1. The Chronic Lymphocytic LeukemiaThe Chronic Lymphocytic Leukemia
(CLL)(CLL)
Dr.manoj toshniwalDr.manoj toshniwal

2. • B-CLL is a neoplastic disease characterized by
proliferation and accumulation of small, mature, long-
living lymphocytes in blood, marrow and lymphoid
tissues (lymph nodes, spleen)
• IWCLL 2008 criteria- an absolute malignant b
lymphocyte count >5000
The B-CLL - definition

3. • SLL- ALC <5000, LN/Spleenomegaly
• MBL-precursor to CLL,
immunophenotypicaly consistent
LN<1.5cm,
ALC<5000,
no cytopenias,
Rate of progression 1.1% / yr
• PLL- prolymphocytes exceed 55% of
lymphoid cells in peripheral blood

4. • Most common adult leukemia in Europe and North
America (in USA incidence of about 3/100.000
population)
• predominantly, CLL is a disease of elderly
• 40% of leukemias in patients over 60 years old
• men affect twice as often as women; 2:1 ratio of male to
female
• CLL morbidity rapidly increases with age (especially
between 50 and 60 years of age)
B-CLL epidemiology
≥ 65 years
55–64
years
20–54 years
72
%
25
%
3%

5. • the cause of CLL is unknown
• there is increased incidence in farmers, rubber
manufacturing workers and tire repair workers
• genetics factors have been postulated to play a role
in high incidence of CLL in some families (10%)
B-CLL etiology & pathogenesis

6. • often none! - 40% of patients are asymptomatic and the
diagnosis is typically accidental
• unspecific: night sweats, fever, weakness (many patients have
fatigue, reduced exercises tolerance or malaise, weight loss)
• recurrent infections (bacterial, viral – Herpes Zoster, fungal) –
they are the most common cause of death
• bleeding and symptoms of anemia and thrombocytopenia
• Lymphadenopathy (lymph node enlargement)
– at diagnosis - nontender in 80% of patients
– later - may become very large
• splenomegaly - mild to moderate in 50% of patients
• hepatomegaly
• some organs infiltration (lungs, pleura, skin and soft tissue)
B-CLL clinical symptoms

7. CLL – Initial symptoms
• Approximately 40% are asymptomatic at diagnosis –
discovered by a CBC
• In symptomatic cases the most common complaint is
fatigue
• Well’s syndrome – increase sensitivity to insects bites
• B symptoms – fever, sweats, weight loss
• Less often the initial complaint are enlarged nodes or
the development of an infection (bacterial)

8. B-CLL clinical symptoms
Cervical
limfadenopathy in
patient with B-CLL

9. B-CLL clinical symptoms
The CLL
patient can
have
splenomegaly

10. Diagnosis…Diagnosis…

16. B-CLL laboratory features
• Bone Marrow smear (cytological examination)
– extensive replacement of marrow element by mature
lymphocytes (more than 30%)

17. Prognosis: histological bone marrow
patterns
Interstitial
(low risk)
Diffuse
(high risk)
Nodular
(low risk)

18. – CD5+/CD19+/CD23+/ dim CD20+
– 90% of the patient have a very weak expression of
surface immunoglobulin (kappa or lambda light chain,
IgM, IgD)
– sometimes also CD38+,
– Dim expression of CD20, CD25, CD11c;
– lack expression of CD 10, CD 103, CD79a, FMC7
Immunophenotyping

19. CLL - Immunophenotype scoring
system (Matutes score)
Scoring system for B-CLL
Membrane
marker
Points
1 0
Smlg Weak Moderate/strong
CD5 Positive Negative
CD23 Positive Negative
FMC7 Negative Positive
CD79b (SN8) Negative Positive
1. Matutes E, et al. Leukemia. 1994;8:1640-1645.
2. Moreau EJ, et al. Am J Clin Pathol. 1997;108:378-382.
In 1994, Proffessor E. Matutes proposed a scoring system
range between 5 (typical B-CLL cases)
and 3 (less typical B-CLL cases)

20. • Conventional metaphase cyto difficult d/t very low
proliferation activity of leukemic cells
• Cytogenetic examinations - clonal chromosomal
abnormalities are detected in approximately 30- 50% of
CLL patients
– deletion 13 (13q14.3)
– trisomy 12
– structural abnormalities of chromosomes 11 (11q-), 14,
17
B-CLL laboratory features

21. FISH
• FISH positive in 80% of cases
• m/c del13 q (55%), f/b del 11q (18%), trisomy
12(16%), del17p(7%), del 6q(7%)
• Good- 13q
• Neutral- normal, 12+
• Bad- 17p, 11q
• Addition of an alkylating agent to fludarabine may
help to overcome adverse prognostic sign of 11q

23. CLL - Genetic abnormalities
Genetic
abnormality
Incidence
(%)
Median
survival
(months)
Clinical correlation
13q14 55-62 133-292 Typical morphology
Mutated VH genes
Stable disease
+ 12 16-30 114-122 Atypical morphology
Progressive disease
del 11q23 18 79-117 Bulky lymphadenopathy
Unmutated VH genes
Progressive disease
Early relapse
post autograft
p53
loss/mutation
7 32-47 Atypical morphology
Unmutated VH genes
Advanced disease
Drug resistance
1. DÖhner H, et al. N Engl J Med. 2000;343:1910-1916.
2. Oscier DG, et al. Blood. 2002;100:1177-1184.

24. CLL genomics: Recurrently
mutated genes and survival
• TP53: major negative effect, short OS.
• ATM: Little or no effect on OS.
• NOTCH1: conflicting data, additional prospective
evaluations are needed, association with Richter’s
transformation.
• SF3B1: likely minor effects on PFS but further
research is needed.
• Others: unknown.

25. Diagnosis of B-CLL
Blood test lymphocytosis ≥ 5G/l
Morphology monoclonal population of small mature
lymphocyte
B-cell CLL phenotype clonal CD5+/CD19+ population of lymphocyte
Markers of clonality κ/λ light chain restriction; cytogenetical
abnormalities
Bone marrow infiltration > 30% of nucleated cells on aspirate
Lymph node diffuse infiltrate of small lymphocytes

26. Staging…Staging…

27. Rai’s clinical staging system
Stage Clinical Features at Diagnosis Median
Survival
(years)
0
Low risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
>12,5
I
Intermediate
risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged lymph nodes
8
II
Intermediate
risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged spleen and/or liver
6
III
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and anemia (Hb < 11g/dl)
1,5-2
IV
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and thrombocytopenia(< 100 000 /ul)
1,5-2

28. CLL – Rai stages

29. Binet’s clinical staging system
Stage Clinical Features at Diagnosis Median
Survival
(month)
A Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and less than 3 areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and
thrombocytopenia
> 120
month
B Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and 3 and more areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and
thrombocytopenia
60 month
C Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
with anemia (Hgb <10g/dL) or thrombocytopenia (Plt
<100.000/uL)
24 month

30. CLL – Binet’s stages

31. Prognostication…Prognostication…

32. Major phenomena underlying
CLL clinical behavior
• CLL has a highly varied clinical course.
• Phase 1: Diagnosis to need of first therapy (TTFT).
• Short TTFT independently associates with expression of
ZAP70, IgVH-UM status, INSR expression/del11q, TP53
mutations/del17p and elevated genomic complexity.
• Phase 2: Time from first therapy to death (Survival).
• Short survival is determined by TP53 mutations/del17p,
del11q status and most comprehensively SNP array-based
elevated genomic complexity.
• Most CLL markers are unstable longitudinally necessitating
outcome analysis from the dates of marker measurements.

33. Prognostic factor Good prognosis Bad prognosis
Clinical stage according to
Binet
Rai
A
0
B, C
I, II, III, IV
Bone marrow infiltration in
- bone marrow biopsy
- cytological examination
Leucocytosis
Prolymphocytes in
peripheral blood
Leukemia cell doubling
time
Non-Difussed
infiltration
<=80% lymphocytes
<= 50 x 109/l
<= 10%
> 12 months
Difussed
infiltration
> 80% lymphocytes
> 50 x 109/l
>10%
<= 12 months
New prognostic indicators in
B-CLL (1)

34. Prognostic factor Good prognosis Bad prognosis
Serum markers:
- lactate dehydrogenase activity
(LDH)
- ß2-microglobulin activity
- lymphocyte’s thymidine kinase
activity (TKA)
- sCD23 expression
Normal range Elevated
Clonal chromosomal
abnormalities
Normal
karyotype
isolated del
(13q)
Del (11q)
Del (17p)
CD 38 expression <= 30 % > 30%
New prognostic indicators in B-CLL
(2)

35. Prognostic factor Good prognosis Bad prognosis
The mutational status of
immunoglobulin variable region
of heavy chain genes (IgvH)
mutated unmutated
ZAP–70 expression low (< 20%) high ( > 20 %)
Survivin absence presence
New prognostic indicators in
B-CLL (3)

36. • clinical stage
• bone marrow histology (diffuse replacement carries worst
prognosis)
• leukemia cell doubling time (less than 1 year - worse
prognosis)
• percentage of prolymphocyte
• high cell-surface expression of CD38
• ZAP-70 expression
• serum level of: B2-microglobulin; thymidine kinaze, LDH,
sCD23
• IgVH mutational status
• genetic features - FISH cytogenetic
– low-risk: normal kariotype; isolated del(13q)
– high-risk: del(17p0, del(11q), trisomy 12
New prognostic indicators in
B-CLL - summary

37. CLL : ZAP-70

38. CLL : CD38 Expression
Months
1. Orchard JA, et al. Lancet. 2004;363:105-111.
Percentsurviving(%)
CD38 ≥30%
Mean = 163.2 months
CD38 <30%
Mean = 288 months
N=162
P=.008
100
80
60
40
0
20
90
70
50
30
10
0 100 200 300 400 500

39. CLL: lymphocyte doubling time
Survival time according to LDT (all stages)
Months
Probabilityofsurvival
1600 20 40 60 80 100 120 140
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Doubling time ≤12 months
Doubling time >12 months
1. Montserrat E, et al. Br J Haematol. 1986;62:567-575.

40. Effect of genetic abnormalities
on survival
1. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.

41. Treatment…Treatment…

42. • We have to remember:
– B-CLL – indolent lymphoma, but incurable
– Elderly patients – risk of additional diseases
– Course of the disease can be very long, indolent for many years,
patient can die because of another reason which is not connected
to B-CLL.
• Decision about treatment depends on clinical stage, prognostic factors
and patient’s condition
CLL – treatment

43. CLL Therapy 1960-2014
Many things have changed…
• From chlorambucil (<10% CR) to chemoimmunotherapy
(60%-70% CR)
• Chemoimmunotherapy new gold-standard for CLL
therapy
• MRD- negativity CRs correlates with better outcome
• Improved PFS and OS

44. Indications to treatment:
• leukemia cell doubling time <6 (12) months
• Grade 2 or greter fatigue
• B symptoms for >2weeks
• Lymph nodes of >10 cm
• Symptomatic liver or splenic enlargement
• Anemia hb <11 gm%
• Thrombocytopenia <1 lac platelets
• Wbc count >3 lac on 2 occasions 2 weeks apart
• Severe paraneoplastic process related to CLL

45. • Watch and wait
• Monotherapy
– Glucocorticoids (autoimmunological complications)
– alkylating agents (Chlorambucil, Cyclophosphamide)
– purine analogues (Fludarabine, Cladribine, Pentostatin)
• Combination chemotherapy
– Chlorambucil/Cyclophosphamide + Prednisone
– purine analog (Fludarabine) + Cyclophosphamide +/- Mitoxantrone
– CVP, CHOP (Cyclophosphamide, Doxorubicin, Vincristin,
Prednisone)
• Monoclonal antibodies (monotherapy and in combination)
– Alemtuzumab (anti-CD52) = CAMPATH
– Rituximab (anti-CD20) = Mabthera
– antiCD23 etc.
– monoclonal antibodies conjugated with radionuclides =
Ibritumomab tiuxetan = Zevalin
CLL – treatment

46. • Hematopoietic stem cell transplantation
– autologous - still no cure with auto-SCT
– allogenic with reduced intensity conditioning
• Even RIC-SCT is still a risky procedure - indicated only in
high-risk disease
• New and novel agents
– Oblimersen – bcl2-directed antisense oligonucleotide
– Lenalidomide
– Flavopiridol
– Anti-CD23
– Anti-CD40
• Vaccine strategies
• Supportive therapy (allopurinol, G-CSF, blood and platelet
transfusion, immunoglobulins, antibiotics)
CLL – treatment

47. • Complete response (for at least 2 months)
– clinical features – normal
– morphology – normal (Hb>11 g/dl; Pt>100 000 /ul, lymphocytes
<4000 G/l; neutrofiles >1500 G/l))
– bone marrow - lymphocytosis less than 30%
• Partial response
• Stable Disease
• Progressive Disease: at least 50% increse in ALC/spleen/liver,
new lesions, ds related cytopenias
• Relapse: evidence of disease progression after 6 months or
more of initial CR/PR
• Refractory disease: failure to achieve a response or having
disease progression in 6 months of last Rx
Response criteria
(NCI working group 1996)

48. Partial response :
A partial response (PR) is defined (NCI criteria) as presence of
all of the following for two or more months:
- A reduction in previously enlarged nodes, spleen, and liver by at least
50 percent and
-Absolute neutrophil count >1,500/µL or
-Platelet count >100,000/µL or
-Hemoglobin concentration >11 g/dL or
50 percent improvement over pretherapy reductions in hemoglobin
concentration and/or platelet count

49. Complete remission :
A complete remission in CLL requires all of the following to be
present for two or more months
-Absence of symptoms attributable to CLL.
-Normal findings on physical examination.
-Absolute lymphocyte count <4,000/µL.
-Absolute neutrophil count >1,500/µL.
-Platelet count >100,000/µL.
-Hemoglobin concentration >11 g/dL (untransfused).
-Bone marrow lymphocytosis <30 percent.
-No nodules (lymphoid aggregates) on BM biopsy.

50. 1. Cheson BD, et al. Blood. 1996;87:4990-4997.
Variable NCI IWCLL
Response criteria
CR
Physical exam Normal Normal
Symptoms None None
Lymphocytes (x 109
/L) ≤4 <4
Neutrophils (x 109
/L) ≥1.5 >1.5
Platelets (x 109
/L) >100 >100
Hemoglobin (g/dL) >11 (untransfused) Not stated
Bone marrow lymphs (%) <30, no nodules Normal, allowing nodules or
focal infiltrates
PR
Physical exam (nodes and/or
liver, spleen)
≥50% decrease Downshift in stage
Plus ≥1 of:
Neutrophils (x 109
/L) ≥1.5
Platelets (x 109
/L) >100
Hemoglobin (g/dL) >11 or 50%
improvement
Duration of CR or PR ≥2 months Not stated

51. Professional Experience Required to
“Tailor” CLL Therapy
• Median age at diagnosis: 72 years1
• Elderly patients may be fit or have comorbidities
1
Ries LAG et al. SEER Cancer Statistics Review 1975–2005.
2
Yancik R. Cancer 1997; 80:1273–83.
Age at CLL
diagnosis
(years)
Patients
1
(%)
Mean
comorbidities2
(all cancer
types, n)
≤54 11 n/a
55–64 19 2.9
65–74 27 3.6
75+ 43 4.2
Mean no. of co-morbidities
2.9
3.6
4.2
n/a

52. Gribben JG. Blood 2009;114:3359-60; Balducci L, Extermann M. Oncologist 2000;5:224-37.
Classification of Patients by a Comprehensive
Geriatric Assessment (CGA)
GO
SLOW
NO
Suitable for
standard
treatment
Suitable for
reduced
treatment
Suitable for
supportive care
Cumulative Illness
Rating Scale

53. CLL7 protocol of the GCLLSG/FCLLSG
Patients at Binet stage A or B without symptoms
Assessment of 4
prognostic factors:
• 11q- or 17p- deletion
• Unmutated IgVH-Status
• Serum thymidine kinase
> 10 U/L
• Lymphocyte doubling
time < 12 months
Low risk:
< 2 factors
positive
High risk: 2 or
more factors
positive
FCR
watch and wait
watch and wait
Aim and Rationale: Complete (MRD-) eradication of early high risk
disease
2/3 of patients
1/3 of patients

54. Comparison of Fludarabine (F), Bendamustine (Ben),
Alemtuzumab (Al) and Chlorambucil (Chl) as Single
Agents
Rai 20001
Hillmen 20072
Knauf 20093
Regimen
N
F Chl
179 193
Al
149
Chl
148
Ben
157
Chl
157
Median age,
years
64 62 59 60 63 66
Rai Stage III-IV or
Binet C, %
39 41 34 33 29 29
Grade 3/4 ↓ ANC,
%
27 19 41 25 23 10.6
CR, % 20 4 24 2 31 2
OR, % 63 37 83 55 68 31
Med. PFS (mo) 20 14 14.6 11.7 21.6 8.3
1
Rai KR et al. N Engl J Med 2000;343:1750–57. 2
Hillmen P et al. J Clin Oncol 2007;25:5616–
23.
3
Knauf W et al. J Clin Oncol 2009;27:4378-84.

55. CLL5 protocol for elderly patients
with advanced CLL
6 x Fludarabine
phosphate
F 25 mg/m², Days 1–
5
q 28 days
Chlorambucil
(up to a maximum of
12 months)
Clb 0.4 mg/kg body weight
increasing 0.1 mg up to
0.8 mg/kg body weight
q 15 days
CLL, > 65 years, untreated,
Binet stage C or
symptomatic A/B

56. CLL5 protocol
Overall Survival (OS)
Median OS: F 45.8 months; Clb 63.6 months
Overall survival in months
908478726660544842363024181260
CumSurvival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
CLB-censored
F-censored
CLB
F
random
p = 0.15

57. CLL5 protocol
Cause of death
66%3%
25%
6%
CLL related
Treatment related
Secondary disease
Unknown
Clb arm: 32 patients
died
54%
10%
31%
5%
CLL related
Treatment related
Secondary disease
Unknown
F arm: 42 patients died

58. Chlorambucil (Chl) plus Rituximab (R)
in Older CLL Patients
Hillmen et al, ASH 2010
Foa et al, ASH 2010
Trial Therapy n
Response
CR OR SD/PD
Chl-R
(Foa)
A 54 (of 98) 16.7% 81.4% 7.4%
Chl-R
(Hillmen)
B 100 9 (9%) 82 (82%) 15 (15%)
UK CLL4
(Chl only)
C 200 12 (6%) 132 (66%) 60 (30%)
A) CLB 8 mg/m2
d1-7 q28d up to 8x + R 375 mg/m2
c1-2, 500 mg/m2
c3-8,
followed by R-maintenance 375 mg/m2
q 2 m for 2 yrs
B) CLB 10 mg/m2
d1-7 q28d up to 6x + R 375 mg/m2
c1, 500 mg/m2
c2-6
C) CLB like B without R

59. FC Improves Overall Survival in
Non-High Risk CLL
GCLLSG CLL4 protocol
- 375 patients (<66 years) with advanced CLL were randomly
assigned to fludarabine 25 mg/m2
x 5d IV q28d vs FC
(fludarabine 30 mg/m2
and cyclophosphamide
250 mg/m2
x 3d IV q28d)
- Complete remission rate, 24% vs 7% (p < 0.001)
- Overall response rate, 94% vs 83% (p = 0.001)
- Progression-free survival, 48 mo vs 20 mo (p = 0.001)
- Treatment-free survival, 37 mo vs 25 mo (p < 0.001)
Eichhorst BF et al. Blood 2006;107(3):885-91.

60. Outcome n 6-year OS p-value
F 190 54%
F + (M or C) 140 59%
R-FC 300 77%
p = 0.37
p < 0.001
Improved Efficacy by Combining FC
Chemotherapy with Rituximab
(MD Anderson, historical comparison)
Tam CS et al. Blood 2008;112:975–80.
F = fludarabine; M = mitoxantrone; C = cyclophosphamide;
R-FC = fludarabine, cyclophosphamide and rituximab

61. The CLL-8 trial:
R-FC vs. FC in previously untreated CLL
R
A
N
D
O
M
I
S
E
R-FC q4wk ×
3
FC q4wk × 3
R
E
S
T
A
G
E
R-FC q4wk ×
3
FC q4wk × 3
SD, PD off study
CR, PR
Rituximab
Cycle 1: 375mg/m2
Cycles 2–6: 500mg/m2
Fludarabine
25mg/m2
iv, day 1–3
Cyclophosphamide
250mg/m2
iv, day 1–3

Untreated B-CLL

Binet B requiring
treatment or
Binet C

ECOG PS 0–1

n=817
Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174
ECOG PS = Eastern Cooperative Oncology
Group performance status; q4wk = every 4 weeks
SD = stable disease; progressive disease

62. FC FCR
Evaluable
patients
409 408
ORR (%) 80 90
CR (%) 22 44
PFS
(median)
~33 m. ~ 52 m.
OS @ 5 yrs 60% 75%
The CLL-8 trial:
R-FC vs. FC in previously untreated CLL
Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174

63. Bendamustine in CLL therapy
• Reference Phase Regime Pat. prev. ORR CR
n= ther. (%)
• Kath et al., 2001 II B 5x60mg/m2 23 10/23 75 30
• Bremer et al., 2002 II B 5x60mg/m2 15 yes 77 7
• Aivado et al., 2002 II B 2x100mg/m2 23 yes 67 29
• Köppler et al., 2004 I/II BM 2x75mg/m2
22 yes 86 27
• Bergmann, 2005 I/II B 2x70mg/m2 16 yes 56 12,5
• Lissitchkov, 2005 I/II B 2x100mg/m2 15 yes 60 27

64. Phase III Randomized Study of
Bendamustine Compared With
Chlorambucil in Previously Untreated
Patients With Chronic Lymphocytic
Leukemia
Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati,
Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard
Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans-
Joerg Fricke, Francoise Huguet, Ilaria Del Giudice, Peter Klein,
Lothar Tremmel, Karlheinz Merkle, and Marco Montillo
Journal of Clinical Oncology 27:4378-4384

65. European Phase III ‘Intergroup’
CLL Study: progression-free survival
Median progression-free survival: bendamustine 21.6 months;
chlorambucil 8.3 months; p<0.0001
Survival distribution function
Bendamustine (n=162)
Chlorambucil (n=157)
Censored observations
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30 36 42 48 54 60
Time (months)
• Median observation time: 35 months (range, 1-68) at the time of the
analysis

66. 1st-line therapy with single-
agent bendamustine in CLL
• Most patients with CLL are aged over 65 years and
have at least 2 co-morbidities
• A large proportion of patients are therefore not
suitable for intensive chemotherapy
• Studies with bendamustine as first-line therapy for
CLL show that it:
– Provides significantly greater efficacy than chlorambucil
both in terms of RR and PFS
– Has a manageable toxicity profile

67. Bendamustine plus Rituximab
Fischer et al, ASH 2009;Abstract 205.
Response N %
ORR 100 90.9
CR 36 32.7
nPR 3 2.7
PR 61 55.5
SD 10 9.1
PD - -

68. Recommended doses
for bendamustine in CLL
Pre-treated Patients:
Bendamustine 70 mg/m2, day 1+2 every 4 weeks
BR – Rituximab 375 mg/m2 day1 (2nd+ cy 500 mg/m2) +
bendamustine 70 mg/m2 day 1+2 q4 weeks
Primary therapy:
Bendamustine 100 mg/m2, day 1+2 q4 weeks

69. CD20 Targeting
RITUXIMAB OFATUMUMAB GA101
STATUS Licensed Licensed Phase III
TYPE Chimeric Humanized Humanized
EPITOPE Type I Type I Type II
ADCC + + +++
CDC + ++ –
CELL DEATH + ± +++
0

70. 3rd generation of trials of the GCLLSG:
Risk, stage and fitness adapted
W&
W
Inactive Binet A Active disease + all Binet C, not del(17p)
CLL12 CLL10 CLL11
Go Go Slow go
Which is the best score to
define high risk?
yesno
CLB CLB + RBR FCRtreatW&W
Disease (MRD) eradication?
Longer survival?
Symptom control?
longer disease-free survival?

71. R
Fludarabin
Cyclophosphamid
Rituximab
(FCR)
Bendamustin
Rituximab
(BR)
CLL 10 protocol
Fludarabine 25 mg/m² i.v., days 1-3
Cyclophosphamide 250 mg/m², days 1-3,
Rituximab: 375 mg/ m2
i.v. day 0, cycle 1
Rituximab: 500 mg/m² i.v. day 1, cycle 2-6
Bendamustine 90mg/m² day 1-2
Rituximab 375 mg/m² day 0, cycyle 1
Rituximab 500 mg/m² day 1, cycyle 2-6
Similar efficacy of BR in comparison to
FCR?
Lower toxicity rate of BR?

72. • Median observation time: 27.9 mos
• Median PFS:
– FCR: NR versus BR: 44.9 mos (P = .04)
• 2-yr OS
– FCR: 94.2% v. BR: 95.8% (P = .59)
Response, % FCR (n = 274) BR (n = 273)
CR (CR + CRi) 47.4 38.1
CR 40.1 36.3
CRi 7.3 1.8
PR 50.4 59.7
ORR 97.8 97.8
CLL10: Ph3 FCR v BR in Frontline
Eichhorst B, et al. ASH 2013. Abstract 526

73. Adverse Events, % FCR BR P Value
All 90.8 78.5 < .001
Hematologic 90.0 66.9 < .001
Neutropenia 81.7 56.8 < .001
Anemia 12.9 9.7 .28
Thrombocytopenia 21.5 14.4 .03
Infection 39.0 25.4 .001
CLL10: Ph3 FCR v BR in Frontline
Eichhorst B, et al. ASH 2013. Abstract 526

74. CLL11 Protocol
for Unfit, Slow Go Patients
Chlorambucil
combined with GA101
GChl
Randomization
Chlorambucil
Chl
Chlorambucil
combined with rituximab
RChl

75. CLL11 Trial
Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014

76. Grade ≥ 3, % Obinutuzumab +
Chlorambucil, n = 336*
Rituximab +
Chlorambucil, n = 321*
Any 70 55
Infusion-related reaction 20 4
Neutropenia 33 28
Anemia 4 4
Thrombocytopenia 10 3
Infection 12 14
Pneumonia 4 5
*Includes 5 patients randomized to who mistakenly received obinutuzumab-chlorambucil.
CLL11 Trial
Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]

77. Implications for Practice?
• CR more common after FCR v. BR for tx-naïve CLL
– ORR are similar
– PFS significantly longer with FCR
– Acute (and long-term?) toxicity greater with BR
• Obinituzumab (now approved) + chlorambucil is an
effective, well-tolerated therapy for tx-naïve CLL
– Most appropriate for elderly
– Begs question of whether obinituzumab is superior to rituximab
in other clinical contexts

78. CLL Treatment
Binet Stage Fitness First line treatment GCLLSG trial
A, asymptomatic B Irrelevant None CLL7CLL12
C, symptomatic B
Go Go
FCR (BR, FR, FCA)
Del(17p): FCA AlloTx
CLL10
Slow Go
CLB, Bendamustine F (+C?
+R?, reduced dose)
CLL11
Relapse Fitness Second line GCLLSG trial
Early (< 1 year) =
refractory disease
Go Go Alemtuzumab, FC-A Allo Tx
CLL2O, CLL2L,
CLLX2
Slow Go
Alemtuzumab (17p-),
Bendamustine (+R), R-CHOP,
lenalidomide?
CLL2O, CLL2P
Late (> 1 year)
Go Go & Slow
Go
Repeat first line

79. What's New……What's New……

80. • Ibrutinib - Specifically target and selectively
inhibit BTK
• Irreversible inhibitor, oral, once daily.
• Idelalisib - is a first-in-class, oral small molecule
that is a highly selective inhibitor of the delta
isoform of phosphatidalyinositol-3-kinase (PI3K-
δ) -

81. Ibrutinib in Treatment-Naïve CLL

82. Ibrutinib for Untreated CLL: Toxicity
Treatment Naive (n=31)
Grade 3Grade 1 Grade 2 Grade 4
SM O’Brien et al. Lancet Oncol 2014; 15:48-58

83. Ibrutinib for Untreated CLL: Response
PR w/ lymphs
SM O’Brien et al. Lancet Oncol 2014; 15:48-58

84. Idelalisib + Rituximab in Frontline CLL
SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

85. Idelalisib + Rituximab in Frontline CLL
Nodal Response at 8wks Best Nodal Response
SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

86. Idelalisib + Rituximab in Frontline CLL
SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

87. *Patients with disease progression continued on idelalisib Extension Study 117.
†
Rituximab schedule: 375 mg/m2
, then 500 mg/m2
every 2 wks x 4, then 500 mg/m2
every 4 wks x 3.
Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]
Rituximab†
(6 mos)
Patients
with heavily
pretreated,
relapsed CLL Placebo BID
n = 110
Idelalisib 150 mg BID
n = 110
Disease progression,* death, or discontinuation due to AE
Primary Study 116 Extension Study 117
Rituximab†
(6 mos)
Idelalisib 300 mg BID
Idelalisib 150 mg BID
Stratified by del(17p)/TP53
mutation, IGHV mutation status
Planned interim analyses at 50% and 75% of events
Clinical Endpoints
Primary: PFS as assessed by IRC
Events: Disease progression or death
Secondary: ORR, LNR, OS
Idelalisib and Rituximab for Relapsed CLL

88. R-Idelalisib for Relapsed CLL: Survival
Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]

89. Ph2 Ibrutinib+Rituximab for High-Risk CLL
• Rituximab 375 mg/m2
– Cycle 1 (Mo 1), Days 1, 8, 15, 21
– Cycle 2 (Mos 2-6), on Day 1 of each mo
• Ibrutinib given 420 mg orally once daily
– Continually for duration of trial
– If patients benefited after 12 cycles, they could continue ibrutinib
alone
• Eligibility criteria:
– High-risk CLL/SLL previously treated with ≤ 3 courses or previous therapy
– Presence of del(17p) or del(11q) or TP53 (treated or untreated)
– Remission duration of < 3 yrs after previous frontline chemoimmunotherapy
treatment indicated per 2008 IWCLL
– ECOG PS 0/1
– Adequate renal and hepatic function
Burger J, et al. ASH 2013. Abstract 675.

90. • Lymphocytosis peaked at 1 wk, decreased >50% from BL in ≤12
wks
• Marrow lymphs decreased by approx 50% after 12 mo (P < .
00001)
• Majority showed > 50% decreases in both spleen and node size
• PFS at 18 mos: All patients: 78%; Del(17p): 72%; Others: 84%
• OS at 18 mos: All patients: 84%; Del(17p): 78%; Others: 89%
Burger J, et al. ASH 2013. Abstract 675.
Best Response,* n (%) Patients (N = 40)
CR†
4 (10)
PR 34 (85)
ORR 37 (95)
NR 2 (5)
Ph2 Ibrutinib+Rituximab for High-Risk CLL

91. Ibrutinib + Rituximab in High-Risk CLL
Burger et al. ASH Annual Meeting
2012, Abstract 187

92. • del(5q) MDS
Inhibition of del(5q) erythroid progenitors ( SPARC and↑
actinin)1
• Multiple Myeloma
Changes in BM microenviroment, apoptosis, cell adhesion↑ ↓ 2
• CLL (??)
↑ immunological synapses formation
↑ T-cell and NK-cells function
Interference with the microenvironment
↓pro-survival cytokines (TNF-α, VEGF, IL-8, IL-6)
Pro-apoptotic effect
Lenalidomide: Mechanisms of Action

93. Trial Design: Lenalidomide in
Recurrent/Refractory CLL
• Phase II
• Previous treatment (purine analogue-based
chemotherapy)
• Lenalidomide 10 mg/day
– titrate up by 5 mg every 28 days to 25 mg daily
(minimum 5 mg, days 1–21)
• Treatment continued until progression
Ferrajoli A, et al. Blood. 2008;111:5291-7.

94. Characteristic N = 44
Median age (range), years 64 (49–86)
Number (range) of prior therapies 5 (1–15)
Serum β2-microglobulin (range), g/ml 4.3 (1.6–10.1)
Rai disease stage III or IV, % 45
Fludarabine refractory, n (%) 12 (27)
Alkylating-agent refractory, n (%) 11 (25)
Bulky lymphadenopathy, n (%) 17 (39)
Unfavourable cytogenetic features, n (%)
del(11q23) 18 (41)
del(17p) 8 (18)
Unmutated VH, n (%)* 29 (66)
* Not tested, n = 11.
VH = immunoglobulin variable heavy chain.
Lenalidomide in Recurrent/Refractory CLL: Patient
Characteristics
Ferrajoli A, et al. Blood. 2008;111:5291-7.

95. Response
Patients, n (%)
(N = 44)
Complete response 3 (7)
Nodular partial response 1 (2)
Partial response 10 (23)
Stable disease* 11 (25)
Progressive disease‡
19 (43)
ORR 32%
Responses evaluated according to
1996 NCI-WG guidelines
Lenalidomide in Recurrent/Refractory CLL:
Responses
Ferrajoli A, et al. Blood. 2008;111:5291-7.

96. Lenalidomide in Recurrent/Refractory CLL:
Conclusions
• Responses seen with an immunomodulatory agent
• Patients treated with oral therapy on a daily basis
• Time to response is prolonged, best responses seen
after 6-9 months
• The toxicity profile is manageable and the treatment
can be safely given as outpatient
• Myelosuppression is frequent, requires dose reduction

97. Supportive care
1.Infections: antimicrobials, Serum IgG <500, Give
prophylactic MONTHLY IVIG 0.5 g/kg
2.Vaccination
3.Prophylaxis drugs
4.Irradiated blood products

98. • is always the transformation of CLL into an aggressive
Lymphoma – diffuse large cell lymphoma (DLCL) or Hodgkin‘s
lymphoma
• usually evolves after a long indolent course -
• can occur as 1st manifestation of CLL: Primary Richter‘s - but
still CLL
• has a poor prognosis
Richter’s Syndrome

99. Approach to CLL patients
with del17p/TP53 mutations
• Young and medically fit: Induction followed by RIC-SCT in first
remission.
• Regimens: FCR, other CIT combinations, alemtuzumab, high
dose methylprednisone plus rituximab, high dose
methylprednisone plus alemtuzumab, induction on a clinical
protocol.
• Ideal patient group for targeted clinical trials with novel agent
acting through non-genotoxic pathways.

100. Indications for RIC-allo-
PBSCT
• Young (<65-70 years) and medically fit and
• Del17p or
• TP53 mutations or
• Complex karyotype or even complex FISH or
• Remission durations following chemoimmunotherapy
(FCR, FR, BR, PCR) of <2 years.

101. THANK YOU……THANK YOU……