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