chronic lymphocytic leukemia

• 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

• 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

• 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 years55–64 years

20–54 years

72%

25%

3%

• 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

• 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

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)


Cervical limfadenopathy in patient with B-CLL


The CLL patient can have splenomegaly

Diagnosis…Diagnosis…

B-CLL laboratory features • Bone Marrow smear (cytological examination)

– extensive replacement of marrow element by mature lymphocytes (more than 30%)

Prognosis: histological bone marrow patterns

Interstitial(low risk)

Diffuse(high risk)

Nodular(low risk)

– 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

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)

• 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

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

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

p53loss/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.

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.

Diagnosis of B-CLLBlood 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

Staging…Staging…

Rai’s clinical staging systemStage Clinical Features at

DiagnosisMedian Survival (years)

0Low risk

Blood lymphocytosis>5G/l,Bone marrow lymphocytosis>30%

>12,5

IIntermediate

risk

Blood lymphocytosis>5G/l,Bone marrow lymphocytosis>30%and enlarged lymph nodes

8

IIIntermediate

risk

Blood lymphocytosis>5G/l,Bone marrow lymphocytosis>30%and enlarged spleen and/or liver

6

IIIHigh risk

Blood lymphocytosis>5G/l,Bone marrow lymphocytosis>30%and anemia (Hb < 11g/dl)

1,5-2

IVHigh risk

Blood lymphocytosis>5G/l,Bone marrow lymphocytosis>30%and thrombocytopenia(< 100 000 /ul)

1,5-2

CLL – Rai stages

Binet’s clinical staging systemStag

eClinical 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

CLL – Binet’s stages

Prognostication…Prognostication…

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.

Prognostic factor Good prognosis Bad prognosis

Clinical stage according to BinetRai

A0

B, CI, II, III, IV

Bone marrow infiltration in - bone marrow biopsy- cytological examinationLeucocytosisProlymphocytes in peripheral bloodLeukemia 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)

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%


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


• 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

CLL : ZAP-70

CLL : CD38 Expression

Months

1. Orchard JA, et al. Lancet. 2004;363:105-111.

Perc

ent

surv

ivin

g (

%)

CD38 ≥30%Mean = 163.2 months

CD38 <30%Mean = 288 months

N=162P=.008

100

80

60

40

0

20

90

70

50

30

10

0 100 200 300 400 500

CLL: lymphocyte doubling time

Survival time according to LDT (all stages)

Months

Pro

babili

ty o

f su

rviv

al

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 monthsDoubling time >12 months

1. Montserrat E, et al. Br J Haematol. 1986;62:567-575.

Effect of genetic abnormalities on survival

1. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.

Treatment…Treatment…

• 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

CLL Therapy 1960-2014Many 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

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

• 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

• 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

• 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)

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

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.

1. Cheson BD, et al. Blood. 1996;87:4990-4997.

Variable NCI IWCLLResponse criteria CRPhysical exam Normal NormalSymptoms None NoneLymphocytes (x 109/L) ≤4 <4Neutrophils (x 109/L) ≥1.5 >1.5Platelets (x 109/L) >100 >100Hemoglobin (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

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)

Patients1 (%)

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

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 reducedtreatment

Suitable for supportive care

Cumulative Illness

Rating Scale

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

Comparison of Fludarabine (F), Bendamustine (Ben), Alemtuzumab (Al) and

Chlorambucil (Chl) as Single Agents

Rai 20001 Hillmen 20072 Knauf 20093

RegimenN

F Chl179 193

Al 149

Chl148

Ben157

Chl157

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.

CLL5 protocol for elderly patients with advanced CLL

6 x Fludarabine phosphateF 25 mg/m², Days 1–5q 28 days

Chlorambucil(up to a maximum of 12 months)Clb 0.4 mg/kg body weightincreasing 0.1 mg up to 0.8 mg/kg body weightq 15 days

CLL, > 65 years, untreated, Binet stage C or symptomatic A/B

CLL5 protocol

Overall Survival (OS)

Median OS: F 45.8 months; Clb 63.6 months

Overall survival in months908478726660544842363024181260

Cu

m S

urv

ival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

CLB-censoredF-censoredCLBF

random

p = 0.15

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

Chlorambucil (Chl) plus Rituximab (R)

in Older CLL PatientsHillmen et al, ASH 2010

Foa et al, ASH 2010

TrialTherap

y 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

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.

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

The CLL-8 trial:R-FC vs. FC in previously untreated CLL

RANDOMISE

R-FC q4wk 3

FC q4wk 3

RESTAGE

R-FC q4wk 3

FC q4wk 3

SD, PD off study

CR, PR

RituximabCycle 1: 375mg/m2

Cycles 2–6: 500mg/m2

Fludarabine25mg/m2 iv, day 1–3

Cyclophosphamide250mg/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 weeksSD = stable disease; progressive disease

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

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

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

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

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

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 - -

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

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

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 goWhich 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?

R

Fludarabin Cyclophosphamid Rituximab(FCR)

BendamustinRituximab (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?

• 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

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

CLL11 Protocolfor Unfit, Slow Go

Patients

Chlorambucil combined with GA101

GChl

Randomization

Chlorambucil

Chl

Chlorambucil combined with rituximab

RChl

CLL11 Trial

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

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]

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

CLL Treatment

Binet Stage Fitness First line treatment GCLLSG trial

A, asymptomatic B Irrelevant None CLL7CLL12

C, symptomatic B

Go GoFCR (BR, FR, FCA)Del(17p): FCA AlloTx

CLL10

Slow GoCLB, Bendamustine F (+C? +R?, reduced dose)

CLL11

Relapse Fitness Second line GCLLSG trial

Early (< 1 year) = refractory disease

Go GoAlemtuzumab, FC-A Allo Tx

CLL2O, CLL2L, CLLX2

Slow GoAlemtuzumab (17p-), Bendamustine (+R), R-CHOP, lenalidomide?

CLL2O, CLL2P

Late (> 1 year)Go Go & Slow Go

Repeat first line

What's What's New……New……

• 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) -

Ibrutinib in Treatment-Naïve CLL

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

Ibrutinib for Untreated CLL: Response

PR w/ lymphs

SM O’Brien et al. Lancet Oncol 2014; 15:48-58

Idelalisib + Rituximab in Frontline CLL

SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)


Nodal Response at 8wks

Best Nodal Response


*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)

Patientswith heavily pretreated,

relapsed CLL Placebo BIDn = 110

Idelalisib 150 mg BIDn = 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 EndpointsPrimary: PFS as assessed by IRCEvents: Disease progression or death Secondary: ORR, LNR, OS

Idelalisib and Rituximab for Relapsed CLL

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]

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.

• 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

Ibrutinib + Rituximab in High-Risk CLL

Burger et al. ASH Annual Meeting 2012, Abstract 187

• del(5q) MDS

Inhibition of del(5q) erythroid progenitors (↑SPARC and actinin)1

• Multiple Myeloma

Changes in BM microenviroment, ↑apoptosis, ↓cell adhesion2

• CLL (??) immunological synapses formation T-cell and NK-cells function Interference with the microenvironment pro-survival cytokines (TNF-, VEGF, IL-8, IL-6) Pro-apoptotic effect

Lenalidomide: Mechanisms of Action

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.

Characteristic N = 44

Median age (range), years 64 (49–86)

Number (range) of prior therapies 5 (1–15)

Serum 2-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


ResponsePatients, 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


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

Supportive care

1.Infections: antimicrobials, Serum IgG <500, Give prophylactic MONTHLY IVIG 0.5 g/kg

2.Vaccination3.Prophylaxis drugs4.Irradiated blood products

• 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

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.

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.

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