Chronic lymphocytic leukemia

1. The Chronic Lymphocytic LeukemiaThe Chronic Lymphocytic Leukemia (CLL)(CLL) Dr.manoj toshniwalDr.manoj toshniwal

2. • B-CLL is a neoplastic disease characterized by proliferation and accumulation of small, mature, long- living lymphocytes in blood, marrow and lymphoid tissues (lymph nodes, spleen) • IWCLL 2008 criteria- an absolute malignant b lymphocyte count >5000 The B-CLL - definition

3. • SLL- ALC <5000, LN/Spleenomegaly • MBL-precursor to CLL, immunophenotypicaly consistent LN<1.5cm, ALC<5000, no cytopenias, Rate of progression 1.1% / yr • PLL- prolymphocytes exceed 55% of lymphoid cells in peripheral blood

4. • Most common adult leukemia in Europe and North America (in USA incidence of about 3/100.000 population) • predominantly, CLL is a disease of elderly • 40% of leukemias in patients over 60 years old • men affect twice as often as women; 2:1 ratio of male to female • CLL morbidity rapidly increases with age (especially between 50 and 60 years of age) B-CLL epidemiology ≥ 65 years 55–64 years 20–54 years 72 % 25 % 3%

5. • the cause of CLL is unknown • there is increased incidence in farmers, rubber manufacturing workers and tire repair workers • genetics factors have been postulated to play a role in high incidence of CLL in some families (10%) B-CLL etiology & pathogenesis

6. • often none! - 40% of patients are asymptomatic and the diagnosis is typically accidental • unspecific: night sweats, fever, weakness (many patients have fatigue, reduced exercises tolerance or malaise, weight loss) • recurrent infections (bacterial, viral – Herpes Zoster, fungal) – they are the most common cause of death • bleeding and symptoms of anemia and thrombocytopenia • Lymphadenopathy (lymph node enlargement) – at diagnosis - nontender in 80% of patients – later - may become very large • splenomegaly - mild to moderate in 50% of patients • hepatomegaly • some organs infiltration (lungs, pleura, skin and soft tissue) B-CLL clinical symptoms

7. CLL – Initial symptoms • Approximately 40% are asymptomatic at diagnosis – discovered by a CBC • In symptomatic cases the most common complaint is fatigue • Well’s syndrome – increase sensitivity to insects bites • B symptoms – fever, sweats, weight loss • Less often the initial complaint are enlarged nodes or the development of an infection (bacterial)

8. B-CLL clinical symptoms Cervical limfadenopathy in patient with B-CLL

9. B-CLL clinical symptoms The CLL patient can have splenomegaly

10. Diagnosis…Diagnosis…

16. B-CLL laboratory features • Bone Marrow smear (cytological examination) – extensive replacement of marrow element by mature lymphocytes (more than 30%)

17. Prognosis: histological bone marrow patterns Interstitial (low risk) Diffuse (high risk) Nodular (low risk)

18. – CD5+/CD19+/CD23+/ dim CD20+ – 90% of the patient have a very weak expression of surface immunoglobulin (kappa or lambda light chain, IgM, IgD) – sometimes also CD38+, – Dim expression of CD20, CD25, CD11c; – lack expression of CD 10, CD 103, CD79a, FMC7 Immunophenotyping

19. CLL - Immunophenotype scoring system (Matutes score) Scoring system for B-CLL Membrane marker Points 1 0 Smlg Weak Moderate/strong CD5 Positive Negative CD23 Positive Negative FMC7 Negative Positive CD79b (SN8) Negative Positive 1. Matutes E, et al. Leukemia. 1994;8:1640-1645. 2. Moreau EJ, et al. Am J Clin Pathol. 1997;108:378-382. In 1994, Proffessor E. Matutes proposed a scoring system range between 5 (typical B-CLL cases) and 3 (less typical B-CLL cases)

20. • Conventional metaphase cyto difficult d/t very low proliferation activity of leukemic cells • Cytogenetic examinations - clonal chromosomal abnormalities are detected in approximately 30- 50% of CLL patients – deletion 13 (13q14.3) – trisomy 12 – structural abnormalities of chromosomes 11 (11q-), 14, 17 B-CLL laboratory features

21. FISH • FISH positive in 80% of cases • m/c del13 q (55%), f/b del 11q (18%), trisomy 12(16%), del17p(7%), del 6q(7%) • Good- 13q • Neutral- normal, 12+ • Bad- 17p, 11q • Addition of an alkylating agent to fludarabine may help to overcome adverse prognostic sign of 11q

23. CLL - Genetic abnormalities Genetic abnormality Incidence (%) Median survival (months) Clinical correlation 13q14 55-62 133-292 Typical morphology Mutated VH genes Stable disease + 12 16-30 114-122 Atypical morphology Progressive disease del 11q23 18 79-117 Bulky lymphadenopathy Unmutated VH genes Progressive disease Early relapse post autograft p53 loss/mutation 7 32-47 Atypical morphology Unmutated VH genes Advanced disease Drug resistance 1. DÖhner H, et al. N Engl J Med. 2000;343:1910-1916. 2. Oscier DG, et al. Blood. 2002;100:1177-1184.

24. CLL genomics: Recurrently mutated genes and survival • TP53: major negative effect, short OS. • ATM: Little or no effect on OS. • NOTCH1: conflicting data, additional prospective evaluations are needed, association with Richter’s transformation. • SF3B1: likely minor effects on PFS but further research is needed. • Others: unknown.

25. Diagnosis of B-CLL Blood test lymphocytosis ≥ 5G/l Morphology monoclonal population of small mature lymphocyte B-cell CLL phenotype clonal CD5+/CD19+ population of lymphocyte Markers of clonality κ/λ light chain restriction; cytogenetical abnormalities Bone marrow infiltration > 30% of nucleated cells on aspirate Lymph node diffuse infiltrate of small lymphocytes

26. Staging…Staging…

27. Rai’s clinical staging system Stage Clinical Features at Diagnosis Median Survival (years) 0 Low risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% >12,5 I Intermediate risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and enlarged lymph nodes 8 II Intermediate risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and enlarged spleen and/or liver 6 III High risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and anemia (Hb < 11g/dl) 1,5-2 IV High risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and thrombocytopenia(< 100 000 /ul) 1,5-2

28. CLL – Rai stages

29. Binet’s clinical staging system Stage Clinical Features at Diagnosis Median Survival (month) A Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and less than 3 areas of palpable lymphoid-tissue enlargement Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia > 120 month B Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and 3 and more areas of palpable lymphoid-tissue enlargement Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia 60 month C Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% with anemia (Hgb <10g/dL) or thrombocytopenia (Plt <100.000/uL) 24 month

30. CLL – Binet’s stages

31. Prognostication…Prognostication…

32. Major phenomena underlying CLL clinical behavior • CLL has a highly varied clinical course. • Phase 1: Diagnosis to need of first therapy (TTFT). • Short TTFT independently associates with expression of ZAP70, IgVH-UM status, INSR expression/del11q, TP53 mutations/del17p and elevated genomic complexity. • Phase 2: Time from first therapy to death (Survival). • Short survival is determined by TP53 mutations/del17p, del11q status and most comprehensively SNP array-based elevated genomic complexity. • Most CLL markers are unstable longitudinally necessitating outcome analysis from the dates of marker measurements.

33. Prognostic factor Good prognosis Bad prognosis Clinical stage according to Binet Rai A 0 B, C I, II, III, IV Bone marrow infiltration in - bone marrow biopsy - cytological examination Leucocytosis Prolymphocytes in peripheral blood Leukemia cell doubling time Non-Difussed infiltration <=80% lymphocytes <= 50 x 109/l <= 10% > 12 months Difussed infiltration > 80% lymphocytes > 50 x 109/l >10% <= 12 months New prognostic indicators in B-CLL (1)

34. Prognostic factor Good prognosis Bad prognosis Serum markers: - lactate dehydrogenase activity (LDH) - ß2-microglobulin activity - lymphocyte’s thymidine kinase activity (TKA) - sCD23 expression Normal range Elevated Clonal chromosomal abnormalities Normal karyotype isolated del (13q) Del (11q) Del (17p) CD 38 expression <= 30 % > 30% New prognostic indicators in B-CLL (2)

35. Prognostic factor Good prognosis Bad prognosis The mutational status of immunoglobulin variable region of heavy chain genes (IgvH) mutated unmutated ZAP–70 expression low (< 20%) high ( > 20 %) Survivin absence presence New prognostic indicators in B-CLL (3)

36. • clinical stage • bone marrow histology (diffuse replacement carries worst prognosis) • leukemia cell doubling time (less than 1 year - worse prognosis) • percentage of prolymphocyte • high cell-surface expression of CD38 • ZAP-70 expression • serum level of: B2-microglobulin; thymidine kinaze, LDH, sCD23 • IgVH mutational status • genetic features - FISH cytogenetic – low-risk: normal kariotype; isolated del(13q) – high-risk: del(17p0, del(11q), trisomy 12 New prognostic indicators in B-CLL - summary

37. CLL : ZAP-70

38. CLL : CD38 Expression Months 1. Orchard JA, et al. Lancet. 2004;363:105-111. Percentsurviving(%) CD38 ≥30% Mean = 163.2 months CD38 <30% Mean = 288 months N=162 P=.008 100 80 60 40 0 20 90 70 50 30 10 0 100 200 300 400 500

39. CLL: lymphocyte doubling time Survival time according to LDT (all stages) Months Probabilityofsurvival 1600 20 40 60 80 100 120 140 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Doubling time ≤12 months Doubling time >12 months 1. Montserrat E, et al. Br J Haematol. 1986;62:567-575.

40. Effect of genetic abnormalities on survival 1. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.

41. Treatment…Treatment…

42. • We have to remember: – B-CLL – indolent lymphoma, but incurable – Elderly patients – risk of additional diseases – Course of the disease can be very long, indolent for many years, patient can die because of another reason which is not connected to B-CLL. • Decision about treatment depends on clinical stage, prognostic factors and patient’s condition CLL – treatment

43. CLL Therapy 1960-2014 Many things have changed… • From chlorambucil (<10% CR) to chemoimmunotherapy (60%-70% CR) • Chemoimmunotherapy new gold-standard for CLL therapy • MRD- negativity CRs correlates with better outcome • Improved PFS and OS

44. Indications to treatment: • leukemia cell doubling time <6 (12) months • Grade 2 or greter fatigue • B symptoms for >2weeks • Lymph nodes of >10 cm • Symptomatic liver or splenic enlargement • Anemia hb <11 gm% • Thrombocytopenia <1 lac platelets • Wbc count >3 lac on 2 occasions 2 weeks apart • Severe paraneoplastic process related to CLL

45. • Watch and wait • Monotherapy – Glucocorticoids (autoimmunological complications) – alkylating agents (Chlorambucil, Cyclophosphamide) – purine analogues (Fludarabine, Cladribine, Pentostatin) • Combination chemotherapy – Chlorambucil/Cyclophosphamide + Prednisone – purine analog (Fludarabine) + Cyclophosphamide +/- Mitoxantrone – CVP, CHOP (Cyclophosphamide, Doxorubicin, Vincristin, Prednisone) • Monoclonal antibodies (monotherapy and in combination) – Alemtuzumab (anti-CD52) = CAMPATH – Rituximab (anti-CD20) = Mabthera – antiCD23 etc. – monoclonal antibodies conjugated with radionuclides = Ibritumomab tiuxetan = Zevalin CLL – treatment

46. • Hematopoietic stem cell transplantation – autologous - still no cure with auto-SCT – allogenic with reduced intensity conditioning • Even RIC-SCT is still a risky procedure - indicated only in high-risk disease • New and novel agents – Oblimersen – bcl2-directed antisense oligonucleotide – Lenalidomide – Flavopiridol – Anti-CD23 – Anti-CD40 • Vaccine strategies • Supportive therapy (allopurinol, G-CSF, blood and platelet transfusion, immunoglobulins, antibiotics) CLL – treatment

47. • Complete response (for at least 2 months) – clinical features – normal – morphology – normal (Hb>11 g/dl; Pt>100 000 /ul, lymphocytes <4000 G/l; neutrofiles >1500 G/l)) – bone marrow - lymphocytosis less than 30% • Partial response • Stable Disease • Progressive Disease: at least 50% increse in ALC/spleen/liver, new lesions, ds related cytopenias • Relapse: evidence of disease progression after 6 months or more of initial CR/PR • Refractory disease: failure to achieve a response or having disease progression in 6 months of last Rx Response criteria (NCI working group 1996)

48. Partial response : A partial response (PR) is defined (NCI criteria) as presence of all of the following for two or more months: - A reduction in previously enlarged nodes, spleen, and liver by at least 50 percent and -Absolute neutrophil count >1,500/µL or -Platelet count >100,000/µL or -Hemoglobin concentration >11 g/dL or 50 percent improvement over pretherapy reductions in hemoglobin concentration and/or platelet count

49. Complete remission : A complete remission in CLL requires all of the following to be present for two or more months -Absence of symptoms attributable to CLL. -Normal findings on physical examination. -Absolute lymphocyte count <4,000/µL. -Absolute neutrophil count >1,500/µL. -Platelet count >100,000/µL. -Hemoglobin concentration >11 g/dL (untransfused). -Bone marrow lymphocytosis <30 percent. -No nodules (lymphoid aggregates) on BM biopsy.

50. 1. Cheson BD, et al. Blood. 1996;87:4990-4997. Variable NCI IWCLL Response criteria CR Physical exam Normal Normal Symptoms None None Lymphocytes (x 109 /L) ≤4 <4 Neutrophils (x 109 /L) ≥1.5 >1.5 Platelets (x 109 /L) >100 >100 Hemoglobin (g/dL) >11 (untransfused) Not stated Bone marrow lymphs (%) <30, no nodules Normal, allowing nodules or focal infiltrates PR Physical exam (nodes and/or liver, spleen) ≥50% decrease Downshift in stage Plus ≥1 of: Neutrophils (x 109 /L) ≥1.5 Platelets (x 109 /L) >100 Hemoglobin (g/dL) >11 or 50% improvement Duration of CR or PR ≥2 months Not stated

51. Professional Experience Required to “Tailor” CLL Therapy • Median age at diagnosis: 72 years1 • Elderly patients may be fit or have comorbidities 1 Ries LAG et al. SEER Cancer Statistics Review 1975–2005. 2 Yancik R. Cancer 1997; 80:1273–83. Age at CLL diagnosis (years) Patients 1 (%) Mean comorbidities2 (all cancer types, n) ≤54 11 n/a 55–64 19 2.9 65–74 27 3.6 75+ 43 4.2 Mean no. of co-morbidities 2.9 3.6 4.2 n/a

52. Gribben JG. Blood 2009;114:3359-60; Balducci L, Extermann M. Oncologist 2000;5:224-37. Classification of Patients by a Comprehensive Geriatric Assessment (CGA) GO SLOW NO Suitable for standard treatment Suitable for reduced treatment Suitable for supportive care Cumulative Illness Rating Scale

53. CLL7 protocol of the GCLLSG/FCLLSG Patients at Binet stage A or B without symptoms Assessment of 4 prognostic factors: • 11q- or 17p- deletion • Unmutated IgVH-Status • Serum thymidine kinase > 10 U/L • Lymphocyte doubling time < 12 months Low risk: < 2 factors positive High risk: 2 or more factors positive FCR watch and wait watch and wait Aim and Rationale: Complete (MRD-) eradication of early high risk disease 2/3 of patients 1/3 of patients

54. Comparison of Fludarabine (F), Bendamustine (Ben), Alemtuzumab (Al) and Chlorambucil (Chl) as Single Agents Rai 20001 Hillmen 20072 Knauf 20093 Regimen N F Chl 179 193 Al 149 Chl 148 Ben 157 Chl 157 Median age, years 64 62 59 60 63 66 Rai Stage III-IV or Binet C, % 39 41 34 33 29 29 Grade 3/4 ↓ ANC, % 27 19 41 25 23 10.6 CR, % 20 4 24 2 31 2 OR, % 63 37 83 55 68 31 Med. PFS (mo) 20 14 14.6 11.7 21.6 8.3 1 Rai KR et al. N Engl J Med 2000;343:1750–57. 2 Hillmen P et al. J Clin Oncol 2007;25:5616– 23. 3 Knauf W et al. J Clin Oncol 2009;27:4378-84.

55. CLL5 protocol for elderly patients with advanced CLL 6 x Fludarabine phosphate F 25 mg/m², Days 1– 5 q 28 days Chlorambucil (up to a maximum of 12 months) Clb 0.4 mg/kg body weight increasing 0.1 mg up to 0.8 mg/kg body weight q 15 days CLL, > 65 years, untreated, Binet stage C or symptomatic A/B

56. CLL5 protocol Overall Survival (OS) Median OS: F 45.8 months; Clb 63.6 months Overall survival in months 908478726660544842363024181260 CumSurvival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 CLB-censored F-censored CLB F random p = 0.15

57. CLL5 protocol Cause of death 66%3% 25% 6% CLL related Treatment related Secondary disease Unknown Clb arm: 32 patients died 54% 10% 31% 5% CLL related Treatment related Secondary disease Unknown F arm: 42 patients died

58. Chlorambucil (Chl) plus Rituximab (R) in Older CLL Patients Hillmen et al, ASH 2010 Foa et al, ASH 2010 Trial Therapy n Response CR OR SD/PD Chl-R (Foa) A 54 (of 98) 16.7% 81.4% 7.4% Chl-R (Hillmen) B 100 9 (9%) 82 (82%) 15 (15%) UK CLL4 (Chl only) C 200 12 (6%) 132 (66%) 60 (30%) A) CLB 8 mg/m2 d1-7 q28d up to 8x + R 375 mg/m2 c1-2, 500 mg/m2 c3-8, followed by R-maintenance 375 mg/m2 q 2 m for 2 yrs B) CLB 10 mg/m2 d1-7 q28d up to 6x + R 375 mg/m2 c1, 500 mg/m2 c2-6 C) CLB like B without R

59. FC Improves Overall Survival in Non-High Risk CLL GCLLSG CLL4 protocol - 375 patients (<66 years) with advanced CLL were randomly assigned to fludarabine 25 mg/m2 x 5d IV q28d vs FC (fludarabine 30 mg/m2 and cyclophosphamide 250 mg/m2 x 3d IV q28d) - Complete remission rate, 24% vs 7% (p < 0.001) - Overall response rate, 94% vs 83% (p = 0.001) - Progression-free survival, 48 mo vs 20 mo (p = 0.001) - Treatment-free survival, 37 mo vs 25 mo (p < 0.001) Eichhorst BF et al. Blood 2006;107(3):885-91.

60. Outcome n 6-year OS p-value F 190 54% F + (M or C) 140 59% R-FC 300 77% p = 0.37 p < 0.001 Improved Efficacy by Combining FC Chemotherapy with Rituximab (MD Anderson, historical comparison) Tam CS et al. Blood 2008;112:975–80. F = fludarabine; M = mitoxantrone; C = cyclophosphamide; R-FC = fludarabine, cyclophosphamide and rituximab

61. The CLL-8 trial: R-FC vs. FC in previously untreated CLL R A N D O M I S E R-FC q4wk × 3 FC q4wk × 3 R E S T A G E R-FC q4wk × 3 FC q4wk × 3 SD, PD off study CR, PR Rituximab Cycle 1: 375mg/m2 Cycles 2–6: 500mg/m2 Fludarabine 25mg/m2 iv, day 1–3 Cyclophosphamide 250mg/m2 iv, day 1–3  Untreated B-CLL  Binet B requiring treatment or Binet C  ECOG PS 0–1  n=817 Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174 ECOG PS = Eastern Cooperative Oncology Group performance status; q4wk = every 4 weeks SD = stable disease; progressive disease

62. FC FCR Evaluable patients 409 408 ORR (%) 80 90 CR (%) 22 44 PFS (median) ~33 m. ~ 52 m. OS @ 5 yrs 60% 75% The CLL-8 trial: R-FC vs. FC in previously untreated CLL Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174

63. Bendamustine in CLL therapy • Reference Phase Regime Pat. prev. ORR CR n= ther. (%) • Kath et al., 2001 II B 5x60mg/m2 23 10/23 75 30 • Bremer et al., 2002 II B 5x60mg/m2 15 yes 77 7 • Aivado et al., 2002 II B 2x100mg/m2 23 yes 67 29 • Köppler et al., 2004 I/II BM 2x75mg/m2 22 yes 86 27 • Bergmann, 2005 I/II B 2x70mg/m2 16 yes 56 12,5 • Lissitchkov, 2005 I/II B 2x100mg/m2 15 yes 60 27

64. Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans- Joerg Fricke, Francoise Huguet, Ilaria Del Giudice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, and Marco Montillo Journal of Clinical Oncology 27:4378-4384

65. European Phase III ‘Intergroup’ CLL Study: progression-free survival Median progression-free survival: bendamustine 21.6 months; chlorambucil 8.3 months; p<0.0001 Survival distribution function Bendamustine (n=162) Chlorambucil (n=157) Censored observations 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 42 48 54 60 Time (months) • Median observation time: 35 months (range, 1-68) at the time of the analysis

66. 1st-line therapy with single- agent bendamustine in CLL • Most patients with CLL are aged over 65 years and have at least 2 co-morbidities • A large proportion of patients are therefore not suitable for intensive chemotherapy • Studies with bendamustine as first-line therapy for CLL show that it: – Provides significantly greater efficacy than chlorambucil both in terms of RR and PFS – Has a manageable toxicity profile

67. Bendamustine plus Rituximab Fischer et al, ASH 2009;Abstract 205. Response N % ORR 100 90.9 CR 36 32.7 nPR 3 2.7 PR 61 55.5 SD 10 9.1 PD - -

68. Recommended doses for bendamustine in CLL Pre-treated Patients: Bendamustine 70 mg/m2, day 1+2 every 4 weeks BR – Rituximab 375 mg/m2 day1 (2nd+ cy 500 mg/m2) + bendamustine 70 mg/m2 day 1+2 q4 weeks Primary therapy: Bendamustine 100 mg/m2, day 1+2 q4 weeks

69. CD20 Targeting RITUXIMAB OFATUMUMAB GA101 STATUS Licensed Licensed Phase III TYPE Chimeric Humanized Humanized EPITOPE Type I Type I Type II ADCC + + +++ CDC + ++ – CELL DEATH + ± +++ 0

70. 3rd generation of trials of the GCLLSG: Risk, stage and fitness adapted W& W Inactive Binet A Active disease + all Binet C, not del(17p) CLL12 CLL10 CLL11 Go Go Slow go Which is the best score to define high risk? yesno CLB CLB + RBR FCRtreatW&W Disease (MRD) eradication? Longer survival? Symptom control? longer disease-free survival?

71. R Fludarabin Cyclophosphamid Rituximab (FCR) Bendamustin Rituximab (BR) CLL 10 protocol Fludarabine 25 mg/m² i.v., days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab: 375 mg/ m2 i.v. day 0, cycle 1 Rituximab: 500 mg/m² i.v. day 1, cycle 2-6 Bendamustine 90mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycyle 1 Rituximab 500 mg/m² day 1, cycyle 2-6 Similar efficacy of BR in comparison to FCR? Lower toxicity rate of BR?

72. • Median observation time: 27.9 mos • Median PFS: – FCR: NR versus BR: 44.9 mos (P = .04) • 2-yr OS – FCR: 94.2% v. BR: 95.8% (P = .59) Response, % FCR (n = 274) BR (n = 273) CR (CR + CRi) 47.4 38.1 CR 40.1 36.3 CRi 7.3 1.8 PR 50.4 59.7 ORR 97.8 97.8 CLL10: Ph3 FCR v BR in Frontline Eichhorst B, et al. ASH 2013. Abstract 526

73. Adverse Events, % FCR BR P Value All 90.8 78.5 < .001 Hematologic 90.0 66.9 < .001 Neutropenia 81.7 56.8 < .001 Anemia 12.9 9.7 .28 Thrombocytopenia 21.5 14.4 .03 Infection 39.0 25.4 .001 CLL10: Ph3 FCR v BR in Frontline Eichhorst B, et al. ASH 2013. Abstract 526

74. CLL11 Protocol for Unfit, Slow Go Patients Chlorambucil combined with GA101 GChl Randomization Chlorambucil Chl Chlorambucil combined with rituximab RChl

75. CLL11 Trial Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014

76. Grade ≥ 3, % Obinutuzumab + Chlorambucil, n = 336* Rituximab + Chlorambucil, n = 321* Any 70 55 Infusion-related reaction 20 4 Neutropenia 33 28 Anemia 4 4 Thrombocytopenia 10 3 Infection 12 14 Pneumonia 4 5 *Includes 5 patients randomized to who mistakenly received obinutuzumab-chlorambucil. CLL11 Trial Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]

77. Implications for Practice? • CR more common after FCR v. BR for tx-naïve CLL – ORR are similar – PFS significantly longer with FCR – Acute (and long-term?) toxicity greater with BR • Obinituzumab (now approved) + chlorambucil is an effective, well-tolerated therapy for tx-naïve CLL – Most appropriate for elderly – Begs question of whether obinituzumab is superior to rituximab in other clinical contexts

78. CLL Treatment Binet Stage Fitness First line treatment GCLLSG trial A, asymptomatic B Irrelevant None CLL7CLL12 C, symptomatic B Go Go FCR (BR, FR, FCA) Del(17p): FCA AlloTx CLL10 Slow Go CLB, Bendamustine F (+C? +R?, reduced dose) CLL11 Relapse Fitness Second line GCLLSG trial Early (< 1 year) = refractory disease Go Go Alemtuzumab, FC-A Allo Tx CLL2O, CLL2L, CLLX2 Slow Go Alemtuzumab (17p-), Bendamustine (+R), R-CHOP, lenalidomide? CLL2O, CLL2P Late (> 1 year) Go Go & Slow Go Repeat first line

79. What's New……What's New……

80. • Ibrutinib - Specifically target and selectively inhibit BTK • Irreversible inhibitor, oral, once daily. • Idelalisib - is a first-in-class, oral small molecule that is a highly selective inhibitor of the delta isoform of phosphatidalyinositol-3-kinase (PI3K- δ) -

81. Ibrutinib in Treatment-Naïve CLL

82. Ibrutinib for Untreated CLL: Toxicity Treatment Naive (n=31) Grade 3Grade 1 Grade 2 Grade 4 SM O’Brien et al. Lancet Oncol 2014; 15:48-58

83. Ibrutinib for Untreated CLL: Response PR w/ lymphs SM O’Brien et al. Lancet Oncol 2014; 15:48-58

84. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

85. Idelalisib + Rituximab in Frontline CLL Nodal Response at 8wks Best Nodal Response SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

86. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

87. *Patients with disease progression continued on idelalisib Extension Study 117. † Rituximab schedule: 375 mg/m2 , then 500 mg/m2 every 2 wks x 4, then 500 mg/m2 every 4 wks x 3. Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print] Rituximab† (6 mos) Patients with heavily pretreated, relapsed CLL Placebo BID n = 110 Idelalisib 150 mg BID n = 110 Disease progression,* death, or discontinuation due to AE Primary Study 116 Extension Study 117 Rituximab† (6 mos) Idelalisib 300 mg BID Idelalisib 150 mg BID Stratified by del(17p)/TP53 mutation, IGHV mutation status Planned interim analyses at 50% and 75% of events Clinical Endpoints Primary: PFS as assessed by IRC Events: Disease progression or death Secondary: ORR, LNR, OS Idelalisib and Rituximab for Relapsed CLL

88. R-Idelalisib for Relapsed CLL: Survival Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]

89. Ph2 Ibrutinib+Rituximab for High-Risk CLL • Rituximab 375 mg/m2 – Cycle 1 (Mo 1), Days 1, 8, 15, 21 – Cycle 2 (Mos 2-6), on Day 1 of each mo • Ibrutinib given 420 mg orally once daily – Continually for duration of trial – If patients benefited after 12 cycles, they could continue ibrutinib alone • Eligibility criteria: – High-risk CLL/SLL previously treated with ≤ 3 courses or previous therapy – Presence of del(17p) or del(11q) or TP53 (treated or untreated) – Remission duration of < 3 yrs after previous frontline chemoimmunotherapy treatment indicated per 2008 IWCLL – ECOG PS 0/1 – Adequate renal and hepatic function Burger J, et al. ASH 2013. Abstract 675.

90. • Lymphocytosis peaked at 1 wk, decreased >50% from BL in ≤12 wks • Marrow lymphs decreased by approx 50% after 12 mo (P < . 00001) • Majority showed > 50% decreases in both spleen and node size • PFS at 18 mos: All patients: 78%; Del(17p): 72%; Others: 84% • OS at 18 mos: All patients: 84%; Del(17p): 78%; Others: 89% Burger J, et al. ASH 2013. Abstract 675. Best Response,* n (%) Patients (N = 40) CR† 4 (10) PR 34 (85) ORR 37 (95) NR 2 (5) Ph2 Ibrutinib+Rituximab for High-Risk CLL

91. Ibrutinib + Rituximab in High-Risk CLL Burger et al. ASH Annual Meeting 2012, Abstract 187

92. • del(5q) MDS Inhibition of del(5q) erythroid progenitors ( SPARC and↑ actinin)1 • Multiple Myeloma Changes in BM microenviroment, apoptosis, cell adhesion↑ ↓ 2 • CLL (??) ↑ immunological synapses formation ↑ T-cell and NK-cells function Interference with the microenvironment ↓pro-survival cytokines (TNF-α, VEGF, IL-8, IL-6) Pro-apoptotic effect Lenalidomide: Mechanisms of Action

93. 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.

94. Characteristic N = 44 Median age (range), years 64 (49–86) Number (range) of prior therapies 5 (1–15) Serum β2-microglobulin (range), g/ml 4.3 (1.6–10.1) Rai disease stage III or IV, % 45 Fludarabine refractory, n (%) 12 (27) Alkylating-agent refractory, n (%) 11 (25) Bulky lymphadenopathy, n (%) 17 (39) Unfavourable cytogenetic features, n (%) del(11q23) 18 (41) del(17p) 8 (18) Unmutated VH, n (%)* 29 (66) * Not tested, n = 11. VH = immunoglobulin variable heavy chain. Lenalidomide in Recurrent/Refractory CLL: Patient Characteristics Ferrajoli A, et al. Blood. 2008;111:5291-7.

95. Response Patients, n (%) (N = 44) Complete response 3 (7) Nodular partial response 1 (2) Partial response 10 (23) Stable disease* 11 (25) Progressive disease‡ 19 (43) ORR 32% Responses evaluated according to 1996 NCI-WG guidelines Lenalidomide in Recurrent/Refractory CLL: Responses Ferrajoli A, et al. Blood. 2008;111:5291-7.

96. 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

97. Supportive care 1.Infections: antimicrobials, Serum IgG <500, Give prophylactic MONTHLY IVIG 0.5 g/kg 2.Vaccination 3.Prophylaxis drugs 4.Irradiated blood products

98. • is always the transformation of CLL into an aggressive Lymphoma – diffuse large cell lymphoma (DLCL) or Hodgkin‘s lymphoma • usually evolves after a long indolent course - • can occur as 1st manifestation of CLL: Primary Richter‘s - but still CLL • has a poor prognosis Richter’s Syndrome

99. Approach to CLL patients with del17p/TP53 mutations • Young and medically fit: Induction followed by RIC-SCT in first remission. • Regimens: FCR, other CIT combinations, alemtuzumab, high dose methylprednisone plus rituximab, high dose methylprednisone plus alemtuzumab, induction on a clinical protocol. • Ideal patient group for targeted clinical trials with novel agent acting through non-genotoxic pathways.

100. Indications for RIC-allo- PBSCT • Young (<65-70 years) and medically fit and • Del17p or • TP53 mutations or • Complex karyotype or even complex FISH or • Remission durations following chemoimmunotherapy (FCR, FR, BR, PCR) of <2 years.

101. THANK YOU……THANK YOU……

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