Stem Cell Mobilization With Plerixafor in Diabetic vs Control Subjects
Condition: Diabetes
Study type: Interventional
Phase: Phase 4

Summary: 
      The objective of this study is to assess whether there are differences in the mobilization of
      CD34+ cells and EPC in response to Mozobil in patients with diabetes mellitus compared to
      subjects without diabetes. Currently, there are no non-invasive methods for the study of bone
      marrow function in humans. This project aims to evaluate in patients with type 1 or type 2
      diabetes mellitus the ability to mobilize CD34+ cells and EPC from the bone marrow to the
      periphery in response to the exogenous mobilizing agent AMD3100 / plerixafor (Mozobil),
      compared with a group of non-diabetic individuals. While it has been recently shown that
      diabetic patients do not respond to mobilization induced by G-CSF (Filgrastim), the
      investigators herein hypothesize that diabetic patients can adequately respond to
      mobilization induced by Plerixafor
    

Detailed description: 
      Scientific background. Diabetes mellitus is associated with an increased prevalence and
      incidence of cardiovascular diseases. It is believed that the high cardiovascular risk in
      diabetes is attributable to the adverse effects of glucotoxicity and lipotoxicity on
      endothelial cells. Recent data indicate that endothelial repair mechanisms play an important
      role in determining the integrity of the endothelium and thus the global health of the
      cardiovascular system. Data from our research group demonstrated that the cells involved in
      endothelial regeneration and neo-angiogenesis (including CD34+ cells and endothelial
      progenitor cells, EPC) are reduced in number and dysfunctional in patients with diabetes
      mellitus. EPC belong to the CD34+ cell population and are defined based on the co-expression
      of endothelial-lineage markers, such as VEGF receptor 2 (VEGFR2 or KDR). These cells are
      further impaired in diabetic patients with cardiovascular disease. It is believed that these
      changes represent one of the causes of cardiovascular damage in diabetes.

      The mechanisms underlying the decrease of EPC and other progenitor cells in diabetes are not
      fully understood. Normally, EPC reside in the bone marrow and their circulating levels in
      peripheral blood are very low. In response to ischemic injury or vascular damage, EPC are
      mobilized from the bone marrow to peripheral blood. Data obtained in experimental models of
      diabetes mellitus indicate a defect in EPC mobilization from the bone marrow to the
      peripheral circulation in response to ischemia, which results in an impairment of the
      post-ischemic neo-angiogenetic processes. Similar experimental results were obtained by
      different research groups. Our data also show that experimental diabetes reduces the marrow
      response to exogenous mobilizing agents such as G-CSF and SCF. Other clinical data in humans
      from our and other research groups confirm the hypothesis of a defect in the bone marrow of
      patients with diabetes mellitus. In particular, diabetes causes profound alterations of the
      bone marrow microenvironment associated with microangiopathy and alteration of the stem cells
      niche. These results confirm a study in the mouse model of type 1 diabetes, in which it was
      for the first time identified a specific form of microangiopathy causing depletion of CD34+
      cells and EPC in the bone marrow.

      As a consequence of this bone marrow damage, our research group has recently shown that the
      mobilization of CD34+ cells and EPC phenotypes is profoundly defective in patients with type
      1 and 2 diabetes mellitus.

      To reach this conclusion, the investigators used a test of bone marrow reserve by
      administering low dose human recombinant G-CSF (Filgrastim). The study showed that a
      sub-maximal marrow stimulation is able to highlight differences between diabetics and
      non-diabetics and is absolutely safe, since there have been no significant side effects. In a
      hematology context, it was also previously shown that diabetes is a factor predictive of
      "poor mobilization" exposing patients to an increased risk of failing stem cell collection
      for autologous stem cell transplantation.

      From a functional/mechanistic standpoint, it has been demonstrated that an impairment of the
      CXCL12/CXCR4 axis probably contributes to the lack of mobilization of bone marrow
      stem/progenitor cells associated with diabetes. The drug AMD3100 / plerixafor (Mozobil ®) is
      a direct antagonist of CXCR4 and inhibits the cellular signal keeping stem / progenitor cells
      within the bone marrow. For this reason, AMD3100 / Plerixafor is rapidly effective for the
      mobilization of bone marrow stem cells. From an experimental point of view, it was observed
      that diabetic animals, although not responsive to mobilization induced by ischemia and G-CSF,
      are responsive to mobilization induced by AMD3100 / Plerixafor. Mozobil is currently approved
      in Italy for stem cell mobilization in patients with multiple myeloma or lymphoma for the
      purpose of auto-transplantation, in combination with G-CSF, in poorly mobilizing patients
      (see SmPC). At this stage, the effectiveness of Mozobil in inducing mobilization of stem /
      progenitor cells in diabetic patients has not yet been tested.

      Scientific question. The objective of this study is to assess whether there are differences
      in the mobilization of CD34+ cells and EPC in response to Mozobil in patients with diabetes
      mellitus compared to subjects without diabetes. Currently, there are no non-invasive methods
      for the study of bone marrow function in humans. This project aims to evaluate in patients
      with type 1 or type 2 diabetes mellitus the ability to mobilize CD34+ cells and EPC from the
      bone marrow to the periphery in response to the exogenous mobilizing agent AMD3100 /
      plerixafor (Mozobil), compared with a group of non-diabetic individuals. While it has been
      recently shown that diabetic patients do not respond to mobilization induced by G-CSF
      (Filgrastim), the investigators herein hypothesize that diabetic patients can adequately
      respond to mobilization induced by Plerixafor.

      Plausibility and clinical relevance. It is believed that alterations of stem/progenitor cells
      secondary to a bone marrow defect contribute to the development of clinical diabetic
      microangiopathy and macroangiopathy. For this reason, it is of great interest to explore the
      mechanisms causing an progenitor cell defects in diabetes and the possible strategies to cope
      with this. A wealth of data coming from animal, human and epidemiologic studies indicate that
      the mobilizing response to G-CSF is impaired in diabetic patients. Therefore, stem
      mobilization in diabetes has to be considered an "unmet clinical need". On the other side,
      preclinical experimental data in animal models of diabetes indicate that AMD3100 / Plerixafor
      is able to mobilize stem and progenitor cells. The clinical relevance of the project lies in
      the possibility to identify a treatment able to restore stem/progenitor cell mobilization in
      diabetes. This can have favorable implications for chronic diabetic complications, such as
      microangiopathy and cardiovascular diseases. In fact, this project is relevant from a
      pathophysiological point of view, since it is believed that EPC should protect against
      vascular complications of diabetes. Furthermore, from a hematologic standpoint, being aware
      that diabetic patients are hyporesponsive to G-CSF whilst responding adequately to Plerixafor
      would allow to individualize mobilization protocols in view of an autologous hematopoietic
      stem cell transplantation.

      Expected adverse events. Treatment with Mozobil in combination with G-CSF may be associated
      with mild adverse events (see SmPC). Compared to placebo + G-CSF, the use of Mozobil + G-CSF
      in patients from two clinical trials induced a significantly higher number of grade 1-2
      adverse reactions: diarrhea (37% vs 17%), nausea (34% vs 22%), flatulence (7% vs 3%),
      injection site reactions (34% vs 10%), dizziness (11% vs 6%). No side effects of grade 3-4
      were reported.

      In the present study Mozobil will be given as monotherapy, ie not in combination with G-CSF.
      Based on literature data, adverse events that may be expected with this type of treatment are
      mild:

        -  In a study of 20 healthy volunteers grade 1 side effects were reported in response to a
           monotherapy treatment with Mozobil sc: cramps or bloating, flatulence, dry mouth.

        -  In a study that involved 10 healthy volunteers treated with Mozobil sc monotherapy the
           following mild side effects were observed (grade 1): erythema or itching at the site of
           injection, headache, perioral paresthesia, nausea, abdominal swelling.

        -  A study that involved 25 healthy donors treated with Mozobil sc monotherapy reported the
           following adverse events of grade 1 (mild): dizziness, nausea, flatulence, discomfort or
           feeling of warmth at the injection site, perioral paresthesias, sweating, cephalea.

      On the basis of these data, it can be assumed that the use of Mozobil monotherapy is safe and
      expected side effects are mild and tolerable for the patient.

      In addition, as with almost all drugs, Mozobil can induce allergic reactions and anaphylaxis.
    

Intervention name(s): Mozobil
Intervention type(s): Drug
Intervention description(s): Subcutaneous injection of 0.24 mg/kg Mozobil once at 8:30am
Other intervention name(s): Plerixafor; AMD3100
Intervention MeSH terms: Plerixafor
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Stem cells; Bone marrow