg QD,

No CHR at 3 months(BCR-ABL > 10% a 3 months)

ConsiderDasatinib / Nilotinib

BCR-ABL > 10% at 6moBCR-ABL > 0.1% at 12mo

ConsiderDasatinib / Nilotinib

No

Yes

Si

No (continue Imatinib)

Continue Imatinib


“Achievement of complete cytogenetic response (CCyR) by 12 months of imatinib (or in 3-6 months with nilotinib/dasatinib) therapy and its persistence later, the only consistent prognostic factor associated with survival is the main therapeutic endpoint in CML”

Both molecular and cytogenetic (ie, FISH) are used frequently until CCyR is achieved.

“Earlier response has been identified as a prognostic factor for LT outcome, including partial cytogenetic response by 3-6 monts of therapy (BCR-ABL1 transcripts less than 10%)”.



European leukemia-net – response definitions

ces 2016 02 - acute and chronic myeloid leukemias

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