CLL2-BXX Phase II Trials: Sequential, Targeted Treatment for Eradication of Minimal Residual Disease in Chronic Lymphocytic Leukemia

References

• Eichhorst BF , BuschR, StilgenbauerSet al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood114(16), 3382–3391 (2009).
   PubMed Web of Science ®Google Scholar
• Han T , EzdinliEZ, ShimaokaK, DesaiDV. Chlorambucil vs. combined chlorambucil–corticosteroid therapy in chronic lymphocytic leukemia. Cancer31(3), 502–508 (1973).
   PubMed Web of Science ®Google Scholar
• Knospe WH , LoebVJr. Biweekly chlorambucil treatment of lymphocytic lymphoma. Clin. Trials3(4), 329–336 (1980).
   Web of Science ®Google Scholar
• Eichhorst BF , BuschR, HopfingerGet al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood107(3), 885–891 (2006).
   PubMed Web of Science ®Google Scholar
• Flinn IW , NeubergDS, GreverMRet al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J. Clin. Oncol.25(7), 793–798 (2007).
   PubMed Web of Science ®Google Scholar
• Catovsky D , RichardsS, MatutesEet al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial. Lancet370(9583), 230–239 (2007).
   PubMed Web of Science ®Google Scholar
• Hallek M , FischerK, Fingerle-RowsonGet al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, Phase III trial. Lancet376(9747), 1164–1174 (2010).
   PubMed Web of Science ®Google Scholar
• Fischer K , BahloJ, FinkAMet al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood127(2), 208–215 (2016).
   PubMed Web of Science ®Google Scholar
• Goede V , FischerK, BuschRet al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N. Engl. J. Med.370(12), 1101–1110 (2014).
   PubMed Web of Science ®Google Scholar
• Goede V , FischerK, EngelkeAet al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia29(7), 1602–1604 (2015).
   PubMed Web of Science ®Google Scholar
• Byrd JC , RaiK, PetersonBLet al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood105(1), 49–53 (2005).
   PubMed Web of Science ®Google Scholar
• Eichhorst B , FinkAM, BahloJet al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, Phase III, non-inferiority trial. Lancet Oncol.17(7), 928–942 (2016).
   PubMed Web of Science ®Google Scholar
• Robak T , DmoszynskaA, Solal-CelignyPet al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J. Clin. Oncol.28(10), 1756–1765 (2010).
   PubMed Web of Science ®Google Scholar
• Tam CS , O’BrienS, WierdaWet al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood112(4), 975–980 (2008).
   PubMed Web of Science ®Google Scholar
• Herman SE , GordonAL, WagnerAJet al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood116(12), 2078–2088 (2010).
   PubMed Web of Science ®Google Scholar
• Maddocks K , JonesJA. Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia. Semin. Oncol.43(2), 251–259 (2016).
   PubMed Web of Science ®Google Scholar
• Byrd JC , BrownJR, O’BrienSet al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med.371(3), 213–223 (2014).
   PubMed Web of Science ®Google Scholar
• Furman RR , SharmanJP, CoutreSEet al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med.370(11), 997–1007 (2014).
   PubMed Web of Science ®Google Scholar
• Byrd JC , FurmanRR, CoutreSEet al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med.369(1), 32–42 (2013).
   PubMed Web of Science ®Google Scholar
• O’Brien S , JonesJA, CoutreSEet al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a Phase III, open-label, multicentre study. Lancet Oncol.17(10), 1409–1418 (2016).
   PubMed Web of Science ®Google Scholar
• Byrd JC , FurmanRR, CoutreSEet al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood125(16), 2497–2506 (2015).
   PubMed Web of Science ®Google Scholar
• O’Brien S , FurmanRR, CoutreSEet al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, Phase Ib/II trial. Lancet Oncol.15(1), 48–58 (2014).
   PubMed Web of Science ®Google Scholar
• Jones JA , RobakT, BrownJRet al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised Phase III trial. Lancet Haematol.4(3), e114–e126 (2017).
   PubMed Web of Science ®Google Scholar
• Zelenetz AD , BarrientosJC, BrownJRet al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a Phase III, randomised, double-blind, placebo-controlled trial. Lancet Oncol.18(3), 297–311 (2017).
   PubMed Web of Science ®Google Scholar
• O’Brien SM , LamannaN, KippsTJet al. A Phase II study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood126(25), 2686–2694 (2015).
   PubMed Web of Science ®Google Scholar
• Burger JA , KeatingMJ, WierdaWGet al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, Phase II study. Lancet Oncol.15(10), 1090–1099 (2014).
   PubMed Web of Science ®Google Scholar
• Cory S , AdamsJM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer2(9), 647–656 (2002).
   PubMed Web of Science ®Google Scholar
• Scarfo L , GhiaP. Reprogramming cell death: BCL2 family inhibition in hematological malignancies. Immunol. Lett.155(1–2), 36–39 (2013).
   PubMed Web of Science ®Google Scholar
• Roberts AW , SeymourJF, BrownJRet al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a Phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol.30(5), 488–496 (2012).
   PubMed Web of Science ®Google Scholar
• Souers AJ , LeversonJD, BoghaertERet al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med.19(2), 202–208 (2013).
   PubMed Web of Science ®Google Scholar
• Fischer K , Al-SawafO, FinkAMet al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood129(19), 2702–2705 (2017).
   PubMed Web of Science ®Google Scholar
• Roberts AW , StilgenbauerS, SeymourJF, HuangDC. Venetoclax in patients with previously treated chronic lymphocytic leukemia.Clin. Cancer Res.23(16), 4527–4533 (2017).
   PubMed Web of Science ®Google Scholar
• Stilgenbauer S , EichhorstB, ScheteligJet al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, Phase II study. Lancet Oncol.17(6), 768–778 (2016).
   PubMed Web of Science ®Google Scholar
• Hallek M , ChesonBD, CatovskyDet al. 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(12), 5446–5456 (2008).
   PubMed Web of Science ®Google Scholar
• Hallek M , ChesonB, CatovskyDet al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes. Blood doi:https://doi.org/10.1182/blood-2007-06-093906 (2012).
   Google Scholar
• Burger JA , LiK, KeatingMet al. Functional evidence from deuterated water labeling that the Bruton tyrosine kinase inhibitor ibrutinib blocks leukemia cell proliferation and trafficking and promotes leukemia cell death in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. Blood124(21), 326 (2014).
   Web of Science ®Google Scholar
• Davids MS , BrownJR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk. Lymphoma53(12), 2362–2370 (2012).
   PubMed Web of Science ®Google Scholar
• Hoellenriegel J , MeadowsSA, SivinaMet al. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood118(13), 3603–3612 (2011).
   PubMed Web of Science ®Google Scholar
• Herman SE , GordonAL, HertleinEet al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood117(23), 6287–6296 (2011).
   PubMed Web of Science ®Google Scholar
• Dreger P , ScheteligJ, AndersenNet al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 124(26), 3841–3849 (2014).
   PubMed Web of Science ®Google Scholar
• Sharman JP , CoutreSE, FurmanRRet al. Second interim analysis of a Phase III study of idelalisib (ZYDELIG®) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood124(21), 330 (2014).
   Web of Science ®Google Scholar
• Woyach JA , FurmanRR, LiuTMet al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N. Engl. J. Med.370(24), 2286–2294 (2014).
   PubMed Web of Science ®Google Scholar
• Liu TM , WoyachJA, ZhongYet al. Hypermorphic mutation of phospholipase C, gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood126(1), 61–68 (2015).
   PubMed Web of Science ®Google Scholar
• Burger JA , LandauDA, Taylor-WeinerAet al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat. Commun.7, 11589 (2016).
   PubMed Web of Science ®Google Scholar
• Landau DA , TauschE, Taylor-WeinerANet al. Mutations driving CLL and their evolution in progression and relapse. Nature526(7574), 525–530 (2015).
   PubMed Web of Science ®Google Scholar
• Hallek M . Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood122(23), 3723–3724 (2013).
   PubMed Web of Science ®Google Scholar
• Fischer K , CramerP, BuschRet al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter Phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol.30(26), 3209–3216 (2012).
   PubMed Web of Science ®Google Scholar
• Fischer K , CramerP, BuschRet al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter Phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol.29(26), 3559–3566 (2011).
   PubMed Web of Science ®Google Scholar
• Knauf WU , LissitchkovT, AldaoudAet al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized Phase III trial. Br. J. Haematol.159(1), 67–77 (2012).
   PubMed Web of Science ®Google Scholar
• Hillmen P , FurmanR, CoutreSet al. Pre-treatment with idelalisib markedly reduces rituximab infusion-related reactions and infusion interruptions in patients with CLL. EHA Annual Meeting. Milan, Italy, 12–15 June 2014 ( Poster 236).
   Google Scholar
• Sehn LH , GoyA, OffnerFCet al. Randomized Phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J. Clin. Oncol.33(30), 3467–3474 (2015).
   PubMed Web of Science ®Google Scholar
• Sehn LH , ChuaN, MayerJet al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, Phase III trial. Lancet Oncol.17(8), 1081–1093 (2016).
   PubMed Web of Science ®Google Scholar
• Kluin-Nelemans HC , HosterE, HermineOet al. Treatment of older patients with mantle-cell lymphoma. N. Engl. J. Med.367(6), 520–531 (2012).
   PubMed Web of Science ®Google Scholar
• Flinn IW , RuppertAS, HarwinWet al. A Phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic, previously untreated chronic lymphocytic leukemia. Am. J. Hematol.91(10), 1020–1025 (2016).
   PubMed Web of Science ®Google Scholar
• Van Oers MH , KuliczkowskiK, SmolejLet al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised Phase III study. Lancet Oncol.16(13), 1370–1379 (2015).
   PubMed Web of Science ®Google Scholar
• Bottcher S , StilgenbauerS, BuschRet al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis. Leukemia23(11), 2007–2017 (2009).
   PubMed Web of Science ®Google Scholar
• Bottcher S , RitgenM, FischerKet al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J. Clin. Oncol.30(9), 980–988 (2012).
   PubMed Web of Science ®Google Scholar
• Kovacs G , RobrechtS, FinkAMet al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis of two Phase III studies of the German CLL study group. J. Clin. Oncol.34(31), 3758–3765 (2016).
   PubMed Web of Science ®Google Scholar
• Bottcher S . Paving the road to MRD-guided treatment in CLL. Blood123(24), 3683–3684 (2014).
   PubMed Web of Science ®Google Scholar
• Strati P , KeatingMJ, O’BrienSMet al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood123(24), 3727–3732 (2014).
   PubMed Web of Science ®Google Scholar
• von Tresckow J , CramerP, BahloJet al. CLL2-BIG – a novel treatment regimen of bendamustine followed by GA101 and ibrutinib followed by ibrutinib and GA101 maintenance in patients with chronic lymphocytic leukemia (CLL): interim results of a Phase II-trial. Blood126(23), 4151 (2015).
   Web of Science ®Google Scholar
• Cramer P , von TresckowJ, BahloJet al. Low incidence of tumor lysis syndromes (TLS) and infusion related reactions (IRR) in the CLL2-BAG trial evaluating a sequential treatment of bendamustine (B), obinutuzumab (GA101, G) and venetoclax (ABT-199, A) in patients with chronic lymphocytic leukemia (CLL): interim safety results of a Phase-II-trial of the German CLL study group (GCLLSG). Blood126(24), 2646–2659 (2016).
   Google Scholar
• von Tresckow J , CramerP, BahloJet al. CLL2-BIG – a novel treatment regimen of bendamustine followed by GA101 and ibrutinib followed by ibrutinib and GA101 maintenance in patients with chronic lymphocytic leukemia (CLL): results of a Phase II-trial. Blood126(23), 4151 (2016).
   Web of Science ®Google Scholar