Update on lymphoma and myeloma 2011 Michele Ghielmini Oncology Institute of Southern Switzerland (IOSI) Swiss Group for Cl...
A „burning“ question in … <ul><li>HL : is ABVD still the golden standard? </li></ul><ul><li>DLBCL : should interim PET gui...
Is ABVD still the gold standard for  advanced  Hodgkin’s lymphoma?
ABVD superior to MOPP or  MOPP-ABVD Failure-free Survival  Overall Survival Cannellos, NEJM, 2002 Same efficacy, less toxi...
Randomised ABVD vs Stanford V  vs MOPPEVCAD Gobbi et al, JCO, 2005 Overall Survival Freedom From Progression Irradiation o...
UKLG LY09 study for advanced HL <ul><li>ABVD vs. one prespecified multidrug regimens either  alternating ChlVPP/PABlOE  or...
Stanford V regimen vs COPP-ABVD Hoskin et al, JCO 2009
COPPEBVCAD vs BEACOPP vs ABVD Federico et al, JCO 2009
Standard or escalated BEACOPP vs COPP-ABVD Engert et al, JCO 2009 Arm A = COPP-ABVD Arm B = BEACOPP Standard Arm C = BEACO...
Standard or escalated BEACOPP vs COPP-ABVD Engert et al, JCO 2009 Incidence of secondary AML/MDS Benfit by International P...
Competing Causes of Mortality in HD Long-term side-effects of  HL treatment
Conclusions <ul><li>First line ABVD obtains similar survival results as hybrid regimens, Stanford V or esc. BEACOPP </li><...
Should interim PET guide treatment in aggressive NHL (DLBCL)?
High-risk patients have a bad outcome with standard chemotherapy <ul><li>Age-Adjusted (aaIPI) Age  ≤ 60 </li></ul><ul><li>...
Retrospective:  end of treatment  PET
Retrospective: interim PET
Prospective: French study <ul><li>112 </li></ul><ul><li>PET C2   PET-neg  PET-pos </li></ul><ul><li>62.5% (n=70)  37.5% (n...
Progression Free Survival according to PET after C2 Pet-neg (n=70) Pet-pos (n=42) P <0.0001 Median Follow-up 38 months (mo...
Prospective USA study <ul><li>50 DLBCL given 6x R-CHOP21 </li></ul><ul><li>FDG-PET/CT after cycle 2 and 6 </li></ul>A. Cas...
Post-therapy but not interim PET predicts outcome in DLBCL A. Cashen, et al . ASH 2008 abs.# 371
Italian study in DLBCL 18-months PFS Interim PET 18-months PFS Final PET ASH 2009, Abstract 99, Pregno et al PET positive ...
Conclusions <ul><li>In DLBCL </li></ul><ul><li>A positive PET at the end of treatment is  prognostic  for worse outcome </...
Watch and wait or R-CHOP in follicular lymphoma ?
FL remains an incurable disease, but new therapies improved survival Fisher et al, JCO, 2005 Liu et al, JCO, 2006 MD Ander...
Waiting does not increase  the incidence of transformation Al Tourah et al., JCO, 2008 BC cancer agency, Vancouver
3 randomised studies of W + W vs immediate chemotherapy Overall survival Ardeshna   et al, The Lancet 2003 W+W vs  ProMACE...
Potential advantages of waiting <ul><li>Delayed acute side-effects of treatment </li></ul><ul><li>Delayed late side-effect...
Prolonged remission does not mean longer survival Peterson et al., JCO 2003 Relapse-free survival CTX CTX CHOP-B P = 0.009...
EFS according to response to rituximab induction treatment P<0.0001 P<0.0001 35% of responders still in remission at 8 yea...
W + W or single agent rituximab ? Proportion  of patients  with  no  new  treatment  initiated 19 192 19 84 83 187 Events ...
PFS by subentities for R-bendamustine vs R-CHOP 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36...
First line approach in FL EVALUATE Symptoms No Mild Life / Organ threatening CHOOSE AMONG Prognosis Stage FLIPI Grade (Gen...
Mantle Cell Lymphoma: should anybody be transplanted in first line?
MCL, a bad luck disease:  the worse of FL and DLBCL <ul><li>Centrocytic lymphoma </li></ul>IOSI Database
Combination chemotherapy (series with n = 26-62) Ghielmini and Zucca, Blood 2009 Regimen RR (%) EFS (mos) 2yOS (%) CVP 60-...
HD-AraC schemes for MCL <ul><li>R-Hyper CVAD as per MDACC protocol (first-line) </li></ul>Epner, abstr. 387, ASH 2007 n CR...
European MCL Network Progression Free Survival  N=122 Median PFS,  39  mos. (ASCT)  vs . 17 mos  (IFN) Dreyling et al. Blo...
Analysis of 3 pooled trials: ASCT vs. IFN Overall survival Dreyling et al, ASCO 2009
The Nordic trial of PBSCT in MCL n = 160 Age < 66 MCL 2 R-maxi CHOP  R-HD-AraC  R-in-vivo purging  BEAM MCL 1 maxi CHOP...
MCL Younger < 65 years Dexa BEAM Cyclo TBI + Autograft P B S C harvest Ara-C, Melphalan TBI + Autograft 3-monthly follow-u...
Time to treatment failure p=0.0382 (one sided sequential test) Hazard Ratio 0.68 Hermine et al., ASH 2010
Conclusions <ul><li>MCL is neither an indolent nor a curable disease </li></ul><ul><li>No randomised trial gives clear hin...
CLL:  is there a standard first line treatment?
CLL: watch and wait vs treatment in early stage (Binet A) <ul><li>49 % stable after 11 years </li></ul><ul><li>27 % died o...
Adverse prognostic factors Rai Binet Classical  New <ul><li>lymphadenopathy </li></ul><ul><li>splenomegaly </li></ul><ul><...
New prognostic factors Döhner, NEJM, 2000 Orchard, Lancet, 2004 Cytogenetics Ig VH status
Alkylators or fludarabine  in advanced CLL (Binet B or C) (randomised studies) OS Rai et al, NEJM, 2000 Leporrier et al, B...
Fludarabine +/- Rituximab  in advanced CLL  (retrospective, historical comparison) Byrd et al, Blood, 2005
R-FC vs. FC in CLL The Lancet 2010; 376:1164-74
Transplantation for CLL  with unmutated VH gene No randomised, large study available ! Dreger, Blood, 2004 Moreno, JCO, 20...
Alemtuzumab in refractory CLL patients <ul><li>n  = 103 pts </li></ul><ul><li>Response = CR 4%, PR 30% </li></ul><ul><li>T...
Conclusions <ul><li>No sufficient clinical data to use new prognostic markers for therapeutic decisions </li></ul><ul><li>...
What is the role  of new drugs in the treatment of multiple myeloma?
Evolution of myeloma mortality Survival Months Kumar SK, Blood 2008
MM: Autologous transplant improves survival Attal, NEJM, 1996 Child, NEJM, 2003 Overall 1 year of life gained Meta-analysi...
New drugs active in myeloma <ul><li>Thalidomide :  +  oral, cheap </li></ul><ul><li>  -  cumulative neurotoxicity, DVT(<25...
Induction regimens for MM Stewart et al, Blood, 2009 Caution : small single centre experiences no evidence that    respon...
VEL-DEX vs VAD Harousseau et al, ASH, 2009 Study IFM 2005 – 01 Vel/Dex (n=79) VAD (n=82) CR + VGPR CR/VGPR post PBSCT 43% ...
Vel/Thal/Dex vs Thal/Dex Cavo et al, ASH, 2009 Randomised trial The addition of Bortezomib seems to abolish the negative p...
Where we are with remission induction before PBSCT for Myeloma <ul><ul><li>VAD </li></ul></ul><ul><ul><li>Thal/Dex  inappr...
Novel drugs as induction? <ul><li>Pros </li></ul><ul><li>high CR rates, beeing a surrogate for long PFS (OS?) </li></ul><u...
Curability of Myeloma MD Anderson Cancer Center 829 pts 1987-2008 54% received HDT CR Dex 16% Thal  29% Vel/Len  42% predi...
1 1 -ICML 1 1 th INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Palazzo dei Congressi, Lugano, Switzerland June  15 - 18 ,...
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MCO 2011 - Slide 6 - M. Ghielmini - Spotlight session - Haematological diseases (lymphoma and myeloma)

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  • Pts with advanced HL (stage IIAX-IV) were randomised between ABVD and one of two prespecified multidrug regimens (MDRs): Alternating ChlVPP/PABlOE or Hybrid ChlVPP/EVA Six cycles were planned, plus two extra for slow responses. Involved field RT was recommended for incomplete response or bulk disease at presentation Pts with advanced HL (stage IIAX-IV) were randomised between ABVD and one of two prespecified multidrug regimens (MDRs): Alternating ChlVPP/PABlOE or Hybrid ChlVPP/EVA Six cycles were planned, plus two extra for slow responses. Involved field RT was recommended for incomplete response or bulk disease at presentation
  • 50 untreated DLBCL Stage III (n=15) or IV (n=35) received standard R-CHOP21 x 6 Patients had FDG-PET/CT scans performed after cycle 2 (or 3) and at the completion of therapy.  Two medical oncologists reviewed the FDG-PET/CT reports and interpreted them as positive, negative, or equivocal.  A nuclear medicine radiologist then reviewed the scans and applied the consensus response criteria to score each case as positive or negative. 
  • 2 2 We kno from basic studies in the early 80´s, that 2-CdA is inducing apoptosos in dividing but also in resting cells independent from cell cycle. This observation lead to the idea, that this could be an advantage in the therapy of indolent lymphomas. It is well known that 2-CdA is very effective in the treatment of HCL, inducing very long lasting complete remissions. But 2-Cda has also been demonstrated to be effective in other indolent lymphoproliferative disorders like low-grade NHL, CLL and cutaneous lymphomas and also in relapsed ALL. It was in 1992, that the Group from the Scripps-Clinic in San Diego, and in 1995 also Liliemark and Juliusson demonstrated the efficacy of cladribine in pretreated patients with NHL. However, in these heavily pretreated patients a high rate of severe infectious problems was reported in the range of about 20-40%, probably due to the extensive pretreatment. In 1995, again Saven and Piro from the Scripps Clinic, demonstrated the activity of Cladribine for the first time in untreated indolent NHL. They used the 7-day continous infusion regimen with 0,1 mg/kg/d, which is the approved schedule in the USA using 2-CdA.
  • Progression-free survival in all patients (A) and in patients with Binet stage B and C chronic lymphocytic leukaemia (B) Chemoimmunotherapy=fludarabine, cyclophosphamide, and rituximab. Chemotherapy=fludarabine and cyclophosphamide.
  • MCO 2011 - Slide 6 - M. Ghielmini - Spotlight session - Haematological diseases (lymphoma and myeloma)

    1. 1. Update on lymphoma and myeloma 2011 Michele Ghielmini Oncology Institute of Southern Switzerland (IOSI) Swiss Group for Clinical Cancer Research (SAKK)
    2. 2. A „burning“ question in … <ul><li>HL : is ABVD still the golden standard? </li></ul><ul><li>DLBCL : should interim PET guide treatment? </li></ul><ul><li>FL : watch and wait or R-CHOP? </li></ul><ul><li>MCL : should anybody be transplanted in first line? </li></ul><ul><li>CLL : is there a standard first line treatment? </li></ul><ul><li>MM : what is the role of new drugs? </li></ul>
    3. 3. Is ABVD still the gold standard for advanced Hodgkin’s lymphoma?
    4. 4. ABVD superior to MOPP or MOPP-ABVD Failure-free Survival Overall Survival Cannellos, NEJM, 2002 Same efficacy, less toxicity
    5. 5. Randomised ABVD vs Stanford V vs MOPPEVCAD Gobbi et al, JCO, 2005 Overall Survival Freedom From Progression Irradiation of maximum 2 sites
    6. 6. UKLG LY09 study for advanced HL <ul><li>ABVD vs. one prespecified multidrug regimens either alternating ChlVPP/PABlOE or hybrid ChlVPP/EVA </li></ul><ul><li>IF RT recommended for incomplete response or bulky disease </li></ul>Johnson et al. JCO 2005 No significant difference in EFS or OS between ABVD and MDRs, either overall or if the two MDRs are considered separately
    7. 7. Stanford V regimen vs COPP-ABVD Hoskin et al, JCO 2009
    8. 8. COPPEBVCAD vs BEACOPP vs ABVD Federico et al, JCO 2009
    9. 9. Standard or escalated BEACOPP vs COPP-ABVD Engert et al, JCO 2009 Arm A = COPP-ABVD Arm B = BEACOPP Standard Arm C = BEACOPP Escalated
    10. 10. Standard or escalated BEACOPP vs COPP-ABVD Engert et al, JCO 2009 Incidence of secondary AML/MDS Benfit by International Prognostic Score Arm A = COPP-ABVD Arm B = BEACOPP Standard Arm C = BEACOPP Escalated
    11. 11. Competing Causes of Mortality in HD Long-term side-effects of HL treatment
    12. 12. Conclusions <ul><li>First line ABVD obtains similar survival results as hybrid regimens, Stanford V or esc. BEACOPP </li></ul><ul><li>It is less toxic and cheaper </li></ul><ul><li>We still do not know the long-term toxicity of escalated BEACOPP </li></ul>
    13. 13. Should interim PET guide treatment in aggressive NHL (DLBCL)?
    14. 14. High-risk patients have a bad outcome with standard chemotherapy <ul><li>Age-Adjusted (aaIPI) Age ≤ 60 </li></ul><ul><li>Prognostic Factors (PLS) </li></ul><ul><ul><li>Performance status ≥ 2 </li></ul></ul><ul><ul><li>LDH > 1 x normal </li></ul></ul><ul><ul><li>Stage III or IV </li></ul></ul>Shipp et al. N Engl J Med. 1993
    15. 15. Retrospective: end of treatment PET
    16. 16. Retrospective: interim PET
    17. 17. Prospective: French study <ul><li>112 </li></ul><ul><li>PET C2 PET-neg PET-pos </li></ul><ul><li>62.5% (n=70) 37.5% (n=42) </li></ul><ul><li>CT-scan C4 </li></ul><ul><li>CR/CRu 53 16 </li></ul><ul><li>PR 10 14 </li></ul><ul><li><PR 0 7 </li></ul><ul><li>NA 7 5 </li></ul>ASH 2009, Abstract 98, Safar et al
    18. 18. Progression Free Survival according to PET after C2 Pet-neg (n=70) Pet-pos (n=42) P <0.0001 Median Follow-up 38 months (months) 5-y PFS : PET-neg = 81% [CI95%:70%-92%] PET-pos = 47% [CI95%:32%-62%] ASH 2009, Safar et al
    19. 19. Prospective USA study <ul><li>50 DLBCL given 6x R-CHOP21 </li></ul><ul><li>FDG-PET/CT after cycle 2 and 6 </li></ul>A. Cashen, et al., ASH 2008, abs.#371
    20. 20. Post-therapy but not interim PET predicts outcome in DLBCL A. Cashen, et al . ASH 2008 abs.# 371
    21. 21. Italian study in DLBCL 18-months PFS Interim PET 18-months PFS Final PET ASH 2009, Abstract 99, Pregno et al PET positive 61% PET negative 84% PET positive 74% PET negative 84% p.198 p. 015
    22. 22. Conclusions <ul><li>In DLBCL </li></ul><ul><li>A positive PET at the end of treatment is prognostic for worse outcome </li></ul><ul><li>A positive interim PET is not necessarely predictive of treatment efficacy </li></ul><ul><li>It should NOT be used to guide treatment </li></ul>
    23. 23. Watch and wait or R-CHOP in follicular lymphoma ?
    24. 24. FL remains an incurable disease, but new therapies improved survival Fisher et al, JCO, 2005 Liu et al, JCO, 2006 MD Anderson SWOG
    25. 25. Waiting does not increase the incidence of transformation Al Tourah et al., JCO, 2008 BC cancer agency, Vancouver
    26. 26. 3 randomised studies of W + W vs immediate chemotherapy Overall survival Ardeshna et al, The Lancet 2003 W+W vs ProMACE-MOPP 89 pts Young 1988 W+W vs Prednimustine 130 pts Brice 1997 W+W vs Chlorambucil 309 pts Ardeshna, 2003
    27. 27. Potential advantages of waiting <ul><li>Delayed acute side-effects of treatment </li></ul><ul><li>Delayed late side-effects </li></ul><ul><li>Delayed infertility or menopause </li></ul>Ardeshna et al., Lancet 2003 Median time to treatment: 3 years 25% of patients still not in need of treatment at 10 years
    28. 28. Prolonged remission does not mean longer survival Peterson et al., JCO 2003 Relapse-free survival CTX CTX CHOP-B P = 0.009 Overall survival CHOP-B CTX P = 0.107
    29. 29. EFS according to response to rituximab induction treatment P<0.0001 P<0.0001 35% of responders still in remission at 8 years Ghielmini et al, ASCO 2009
    30. 30. W + W or single agent rituximab ? Proportion of patients with no new treatment initiated 19 192 19 84 83 187 Events Totals W+W R4 R4 + M 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years from randomisation 0 1 2 3 4 5 % not requiring Rx at 3yr W+W=48% R4=80% R4+RM=91% Ardeshna et al, ASH 2010
    31. 31. PFS by subentities for R-bendamustine vs R-CHOP 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 Marginal zone p = 0.6210 Waldenström B-R B-R B-R B-R CHOP-R CHOP-R CHOP-R CHOP-R p = 0.0024 ASH 2009, Abstract 405, Rummel et al 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 Marginal zone p = 0.6210 Waldenström B-R B-R B-R B-R CHOP-R CHOP-R CHOP-R CHOP-R p = 0.0024
    32. 32. First line approach in FL EVALUATE Symptoms No Mild Life / Organ threatening CHOOSE AMONG Prognosis Stage FLIPI Grade (Gene Expression Profile) Patients priority Longer Survival Better Quality of Life Long Remission Watch and Wait <ul><li>&quot;soft&quot; treatment </li></ul><ul><li>rituximab for 1-2 years </li></ul><ul><ul><li>(R-) chlorambucil / cyclophosphamide </li></ul></ul><ul><ul><li>(R-) fludarabine / 2 CDA </li></ul></ul><ul><ul><li>(R-) bendamustine </li></ul></ul><ul><ul><li>Zevalin </li></ul></ul>&quot;intensive&quot; treatment R-CHOP R-CVP R-FCM R-MCP ev. + R-maintenance or + Zevalin consolidation Feuerlein, Leuk Lymphoma 2009
    33. 33. Mantle Cell Lymphoma: should anybody be transplanted in first line?
    34. 34. MCL, a bad luck disease: the worse of FL and DLBCL <ul><li>Centrocytic lymphoma </li></ul>IOSI Database
    35. 35. Combination chemotherapy (series with n = 26-62) Ghielmini and Zucca, Blood 2009 Regimen RR (%) EFS (mos) 2yOS (%) CVP 60-84 10-20 45-65 CHOP 75-88 7-21 60-76 MCP 63-73 13-15 85 R-CHOP 94-96 17-20 76 R-MCP 71 18 - CR rates w/o R: 10-40% CR rates w R: 30-50%
    36. 36. HD-AraC schemes for MCL <ul><li>R-Hyper CVAD as per MDACC protocol (first-line) </li></ul>Epner, abstr. 387, ASH 2007 n CR RR 2y PFS MDACC 97 87% 97% 90% SWOG 49 58% 88% 63%
    37. 37. European MCL Network Progression Free Survival N=122 Median PFS, 39 mos. (ASCT) vs . 17 mos (IFN) Dreyling et al. Blood 2005 4-6x CHOP-like induction 2x CHOP-like consolidation IFN- α maintenance Dexa-BEAM mobilization Cyclo-TBI ASCT PR, CR R E L A P S E
    38. 38. Analysis of 3 pooled trials: ASCT vs. IFN Overall survival Dreyling et al, ASCO 2009
    39. 39. The Nordic trial of PBSCT in MCL n = 160 Age < 66 MCL 2 R-maxi CHOP  R-HD-AraC  R-in-vivo purging  BEAM MCL 1 maxi CHOP  BEAM Geisler et al., Blood 2008
    40. 40. MCL Younger < 65 years Dexa BEAM Cyclo TBI + Autograft P B S C harvest Ara-C, Melphalan TBI + Autograft 3-monthly follow-up 1 9 5 13 17 week R-CHOP/R-DHAP alternating 3-weekly 1 9 5 13 17 week R-CHOP 3-weekly 3-monthly follow-up P B S C harvest MRD MRD 2-3 monthly intervals MCL younger < 65 yrs. MCL European Network Study Hermine et al., ASH 2010 R
    41. 41. Time to treatment failure p=0.0382 (one sided sequential test) Hazard Ratio 0.68 Hermine et al., ASH 2010
    42. 42. Conclusions <ul><li>MCL is neither an indolent nor a curable disease </li></ul><ul><li>No randomised trial gives clear hint on the best treatment strategy </li></ul><ul><li>Retrospective series suggest that the addition of </li></ul><ul><ul><ul><li>Rituximab </li></ul></ul></ul><ul><ul><ul><li>HD-AraC </li></ul></ul></ul><ul><ul><ul><li>PBSCT </li></ul></ul></ul><ul><li>could be beneficial </li></ul><ul><li>Treat patients in clinical trials </li></ul>
    43. 43. CLL: is there a standard first line treatment?
    44. 44. CLL: watch and wait vs treatment in early stage (Binet A) <ul><li>49 % stable after 11 years </li></ul><ul><li>27 % died of CLL </li></ul><ul><li>No benefit of treatment </li></ul>Dighiero et al, NEJM, 1998
    45. 45. Adverse prognostic factors Rai Binet Classical New <ul><li>lymphadenopathy </li></ul><ul><li>splenomegaly </li></ul><ul><li>hepatomegaly </li></ul><ul><li>anemia </li></ul><ul><li>thrombocytopenia </li></ul><ul><li>cytogenetics </li></ul><ul><li>(17p-, 11q-) </li></ul><ul><li>lymphocyte doubling time </li></ul><ul><ul><li> β 2-microglobuline </li></ul></ul><ul><ul><li> serum CD23 </li></ul></ul><ul><li>unmutated Ig VH status </li></ul><ul><ul><li>Zap 70 + </li></ul></ul><ul><ul><li>CD 38 + </li></ul></ul><ul><ul><li> serum thymidine kinase </li></ul></ul>
    46. 46. New prognostic factors Döhner, NEJM, 2000 Orchard, Lancet, 2004 Cytogenetics Ig VH status
    47. 47. Alkylators or fludarabine in advanced CLL (Binet B or C) (randomised studies) OS Rai et al, NEJM, 2000 Leporrier et al, Blood, 2001 OS
    48. 48. Fludarabine +/- Rituximab in advanced CLL (retrospective, historical comparison) Byrd et al, Blood, 2005
    49. 49. R-FC vs. FC in CLL The Lancet 2010; 376:1164-74
    50. 50. Transplantation for CLL with unmutated VH gene No randomised, large study available ! Dreger, Blood, 2004 Moreno, JCO, 2005 Autologous (OS, 29 + 29 matched controls) Allogeneic (n=14 allo, 20 auto, historical)
    51. 51. Alemtuzumab in refractory CLL patients <ul><li>n = 103 pts </li></ul><ul><li>Response = CR 4%, PR 30% </li></ul><ul><li>Time to treatment failure = median 6 months </li></ul><ul><li>Overall survival = median 19 months </li></ul>Stilgenbauer et al., JCO 2009
    52. 52. Conclusions <ul><li>No sufficient clinical data to use new prognostic markers for therapeutic decisions </li></ul><ul><li>Early stage: observation </li></ul><ul><li>Advanced stage: possible options: </li></ul><ul><ul><li>R-FC in younger and fit </li></ul></ul><ul><ul><li>R-bendamustine in less fit </li></ul></ul><ul><ul><li>Chlorambucil in unfit </li></ul></ul><ul><li>17p- at any stage: alemtuzumab first line </li></ul><ul><li> </li></ul><ul><li>Consider transplantation for young and fit Zap70 pos. with suitable donor </li></ul>
    53. 53. What is the role of new drugs in the treatment of multiple myeloma?
    54. 54. Evolution of myeloma mortality Survival Months Kumar SK, Blood 2008
    55. 55. MM: Autologous transplant improves survival Attal, NEJM, 1996 Child, NEJM, 2003 Overall 1 year of life gained Meta-analysis of 3 trials
    56. 56. New drugs active in myeloma <ul><li>Thalidomide : + oral, cheap </li></ul><ul><li> - cumulative neurotoxicity, DVT(<25%), constipation, fatigue </li></ul><ul><li>Velcade : + no DVT. </li></ul><ul><li>(Bortezomib) - expensive, 4 x i.v. within 11d, neurotoxicity, trombocytopenia, VZV prophylaxis. </li></ul><ul><li>Revlimid : + oral, no cumulative toxicity </li></ul><ul><li>(Lenalidomide) - expensive, GI toxicity, infections (20%), dyselectrolytemia, moderate risk for DVT </li></ul><ul><li> </li></ul><ul><li>CAVE: RENAL FUNCTION (CCr 50 ml/Min) </li></ul>
    57. 57. Induction regimens for MM Stewart et al, Blood, 2009 Caution : small single centre experiences no evidence that  response =  survival
    58. 58. VEL-DEX vs VAD Harousseau et al, ASH, 2009 Study IFM 2005 – 01 Vel/Dex (n=79) VAD (n=82) CR + VGPR CR/VGPR post PBSCT 43% 68% 26% 47% P< 0.05 Side effects Mucositis G3/4 Neuropathy AE causing off-study 1% 27% 2% 10% 7% 4%
    59. 59. Vel/Thal/Dex vs Thal/Dex Cavo et al, ASH, 2009 Randomised trial The addition of Bortezomib seems to abolish the negative prognostic effect of unfavorable cytogenetics (del13, del 17, t(4;14)) VTD (n=92) TD (n=95) > PR > VGPR pre-PBSCT > VGPR post-PBSCT 93% 61% 88% 74% 28% 72%
    60. 60. Where we are with remission induction before PBSCT for Myeloma <ul><ul><li>VAD </li></ul></ul><ul><ul><li>Thal/Dex inappropriate for high risk cytogenetics </li></ul></ul><ul><ul><li>Vel/Dex </li></ul></ul><ul><ul><li>Vel/Thal/Dex </li></ul></ul><ul><ul><li>Rev/Dex SC harvest before 4 cycles </li></ul></ul><ul><ul><li>Rev/Vel/Dex SC harvest before 4 cycles </li></ul></ul>
    61. 61. Novel drugs as induction? <ul><li>Pros </li></ul><ul><li>high CR rates, beeing a surrogate for long PFS (OS?) </li></ul><ul><li>some pts may have a curative potential </li></ul><ul><li>Cons </li></ul><ul><li>High costs </li></ul><ul><li>Missing approval for first line therapy (Vel, Len) </li></ul><ul><li>Options in case of PD? </li></ul>
    62. 62. Curability of Myeloma MD Anderson Cancer Center 829 pts 1987-2008 54% received HDT CR Dex 16% Thal 29% Vel/Len 42% predicitve factors for prolonged CR: younger age early HDT CR > 10 years: 2% Delasalle ASH 2009,
    63. 63. 1 1 -ICML 1 1 th INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Palazzo dei Congressi, Lugano, Switzerland June 15 - 18 , 20 11 ORGANIZING COMMITTEE: M. Ghielmini (Bellinzona), Chair R.D. Gascoyne (Vancouver) J.O. Armitage (Omaha) M.K. Gospodarowicz (Toronto) F.E. Cotter (London) P.W.M. Johnson (Southampton) M.F. Fey (Bern) E. Zucca (Bellinzona) F. Cavalli (Bellinzona), President

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