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Journal of Clinical Oncology, Vol 22, No 6 (March 15), 2004: pp. 1095-1102 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.131 Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and Non-Hodgkin's LymphomaFrom the Washington University School of Medicine, St Louis, MO; Thomas Jefferson University, Philadelphia, PA; Medical College of Wisconsin, Milwaukee, WI; University of Rochester, Rochester, NY; University of Minnesota, Minneapolis, MN; and AnorMed Inc, Langley, British Columbia, Canada. Address reprint requests to Steven M. Devine, MD, 660 S Euclid Ave, Campus Box 8007, St Louis, MO 63110; e-mail: sdevine{at}im.wustl.edu
PURPOSE: Interactions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirteen patients (MM, n = 7; NHL, n = 6) received AMD3100 at a dose of either 160 µg/kg (n = 6) or 240 µg/kg (n = 7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection. RESULTS: AMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 ± 0.7/µL (mean ± SE) to 15.6 ± 3.9/µL and 16.2 ± 4.3/µL at 4 hours (P = .002) and 6 hours after injection (P = .003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 µg/kg group (19.3 ± 6.9/µL and 20.4 ± 7.6/µL, respectively) compared with the 160 µg/kg group (11.3 ± 2.7/µL and 11.3 ± 2.5/µL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered. CONCLUSION: AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimuating factor in patients with lymphoid malignancies are warranted.
Mobilized peripheral blood (PB) has replaced bone marrow as the preferred source of hematopoietic rescue for patients undergoing high-dose chemoradiotherapy because of improved neutrophil and platelet engraftment, shortened hospital stay, and lower overall cost [1-5]. However, the optimal method to mobilize and collect PB progenitor cells (PBPC) for hematopoietic rescue following autologous transplantation is unknown. Although chemotherapy-based mobilization typically results in collection of greater numbers of CD34+ cells compared with granulocyte colony-stimulating factor (G-CSF) alone, it is also associated with greater morbidity due to infectious complications and has not clearly improved clinical outcomes following transplantation [4,6-11]. Previous strategies designed to improve CD34+ cell yield following G-CSF based PBPC mobilization through combination with other hematopoietic cytokines have met with limited success because of lack of efficacy or increased toxicity [4,9,12-17]. Novel strategies are required, particularly for those patients who have been heavily pretreated and who are predicted to have poor stem-cell mobilization with current approaches. Recent data suggest the interaction between the CXC chemokine receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1) plays a key role in stem-cell mobilization [18-22]. CXCR4 is a member of the large family of seven transmembrane domain receptors coupled to heterotrimeric G1 proteins [23]. Binding with its only known ligand SDF-1 (also known as CXCL12) results in activation of multiple signal transduction pathways ultimately triggering chemotaxis. Targeted disruption of either molecule is lethal in mice, resulting in failure of hematopoietic stem-cell (HSC) migration from liver to bone marrow, defects in B-lymphopoeisis, and cerebellar dysgenesis [24-26]. Interactions between SDF-1 and CXCR4 critically regulate the homing and migration of human SCID repopulating cells from bone marrow (BM), umbilical cord blood, and G-CSF mobilized PB transplanted into non-obese diabetic/SCID recipients [27,28]. Mobilization of murine stem and progenitor cells occurs following injection of adenovirus expressing SDF-1, resulting in a gradient of SDF-1 from BM to PB [29,30]. Treatment of mice and primates with sulfated polysaccharides (eg, fucoidan) results in a rapid increase in circulating SDF-1 and subsequent stem-cell mobilization [31,32]. Sustained downregulation of surface CXCR4 by a methionine-SDF-1ßanalog induces mobilization of murine hematopoietic progenitors [33]. Lapidot and Petit [18] have recently suggested a model wherein G-CSF stimulation induces proteases such as neutrophil elastase and other matrix metalloproteases that markedly reduce local bone marrow levels of SDF-1, resulting in the egress of hematopoietic stem and progenitor cells from the BM into the PB [20,34]. Together, mounting evidence supports a primary role for the CXCR4/SDF-1 axis in both murine and human stem- and progenitor-cell mobilization, suggesting this interaction provides a novel target to induce the migration of HSC and progenitors from BM into PB. The bicyclam molecule AMD3100 was first described for its potent and selective inhibition of HIV type 1 and 2 replication through binding to the chemokine receptor CXCR4, used by T-tropic HIV for entry into CD4+ cells [35-41]. AMD3100 also reversibly blocks the binding of CXCR4 with SDF-1 but has no effect on other cell surface chemokine receptors [39,42-44]. Initial clinical trials of AMD3100 evaluated its safety and efficacy in the treatment of patients with HIV-1 infection [45]. In these studies, transient increases in WBC counts were observed immediately following injection of AMD3100. Similar findings were also noted in healthy volunteers [46]. These observations prompted studies to evaluate the effects of AMD3100 on mobilization of hematopoietic stem and progenitor cells. Broxmeyer et al [47,48] demonstrated a 40-fold increase in the mobilization of hematopoietic progenitors within one hour of AMD3100 injection in mice. In contrast with G-CSF based progenitor cell mobilization, this effect did not appear to be mouse-strain dependent [48]. Studies in healthy volunteers demonstrated up to a 12-fold increase in CD34+ cell mobilization within 4 to 6 hours of AMD3100 at well tolerated doses [49]. AMD3100 has also been combined with G-CSF in healthy volunteers, resulting in a synergistic increase in CD34+ cell mobilization within 6 hours of injection [50]. These preliminary data suggested AMD3100 may be effective in increasing the yield of CD34+ cells collected when combined with G-CSF. In order to determine whether AMD3100 was effective not only in normal volunteers but also in patients who had received prior chemotherapy, we performed this phase I study to assess the effects of AMD3100 alone in patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).
Patients Patients with a diagnosis of MM or NHL who were considered autologous PBPC transplant candidates were eligible for this study. Additional eligibility criteria included age between 18 and 70 years, inclusive; receipt of last dose of chemotherapy between 4 and 8 weeks before study entry; no other significant medical conditions, including cardiac abnormalities; liver function tests less than three times upper limit of normal; estimated creatinine clearance greater than 60 mL/min; hematocrit greater than 25%; WBCs within normal limits; neutrophils greater than or equal to 2,000/µL; platelets greater than 100,000/µL; no receipt of other investigational drug or hematopoietic cytokine within 35 days and 10 days of study drug, respectively; no prior stem-cell transplant; no evidence of infection; and no history of known hypersensitivity to AMD3100 or its components. No patient could have ever received pegylated G-CSF. The study was performed after approval by the local Human Investigations Committee at each participating institution in accord with an assurance filed with and approved by the United States Department of Health and Human Services. Informed consent was obtained from each subject or subject's guardian.
Investigational Drug
Study Design
Analysis of Peripheral Blood CD34+ Cells
Statistical Analysis Data were expressed as means ± SE. Means of continuous variables were assessed by a paired t-test. Correlations were assessed by the Spearman correlation coefficient test. The n-fold increase in CD34+ cell number was calculated as the PB CD34+ cell count at 4 or 6 hours after AMD3100 injection divided by baseline PB CD34+ cell count, where the baseline CD34+ cell count was obtained from the sampling immediately before receipt of study drug. All patients receiving any amount of AMD3100 were considered evaluable for safety and efficacy.
Patients The characteristics of the patients enrolled onto the study are outlined in Table 1. A total of 13 patients were enrolled, seven with a diagnosis of MM and six with NHL. A seventh patient was added at the 240 µg/kg dose because one patient at this dose level had a lab sample for CD34+ cell analysis mishandled. It was later determined that the sample was fully evaluable. The median age was 53 years (range, age 39 to 67 years). There were 10 males and 3 females. Four patients—two with NHL and two with MM—had received prior radiation therapy. The median number of prior regimens of chemotherapy was one. The median numbers of cycles of prior chemotherapy was six (range, two to 12).
Toxicity The toxicities associated with AMD3100 injection are listed in Table 2. Toxicities due to AMD3100 were limited and all were grade 1 only by the WHO scale. The most common overall toxicity was erythema or edema at the injection site experienced by ten patients. This did not require treatment. The most common noncutaneous toxicities considered to be possibly or probably related to the study drug were gastrointestinal in nature and included a sensation of abdominal bloating, discomfort, or cramping in five patients, flatulence in three patients, diarrhea or soft stools in three patients, and nausea in two patients. Three patients experienced perioral or facial paresthesias, two patients lightheadedness, one patient a warm sensation, one patient mild hypotension, and one patient a neck rash for which antihistamines were used but not required. This was the only recipient of AMD3100 who received any intervention for toxicity. Toxicities did not appear to be dose-related. One of the thirteen patients had no symptoms whatsoever. All symptoms had disappeared completely by day 2 of study. No long-term toxicities were observed.
Hematologic Effects of AMD3100 The baseline WBC count for all patients was 4,732 ± 648/µL. This increased to 12,366 ± 1,849/µL and 13,568 ± 1,971/µL, at 4 and 6 hours following injection, respectively. This change from baseline was significant at both 4 (P < .001) and 6 (P < .001) hours (Fig 1), irrespective of dose received. On day 2, the mean baseline WBC count was 11,613 ± 1,596/µL, still significantly elevated compared with baseline. There was no statistically significant change from baseline in the circulating levels of platelets or erythrocytes at any time point at either dose level (data not shown). The relative proportion of WBC subsets did not change significantly during the 4 or 6 hour time points, although an increase in the proportion of neutrophils relative to lymphocytes, monocytes, and basophils was observed on day 2 (Table 3). The frequency of eosinophils increased slightly from a baseline level of 2.7% ± 0.4% to 4.0% ± 0.8% and 4.5% ± 0.8% at 4 and 6 hours following injection, respectively (P = .002).
The baseline frequency of CD34+ cells in the PB was 0.06% ± 0.02%. This increased to a mean of 0.13% ± 0.03% and 0.13% ± 0.03% at 4 and 6 hours following injection, respectively. The mean baseline PB absolute CD34+ cell count was 2.6 ± 0.7/µL. A statistically significant increase to a mean of 15.6 ± 4.0/µL (P = .002) and 16.2 ± 4.3/µL (P = .003) was observed at 4 and 6 hours after AMD3100, respectively (Fig 1). The mean fold increase in the absolute CD34+ cell count was similar at both time points, being 5.9 ± 0.8 and 6.1 ± 0.7, at 4 and 6 hours after AMD3100, respectively. The results observed in individual patients are presented in Table 1. Changes in the frequency of CD34+ cells and in absolute CD34+ cell number compared with baseline were significant at both dose levels (Table 4). Patients receiving the 240 µg/kg injection of AMD3100 experienced a greater increase in absolute CD34+ cell count as well as a greater fold increase at both 4 and 6 hours after injection compared with the 160 µg/kg dose, although because of small numbers, this difference was not statistically significant (Table 4). There was a trend toward a greater increase in the absolute CD34+ cell count at both 4 and 6 hours posttreatment in MM patients, compared with the NHL patients. However, when one outlier patient (patient 401; Table 1) with a high baseline circulating CD34+ cell count was removed from the analysis, the differences in CD34+ cell mobilization between MM and NHL patients were not nearly as striking.
This study demonstrated that a single subcutaneous injection of AMD3100 at doses of 160 µg/kg or 240 µg/kg was well tolerated and not associated with significant toxicity in patients with MM and NHL. Within 4 hours of injection of AMD3100, a significant increase in WBC count and PB CD34+ cell count was observed. All patients treated achieved the study definition of efficacy (a threefold increase in absolute CD34+ cell count at each time point). A mean sevenfold increase in circulating CD34+ cell count was noted 6 hours following the 240 µg/kg dose of AMD3100. The observed increase in absolute CD34+ cell count appears to be dose related, although the differences were not statistically significant because of the small number of patients studied. These preliminary findings warrant the continued evaluation of this new stem-cell mobilizing agent either in combination with G-CSF in patients or possibly as a single agent in allogeneic PB stem-cell donors. Ultimately, AMD3100 when combined with either G-CSF or chemotherapy, may allow sufficient PB CD34+ cell mobilization to support high-dose therapy in patients who either fail to mobilize with conventional strategies or who are predicted at baseline to have poor stem-cell yields. Both the 160 µg/kg and 240 µg/kg doses of AMD3100 were well tolerated. All toxicities were mild (grade 1) and transient in nature. Concern regarding the cardiac toxicity of AMD3100 had been raised previously based on the observation of premature ventricular contractions in two patients with HIV infection. However, no cardiac toxicities and, specifically, no dysrhythmias were seen in any patient on the current study. One patient with a history of hypertension experienced mild and transient hypotension believed related to a recent change in antihypertensive medication. This was not believed to be primarily cardiac related. Overall, these findings suggest that doses of AMD3100, which rapidly induce the peripheralization of CD34+ cells in patients with MM and NHL, are well tolerated and may not add significantly to the toxicity associated with G-CSF. Previous studies in murine models and healthy volunteers predicted that AMD3100 would cause the rapid mobilization of CD34+ cells [47,48,50,52]. However, the magnitude of the fold increase in circulating CD34+ cells in these patients was less than observed in volunteers [49]. This finding was predictable based on the amount of prior chemotherapy received by the patients in this study. The low numbers of individuals studied precluded any informative analysis of the correlation between the amount of prior chemotherapy and the likelihood of CD34+ cell mobilization by AMD3100. Previous studies have clearly demonstrated a negative association between the amount of prior chemotherapy and/or radiation therapy and the magnitude of CD34+ cell mobilization capacity following either chemotherapy or cytokine based mobilization schemes [4,6,7,53-56]. The MM patients mobilized slightly better than the NHL patients, possibly reflecting the heavier pretreatment in patients with NHL. This will require further study with larger patient samples. The mechanism by which AMD3100 induces stem-cell mobilization is under study. Recent data indicate that continued signaling through the CXCR4 receptor may be required for the retention of HSC within the bone marrow microenvironment [22]. Biochemical studies have demonstrated that the positively charged cyclam moiety of AMD3100 interacts with negatively charged aspartic acid residues on the fourth and the sixth extracellular transmembrane loops of CXCR4 [44]. The AMD3100 molecule occupies a binding groove within the receptor normally used by SDF-1. This interaction may result in the displacement of SDF-1 and subsequent disruption of SDF-1/CXCR4 signaling, causing the egress of hematopoietic stem and progenitor cells into the periphery [22]. Further mechanistic studies are needed. The key feature of this chemokine receptor/ligand interaction is the rapidity of the mobilization process and stands in clear contrast to G-CSF based mobilization in which up to four days of G-CSF treatment is required before significant increases in circulating CD34+ cells are observed [4]. Although in this study we did not measure PB CD34+ cell counts at 24 hours following injection, a previous study by Liles et al [49] in normal volunteers demonstrated that following AMD3100injection, CD34 values return to near baseline within 24 hours. This rapid and transient mobilization is akin to that observed with other chemokine receptor/ligand interactions such as IL-8 and Gro-ß [57,58]. However, these agents have pleiotropic effects on neutrophils and may cause undesirable toxicities. Although the magnitude of the fold increase in circulating CD34+ cells appears lower than that seen following 4 to 6 days of G-CSF stimulation (five- to sevenfold v ten- to 30-fold), [4,59] the rapidity of the increase observed following AMD3100 may be exploitable. In a recent study in healthy volunteers, a single injection of AMD3100 given on the fifth day of G-CSF stimulation resulted in a striking 50-fold increase in the number of circulating CD34+ cells [50]. Of note, in eight of the thirteen patients we treated the absolute number of circulating CD34+ cells exceeded 10/µL at 6 hours following AMD3100 injection (Table 1). It is conceivable that in such patients, large volume leukapheresis could result in the collection of a numerically sufficient autograft after only one or two injections of AMD3100. Furthermore, Liles et al [50] recently demonstrated that a 240 µg/kg injection of AMD3100 followed the same day by a single large volume leukapheresis yielded a mean of 3.1 x 106 CD34+ cells/kg. Such data suggest that in addition to improving the efficacy of G-CSF based mobilization in patients with malignant diseases, AMD3100 also may be safe and effective for the mobilization of PB stem cells from healthy donors in a same-day procedure. Given the modest but significant morbidity associated with G-CSF stimulated PB donation, these preliminary data suggest AMD3100 should be studied further in the allogeneic setting as well [60,61]. Whether PBPC mobilized following AMD3100 will possess adequate homing and engraftment capacity following transplantation will require definitive testing in clinical trials. Data generated recently in murine engraftment models, however, preliminarily suggest no deleterious effects of prior treatment of AMD3100 on hematopoietic engraftment [47]. In summary, AMD3100 is well tolerated and results in the rapid mobilization of WBCs and CD34+ cells in patients with MM and NHL. Further study in combination with G-CSF in patients with hematologic malignancies is clearly warranted.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Karin Badel, AnorMed Inc; Gary Calandra, AnorMed, Inc. Received more than $2,000 a year from a company for either of the last 2 years: Karin Badel, AnorMed Inc; Gary Calandra, AnorMed Inc.
We gratefully acknowledge the research assistance of Debbie Hendricks and Kerry Williams, as well as the assistance of Dianne Oliver, in preparing this manuscript.
Research support provided by Anormed, Inc, Langley, British Columbia. Presented in part at the 8th Annual European Hematology Association Meeting, Lyon, France, June 14, 2003 Authors' disclosures of potential conflicts of interest are found at the end of this article.
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TOP
ABSTRACT
INTRODUCTION
