The document discusses chronic lymphocytic leukemia (CLL) covering its diagnosis, treatment guidelines, and clinical presentations. Key points include the importance of accurate diagnosis through blood tests and morphology assessment, risk stratification for treatment decisions, and the evolving strategies for treatment that prioritize patient quality of life and long-term survival. The document also highlights recent advancements in therapy, including both chemotherapy and novel agents, emphasizing personalized treatment approaches based on patient comorbidities and prognosis.

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

2. Issue to be discussed How to diagnose chronic lymphocytic leukemia When to treat CLL Treatment Guideline/ Regimen selection Response evaluation

3. Clinical Presentation of CLL Asymptomatic lymphocytosis Generalized lymphadenopathy with or without splenomegaly Autoimmune disorders: AIHA, ITP, vasculitis, nephrotic syndrome, etc. Recurrent bacterial infection

4. Complete Blood Count Hb 11.2 g/dl, Hct 35%, MCV 94 fl, WBC 72 x 10 9 /l, N 5, L 90, M 3, Platelet 225 x 10 9 /l

5. Diagnostic approach to LPD First step – look at CBC  absolute lymphocytosis (>5,000/mm 3 ) Second step – assess morphology of lymphocytes in blood smear Small, non-cleaved lympocytes with many smudge cells  B-CLL Large lymphocytes with prominent nucleolus  PLL (either B or T-cell), blastoid variant of mantle cell lymphoma (MCL), large B-cell lymphoma Lymphoplasmacytic cells  LPL, CLL, MZL, plasma cell leukemia Medium size lymphocyte with projection  SMZL/VL, Hairy cell leukemia and variants Large granular lymphocytes  LGL, NK-cell leukemia Small, cleaved lymphocytes  mantle cell, follicular or marginal zone lymphoma (MZL), T-ALL/LBL, ATLL, CTCL or PTCL-U Blasts  ALL or AML-M0

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

22. Diagnostic Criteria of CLL CLL = presence of monoclonal B-cells with CLL phenotype ≥ 5,000/mm 3 in the peripheral blood Monoclonal B-lymphocytosis = monoclonal B-cells with CLL phenotype < 5,000/mm 3 in the peripheral blood without lymphadenopathy or organomegaly ( as defined by physical examination or CT scans ) , cytopenias, or disease - related symptoms SLL = presence of lymphadenopathy and / or splenomegaly . monoclonal B-cells with CLL phenotype < 5,000/mm 3 in the peripheral blood ใ Histopathology of a lymph node biopsy should be confirmed whenever possible . Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia : a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 2008:111;5446-5456

23. Adverse Prognostic Factors in CLL Advanced age Male Performance Status Staging Lymphocyte doubling time < 12 mo

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

32. Signs & Symptoms of active disease Progressive marrow failure, worsening of anaemia, thrombocytopenia Massive >6 cm below costal margin or progressive or symptomatic splenomegaly Bulky node >10 cm or progressive lymphadenopathy Progressive lymphocytosis; increase 50% in 2 mo or lymphocyte doubling time (LDT) < 6 mo Autoimmune hemolytic anemia and/ or thrombocytopenia poorly response to standard corticosteroid treatment Any of the following symptom Wt loss > 10% in 6 mo ECOG ≥ 2 Fever > 38 ºC for > 2wk Night sweat >1 mo

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

35. Watch-and-wait versus upfront therapy for early-stage CLL patients Meta-analysis of six randomised trials with immediate or deferred chlorambucil-based chemotherapy 1 No significant difference in survival at 10 years ( p > 0.1) Ongoing CLL7 randomised Phase III trial of immediate vs deferred R-FC Binet stage A patients with high-risk characteristics including 11q del and unmutated IgV H Results awaited CLL Trialists’ Collaborative Group. J Natl Cancer Inst 1999; 91:861–868.

36. Treatment of Advanced Stage CLL Goal of therapy in CLL has been palliative Historically, few patients achieved CR Recent progress reveals improvement in response rates and duration Disease remission is associated with improved quality of life? The primary goal of CLL therapy should be to improve long-term outcomes or improved survival

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

38. CLL: Evolution of therapy Chemotherapy Monotherapy or combinations (e.g. fludarabine, FC, other purine analogues) Immunochemotherapy MabThera + chemo (fludarabine-based, bendamustine, chlorambucil etc), alemtuzumab + chemo Transplantation Auto, allo, RIC allo ± DLI Investigational agents e.g. lenalidomide, ofatumumab, GA101, lumiliximab, galiximab, etc Past Present Watch-and-wait Chlorambucil Conservative approach

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

50. Patient-adapted Treatment according to Comorbidity and Life Expectancy ‘ Go-go’ Completely independent No co-morbidity Normal life expectancy  Aggressive chemotherapy ‘ No-go ’ Severely handicapped High co-morbidity Reduced life expectancy  Palliative care R-FC is the standard of care ‘ Slow-go’ Some co-morbidity Impaired organ function Reduced performance status  Less aggressive approach R-chemo is the standard of care? e.g. R-HDMP, R-FC-‘lite’, R plus bendamustine or chlorambucil Foon KA, et al. J Clin Oncol 2009; 27:498–503.

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

52. Phase III study of bendamustine versus chlorambucil in previously untreated CLL J Clin Oncol 2009;27:4378-4384. Bendamustine (n = 162) Chlorambucil (n = 157) p -value ORR, n (%) 108 (67) 47 (30) < 0.0001 CR 51 (32) 3 (2) nPR 16 (10) 4(3) PR 41 (25) 40 (26) ORR by Binet stage, n (%) Binet B 80 (69) 37 (33) Binet C 28 (61) 10 (22) Median PFS, months 21.5 8.3 < 0.0001 Median duration of CR, months 27 8.15 Median duration of PR, months 18.8 8.1

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%

55. Previously treated CLL patients Various issues need to be considered: Time of relapse (early or late) Number of previous treatment regimens Age (‘elderly’ vs younger patients) Individual expectations, quality of life Comorbidities: greater in previously treated patients and in older patients Fit vs unfit (biological age) First-line treatment (fludarabine-based or not) Biological features at relapse

56. Second Line Therapy for CLL Fludarabine and other nucleoside analogs Chemoimmunotherapy: R-FC, R-bendamustine, alemtuzumab, CFAR New monoclonal Ab: Ofatumumab, GA101, Lumiliximab Lenalidomide Flavopiridol (Alvocidib) Oblimersen

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

61. Lenalidomide in relapsed/refractory CLL 1. Chanan-Khan A, et al. IWCLL, London, UK, 14–16 Sep 2007. 2. Chanan-Khan A, et al. J Clin Oncol 2006; 24:2343–2349. 3. Ferrajoli A, et al. IWCLL, London, UK, 14–16 Sep 2007. 4. Ferrajoli A, et al. Blood 2006; 108:Abstract 305. * Median dose not calculated to date; † Molecular remission (by PCR) in 3 patients. RPCI 1,2 (n = 45) MDACC 3,4 (n = 44) Starting dose, mg 25 10 Median dose, mg TBD* 10 Response, n (%) CR 4 (9) † 3 (7) nPR 1 (2) PR 17 (38) 11 (25) ORR 21 (47) 15 (34) SD 8 (18) 10 (23)

62. Patient-adapted Treatment is still valid in Relapsed CLL ‘ Go-go’ Completely independent No co-morbidity Normal life expectancy  Aggressive chemotherapy ‘ No-go ’ Severely handicapped High co-morbidity Reduced life expectancy  Palliative care R-FC Alemtuzumab C-FAR Auto +/- miniallo ‘ Slow-go’ Some co-morbidity Impaired organ function Reduced performance status  Less aggressive approach R-bendamusti ne R-chlorambucil Lenalidomide New monoclonal Ab or novel therapy

64. Inclusion Criteria : confirmed and active CLL requiring treatment at least one previous treatment for CLL and having achieved a complete or partial remission/response but after a period of 6 or more months, shows evidence of disease progression Exclusion Criteria: diagnosis of refractory CLL (failure to achieve a complete or partial remission/response or disease progression within 6 months of last anti-CLL treatment abnormal/inadequate blood values, liver and kidney function certain heart problems, serious significant diseases, AIHA, other current cancers or within the last 5 years active or chronic infections use of drugs to suppress allergic or inflammatory responses (glucocorticoids) CLL transformation CLL central nervous system involvement

65. Conclusion CLL and MBL may be the most common hematologic malignancies in the Western but the majority of patients do not require aggressive treatment Accurate diagnosis and risk stratification are the most essential parts of clinical decision Treatment plan should aim at improvement of quality of life and long-term survival rather than eradication of disease alone

66. Thank You for Your attention