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Topics uit de hematologie
Gregor Verhoef, afdeling
Hematologie, Leuven
29 november 2018
Lichtman, M. A. Oncologist 2008;13:126-138
56-jarige vrouw, blanco VG, geen medicatie, nu viraal
beeld, Splenomegalie (3 cm).
• Hb 11.5 g/dL
• Platelets 560 x 109/L
• WBC: 45 x 109/L
• Segmented neutrophils: 44%
• Band neutrophils: 4%
• Lymphocytes: 10%
• Eosinophils: 3%
• Basophils: 7%
• Promyelocytes: 2%
• Myelocytes 19%
• Metamyelocytes 10%
perifeer bloed
t(9;22)(q34;q11.2)
Bloedaanmaak
• Bloed wordt aangemaakt in de
beenmergholten (schedel, wervels,
borstbeen, bekken)
– 150 miljard witte bloedcellen (of leucocyten)/dag
– 200 miljard rode bloedcellen (of erythrocyten)/dag
– 45 miljard bloedplaatjes (of thrombocyten)/dag
• Gespecialiseerde cellen “de hemopoietische
stamcellen” zorgen, al naar gelang de nood,
voor de productie hiervan
Four types of leukemias
CML (14%)
CLL (30%)
AML
(30%)
ALL
(26%)
ALL= acute lymphocytic leukemia CLL= chronic lymphocytic leukemia
AML= acute myeloïd leukemia CML= chronic myeloïd leukemia
Chronic lymphoidAcute myeloid
10
8
6
4
2
0
Rate
Acute lymphoblastic Chronic myeloid
male
female
Age
100
10
1
0.1
0.01
Rate
Age
100
10
1
0.1
Ra
te
Age
100
10
1
0.1
0.01
0 10 20 30 40 50 60 70 80
Age
Ra
te
male
female
male
female
male
female
0 10 20 30 40 50 60 70 80
0 10 20 30 40 50 60 70 80
0 10 20 30 40 50 60 70 80
Leukemia: age-specific incidence rates per 100.000 population
National Cancer Registry
Disease Incidence Male
(/100.000)
Incidence Female
(/100.000)
GI 72 63
Respiratory 86 15
Breast 1 95
Skin 9 11
Urinary tract 31 13
CML 1.2 1.0
Clinical presentation of CML
• 20-40 % of patients are asymptomatic and are diagnosed
when a blood cell count performed at the time of routine
medical examination is found to be abnormal
• Median age: 50-60 years, slight male predominance
• Clinical findings: asymptomatic, fatigue, weight loss, night
sweats, splenomegaly and anemia
• Leucocytosis, trombocytosis, non-severe anemia
• Presentation in accelerated or blast crisis is rare (<10 %)
• incidence: 1-2 cases per 100.000 population
• Median survival in the pre-TKI period was 5-6 yr
Three phases of the Disease(before imatinib)
chronic phase accelerated blast phase
36-48 months 6 months 3-6 months
Surv
ivin
g p
erce
nt
Years after diagnosis
Treatment of CML before 2000
• Busulfan
• hydroxyurea
• interferon
• Standard treatment if no donor available:
interferon and low dose of Ara-C
• Standard treatment if donor available:
allo-SCT
CML in Hydrea© tijdperk (1975-1985) en
interferon (1985-2000)
Chronische fase acceleratie blastenfase
36-48 maanden 6 mnd 3-6 mnd
•gemakkelijke toediening (tablet)
•gemakkelijke controle van bloedbeeld
•weinig nevenwerkingen
•natuurlijk beloop onveranderd
•Ziekte wordt (is) weerstandig
•Patient voelt zich slecht
Lessons from allogeneic stem cell
transplantation in CML?
If you and/or your patient consider an
allogeneic SCT • At present the only proven curative therapy (for 18% of all CML
patients), thus certainly not for all patients !
• Only available for 30 % of all CML patients
• Molecular remissions are frequent!
• Rather toxic treatment!
• Start treatment in chronic phase of CML and don’t wait to long!
Transplant activities Europa 2004
Gratwohl et al, The Hematology Journal 2006, 91(4)
Research in CML
Janet Rowley, 1973Nowell and Hungerford, 1960
1984: John Groffen, Nora Heisterkamp
Gerard Grosveld, Owen Witte
Brian Druker1992: CGP57148B
Cytogenetic Abnormality of CML:
the Ph Chromosome
1 2 3 4 5
6 7 8 10 119 12
13 14 15 16 17 18
19 20 21 22 x Y
Goldman et al. N Engl J Med 2003; 349:1451-64
Goldman et al. N Engl J Med 2003; 349:1451-64
↑Proliferation ↓Adherence ↓Apoptosis
NEJM, 346, 683, 2002
Imatinib targets CML at its source [t(9;22)]
Outcome of patients treated first with imatinib
Study patients High risk PFS OS
IRIS 553 18% 92% 85%
Hammersmith 204 29% 83% 83%
Houston 258 8% 92% 97%
PETHEMA 210 16% 94% 97%
Czech 342 22% 90% 88%
Spirit 319 24% 92% NR
GINEMA 559 22% 87% 90%
German CML 1551 12% 86% 88%
Seoul 363 22% 88% 94%
TKIs: Changing the course of a
disease
Adapted from: Björkholm M, et al. J Clin Oncol 29:2514-20.
Cu
mu
lative
Re
lative
Su
rviv
al
Time Since Diagnosis (years)
1 2 3 4 5 6 7 8 9 10
0.20
0.40
0.60
0.80
1.00
0
1973 - 1979
1980 – 1986
1987 – 1993
1994 – 2000
2001 - 2008
Survival of patients with CML
Life expectancy of the general population and of patients with chronic myeloid leukemia in
Sweden, over year of diagnosis, by age at diagnosis and sex.
Hannah Bower et al. JCO 2016;34:2851-2857
Loss in expectation of life of patients with chronic myeloid leukemia in Sweden, over year of
diagnosis, by age at diagnosis and sex.
Hannah Bower et al. JCO 2016;34:2851-2857
Patients of all ages diagnosed in
2013 will, on average, loss<3 life-
years as a result of CML
Bower et all; J Clin Oncol 34:2851-2857, 2016
Costs Imatinib (in dollars)
0
10000
20000
30000
40000
50000
60000
70000
1ste
jaar
2de
jaar
3de
jaar
4de
jaar
5de
jaar
Xde
jaar
400
600
800
European recommendations for
optimal care
• Other recommendations and/or guidelines do exist
• These recommendations will evolve as knowledge about CML and its
treatment increases
Treatment-free remission
Study Treatment free remission
STIM 40%
TWISTER 40%
A-STIM 64%
EuroSKI 60%
KIDS 59%
STIM2 60%
DADI 58%
Stop 2GTKI 42 versus 67%
BHS* 44%
*Belgian Journal of Hematology, volume 7, 5, 184-186
Hughes et al, Blood, 128(1): 17-23
1864 1903 1953 1964 1975 1983 1999 2005 2007 2008 2009
Palliative therapy Currative therapy
arsenic
Spleen irradication
Busulfan
Hydroxyurea
Stem cell transplantation
Combination chemo
Interferon
Imatinib
Dasatinib
Nilotinib
Bosutinib
“first generation TKI”
“second generation TKI”
Ponatinib, K0706“third generation TKI”
Developments of treatment for CML
2016
“Fourth generation TKI” ABL001
61-jarige man
• Sinds enkele maanden nachtzweten,
gewichtsvermindering, moe, geen eetlust
• LO: kliervergrotingen in de hals,
• Labo: normochrome anemie, gestegen
LDH
CD20 Ki67
Diffuse Large B-cell Lymphoma
Nationaal Kankerregistratie
Aandoening Incidentie Man
(/100.000)
Incidentie Vrouw
(/100.000)
Spijsvertering 72 63
Ademhalingsstelsel 86 15
Borstklier 1 95
Huid 9 11
Urinair stelsel 31 13
lymfoom 12 10
Verschillende mensen
Verschillende soorten van lymfomen
Diffuse large B-cell lymphoma: 30% of NHL
Cases
Follicular
(25%)
Small lymphocytic
(7%)
MALT type
marginal zone
B cell (7.5%)
Nodal type
marginal zone
B cell (< 2%)
Lymphoplasmacytic
(< 2%)
Diffuse
large B cell
(30%)
T and NK cell
(12%)
Other subtypes
(9%)
Burkitt
(2.5%)
Mantle cell
(6%)
Lichtman. Williams Hematology, 7th edition. 2006;1408
41
Verschillende soorten van lymfomen
Behandeling met lage dosis van chemotherapie:
10% kans op genezing
Behandeling met hoge dosis van chemotherapie:
80% kans op genezing
De eerste jaren geen behandeling
Standaard chemotherapie:
90% op genezing
Behandeling met antibiotica
Diagnosis and outcome of DLBCL subtypes by GEP. (A) Heat map showing differential
expression of genes in GCB, ABC, and PMBL DLBCL subtypes.
Wilson W H Hematology 2013;2013:584-590
©2013 by American Society of Hematology
Beperkingen van chemotherapie bij
de behandeling van het lymfoom
100
80
60
40
20
00 5 10 15
CHOP
MACOP-B
ProMACE-CytaBOM
m-BACOD
ABCDEFGHIJKLMNOPQRS
Years
Fisher. N Engl J Med 1993;328:1002–6
Overa
ll s
urv
iva
l (%
)
You see we must take aim-aim by chemical variation!
The marvellous effect of an antibody in the serum is due
to the fact that in no case it has affinity for the body
substances but flies straight onward without deviation,
on the parasites. The antibodies are therefore MAGIC
BULLETS which find the targets themselves….. We
must therefore concentrate all our powers and abilities
on making the aim as accurate as we can contrive, so
as to strike the parasites as hard and the body cells as
lightly as possible
Paul Ehrlich, circa 1904
Uitlokken van een immuunrespons dmv
antistoffen bij de behandeling van kanker
apoptosis
blocking growth
differentiation
Antibody dependent
cellular cytotoxicity
Complement
dependent
cytotoxicity
lymfoom-specifiek
antigen
antistof
Lymfoom
cel
MabThera®: A Mouse/Human
Chimeric MoAb
Murine variable regions bind
specifically to CD20 on B cells
Human kappa constant regions
Human IgG1 Fc domain works in synergywith human effector mechanisms
Chimeric IgG 1
Adapted from Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.
Rituximab mechanisms of action
apoptosis
blocking growth
differentiation
Antibody dependent
cellular cytotoxicity
Complement
dependent
cytotoxicity
CD20
Rituximab
B cell
LNH-98.5: median follow-up of 3
years
Years
Event-free survival Survival1.0
0.8
0.6
0.4
0.2
0.00 1.0 2.0 3.0 4.0 5.0
Years
1.0
0.8
0.6
0.4
0.2
0.00 1.0 2.0 3.0 4.0 5.0
Coiffier B et al. EHA 2003 (Abstract 356)
R-CHOP
CHOP
R-CHOP
CHOP
Tran E et al. N Engl J Med 2017;377:2593-2596
CAR-T cells
Tran E et al. N Engl J Med 2017;377:2593-2596
CAR-T cells
Neelapu SS et al. N Engl J Med 2017;377:2531-2544.
Neelapu SS et al. N Engl J Med 2017;377:2531-2544.
Schuster SJ et al. N Engl J Med 2017;377:2545-2554.
20-jarige vrouw
• Altijd gezond, geen medicatie
• Nu klier hals en supraclaviculair rechts,
neemt in grootte toe
• Verder LO: gda
• Maakt zich zorgen
• Labo: hoog CRP, WBC 11 x 109/L, lichte
eosinofilie, lymfopenie, verder gb
Survival Hodgkin’s Lymphoma
Schaapveld M et al. N Engl J Med 2015;373:2499-2511.
Nieuwe ontwikkelingen bij Hodgkin lymfoom
• Minder therapie met de hulp van PET-CT
• Nieuwe antistoffen, meer “doelgericht”
• Eigen afweersysteem stimuleren:
– nivolumab
Johnson P et al. N Engl J Med 2016;374:2419-2429.
Progression-free and Overall Survival.Randomisatie na 2 kuren ABVD
behandeling
“verleden, heden” “heden, toekomst”
Nieuwe ontwikkelingen bij Hodgkin lymfoom
• Minder therapie met de hulp van PET-CT
• Nieuwe antistoffen, meer “doelgericht”
• Eigen afweersysteem stimuleren:
– nivolumab
Secondary end points of overall survival (A) and progression-free survival (B).
Anas Younes et al. JCO 2012;30:2183-2189
©2012 by American Society of Clinical Oncology
PFS in 102 HL patients treated with BV
Brad S. Kahl Blood 2016;128:1540-1541
Nieuwe ontwikkelingen bij Hodgkin lymfoom
• Minder therapie met de hulp van PET-CT
• Nieuwe antistoffen, meer “doelgericht”
• Eigen afweersysteem stimuleren:– Checkpoint inhibitie met Nivolumab/Pembrolizumab
Lymphoma immune evasion mechanisms.
Marie de Charette, and Roch Houot Haematologica 2018;103:1256-1268
Prize motivation: "for their discovery of cancer therapy by inhibition of negative immune regulation."
James P. Allison Tasuku Honjo
Clinical Activity in Nivolumab-Treated Patients.
Ansell SM et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1411087
Lichtman, M. A. Oncologist 2008;13:126-138
Van fatale ziekte naar chronische
ziekte en misschien genezing
Afhankelijk van type
lymfoom, maar
sowieso verbetering
77
Elderly AML
High grade
Lymphoma
CML
Vooruitgang in de hematologie
HL
AML<50 yr
DLBCL