This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colonystimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 g/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 g/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 ؋ 10 6 CD34 ؉ cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 ؋ 10 6 CD34 ؉ cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34 ؉ cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www. clinicaltrials.gov as #NCT00103662. (Blood. 2009;113:5720-5726)
The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remissions in 33% of chronic myelogenous leukemia (CML) patients in a phase I trial (Druker et al 1999). Combination therapy may increase this proportion. We tested whether combinations of STI571 and cytarabine or other chemotherapeutic agents such as hydroxyurea, mafosfamide or etoposide would display synergistic activity in BCR-ABL-positive chronic myelogenous leukemia (CML) cell lines derived from patients in blast crisis. In addition, the toxicity of these combinations on BCR-ABL-negative cells was investigated. A tetrazolium-based MTT assay was used to quantify growth inhibition after 48 h of exposure to cytotoxic agents alone and in simultaneous combination with STI571. The drug interactions were analyzed using the median-effect method of Chou and Talalay. The combination index (CI) was calculated according to the classic isobologram equation. At growth inhibition levels of over 50%, STI571 + cytarabine as well as STI571 + etoposide were significantly synergistic (CI Ͻ 1, P Ͻ 0.05) in the BCR-ABL-positive cell lines evaluated. At 60% inhibition or higher, a similar synergistic pattern became apparent for STI571 + mafosfamide (P Ͻ 0.05), while STI571 + hydroxyurea showed ambiguous, cell line-dependent synergism (BV173), additivity (EM-3) or antagonism (K562) in CML cell lines. Furthermore, the BCR-ABL-negative HL-60, KG1a and normal CD34 + progenitor cells were not affected by 0.8 M STI571, a concentration which produced more than 50% growth inhibition in all BCR-ABL-positive cells tested, and no potentiation of growth inhibition was observed in these BCR-ABL-negative cells when STI571 was combined with chemotherapeutic agents. Our in vitro data with CML blast crisis cell lines strongly suggest that combinations of STI571 with cytarabine or etoposide be rapidly considered for clinical testing. Leukemia (2001) 15, 342-347.
Increasing use of hematopoietic stem cells for retroviral vector-mediated gene therapy and recent reports on insertional mutagenesis in mice and humans have created intense interest to characterize vector integrations on a genomic level. We studied retrovirally transduced human peripheral blood progenitor cells with bone marrow-repopulating ability in immune-deficient mice. By using a highly sensitive and specific ligation-mediated polymerase chain reaction (PCR) followed by sequencing of vector integration sites, we found a multitude of simultaneously active human stem cell clones 8 weeks after transplantation. Vector integrations occurred with significantly increased frequency into chromosomes 17 and 19 and into specific regions of chromosomes 6, 13, and 16, although most of the chromosomes were targeted. Preferred genomic target sites have previously only been reported for wild-type retroviruses. Our findings reveal for the first time that retroviral vector integration into human marrow-repopulating cells can be nonrandom (P ؍ .000 37). (Blood. 2003;
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