CES 2016 02 - Acute and Chronic myeloid leukemias
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Transcript of 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
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Leucemias
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Leucemias Aguda• Acumulación de blastos en la medula ósea
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Manifestaciones Clínicas leucemias agudas
• Síntomas debido a:– Falla medular– Infiltración tisular– Leucostasis– Síntomas constitucionales– Otros (CID)
• Duración corta de síntomas
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Falla medular• Neutropenia:
– Infecciones y sepsis• Anemia:
– Fatiga, palidez• Trombocitopenia:
– Sangrado
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Infiltración de tejidos y órganos
• Bazo, hígado y GL agrandados• Hipertrofia gingival• Dolor óseo• Otros órganos: CNS, piel, testiculo
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Leucostasis• Acumulación de blastos en la
microcirculación afectando la microcirculación
• Pulmones: hipoxemia, infiltrados pulmonares
• SNC: stroke• WBC > 50 x 109/L
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Síntomas Constitucionales• Fiebre y sudoración (Común)• Pérdida de peso (menos común)
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Examen físico• Fiebre• Esplenomegalia• Hematomegalia• Linfadenopatía• Dolor esternal• Sangrado: GI, SNC, cutáneo• Coagulopatía• Infiltración gingival• Infiltración meníngea• Sangrado retiniano
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Médula Ósea en Leucemia Aguda
• Necesaria para el diagnóstico• Útil para determinar el tipo• Útil para el pronóstico
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Distinción de LMA de LLA• Microscopía de luz
– LMA: Auer, gránulos citoplásmicos– LLA: no Auer rods ni granulos.
• Tinciones especiales (cytochemistry)• Citometría de flujo
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
LMA
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
Bastones de Auer en LMA
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
LLA
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
Acute myeloid leukemia
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
Harrisons’s, 19th Ed.
Page 34
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.
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
Harrisons’s, 19th Ed.
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.
Acute Myeloid Leukemia
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)
Harrisons’s, 19th Ed.
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
Acute myeloid leukemia
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
Page 42Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
Diagnosis AML
CBF AML Low-Risk CN-AML High-Risk AML
Daunorubicin-Cytarabine induction
chemotherapy
Daunorubicin-Cytarabine induction
chemotherapy
Daunorubicin-Cytarabine induction
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
Acute Myeloid Leukemia
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
Harrisons’s, 19th Ed.
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
Page 57
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.
Harrisons’s, 19th Ed.
Chronic myeloid leukemia (CML)
“Presence of BCR-ABL1 abnormality in a patient with a myeloproliferative neoplasm”
Kantarjian H, Cortes J.
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
CML: symptoms
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
CML: symptoms
Unusual presentation Bleeding
Retinal hemorrhages GI Bleed
Accelerated phase Fever Cachexia Severe fatigue Bone and joint aches Bleeding Thrombotic events Infections
Harrisons’s, 19th Ed.
Chronic myeloid leukemia: signs
Splenomegaly (20-70%) Hepatomegaly Lymphadenopathy Extramedullary disease (CML transformation) High basophil may cause histamine:
Pruritus, Diarrhea, Flushing and GI ulcers
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
neutrófilo
basófilo
metamielocitos
mielocitos
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004
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
Harrisons’s, 19th Ed.
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
Harrisons’s, 19th Ed.
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
Chronic myeloid leukemia (CML)
Prognosis for CML patients today are dependent on depth of response to TKI therapy.
Kantarjian H, Cortes J.
Harrisons’s, 19th Ed.
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
Harrison’s, 19th Ed.
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
Harrison’s, 19th Ed.
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
Chronic myeloid leukemia (CML)
“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%)”.
Kantarjian H, Cortes J.
Harrisons’s, 19th Ed.
European leukemia-net – response definitions