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B-cell Chronic lymphocytic leukemia . Most frequent leukemia in Western world . . Monoclonal mature B cellsCD5 CD23 sIg low CD22/CD79b lowFMC7
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1. Chronische Lymfatische Leukemie: alles anders? M.H.J.van Oers
Dept Hematology
Academic Medical Center Amsterdam
2. B-cell Chronic lymphocytic leukemia Most frequent leukemia in Western world
3. B-CLL : Clinical features asymptomatic: 40 % !! B-CLL wordt nogal eens bij toeval ontdekt, naar aanleiding van een bloedonderzoek dat om een andere reden wordt verricht. Bij de klinische presentatie zijn er dan geen CLL-gerelateerde klachten, of het moet vermoeidheid zijn, een veel gehoorde en weinig specifieke klacht. Koorts en gewichtsverlies zijn symptomen van een meer gevorderde ziekte. Als er lymfkliervergrotingen bestaan, dan zijn deze onpijnlijk, diffuus, meestal symmetrisch en nogal eens gegeneraliseerd. Er kan tevens hepatosplenomegalie bestaan.
In verder gevorderde stadia kan, door beenmergverdringing, anemie en trombocytopenie optreden, met anemische symptomen en bloedingen van het purpura type. Deze kunnen echter ook het gevolg zijn van autoimmuniteit, en in elk stadium van de ziekte optreden.
Recidiverende bacteriële (luchtweg, long) en virale (bijv. herpes zoster) infecties ten gevolge van neutrocytopenie, alsook van een sterk verminderde cellulaire en humorale afweer (secundaire hypogamaglobulinemie), kunnen een groot probleem gaan vormen en nopen tot het nemen van profylactische maatregelen (antibiotica, virostatica, gammaglobulineinfusen).
Een leukostasesyndroom door hyperleukocytose is bij B-CLL zeldzaam; de cellen zijn betrekkelijk klein en goed vervormbaar. Bovendien neigen ze niet tot aggregatie. B-CLL wordt nogal eens bij toeval ontdekt, naar aanleiding van een bloedonderzoek dat om een andere reden wordt verricht. Bij de klinische presentatie zijn er dan geen CLL-gerelateerde klachten, of het moet vermoeidheid zijn, een veel gehoorde en weinig specifieke klacht. Koorts en gewichtsverlies zijn symptomen van een meer gevorderde ziekte. Als er lymfkliervergrotingen bestaan, dan zijn deze onpijnlijk, diffuus, meestal symmetrisch en nogal eens gegeneraliseerd. Er kan tevens hepatosplenomegalie bestaan.
In verder gevorderde stadia kan, door beenmergverdringing, anemie en trombocytopenie optreden, met anemische symptomen en bloedingen van het purpura type. Deze kunnen echter ook het gevolg zijn van autoimmuniteit, en in elk stadium van de ziekte optreden.
Recidiverende bacteriële (luchtweg, long) en virale (bijv. herpes zoster) infecties ten gevolge van neutrocytopenie, alsook van een sterk verminderde cellulaire en humorale afweer (secundaire hypogamaglobulinemie), kunnen een groot probleem gaan vormen en nopen tot het nemen van profylactische maatregelen (antibiotica, virostatica, gammaglobulineinfusen).
Een leukostasesyndroom door hyperleukocytose is bij B-CLL zeldzaam; de cellen zijn betrekkelijk klein en goed vervormbaar. Bovendien neigen ze niet tot aggregatie.
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
< 98 % homology to germline VH gene
8. 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
11. 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
12. Chronic Lymphocytic Leukemianew prognostic factors
Cytogenetics
IgVH mutation status
CD38 expression
ZAP 70 expression
16. Chronic Lymphocytic Leukemianew prognostic factors
Cytogenetics
IgVH mutation status
CD38 expression
ZAP 70 expression
17. CLL : prognosis and IgVH mutation status
19. 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?)
20. 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 < 55 yrs in case of early relapse and/or resistance
22. FC versus F in previously untreated CLL
23. Fludarabine, Cyclophosphamide and Rituximab (FCR) in CLL
24. Relationship between genetic markers and Fludarabine-based therapy High-risk interphase cytogenetics and IgVH mutational status do not affect response rates to F+R (Byrd, et al. ASH 2004. Abstr 476.) or F+C ( Grever et al. ASH 2004. Abstr. 3487)
However, both are predictive of
Significantly shorter progression-free survival
Significantly shorter overall survival
In summary, neither molecular abnormalities nor mutation status impacted the response to fludarabine plus rituximab; however, both of those high risk features are associated with shorter progression-free and overall survival. Additionally, although the numbers were small patients with the 17p deletion appeared to do very poorly with fludarabine-based therapy. The British study showed that the key cut point for the 17p deletion appears to be 20%, as very few patients with more than 20% of cells containing the 17p deletion responded to fludarabine with or without cyclophosphamide. In the long run, risk-adapted therapy for patients with various molecular abnormalities may be necessary. To achieve this, we must first know which therapy works best for what abnormality; this data is just emerging. However, anecdotal data suggests that patients with 17p deletions may respond favorably to alemtuzumab, because alemtuzumab does not rely on an intact p53 system for response.In summary, neither molecular abnormalities nor mutation status impacted the response to fludarabine plus rituximab; however, both of those high risk features are associated with shorter progression-free and overall survival. Additionally, although the numbers were small patients with the 17p deletion appeared to do very poorly with fludarabine-based therapy. The British study showed that the key cut point for the 17p deletion appears to be 20%, as very few patients with more than 20% of cells containing the 17p deletion responded to fludarabine with or without cyclophosphamide. In the long run, risk-adapted therapy for patients with various molecular abnormalities may be necessary. To achieve this, we must first know which therapy works best for what abnormality; this data is just emerging. However, anecdotal data suggests that patients with 17p deletions may respond favorably to alemtuzumab, because alemtuzumab does not rely on an intact p53 system for response.
25. Relapsed, fludarabine resistant CLL
T-PLL
Other T cell Malignancies
CTCL
T-NHL
(GvHD)
Alemtuzumab (anti-CD52) application in hematological malignancies
26. Alemtuzumab pivotal trial in relapsed CLL Overall Survival (n=93) Median overall survival was 16 months for all patients. Median survival among responders has not yet been reached.
Keating et al. Blood. 1999;94(No. 10, suppl 1). Abstract 3118.
Data on file, Berlex laboratories, Richmond, CA 2000.Median overall survival was 16 months for all patients. Median survival among responders has not yet been reached.
Keating et al. Blood. 1999;94(No. 10, suppl 1). Abstract 3118.
Data on file, Berlex laboratories, Richmond, CA 2000.
27. 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
Another trial looked at patients with fludarabine-refractory CLL who received standard dose, subcutaneous alemtuzumab three times weekly. This study is important as many physicians have started to use subcutaneous alemtuzumab because of published data suggesting that this markedly abrogates the infusion-related side effects seen with intravenous alemtuzumab. The important question is will subcutaneous administration be as effective as intravenous? Until now, it was unclear, because the only published trial using the subcutaneous route was performed in previously untreated patients. Most of the intravenous data comes from the pivotal trial in which all patients were fludarabine–refractory; thus, the two patient groups were completely different in terms of prognosis, and are difficult to compare.
In the present study, the investigators have essentially redone the pivotal trial. The patients were fludarabine-refractory, but alemtuzumab was given subcutaneously rather than intravenously by standard dose and schedule for up to 12 weeks. As might be expected in a fludarabine-refractory population, this was a very heavily pretreated group with a significantly higher incidence of 17p deletions.
For more information, please go online to:
http://www.clinicaloptions.com/onco/conf/ash2004/cs/478.aspAnother trial looked at patients with fludarabine-refractory CLL who received standard dose, subcutaneous alemtuzumab three times weekly. This study is important as many physicians have started to use subcutaneous alemtuzumab because of published data suggesting that this markedly abrogates the infusion-related side effects seen with intravenous alemtuzumab. The important question is will subcutaneous administration be as effective as intravenous? Until now, it was unclear, because the only published trial using the subcutaneous route was performed in previously untreated patients. Most of the intravenous data comes from the pivotal trial in which all patients were fludarabine–refractory; thus, the two patient groups were completely different in terms of prognosis, and are difficult to compare.
In the present study, the investigators have essentially redone the pivotal trial. The patients were fludarabine-refractory, but alemtuzumab was given subcutaneously rather than intravenously by standard dose and schedule for up to 12 weeks. As might be expected in a fludarabine-refractory population, this was a very heavily pretreated group with a significantly higher incidence of 17p deletions.
For more information, please go online to:
http://www.clinicaloptions.com/onco/conf/ash2004/cs/478.asp
28. Alemtuzumab active in all genetic subgroups
Overall response : 37%
OR with 17p- : 53.8%
Similar survival rates seen in all genetic subgroups Relationship between genetic markers and response to Alemtuzumab The bar graph in this slide shows response based on the pretreatment molecular abnormality. Patients with 17p were very likely to respond to therapy; the overall response rate in this group was 53%, whereas the overall response for all groups combined was 37%. This is the first prospective data suggesting that alemtuzumab may be particularly important as a treatment for patients with p53 deletions.
For more information, please go online to:
http://www.clinicaloptions.com/onco/conf/ash2004/cs/478.aspThe bar graph in this slide shows response based on the pretreatment molecular abnormality. Patients with 17p were very likely to respond to therapy; the overall response rate in this group was 53%, whereas the overall response for all groups combined was 37%. This is the first prospective data suggesting that alemtuzumab may be particularly important as a treatment for patients with p53 deletions.
For more information, please go online to:
http://www.clinicaloptions.com/onco/conf/ash2004/cs/478.asp
29. 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
30. CLL : clinical trials (Netherlands) Previously untreated CLL
Nordic-Dutch CLL-1 Trial (Hovon 68)
31. Nordic-Dutch CLL-1 Trial (Hovon 68) study design A phase III intergroup collaborative study (EORTC 20981) is being conducted to evaluate the efficacy of both combination therapy with MabThera® + CHOP and maintenance therapy with MabThera® in patients with relapsed CD20+ follicular NHL.
Patients are being randomized to receive either CHOP (750 mg/m2 cyclophosphamide on day 1, 50 mg/m2 doxorubicin on day 1, 1.4 mg/m2 vincristine on day 1, and 100 mg oral prednisolone on days 1–5, administered every 3 weeks for a maximum of 6 cycles) or MabThera® + CHOP (375 mg/m2 as a slow infusion on day 1). Patients are assessed after 3 cycles, and patients with no change or progressive disease are taken off the study.
Patients who achieve a PR or CR are then randomized to receive MabThera® (375 mg/m2) administered as a slow IV infusion once every 3 months until relapse or for a maximum of 2 years. A phase III intergroup collaborative study (EORTC 20981) is being conducted to evaluate the efficacy of both combination therapy with MabThera® + CHOP and maintenance therapy with MabThera® in patients with relapsed CD20+ follicular NHL.
Patients are being randomized to receive either CHOP (750 mg/m2 cyclophosphamide on day 1, 50 mg/m2 doxorubicin on day 1, 1.4 mg/m2 vincristine on day 1, and 100 mg oral prednisolone on days 1–5, administered every 3 weeks for a maximum of 6 cycles) or MabThera® + CHOP (375 mg/m2 as a slow infusion on day 1). Patients are assessed after 3 cycles, and patients with no change or progressive disease are taken off the study.
Patients who achieve a PR or CR are then randomized to receive MabThera® (375 mg/m2) administered as a slow IV infusion once every 3 months until relapse or for a maximum of 2 years.
32. Nordic-Dutch CLL-1 Trial (Hovon 68)objectives
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)
33. Study Design Reach (BO17072)
34. CLL: management outside of trials 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
35. First line Chlorambucil still tenable
no cures or improved survival by new regimens
least toxic
salvage after combined modality like FCR ? CLL: management outside of trials
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
38. 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
39. 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
42. CLL7: Study design
43. ZAP-70 expression and time to initial therapy
44. 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 - ? +)
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 > 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
< 98 % homology to germline VH gene
48. Subcutaneous Alemtuzumab (anti-CD52) in previously untreated CLL: a phase II trial Lundin et al
http://www.bloodjournal.org/cgi/content/abstract/100/3/768Lundin et al
http://www.bloodjournal.org/cgi/content/abstract/100/3/768
49. FC versus F in first line CLL
52. 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 n=167
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)