New Agents in Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports

Volumn 5, Issue 1, 2010, Pages 29-34

  Lin, Thomas S ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Chronic lymphocytic leukemia; CLL; Phase I studies

Indexed keywords

4 [4 [2 (4 CHLOROPHENYL) 5,5 DIMETHYL 1 CYCLOHEXEN 1 YLMETHYL] 1 PIPERAZINYL] N [4 [3 MORPHOLINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 (TRIFLUOROMETHYLSULFONYL)BENZENESULFONYL]BENZAMIDE; ALEMTUZUMAB; ANTINEOPLASTIC AGENT; CAL 101; CD37 ANTIGEN; CYCLOPHOSPHAMIDE; FLAVOPIRIDOL; FLUDARABINE; FOSTAMATINIB; LENALIDOMIDE; OBATOCLAX; OBLIMERSEN; OFATUMUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; PROTEIN KINASE SYK; PROTEIN KINASE ZAP 70; RITUXIMAB; TRU 016; UNCLASSIFIED DRUG; VELTUZUMAB;

AMINOTRANSFERASE BLOOD LEVEL; ANTINEOPLASTIC ACTIVITY; ATAXIA; BLOOD TOXICITY; BONE MARROW SUPPRESSION; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL TRIAL; CONTINUOUS INFUSION; CYTOKINE RELEASE; DOSAGE SCHEDULE COMPARISON; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG DOSE REGIMEN; DRUG ERUPTION; DRUG FATALITY; DRUG INTERMITTENT THERAPY; DRUG RESPONSE; DRUG SAFETY; DRUG SELECTIVITY; DRUG TARGETING; DRUG TOLERABILITY; DYSPHORIA; EUPHORIA; FATIGUE; HUMAN; HYPERGLYCEMIA; HYPOXIA; LOW DRUG DOSE; MULTIPLE CYCLE TREATMENT; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; OPTIMAL DRUG DOSE; PROTEIN EXPRESSION; REVIEW; SEPSIS; SIDE EFFECT; SOMNOLENCE; THROMBOCYTOPENIA; TUMOR FLARE; TUMOR LYSIS SYNDROME; UNSPECIFIED SIDE EFFECT;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; DRUG DELIVERY SYSTEMS; DRUGS, INVESTIGATIONAL; FLAVONOIDS; HUMANS; IMMUNOLOGIC FACTORS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; NEOPLASM PROTEINS; PIPERIDINES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-BCL-2; THALIDOMIDE;

EID: 76649092619     PISSN: 15588211     EISSN: 1558822X     Source Type: Journal    
DOI: 10.1007/s11899-009-0039-9     Document Type: Review

References (32)

1. A Chanan-Khan KC Miller L Musial, et al. 2006 Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study J Clin Oncol 24 5343 5349 10.1200/JCO.2005.05.0401 1:CAS:528:DC%2BD2sXisVSjtg%3D%3D 17088571 (Pubitemid 46623164)
2. A Ferrajoli BN Lee EJ Schlette, et al. 2008 Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia Blood 111 5291 5297 10.1182/blood-2007-12-130120 1:CAS:528:DC%2BD1cXntFWnsr4%3D 18334676 This paper describes a phase 2 study that highlighted the clinical activity of lenalidomide in relapsed CLL, but also the hematologic toxicity and tumor flare reaction observed with its use.
3. Ferrajoli A, Keating MJ, Wierda WG, et al.: Lenalidomide is active in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) carrying unfavorable chromosomal abnormalities [abstract]. Blood (ASH Annual Meeting Abstracts) 2007, 110:Abstract 754.
4. Wendtner CM, Mahadevan D, Stilgenbauer S, et al.: Preliminary results of a phase 1/2, multi-center, open-label study (CLL-001) investigating a stepwise dose-escalation schedule of lenalidomide in relapsed or refractory chronic lymphocytic leukemia [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 2104.
5. LA Andritsos AJ Johnson G Lozanski, et al. 2008 Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia J Clin Oncol 26 2519 2525 10.1200/JCO.2007.13.9709 1:CAS:528:DC%2BD1cXnsVKhurg%3D 18427150
6. C Chen H Paul W Xu, et al. 2008 A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL) [abstract 44] Blood 112 23
7. Ferrajoli A, O'Brien S, Wierda W, et al.: Lenalidomide as initial treatment of elderly patients with chronic lymphocytic leukemia (CLL) [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 45.
8. TS Lin OM Howard DS Neuberg, et al. 2002 Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma Leuk Lymphoma 43 793 797 10.1080/10428190290016908 1:CAS:528:DC%2BD38XntVarsrs%3D 12153166 (Pubitemid 34428666)
9. IW Flinn JC Byrd N Bartlett, et al. 2005 Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity Leuk Res 29 1253 1257 10.1016/j.leukres.2005.03.010 1:CAS:528:DC%2BD2MXhtVWgs7%2FL 15916806 (Pubitemid 41297636)
10. JC Byrd BL Peterson J Gabrilove, et al. 2005 Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805 Clin Cancer Res 11 4176 4181 10.1158/1078-0432.CCR-04-2276 1:CAS:528: DC%2BD2MXks1GksL8%3D 15930354 (Pubitemid 40791583)
11. BA Christian B Fischer KA Blum, et al. 2007 Flavopiridol in chronic lymphocytic leukemia (CLL) Clin Leuk 1 292 297 10.3816/CLK.2007.n.020 1:CAS:528:DC%2BD2sXhtlCqsLrE
12. BA Christian MR Grever JC Byrd TS Lin 2007 Flavopiridol in the treatment of chronic lymphocytic leukemia Curr Opin Oncol 19 573 578 10.1097/CCO. 0b013e3282efb9da 1:CAS:528:DC%2BD2sXhtFSnu7zL 17906454 (Pubitemid 47508863)
13. JC Byrd TS Lin JT Dalton, et al. 2007 Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia Blood 109 399 404 10.1182/blood-2006-05-020735 1:CAS:528:DC%2BD2sXivVyktbk%3D 17003373 (Pubitemid 46105932)
14. MA Phelps TS Lin AJ Johnson, et al. 2009 Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia Blood 113 2637 2645 10.1182/blood-2008-07-168583 1:CAS:528:DC%2BD1MXjslSku7c%3D 18981292
15. • Lin TS, Ruppert AS, Johnson AJ, et al.: Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 2009 Oct 13 (Epub ahead of print) This paper summarizes a phase 2 study confirming the clinical activity of flavopiridol in genetically high-risk relapsed CLL and describes modifications to the dosing schedule to reduce cytokine release syndrome symptoms, improve tolerability, and improve treatment delivery.
16. Lin TS, Heerema NA, Lozanski G, et al.: Flavopiridol (alvocidib) induces durable responses in relapsed chronic lymphocytic leukemia (CLL) patients with high-risk cytogenetic abnormalities [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 46.
17. Lin TS, Blum KA, Fischer B, et al.: Flavopiridol, fludarabine and rituximab (FFR) is an active regimen in mantle cell lymphoma, indolent B-cell lymphomas and chronic lymphocytic leukemia. J Clin Oncol 2010 (in press).
18. BA Christian TS Lin 2008 Antibody therapy for CLL Semin Hematol 45 95 103 10.1053/j.seminhematol.2008.02.001 1:CAS:528:DC%2BD1cXmvV2ltb0%3D 18381104
19. JL Teeling RR French MS Cragg, et al. 2004 Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas Blood 104 1793 1800 10.1182/blood-2004-01-0039 1:CAS:528: DC%2BD2cXns1Oktbc%3D 15172969 (Pubitemid 39202289)
20. B Coiffier S Lepretre LM Pedersen, et al. 2008 Safety and efficacy of ofatumumab, a fully humanized monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: A phase 1-2 study Blood 111 1094 1100 10.1182/blood-2007-09-111781 1:CAS:528:DC%2BD1cXhvFejsbs%3D 18003886 (Pubitemid 351213387)
21. Osterborg A, Kipps TJ, Mayer J, et al.: 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 [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 328.
22. Allen SL, Rai KR, Elstrom R, et al.: Subcutaneous injections of low doses of veltuzumab (humanized anti-CD20 antibody): objective responses in B-cell malignancies. J Clin Oncol 2009, 27 (suppl):Abstract 8530.
23. S O'Brien CC Cunningham AK Golenkov, et al. 2005 Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia J Clin Oncol 23 7697 7702 10.1200/JCO.2005.02.4364 16186597 (Pubitemid 46291834)
24. S O'Brien JO Moore TE Boyd, et al. 2007 Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia J Clin Oncol 25 1114 1120 10.1200/JCO.2006.07.1191 17296974 (Pubitemid 46596764)
25. O'Brien S, Wu J, Novick SC, Rai KR: 5-year follow-up of patients with relapsed/refractory CLL treated with standard chemotherapy with or without oblimersen in randomized phase III trial: prognostic factors and predictive factors for treatment effect [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 4201.
26. SM O'Brien DF Claxton M Crump, et al. 2009 Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia Blood 113 299 305 10.1182/blood-2008-02-137943 18931344
27. C Tse AR Shoemaker J Adickes, et al. 2008 ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor Cancer Res 68 3421 3428 10.1158/0008-5472. CAN-07-5836 1:CAS:528:DC%2BD1cXltlSltrs%3D 18451170
28. Wilson WH, O'Connor OA, Roberts AW, et al.: ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) [abstract]. J Clin Oncol 2009, 27(suppl):Abstract 8574.
29. Andritsos LA, Furman RR, Flinn IW, et al.: A phase I trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SMIP) in relapsed and refractory CLL [abstract]. J Clin Oncol 2009, 27(suppl):Abstract 3017.
30. Friedberg JW, Sharman J, Schaefer-Cutillo J, et al.: Fostamatinib 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) [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 3.
31. May SE, Kashishian A, Lin TS, et al.: CAL-101, a selective inhibitor of the p110d isoform of phosphatidylinositol 3-kinase, effectively induces apoptosis in primary chronic lymphocytic leukemia cells providing a novel therapeutic strategy for the treatment of this disease [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:Abstract 3165.
32. Flinn IW, Byrd JC, Furman RR, et al.: Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p110d isoform of phosphatidylinositol 3-kinase (PI3K), in patients with select hematologic malignancies. J Clin Oncol 2009, 27 (suppl):Abstract 3543.