Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study.
Resistance to chemotherapy-induced apoptosis in CLL is associated with overexpression of antiapoptotic proteins induced by signals from the microenvironment. In vitro, dasatinib effectively inhibits expression of anti-apoptotic regulators and restores fludarabine sensitivity in activated CLL. The aim of this study was to evaluate efficacy of one cycle of dasatinib monotherapy (100mg/day, days 1-28) followed by combination of dasatinib with fludarabine (40mg/m²/day, days 1-3 every 28 day) for a total of 6 cycles in fludarabine-refractory CLL. The primary endpoint was overall response rate according to the IWCLL'08 criteria. 20 patients were enrolled: 18 completed at least one cycle of treatment of which 67% finished at least 2 cycles of combination treatment. 3 of these 18 patients reached a formal PR (16.7%). Majority of patients obtained some reduction in lymph node (LN) size. Most frequent toxicity was related to myelosuppression. NF-κB RNA expression levels of circulating CLL cells decreased whereas the levels of pro-apoptotic NOXA increased during treatment. In conclusion, dasatinib/fludarabine combination has modest clinical efficacy in fludarabine-refractory patients.
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands; LYMMCARE (Lymphoma and Myeloma Center Amsterdam), The Netherlands. Electronic address: a.p.kater@amc.nl.
Arnon P
AP
Kater
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
Marjolein
M
Spiering
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
Roberto D
RD
Liu
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
G
G
Doreen Te Raa
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
E
E
Slinger
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands; LYMMCARE (Lymphoma and Myeloma Center Amsterdam), The Netherlands.
Sanne H
SH
Tonino
University Medical Centre Groningen, The Netherlands.
Marielle M
MM
Beckers
University Medical Centre Groningen, The Netherlands.
Simon
S
Daenen
Erasmus Medical Centre, Rotterdam, The Netherlands.
Jeanette K
JK
Doorduijn
Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nienke A G
NA
Lankheet
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
Dieuwertje M
DM
Luijks
Laboratory of Experimental Medicine, Academic Medical Centre, Amsterdam, The Netherlands; LYMMCARE (Lymphoma and Myeloma Center Amsterdam), The Netherlands.
Eric
E
Eldering
Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands; LYMMCARE (Lymphoma and Myeloma Center Amsterdam), The Netherlands.
Marinus H J
MH
van Oers
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069439:Dasatinib; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D009325:Nausea / Q000139:chemically induced; D011014:Pneumonia / Q000139:chemically induced; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
D016328:NF-kappa B; D011743:Pyrimidines; D013844:Thiazoles; D014740:Vidarabine; C024352:fludarabine; D000069439:Dasatinib
CLL; Dasatinib; Fludarabine refractory; Kinase inhibitor; Microenvironment; NOXA