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Clinical Advances and Research Progress in Chronic Lymphocytic Leukemia

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Clinical Advances and Research Progress in Chronic Lymphocytic Leukemia

  1. 1. Clinical Advances and Research Progress in Chronic Lymphocytic Leukemia Farrukh A. Awan, MD, MS Associate Professor of Internal Medicine The Ohio State University Comprehensive Cancer Center
  2. 2. Disclosures Dr. Awan discloses the following commercial relationships: ◼ Advisory Board: Gilead, Pharmacyclics ◼ Grants/Research Support: Pharmacyclics
  3. 3. Learning Objectives ▶ Evaluate criteria to risk stratify patients with CLL ▶ Describe mechanisms of treatment resistance in CLL ▶ Differentiate emerging data on novel therapeutic approaches for patients with previously untreated and relapsed/refractory CLL CLL = chronic lymphocytic leukemia.
  4. 4. Essential Tests at Initial Presentation: Beyond the Basics ▶ Diagnostic ◼ Peripheral blood-flow cytometry ◼ Bone marrow biopsy – Conventional karyotyping ▶ Prognostic ◼ Interphase FISH ◼ IGHV mutational analysis ◼ TP53 mutational analysis ◼ Beta-2-microglobulin ◼ LDH FISH = fluorescence in situ hybridization; IGHV = immunoglobulin heavy-chain variable; LDH = lactate dehydrogenase.
  5. 5. Other Considerations ▶ Direct antiglobulin test (Coombs) ▶ Quantitative immunoglobulins ▶ CT scan of the chest/abdomen/pelvis ▶ Infectious serology CT = computed tomography.
  6. 6. Risk Stratification
  7. 7. Prognostic Markers ▶ Interphase cytogenetics by FISH ▶ IGHV mutational status
  8. 8. Interphase FISH Correlates With OS OS = overall survival. Döhner et al, 2000. 17p deletion 11q deletion 12 trisomy Normal 13q deletion as sole abnormality PatientsSurviving(%) 100 80 60 40 20 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 Months
  9. 9. Outcome by Interphase FISH Abnormalities at Diagnosis Döhner et al, 2000. Abnormality Detected by FISH Median Time to Treatment (mo) Median OS (mo) % of Patients del(17p) 9 32 7 del(11q) 13 79 18 Trisomy 12q 33 114 16 del(13q) 92 133 55 Normal 49 111 18
  10. 10. Prognostic Markers ▶ Interphase cytogenetics by FISH ▶ IGHV mutational status
  11. 11. Significance of IGHV in CLL ▶ Mutational status of IGHV predicts clinical outcome Mutated IGHV is defined as <98% sequence homology to established germline sequence ▶ Unmutated IGHV predicts earlier therapy, poorer response, inferior survival, and risk for Richter’s transformation ▶ IGHV correlates with disease positive for CD38 and ZAP-70 Damle et al, 1999; Pepper et al, 2012.
  12. 12. IGHV Mutational Status Predicts Survival Hamblin et al, 1999. 0 25 50 75 100 125 150 175 200 225 250 275 300 325 Months Surviving(%) 0 10 20 30 40 50 60 70 80 90 100 Mutational Status Patients N=84 n (%) Median Survival (mo) Mutated 46 (54.8) 293 Unmutated 38 (45.2) 117 P=0.001 Mutated Unmutated
  13. 13. Prognostic Factors in CLL: Summary ▶ Interphase FISH is standard of care at diagnosis and RELAPSE ◼ Chromosomal abnormalities may change with time ◼ Consider repeat interphase FISH prior to starting the next therapy to assess for clonal evolution ▶ IGHV status does not change with time ▶ CD38 and ZAP-70 correlate with IGHV
  14. 14. Timing of Therapy
  15. 15. Early Treatment Does Not Improve Survival Clb = chlorambucil; P = prednisolone; Obs = observed; Exp = expected; NS = not statistically significant. CLL Trialists’ Collaborative Group, 1999. Start Year Study Name Treatment Death/Patients Immediate Deaths Ratio of Annual Death Rates Allocated Immediate Allocated Deferred Obs – Exp Variance of Obs – Exp 1976 CALGB Clb 7/22 9/25 –0.5 2.7 1978 MRC-CLL-1 Clb 31/37 32/41 3.7 15.1 1980 FRE-CLL-80 Clb 175/300 169/307 10.1 85.6 1984 MRC-CLL-2 Clb 76/121 73/118 5.2 36.6 1985 FRE-CLL-85 Clb+P 122/457 126/462 –2.0 62.0 1988 PETHEMA Clb+P 21/77 21/81 0.5 10.4 Total 432/1014 (42.6%) 430/1034 (41.6%) 16.9 212.3 Heterogeneity between 6 trials: 𝟀 𝟓 𝟐 = 1.7; P>0.1; NS 99% or 95% confidence intervals 1.08 (SD = 0.07) Immediate Better Deferred Better Treatment effect P>0.1; NS, adverse 0.0 0.5 1.0 1.5 2.0 Immediate Deferred
  16. 16. Indications for Initiating Therapy ▶ Objective laboratory/radiographic findings: ◼ Reminiscent of Rai staging system ◼ Worsening anemia and/or thrombocytopenia – Hemoglobin <11 g/dL – Platelets <100,000/uL ◼ Spleen ≥6 cm below the left costal margin ◼ Lymph nodes ≥10 cm ▶ Constitutional symptoms: ◼ Unintentional weight loss of ≥10% within the previous 6 months ◼ Significant fatigue (ECOG PS 2 or worse) ◼ Fevers >100.5°F for ≥2 weeks without other evidence of infection ◼ Night sweats for >1 month without evidence of infection ECOG = Eastern Cooperative Oncology Group. Hallek et al, 2008.
  17. 17. Review of Standard and Novel Frontline Strategies
  18. 18. Young, Healthy Patients Age ≤65 Years, Without del(17p)/TP53 Mutation
  19. 19. FC vs FCR: GCLLSG-8 Trial FC = fludarabine + cyclophosphamide; FCR = FC + rituximab; ORR = overall response rate; CR = complete remission; PFS = progression-free survival. Hallek et al, 2010. N=817 FC n=409 (%) FCR n=408 (%) ORR 80 90a CR 22 44a 3-year PFS 45 65a 3-year OS 83 87b PFS ProportionWithoutProgression(%) Chemoimmunotherapy Chemotherapy 100 0 90 80 70 60 50 40 30 20 10 0 6 12 18 24 30 36 42 48 54 60 66 FCR FCaP<0.0001; bP=0.012
  20. 20. FCR vs BR: CLL-10 GCLLSG Trial BR = bendamustine + rituximab; TRM = treatment-related mortality. Eichhorst et al, 2016. FCR n=282 BR n=279 P Value ORR (%) 97.8 97.8 NS CR (%) 40.7 31.5 0.026 Median PFS (mo) 53.7 43.2 0.001 OS at 3 years (%) 90.6 92.2 NS Severe neutropenia (%) 87.7 67.8 <0.001 Severe infections (%) 39.8 25.4 0.001 TRM (%) 3.9 2.1 —
  21. 21. CLL10 Trial: Minimal Residual Disease MRD = minimal residual disease; PB = peripheral blood; BM = bone marrow. Eichhorst et al, 2016; Kovacs et al, 2016. No. of patients: 72/180 44/156 137/185 107/170 75/129 31/98 100 90 80 70 60 50 40 30 20 10 0 MRD-NegativePatients(%) Interim PB Final PB Final BM P=0.023 P=0.024 P<0.001 FCR BR
  22. 22. FCR: A Possible Cure for CLL? ▶ Median PFS was not reached at 12.8 years in the IGHV-mutated group ▶ Approximately 50% of IGHV-mutated patients achieved MRD negativity ▶ No relapses have been seen beyond 10 years in IGHV-mutated patients ▶ FCR vs ibrutinib as preferred frontline therapy? Thompson et al, 2016. PFS(%) Time (yr) 100 25 50 75 0 0 1 12 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Patients (n) Prog-Free (n) IGHV-mutated 88 49 IGHV-unmutated 126 12 P=0.0001 IGHV mutated IGHV unmutated
  23. 23. Older Patients Age >65 Years
  24. 24. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6 12 18 24 30 36 42 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6 12 18 24 30 36 4842 Chemotherapy for Older Patients ▶ Avoid fludarabine-based regimens ▶ Bendamustine + rituximab ◼ Slightly higher toxicity rate but feasible in this population aAll patients in the intent-to-treat group. PD = progressive disease. Fischer et al, 2012; Hillmen et al, 2015. CumulativeSurvival (Probability) Time to New CLL Therapy, PD, or Death (mo) Time to Death (mo) CumulativeSurvival (Probability) Event-Free Survivala Overall Survivala
  25. 25. CLL-11 Trial: Obinutuzumab + Chlorambucil ▶ Obinutuzumab is an engineered anti-CD20 monoclonal antibody ▶ It is well tolerated in patients with comorbidities and median age of 73. ▶ Improved PFS when compared with R + Clb and Clb alone G-Clb = obinutuzumab/chlorambucil; R-Clb = rituximab/chlorambucil. Goede et al, 2014. G-Clb (n=238) G-ClbP<0.001 P<0.001 P<0.001 P<0.001 G-Clb R-Clb R-Clb (n=233) Clb (n=118) 100 90 80 70 60 50 40 30 20 10 0 R-Clb Clb Bone Marrow Blood 100 90 80 70 60 50 40 30 20 10 0 22.3 7.3 58.4 55.0 31.4 19.5 37.7 2.6 3.3 MRD-NegativePatients(%) PatientsWithaResponse(%) PR CR PR PR CR CR
  26. 26. Obinutuzumab + Chlorambucil for Untreated CLL HR = hazard ratio; CI = confidence interval. Goede et al, 2014. R-Clb 0 3 6 9 12 15 18 21 24 27 30 33 36 39 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 ProbabilityofPFS Months 15.2 26.7 G-Clb Stratified HR = 0.39 95% CI: 0.31–0.49 P<0.001
  27. 27. Ibrutinib as Frontline Therapy All Ages
  28. 28. Targeting Kinases in CLL BTK = Bruton’s tyrosine kinase; PI3K = phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP3 = phosphatidylinositol—3,4,5,-trisphosphate; DAG = diacylglycerol; PKC = protein kinase C; GSK = glycogen synthase kinase; NFAT = nuclear receptor of activated T cells. Awan & Byrd, 2014.
  29. 29. Ibrutinib ▶ Highly potent BTK inhibition at IC50 = 0.5 nM ▶ Administered orally with once-daily dosing, resulting in 24-hour target inhibition ▶ No cytotoxic effect on T cells or NK cells ▶ Promotes apoptosis and inhibits migration and adhesion in CLL cells NK = natural killer.
  30. 30. Ibrutinib for High-Risk CLL: PFS Results Byrd et al, 2015. 1.0 18 0.8 0.6 0.4 0.2 126 3630 42240 Censored Logrank p=0.0031 0.0 Months From Initiation of Study Treatment PFS(Proportion) 30-Month Estimated PFS del(17p) 48% del(11q_ 74% No del(17p) or del(11q) del(11q) del(17p)
  31. 31. Ibrutinib vs Chlorambucil (RESONATE-2) Burger et al, 2015; AbbVie Inc, 2016. PFS(%) Months 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 Ibrutinib Chlorambucil Median PFS (mo) Chlorambucil 18.9 Ibrutinib NR HR (95% CI) 0.16 (0.09–0.28) P= 0.001 ▶ Ibrutinib is superior to chlorambucil in patients >65 years with previously untreated CLL ◼ Approval in March 2016 for all untreated CLL patients
  32. 32. Novel Therapy for Relapsed CLL Kinase Inhibitors
  33. 33. RESONATE Trial: PFS Results Byrd et al, 2014. Months PFS(%) 195 183 116 38 7 196 161 83 15 1 0 Ofatumumab Ibrutinib 0 100 90 80 70 60 50 40 30 20 10 0 3 6 9 12 15 Censored Median PFS (mo) Ofatumumab 8.1 Ibrutinib NRa HRb (95% CI) 0.22 (0.15-0.32) P=0.001 by log-rank test aNot reached at median follow-up of 9.4 months; bHR for progression or death. No. at risk Ibrutinib Ofatumumab
  34. 34. Months 550 450 350 250 150 50 –50 ALC 0 111 2 3 4 5 6 7 8 9 10 Months 25 0 –25 –50 –75 –100 SPD 0 111 2 3 4 5 6 7 8 9 10 MedianChangeFromBaselineinALC(%) MedianChangeFromBaselineinSPD(%) Pattern of Response: Blood Lymphocytes vs Lymph Nodes ALC = absolute lymphocyte count; SPD = sum of the products of perpendicular diameters of lymph nodes. Byrd et al, 2013.
  35. 35. Ibrutinib: Long-Term Follow-up Byrd et al, 2015. Months From Initiation of Study Treatment PFS(Proportion) 1.0 18 0.8 0.6 0.4 0.2 128 36 4224 300 Censored 0.0 Relapsed/refractory Treatment-naive
  36. 36. Ibrutinib Discontinuation and Richter’s Transformation Maddocks et al, 2015. CumulativeIncidenceof IbrutinibDiscontinuation No. at risk: 308 261 169 135 86 58 34 10 0 Months 30 0 6 12 18 24 30 36 42 48 25 20 15 10 5 0 CLL progression Richter’s transformation Other event
  37. 37. Ibrutinib-Related Adverse Events ▶ Disrupts collagen-induced platelet aggregation ▶ vWF binding vWF = von Willebrand factor. Lipsky et al, 2015. Months on Study CumulativeIncidenceofEvents Incidence Confidence intervals At risk: 85 38 34 20 18 4 On drug: 85 81 70 43 40 4
  38. 38. Management of Ibrutinib Bleeding Issues ▶ Avoid aspirin, NSAIDs, fish oil ▶ Avoid warfarin ◼ May consider alternative anticoagulants with caution NSAIDs = nonsteroidal anti-inflammatory drugs. Imbruvica® prescribing information, 2017; Lipsky et al, 2015.
  39. 39. Other AEs Associated With Ibrutinib ▶ Bruising ▶ Diarrhea ▶ Fatigue ▶ Upper respiratory tract infection ▶ Rash ▶ Nausea ▶ Arthralgia ▶ Atrial fibrillation ▶ Cytopenias Treatment discontinuation due to AEs = 6-20% No evidence of cumulative toxicity AEs = adverse events. Imbruvica® prescribing information, 2017.
  40. 40. 100 12 75 50 25 0 24 36 480 100 12 75 50 25 0 24 36 480 Del 17pDel 11 qNeither del 17p nor del 11q Complex karyotypeNo complex karyotype Ibrutinib Has Inferior PFS in Patients With Complex Karyotype Thompson et al, 2015. Event-FreeSurvival(%) Time (mo) Event-FreeSurvival(%) Time (mo) P=0.02 P<0.0001 n Event-Free Neither del 17p nor del 11q 24 18 (75.0%) del 11q 28 22 (78.6%) del 17p 34 17 (50.0%) n Event-Free No complex karyotype 35 28 (80.0%) Complex karyotype 21 7 (33.3%)
  41. 41. BTK C481S-Resistant Clones Detected at an Estimated Median of 9.3 Months Before Relapse UPN = unique patient number. Woyach et al, 2017.
  42. 42. Managing Resistance to Ibrutinib ▶ Mechanisms for resistance to ibrutinib have been identified ▶ Testing not widely available ▶ Management of resistance not clearly defined ▶ Resistance mechanisms for other agents not defined ▶ Referral to a CLL center required Woyach & Johnson, 2015.
  43. 43. Ibrutinib: Conclusion ▶ Approved frontline therapy for all CLL patients ◼ May not be the best frontline choice for patients <65 years ▶ Promising responses ~90% ▶ Low incidence of complete responses (2-7%) ▶ Response deepens over time ◼ Median time to response: 4 months ◼ Median time to best response: 12 months ▶ del(17p) responds but PFS is shorter ▶ Use full dose and avoid disruptions ▶ Avoid using with anticoagulation ▶ Follow stopping rules prior to surgical interventions
  44. 44. Targeting Kinases in CLL Awan & Byrd, 2014.
  45. 45. Idelalisib ▶ Selective PI3K delta inhibitor ▶ Single-agent response rate: 72% ◼ 39% PR and 33% PR + L PR = partial response; PR + L = partial response with treatment-induced lymphocytosis. Brown et al, 2014.
  46. 46. Idelalisib for Relapsed/Refractory CLL Brown et al, 2014. Median PFS: 15.8 months Median OS: not reached 100 75 50 25 0 0 6 12 18 24 30 36 42 100 75 50 25 0 0 6 12 18 24 30 36 42 Months From Start of Idelalisib Months From Start of Idelalisib PFS (N=54) OS (N=54) PFS(%) OS(%)
  47. 47. Time (mo) PFS(%) Phase III Trial: Idelalisib + Rituximab vs Placebo + Rituximab for Relapsed CLL Sharman et al, 2014. Idelalisib + R Placebo + R 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Study Arm n Median PFS (mo) Idelalisib + R 110 19.4 Placebo + R 110 7.3
  48. 48. Idelalisib + Rituximab in Relapsed CLL Furman et al, 2014. 180,000 120,000 60,000 40,000 30,000 20,000 10,000 0 0 6 12 18 24 30 36 42 48 Weeks AbsoluteLymphocyteCount(permm3) Idelalisib + Rituximab Placebo + Rituximab
  49. 49. 125 100 75 50 25 -25 -50 -75 -100 0 Idelalisib in del(17p) CLL Mut = mutation. Coutre et al, 2014. Best%ChangeinSPD Idelalisib + Rituximab (n=102) Placebo + Rituximab (n=101) Neither del(17p) or TP53 Mut del(17p) and/or TP53 Mut neither del(17p) or TP53 TP53 mut del(17p) and/or TP53 mut
  50. 50. del(17p)/TP53 Mutation IGHV-Unmutated Idelalisib OS in High-Risk CLL Sharman et al, 2014. Placebo + R Idelalisib + R OverallSurvival(%) Time (mo) 100 80 60 40 20 0 0 2 2624222018161412104 6 8 Time (mo) OverallSurvival(%) 100 80 60 40 20 0 0 2 2624222018161412104 6 8 Study Arm n Median OS (mo) Idelalisib + R 46 >18 Placebo + R 49 14.8 P=0.001 Study Arm n Median OS (mo) Idelalisib + R 91 >19 Placebo + R 93 18.1 P=0.0003 Idelalisib + R Placebo + R
  51. 51. Adverse Events With Idelalisib ▶ Pneumonitis ◼ Distinguish from infectious issues ◼ Leading cause of discontinuation ▶ Diarrhea ◼ Early onset ◼ Late onset ◼ Colitis (secondary to T-cell activation) ▶ Transaminitis Zydelig® prescribing information, 2016.
  52. 52. Deciding Between Ibrutinib and Idelalisib Choose Ibrutinib if Patient Has: Choose Idelalisib if Patient Has: Allergy to rituximab Need for anticoagulation Inflammatory bowel disease Atrial fibrillation Liver problems Need for concurrent azoles (CYP3A inhibitors) Lung problems
  53. 53. 1.00 0.25 0.50 0.75 0.00 2520151050 1.00 0.25 0.50 0.75 0.00 2520151050 Sequencing Ibrutinib and Idelalisib ▶ Overall response rate ◼ Idelalisib after ibrutinib: 50% ◼ Ibrutinib after idelalisib: 77% ▶ PFS ◼ Alternate KI: not reached – Median follow-up of 5 months ◼ Non-kinase inhibitor: 7 months KI = kinase inhibitor; Ibr = ibrutinib; Ide = idelalisib. Mato et al, 2015. PFS: Alternate KI Therapy Following Ibr/Ide Discontinuation PFS: Non-KI Therapy Following Ibr/Ide Discontinuation Months Months
  54. 54. Kinase Inhibitor Efficacy ▶ Effective in patients with previously untreated and relapsed CLL ▶ Effective in patients with otherwise limited therapeutic options, including those who have progressed on kinase inhibitors ▶ Effective in patients with conventional high-risk features
  55. 55. Bcl-2 Pathway: Balancing Bcl-2 and BAX BCR = B-cell receptor; IgL = immunoglobulin light chain; IgH = immunoglobulin heavy chain; BCL = B-cell lymphoma; CARD11 = caspase recruiting domain-11; IKKa = inhibitor of NF-κB kinase; MALT1 = mucosa-associated lymphoid tissue translocation protein 1; MAPK = mitogen-activated protein kinase; MAPKK = MAPK kinase; Mcl-1 = myeloid cell leukemia differentiation protein-1; NfκB = nuclear factor κB; P = phosphorylation; PKCb = protein kinase C beta; SFK = SRC family kinase; SYK = spleen tyrosine kinase; Y = tyrosine. Cheson, 2014.
  56. 56. Venetoclax (ABT-199) ▶ Highly selective inhibitor of Bcl-2 ▶ Bcl-2 is central to the survival of CLL cells ◼ Inhibition triggers apoptosis ▶ First in human, phase I dose-escalation study of daily oral venetoclax with expansion cohort ▶ Relapsed/refractory population ▶ 89% were considered high risk Roberts et al, 2016.
  57. 57. 100 –100 0 –50 50 –100 0 –50 50 200 mg 200 mg 150 mg 800 mg Expansion (400 mg) 1,200 mg 300 mg 600 mg 400 mg 200 mg 200 mg 150 mg 800 mg Expansion (400 mg) 1,200 mg 300 mg 600 mg 400 mg Venetoclax for Progressive CLL: Response Roberts et al, 2016. ▶ Overall response rate was 79% (n = 116) ▶ Complete remissions occurred in 20% ▶ Minimal residual disease negativity was achieved in 5% ▶ Overall response rate did not vary on the basis of the number of previous therapies or other usual risk factors Absolute Lymphocyte Count Nodal Mass ChangeFromBaseline(%) ChangeFromBaseline(%)
  58. 58. 100 25 50 75 0 0 302724211815 400-mg group >400-mg group <400-mg group 12963 100 25 50 75 0 0 30272421181512963 Venetoclax for Progressive CLL: PFS Results ▶ Median duration of follow-up was 17 months ▶ 15-month PFS was 69% in the 400-mg group ▶ 51 patients remained on treatment at the time of publication ▶ Richter’s transformation occurred in 16% (n=18) ▶ 2-year overall survival was 84% Roberts et al, 2016. PFS(%) Month PatientsWithResponse(%) Month Partial response Complete response
  59. 59. Venetoclax for Patients With del(17p) CLL: PFS Results ▶ Patients with del(17p) had: ◼ Overall response rate: 71% ◼ Complete response rate: 16% ▶ Approved for second-line therapy in patients with del(17p) in April 2016 Roberts et al, 2016; FDA, 2016. PFS(%) Month Patients without del(17p) Patients with del(17p) 100 25 50 75 0 0 30272421181512963 Median PFS: 16 months
  60. 60. Venetoclax: Tumor Lysis Syndrome ▶ First three patients received initial dose of 200 mg ◼ All three developed TLS ▶ Stepwise ramp-up dosing was developed in response ▶ Amendment to protocol included TLS prophylaxis and inpatient observation on D1 and D8 ▶ Patients with bulky disease required inpatient observation for all dose escalations TLS = tumor lysis syndrome. Roberts et al, 2016. Dose-Escalation Cohort Expansion Cohort Day –7 Wk 1 Wk 2 Wk 3 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 50 mg 50 mg Step- up dose Target group dose 20 mg 50 mg 100 mg 200 mg 400 mg
  61. 61. Venetoclax: Dose-Limiting Toxicities aInitial cohort prior to protocol amendment instituting dose ramp-up. bSudden death. Roberts et al, 2016. Dose (mg) TLS n (%) Neutropenia n (%) Muscle Spasms n (%) Vomiting n (%) Thrombocytopenia n (%) 200a 3 (100) 0 0 0 0 150 0 0 0 0 0 200 0 0 0 0 0 300 1 (14) 0 0 0 0 400 0 0 1 (14) 1(14) 1 (14) 600 0 1(7) 0 0 0 800 0 0 0 0 0 1200 1 (20)b 0 0 0 0
  62. 62. Emerging Data on Novel Targeted Therapies
  63. 63. Acalabrutinib (ACP-196): In Vitro Data ▶ More selective, second-generation, irreversible BTK inhibitor ▶ Designed to improve upon the safety and efficacy of first- generation BTK inhibitors ◼ Ibrutinib irreversibly inhibits alternative kinase targets in addition to BTK: EGFR, TEC, ITK, TXK ◼ Associated with rash, diarrhea, bleeding, atrial fibrillation EGFR = epidermal growth factor receptor; TEC = tyrosine kinase expressed in hepatocellular carcinoma; ITK= interleukin-2-inducible T-cell kinase; TXK = T-cell X chromosome kinase. Byrd et al, 2016.
  64. 64. Adverse Events With Acalabrutinib URI = upper respiratory infection. Byrd et al, 2016. All Grades (%) Grades 1/2 (%) Grades 3/4 (%) Headache 43 43 0 Diarrhea 39 38 2 Pyrexia 23 20 3 URI 23 23 0 Fatigue 21 18 3 Peripheral edema 21 21 0 Hypertension 20 13 7 Contusion/petechiae 34 34 0 Arthralgia 16 15 2
  65. 65. Acalabrutinib: BTK Occupancy QD = once daily; BID = twice daily. Byrd et al, 2016. ▶ Low rates of adverse events allowed safe administration of twice-daily dosing ▶ Full target coverage may reduce drug resistance BTK Occupancy, 100 mg, Twice-Daily Cohort Cohort Time of Assessment BTKOccupancy(%)BTKOccupancy(%) BTK Occupancy, All Cohorts 100 Before 100 mg QD (N = 8) Median Median After 89% Day 1, 4 hr after dosing Day 8, 4 hr after dosing Day 2 before dosing Day 8 before dosing Day 28, 4 hr after dosing Day 28 before dosing 97% 95% 97% 97%99% 99% 99% Before 175 mg QD (N = 8) After 87% 99% Before 250 mg QD (N = 7) After 92% 100% Before 400 mg QD (N = 6) After 95% 100% Before 100 mg BID (N = 27) After 97% 100% 90 80 70 60 10 0 100 0 50 80 90 N = 28 N = 26 N = 27 N = 28N = 27 N = 19
  66. 66. 25 –100 0 0 100 200 300 400 500 600 700 –100 –100 –90 –80 –70 –60 –50 –40 –30 –20 –10 0 –75 –50 –25 9876543210 Acalabrutinib: Change in ALC and SPD ▶ Median of 3 previous CLL therapies ▶ 31% with del(17p) ▶ 75% with unmutated IGHV genes Byrd et al, 2016. MedianChangeFromBaselineinALC(%) MedianChangeFromBaselineinSPD(%) PatientCycle ALC (N = 61) SPD (N = 56) MaximumChangeinSPD(%) Stable disease Partial response Partial response with lymphocytosis
  67. 67. 100 90 80 70 60 50 40 30 20 10 0 0 No. at risk: 2 4 6 8 10 12 14 16 18 61 59 59 58 57 48 32 20 16 3 Median follow-up (mo) 14.3 19.2 17.8 16.4 14.6 11.8 20 90 80 70 60 50 40 30 20 10 0 0 0 0 0 5 100 10 10 25 13 Acalabrutinib: Response ▶ Median follow-up of 14.3 months ▶ Overall response rate was 95% ▶ No cases of Richter’s transformation ▶ Only one case of CLL progression has occurred Byrd et al, 2016. BestResponse(%) Cohort Month PFS(%ofPatients) Stable disease Partial response Partial response with lymphocytosis (N = 60) (N = 8) (N = 8) (N = 7) (N = 6) (N = 31)
  68. 68. Chimeric Antigen Receptor-Modified T Cells Porter et al, 2011; Casucci & Bondanza, 2011. ▶ Lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19 ▶ Coupled with CD137 and CD3-zeta (costimulatory receptors in T Cells) ▶ Transduced into autologous T cells and reinfused Proliferation/cytokine production Survival Cytotoxicity 1G CD3 2G 3G ZAP-70 CD28 PI3K 4-1BB, OX40TRAF2 VH VL CD34-1BBHinge & TM Truncated env Truncated gag/pol RRE cPPT/CTS5ʹLTR pELPS 19-BB- 11556 bp 3ʹLTR (truncated) Amp R Bovine GH Poly A Bacterial replication origin FMC63 U3 (truncated) R region (truncated) R region WPRE CD19 BB scFv Lentiviral Vector Generations of Chimeric Antigen Receptors
  69. 69. Chimeric Antigen Receptor-Modified T Cells: Contrast-Enhanced CT Scans Porter et al, 2011. Axial Coronal Before therapy 1 month of treatment 3 months of treatment
  70. 70. Future Directions ▶ Early results with kinase inhibitors are extremely promising ▶ Similar agents also in clinical development: ◼ Monoclonal antibodies – Ublituximab (CD20) ◼ PI3K inhibitors – TGR 1202 – Duvelisib/IPI145 ▶ Novel combinations under investigation: ◼ Obinutuzumab + venetoclax (CLL-14) ◼ Bendamustine + rituximab + venetoclax/ibrutinib/idelalisib
  71. 71. Key Takeaways ▶ Interphase FISH is standard of care at diagnosis and relapse ▶ Early treatment does not improve survival ▶ FCR is effective in young, healthy patients without del (17p)/TP53 mutation ▶ Kinase inhibitors are effective in patients with previously untreated and relapsed disease, including those with high-risk features ▶ As new therapies emerge, cost, prescription coverage, and long-term side effects will be increasingly important issues, especially with drug combinations
  72. 72. Case Studies
  73. 73. Case 1: Cal ▶ Cal is a 77-year-old man with del(13q), IGHV-unmutated CLL who presents for follow-up ▶ Past medical history includes CAD, hypertension, mild CHF, and hyperlipidemia ▶ Previously treated with FCR 6 years ago and achieved a complete remission that lasted for 4 years and with mutated IGHV ▶ Followed with watchful waiting after his relapse until now when he started experiencing progressive fatigue, lymphadenopathy, and splenomegaly ▶ Laboratory evaluation reveals: ◼ WBC count: 105,000 cells/µL ◼ Hemoglobin: 10.5 mg/dL ◼ Platelet count: 96,000 cells/µL CAD = coronary artery disease; CHF = congestive heart failure; WBC = white blood cell.
  74. 74. Case 1 Question Which of the following therapies would you recommend for Cal? a. Chlorambucil b. Fludarabine + rituximab c. Fludarabine + cyclophosphamide + rituximab d. Bendamustine + rituximab e. Chlorambucil + obinutuzumab f. Chlorambucil + ofatumumab g. Idelalisib + rituximab h. Ibrutinib
  75. 75. Case 1 Question (cont.) Which of the following therapies would you recommend for Cal? a. Chlorambucil b. Fludarabine + rituximab c. Fludarabine + cyclophosphamide + rituximab d. Bendamustine + rituximab e. Chlorambucil + obinutuzumab f. Chlorambucil + ofatumumab g. Idelalisib + rituximab h. Ibrutinib
  76. 76. Case 2: Fred ▶ Fred is a 57-year-old man who was diagnosed with del(17p), IGHV-unmutated CLL 6 months ago ▶ Presents with progressive fatigue, lymphadenopathy in the axillary and inguinal regions, and palpable splenomegaly of 7 cm below the costal margin while he is taking ibrutinib ▶ Only significant past medical history is for hypertension, for which he takes hydrochlorothiazide ▶ Laboratory evaluation reveals: ◼ WBC count: 88,000 cells/µL ◼ Hemoglobin: 9.8 mg/dL ◼ Platelet count: 102,000 cells/µL
  77. 77. Case 2 Question What is the optimal treatment for this patient? a. Idelalisib b. FCR c. Lenalidomide d. Venetoclax e. Steroids
  78. 78. Case 2 Question (cont.) What is the optimal treatment for this patient? a. Idelalisib b. FCR c. Lenalidomide d. Venetoclax e. Steroids
  79. 79. Questions?
  80. 80. References AbbVie Inc (2016). Imbruvica (ibrutinib) approved by U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. Chicago, IL. Available at: https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm Awan FT & Byrd JC (2014). New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin Cancer Res, 20(23):5869-5874. DOI:10.1158/1078-0432.ccr-14-1889 Brown JR, Byrd JC, Coutre SE, et al (2014). Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110ō, for relapsed/refractory chronic lymphocytic leukemia. Blood, 123(22):3390-3397. DOI:10.1182/blood-2013-11-535047 Burger JA, Tedeschi A, Barr PM, et al (2015). Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med, 373(25):2425-2437. DOI:10.1056/nejmoa1509388 Byrd JC, Brown JR, O’Brien S, et al (2014). Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med, 371(3):213-223. DOI:10.1056/nejmoa1400376 Byrd JC, Furman RR, Coutre SE, et al (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med, 369(1):32-42. DOI:10.1056/nejmoa1215637 Byrd JC, Furman RR, Coutre SE, et al (2015). Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, 125(16):2497-2506. DOI:10.1182/blood-2014-10-606038 Byrd JC, Harrington B, O’Brien S, et al (2016). Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med, 374(4):323-332. DOI:10.1056/nejmoa1509981 Casucci M & Bondanza A (2011). Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes. J Cancer, 2:378-382. DOI:10.7150/jca.2.378 Cheson BD (2014). CLL and NHL: the end of chemotherapy? Blood, 123(22):3368-3370. DOI:10.1182/blood-2014-04-563890 CLL Trialists’ Collaborative Group (1999). Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Canc Inst, 91(10):861-868. Coutre SE, Furman RR, Sharman JP, et al (2014). Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol (ASCO Annual Meeting Abstracts), 32(Suppl 15). Abstract 7012. Damle RN, Wasil T, Fais F, et al (1999). Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood, 94(6):1840-1847.
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