Prognosis and treatment of Chronic Lyphocytic Leukemia

Diagnosis of CLL

• Peripheral blood:

>5.0 x 109 B lymphocytes /L

Immunophenotype of CLL cells:

CD5+, CD19+, CD20+, CD23+

(low level expression sIg, CD20,CD79b)

• Molecular cytogenetics• Mutational status• Serum markers• Bone marrow examination

Prognostic Factors

• 1980sClinical: Stage Binet or Rai

• 1990sLymphocyte doubling time <12 m

Serum markers: beta-2 microglobulin, thymidine kinase• 2000>• Molecular cytogenetics/molecular genetics:

Deletion 11q or 17pMutational status:Unmutated IGVH gene, IGHV3-21 gene

• Flow cytometry: CD38, ZAP-70• MRD

1. Rai KR, et al. Blood 1975; 46:219-234.2. Binet JL, et al. Cancer 1981; 48:198-206.

Rai staging

0: Bone marrow and blood lymphocytosis only

1: Lymphocytosis with enlarged nodes

2: Lymphocytosis with enlarged spleen and/or liver

3: Lymphocytosis with anaemia

4: Lymphocytosis with thrombocytopenia

Binet staging

A: Fewer than three enlarged nodes/nodal groups, Hb > 100 g/L; platelets > 100 x 109/L

B: Three or more enlarged nodes/nodal groups

Hb > 100 g/L; platelets > 100 x 109/L

C: Hb < 100 g/L; platelets < 100 x 109/L regardless of number of lymphoid areas involved

Lo

w risk In

terme

diate H

igh

risk

Wa

tch

an

d w

ait B

eg

in tre

atm

en

t

Survival (yrs)

14–17

5–7

3

CLL stage predicts survival and informs treatment decisions

Survival according to Binet Stage

Time (Months)0 80 100 120 140 16020 40 60

0.0

0.5

0.6

0.7

0.8

0.9

1.0

0.4

0.3

0.2

0.1

Pro

bab

ilit

y o

f su

rviv

al

Binet stage ABinet stage BBinet stage C

1. Dohner H, et al. N Engl J Med 2000;343:1910–16.2. Rai K, et al. Hematology 2001:140–56.

3. Krober A, et al. Blood 2002;100:1410–16.

0 24 48 72 96 120 144 168 192 216

Genomic aberrations (n=325)1 IgVH mutation status (n=211)2,3

100

75

50

25

0

Mutated

UnmutatedP < 0.0001

Time (months)

0 24 48 72 96 120 144 168

Time (months)

Su

rviv

al (

%)

17p del

11q del12q trisomy

Normal

13q del only100

75

50

25

0

Su

rviv

al (

%)

Survival according to FISH and IGVH Mutation Status

Crespo M, et al. N Engl J Med 2003;348:1764–75.

ZAP-70 expression and IgVH mutation status

ZAP-70 expression and survival probability

80

60

40

20

0ZA

P-7

0-p

os

itiv

e c

ell

s (

%)

Mutated 100

80

60

40

20

00 4 8 12 16 20 24 28 32 120

Year after diagnosis

Pro

ba

bil

ity

of

su

rviv

al

(%) < 20% ZAP-70-positive cells

≥ 20% ZAP-70-positive cells

p=0.01

Unmutated

IgVH

ZAP-70 Expression

Treatment is not necessary for most patients

Per

cen

tag

e o

f p

atie

nts 80

60

40

20

100

~70%

~30%

Asymptomatic at diagnosis• ~70% of patients1 • Many will never progress• Treatment is usually not required

1. Hamblin TJ, et al. Br J Haematol 1987; 66:21–26.

Symptomatic at diagnosis• ~30% of patients1 • Shortened life expectancy• Effective treatment becomes essential

Rai KR, et al. Blood 1975; 46:219-234.Binet JL, et al. Cancer 1981; 48:198-206.

Patients with intermediate, high-risk, or active disease have significantly reduced life expectancy and require effective treatment

Active disease defined as any of the following:─ Progressive marrow failure─ Massive/progressive/symptomatic splenomegaly─ Massive nodes or progressive/symptomatic lymphadenopathy─ Progressive lymphocytosis─ Refractory autoimmune anaemia and/or thrombocytopenia─ Weight loss, significant fatigue, fever, night sweats

Which patients are eligible for treatment?

PAST

Watch and wait

ChlorambucilCAP

CHOP

Conservative approach

PRESENT

Fludurabine CR

Combined chemotherapy (F+C)

MAbs: (alemtuzumab, rituximab)

First-line treatment:

Chemo + MAb (R-FC, HMP+Cam)

Transplantation programs (auto, allo)

Tratment of CLL

FC significantly extends PFSbut has no impact on OS

• Studies show that fludarabine plus cyclophosphamide (FC) extends PFS but not OS1–3

Pro

gre

ssio

n f

ree

(%)

FC

F

Clbp = 0.00005

Su

rviv

ing

(%

)

FC

F

Clb

p = 0.4

Time (years)0 51 2 3 4

Time (years)0 51 2 3 4

0

50

100

1. Catovsky D, et al. Lancet 2007; 370:230–239.2. Eichhorst B, et al. Blood 2006; 107:885–891.3. Flinn IW, et al. J Clin Oncol 2007; 25:793–798.

PFS1 OS1

Tam CS, et al. Blood 2008; 112:975-980.

Time (months)

120 24 36 48 60 72 84 96 108

Pro

bab

ilit

y

0.8

0.6

0.4

0.2

0

1.0Outcome n 6-year OS p - value

F 190 54%

F±M/C 140 59%

R-FC 300 77%

p = 0.37

p < 0.001

Rituximab (375) 500 mg/m2 plus chemo improves survival vs historical controls in first-line CLL

Median PFS: 32.3 months for FC vs 42.8 months for FCR

Median observation time 25.5 months

p = 0.000007

Cu

mu

lati

ve s

urv

ival

1.0

0.8

0.6

0.4

0.0

0.2

PFS (months)42363024181260 48 54

Progression-free survival:FCR versus FC (CLL8 study)

FCR

FC

Hallek M, Fingerle Rowson G, Fink AM et al. Blood 2008; 112; abstract 325.

Conclusion

In CLL patients new prognostic markers are of increasing importance for novel treatment decisions.

CLL – when to treat

Outline

• Why is that important?• Theoretical background

– Glossary – Concept of clinical stages– Evolution modalities– Examples

• What we learned in the past?• Current gudeliness – how helpfull?• Call for clinical trials

16

Why is that important?

• If we had efficient and non toxic therapy it would be logical and self evident to start as soos as diagnosis is made! The therapy should:– Prevent progression to full blown disease with end

organ damage, especially BMF and immune deficiency and/or malfunction etc., thus assuring normal quality and quantity of life

– Help to repair (reverse) disrupted intrinsic regulation mechanism(s) and regain the control over proliferation/apoptosis of neoplastic clone etc.

• However, early treatment studied failed to fullfil what was hoped, athough effectivly suppressing the disease, overal benefit is doubtful (and even questioned), so that “when to treat” question remains open. WHY?

Theoretical background

• Glossary:– Early vs advanced disease (related to clinical

stages)– Stable vs progressive disease (related to

evolution type)– Prognostic factor – individual predictor of

prognosis (or risk to progress), and large number of new predictors have been identified

– Prognostic index – composite predictor of prognosis (or risk to progress)

18

Concept of clinical stages

19

stages

A

B

C

Diagnostic treshold

death

start

early advanced

Categories,Not continuous, Not quantitative,C is defined by BMF

Clinical evolution

20

death

start

TTMs

progressive

stable

ContinuousQuantitative

DT

Clinical evolution(stable)

21

0

TTMs

dg. theshold

th. theshold

Early/stable

Advanced/stable

9

years

The level ofadvanced isabitratry!

Clinical evolution(progressive)

22

0

TTMs

9

years

Early/progressive

Advanced/progressive

Early/ veryprogressive

Advanced/ veryprogressive

The measurement of progression require unbiased parameters!Several diseasefeatures besides tumorload can changein time (ie, BMF orimmunodefficiency etc)

Clinical evolution(acceleration)

23

0

TTMs

9

Early/ stable

Advanced/ veryprogressive

APOPTOSIS RESISTANCE/

ACCUMULATION

ACTIVATION/PROLIFERATION

PROGRESSIONSTABLE

REMISSION

Factors controllingprogression/stabilityshould be investigated,and become therapeutictargets!

What we learned in the past?

• Clinical trials in early ‘80

• IGCI-01

• Franch trials

• Meta-analysis

24

25

B-CLL

EARLY/STABLEEARLY/STABLETTMS<9

and DT>12mo

and No BMF

ADVANCED/PRTTMS>9

or DT<12mo

or BMF

R1

R1

HDCLB

WAIT

SDCLB

IGCI-01 TRIAL DESIGN (1982)IGCI-01 TRIAL DESIGN (1982)

Jaksic B, Brugiatelli M,Nouv Rev Fr Hematol1988;30:437-442

Logrank=1.12, NS

Histogram: BINET

K-S d=,31523, p<,01 ; Lilliefors p<,01

Expected Normal

Include condition: STUDY=1

0,5 1,0 1,5 2,0 2,5 3,0

X <= Category Boundary

0

20

40

60

80

100

120

140

160

No.

of o

bs.IGCI-01 FOLLOW-UPIGCI-01 FOLLOW-UP

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Include condition: BINET=1 AND STUDY=1

0 1

0 50 100 150 200 250

Time

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ng

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Include condition: STUDY=1 AND TTMS<9

0 1

0 50 100 150 200 250

Time (months)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ng

p = 0.87522p = 0.43159

Survival Function

Complete Censored

Include condition: STUDY=1 AND TTMS<9

0 50 100 150 200 250

Survival Time (months)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ngSurvival Function

Complete Censored

Include condition: BINET=1 AND STUDY=1

0 50 100 150 200 250

Survival Time

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ng

IGCI-01

Dighiero G et al. N Engl J Med 1998;338:1506-1514

Overall Survival in the First Trial

Overall Survival in the Second Trial

29

CLL Trialists’ Collaborative Group – Meta-analysis (Journal of the National Cancer Institute, 1999;91:861)

What we learned from performed trials:

• No advantage nor harm from alkylator early treatment

• No survival difference in spite of high response rate• More than 50% of patients in early stage never

progress!• Insight into the “natural course” of disease,

awareness of the complex cellular interactions that control disease progression, bringing up more Q then A . Need for new approaches! (This has impact to general th strategy!)

• However, clinical trials of these issues were abandoned, focus moved to new treatments (supported by Pharma). Should be revisited! Academic trials?

30

Current guideliness – how heplful?

• NCI & iwCLL guidelines• Indication for treatment: Advanced stages

or BMF, or else + “active” (progressive/symptomatic) disease

• Criteria are composite, based on different principles: – Longitudinal follow-up of quantitative

parameters– Quantitative (Mass) parameters: defined level! – Qualitative (symptomatic, response)

31

32

NCI criteria for active (progressive/symptomatic) disease

(Hallek, Blood, 2008)

cat

1. Evidence of progressive marrow failure manifested by development of, or worsening of anaemia and/or thrombocytopenia.

P

2. Massive (ie, at least 6 cm below left costal margin) or progressive or symptomatic splenomegaly

M, PQual

3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy

M, PQual

4. Progressive lymphocytosis with an increase of more then 50% over a 2-month period, or lymphocyte doubling time (LDT) of less then 6 months. LDT can be obtained by linear regression extrapolation of 2 week over an observation period of 2-3 months. In patients with initial blood lymphocyte counts of less then 30x109/l LDT should not be used as single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other then CLL (eg, infections) should be excluded.

P

5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy

MQual

6. Constitutional symptoms defiend as any one or more of the following disease related symptoms and signs:

a. Unintentional weight loss of 10% within the prevoious 6 months;b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual

activities);c. Fevers >380C for 2 or more weeks without other evidence of infection; ord. Night sweats for more then one months without evidence of infection

MQual

Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia nor absolute lymphocyte count do not by themselves constitute indication for therapy.

33

NCI criteria for active (progressive/symptomatic) disease

(Hallek, Blood, 2008)

cat

1. Evidence of progressive marrow failure manifested by development of, or worsening of anaemia and/or thrombocytopenia.

P

2. Massive (ie, at least 6 cm below left costal margin) or progressive or symptomatic splenomegaly

M, PQual

3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy

M, PQual

4. Progressive lymphocytosis with an increase of more then 50% over a 2-month period, or lymphocyte doubling time (LDT) of less then 6 months. LDT can be obtained by linear regression extrapolation of 2 week over an observation period of 2-3 months. In patients with initial blood lymphocyte counts of less then 30x109/l LDT should not be used as single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other then CLL (eg, infections) should be excluded.

P

5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy

MQual

6. Constitutional symptoms defiend as any one or more of the following disease related symptoms and signs:

a. Unintentional weight loss of 10% within the prevoious 6 months;b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual

activities);c. Fevers >380C for 2 or more weeks without other evidence of infection; ord. Night sweats for more then one months without evidence of infection

MQual

Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia nor absolute lymphocyte count do not by themselves constitute indication for therapy.

Current guideliness – how heplful with regard to treatment iniciation

• Based on convention, not EBM– Why given level of anemia, thrombocytopenia

or limphadenopathy or splenomegaly?

• Somehow loose, ambigous & imprecise• Allow broad range of variation• Endpoint “Time to treatment” is weak!• However, parameters of “active disease”

can help define treatment goals • All aspects should be validated (EBM)!

34

∑:Call for clinical rials

• A number of imminent uncertenties should be addressed in controlled clinical setting

• Pending questions are important for improving and individualizing treatment

• Translational studies may open new avenues, number of new parameters should be validated

• There is a need to develop means to motivate, support and re-institute collaborative trials to answer pending open questions

• Therefore, I call for clinical trials in this area!

35

CLL – what is the best1st line therapy ?

CLL active disease criteria

• Evidence of progressive marrow failure (worsening of anemia or

thrombocytopenia)

• Massive (progressive) symptomatic splenomegalia

• Massive nodes or progressive, symptomatic lymphadenopathy

• Progressive lymphocytosis (increase of >50% over 2 months, or

lymphocyte doubling time of < 6 months)

• Autoimmune anemia and/or thrombocytopenia poorly responsive to

standard therapy

• Disease-related symptoms: weigh loss ≥ 10% within 6 months,

significant fatigue (ECOG>2), fever>38,0°C ≥2 weeks, night sweats for

>1 months

Blood,2008. Hallek M et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international Workshop on Chronic Lymphocytic Leukemia updating the NCI-Working Group 1996

guidelines

Treatment options for previously untreated CLL

Chemotherapy:

• Alkylating agents (chlorambucil, cyclophosphamide,

bendamustine)

• Nucleoside analogues (fludarabine,cladribine, pentostatine)

Immunotherapy - monoclonal antibodies:

• Rituximab - anti CD20 antibody

• Alemtuzumab - anti CD52 antibody

Steroids

Chlorambucil• Alkylating agents used most frequently:

– Chlorambucil

• is used as monotherapy

• optimum dose and schedule have not been defined

CLB 0,4-0,8 mg/kg q 2 wks.

GCLLSG Good tolerability

CLB 40 mg/m2 q 4 wks.

USA nausea & vomiting

HD-CLB 10 mg/m2/7d q 3-4 wks.

UK Good tolerability

HD-CLB 15 mg /cont. EORTC Good tolerability Jaksic et al. 1988 compared continuous vs. intermittent HD-CLB - improved RR and OS with continuous HD-CLB

Our experience with chlorambucil

Patients’ characteristics

• 88 patients 70 M 18 F

• age 38-88 y (median 64)

• Binet A =19 B= 38 C =31

• Rai 0 =2 1=27 2=38 3=6 4=25

• TTM 21 < 9 59 > 9

• dose of CLB 10-20 mg daily (median 15 mg)

• Treatment duration 2-20 weeks (median 5)

• 47 (53%) patients received CLB maintenance

Overall survival and time to treatment

failure

OS-53 months

TTF-20 months

Progression free survival

PFS-15 months

Survival according to stage

OS - 60 vs.44 months

p=0,067

TTF - 30 vs. 11 months

p=0,058

Survival according to age

No difernece in OS

Survival according to TTM

OS- 78 vs. 44 months

p=0,021

Toxicity

• 3 patients had serious infections

• 2 died

• 5 (6%) had severe hematological toxicity, mostly thrombocytopenia.

• Only 1 patient had severe nausea.

• Our results seem superior to pulse-dosed CLB

• R + HD-CLB continuos ?

Nucleoside analogues

Fludarabine

• most widely studied and most effective purine analogue

Fludarabine monotherapy

• Several phase III studies compared efficacy of fludarabine monotherapy with

CLB , CVP, CHOP

– Fludarabine generally induced higher RR and PFS, no difference in OS

Fludarabine-based combination

• Different combinations were studied

– cyclophosphamide + fludarabine – the most investigated

– improves RR 69-91%, PFS 31-48 months

– no difference in OS

– acceptable toxicity (neutropenia, thrombocytopenia, infections)

Trials in Previously Untreated CLL Patients

OS – no difference in any of the trials

Reference

Regimen

Phase No. Pts. CR, %ORR, %

PFS

Eichhorst, 2006

Flu III 164 7 83 20 mo.

Flu + Cy

164 24 94 48 mo.

Flinn, 2007

Flu III 137 5 59 19 mo.

Flu + Cy

141 23 74 32 mo.

Catovsky, 2007

Chl III 387 7 7210% at 5 y.

Flu 194 15 8010% at 5 y.

Flu + Cy

196 38 9436% at 5 y.

Monoclonal antibodies-Rituximab

• Different combinations studied

– Rituximab + fludarabine

• improved OR, CR and PFS

– Rituximab + fludarabine + cyclophosphamide

• highest OR 90-95%, CR 70-72%

• acceptable toxicity

– Rituximab + fludarabine + cyclophosphamide in reduced doses

(R-FC lite)

• reduced toxicity, results similar to R-FC

– Rituximab + pentostatine + cyclophosphamide

• in patients older than 70 years results are same as in younger

Trials in Previously Untreated CLL Patients

Reference

Regimen

Phase No. Pts. CR, % ORR, %

Median PFS (months)

Keating, 2005

FCR II 300 72 94 NR

Hallek, 2008

FC III 409 27 88 32

FCR 408 52 95 43

Kay, 2007 PCR II 64 41 91 31

Kay, 2008 PR II 33 30 79 12

Reynolds, 2008

PCR III 92 7 45 Not Rep

FCR 92 17 58 Not RepOS – no difference in any of the trials

Our experience with rituximab in CLL

• Rituximab 375 mg/m2

– monotherapy 2 – COP 8 – CHOP 4 – CLB 11– FND 15– FC 4– F 1

Patients’ characteristics

– 45 patients: 29 M 16 F

– age 41-82 y (median 60)

– Rai 0=2 1=13 2=15 3=1 4=14

– Binet A=5 B=25 C=15

– TTM <9=18 >9=15

– 0-5 line of therapy (median 1)

– time from dg. 0-60 mo (median 10)

• Alive 33 Dead 12• Follow up 6-44 months (median 17)

Response to therapy

Sveukupno

32%

54%

14%

KR

PR

NR

1.linija

2. linija

47%53%

24%

56%

20%

T O T A L 1st line therapy

2nd line therapy

PREŽIVLJAVANJE

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36

mjeseci

%

Sveukupno

1. linija

2. linija

n=15

n=44n=25

Overall survival

1st line therapy

All patients

2nd line therapy

months

Toxicity

• Acute infusion reaction– 1 death

• Anaphylaxis during 2. infusion

• M, 78 y, R-CVP, 5.

• Infection grade 3/4– 1. line 0/15

– >1. line 7/29

Monoclonal antibodies

• Alemtuzumab –anti CD 52

– first monoclonal antibody approved for treatment of CLL in USA,

– alemtuzumab compared with pulse-doses of chlorambucil in untreated

patients improved

• PFS,OR and CR

• time to alternative treatment

• increased minimal residual disease-negative remissions

• predictable and manageable toxicity

Hellman et al. 2007 alemtuzumab vs. CLB

• OR 83% vs. 55%, CR 24 vs 2 %, PFS 14,6 vs 11,7 months,TTF 88 vs

36 weeks

New drugs

Bendamustine• promising results• significant toxicity

– Knauf et al 2008 compared bendamustine versus chlorambucil

• ORR 68% vs. 31% , PFS 21,6 months vs. 8,3 months , sever infection 8%

vs 3%

• ongoing trial bendamustin + rituximab vs FCR

Lenalidomide• immunomodulatory drug• dosing regimen not yet defined• continuous low dose may be most effective and less toxic

Steroids• high dose methylprednisolon + rituximab

Conclusions

• Advances in the treatment of chronic lymphocytic leukemia

improved

– overall response rates

– complete response rates

– progression free survival

• However, there is still no difference in overal survival.

• CLL remains incurable with standard therapies.

• Thus, more effective therapy is needed, particularly for patients with

high-risk CLL.

Conclusions

• The “best” initial treatment for CLL depends on desired goals.

– disease control vs. disease eradication

– higher tolerability vs increased toxicity

• FC results in best RR and PFS but without affecting OS

• Chlorambucil is a viable alternative, specially if given continuously

in high doses

• Rituximab is not toxic, can be combined with any chemotherapy

and improves RR ,CR and PFS

– Therefore FCR > FC and R-HD-CLB > HD-CLB

• Role for alemtuzumab – frontline or consolidation, combination

with chemotherapy

Thanks

• Division of Hematology– prof. dr B. Labar– doc. dr S. Zupančić-Šalek– doc. dr M. Mrsić– dr I. Radman-Livaja– dr D. Sertić– dr R. Serventi-Seiwerth– dr D. Dujmović

– prof. dr D. Batinić– K. Dubravčić

– prof. dr M. Sučić– dr M. Marković-Glamočak– dr S. Ries– dr K. Gjadrov-Kuveždić

– prof. dr M. Nola †– dr I. Ilić– dr S. Dotlić