chronic lymphocytic leukemia

Review and new Insights

Pts Died

2M

445 53 <2.1429 95 2.1-3.0183 53 3.1-4.0175 67 >4.0

Effect of 2-microglobulin on survival in untreated CLL

Years

Pro

port

ion s

urv

ivin

g

160 2 4 6 8 10 12 14

1.0

18

0.8

0.6

0.4

0.0

0.2

1. Keating M. Unpublished data.2. Hallek M, et al. Leuk Lymphoma. 1996;22:439-447.3. Sarfati M, et al. Blood. 1996;88:4259-4264.

4. Fayad L, et al. Blood. 2001;97:256-263.

Pts Died

2M

445 53 <2.1429 95 2.1-3.0183 53 3.1-4.0175 67 >4.0

Effect of 2-microglobulin on survival in untreated CLL

Years

Pro

port

ion s

urv

ivin

g

160 2 4 6 8 10 12 14

1.0

18

0.8

0.6

0.4

0.0

0.2

1. Keating M. Unpublished data.2. Hallek M, et al. Leuk Lymphoma. 1996;22:439-447.3. Sarfati M, et al. Blood. 1996;88:4259-4264.4. Fayad L, et al. Blood. 2001;97:256-263.

Clonal disorder of B and T lymphocytes

Elderly patients usually10% are < 50 yrs

50% are asymptomatic at diagnosisLymph nodesSplenomegalyFatigueInfections

Symptomatic patientsLymphadenopathySplenomegalyAnemiaAcquired Inhibitors to VIII/VWFBruising and bleedingHypogammaglobulinemiaRecurrent infections

Sustained lymphocytosis of > 10,000: mature lymphocytes

Marrow > 30% lymphs

CD 5+ lymphs

PBS lymphs > 5000

CD19, CD20, CD 23, CD5

Kappa or lambda chain (not both)

Marrow > 30% lymphs

NCI WG (1986)

Diagnosis: NCI vs IWCLL guidelines for CLL

Variable NCI IWCLLDiagnosis

Lymphocytes (x 109/L) ≥5; ≥ B-cellMarker (CD19, CD20,CD23) + CD5

≥10 + B phenotype orbone marrow involved<10 + both of above

Atypical cells (%) <55 Not stated

Duration of lymphocytosis

None required Not stated

Bone marrow lymphocytes (%)

≥30 >30

Staging Modified Rai,correlate with Binet

IWCLL

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

Clinical staging systems for CLLStage

Value Rai Binet Median survival

Lymphocytosis (>15,000/mm3) 0 -

150 months (12.5 years)

Lymphocytosis plus nodal involvement

I A <3node groups

101-108 months

(8.5-9 years)

Lymphocytosis plus organomegaly

II B >3node groups

60-71 months(5-6 years)

Anemia (RBCs) IIIHgb <11 g/dL

C

Hgb <10 g/dL 19-24 months

(1.5-2 years)

Lymphocytosis plus thrombocytopenia(platelets)

IVPLT

<100,000/mm3

PLT <100,000/mm3

.

Comparison of CLL and Comparison of CLL and PLLPLL

CLL PLLslg + ++

CD19 ++ ++

CD20 ++ ++

CD5 ++ -/+

Courtesy of Randy Gascoyne, MD.1. Bennett JM, et al. J Clin Pathol. 1989;42:567-584.

Approximately 80% of patients with active CLL have genetic abnormalities that can influence survival1

Use of FISH at diagnosis can help detect chromosomal abnormalities critical to treatment choices2

The assessment of 17p/p53 deletions/mutations can be used to help predict nonresponse to certain B-CLL therapies1,3-6

Response to treatment decreases as the percentage of 17p/p53 deletions increases5-9

Presence of a 17p or 11q deletion is associated with a statistically significantly shorter progression-free survival7

p53 gene alterations were a predictor of poor survival5,6

Chemotherapy is a likely cause of p53 gene alterations10,11

Patients with p53 mutations are generally resistant to treatments

Response to chemotherapies based on p53 status*1

(N=50, P<.001)

1. Döhner H, et al. Blood. 1995;85:1580-1589.

*Response was assessed according to guidelines from the National Cancer Institute.

1.Sturm I, et al. Cell Death Differ. 2003;10:477-484. 2.Lozanski G, et al. Blood. 2004;103:3278-3281.

*All but 18 patients were treated with alkylating agents.†Patients had received a median of 3 prior therapies (range 1 to 12).

In a study of 81 patients with CLL, those with p53 mutations had significantly shorter survival times1

1. Wattel E, et al. Blood. 1994;84:3148-3157.

Response† based on percentages of 17p deletions (n=343, P<.0001)1

1. Catovsky D, et al. Blood. 2004;104:98. Abstract 13.

* Chlorambucil, fludarabine, or fludarabine/cyclophosphamide.† Response data reflect response to all therapies, as the code of individual therapies

has not yet been broken.

Other studies showed:

p53 gene status has been a strong predictor of survival2,3

Patients with p53 aberrations had a worse predicted survival3

The p53 tumor suppressor gene localizes to the short arm of chromosome 174

Patients with >20% p53 deletions were particularly refractory to treatment1,51. Catovsky D, et al. Blood. 2004;104:98. Abstract 13.

2. Giles FJ, et al. Br J Haematol. 2003;121:578-585.3. Lin K, et al. Blood. 2002;100:1404-1409. 4. Döhner H, et al. Blood. 1995;85:1580-1589.5. Wattel E, et al. Blood. 1994;84:3148-3157.

Genetic markers are proving useful in predicting disease course and survival1,2

Approximately 80% of patients with active CLL show genetic abnormalities3

Rai and Binet staging systems do not predict disease course or identify early stage patients who would benefit from aggressive intervention2

1. Chiorazzi N, et al. N Engl J Med. 2005;352:804-815. 2. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.3. Catovsky D, et al. Blood. 2004;104:98. Abstract 13.

Genetic markers are proving useful in predicting disease course and survival1,2

Approximately 80% of patients with active CLL show genetic abnormalities3

Rai and Binet staging systems do not predict disease course or identify early stage patients who would benefit from aggressive intervention2

1. Chiorazzi N, et al. N Engl J Med. 2005;352:804-815. 2. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.3. Catovsky D, et al. Blood. 2004;104:98. Abstract 13.

Months

VH gene/p53 multivariate analysis

1. Krober A, et al. Blood. 2002;100:1410-1416.2. Crespo M, et al. N Engl J Med. 2003;348:1764-1775.3. Oscier DG, et al. Blood. 2002;100:1177-1184.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

03800 38 76 114 152 228190 304266 342

Unmutated VH geneMedian = 119 monthsMutated VH geneMedian = 310 months

p53 loss/mutationMedian = 47 months

Pro

babili

ty o

f su

rviv

al (%

)

Effects of genetic abnormalities on survival in patients with CLL (N=325)1

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

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.

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.

1/3 do not require treatment.Binet ALymphocytes < 30,000. Doubling time > 1 yr.

Normal Hb (survival same as age matched controls)

1/3 require treatment as soon as they are seenSymptomatic, TDT < 1 yr, Increasing

organomegaly1/3 require treatment at some point due to

disease progressionHigh risk: Bulky adenopathy, hemolytic

anemia, low platelets, hepatosplenomegalyGoal is to improve counts,

Alkylating agents.Chlorambucil response 40 – 60%Cytoxan CR 10%

Alkylators + SteroidsPurine Analogs

Fludarabine 40 – 60% long remission duration

CladribinedCF

Flu + CytoxanAdriamycin

Stem Cell TransplantAuto

AlloToxic; donor availability, age.Younger patients with sibling donors Curative TreatmentGraft vs Tumor effect

Monoclonal Antibodies:

Rituximab

Alemtuzumab (Campath)

Arzerra (Ofatumumab)Approved in 12/09

CLL refractory to Campath

B Cell

CD 20

Rituxan

CD 56

CD 20

Arzerra

Campath