CLL       Issues About Therapy- Why do we watch and wait- What is the best front line regimen     - Is it different for di...
Why Not Treat CLL at Diagnosis     -   indolent disease     -   patients often asymptomatic     -   median age early 70’s ...
Survival: Daily Chlorambucil Versus            ObservationDighiero et al N Eng J Med 338(21):1506-14,1998
Newer Prognostic Factors Associated   With Inferior Survival in CLL   FISH cytogenetic abnormalities       17p deletion ...
Early Treatment With FCR vs Deferred  Treatment in High-Risk Binet Stage A             GCLLSG CLL7       Diagnosed within ...
CLL8 Study Design  Patients with                                6 coursesuntreated, active                     FCR    CLL ...
FC vs FCR: Response                          FC (%)       FCR (%)     p     CR                         23       45      <0...
CLL8: Progression-free Survival                  Median observation time 25.5 months                                      ...
CLL8: Overall Survival                     Overall survival 3                     years post                     randomiza...
CLL8 Genetic Analyses: PFSFC                 FCR                             10
CLL8 Genetic Analyses: OSFC                  FCR                            11
CAM307: Response to First-line Therapy With  Alemtuzumab vs Chlorambucil (N = 297)                     IRRP Response Rate ...
CAM307: PFS by Cytogenetic        Abnormality and Treatment Arm                     Alemtuzumab Chlorambucil              ...
Alemtuzumab for Fludarabine-Refractory        B-CLL: Study Results• OR 33% (CR 2%, PR 31%)• 59% of patients had stable dis...
Local Injection-Site Reaction Following SC       Alemtuzumab Administration  Disappeared within 2 weeks of continued thera...
CAM307: Safety                Summary of Infection-Related Adverse Events                100                  90          ...
CMV Viremia with AlemtuzumabTrial     % Pts   Time of OrganNo. Pts. with CMV CMV      Involv. DeathsKeating   93         8...
Prophylaxis TrialInclusion    Patients receiving alemtuzumabExclusion    Cr Cl calculated < 10 cc/minSchema   1: 1 randomi...
Results                                              CMV                         Total             Reactivation  Valtrex  ...
Lymphadenopathy Predicts Poor        Response to Alemtuzumab in          Relapsed/Refractory CLL          Response accordi...
Bendamustine      Bifunctional Antineoplastic Agent?                                                        CH3           ...
Bendamustine combined with rituximab in   first-line therapy of advanced CLL: mutlicenter phase II trial of the German    ...
BR Front-line Response Rate    Response                              N                     %      ORR                     ...
BR Frontline Treatment                Response by FISHResponse                     No.        ORR          (%)       CR   ...
CLL10 protocol of the GCLLSG       Fludarabine      Fludarabine 25 mg/m² i.v., days 1–3       Cyclophosphamide Cyclophosph...
CLL8 Study Design  Patients with                               6 coursesuntreated, active                    FCR    CLL an...
CLL8: Side effects: the effect of age                              FC                           FCR                   < 70...
SOB’s Quick SurveyAll patients with CLL > 70 years seen   by me in clinic last month: N = 14Eligible for CLL8 trial?3 too ...
So if FCR not SOC for Patients with 17p   Deletion or Elderly, Then What Is?17p-: clinical trialelderly:        really old...
Bruton’s Tyrosine Kinase (Btk)                    A Critical B-Cell Signaling Kinase• B-cell antigen receptor (BCR) signal...
PCI-32765: Novel Small Molecule Inhibitor of                                      BTK                                •    ...
Pattern of Response:   Blood Lymphocytes vs Lymph NodesTreatment-Naïve Patients                   600                     ...
Initial (Cycle 2) Response Assessment and Best           Response (420 mg/d Cohorts)                  Treatment-Naïve (420...
Side Effects (All Grades)                    Treatment-Naïve                           Relapsed/Refractory                ...
Best Response by Risk Features              Relapsed/Refractory Patients: 420 mg/d Cohort                                 ...
Improvement in Hematologic Parameters                                   Platelets over time                               ...
In B-Cell Malignancies, PI3K Delta Is at the   Crossroads of Critical Signaling Pathways                                  ...
CAL-101 is an Orally Bioavailable Small Molecule  that Inhibits PI3K Delta Potently and Selectively                       ...
Single-Agent CAL-101 Resulted in Tumor Shrinkage in All   Evaluable Patients with CLL, Including Those with del (17p)     ...
Marked Reductions in Peripheral   Lymphadenopathy Were Observed                     Pretreatment           With CAL-101 Tr...
CAL-101 Treatment Improved CLL-Related   Thrombocytopenia and Anemia                                            14        ...
CAL-101 Has Been Well Tolerated in Patients with CLL  Over Exposure Periods Exceeding One Year                            ...
Conclusions - CLL- FCR is standard of care- 17p- is the mother of all bad prognostic  factors    • clinical trials    • al...
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Newest Strategies in the Treatment of CML/CLL

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Susan O'Brien, M.D., Professor, Dept. of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center: Newest Strategies in the Treatment of CML/CLL presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center.

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Newest Strategies in the Treatment of CML/CLL

  1. 1. CLL Issues About Therapy- Why do we watch and wait- What is the best front line regimen - Is it different for different subsets- Does FISH affect choice of frontline therapy?- What are promising new agents?
  2. 2. Why Not Treat CLL at Diagnosis - indolent disease - patients often asymptomatic - median age early 70’s - no cure
  3. 3. Survival: Daily Chlorambucil Versus ObservationDighiero et al N Eng J Med 338(21):1506-14,1998
  4. 4. Newer Prognostic Factors Associated With Inferior Survival in CLL FISH cytogenetic abnormalities  17p deletion  11q deletion  Complex abnormalities Unmutated (<2% homology with germline) immunoglobulin heavy chain variable gene (IgVH) Expression of ZAP-70 (≥ 20% positive) Expression of CD38 (≥ 30% positive)
  5. 5. Early Treatment With FCR vs Deferred Treatment in High-Risk Binet Stage A GCLLSG CLL7 Diagnosed within 1 year All tested for 4 risk factors: No pretreatment Cytogenetics by FISH Age ≥ 18 years Serum thymidine kinase > 10 U/L Enrollment ~ 825 Predicted LDT < 12 months Unmutated IgVH ≥ 2 risk factors N = 200 0-1 risk factors N = 600 R COHORT I COHORT II COHORT III FCR 6 Watch & wait Watch & waitPrimary objectives: Event-free survival and definition of new prognostic systemAvailable at: http://dcllsg.web.med.uni-muenchen.de/en/cll7/index.php.
  6. 6. CLL8 Study Design Patients with 6 coursesuntreated, active FCR CLL and Follow good physical R up fitness (CIRS ≤ 6, FCcreatinine clearance ≥ 70 ml/min) Updated results of the 2nd analysis Median observation time 37.7 months. Hallek et al Lancet 2010;376:1164-74
  7. 7. FC vs FCR: Response FC (%) FCR (%) p CR 23 45 <0. 01 CRu 5 3 0.22 CRi 2 3 0.52 nPR 5 3 0.15 PR 50 40 <0.01 OR 85 93 <0.01Hallek et al Lancet 2010;376:1164-74
  8. 8. CLL8: Progression-free Survival Median observation time 25.5 months Median PFS: FCR: 51.8 months FC: 32.8 months (N=790 Hazard ratio 0.563, ranges 0.460-0.689, p<0.001) PFS rate 3 yrs post randomization: FCR: 64.9% FC: 44.7% P<0.001Hallek et al Lancet 2010;376:1164-74
  9. 9. CLL8: Overall Survival Overall survival 3 years post randomization: FCR: 87.2% FC: 82.5% n=817, HR 0.664, p=0.012
  10. 10. CLL8 Genetic Analyses: PFSFC FCR 10
  11. 11. CLL8 Genetic Analyses: OSFC FCR 11
  12. 12. CAM307: Response to First-line Therapy With Alemtuzumab vs Chlorambucil (N = 297) IRRP Response Rate to First-line B-CLL Therapy 100 P<0.0001 90 83% ORR 80 CR 70 24% CR PR % Response 60 55% ORR 2% 50 40 30 59% PR 53% PR 52.7 20 10 0 Alemtuzumab ChlorambucilHillmen P et al. J Clin Oncol. 2007;25(35):5553-5.
  13. 13. CAM307: PFS by Cytogenetic Abnormality and Treatment Arm Alemtuzumab Chlorambucil Median PFS Median PFS P-value for Deletion N (mo) N (mo) PFS 17p del 11 10.7 10 2.2 0.2034 11q del 23 8.5 31 8.5 0.3895 (no 17p del) Trisomy 12 (no 17p del, 24 18.3 10 12.9 0. 0815 no 11q del) Normal 25 19.9 26 14.3 0.3477 Sole 13q del 33 24.4 34 13.0 0.0107[Data presented according to hierarchical model of Döhner (NEJM 2000; 343: 1910-6)]P value is calculated using log-rank test
  14. 14. Alemtuzumab for Fludarabine-Refractory B-CLL: Study Results• OR 33% (CR 2%, PR 31%)• 59% of patients had stable disease• Median TTP of responders 9+ months• Fever, chills: 76% Gr 1-2, 20% Gr 3-4• Grade 3-5 infections in 33% of patients Keating et al. Blood 99 (10), 3554-61, 2002.
  15. 15. Local Injection-Site Reaction Following SC Alemtuzumab Administration Disappeared within 2 weeks of continued therapy Skin reactions appear to be much less pronounced in pretreated CLL patients
  16. 16. CAM307: Safety Summary of Infection-Related Adverse Events 100 90 IV Alemtuzumab (n=147) 80 Oral Chlorambucil (n=147) 70 CMV incidence% of Patients 60 50 40 30 20 46 50 53 10 5 3 3 2 16 8 0 Febrile Bacteremia Total Positive CMV Positive CMV Neutropenia /Sepsis Infections* PCR with PCR without symptoms symptoms (*Total infections is excluding patients with any CMV events) Hillmen et al. JCO 2008;25:5616-23
  17. 17. CMV Viremia with AlemtuzumabTrial % Pts Time of OrganNo. Pts. with CMV CMV Involv. DeathsKeating 93 8 on therapy no 0Nguyen 34 10 28 days no 0Ferrajoli 78 20 1st month no 0Lundin* 41 10 on therapy no 0 *initial therapyKeating et al Blood 99(10) 3554-3561 2002, Nguyen et al Clinical Lymphoma 3(2) 105-110, 2002,Ferrajoli et al Cancer 98:773-8 2003, Lundin et al Blood 100:768-773 2002
  18. 18. Prophylaxis TrialInclusion Patients receiving alemtuzumabExclusion Cr Cl calculated < 10 cc/minSchema 1: 1 randomization Valtrex 500 QD vs Valcyte 450 BID 12 weeks therapy endpoint
  19. 19. Results CMV Total Reactivation Valtrex 20 7 p = .004 Valcyte 20 0O’Brien et al. Blood 2008;111(4):1816-19
  20. 20. Lymphadenopathy Predicts Poor Response to Alemtuzumab in Relapsed/Refractory CLL Response according to size of largest lymph node % of patients MRD-Largest NCI Response negativenode No. CR OR responseNone 33 72 87 39<5cm 47 17 40 11>5cm 11 0 9 0Moreton P et al. J Clin Oncol. 2005;23:2971-2979.
  21. 21. Bendamustine Bifunctional Antineoplastic Agent? CH3 N ClH2C N N CO2H ClH2C Purine-like Alkylating Group Benzimidazole Ring Available in Germany, 1971 - 1992 Unique in vitro anti-tumor profile 21Rummel M, et al. J Clin Oncol. 2005;23:3383-3389.
  22. 22. Bendamustine combined with rituximab in first-line therapy of advanced CLL: mutlicenter phase II trial of the German CLL SGKirsten Fischer, MD, Paula Cramer, MD, Stephan Stilgenbauer, MD, Raymonde Busch, Leopold Balleisen, MD, Julia Kilp, MD, Anna-Maria Fink, MD, Sebastian Böttcher, MD, Matthias Ritgen, MD, Michael Kneba, MD, PhD, Peter Staib, MD, Hartmut Döhner, MD, Silke Schulte, Barbara F. Eichhorst, MD, Michael Hallek, MD and Clemens-Martin Wendtner, MDASH 2008 Abstract 205
  23. 23. BR Front-line Response Rate Response N % ORR 100 90.9 CR 36 32.7 nPR 3 2.7 PR 61 55.5 * N=110 (7 pts not yet evaluable)Fischer et al; ASH 2008 Abstract 205: Bendamustine and rituximab
  24. 24. BR Frontline Treatment Response by FISHResponse No. ORR (%) CR (%)+12 19 17 89.5 3 15.811q- 21 19 90.5 9 42.917p- 7 3 42.9 0 0IGHV unmutated 63 56 88.9 25 39.7Fischer et al; ASH 2008 Abstract 205: Bendamustine and rituximab
  25. 25. CLL10 protocol of the GCLLSG Fludarabine Fludarabine 25 mg/m² i.v., days 1–3 Cyclophosphamide Cyclophosphamide 250 mg/m², days 1–3, Rituximab: 375 mg/ m2 i.v. day 0, cycle 1 Rituximab Rituximab: 500 mg/m² i.v. day 1, cycle 2–6 (FCR)R Bendamustine Bendamustine 90mg/m² day 1–2 Rituximab Rituximab 375 mg/m² day 0, cycle 1 (BR) Rituximab 500 mg/m² day 1, cycle 2–6 Similar efficacy of BR in comparison with FCR? Lower toxicity rate of BR?
  26. 26. CLL8 Study Design Patients with 6 coursesuntreated, active FCR CLL and Follow good physical R up fitness (CIRS ≤ 6, FC Creatinine clearance ≥ 70 ml/min) Updated results of the 2nd analysis Median observation time 37.7 months. Hallek et al Lancet 2010;376:1164-74
  27. 27. CLL8: Side effects: the effect of age FC FCR < 70 yrs ≥ 70 yrs < 70 yrs ≥ 70 yrs p p n = 359 n = 37 n = 361 n = 43Total AEs gr 3/4 61.0% 78.4% 0.04 75.6% 83.7% 0.24Anemia 6.7% 8.1% 0.74 5.5% 4.7% 0.81AIHA 1.1% 0.0% 0.52 0.6% 2.3% 0.20Leukocytopenia 12.0% 13.5% 0.79 24.9% 16.3% 0.21Neutropenia 19.5% 35.1% 0.03 32.4% 44.2% 0.12Thrombopenia 11.4% 5.4% 0.26 7.8% 4.7% 0.46Infections, 9.5% 8.1% 0.79 13.0% 18.6% 0.31unspecifiedInfections, 0.7% 5.4% 0.02 1.9% 4.7% 0.26bacterial
  28. 28. SOB’s Quick SurveyAll patients with CLL > 70 years seen by me in clinic last month: N = 14Eligible for CLL8 trial?3 too old, > 80 years, so N = 11Meet creatinine clearance requirement?N=4So 4/14 = 29% eligibleNot counting CIR score
  29. 29. So if FCR not SOC for Patients with 17p Deletion or Elderly, Then What Is?17p-: clinical trialelderly: really old, poor PS → palliative, probably doesn’t matter older but good shape → reduced dose FCR → clinical trial
  30. 30. Bruton’s Tyrosine Kinase (Btk) A Critical B-Cell Signaling Kinase• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation• Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway• Mutations in Btk prevent B cell maturation• Inhibitors of Btk block BCR signaling and induce apoptosis 30
  31. 31. PCI-32765: Novel Small Molecule Inhibitor of BTK • Forms a specific and irreversible bond with cysteine-481 in Btk O • Potent Btk inhibition at IC50 = 0.5 nM • Orally bioavailable with daily dosing NH 2 resulting in 24-hr target inhibition • Inhibits BCR signaling and active in N N spontaneous canine B-cell lymphoma N N • In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA N binding, CpG mediated proliferation O • Inhibits CLL cell migration and adhesion PCI-32765 Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010 Herman SEM et al: : Blood. 2011 Mar 21. [Epub] Ponader, et al., Proc ASH, 2010 31
  32. 32. Pattern of Response: Blood Lymphocytes vs Lymph NodesTreatment-Naïve Patients 600 1.5 % of Base SPD ALC 109/L 400 1.0 200 0.5 0.0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Time (Days) Time (Days)Relapsed/Refractory Patients 600 1.5 % of Base SPD ALC 109/L 400 1.0 200 0.5 0.0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Time (Days) Time (Day) Time (Days) 32
  33. 33. Initial (Cycle 2) Response Assessment and Best Response (420 mg/d Cohorts) Treatment-Naïve (420 mg/d) Relapsed/Refractory (420 mg/d) 67% 59%Response Rate % 48% 41% 33% 24% 19% 19% Cycle 2 Best Response Cycle 2 Best Response (n=21) (n=21) (n=27) (n=27) CR PR Nodal Response 33
  34. 34. Side Effects (All Grades) Treatment-Naïve Relapsed/Refractory 420 mg/d (n=23) 420 mg/d (n=27) Diarrhea 48% 70% Nausea 39% 33% Vomiting 17% 22% Dyspepsia 22% 19% Contusion 4% 33%Muscle spasms 17% 26% Rash 26% 11% 13% 37% URI Fatigue 17% 33% 0% 20% 40% 60% 80% 0% 20% 40% 60% 80% Grade 1 Grade 2 Grade 3 Grade 4 34
  35. 35. Best Response by Risk Features Relapsed/Refractory Patients: 420 mg/d Cohort Best Response (%)Molecular Risk Feature N IWG Response Nodal ResponseOverall 27 48 41 Del17p 9 4/9 (44) 3/9 (33) Del11q 8 5/8 (63) 3/8 (38) IgVH unmutated 17 9/17 (53) 5/17 (29) 35
  36. 36. Improvement in Hematologic Parameters Platelets over time Hemoglobin over time in subjects with plt <50x109/L in subjects with Hgb <9g/dL at study entry at study entry (n=12) (n=8) 150 14Platelets (109/L) HGB (g/dL) 12 100 10 50 8 0 1 15 28 43 56 84 112 140 168 196 224 252 1 15 28 43 56 84 112 140 168 196 224 252 Days on Study Days on Study Subjects from all treatment groups with low baseline measurements are included 36
  37. 37. In B-Cell Malignancies, PI3K Delta Is at the Crossroads of Critical Signaling Pathways Stromal cell T-cell Signaling IL-6 BAFF stimulus CXCL13 BCR IL-6R CXCR5 CD40 BAFFR Malignant B-cell membrane LYN gp130 gp130 JAK TRAF6 SYK JAK LYN/SYK α β γ PI3K STAT BTK Delta STAT BTK PLCγ2 PLCγ2 T308 AKT S473 PKC GSK-3 NF-kβ PI3K Delta Pathway Drives pathway Proliferation mTOR Cell survival p70s6k elf4E TraffickingSlide 37 Reference: Lannutti, Blood, 2011
  38. 38. CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Potently and Selectively CAL-101 Class I PI3K Alpha Beta Gamma Delta Isoform Cell- PDGF- LPA-induced fMLP-induced FcεR1- Based induced pAKT pAKT CD63+ induced Activity CD63+ EC50 (nM) >20,000 1,900 3,000 8 • Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions • No off-target activity against Class II or III PI3K, mTOR, or DNA-PK • No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)Slide 38 Reference: Lannutti, Blood, 2011
  39. 39. Single-Agent CAL-101 Resulted in Tumor Shrinkage in All Evaluable Patients with CLL, Including Those with del (17p) Best On-Treatment Change in Tumor Size (ITT Analysis, N=55) +100 +75 % Change in Lymph Node Area +50 +25 0 -25 -50* -75 Inevaluable (patients without a follow-up tumor assessment) Patients with del (17p) * Criterion for response [Hallek 2008] -100Slide 39
  40. 40. Marked Reductions in Peripheral Lymphadenopathy Were Observed Pretreatment With CAL-101 Treatment 38-year-old patient with refractory CLL and 5 prior therapiesSlide 40
  41. 41. CAL-101 Treatment Improved CLL-Related Thrombocytopenia and Anemia 14 Hemoglobin and Platelet Counts 160 Mean Hemoglobin ± SEM (g/dL) Mean Platelets ± SEM (K/µL) 13 140 12 120 11 Hemoglobin 100 Platelets 10 80 ) ) ) ) ) ) 5) 2) 2 2 1 8 2 1 (2 (2 (5 (5 (5 (3 (3 (3 10 12 0 1 2 4 6 8 Cycle (28 days) (N) Improved thrombocytopenia: Patients with baseline thrombocytopenia (platelets<100,000/uL) had sustained improvement in mean platelet counts Improved anemia: Patients with baseline anemia (hemoglobin <11 g/dL) had sustained improvements in mean hemoglobin valuesSlide 41
  42. 42. CAL-101 Has Been Well Tolerated in Patients with CLL Over Exposure Periods Exceeding One Year Grade 3-4 Adverse Events Occuring in ≥5% of Patients Regardless of Causality (N=55) 100 80 Incidence, % 60 Non-Hematological Hematological 40 24% 20 18% 5% 7% 5% 7% 0 ia ia N ↑ ↓ ia F& on m en ST et ne el p um /A ro at A LT Pl e t eu Pn A N Adverse Event Type • Grade 3-4 adverse events largely due to prior therapy or underlying CLL • No maximum tolerated dose or dose-limiting toxicities • No pattern of drug-related symptomatic adverse eventsSlide 42
  43. 43. Conclusions - CLL- FCR is standard of care- 17p- is the mother of all bad prognostic factors • clinical trials • allo SCT- No real standard of care for elderly patients • all regimens that are effective are also toxic- Several promising new agents in clinical trials

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