1 / 53

Chronische Lymfatische Leukemie: alles anders

B-cell Chronic lymphocytic leukemia . Most frequent leukemia in Western world . . Monoclonal mature B cellsCD5 CD23 sIg low CD22/CD79b lowFMC7

Samuel
Download Presentation

Chronische Lymfatische Leukemie: alles anders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    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 CLL Limitations 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 Leukemia new prognostic factors Cytogenetics IgVH mutation status CD38 expression ZAP 70 expression

    16. Chronic Lymphocytic Leukemia new 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 Leukemia new 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)

More Related