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Lenalidomide : un nuovo farmaco nell’armamentario terapeutico della LLC

Lenalidomide : un nuovo farmaco nell’armamentario terapeutico della LLC

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Lenalidomide : un nuovo farmaco nell’armamentario terapeutico della LLC

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  1. Lenalidomide: un nuovo farmaco nell’armamentario terapeutico della LLC Alessandra Ferrajoli Department of Leukemia The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

  2. Lenalidomide Thalidomide analogue Immunomodulatory drug (IMiD) 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

  3. del(5q) MDS Inhibition of del(5q) erythroid progenitors (↑SPARC and actinin)1 Multiple Myeloma Changes in BM microenviroment, ↑apoptosis, ↓cell adhesion2 CLL (??)  immunological synapses formation3  T-cell and NK-cells function4 Interference with the microenvironment pro-survival cytokines (TNF-, VEGF, IL-8, IL-6) Pro-apoptotic effect Lenalidomide: Mechanisms of Action 1 Pellagatti et al. PNAS 2007; 101:950-68. 2 Mitsiades et al. J Cell Biochem 2007; 104:11406-11. 3 Ramsey G. et al. J. Clin. Invest 2008; 118: 2427-2437 4 Hayashi T et al. Br J. Haem. 2005 128:192-203

  4. Lenalidomide in CLL: Background TNF- and VEGF contribute to CLL proliferation: High levels of VEGFR2 are associated with decreased survival1 TNF- levels are elevated in the plasma of patients with CLL and TNF- is a prognostic factor in CLL2 1. Ferrajoli A, et al. Clin Cancer Res. 2001;7:795-9. 2. Ferrajoli A, et al. Blood. 2002;100:1215-9. TNF- = tumour necrosis factor ; VEGFR2 = vascular endothelial growth factor receptor 2 (KDR).

  5. Trial Design: Lenalidomide in Recurrent/Refractory CLL Phase II Previous treatment (purine analogue-based chemotherapy) Lenalidomide 10 mg/day titrate up by 5 mg every 28 days to 25 mg daily (minimum 5 mg, days 1–21) Treatment continued until progression Ferrajoli A, et al. Blood. 2008;111:5291-7.

  6. Lenalidomide in Recurrent/Refractory CLL: Patient Characteristics * Not tested, n = 11. VH = immunoglobulin variable heavy chain. Ferrajoli A, et al. Blood. 2008;111:5291-7.

  7. Lenalidomide in Recurrent/Refractory CLL: Responses Responses evaluated according to 1996 NCI-WG guidelines ORR 32% * Continued lenalidomide treatment. ‡ Including 2 early deaths. Ferrajoli A, et al. Blood. 2008;111:5291-7.

  8. Lenalidomide in Recurrent/RefractoryCLL: Adverse Events per Course (N=333) **Occurred in 9 of 17 patients with lymph nodes > 5 cm and in 4 of 27 patients with lymph nodes < 5 Ferrajoli A, et al. Blood. 2008;111:5291-7.

  9. Rapid Resolution of Chronic Skin Infection During Lenalidomide Therapy for CLL Infection with Mycobacterium marinum Awais A, et al. Clinical Infect Dis. 2008, 46: 69-71.

  10. Lenalidomide in Recurrent/Refractory CLL: T-cell Counts 60 50 40 30 20 10 0 Baseline Month 3 Month6 3.0 2.5 2.0 CD3 cells (× 103/l) Lymphocytes (× 103/l) 1.5 1.0 0.5 0 Baseline Month3 Month 6 Ferrajoli A, et al. Blood. 2008;111:5291-7.

  11. Lenalidomide in CLL: Plasma Cytokine Levels (N=12) VEGF IL-8 150 30 SD + NR PR + CR 100 20 10 50 0 0 28 days 28 days Baseline Baseline 7days 7days IFN- IL-1 IL-2 IL-6 TNF- IL-10 IL-2R TNF-RI 100 100 25 25 50 20,000 8,000 80 20 80 40 80 20 15,000 6,000 60 60 15 60 15 30 10,000 4,000 40 40 40 10 20 10 10 20 20 5 5 5,000 2,000 20 0 0 0 0 0 0 0 0 28 days 28 days 28 days 28 days 28 days Baseline Baseline Baseline Baseline Baseline 7days 7days 7days 7days 7days 28 days 28 days 28 days Baseline Baseline Baseline 7days 7days 7days Basic FGF 500 300 100 0 28 days Baseline 7days Cytokine concentration (pg/ml) Ferrajoli A, et al. Blood. 2008;111:5291-7. CR = complete response; FGF = fibroblast growth factor; IFN = interferon; IL = interleukin; NR = no response; PR = partial response; SD = stable disease; TNF-R1 = TNF receptor 1.

  12. Lenalidomide in Recurrent/Refractory CLL: Roswell Park Experience Lenalidomide 25mg/day Day 1–21 Response (intent-to-treat analysis) Total number of patients accrued = 45 Evaluable patients = 32 Non-evaluable patients = 13 * Molecular remission occurred in 3 patients with a CR. Chanan-Khan A, et al. Presented at XII IWCLL, 2007.Chanan-Khan A, et al. J Clin Oncol. 2006;24:5343-49.

  13. Lenalidomide in Recurrent/Refractory CLL: Conclusions • Responses seen with an immunomodulatory agent • Patients treated with oral therapy on a daily basis • Time to response is prolonged, best responses seen after 6-9 months • The toxicity profile is manageable and the treatment can be safely given as outpatient • Myelosuppression is frequent, requires dose reduction

  14. Lenalidomide as Initial Treatment of Elderly CLL: Background • Active in relapsed CLL 1,2 • Treatment-naïve patients may benefit from an immunostimulatory agent • No consensus on best treatment for elderly patients • Oral agent 1Chanan-Khan AA et al. J Clin Oncol 2006 2 Ferrajoli A et al. Blood 2008

  15. Lenalidomide in Elderly CLL: Study Design • Phase II, 60 patients (11/07-4/09) • Untreated and symptomatic • Age ≥ 65 yrs • Creatinine <2 mg/dL, bilirubin<2 mg/dL • Zubrod/WHO performance status 0-2 • Response assessment at end of cycle 3, cycle 9 and every 6 cycles

  16. Lenalidomide in Elderly CLL: Doses and Schedule Lenalidomide - 5 mg orally daily x 2 cycles (56 days) -  by 5 mg/cycle (28 days)  max 25 mg daily - Treatment continued until progression Response assessment at 3, 9, 12 and 15 months Allopurinol 300 mg d 1 -14 No antibiotic or anti-viral prophylaxis required No DVT prophylaxis required

  17. Lenalidomide in Elderly CLL: Patient Characteristics (N=60) Updated IWCLL 2009

  18. Lenalidomide in Elderly CLL: Responses Updated IWCLL 2009

  19. Lenalidomide in Elderly CLL: Absolute and T-cell (CD3+) Lymphocytes N=27 p<0.001 p<0.001 p<0.001 Updated IWCLL 2009

  20. %CD8 100 90 %CD4 80 70 60 50 27 25 40 30 17 20 37 30 7 10 21 8 0 Pre- 3 9 15 treatment Number of Cycles Lenalidomide in Elderly CLL: CD4 and CD8 Lymphocytes N=27 p<0.001 p<0.001 p<0.001 % peripheral blood lymphocytes Updated IWCLL 2009

  21. 1400 1200 1000 800 Immunoglobulin G (mg/dl) 600 400 200 0 Pre-treatment 3 9 15 Cycles of therapy Lenalidomide in Elderly CLL: Serum Immunoglobulin G Levels p<0.001 p<0.001 Updated IWCLL 2009

  22. Lenalidomide in Elderly CLL: Regulatory T Cells in Blood Courtesy of B-N Lee

  23. Lenalidomide in Elderly CLL:Overall Survival and Time to Treatment Failure

  24. Lenalidomide in Elderly Patients: Hematological Toxicities (N=60) Updated IWCLL 2009

  25. Lenalidomide in Elderly Patients: Infectious Complications Updated IWCLL 2009

  26. Lenalidomide in Elderly Patients: Grade 1-2 Toxicities Updated IWCLL 2009

  27. Lenalidomide in Elderly Patients: Tumor Flare

  28. Lenalidomide in Elderly Patients: Conclusions Lenalidomide well tolerated in elderly pts with CLL Rapid decrease in lymphocyte count After 15 cycles: OR 58%; CR 5% Response rate improves with continued treatment (2 flow negative CR) Myelosuppression is common No deaths or increased rate of infections More rapid dose escalation and support with growth factors may improve rate and quality of responses

  29. A phase II study of lenalidomide in patients with untreated, symptomatic CLL Chen C.. et al. ASH 2008 abstract # 44

  30. Study activated in October 2006 Patient 1 - 62 yo male rapid lymphocyte decrease reached target dose 25mg week 5 tumor lysis with ARF and MI Patient 2 – 64 yo male Grade 4 neutropenia at 10mg  septic death Modified treatment plan : Lenalidomide Frontline in CLL Chen C.. et al. ASH 2008 abstract # 44

  31. Tumor flare 80% of patients (20/25) frequently associated with rash, nasal coryza, scalp itching 30% of all cycles all grade 1-2 40% required steroids Lenalidomide Frontline in CLL: Toxicities Chen C.. et al. ASH 2008 abstract # 44

  32. Lenalidomide Frontline in CLL: Conclusions Lenalidomide is highly active as a first-line agent in CLL - RR 56% Toxicities Myelosuppression, TLS Tumor flare is mild and manageable Dosing recommendations Start low and go slow Rebound lymphocytosis suggests continuous dosing may be preferable Chen C.. et al. ASH 2008 abstract # 44

  33. Lenalidomide and Rituximab in CLL: Background • Different mechanisms of action • Non-overlapping toxicity profile • Ameliorate the tumor flare reaction

  34. Lenalidomide and Rituximab as Salvage Therapy in CLL: Potential Synergism • Lenalidomide enhances NK-cell and monocyte-mediated ADCC of rituximab-treated NHL and CLL cells 1 • Immunomodulatory drugs stimulate NK-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo 2 • Lenalidomide and rituximab increase MCL cells apoptosis and rituximab-dependent NK-cell mediated cytotoxicity. 3 1 Wu, L. Blake Bartlett J. et al. Clin Cancer Res 2008;14:4650-4657 2 Reddy N. Br J Haematol. 2008 Jan;140(1):36-45. 3 Zhang L. and Wang M. Am. J. Hematol. E-pub, 2009

  35. Lenalidomide and Rituximab as Salvage Therapy in CLL: Potential Antagonism • Lenalidomide down-regulates the CD20 antigen and antagonizes direct and ADCC of rituximab on primary CLL cells 1 • 1 Lapalombella, R., Byrd J. et al. Blood 2008;112:5180-5189

  36. Lenalidomide and Rituximab as Salvage Therapy in CLL: Study Design • Phase II, 42 patients (10/08-7/09) • Prior purine-analogue • Creatinine <2 mg/dL, bilirubin<2 mg/dL • Zubrod/WHO performance status 0-2 • Response assessment at end of cycles 3, 6, 12 and then every 6 cycles

  37. Lenalidomide and Rituximab as Salvage Therapy in CLL: Doses and Schedule • Rituximab (375 mg/m2) Days 1, 8, 15 and 22 and once every four weeks during cycles 3-12. • Lenalidomide 10mg/day started on Day 9 of cycle 1and continued daily for twelve cycles (each cycle consists of 28 days) • Lenalidomide continued until progression in responders Allopurinol 300 mg d 1 -14 No antibiotic or anti-viral prophylaxis No DVT prophylaxis required

  38. Lenalidomide and Rituximab in Recurrent CLL: Patient Characteristics Ferrajoli A, et al. ASH 2009 submitted VH = immunoglobulin variable heavy chain.

  39. Lenalidomide and Rituximab in Recurrent CLL: Toxicities (N=37 )

  40. Lenalidomide: Ongoing Trials Front-line treatment Lenalidomide and rituximab [lenalidomide first] (CLL Research Consortium) Lenalidomide Vs Chlorambucil (age > 65 years, ORIGIN trial, Celgene) Phase I Lenalidomide + Fludarabine + Rituximab (Dana-Farber Cancer Institute) FR Vs FR + lenalidomide cons. Vs FCR (CALG-B) Salvage treatment Bendamustine+ Rituximab+ Lenalidomide ( Univ. Wisconsin) Phase I-II Bendamustine+ Rituximab+ Lenalidomide ( Georgetown Univ.) Phase I-II Lenalidomide+Dasatinib (Scripps Cancer Center) Phase I Lenalidomide + Alvocidib (Ohio State) Phase I-II Lenalidomide + Fludarabine + Cyclophosphamide (GIMEMA) Phase II Lenalidomide + Ofatumumab (MDACC) Consolidation treatment Lenalidomide (MDACC) Lenalidomide after FR as initial therapy (Georgetown Univ.) Lenalidomide after PCR as initial therapy (Mayo Clinic) Lenalidomide Vs placebo after 2nd line therapy (CONTINUUM trial, Celgene)

  41. Thank you!!

  42. Studies Exploring Lenalidomide-based Combination Therapies in CLL Updated June 19, 2009. Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

  43. Studies Exploring Lenalidomide-based Combination Therapies in CLL Updated June 19, 2009. Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

  44. Open Celgene Sponsored Studies That are Actively Accruing Patients • CONTINUUM (NCT 00774345): a phase 3 trial evaluating the role of lenalidomide in the maintenance setting after second-line therapy • To date, there has been no CLL registration study focused on maintenance therapy • Since no CLL patient is “cured,” maintenance presents an opportunity to achieve sustained disease control by extending response rates • ORIGIN (NCT 00910910): a phase 3 trial to assess the role of lenalidomide in treating elderly patients (65 years of age) with CLL • CLL is a disease that mainly impacts the elderly • To date, there has been no registration study focused on patients 65 years of age • Traditional chemotherapy is often poorly tolerated by patients who tend to be infirm and to have comorbidities Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

  45. Ferrajoli Disclosure Information Consultant: Bayer, Genzyme Grant/Research Support: Bayer, Celgene, Genentech Speaker’s Bureau: none Major Stock Shareholder: none The use of lenalidomide for the treatment of CLL is considered off label