chronic lymphocytic leukemia
DESCRIPTION
Dr. Feroze Momin presents Chronic Lymphocytic Leukemia - Review and new Insights. To read about Dr. Feroze Momin: http://conquercancers.com/ourdoctorso1.html To read about Cancer Treatment Center in Michigan: http://conquercancers.comTRANSCRIPT
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 Keating M. Unpublished data.2.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 Keating M. Unpublished data.2.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