Chronic Lymphocytic Leukemia

Transcription

1 Chronic Lymphocytic Leukemia Bruce D. Cheson, M.D. Head of Hematology Georgetown University Hospital Lombardi Comprehensive Cancer Center Washington, D.C.

2 Chronic Lymphocytic Leukemia Most common type of leukemia in US (~12,000 cases/year); 3.7/100,000 Incidence varies world-wide, lower in Asia Median age in the 7th decade of life No clear etiologic factors (agent orange, radiation?)

3 Staging Systems Rai Findings Survival (mo) 0 Lymphocytosis only > 120 I Lymphocytosis plus lymphadenopathy 95 II Lymphocytosis plus > spleen and / or liver 72 III Lymphocytosis plus anemia (Hgb < 11.0 g/dl) 30 IV Lymphocytosis plus platelets < 100,000/mm3 30 Binet Findings Survival (mo) A Hb 10, Plts 100, < 3 involved areas* > 120 B Hb 10, Plts 100, 3 involved areas* 84 C Hb < 10, or Plts < *Involved areas include cervical, axillary, or inguinal nodes, spleen, or liver. Rai KR et al. Blood. 1975;46: ; Binet JL et al. Cancer. 1981;48:

4 Newer Prognostic Factors in CLL Fluorescent in situ hybridization (FISH) CD38 Ig heavy chain gene mutation ZAP-70 Number of smudge cells

5 Current Role of the New Prognostic Factors Further prospective study Not all are available (mutation status) or reliable (ZAP-70) No data that changing therapy alters outcome Possible stratification for clinical trials Consider prognostic factor index Not ready for prime time treatment decisions!

6 Assessment of the Patient with CLL History and physical examination CBC, evaluation of peripheral blood smear Retics, DAT Quantitative Igs BM prior to therapy or to assess cytopenias Kidney, renal function, uric acid, LDH CT scan only when clinically indicated NO PET SCANS!

7 Indications for Treatment of CLL Disease-related symptoms Increasing fatigue* Progressive marrow failure Autoimmune anemia and/or thrombocytopenia Massive +/- progressive hepato/splenomegaly or lymphadenopathy Recurrent infections Rapid lymphocyte doubling time Not just adverse prognostic factors * Should have been included Cheson et al, Blood 87:4990, 1996

8 Options For The Initial Management of CLL Watch and wait ( worry ) Chlorambucil Fludarabine monotherapy Fludarabine combinations Alemtuzumab Chemo-immunotherapy Bendamustine

9 Fludarabine Therapy Pros Higher CR and ORR than alkylating agents Longer duration of response Cons No survival benefit Difficult to salvage Goals Improve CR rate Prolong survival Identify better salvage regimens

10 Flu vs Flu/CY in CLL Eichhorst et al, Blood 107:885, pts, < 66 years old Stage A - 24, B - 183, C F - 30 mg/m, Cy mg/m x 3d, q 4k x 6 RR - FC-94% (24%CR) vs F-83% (7%CR) More toxicity and myelosuppression with FC

11 Progression-free survival Eichhorst, B. F. et al. Blood 2006;107:

12 Overall survival Eichhorst, B. F. et al. Blood 2006;107:

13 Phase II Trial of Rituximab as First- Line and Maintenance Therapy of CLL 44 patients who met indications for therapy RR after first course 51% (4% CR) 28 pts received >1 additional course ORR 58% (9% CR) Median PFS 18.6 months No cumulative toxicity or opportunistic infections Hainsworth et al. J Clin Oncol 2003

14 Response to Fludarabine + Rituximab Treatment Pts CR (%) ORR (%) Concurrent Sequential Byrd et al. Blood 2003;101:6-14

15 (p= 0.004) Proportion Progression Free Survival by Arm CALGB Months Concurrent arm Sequential arm N= 51 N= 53 Events= 35 Events= 42 Chi-square= p-value =

16 (p= 0.004) Proportion Overall Survival by Arm CALGB Months Concurrent arm Sequential arm N= 51 N= 53 Events= 27 Events= 24 Median= Median= Chi-square= p-value =

17 Fludarabine-Rituximab vs Fludarabine in CLL Regimen Pts Fludarabine 179 Flu+rituximab104 Median age %CR % ORR yr PFS yr OS Byrd et al, Blood 105:49, 2004

18 NCI-WG Response to Frontline FC + Rituximab (n=224) Response # Pts (%) CR 156 (70%) Nodular PR 23 (10%) PR 34 (15%) 95% No response 11 (4%) Early death 2 (1%) Keating et al, J Clin Oncol 23: , 2005.

19 FR (CALGB) vs FCR (MDACC) Regimen FR FCR CR/ORR (%) 47/90 69/95 Setting Coop Group Single center Median Age % Stage 0/I-II 0/59 2/67

20 Phase III Trial of Alemtuzumab (CAM) vs Chlorambucil (CHLO) as First-Line Therapy for Patients With Untreated CLL Patients with previously untreated progressive CLL N=297 R A N D O M I Z E n=149 n=148 Primary end point: PFS Secondary endpoints:, OS,ORR, and safety *Alemtuzumab 30 mg IV tiw up to 12 weeks Chlorambucil 40 mg/m2 po q28d up to 12 cycles A S S E S S *CAM patients received prophylactic trimethoprim/sulfamethoxazole DS and famciclovir during treatment until CD4+ counts 200 cells/μl. Hillmen et al. J Clin Oncol 25:5616, 2007

21 Phase III Trial of Alemtuzumab (CAM) vs Chlorambucil (CHLO) as First-Line Therapy for Patients With Untreated CLL: Response Response (IRRP) CAM n=149 % of Patients CHLO n=148 P Value ORR (CR) 83 (24) 55 (2) < Rai Stage I-II ORR 90 (30) 64 (3) < Rai Stage III-IV ORR 78 (14) 41 (0) Median PFS (Rai Stage I-II), mos HR 0.57 (95% CI: ) Median PFS (Rai Stage III-IV), mos HR Hillmen et al. J Clin Oncol 25:5616, 2007

22 Phase III Trial of Alemtuzumab vs Chlorambucil as First-Line Therapy for Patients With Untreated CLL: Toxicities Relevant Grade 3 or 4 AEs CAM (n=149) % of Patients CHLO (n=148) Lymphopenia 97 3 Pyrexia 8 0 CMV events 8 0 Chills 3 0 Thrombocytopenia Anemia Neutropenia Bacteremia/sepsis 3 2 Febrile neutropenia 5 3 Hillmen et al. J Clin Oncol 25:5616, 2007

23 Response to Alemtuzumab in Relapsed/Refractory CLL 46% No Response Partial Response 19% 35% Complete Response No Nodes Nodes <5 cm Nodes >5 cm Moreton P et al. J Clin Oncol. 2005;23: % 11% 71% 16% 57% 27% 82% 18% 0%

24 Alemtuzumab Consolidation Post- Fludarabine-based Therapy in B-CLL (N=21) Time (months) Patients in CR/PR after fludarabine cyclophosphamide Alemtuzumab (n=11) 3 x 30 mg IV 12 weeks No further treatment (n=10) 4 CR 7 PR 2 CR 2 npr 3 PR 3 PD 5 MR* Patients received TMP/SMX. Screening for CMV was performed After a median of 4 weeks, treatment was interrupted in 7 patients treated with alemtuzumab because of grade 3/4 infections *MR: molecular remission, defined by polyclonal IgV H Wendtner, et al. Leukemia. 2004;18:

25 CALGB 10101: Results Toxicities Response Pts Grade 3 Grade 5 PR 34 4 OIs, 3 CMV reactivation, 1 hemorrhagic cystitis EBV+LPD CR 17 2 CMV, 1 crypto Viral meningitis Listeria meningitis Legionella pneum. CMV pneumonia PCP pneumonia

26 Bendamustine: Background Developed in the 1960s in East Germany as a bifunctional molecule with alkylator and antimetabolite properties Non-cross resistant with other alkylating agents Induces durable DNA damage in vitro, resulting in rapid cell death through apoptosis and mitotic catastrophe European studies demonstrate single-agent activity in patients with NHL, CLL, multiple myeloma, and breast cancer

27 Chemical Structure ClH 2 C Bendamustine ClH 2 C N N COOH Carboxylic acid Nitrogen mustard N Benzimidazole ring Cl Cyclophosphamide CH 3 N NH 2 N O O Cl N N Cl N P N H Cladribine HOCH 2 O OH

28 Bendamustine - CLL Study Design Bendamustine 100 mg/m 2, iv, days 1 & 2 of 28 day cycle Randomization Assessment End of Cycle 3 Assessment End of Cycle 5/6 3 monthly follow up Chlorambucil 0.8 mg/kg, po, days 1 & 15 of 28 day cycle PD patients discontinue

29 Promising New Agents for CLL Chemotherapy agents Bendamustine (Treanda) Flavopiridol (alvocidib) Monoclonal antibody-based therapy Immunomodulatory agents Lenalidomide (Revlimid) Apoptosis-inducing agents

30 Kath R, et al. J Cancer Res Clin Oncol 2001;127:48-54; Bergmann MA, et al. Haematologica 2005;90: ; Lissitchkov T, et al. J Cancer Res Clin Oncol 2006;132:99-104;Koppler H, et al. Leuk Lymphoma 2007 (45): Bendamustine Clinical Studies in CLL Investigator Regimen N CR,% ORR,% Kath 2001 B 60 mg/m 2 (<70 yr) or 50 mg/m 2 (>70 yr) D1-5 q 4 weeks Bergmann 2005 B 100 mg/m 2 D1, 2 q 3-4 wk Lissitchkov 2006 B 100 mg/m 2 D1, 2 q4 wk Koppler 2007 B mg/m 2 over D1-3 M 8-10 mg/m 2 D B, bendamustine; M, mitoxantrone

31 Bendamustine in Combination With Rituximab (BR) for Patients With Relapsed CLL Phase II trial in relapsed/refractory B-CLL 81 patients recruited between March 2006 and June 2007, all had relapsed/refractory B-CLL B: 70 mg/m 2 ; R: 375 mg/m 2 on the 1st cycle and 500 mg/m 2 on each subsequent cycle Cycle R B B R B B R B B R B B R B B R B B Follow-up every 3 months up to 3 years until disease progression Day Interim staging Day 85: PD or unacceptable toxicity: end of study B=bendamustine; PD=progressive; R=rituximab. Fischer K et al. Blood. 2007;110:913a (Abstract 3106). Initial response assessment Day 167±7 Final staging Day 225

32 Patients Treated with BR for Relapsed CLL: Efficacy (n=24) Efficacy data were available for 24/31 patients receiving 3 treatment cycles Response Complete Partial Overall Stable disease Progressive disease n (%) 3 (13) 13 (54) 16 (67) 6 (25) 2 (8) Chromosomal abnormalities: 11q del (ORR 5/6) Trisomy 12 (ORR 2/3) 17p del (ORR 0/4) Unmutated IgV H (ORR 7/14) Fischer K et al. Blood. 2007;110:913a (Abstract 3106).

33 Lenalidomide (Revlimid) O O H N N O NH 2 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)- 2,6-piperidinedione Immunomodulatory drug (IMiD) More potent analog of thalidomide Different toxicity profile from thalidomide Targets tumor microenvironment

34 Lenalidomide in CLL Salvage RPCI 1 MDACC 2 N = 45 N = 44 Starting dose 25 mg 10 mg Median dose TBD * 10 mg Response % CR 4 (9) 3 (7) npr 1 (2) PR 17 (38) 11 (25) OR 21 (47) 15 (34) SD 8 (18) 10 (23) * Has not been calculated to date. Molecular remission (PCR) in 3 patients. 1 Chanan-Khan A et al. Oral presentation. XII iwcll; September 14-16, 2007; London, UK; Chanan-Khan A et al. J Clin Oncol. 2006;24: ; 2 Ferrajoli A et al. Oral presentation. XII iwcll; September 14-16, 2007; 34 London, UK; Ferrajoli A et al. Blood. 2006;108(11):94a. Abstract 305.

35 Lenalidomide With Unfavorable Cytogenetics (n=40) Response CR PR OR Study A 17p/11q- (24) % Study B 17p/11q- ( % Ferrajoli et al, ASH abstr 754, 2007

36 Lenalidomide: Adverse Events RPCI 1 MDACC 2 Toxicity (%) Gr < 3 Gr 3 Gr < 3 Gr 3 Fatigue Flare reaction Constipation Diarrhea Rash DVT / PE Neutropenia Thrombocytopenia Anemia Chanan-Khan A et al. Oral presentation. XII iwcll; September 14-16, 2007; London, UK; Chanan-Khan A et al. J Clin Oncol. 2006;24: ; 2 Ferrajoli A et al. Oral presentation. XII iwcll; September 14-16, 2007; 36 London, UK; Ferrajoli A et al. Blood. 2006;108(11):94a. Abstract 305.

37 Lenalidomide Flare Reaction Onset 1-2 days into cycle 1, lasts ~14 days; rarely beyond 1st cycle Clinical characteristics - Tender swelling of involved lymph node sites - Diffuse pruritic rash or overlying erythema - Low-grade fever - Bone pain - Increase in total WBC / ALC count Ibuprofen mg TID decreases pain None required steroids or discontinuation of therapy due to flare Chanan-Khan A et al. J Clin Oncol. 2006;24:

38 Tumor Lysis Syndrome Uncommon, unpredictable Not dose-related Potentially fatal A lower starting dose of lenalidomide followed by closely monitored dose escalation Increased safety monitoring for TLS Prophylaxis with hydration and allopurinol Exclusion of pts with history of renal failure

39 Flavopiridol in R/R CLL: Efficacy Results (n=89) 8 pts received only 1 dose due to tumor lysis syndrome Response 41 (46%) Partial Complete (both with trisomy 12) 39 (44%) 2 (2%) Del (17p13) 14 of 29 (48%) Del (11q22) 22 of 37 (59%) Complex karyotype 20 of 47 (43%) Bulky adenopathy (>5cm) 33 of 70 (47%) Heerema et al, Abstract 3107, ASH 2007

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41 Apoptosis as a Therapeutic Target Drug Target Company Oblimersen BCL2 Genta Obatoclax BCL2 family GeminX YM155 Survivin Astellas AT-101 BCL2, BCLXL, MCL1 Ascenta ABT-263 BCL2, BCLXL, BCLW Abbott APO2L/TRAIL DR4, DR5 Genentech Agonistic mab s DR4, DR5 HGS DR4 = TRAIL-R1 (approved gene name TNFRSF10A) DR5 = TRAIL-R2 (approved gene name TNFRSF10B)

42 Alemtuzumab Pivotal Trial: Results 33% overall response rate (PR, 31%) 54% stable disease Median survival 16 months 45% (42/93) survived 18+ months Median survival among responders 32+ months Keating et al. Blood 2002

43 Rituximab in Relapsed/Refractory CLL/SLL Investigator Pts CR (%) RR (%) Maloney McLaughlin Nguyen Piro* Winkler Foran Huhn *8 infusions

44 Ofatumumab (HuMax-CD20) -Human IgG1, κ - High binding affinity; slow off-rate - Potent ADCC & CDC -Epitope distinct from rituximab epitope Ofatumumab Rituximab

45 Results of Phase I/II Study CLL (n=33) ORR 44%; Cohort C 46% (13 of 27) No complete responses Confirmed response rate: 35% (9/27) had sustained response at Week 19 Median PFS: 106 days 1 PR/7 pts with prior rituximab monotherapy or combined with chemotherapy Coiffier B et al. Blood. 2008;111:

46 Safety Results of Phase I/II Study CLL Infusion reactions consistent with Rituxan when infusion rate slowed 51% had infections compared with Rituxan, 31% any grade; 1% grade 3/4* 9 SAEs; 1 death due to interstitial lung disease Coiffier B et al. Blood. 2008;111:

47 Lumiliximab CD23 45-kDa transmembrane glycoprotein Normally functions as the low-affinity IgE receptor Highly expressed on B-CLL B cells Properties of lumiliximab IgG1 chimeric (macaque-human) anti-cd23 monoclonal antibody Structurally indistinguishable from human antibodies Synergistic with fludarabine and rituximab in preclinical models

48 Phase I - Clinical Activity 42 of 46 (91%) patients had a decrease in absolute lymphocyte count (ALC) 22 of 35 (63%) patients evaluated for lymphadenopathy had a decrease in lymph node bulk Reductions in lymphadenopathy and ALC were transient No NCI-confirmed responses Byrd et al, Clin Cancer Res 13:4448, 2007

49 Study Efficacy Compared with Published Data (MD Anderson Cancer Center*) L + FCR (N = 31) n (%) *MDACC FCR (N=177) n (%) Overall response 22 (71%) 130 (73%) Complete response 15 (48%) 45 (25%) Partial response 3 (10%) 85 (48%) Unconfirmed partial response 2 4 (13%) 1 CR and PR (response criteria) are the same for both studies 2 Unconfirmed partial responses are included in the overall response.

50 LUCID Study Schema Cycle 1 Rituximab Day 1: 50 mg/m 2 Day 3: 325 mg/m 2 Lumiliximab Day 2: 50 mg/m 2 Day 4: 325 or 450 g/m 2 Fludarabine Days 2-4: 25 mg/m 2 Cyclophosphamide Days 2-4: 250 mg/m 2 Cycles 2 to 6 Rituximab Day 1: 500 mg/m 2 Lumiliximab Day 1: 375 or 500 mg/m 2 Fludarabine Days 1-3: 25 mg/m 2 Cyclophosphamide Days 1-3: 250 mg/m 2 Follow-up through Month 48 Week 1 Weeks Month 48 Response Assessment Response Assessment

51 Activity of New Agents in Relapsed/Refractory CLL/SLL Drug Bendamustine Flavopiridol Lenalidomide Ofatumumab CR (%) ORR (%)

52 Conclusions Wealth of new agents for CLL/SLL Challenges Prioritization Study design Rituximab until resistant Rational combinations Essential to accrue patients to clinical trials