Gregor Verhoef, afdeling Hematologie, Leuven 29 november 2018 · Clinical presentation of CML •...

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