The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cells in patients with multiple myeloma.
OBJECTIVE
CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.


METHODS
Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m(2) cyclophosphamide (day 0), followed by granulocyte colony-stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.


RESULTS
BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34(+) cells (20.6 ± 6.9 × 10(6)/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 10(6) CD34(+) cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).


CONCLUSIONS
When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34(+) cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment.
Authors' Affiliations: Hematology Division and BMT, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem; Biokine Therapeutics Ltd., Science Park, Ness Ziona; and Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Technion, Haifa, Israel.
Amnon
A
Peled
Michal
M
Abraham
Irit
I
Avivi
Jacob M
JM
Rowe
Katia
K
Beider
Hanna
H
Wald
Lena
L
Tiomkin
Lena
L
Ribakovsky
Yossi
Y
Riback
Yaron
Y
Ramati
Sigal
S
Aviel
Eithan
E
Galun
Howard Laurence
HL
Shaw
Orly
O
Eizenberg
Izhar
I
Hardan
Avichai
A
Shimoni
Arnon
A
Nagler
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001772:Blood Cell Count; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000628:therapy*; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C577220:BKT140; D009842:Oligopeptides; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor