RESUMO
AMD11070 binds to the chemokine receptor CXCR4, with anti-HIV-1 activity in vitro and in vivo. We conducted a phase IB/IIA proof-of-concept dose-escalating, open-label study to determine safety and antiviral activity of AMD11070 administered over 10 days to HIV-1-infected participants who harbored CXCR4-tropic virus. Primary endpoints were ≥1 log10 rlu (relative luminescence units) reduction in CXCR4-tropic virus during 10 days of AMD11070 treatment or in the 7 days following treatment discontinuation, rlu changes over 10 days of treatment, and safety. Plasma pharmacokinetic parameters, HIV-1 RNA, and safety labs were obtained over 90 days of study. The study was stopped early due to emerging AMD11070 animal toxicity data. Six HIV-infected participants with plasma HIV-1 RNA ≥5,000 copies/mL on no antiretroviral therapy for 14 days before entry were treated. AMD11070 was well-tolerated when administered at 200 mg orally every 12 h for 10 days. All enrolled participants had dual/mixed (D/M) viruses. Reductions of almost 1 log10 rlu or more in CXCR4 virus were seen in three of six participants after 10 days of treatment. No participants had ≥1 log10 decline in plasma HIV-1 RNA from baseline at day 10. No clear relationship between pharmacokinetic parameters and response to therapy (X4 log rlu reduction) was observed. AMD11070 demonstrated in vivo activity as measured by reductions in CXCR4 rlu signal. Despite the finding of discordant rlu and plasma HIV RNA responses in these participants with D/M viruses, exploration of other HIV-1 CXCR4 antagonist therapies is possible.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Receptores CXCR4/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Adulto , Aminoquinolinas , Fármacos Anti-HIV/efeitos adversos , Benzimidazóis , Butilaminas , Linfócitos T CD4-Positivos/virologia , Feminino , HIV-1/genética , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Masculino , Estudo de Prova de Conceito , RNA Viral/sangue , Receptores CXCR4/metabolismo , Estados UnidosRESUMO
Hematopoietic stem cells can be mobilized from healthy donors using single-agent plerixafor without granulocyte colony-stimulating factor and, following allogeneic transplantation, can result in sustained donor-derived hematopoiesis. However, when a single dose of plerixafor is administered at a conventional 240 µg/kg dose, approximately one-third of donors will fail to mobilize the minimally acceptable dose of CD34+ cells needed for allogeneic transplantation. We conducted an open-label, randomized trial to assess the safety and activity of high-dose (480 µg/kg) plerixafor in CD34+ cell mobilization in healthy donors. Subjects were randomly assigned to receive either a high dose or a conventional dose (240 µg/kg) of plerixafor, given as a single subcutaneous injection, in a two-sequence, two-period, crossover design. Each treatment period was separated by a 2-week minimum washout period. The primary endpoint was the peak CD34+ count in the blood, with secondary endpoints of CD34+ cell area under the curve (AUC), CD34+ count at 24 hours, and time to peak CD34+ following the administration of plerixafor. We randomized 23 subjects to the two treatment sequences and 20 subjects received both doses of plerixafor. Peak CD34+ count in the blood was significantly increased (mean 32.2 versus 27.8 cells/µL, P=0.0009) and CD34+ cell AUC over 24 hours was significantly increased (mean 553 versus 446 h cells/µL, P<0.0001) following the administration of the 480 µg/kg dose of plerixafor compared with the 240 µg/kg dose. Remarkably, of seven subjects who mobilized poorly (peak CD34+ ≤20 cells/µL) after the 240 µg/kg dose of plerixafor, six achieved higher peak CD34+ cell numbers and all achieved higher CD34+ AUC over 24 hours after the 480 µg/kg dose. No grade 3 or worse drug-related adverse events were observed. This study establishes that high-dose plerixafor can be safely administered in healthy donors and mobilizes greater numbers of CD34+ cells than conventional-dose plerixafor, which may improve CD34+ graft yields and reduce the number of apheresis procedures needed to collect sufficient stem cells for allogeneic transplantation. (ClinicalTrials.gov, identifier: NCT00322127).
Assuntos
Antígenos CD34/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/administração & dosagem , Doadores de Tecidos , Adulto , Benzilaminas , Ensaio de Unidades Formadoras de Colônias , Estudos Cross-Over , Ciclamos , Feminino , Voluntários Saudáveis , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
Plerixafor (Mozobil) is a CXCR4 antagonist that rapidly mobilizes CD34(+) cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T cells, the effects of plerixafor mobilization on T cells have not been well characterized. In this study, we show that alterations in the T cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur after mobilization with plerixafor. Compared with nonmobilized T cells, plerixafor-mobilized T cells had similar phenotype, mixed lymphocyte reactivity, and Foxp3 gene expression levels in CD4(+) T cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast with plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8(+) T cells and altered expression levels of 16 cytokine-associated genes in CD3(+) T cells. To assess the clinical relevance of these findings, we explored a murine model of graft-versus-host disease in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility-mismatched donors; recipients of plerixafor mobilized peripheral blood stem cells had a significantly higher incidence of skin graft-versus-host disease compared with mice receiving G-CSF mobilized transplants (100 versus 50%, respectively, p = 0.02). These preclinical data show plerixafor, in contrast with G-CSF, does not alter the phenotype and cytokine polarization of T cells, which raises the possibility that T cell-mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared with G-CSF.
Assuntos
Citocinas/genética , Regulação da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Benzilaminas , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Ciclamos , Citocinas/biossíntese , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Linfopoese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Quimera por Radiação , Receptores CXCR4/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Subpopulações de Linfócitos T/imunologiaRESUMO
Many institutions have adopted algorithms based on preapheresis circulating CD34+ cell counts to optimize the use of plerixafor. However, a circulating peripheral blood CD34+ cell threshold that predicts mobilization failure has not been defined. The superiority of plerixafor + granulocyte colony-stimulating factor (G-CSF) over placebo + G-CSF for hematopoietic stem cell mobilization and collection was shown for patients with non-Hodgkin lymphoma in a phase III, prospective, randomized, controlled study. The question remains as to which patients may benefit most from the use of plerixafor. In this post hoc retrospective analysis, mobilization outcomes were compared between the 2 treatment arms in patients stratified by peripheral blood CD34+ cell count (<5, 5 to 9, 10 to 14, 15 to 19, or ≥20 cells/µL) obtained before study treatment and apheresis. Compared with placebo plus G-CSF, plerixafor plus G-CSF significantly increased the peripheral blood CD34+ cells/µL over prior day levels in all 5 stratified groups. The probability of subsequent transplantation without a rescue mobilization was far greater in the plerixafor-treated patients for the lowest initial (day 4) peripheral blood CD34+ cells/µL groups (<5, 5 to 9, or 10 to 14). Engraftment and durability were the same for the 2 treatment groups for all strata, but the effect in the lower strata could be altered by the addition of cells from rescue mobilizations. These findings may provide insight into the optimal use of plerixafor in all patients undergoing stem cell mobilization.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Linfoma não Hodgkin/terapia , Adulto , Idoso , Antígenos CD34/imunologia , Benzilaminas , Remoção de Componentes Sanguíneos , Contagem de Linfócito CD4 , Ciclamos , Método Duplo-Cego , Feminino , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Placebos , Transplante AutólogoRESUMO
BACKGROUND: Previous reports suggested that rituximab may impair stem cell collection and posttransplant engraftment in lymphoma patients undergoing autologous hematopoietic progenitor cell transplantation. STUDY DESIGN AND METHODS: A prospective biologic allocation study examined the effect of adding rituximab to a mobilization regimen of plerixafor and granulocyte-colony-stimulating factor (G-CSF) for patients with CD20+ lymphoma compared with CD20- lymphoma patients mobilized without rituximab. The primary endpoint was safety of the rituximab-containing regimen; secondary endpoints compared the efficiency of stem cell collection, posttransplant engraftment, graft characteristics, mobilization kinetics, immune reconstitution, and engraftment durability between the cohorts of patients with CD20+ and CD20- lymphoma. RESULTS: Fifteen subjects assigned to each treatment arm were accrued. Both mobilization regimens had similar toxicities. The median number of CD34+ cells collected (7.4 × 10(6) /kg vs. 6.4 × 10(6) /kg) and the median numbers of days of apheresis needed to collect stem cells were not different between the CD20+ and CD20- cohorts. No significant differences in neutrophil engraftment (median, 13.5 days vs. 13 days) or platelet engraftment (22 vs. 21 days) or in graft durability were seen comparing patients with CD20+ versus CD20- lymphoma. There were no significant differences in the kinetics of blood T-cell or natural killer-cell reconstitution comparing the two groups. B-cell reconstitution was delayed in the CD20+ lymphoma group, but this did not translate into a significant increase in infectious complications. CONCLUSION: Rituximab can be safely added to the combination of plerixafor and G-CSF as a mobilization strategy without excess toxicity or posttransplant engraftment delays for patients with chemosensitive lymphoma undergoing autologous hematopoietic progenitor cell transplantation.
Assuntos
Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/uso terapêutico , Linfoma/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzilaminas , Ciclamos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Compostos Heterocíclicos/administração & dosagem , Humanos , Linfoma/metabolismo , Linfoma/terapia , Rituximab , Transplante de Células-TroncoRESUMO
This study evaluated the safety and CD34+ cell mobilizing activity of escalating doses of plerixafor in healthy volunteers. Three cohorts of six subjects received two different doses of plerixafor separated by at least 2 weeks to allow for adequate pharmacodynamic wash-out. The following dosing cohorts were evaluated: 0·24 and 0·32 mg/kg (Cohort 1); 0·32 and 0·40 mg/kg (Cohort 2); and 0·40 and 0·48 mg/kg (Cohort 3). Circulating CD34+ cells were measured 0, 2, 4, 6, 8, 10, 12, 14, 18 and 24 h after each dose. Blood colony-forming units were measured at baseline and 6 h after each dose. Common adverse events were diarrhoea, injection site erythema, perioral numbness, sinus tachycardia, headache, nausea, abdominal distention and injection site pain. No dose limiting toxicities occurred. When higher doses of plerixafor were administered, there was a trend towards higher peak CD34+ counts and CD34+ area under the curves, although these differences did not achieve statistical significance, perhaps due to intra-subject variability. Together, these data show that the higher doses of plerixafor evaluated in this study are reasonably safe and suggest that a larger study should be performed to definitively answer whether increased numbers of CD34+ cell are mobilized with higher doses of plerixafor.
Assuntos
Antígenos CD34/análise , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Adolescente , Adulto , Benzilaminas , Estudos de Coortes , Ensaio de Unidades Formadoras de Colônias , Ciclamos , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptores CXCR4/antagonistas & inibidores , Adulto JovemRESUMO
Pharmacological manipulation of CXCR4 has proven clinically useful for mobilization of stem and progenitor cells and in several preclinical models of disease. It is a key component in the localization of leukocytes and stem cells. For patients with multiple myeloma and non-Hodgkin's Lymphoma, treatment with plerixafor, an inhibitor of CXCL12 binding to CXCR4, plus G-CSF mobilizes stem cells for autologous transplantation to a greater degree than the treatment with G-CSF alone, and in some cases when patients could not be mobilized with cytokines, chemotherapy, or the combination. Stem cells from healthy donors mobilized with single agent plerixafor have been used for allogeneic transplantation in acute myelogenous leukemia (AML) patients, although this is still in the early phase of clinical development. Plerixafor is also undergoing evaluation to mobilize tumor cells in patients with AML and chronic lymphocytic leukemia (CLL) to enhance the effectiveness of chemotherapy regimens. Plerixafor's effect on neutrophils may also restore circulating neutrophil counts to normal levels in patients with chronic neutropenias such as in WHIMs syndrome. Other areas where inhibition of CXCR4 may be useful based upon preclinical or clinical data include peripheral vascular disease, autoimmune diseases such as rheumatoid arthritis, pulmonary inflammation, and HIV.
Assuntos
Doenças Hematológicas/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Animais , Benzilaminas , Ensaios Clínicos como Assunto , Ciclamos , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doenças Hematológicas/imunologia , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Transplante de Células-TroncoRESUMO
Rapid and durable recovery of hematopoietic function after hematopoietic stem cell transplantation (HSCT) requires the infusion of a sufficient number of hematopoietic stem cells (HSC). Granulocyte colony-stimulating factor (G-CSF), either alone or with chemotherapy, has been the traditional backbone of regimens used to mobilize HSC. Plerixafor (previously known as AMD3100), a selective antagonist of CXCR4, has recently been approved for autologous HSC mobilization in combination with G-CSF. The current study assessed the safety and efficacy of plerixafor as a single agent when given subcutaneously and followed by apheresis 6 hours later for the mobilization of HSC for transplantation in 9 patients with multiple myeloma (MM). All patients mobilized enough cells for at least 1 transplant, and demonstrated prompt recovery of hematopoietic function. Median time to engraftment was 10.5 days for neutrophils and 21 days for platelets. Significant adverse events were not observed. Recovery of peripheral blood cell counts was durable in all surviving patients. Despite these successes, mobilization with plerixafor alone was modest. However, in clinical circumstances where G-CSF or chemotherapy based-mobilization should not be used, mobilization with plerixafor alone may be required and effective. Further research into single agent use should focus on alternate route of administration as well as adjustment of the timing of the apheresis to improve cell HSC yield.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Benzilaminas , Remoção de Componentes Sanguíneos/métodos , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Cinética , Masculino , Receptores CXCR4/antagonistas & inibidores , Transplante Autólogo , Adulto JovemRESUMO
Plerixafor is a selective antagonist of CXCR4 used for mobilization of hematopoietic stem cells (HSCs) for autologous stem cell transplantation (SCT) in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This Phase 1 open-label study in healthy subjects was conducted to evaluate the pharmacokinetic characteristics of plerixafor in subjects with renal impairment. All subjects received a single 0.24 mg/kg subcutaneous dose of plerixafor. Subjects were stratified into 4 cohorts based on creatinine clearance determined from a 24-hour urine collection: control (>90 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (31-50 mL/min), and severe renal impairment (<31 mL/min, not requiring dialysis). Eleven female subjects (48%) and 12 male subjects (52%), ranging in age from 35 to 73 years, were enrolled. Plerixafor clearance was reduced in subjects with renal impairment and was positively correlated with creatinine clearance. The mean area under the concentration- versus-time curve from time 0 to 24 hours postdose of plerixafor in subjects with mild, moderate, and severe renal impairment was 7%, 32%, and 39% higher, respectively, than that in subjects with normal renal function. Renal impairment had no effect on maximal plasma concentrations. The safety profile was similar among subjects with renal impairment and controls. No renal impairment-related trends in the incidence of adverse events were apparent. A plerixaflor dose reduction to 160 microg/kg in patients with a creatinine clearance value Assuntos
Compostos Heterocíclicos/farmacocinética
, Receptores CXCR4/antagonistas & inibidores
, Insuficiência Renal/metabolismo
, Adulto
, Idoso
, Benzilaminas
, Estudos de Coortes
, Creatinina/metabolismo
, Creatinina/urina
, Ciclamos
, Feminino
, Mobilização de Células-Tronco Hematopoéticas
, Compostos Heterocíclicos/efeitos adversos
, Compostos Heterocíclicos/sangue
, Compostos Heterocíclicos/urina
, Humanos
, Testes de Função Renal
, Masculino
, Taxa de Depuração Metabólica
, Pessoa de Meia-Idade
, Insuficiência Renal/sangue
, Insuficiência Renal/fisiopatologia
, Insuficiência Renal/urina
RESUMO
BACKGROUND AIMS: Previous studies in xenograft models have shown that human peripheral blood progenitor cells (PBPC) mobilized with the CXCR4 antagonist plerixafor (AMD3100) have a higher bone marrow (BM) reconstitution potential than granulocyte-colony-stimulating factor (G-CSF)-mobilized PBPC. METHODS: PBPC obtained during G-CSF-supported mobilization before and after a supplementary administration of AMD3100 from patients with multiple myeloma and non-Hodgkin's lymphoma (n=15; phase II study) were investigated for co-expression of primitive and lineage-associated markers, their proliferative activity in vitro and repopulation potential after clinical transplantation. RESULTS: A significant increase in primitive CD34+ CD38(-) cells was observed in intraindividual comparisons of all patients after administration of G-CSF+AMD3100 (peripheral blood: median 8-fold, range 2,4-fold - 39-fold) compared with G-CSF alone. Using a long-term culture-initiating cell assay, this increase was confirmed. After transplantation of G-CSF+AMD3100-mobilized PBPC, the time to leukocyte reconstitution > 1 x 10(3)/microL and platelet reconstitution > 2 x 10(4)/microL was 14 (10-19 days) and 13 days (10-15 days), respectively. A complete and stable hematologic reconstitution (platelets > 1.5 x 10(5)/microL) was observed in 91% of all patients within 35 days. CONCLUSIONS: An additional application of AMD3100 to a standard G-CSF mobilization regimen leads to a significant increase in primitive PBPC with high repopulation capacity.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Antígenos CD34/metabolismo , Benzilaminas , Técnicas de Cultura de Células , Ciclamos , Quimioterapia Combinada , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de TempoRESUMO
BACKGROUND AIMS: Bone marrow (BM)-derived cells may repair cardiovascular injury but populations of interest circulate in small numbers. Cytokines such as granulocyte-colony-stimulating factor mobilize cells under investigation for this purpose, including CD133+ but require injections over multiple days and may promote inflammation. The purpose of this study was to evaluate the effects of a novel CXCR4 inhibitor (plerixafor), previously shown to mobilize CD34+ stem cells, on CD133+ mobilization and markers of inflammation. METHODS: Healthy subjects received a single subcutaneous injection of plerixafor in escalating doses: 240 mcg/kg (n = 3), 320 mcg/kg (n = 5) and 400 mcg/kg (n = 7). CD133+ and CD133+/VEGFR-2+ cells were measured by flow cytometry at baseline, then 4-6 h following plerixafor injection. Markers of inflammation in serum were measured at baseline, then again 10 h following injection of the 400 mcg/kg dose. RESULTS: Across all doses, white blood cells increased on average three-fold from baseline values. CD133+ cells increased on average 24-fold (from 616 +/- 141 cells/mL to 14 713 +/- 4423 cells/mL, P = 0.0064) without clear evidence of a dose effect. CD133+/VEGFR-2+ cells ranged from 0 to 20 cells/mL at baseline and from 0 to 124 cells/mL following plerixafor administration, although the rarity of these cells precluded a statistical analysis of this population. C-reactive protein and serum amyloid type A were not increased after the 400 mcg/kg dose. Pro-inflammatory cytokine levels were undetectable before and after plerixafor, except for macrophage inflammatory protein-1 beta, which increased slightly but significantly after the 400 mcg/kg dose of plerixafor (P = 0.0156). CONCLUSIONS: CD133+ cells are mobilized into the circulation following a single injection of the CXCR4 antagonist plerixafor, without clear evidence for systemic activation of inflammation. This effect may be of importance in cell-based approaches for treating cardiovascular diseases.
Assuntos
Doenças Cardiovasculares/terapia , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Antígeno AC133 , Adulto , Antígenos CD/metabolismo , Benzilaminas , Contagem de Células Sanguíneas , Ciclamos , Feminino , Citometria de Fluxo , Glicoproteínas/metabolismo , Humanos , Masculino , Peptídeos/metabolismoRESUMO
In a phase 3 multicenter, randomized, double-blinded, placebo-controlled study of 298 patients with non-Hodgkin lymphoma (NHL), granulocyte colony-stimulating factor (G-CSF) plus plerixafor increased the proportion of patients who mobilized >or=5 x 10(6) CD34(+) hematopoietic stem cells (HSCs)/kg compared with placebo plus G-CSF (P < .001). Patients in either study arm who failed mobilization (< 0.8 x 10(6) CD34(+) cells/kg in 2 collections or <2 x 10(6) CD34(+) cells/kg in 4 collections) were eligible to enter the opened-label rescue protocol. Following a 7-day minimum rest period, these patients received G-CSF (10 microg/kg/day) for 4 days, followed by daily plerixafor (0.24 mg/kg) plus G-CSF and apheresis for up to 4 days. Of the 68 patients failing initial mobilization (plerixafor, n = 11; placebo, n = 57), 62 patients (91%) entered the rescue procedure (plerixafor, n = 10; placebo, n = 52). Four of 10 patients (40%) from the plerixafor group and 33 of 52 (63%) from the placebo group mobilized sufficient CD34(+) cells (>or= 2 x 10(6) cells/kg) for transplantation from the rescue mobilization alone (P = .11). Engraftment of neutrophils (11 days) and platelets (20 days) was similar to that in patients who did not fail initial mobilization, and all patients had durable grafts at the 12-month follow-up. Common plerixafor-related adverse events (AEs) included mild gastrointestinal (GI) effects and injection site reactions. There were no drug-related serious AEs. These data support that plerixafor plus G-CSF can safely and effectively remobilize patients with NHL who have failed previous mobilization.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Benzilaminas , Remoção de Componentes Sanguíneos/métodos , Terapia Combinada , Ciclamos , Método Duplo-Cego , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/efeitos adversos , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/cirurgia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: This study evaluates the safety and efficacy of plerixafor (AMD3100), a CXCR4 antagonist, in mobilizing hematopoietic stem cells for autologous stem-cell transplantation in non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: This is a phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study. Patients with non-Hodgkin's lymphoma requiring an autologous hematopoietic stem-cell transplantation in first or second complete or partial remission were eligible. Patients received granulocyte colony-stimulating factor (G-CSF; 10 microg/kg) subcutaneously daily for up to 8 days. Beginning on evening of day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until > or = 5 x 10(6) CD34+ cells/kg were collected. The primary end point was the percentage of patients who collected > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis days. RESULTS: This report presents all data for all patients (n = 298) through 12 months follow-up. Eighty-nine (59%) of 150 patients in the plerixafor group and 29 (20%) of 148 patients in the placebo group met the primary end point (P < .001). One hundred thirty-five patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation after initial mobilization. Median time to engraftment was similar in both groups. The most common plerixafor-associated adverse events were GI disorders and injection site reactions. CONCLUSION: Plerixafor and G-CSF were well tolerated and resulted in a significantly higher proportion of patients with non-Hodgkin's lymphoma achieving the optimal CD34+ cell target for transplantation in fewer apheresis days, compared with G-CSF alone.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Adulto , Idoso , Benzilaminas , Ciclamos , Diarreia/etiologia , Método Duplo-Cego , Feminino , Cefaleia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Infusões Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Estudos Prospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Despite Imatinib's remarkable success in chronic myelogenous leukemia treatment, monotherapy frequently causes resistance, underlining the rationale for combination chemotherapy. A potential approach would be interrupting the SDF-1/CXCR4 axis using the selective CXCR4 antagonist Plerixafor (previously AMD3100), as this axis has been reported to provide survival-enhancing effects to myeloid progenitor cells. By efficient CXCR4 blocking in the CXCR4(+)/BCR-ABL(+) cell line BV-173, plerixafor (1-100 muM) significantly inhibits SDF-1alpha-mediated chemotaxis and cell migration toward the murine stroma cell line FBMD-1. Furthermore, plerixafor also significantly (10-100 muM) increased the detachment rate of SDF-1-mediated/VCAM-1-associated cell adherence under shear stress. Using a stroma-dependent coculture assay, plerixafor sensitized BCR-ABL(+) cells toward tyrosine kinase inhibitor therapy. Because the level of cell killing nearly reached that of samples cultured without stroma, a cell-cell interaction disruption seems to improve the efficacy of BCR-ABL-targeting drugs. In addition, we could show that exposure of BCR-ABL(+) cells to Imatinib or Nilotinib induced an increase in surface CXCR4 expression. Our data suggest that for BCR-ABL(+) leukemia, the selective blocking of the SDF-1/CXCR4 axis by plerixafor is a potential mechanism to overcome the protective effect of the bone marrow environment, thereby increasing the therapeutic potency of anti-BCR-ABL drugs and the therapeutic window.
Assuntos
Quimiocina CXCL12/antagonistas & inibidores , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Compostos Heterocíclicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Receptores CXCR4/antagonistas & inibidores , Animais , Benzamidas , Benzilaminas , Adesão Celular/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/enzimologia , Linhagem Celular Tumoral/patologia , Técnicas de Cocultura , Ciclamos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptores CXCR4/biossíntese , Receptores CXCR4/química , Receptores CXCR4/genética , Células Estromais/citologiaRESUMO
This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/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 microg/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 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 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.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Benzilaminas , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/cirurgia , Transplante AutólogoRESUMO
BACKGROUND: The X4 Antagonist Concept Trial investigates the safety and antiviral activity of AMD11070, a potent inhibitor of X4-tropic human immunodeficiency virus (HIV) in vitro in HIV-infected patients harboring X4-tropic virus. METHODS: Patients enrolled in the study had an X4 virus population 2000 relative luminescence units (rlu; by the Monogram Trofile Assay) and an HIV-1 RNA level 5000 copies/mL. Patients received AMD11070 monotherapy for 10 days. Coreceptor tropism, plasma HIV-1 RNA level, and CD4 cell count were measured at study entry, on day 5, and on day 10. Daily predose and serial samples on the last day of treatment were obtained for determination of plasma AMD11070 concentration. RESULTS: Ten patients were given AMD11070 monotherapy (200 mg to 8 patients and 100 mg to 2 patients) twice daily for 10 days. The median baseline CD4 cell count was 160 cells/mm(3), and the median HIV-1 RNA level was 91,447 copies/mL. Four of 9 evaluable patients achieved a reduction in X4 virus population of >or= rlu. The median change in X4 virus population at the end of treatment was -0.22 log(10) rlu (range, -1.90 to 0.23 log(10) rlu). Three of 4 patients who responded to therapy showed a tropism shift from dual- or mixed-tropic viruses to exclusively R5 virus by day 10. There were no drug-related serious adverse events, adverse events of greater than grade 2, or laboratory abnormalities. CONCLUSION: These results demonstrate the activity of AMD11070, the first oral CXCR4 antagonist, against X4-tropic HIV-1. The drug was well tolerated, with no serious safety concerns. AMD11070 is on clinical hold because of histologic changes to the liver observed in long-term animal studies; additional preclinical safety assessments are pending.
Assuntos
Aminoquinolinas/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adulto , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Butilaminas , Contagem de Linfócito CD4 , Feminino , HIV-1/classificação , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Receptores de HIV , Resultado do Tratamento , Carga ViralRESUMO
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) studies in healthy volunteers demonstrated that plerixafor (AMD3100), a CXCR4 antagonist, administered either alone or with granulocyte colony-stimulating factor (G-CSF), resulted in dose-dependent mobilization of CD34(+) cells in the peripheral blood. The purpose of this study was to evaluate the safety and the PK and PD of plerixafor with G-CSF in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). This was a phase II, open-label, single-arm study conducted in 2 centers in Canada. Patients aged 18 to 70 years with NHL or MM eligible for autologous transplantation were eligible. A total of 22 patients (8 with NHL and 14 with MM) were enrolled in the study. The patients were given G-CSF (10 microg/kg/day subcutaneously [s.c.]) for 4 days in the morning and plerixafor 240 microg/kg s.c. on the evening before each day of apheresis. Apheresis was initiated 10 to 11 hours after each evening dose of plerixafor and after the morning dose of G-CSF. This regimen was repeated for up to 5 days or until > or = 5 x 10(6) CD34(+) cells/kg were collected. The objectives were to determine the safety and efficacy of plerixafor in patients with NHL and MM, and the PK and PD of a single 240-microg/kg dose of plerixafor administered after 4 days of G-CSF mobilization in these patients. The median absolute peripheral blood CD34(+) cell count increased from 24.0 cells/microL before plerixafor administration to 75.0 cells/microL before the first apheresis (10 to 11 hours after treatment with plerixafor). The median number of CD34(+) cells collected in a median of 1 day was 5.7 x 10(6) cells/kg in the patients with NHL and 12.0 x 10(6) cells/kg in those with MM. All patients underwent transplantation with prompt and durable engraftment. The PK profile of plerixafor was characterized in 13 patients (5 with NHL and 8 with MM). Overall, the PK parameters were comparable in the patients with NHL and those with MM. Plerixafor was rapidly absorbed after s.c. administration with no observable lag time, with peak plasma concentrations occurring 0.5 hour after administration in most patients. Plerixafor was rapidly cleared, with a median terminal half-life of 4.6 hours. The median maximum increase in the number of circulating cells from baseline was 4.2-fold (range, 3.0- to 5.5-fold), with the maximum fold increase occurring approximately 10 hours after plerixafor injection for all patients. The plerixafor PK and PD profiles in the study patients were consistent with those in healthy volunteers and support the current dosing regimen and timing of apheresis. Plerixafor was safe and effective in mobilizing CD34(+) cells for transplantation.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Antígenos CD34 , Benzilaminas , Remoção de Componentes Sanguíneos/métodos , Ciclamos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Humanos , Linfoma não Hodgkin/terapia , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Farmacocinética , Receptores CXCR4/antagonistas & inibidores , Transplante AutólogoRESUMO
We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Adulto , Idoso , Antígenos CD34 , Benzilaminas , Remoção de Componentes Sanguíneos , Contagem de Células , Ciclamos , Quimioterapia Combinada , Feminino , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/normas , Células-Tronco Hematopoéticas/citologia , Compostos Heterocíclicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/antagonistas & inibidoresRESUMO
Collection of an adequate number of hematopoietic stem cells can be difficult in patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation (ASCT). Plerixafor (AMD3100), an inhibitor of the interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4, is an effective hematopoietic stem cell mobilization agent in patients with multiple myeloma and non-Hodgkin lymphoma (NHL). This study was undertaken to investigate the efficacy and safety of hematopoietic stem cell mobilization with plerixafor in patients with HL. Twenty-two patients with HL who were candidates for ASCT underwent hematopoietic stem cell mobilization with a combination of granulocyle-colony stimulating factor (G-CSF), 10 microg/kg daily, and plerixafor, 240 microg/kg subcutaneous, 10-11 hours prior to apheresis. The primary endpoint was the proportion of patients who collected>or=5x10(6) CD34+ cells/kg. Outcomes were compared to a historical control population of HL patients mobilized with G-CSF alone. Pharmacokinetic (PK) analysis of plerixafor was performed in a subset of patients. Fifteen patients (68%) collected>or=5x10(6) CD34+ cells/kg, and 21 patients (95%) achieved the minimum collection of >or=2x10(6) CD34+ cells/kg, in a median 2 apheresis procedures. Both the proportion of patients collecting>or=5x10(6) CD34+ cells/kg and the median CD34+ cells collected in days 1-2 of apheresis were significantly improved over historical controls. The PK of plerixafor in this patient population was similar to that previously seen in healthy volunteers. The regimen was generally safe and well tolerated.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Doença de Hodgkin , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/farmacocinética , Antígenos CD34 , Benzilaminas , Remoção de Componentes Sanguíneos , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Compostos Heterocíclicos/farmacocinética , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
Allografts from HLA-matched sibling donors were mobilized and collected without granulocyte colony-stimulating factor (G-CSF) using AMD3100, a direct antagonist of CXCR4/stromal-derived factor 1 (SDF-1/CXCL12). Donors (N = 25) were treated with AMD3100 at a dose of 240 mug/kg by subcutaneous injection, and leukapheresis was then initiated just 4 hours later. Two-thirds of the donors collected an allograft with a CD34(+) cell dose sufficient for transplantation after just one dose of AMD3100. No donor experienced more than grade 1 toxicity. After a myeloablative regimen, 20 patients with hematologic malignancies received allografts collected after AMD3100 alone. All patients engrafted neutrophils (median day 10) and platelets (median day 12) promptly. Acute graft-versus-host disease (GVHD) grades 2 through 4 occurred in 35% of patients. One patient died due to complications related to acute GVHD. No unexpected adverse events were observed in any of the recipients. All 14 patients surviving in remission have robust trilineage hematopoiesis and are transfusion-free with a median follow-up of 277 days (range, 139-964 days). Direct antagonism of CXCR4 by AMD3100 may provide a more rapid and possibly less toxic and cumbersome alternative to traditional G-CSF-based mobilization in normal donors. This trial was registered as no. NCT00241358 at www.ClinicalTrials.gov.