Therapy of CLL - where are we going?

Transcription

1 CCK CancerCenterKarolinska Therapy of CLL - where are we going? An update on emerging therapeutic trends and safety aspects Anders Österborg Professor of Oncology Karolinska Institute and Hospital Stockholm, Sweden

2 CLL the old view B-CLL: just an indolent disease in elderly persons.? Accumulation of small clonal lymphocytes mature appearing Bone marrow not required for diagnosis and CT not required for staging Chlorambucil is sufficent, if treatment is at all needed

3 B-CLL: Only in the elderly? Incidence: 3 (2-4,5) / /year western hemisphere (>70 years: 50/ /year) Median age: The incidence is increasing in younger pts Now 20 30% diagnosed < 55 years

4 New CLL Biology results in new Prognostic tools in CLL: the list is growing. IGHV mutation status CD38, ZAP-70 CD49d Telomere length LPL TCL-1 CLL-U1 IGHV gene usage, such as IGHV3-21 (irrespective of stereotyped or not) Stereotyped receptors, especially if combined with certain gene families (ex IGHV4-34/IGKV2-30) Ki-67 in plasma NK-cell G2D receptors or ligands Angiopoetin-2 Gene polymorphisms (SNP) microrna (such as mir-34a, mir181b, mir-21, mir-222, in 17ppatients ) Or combinations to create a prognostic score

5 Risk-adapted therapy emerging: New prognostic markers: Recommendations outside trials FISH: before deciding on every line of CLL therapy p53 mutation test to be included in relapsed/refractory CLL Mutational status has limited impact on decision-making ZAP-70: await standardization (IHC may be used) CD38: not recommended Other new emerging markers: in clinical studies only Swedish CLL group 2011

6 Multi-agent First-line therapy may result in difficulties to choose optimal later-line therapies Aim of therapy: mabs IMiDS Complete remission Molecular remission Transplantation allo-ric R-FC Remission R-FCM Cure? Fludarabine R-Benda CdA Palliation CVP CFAR Chlorambucil Bendamustine A-FC?

7 First-line therapy, with CFAR as an example: Use most active drugs upfront?? n = 48 69% CR, ORR 94% (= similar to FCR) 17p- : 54% CR, 77% OR (FCR: 33% CR, 67% OR) Infections similar to FCR (except 18% CMV) Myelosuppr: similar to FCR, but fewer cycles then FCR due to long-lasting cytopenias in some patients PFS appears similiar to FCR Active and tolerated as 1st line, but not clearly better than FCR 1st line. To be used in 17p-? CFAR in Relapsed CLL: active and tolerated but does it add to current regimens? Wierda et al, submitted

8 Chlorambucil: still an option? Long-term survival analysis of the US Intergroup Study C9011 Comparing Fludarabine (Flu) and Chlorambucil (Chlor) in previously untreated patients with CLL p = 0.04 Rai et al, ASH 2009 (abstr. 536)

9 Evidence-based risk-adapted therapy: FC is better than F: evidence from 3 large randomized studies F FC p Eichhorst et al, Blood 2005 (n=375) OR rate (%) CR rate (%) TTTF (mo) Catovsky et al, Lancet 2007 (n=707) OR rate (%) CR rate (%) TTTF (mo) Neutro- and/or thrombocytopenia may be significant in elderly patients; F alone or dose reduction may be considered Data confirmed in the US intergroup trial (Flinn et al JCO 2007)

10 CLL8: Overall survival of FC vs FC-R 1.0 R-FC 87.2% Cumulative survival HR p = Time (years) FC 82.5% Hallek et al. Lancet 2010.

11 CLL8: CR in different genetic subgroups n FC (%) R-FC (%) Δ p value All patients x < q single x < q x < Trisomy x < p na 0.3 None x 0.27 Mutated IgV H x < Unmutated IgV H x < Note: 17p- patients has almost identical PFS with FC as with FCR Hallek et al. Lancet 2010.

12 FCR may not be an optimal choice in elderly patients (> 70 y) Among 280 patients with relapsed CLL treated at MDACC, only 13% of those >70 y achieved a CR >70 y were less likely to receive 6 courses (13%) Median TTF 14 mo and OS 22 mo Cytopenias and infections were common Badoux et al, iwcll 2009 (abstr 10.32)

13 French/European Cooperative Group CLL study on first-line therapy FCR vs FCA Combination of FC oral with rituximab or alemtuzumab <66 years, stages B & C, non del 17p FC-R vs. FC-A Primary endpoint: EFS at 3 years FC oral, 6 cycles : F: 40 mg/m 2 /d x 3 + C 250 mg/m 2 /d x 3 R: 375 mg/m 2 iv d1 C1, 500 mg/m 2 d1 C2 6 A: 30 mg sc day 1 3, cycle Trial stopped (Jan -09) due to increased number of deaths in the FC-A group - Other trials on alemtuzumab combinations have not observed similar toxicity

14 Ofatumumab + FC in previously untreated CLL: 407 study R A N D O M I Z E Treatment 500 mg O-FC q4wk 6 courses 1000 mg O-FC q4wk 6 courses Follow up At Month 1 after last course, Month 3 and q3mo thereafter Course Ofatumumab Fludarabine Cyclophosphamide mg d1 25 mg/m 2 IV d mg/m 2 IV d or 1000 mg d1 25 mg/m 2 IV d mg/m 2 IV d1 3 Wierda et al. Blood 2011, In press

15 O-FC in CLL: 1996 NCI-WG Responses Response, n (%) Ofatumumab 500 mg (N=31) Ofatumumab 1000 mg (N=30) Overall 24 (77) 22 (73) CR 10 (32) 15 (50) npr 1 (3) 1 (3) PR 13 (42) 6 (20) SD 3 (10) 2 (7) PD 2 (6) 5 (17) NE 2 (6) 1 (3) Wierda et al. Blood 2011, In press

16 Second line therapy??

17 NCCN Guidelines for Second-Line Treatment of CLL: not an easy choice! Establish treatment is indicated Cytogenetic evaluation CLL without 17p deletion* CLL with 17p deletion* Long response >3 years Short response <2 years Age 70 years Age <70, or older w/o significant co-morbidities Retreat as in first-line therapy until short response Chemoimmunotherapy Reduced-dose FCR Reduced-dose PCR Bendamustine ± R HDMP + R Chlorambucil ± prednisone Ofatumumab Dose-dense R Chemoimmunotherapy FCR PCR Bendamustine ± R F + Alemtuzumab CHOP-R HyperCVAD + R EPOCH + R OFAR Ofatumumab Alemtuzumab R HDMP + R CHOP + R FCR + alemtuzumab Hyper CVAD + R OFAR Ofatumumab Alemtuzumab R High-dose dexamethasone Bendamustine *Listed in order of preference.?????? 17

18 Bendamustine + rituximab: CLL2M study ORR: 80% Response N ORR CR Fludarabine sensitive Fludarabine refractory Cross-resistance vs FC or not??? Fisher K, et al. Blood (ASH Annual Meeting Abstracts). 2008;112. Abstract 330.

19 How to treat fludarabinerefractory CLL???

20 CLL Poor prognosis when F - refractory! Fludarabine-refractory CLL: Survival Overall survival (%) Failed alkylating agents Total Died Subgroup Initial diagnosis st therapy st fludarabine salvage fludarabine refractory Failed fludarabine Time (months) Keating et al, Leuk Lymph 2002

21 No place for rituximab as single agent therapy in advanced CLL Study No. Pts Response % Response Duration (mo) McLaughlin, et al ND Winkler, et al ND Nguyen, et al Huhn, et al Itälä, et al 5* *85% had a PR in lymph nodes, but only 11% had a tumor reduction in BM Note: Refractoriness to fludarabine was associated with a low OR rate (20%) even with dose intense rituximab (up to 2250 mg/m 2 ) 6 1 McLaughlin P, et al. J Clin Oncol. 1998;16: Huhn D, et al. Blood. 2001;98: Winkler U, et al. Blood. 1999;94: Itälä M, et al. Eur J Haematol. 2002;69: Nguyen DT, et al. Eur J Haematol. 1999;62: O Brien S, et al. J Clin Oncol. 201;19:

22 Selection of patients is crucial! Study Clinical effects of alemtuzumab as a single agent: Advanced disease Tumor type Disease phase No. of patients Response rate Response duration Österborg et al 1 B-CLL Alkylating-agent refractory 29 42% 12 mo Keating et al 2 B-CLL F-Refractory 93 33% 9 mo Rai et al 3 B-CLL F-Refractory % Not stated Lozanski et al 4 B-CLL F-Refractory, 17p % 8 mo Stilgenbauer et al 5 B-CLL F-Refractory, SC % 8 mo Karlsson et al 6 B-CLL F-Refractory, SC 30mg frontloading 20 75% 20 mo 1 Österborg et al. J Clin Oncol 1997;15: Keating et al. Blood 2002;99: Rai et al. Blood 2002;100: abstr Lozanski et al. Blood 2004;103: Stilgenbauer et al. J Clin Oncol 2009;24: Karlsson et al, Br J Haematol 2009;144:78-85

23 Selection of patients: Lymph nodes Lymphadenopathy predicts poor response to alemtuzumab in refractory CLL but not in 1st line treated patients Partial response No response Complete response Reason why lymph nodes are less sensitive remains unclear

24 Overall survival with salvage therapy in multi-agent refractory CLL: MDACC data Double-refractory: both to fludarabine and alemtuzumab Tam el al, Leuk Lymphoma 2007

25 Salvage therapy in refractory CLL Need for active, new agents Poor prognosis for fludarabine-refractory CLL 1 Median OS: 10 mo No standard treatment option if also refractory to alemtuzumab, or with bulky lymph nodes 2 Response with salvage regimens ORR 20-26%; median TTF 2-3 mo ORR 0% with antibody therapies Median OS: 8 mo and 14 mo, respectively Major infections: 60% and 45%, respectively How would you treat such a patient?? 1. Keating et al. Leuk Lymphoma 2002; 43: Tam et al. Leuk Lymphoma 2007; 48:1931.

26 Ofatumumab: characteristics 1,2 Ofatumumab binding site Rituximab binding site Human CD20 mab Binds a small-loop epitope of CD20 Potent lysis of B cells More effective in vitro CDC versus rituximab Effective CDC of cells with low CD20 expression, including CLL cells Promising activity in pilot CLL study: ORR 50% in high-dose group (n=27) 3 1. Teeling et al. J Immunol 2006: 177; Teeling et al. Blood 2004: 104; Coiffier et al. Blood 2008; 111:

27 Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, is an Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of an International Pivotal Trial Anders Österborg, Thomas Kipps, Jiří Mayer, Stephan Stilgenbauer, Cathy D Williams, Andrzej Hellmann, Tadeusz Robak, Richard Furman, Peter Hillmen, Marek Trneny, Martin Dyer, Swami Padmanabhan, Magdalena Piotrowska, Tomas Kozak, Geoffrey Chan, Randy Davis, Nedjad Losic, Charlotte Russell, Joris Wilms, and William G Wierda, on behalf of the 406 Study Investigators 27 ASH 2008 (abstr), and Wierda et al, JCO 2010

28 Final Analysis From the International Trial of Single-agent Ofatumumab in Patients with Fludarabine-refractory Chronic Lymphocytic Leukemia Results From a Single-arm, Multicenter, International, Phase III Trial William Wierda, Thomas Kipps, Jiří Mayer, Tadeusz Robak, Martin Dyer, Richard Furman, Peter Hillmen, Stephan Stilgenbauer, Catherine Williams, Marek Trneny, Guillaume Cartron, Francisco Hernandez-Ilizaliturri, Swaminathan Padmanaban, Geoffrey Chan, Ira Gupta, Jennifer Phillips, Randy Davis, Nedjad Losic, Steen Lisby and Anders Österborg on behalf of the HuMax-CD Study Investigators 28

29 Ofatumumab in refractory CLL Objectives and key inclusion criteria Multicenter, open-label, single-arm study: Europe and US Overall study objectives: efficacy and safety Patient population: Double-Refractory (DR) Refractory to fludarabinecontaining regimen ( 2 cycles) Refractory to alemtuzumabcontaining regimen ( 12 doses) Bulky Fludarabine-Refractory (BFR) Refractory to fludarabinecontaining regimen ( 2 cycles) Inappropriate for alemtuzumab due to bulky nodes (>5 cm) No upper age limit ECOG performance status 0 to 2 No exclusions for severe cytopenias 29

30 Ofatumumab in refractory CLL Treatment schedule Screening, Baseline characteristics Ofatumumab 300 mg Ofatumumab 2000 mg Week Pre-medication: Paracetamol (acetaminophen) 1 g PO or eq. Antihistamine (cetirizine) 10 mg PO or eq. Glucocorticoid (prednisolone) 100 mg IV or eq. Median no. of infusions: 12 (range, 1 12) for both groups 30

31 Ofatumumab in refractory CLL Baseline characteristics (N=206) Characteristic FA-ref n=95 BF-ref n=111 Male, % Median age, years (range) 64 (41 86) 64 (43 87) Rai stage III IV, % Binet stage C, % ECOG PS 1 or 2, % Median # of prior therapies (range) 5 (1 14) 4 (1 16) Prior rituximab exposure, % Refractory to prior rituximab, %

32 CI, confidence interval Ofatumumab in refractory CLL Objective responses by IRC evaluation 100 ORR (%) %* 44%* 95% CI 20 0 FA-ref (n=95) BF-ref (n=111) H 0 : ORR = 15% *P< versus H 0 (two-sided exact test) 32

33 Ofatumumab in refractory CLL Time to response and duration Time to response* Duration of response 2.7 mo 3.8 mo 5.7 mo 6.0 mo *Time from start of treatment to response; Time from initial response to progression (assessed by IRC) or death 33

34 Ofatumumab in refractory CLL Response by baseline characteristics FA-ref (n=95) BF-ref n=111) Subgroup n* ORR, % n* ORR, % Prior rituximab No prior rituximab Refractory to FCR Other 5 prior therapies <5 prior therapies *Patient numbers do not add up to n=95 and n=111 for some categories due to missing assessments; FCR or FCMR

35 Ofatumumab in refractory CLL Response by baseline characteristics FA-ref (n=95) BF-ref(n=111) Subgroup n* ORR, % n* ORR, % Age 70 yrs Age <70 yrs Rai stage III IV Rai stage I II 17p del No 17p del 11q del No 11q del *Patient numbers do not add up to n=95 and n=111 for some categories due to missing assessments; P<.05 Fisher s exact test 35

36 Ofatumumab in refractory CLL Median overall survival by response Landmark analysis 1 at Week 12* FA-ref group BF-ref group 23 mo 27.6 mo 10.2 mo 15.5 mo *Analysis included patients who were alive at the Week 12 time point 1. Anderson et al. J Clin Oncol 2008;26:

37 Ofatumumab in refractory CLL Infusion-related reactions* by course Subjects with infusion reactions (%) Grade 3 Grade Treatment cycle Safety analysis population includes 17 patients not included in efficacy analyses; *Infusion-related reactions reported after the start of infusion and up to 24 hours thereafter; No grade 4 5 events were reported, 2 patients were withdrawn due to infusion reactions 37

38 Ofatumumab in refractory CLL Hemoglobin over time* Treatment period Follow-up Screening *By lab assessment 38

39 Ofatumumab in refractory CLL Platelet count over time* Treatment period Follow-up Screening *By lab assessment 39

40 Efficacy and safety of ofatumumab versus historic data 1* Tam et al* Tam et al* DR (n=59) DR (n=54) (n=11 mab only) BFR (n=79) BFR (n=39) (n=3 mab only) ORR 58% 20% 47% 26% CR 0% (0%) 1% (0%) Median PFS, mos Median OS, mos Death within 8 wks Major infections 5.7 TTF TTF % 16% 3% 10% 25% 60% 25% 45% *Data from retrospective study; TTF=time to treatment failure 1. Tam et al. Leuk Lymphoma 2007;48(10):1931.

41 My Conclusions: First- and 2nd line therapy in CLL FCR is the new standard therapy in younger, fit CLL patients without 17p- or TP53 mutation FC or chlorambucil are still cornerstones in the treatment of CLL patients who are older than 70 years Bendamustine: cross-resistance vs FC or not? Alemtuzumab: use as 1st line if 17p- or TP53 mut. 2nd line therapy: choice depends very much on choice/effect of 1st line therapy and the results of FISH testing

42 Ofatumumab in refractory CLL Conclusions Ofatumumab monotherapy has high response rate in highrisk, refractory CLL ORR: 51% for FA-ref; 44% for BF-ref Efficacy independent of prior rituximab, age, stage, and number of prior regimens Responses in 17p del and 11q del subgroups Well tolerated, with no unexpected adverse events Clinical benefit demonstrated; results superior to historic outcomes with salvage therapies in this setting 1 Ongoing investigations in earlier stage, novel combinations, and maintenance 1. Tam et al. Leuk Lymphoma 2007;48:

43 and finally the magic bullets arrive broadly! ocrelizumab,ga101 ofatumumab,tru-015, rituximab, AME-133v, PRO131921, tositumab, veltuzumab, TCR CD4/8 zanolimumab epratuzumab Lym-1, apolizumab lumiliximab CD22 HLA-DR CD23 B cell T cell CD3 CD25 Ontak, daclizumab galiximab alemtuzumab CD80 CD52 CD52 alemtuzumab milatuzumabimmunoliposomes CD74 CD38? Ror-1? dacetuzumab samalizumab TRU-016 (SMIP)

44 CLL: targets and small molecule inhibitors in pipeline Lenalidomide CDK inhibition: flavipiridol, SCH Bcl-2 inhibition: oblimersen, ABT-263 PKC inhibition: enzastaurin PI3-K inhibition: MVP-BEZ235, CAL-101 mtor inhibition: siro-, temsiro- and everolimus HDAC-inhibitors: vorinostat (SAHA), valproic acid HSP 90/ZAP-70 inhibitors: CNF 2024, SNX7081 p53 restoration/activation: Nutlin-3, PRIMA PARP (ATM): AZD2881 SRC/ABL RTK inhibitor: dasatinib VEGF inhibition: sorafenib Lyn kinase inhibition: dasatinib, bafetinib MTA (microtubule targeting agents): PBOX-15 SYK inhibition: fostamatinib BTK inhibition: PCI ROR-1: Wnt-5a inhibitors

45 and what about the signal transduction machinery? "And what about the signal transduction machinery?"

46 Paul Ehrlich, 1890: Antibodies as magic bullets

47 ..Thank you for your attention! On tour in the archipelago of Stockholm