Patients with refractory chronic lymphocytic leukaemia (CLL) still have an unfavourable prognosis and novel treatment strategies are necessary, preferably adjusted to the patient’s individual situation. Refractoriness is no longer limited just to fludarabine (F) but extends to F-combinations with other chemotherapeutic agents (e.g. cyclophosphamide [C] and FC) and antibodies (e.g. rituximab [R], FR, and FCR). Also, refractoriness to alemtuzumab is an increasing problem. New pharmacological developments provide promising approaches. This review focuses on novel therapies such as monoclonal antibodies and small molecules aiming at specific targets of the CLL cell in the refractory situation. Approved therapeutic regimens will be presented as well as investigational approaches. An overview of completed and current clinical trials is offered.
AdamsS.MillerG.T.JessonM.I.WatanabeT.JonesB.WallnerB.P. (2004) PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res64: 5471–5480.
2.
AwanF.T.JohnsonA.J.LapalombellaR.HuW.LucasM.FischerB. (2010) Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. Leuk Lymphoma51: 27–38.
3.
BalakrishnanK.BurgerJ.A.WierdaW.G.GandhiV. (2009) AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood113: 149–153.
4.
BalakrishnanK.WierdaW.G.KeatingM.J.GandhiV. (2008) Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood112: 1971–1980.
5.
BestO.G.MulliganS.P. (2010) The Hsp90 Inhibitor SNX7081 restores the fludarabine sensitivity of chronic lymphocytic leukemia (CLL) cells harbouring mutations of ATM or TP53. Blood116: 2473–2473.
6.
ByrdJ.C.KippsT.J.FlinnI.W.CastroJ.LinT.S.WierdaW. (2009) Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood115: 489–495.
7.
ByrdJ.C.O'BrienS.FlinnI.W.KippsT.J.WeissM.RaiK. (2007) Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res13: 4448–4455.
8.
ByrdJ.C.ShinnC.WaselenkoJ.K.FuchsE.J.LehmanT.A.NguyenP.L. (1998) Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood92: 3804–3816.
9.
CastroJ.E.PradaC.E.LoriaO.KamalA.ChenL.BurrowsF.J. (2005) ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood106: 2506–2512.
10.
CastroJ.E.Sandoval-SusJ.D.BoleJ.RassentiL.KippsT.J. (2008) Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia22: 2048–2053.
11.
Chanan-KhanA.MillerK.C.MusialL.LawrenceD.PadmanabhanS.TakeshitaK. (2006) Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol24: 5343–5349.
12.
ChauletC.CroixC.AlagilleD.NormandS.DelwailA.FavotL. (2011) Design, synthesis and biological evaluation of new thalidomide analogues as TNF-alpha and IL-6 production inhibitors. Bioorg Med Chem Lett21: 1019–1022.
13.
ChenR.KeatingM.J.GandhiV.PlunkettW. (2005) Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood106: 2513–2519.
14.
ChenR.WierdaW.G.ChubbS.HawtinR.E.FoxJ.A.KeatingM.J. (2009) Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood113: 4637–4645.
15.
CoiffierB.LepretreS.PedersenL.M.GadebergO.FredriksenH.van OersM.H. (2008) Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood111: 1094–1100.
16.
ConroyA.StockettD.E.WalkerD.ArkinM.R.HochU.FoxJ.A. (2009) SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemother Pharmacol64: 723–732.
17.
CorralL.G.HaslettP.A.MullerG.W.ChenR.WongL.M.OcampoC.J. (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol163: 380–386.
18.
CotterF.E.AuerR.CorboM.McElwaineS.FrankelS.R. (2003) Oblimersen sodium (G3139) sensitizes malignant B-cells to alemtuzumab (Ab) induced apoptosis. Proc Am Soc Clin Oncol22: 910–910.
19.
DanilovA.V.KleinA.K.LeeH.J.BaezD.V.HuberB.T. (2005) Differential control of G0 programme in chronic lymphocytic leukaemia: a novel prognostic factor. Br J Haematol128: 472–481.
20.
De LuisiA.FerrucciA.ColucciaA.M.RiaR.MoschettaM.de LucaE. (2011) Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Resin press.
21.
DohnerH.FischerK.BentzM.HansenK.BennerA.CabotG. (1995) p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood85: 1580–1589.
22.
DungarwallaM.EvansS.O.RileyU.CatovskyD.DeardenC.E.MatutesE. (2008) High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica93: 475–476.
23.
FerrajoliA.LeeB.N.SchletteE.J.O'BrienS.M.GaoH.WenS. (2008) Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood111: 5291–5297.
24.
FlinnI.W.ByrdJ.C.BartlettN.KippsT.GribbenJ.ThomasD. (2005) Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leuk Res29: 1253–1257.
25.
FriedbergJ.W.SharmanJ.Schaefer-CutilloJ.JohnstonP.B.De VosS.LaCasceA. (2008) Fostaminib disodium (FosD), an oral inhibitor of Syk, is well-tolerated and has significant clinical activity in diffuse-large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (SLL/CLL). Blood112: 3–3.
26.
FurmanR.R.AndritsosL.FlinnI.W.Forero-TorresA.FoonK.A.PagelJ.M. (2010) Phase 1 dose escalation study of TRU-016, an anti-CD37 SMIP protein in relapsed and refractory CLL. Blood116: 56–56.
27.
HallekM.ChesonB.D.CatovskyD.Caligaris-CappioF.DighieroG.DohnerH. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood111: 5446–5456.
28.
HallekM.FischerK.Fingerle-RowsonG.FinkA.M.BuschR.MayerJ. (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet376: 1164–1174.
29.
HermanS.E.GordonA.L.WagnerA.J.HeeremaN.A.ZhaoW.FlynnJ.M. (2010) Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood116: 2078–2088.
30.
HertleinE.WagnerA.J.JonesJ.LinT.S.MaddocksK.J.TownsW.H.III (2010) 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood116: 45–53.
31.
JaglowskiS.M.ByrdJ.C. (2010) Rituximab in chronic lymphocytic leukemia. Semin Hematol47: 156–169.
32.
JohnsonA.J.WagnerA.J.CheneyC.M.SmithL.L.LucasD.M.GusterS.K. (2007) Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia. Br J Haematol139: 837–844.
33.
JonesB.AdamsS.MillerG.T.JessonM.I.WatanabeT.WallnerB.P. (2003) Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. Blood102: 1641–1648.
34.
JonesD.T.AddisonE.NorthJ.M.LowdellM.W.HoffbrandA.V.MehtaA.B. (2004) Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs. Blood103: 1855–1861.
35.
KeatingM.J.FlinnI.JainV.BinetJ.L.HillmenP.ByrdJ. (2002) Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood99: 3554–3561.
36.
KeatingM.J.KantarjianH.TalpazM.RedmanJ.KollerC.BarlogieB. (1989) Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood74: 19–25.
37.
KitadaS.ZapataJ.M.AndreeffM.ReedJ.C. (2000) Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood96: 393–397.
38.
KramanM.BambroughP.J.ArnoldJ.N.RobertsE.W.MagieraL.JonesJ.O. (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science330: 827–830.
39.
LamannaN.KalaycioM.MaslakP.JurcicJ.G.HeaneyM.BrentjensR. (2006) Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol24: 1575–1581.
40.
LanasaM.C.AndritsosL.BrownJ.R.GabriloveJ.Caligaris-CappioF.LarsonR. (2010) Interim analysis of EFC6663, a multicenter phase 2 study of alvocidib (flavopiridol), demonstrates clinical responses among patients with fludarabine refractory CLL. Blood116: 58–58.
41.
LiL.LiuX.GlassmanA.B.KeatingM.J.StrosM.PlunkettW. (1997) Fludarabine triphosphate inhibits nucleotide excision repair of cisplatin-induced DNA adducts in vitro. Cancer Res57: 1487–1494.
42.
LinK.RockliffeN.JohnsonG.G.SherringtonP.D.PettittA.R. (2008) Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells. Oncogene27: 2445–2455.
43.
LinT.S.RuppertA.S.JohnsonA.J.FischerB.HeeremaN.A.AndritsosL.A. (2009) Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol27: 6012–6018.
44.
LoomisR.CarboneR.ReissM.LacyJ. (2003) Bcl-2 antisense (G3139, Genasense) enhances the in vitro and in vivo response of Epstein–Barr virus-associated lymphoproliferative disease to rituximab. Clin Cancer Res9: 1931–1939.
45.
MarcucciG.StockW.DaiG.KlisovicR.B.LiuS.KlisovicM.I. (2005) Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol23: 3404–3411.
46.
MorschhauserF.CartronG.LamyT.MilpiedN.-J.ThieblemontC.TillyH. (2009) Phase I study of RO5072759 (GA101) in relapsed/refractory chronic lymphocytic leukemia. Blood114: 884–884.
47.
MossnerE.BrunkerP.MoserS.PuntenerU.SchmidtC.HerterS. (2010) Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood115: 4393–4402.
48.
NguyenM.MarcellusR.C.RoulstonA.WatsonM.SerfassL.Murthy MadirajuS.R. (2007) Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A104: 19512–19517.
49.
O'BrienS.MooreJ.O.BoydT.E.LarrattL.M.SkotnickiA.B.KozinerB. (2009a) 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol27: 5208–5212.
50.
O'BrienS.M.ClaxtonD.F.CrumpM.FaderlS.KippsT.KeatingM.J. (2009b) Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood113: 299–305.
51.
O'BrienS.M.CunninghamC.C.GolenkovA.K.TurkinaA.G.NovickS.C.RaiK.R. (2005) Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol23: 7697–7702.
52.
PathanN.I.ChuP.HariharanK.CheneyC.MolinaA.ByrdJ. (2008) Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23+ lymphoma cell lines. Blood111: 1594–1602.
53.
PhelpsM.A.LinT.S.JohnsonA.J.HurhE.RozewskiD.M.FarleyK.L. (2009) Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood113: 2637–2645.
54.
PicardD. (2002) Heat-shock protein 90, a chaperone for folding and regulation. Cell Mol Life Sci59: 1640–1648.
55.
RobertsA.W.SeymourJ.F.BrownJ.R.WierdaW.G.KippsT.J.CarneyD. (2009) An ongoing phase 1/2a study of ABT-263; pharmacokinetics (PK), safety and anti-tumor activity in patients (pts) with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood114: 883–883.
56.
StilgenbauerS.CymbalistaF.LeblondV.DelmerA.ZenzT.WinklerD. (2010) Subcutaneous alemtuzumab combined with oral dexamethasone, followed by alemtuzumab maintenance or allo-SCT in CLL with 17p- or refractory to fludarabine - interim analysis of the CLL2O trial of the GCLLSG and FCGCLL/MW. Blood116: 920–920.
57.
StilgenbauerS.ZenzT.WinklerD.BuhlerA.SchlenkR.F.GronerS. (2009) Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol27: 3994–4001.
58.
TaipaleM.JaroszD.F.LindquistS. (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol11: 515–528.
59.
TamC.S.O'BrienS.WierdaW.KantarjianH.WenS.DoK.A. (2008) Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood112: 975–980.
60.
TeelingJ.L.FrenchR.R.CraggM.S.van den BrakelJ.PluyterM.HuangH. (2004) Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood104: 1793–1800.
61.
TeelingJ.L.MackusW.J.WiegmanL.J.van den BrakelJ.H.BeersS.A.FrenchR.R. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol177: 362–371.
62.
TongW.G.ChenR.PlunkettW.SiegelD.SinhaR.HarveyR.D. (2010) Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol28: 3015–3022.
63.
TsimberidouA.M.KantarjianH.M.CortesJ.ThomasD.A.FaderlS.Garcia-ManeroG. (2003) Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer97: 1711–1720.
64.
TsimberidouA.M.WierdaW.G.PlunkettW.KurzrockR.O'BrienS.WenS. (2008) Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol26: 196–203.
65.
VoglerM.DinsdaleD.SunX.M.YoungK.W.ButterworthM.NicoteraP. (2008) A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells. Cell Death Differ15: 820–830.
66.
VoglerM.FurdasS.D.JungM.KuwanaT.DyerM.J.CohenG.M. (2010) Diminished sensitivity of chronic lymphocytic leukemia cells to ABT-737 and ABT-263 due to albumin binding in blood. Clin Cancer Res16: 4217–4225.
67.
WangY.F.CurtisJ.E.LiptonJ.MinkinS.McCullochE.A. (1991) Cytosine arabinoside (ara-C) and cis-dichlorodiammineplatinum II (cisplatin) alone and in combination: effects on acute myeloblastic leukemia blast cells in culture and in vivo. Leukemia5: 522–527.
68.
WierdaW.O'BrienS.WenS.FaderlS.Garcia-ManeroG.ThomasD. (2005) Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol23: 4070–4078.
69.
WierdaW.G.KippsT.J.MayerJ.StilgenbauerS.WilliamsC.D.HellmannA. (2010) Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol28: 1749–1755.
70.
WoyachJ.A.RuppertA.S.BlumK.A.JonesJ.A.FlynnJ.M.JohnsonA.J. (2010) Response, progression-free survival, and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) treated with flavopiridol: impact of poor risk cytogenetic abnormalities. Blood116: 2456–2456.
71.
ZenzT.EichhorstB.BuschR.DenzelT.HabeS.WinklerD. (2010) TP53 Mutation and survival in chronic lymphocytic leukemia. J Clin Oncolin press.
