Acute Leukemia in Adults

Literaturempfehlungen Basisliteratur Spezialliteratur Acute Leukemia in Adults EBMT Swiss Nurses Group 23.11.2013 Markus G. Manz Klinik für Hämatol...
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Literaturempfehlungen Basisliteratur

Spezialliteratur

Acute Leukemia in Adults EBMT Swiss Nurses Group 23.11.2013

Markus G. Manz Klinik für Hämatologie USZ/UZH Zusammenfassungen

MG Manz 05.05.2011, Repetitorium Hämatol. NPL

Overview Introduction to physiology of the hematopoietic system Acute leukemia in adults - Incidence - Ethiology - Pathopysiology - Classification - Clinical presentation and diagnosis - Current risk adapted treatment and outcome - Challenges and future directions

Embryonic, Germline, and Somatic Stem Cells Embryonic Stem Cells (ESC)

Blastocyst

Fertilized Egg

?

Somatic Lineage Stem Cells

SC

SC

SC

Liver

Brain

SC

SC

Blood

Inducible Pluripotent Stem Cells (iPS)

SC

SC

Skin

Primitive Germline Cells (GSC)

SC

SC

Nerve

Genital Ridges

Commitment to Protogamets

Hematopoiesis

HSC Asymetric Cell Fates

HSC Niche

HSC

Progenitor

Hematopoietic Progenitor Cell Niche Tight control of Proliferation and Differentiation

Mature Cells Production of about 1x109 RBCs and 1x108 WBCs / hour (Adult ~70kg BW)

Loss of developmental options

HSC Niche

Proliferative Activity

Functional Maturity

HSC Generation, Expansion and Maintenance

Gestation Amnion, AGM, Liver

Birth Blood, BM

Adult BM

HSC HSC Generation Conception

Maintenance

HSC Expansion

Gestation

Birth

Young Adult

Age

Circulation of HSC

HSC

HSC

HSC HSC

99% in BM ~1% free niches

~1% in circulation HSC

HSC

HSC

HSC

BM 99% of HSCs

Other Tissues 1% of HSCs

HSC-Transplantation

HSC HSC HSC

Soluble Factors

HSC

HSC

Membran bound Factors

HSC “Niche”

HSC

Funktionelle Reife

Proliferative Aktivität

Physiologic Hematopoietic Differentiation

Location of pathologic events in hematopoiesis Hematopoietic Stem and Progentior compartment

Location of pathologic events in hematopoiesis Hematopoietic Stem and Progentior compartment / Mature hematopoietic compartment

Cancer Incidence CH 2009

(4) (6) (8)

(11)

[Prozent] (Quellen für Zahlen: Zahlen Institut für Krebsepidemiologie und –Registrierung NICER)

Epidemiology - Leukemia Incidence central Europe

AML:

~2.5 / 100.000 / y

ALL:

~1.5 / 100.000 / y B-Zell: ~80% T-Zell: ~20% (vergl. NHL)

CLL: ~3 / 100.000 / y CML: ~1 / 100.000 / y

 „disease of the elderly “

Ethiology Acute Leukemia

• Largely unknown • KM-damage (Chemicals, Cytostatics, Irradiation) • Infectious • Genetic Predisposition  Somatic mutation leads to autonomous proliferation advantage with consecutive inhibition of normal hemato-lymphopoiesis

Model for pathogenetic „Events“

Class I Mutation: „Proliferation“

MPN-like

z.B. Nras / Kras Flt3 Mutationen Jak2 Mutationen SHP-2 Mutationen c-Kit Mutationen BCR/ABL

Class II mutation: „Differentiation block“

AL-like

MDS-like

z.B. AML1/ETO CBFb/MYH11 CEBPa Mutation PML/RARa MLL-Fusion PU.1 Mutation

Unraveling the complexity of genetic events in AML

97.3% have «at least» 1 of 18 tested mutations!

Phenotypic consequences of pathogenetic events leading to leukemia

M1, M2

M4

M6

M7

M5

M3

WHO-Classification of Leukemia 2008 Myeloid

Lymphatisch

Typical symptoms in leukemia patients

Signs of bone marrow insufficiency (Cytopenia)

Weakness

Infectious disease

Bleeding signs

(anemia)

(functional leucopenia)

(thrombopenia/ activated coagulation)

B-Symptoms (cytokine-mediated)

„Hem-lymphatic organomegaly“ LN-swelling, hepato-splenomegalia

Diagnosis Acute leukemia? „Hallmark“ >20% „Blasts“ in Bone Marrow

AML vs. ALL ? Zyto-Morphologie Zytochemie Immunophenotype (FACS, Immunhistochemie) Zytogenetik (Metaphasenanalytik/FISH) Molekularbiologie (PCR)

BM-Morphology

Normal

AML

ALL

KM-Zytochemie FAB - Klassifikation Zytochemie

POX

Esterase

PAS

M1

AML ohne Ausreifung

+

-

-

M2

AML mit Ausreifung

++

-

-

M3

Akute Promyelozytenleukämie

+++

-

-

M4

Myelomonozytäre Leukämie

+

+

M5

Monozytäre Leukämie

-

++

M6

Erythroleukämie

+

-

+

M7

Megakaryozytäre Leukämie

-

-

+

M1, M2

M4

M6

M7

M5

M3

MG Manz 04/2013, Akute Leukämien

AML, Peroxidase-Färbung

BM-Flow Cytometry (FACS) AML

ALL

CD19

CD33 cyMPO

CD10

BM-Cytogenetics Normal

46, XX

Example of typical, „recurrent“ translocation

BM-molecular Biology (PCR) Example: Flt3 Muation

Flt3 Rezeptor Tyrosin Kinase Mutation MG Manz 04/2013, Akute Leukämien

Prognosis

• Patient factors („fitness“) •

comorbidities, „fittnes“



leukemia-induced problems (infections, bleeding, impaired organ function)

• Leukemia factors •

A priori risk-classification: cytogenetics, molecular profile



Response to therapy: morphologic, cytogenetic, molecular remission (time to and deepnes of response)

Prognosis all patients combined

• AML 60-65 years

10-20% 5y OS

• ALL < 60-65 years

40-50% 5y OS

• ALL >60-65 years

10-20% 5y OS

Prognostic relevance of cytogenetics AML 16-59 y

Outcome according to age 1973-2005

Pat. ≤60 Jahre

Pat. >60 Jahre

Elderly patients have dismal outcome

Derolf et al., Blood 2008

Complications Most frequent acute complications Infection Bleeding Tox. Organ damage

Long-term complications Infertility Secondary neoplasia Tox. Organ damage

Treatment Related Mortality 5(-40)%

Approach to therapy in AML STUDY

AML

Fit for intensive therapy and significant probability for Remission: AIM for CURE

Intensive Induction Therapy e.g. 1-2x «3+7»

Not fit or No significant Probability for CR upon intensive therapy: AIM for optimal PALLIATION

CR

GR MRD neg Conventional Consolidation

non-GR with donor

Allogeneic HSCT (MAC or RIC)

no CR Palliative Therapy / Study

STUDY General principles similar in ALL therapy

Case Report Patient

-

66 y, subjectively «fit» in comparison to peers

-

Working businessman

-

Former smoker

-

NSCLC 3 y ago, only resected

-

Otherwise «always healthy»

-

Since 4 weeks activity impaired, tired

-

Upon nose cleaning since 4 weeks bloody tissue, since 2 days red dots lower legs

Laboratory values

MG Manz 04/2013, Akute Leukämien

Bone marrow: AML KM Morphologie:

Zytogenetik:

MG Manz 04/2013, Akute Leukämien

Mol-Gen (Multiplex PCR):

Prognostic classification AML with recurrent cytogenetic aberration t(16;16); CBFB-MYH11

CR prob. ca. 90% 5y OS prob. 50-70%

MG Manz 04/2013, Akute Leukämien

Case report: Therapy KM Morphologie: 55% Blasten KM-Morphologie: Leukemia free state KM-Morphologie: Komplette Remission

Leukemia evalulation

Therapie:

Dx

Chemoth. 1 Wk

Complications

Chemoth. 2-3 Wk

Mucositis, Sepsis, Pulm. Infiltrate, ICU Beatmung

1 Wk

Chemoth. 2-3 Wk

1 Wk

Cure ?

Case Report: Molecular Response 1. Induktion 2. Induktion Konsolidierung

Reinduktion MUD RIC Allo-HSCT

KM, PB

Quantitative CBFB-MYH11 / ABL Analytik

Finding a matched donor - 2013 3 - 7% of the patients do not have any potential HLAA,B,DRB1 matched donor in BMDW

>90%

Courtesy of JM Tiercy

≥1 HLA-A,B,DRB1 matched donor 4050%

≥1 HLA 10/10 match

2030%

≥1 HLA 9/10 match

1020%

mismatched CBU/haplo-id

Allo-HSCT (EBMT and CH data)

Absolute nb patients transplanted with allogeneic HSC by donor type (1990-2010) 72% PBSC 22% BM 6% CBU

in Switzerland (2012): 122 unrelated (65%) 63 HLA-id sib (33%) 4 haplo-id (2%) Passweg et al. BMT 2012; 47: 906

Courtesy of JM Tiercy

Case Report: Molecular Response 1. Induktion 2. Induktion Konsolidierung

Reinduktion MUD RIC Allo-HSCT

KM, PB

Pt alive and well

Quantitative CBFB-MYH11 / ABL Analytik

AML outcome 1973-2005 Swedish Acute Leukemia Registry (9729 AML patients 1973-2005)

All AML Patients

Better supportive care (antibiotics etc.) Allogene SCT

Better therapies are needed ! Derolf et al., Blood 2008

(Future) Strategies

Mutations, expression analysis, background genome  Individualized, targeted therapy

Monoclonal antibodies – example anti-CD20 Ab

Cheson B, Leonard J. N Engl J Med 2008;359:613-626

Chimeric antigen receptors – example anti-CD19

Selective Kinase Inhibitors – example Imatinib

Savage et al., NEJM 2002

Modern “specific” Therapy – example AMLSG Study

Summary Acute Leukemia Adults

- Rare diseases - Complex diagnostics - Increasingly subclassified according to genetics - Therapy potential curative but (currently) toxic - Cure rates (5y) between 2-80% (not ONE disease) - Dynamic development in unraveling genetic events but major breakthrough(s) in specific therapies still necessary

Literaturempfehlungen Basisliteratur

Spezialliteratur

Thank you for your attention

 Questions? Zusammenfassungen

MG Manz 05.05.2011, Repetitorium Hämatol. NPL