Chronische Lymfatische Leukemie: alles anders

1
Chronische Lymfatische Leukemie alles anders?

Snapperdag 25-10-2006

• M.H.J.van Oers
• Dept Hematology
• Academic Medical Center Amsterdam

2
B-cell Chronic lymphocytic leukemia

• Most frequent leukemia in Western world

• Monoclonal mature B cells
• CD5
• CD23
• sIg low
• CD22/CD79b low
• FMC7

Score 4 or 5 typical CLL (Matutes score)

• Most cells in Go/G1 ? accumulation by
  deregulated apoptosis

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B-CLL Clinical features

• asymptomatic 40 !!

• fatigue, fever, weight loss
• lymphadenopathy (painless )
• hepato-splenomegaly
• anemia
• thrombocytopenia, bleeding
• recurrent infections
• No curative treatment available

4
CLL a decade of progress and confusion

• 1996
• 1 disease
• prognosis
• clinical stage
• Treatment
• same for all
• chlorambucil

• 2 diseases
• prognosis
• clinical stage
• IgVH mutation status
• cytogenetics
• Treatment
• risk adapted
• new promising regimens
• HOW ??

5
CLL a decade of progress and confusion

• 1996
• 1 disease
• prognosis
• clinical stage
• Treatment
• same for all
• chlorambucil

• 2006
• 2 diseases
• prognosis
• clinical stage
• IgVH mutation status
• cytogenetics
• Treatment
• risk adapted
• new promising regimens
• HOW ??

6
Type I and Type II CLL

• Type I Absence of Ig VH somatic mutation
• Type II Ig VH somatic mutation
• lt 98 homology to germline VH gene

7
Hypothesis on the cellular origin of B-CLL
naive B cell unmutated
Plasma cell
GC
Proliferation VDJ mutation Ig class switch
Memory B mutated
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CLL a decade of progress and confusion

• 1996
• 1 disease
• prognosis
• clinical stage
• Treatment
• same for all
• chlorambucil

• 2006
• 2 diseases
• prognosis
• clinical stage
• IgVH mutation status
• cytogenetics
• Treatment
• risk adapted
• new promising regimens
• HOW ??

9
CLL clinical staging

• Rai
• 0 lymphocytosis
• I lymphadenopathy
• II spleno- and /or hepatomegaly
• III anemia
• IV thrombocytopenia

• Binet
• A ? 2 stations
• B ? 3 stations
• C anemia/ thrombocytopenia

(Cancer 1981)
(Blood 1975)
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CLL survival - Binet Stages
EHFV, Barcelona
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Clinical staging systems for CLLLimitations

• Rai and Binet staging systems are unable to
  identify within the good / intermediate
  prognosis groups ( Binet A / Rai 0 - II
  ) those patients who will progress, require
  treatment and ultimately die from CLL

Early stage increasing ! Binet A up to 75 of
newly diagnosed CLL
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Chronic Lymphocytic Leukemianew prognostic
factors

• Cytogenetics
• IgVH mutation status
• CD38 expression
• ZAP 70 expression

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Cytogenetic abnormalities and prognosis in
CLL (all stages)
N 300
13 q- n117
12 n47
Normal n57
17 p- n23
11 q- n56
Döhner et al NEJM 2000
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Impact of karyotype in CLL Binet A
100
Survival in
80
13q-, 12, normal
60
11q- or 17p-
40
20
0
0
0
36
72
108
144
180
0
Time in Months
Courtesy H. Döhner
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Cellular substrate for influence of karyotype on
prognosis

• 17p locus for tumor suppressor gene p53,
• key role in apoptosis induction and
  proliferation inhibition
• 11q locus for ATM, a p53 regulating kinase

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Chronic Lymphocytic Leukemianew prognostic
factors

• Cytogenetics
• IgVH mutation status
• CD38 expression
• ZAP 70 expression

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CLL prognosis and IgVH mutation status
Döhner ASH 2001
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CLL prognosis and IgVH mutation status in
Binet A
Döhner ASH 2001
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New prognostic factors in CLL conclusions

• At present IgVH mutation status and cytogenetic
  abnormalities seem to be the most powerful
  prognostic factors in CLL, allowing early
  identification of (stage A) patients who will
  progress.
• However, the assays are difficult and expensive
• CD38 alone is not a good surrogate marker. ZAP70
  ??
• Search for (combination of) simple, reliable and
  cheap factors (soluble markers?)

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CLL a decade of progress and confusion

• 1996
• 1 disease
• prognosis
• clinical stage
• Treatment
• same for all
• chlorambucil

• 2006
• 2 diseases
• prognosis
• clinical stage
• IgVH mutation status
• cytogenetics
• Treatment
• risk adapted
• new promising regimens
• HOW ??

21
Treatment of CLL CBO guidelines 2004

• Wait and see !!
• First line Chlorambucil
• Second line Fludarabine (i.v. / orally)
• Third line no evidence based guidelines
• role anti-CD20 (Rituximab) and anti-CD52
  (Alemtuzumab ) ?
• Allogeneic stem cell transplantation
• second or third line in patients lt 55 yrs in
  case of early relapse and/or resistance

Still valid in 2006 ?
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FC versus F in previously untreated CLL
In vitro, fludarabine inhibits repair of DNA
damage induced by cyclophosphamide
Eichhorst FC more myelosuppression CTC
grade 3/4 22 versus 8
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Fludarabine, Cyclophosphamide and Rituximab (FCR)
in CLL
FCR Cycle 1 R 375mg/m2 d 1 FC d
2-4 Cycles 2-6 R 500mg/m2 d 1 FC d 1-3
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Relationship between genetic markers and
Fludarabine-based therapy

• High-risk interphase cytogenetics and IgVH
  mutational status do not affect response rates to
  FR (Byrd, et al. ASH 2004. Abstr 476.) or FC (
  Grever et al. ASH 2004. Abstr. 3487)
• However, both are predictive of
• Significantly shorter progression-free survival
• Significantly shorter overall survival

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Alemtuzumab (anti-CD52) application in
hematological malignancies

• Relapsed, fludarabine resistant CLL
• T-PLL
• Other T cell Malignancies
• CTCL
• T-NHL
• (GvHD)

• Keating et al. Blood 2002993554
• N 93
• 2 CR 31 PR
• Resp.duration 8.7 mo

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Alemtuzumab pivotal trial in relapsed CLL
Overall Survival (n93)
Survival of ITT population Historical control
16 months
10 months n147
0
3
6
9
12
15
18
21
24
27
30
33
36
Survival (months)
Keating, et al. Blood. 2002993554-61.
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Relationship between genetic markers and response
to Alemtuzumab

• 46 patients with fludarabine-refractory CLL
  treated with alemtuzumab in the CLL2H Study
• Median follow-up, 12.2 mos
• Median prior lines of therapy, 4 (range 1-9)
• 17p-, 29 11q-, 27 12, 18 unmutated VH, 73
• Treatment
• IV alemtuzumab dose escalation (3, 10, 30 mg),
  followed by
• SC alemtuzumab 3 x 30 mg weekly for 4-12 wks

Stilgenbauer S, et al. ASH 2004. Abstract 478.
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Relationship between genetic markers and response
to Alemtuzumab

• Alemtuzumab active in all genetic subgroups
• Overall response 37
• OR with 17p- 53.8
• Similar survival rates seen in all genetic
  subgroups

Stilgenbauer S, et al. ASH 2004. Abstract 478.
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Conclusions

• Newer regimens result in
• higher (complete) remission rates
• longer progression free survival
• improved overall survival ??
• Results dependent on genetic risk factors
• Alemtuzumab first choice for patients with p53
  deletions/ mutations ?
• Risk-adapted prospective studies urgently needed

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CLL clinical trials (Netherlands)

• Previously untreated CLL
• Nordic-Dutch CLL-1 Trial (Hovon 68)

• Relapsed CLL
• BO17072 (Reach) - study (Roche)

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Nordic-Dutch CLL-1 Trial (Hovon 68) study design
R A N D O M I S E D
FC x 6 1x/4 wks

• High risk CLL
• Binet A/B indication for treatment
• Binet C
• 18-75 yrs

FC Alemtuzub x 6 1x/4 wks
Fluda 40 mg/m2 p.o d 1-3 Cycloph. 250
mg/m2 p.o d 1-3 Alemtuzumab cycle 1 30 mg
s.c d -1,0, 1 cycle 2-6 30 mg s.c d 1
Total dose 240 mg
Unmutated IgVH genes and/ or del 17p, del
11q, trisomy 12
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Nordic-Dutch CLL-1 Trial (Hovon 68)objectives

• Primary
• Assess the effect of the addition of
  Alemtuzumab sc to oral FC on progression-free
  survival.

• Secondary
• Assess the effect of the addition of Alemtuzumab
  sc to oral FC on
• clinical, flow-cytometric and molecular response
  rates
• overall survival.
• the incidence of severe opportunistic infections
  (notably CMV reactivation and CMV disease)

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Study Design Reach (BO17072)
R a n d o m i z a t i o n
6 Cycles
FCR
624 Relapsed CLL
Follow up
FC
C1
C2
C3
C4
C5
C6
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CLL management outside of trials
Treatment of CLL what is the goal?

• Short term
• Long lasting, complete remissions in young
  patients,resulting in improved overall survival
• Palliation in elderly patients
• High quality of life in all patients

• Long term
• cure by combined modality treatment.

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CLL management outside of trials

• First line Chlorambucil still tenable
• no cures or improved survival by new regimens
• least toxic
• salvage after combined modality like FCR ?

• Younger patients (lt 65) refractory/ early relapse
  after first line treatment
• assess prognostic factors (cytogen. / IgVH mut.)
• immunochemotherapy (17p- alemtuzumab containing)
• explore possibilities for allogeneic SCT (RIST)

36
Conclusions

• In CLL basic and clinical progress as never
  before
• Guidelines as to best clinical practice
  short-lived
• Participation in clinical trials of utmost
  importance

• Key question should poor prognosis (stage A)
  patients receive early ( intensive) treatment?

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Molecular genetics of CLL

• 13 q14 deletion loss of miRNAs (MiR-15/16),
  normally suppressing Bcl2
• 11q22-23 deletion inactivation of ATM tumor
  suppressor. Also mutations described.
  Mechanism?
• Trisomy 12 amplification of MDM2 (12q13-15) ?
  overexpression of p53-inactivating protein
• 17p13.3 deletion deletion of p53

in gt85 of CLL BcL2 overexpression however no
t(1418)
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Chronic Lymphocytic Leukemianew prognostic
factors

• Cytogenetics
• IgVH mutation status
• CD38 expression
• ZAP 70 expression

40
Nordic-Dutch CLL-1 Trial (Hovon 68) statistical
considerations

• Power 80 to detect 50 increase in PFS
• (from 2 to 3 years 2 yrs PFS from 50 to 67)
• Power 80 to detect increase in CR from 20 to
  40
• alpha 0.05
• 268 evaluable patients needed
• Accrual 300 patients, 60/yr, 5 years

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Progr/ Relapse
Allogeneic RIST in CLL TRM and GvL activity n76
EFS
TRM
OS
P.Dreger et al Leukemia (2003) 17, 841-848.
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CLL7 Study design
Untreated CLL patients stage Binet A
no-risk-Gruppe watch and wait

• Risikostratifikation
• 2 von 4 Parametern aus
• Thymidinkinase
• Lymphozytenverdopplungszeit
• unmutierter IgVH-Status
• Zytogenetik

Therapie FCR
at-risk-Gruppe
watch and wait
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ZAP-70 expression and time to initial therapy
Rassenti et al N Engl J Med 2004351893
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CD 38 as a prognostic marker in CLL

• Poor surrogate marker for IgVH mutational status
  (30 discordant)
• Cut-off value ??
• 30 Damle/Hamblin, Blood 1999
• 20 Ibrahim, Blood 2001
• 7 Kröber, Blood 2002
• Although simple, standardisation essential
  (SIHON)
• Changing expression over time (25 mostly - ?
  )

45
Time to treatment-failure of 202 CLL patients
treated with FCR as initial therapy.
Keating, ASH 2003
46
BO17072 study inclusion criteria

• No more than one previous line of chemotherapy
• Not refractory to first line (alkylator or
  Fludarabine)
• ECOG performance status 0-1
• Age above 18
• Life expectancy gt 6 months
• !! Genetic risk factors will be analysed
  afterwards
• !! Fludarabine iv

47
Type I and Type II CLL

• Type I Absence of Ig VH somatic mutation
• Type II Ig VH somatic mutation
• lt 98 homology to germline VH gene

• Incidence Type I Type II - 85 15
• Prevalence Type I Type II - 55 45
• Type II more indolent than Type I
• Probable incidence in the Netherlands
• Type I 500 new cases per year
• Type II 100 new cases per year

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Subcutaneous Alemtuzumab (anti-CD52) in
previously untreated CLL a phase II trial

• Patients ORR CR PR SD PD
• (n) () () () () ()
• All patients 38 87 19 68 8 5
• Rai stage
• I/II 11 100 9 91 0 0
• III/IV 27 81 22 59 11 8
• Age
• gt 65 years 20 90 20 70 5 5
• ? 65 years 18 83 17 66 11 6
• Lymph nodes
• Any node gt 5cm 7 86 0 86 14 0
• All nodes lt 5cm 24 88 21 67 4 8
• No lymphadenopathy 7 86 29 57 14 0

Lundin et al. Blood 200210076873
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FC versus F in first line CLL
Eichhorst Blood 2006 107885
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ZAP-70

• Member of Syk-ZAP70 protein tyrosine kinase
  family
• Normally expressed in T cells and NK cells
• Critical role in T cell signaling
• Expression in subgroup of B CLL patients
• Surrogate marker for IgVH mutation status CLL?

53
ZAP-70 as a prognostic marker in CLL

• Flow cytometry ZAP-70 expression highly
  correlated with non-mutated status
• Crespo et al NEJM 2003 n 56
• Oscier et al Lancet 2004 n167
• Rassenti et al NEJM 2004 n 307
• 10 -23 discordance (in either way)
• Better than mutation status ? (Rassenti et al
  NEJM 2004 )
• Stability over time ? (2/16 change Durig et
  al.2003)
• Cut off level ??
• 10 (Oscier)
• 20 (Crespo,Rassenti)