Slide ประกอบการบรรยายเรื่อง CLL โดย อ.ธัญญพงษ์ ในการประชุมกลางปี สมาคมโลหิตวิทยาแห่งประเทศไทย พ.ศ.2552

1. How I Treat : Chronic Lymphocytic Leukemia Thanyaphong Na Nakorn, MD, PhD Division of Hematology, Department of Medicine Faculty of Medicine, Chulalongkorn University King Chulalongkorn Memorial Hospital

6. B-cell chronic lymphocytic leukemia

7. Mantle cell lymphoma

8. Follicular lymphoma

9. Prolymphocytic Leukemia (B-PLL)

10. T-Prolymphocytic Leukemia (T-PLL)

11. Large B-cell lymphoma

12. Large cell immunoblastic lymphoma

13. Splenic Marginal Zone Lymphoma (with villous lymphocytes)

14. Hairy cell leukemia

15. Lymphoplasmacytic lymphoma

16. Plasma cell leukemia

17. Large granular lymphocytic leukemia

18. BSCH Recommendation for flow cytometry diagnosis of LPD Assess morphology, apply the first line Ab panel ( CD19, CD22, CD23, FMC7, sIgM, kappa, lambda, CD3, CD5 ) and assign CLL score CLL score 3-5 Typical CLL morphology CLL CLL score 0-2 Non-CLL or atypical morphology T-cell Apply second line Ab panel

19. FCM Scoring System for CLL Marker CLL Score sIg (kappa or lambda) weak 1 CD5 pos 1 CD23 pos 1 CD79b/CD22 weak 1 FMC7 neg 1

21. Differential Diagnosis of CD19+ LPD Hamblin GDT. Lancet 2008 ; 371 : 1017-29

24. CLL Staging and Risk Stratification

25. CLL Staging and Survival

26. Biological prognostic factors in CLL Marker Low risk High risk Genomic aberrations Normal, 13q– single 11q–, 17p– IgV H Mutated Unmutated CD38 ≤ 30% > 30% ZAP-70 Negative Positive Serum CD23, TK,  2 microglobulin Low High

27. Genetic Aberrations and prognosis in CLL

28. Activated B-cell markers in CLL ZAP-70 expression (%) 0 20 40 60 80 100 8% 0% Normal Karyotype 88 90 92 94 96 98 100 0 20 40 60 80 100 3% 30% 11q – or 17p – V H Homology (%)

30. Treatment is generally required only in symptomatic CLL patients

31. Hallek M, et al. Blood 2008 ; 111 : 5446-5456

33. Risk Stratification Algorithm for Rai Stage 0-1 Asymptomatic CLL Shanafelt TD, et al. ASH Education Book 2007

34. Recommendation for F/U and treatment in early-stage CLL based on risk stratification Shanafelt TD, et al. ASH Education Book 2007 Low risk Intermediate risk High risk Median expected survival (y) >15 10 3-8 Median expected treatment-free survival (y) >5 3-4 1-4 Recommended F/U mo. 6-12 6-12 3-6 Immediate Treatment indicated No No Consider clinical trial

37. Survival curves for CLL patients younger than 70 years in Binet stage B / C Improving survival in patients with CLL ( 1980-2008 ): the Hospital Cl í nic of Barcelona experience Blood 2009:114; 2044-2050

39. Response Definition after treatment for CLL Hallek M, et al. Blood 2008 ; 111 : 5446-5456

42. CLL: Progress in response over 10 years 1. Rai KR, et al. New Engl J Med 2000; 343:1750–1757. 2. Eichhorst BF, et al. Blood 2006; 107:885–891. 3. Hallek M, et al. Blood 2008; 112:Abstract 325. Therapy n CR (%) ORR (%) Rai et al. 2000 1 Chlorambucil 181 4 33 Fludarabine 170 20 43 GCLLSG CLL4 Eichhorst et al. 2006 2 Fludarabine 164 7 83 FC 164 24 95 GCLLSG CLL8 Hallek et al. 2008 3 FC 409 23 85 R-FC 408 45 93

43. FC significantly improves PFS compared with fludarabine or chlorambucil 1. Catovsky D, et al. Lancet 2007; 370:230–239. See also: Eichhorst BF, et al. Blood 2006; 107:885–891; Flinn IW, et al. J Clin Oncol 2007; 25:793–798. PFS (%) FC F Clb p = 0.00005 Time (years) 0 5 1 2 3 4 0 50 100 PFS 1

44. CLL-8 Pivotal Study : 6x R-FC

45. CLL-8 Patient Characteristics

46. CLL-8 Response Rate

47. CLL-8 Survival PFS OS

48. Progression-free survival according to Binet stage: CLL8 p = 0.44 p < 0.000001 Binet stages A + B Binet stage C FC MabThera-FC PFS 0.8 0.6 0.4 0.2 0 1.0 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 0.8 0.6 0.4 0.2 0 1.0 PFS Time (months) Time (months) MabThera-FC FC Hallek M, et al. Blood 2008; 112:Abstract 325.

49. R-FC had a comparable safety profile

51. Bendamustine: Structural similarities to cyclophosphamide and cladribine N N CH 3 COOH N ClH 2 C ClH 2 C Bendamustine Nitrogen mustard N N N N NH 2 Cl O OH HOCH 2 Cladribine Benzimidazole ring Carboxylic acid N Cl Cl N P O O H Cyclophosphamide

53. Bendamustine 100 mg/m2/d iv on days 1 to 2, or Chlorambucil 0.8 mg/kg orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles

54. Grade 3-4 Toxicity Bendamustine Chlorambucil Hematologic toxicity 40% 19% Neutropenia 23% 10.6% Thrombocytopenia 11.8% 7.9% Infection 8% 3%

57. REACH : Phase III in Relapsed CLL

58. Progression-free survival after R-FC Robak T, et al. Blood 2008 ; abstract LBA 1

59. Grade 3-4 Toxicity Robak T, et al. Blood 2008 ; abstract LBA 1

60. Rituximab plus bendamustine in relapsed CLL patients Fischer K, et al. Blood 2008; 112:Abstract 330. 15 63 ORR = 77% (n = 62) Patients (%) 80 60 40 20 0 100 All patients PR/ nPR 71 Fludara- sensitive Fludara- refractory Unmutated IgV H 11q del 17p del 78 74 92 44 CR n = 41 n = 9 n = 39 n = 13 n = 9 ORR

66. Thank You for Your attention