Collection of blood stem cells from patients with sickle cell anemia

Richard, Robert E.; Siritanaratkul, Noppadol; Jonlin, Erica C.; Skarpidi, Eva; Heimfeld, Shelly; Blau, C. Anthony

doi:10.1016/j.bcmd.2005.06.014

Cited by 17 publications

(12 citation statements)

References 11 publications

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“… 13 , 30 , 31 Factors contributing to baseline CD34 count remain unclear, but our data and others’ suggest that baseline CD34 + concentration may be affected by hydroxyurea-related myelosuppression. 24 , 33 Patient #8, a subject re-enrolled in the study, was particularly instructive regarding this hypothesis. This patient was clinically stable on hydroxyurea at a dose of 27 mg/kg and was enrolled twice at an interval of 13 months.…”

Section: Discussionmentioning

confidence: 99%

“…In brief, because hydroxyurea can decrease ANC and platelet count, 39 hydroxyurea-related myelosuppression may have contributed to the relatively poor CD34 + mobilization obtained in this cohort. However, avoiding hydroxyurea withdrawal might lower the risk of pain crises; 24 we, therefore, plan to explore timing plerixafor administration to the peak rather than nadir of hydroxyurea-related oscillatory hematopoiesis. Finally with regards to hydroxyurea therapy, data from the six patients in whom we enumerated CD34 + CD38 − cells suggest that hydroxyurea may not adversely affect HSC, given that all patients except one (patient 10) were on hydroxyurea and a median 3-fold increase at 12 h was observed.…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxyurea may inhibit mobilization and withholding hydroxyurea for 2 weeks leads to a degree of spontaneous mobilization that abets drug-induced mobilization. 23 , 24 However, Richard et al . showed that two of the three SCD patients whose hydroxyurea was withdrawn for 2 weeks developed painful crises following the withdrawal.…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results

et al. 2018

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Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. Clinicaltrials.gov identifier: NCT02193191.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results

et al. 2018

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“…We decided to discontinue hydroxyurea treatment 3 months before the mobilization in P3 and to submit all the patients to monthly transfusions. The rationale for this decision was based on the following observations: (i) hydroxyurea has no beneficial role in CD34 + cell mobilization in thalassemic patients; 27 (ii) hydroxyurea withdrawal is associated with an increase in the number of circulating CD34 + cells in SCD patients; 28 and (iii) in various clinical settings hydroxyurea has been associated with myelosuppression 29 , 30 suggesting BM toxicity and potential impairment of HSC.…”

Section: Discussionmentioning

confidence: 99%

Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion

et al. 2018

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Sickle cell disease is characterized by chronic anemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected hematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients’ stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of hematopoietic stem and progenitor cells into the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients undergoing red blood cell exchange to decrease the hemoglobin S level to below 30%. The secondary objective was to measure the efficiency of mobilization and isolation of hematopoietic stem and progenitor cells. No adverse events were observed. Large numbers of CD34+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of hematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize hematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing. Clinicaltrials.gov identifier: NCT02212535.

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“…It has been reported that significant numbers of primitive progenitors such as myeloid‐lymphoid‐initiating cells and SCID‐repopulating cells are spontaneously mobilized during pain crises, theoretically yielding sufficient numbers of CD34 + cells/kg 32 . However, severe acute pain was experienced by a nonmobilized SC patient who was scheduled to undergo cytarapheresis and subsequent exchange transfusion for pain management 33 . The pain started 1 h after the initiation of the leukapheresis procedure and culminated during the “rinse‐back” phase when the remaining blood in the ‐hypoxic‐ separation chamber was returned to the patient.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease

Yannaki

Stamatoyannopoulos

2010

Annals of the New York Academy of Sciences

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Effective gene therapy for hemoglobinopathies will require high numbers of autologous gene-engineered hematopoetic stem cells to be reintroduced into the patients. Stem cell mobilization using G-CSF is the most convenient and effective approach to achieve this goal, but it can have severe side effects in sickle cell anemia and be potentially harmful in the case of severe thalassemia. Hence, the optimal way of collection of hematopoetic stem cells from patients with thalassemia and sickle cell disease needs to be determined. In this paper, we review the possible risks of G-CSF mobilization in hemoglobinopathies and we outline the approaches used in an on-going clinical trial in which pretreatment with hydroxyurea is used to reduce potential risks of G-CSF administration to patients with severe beta thalassemia.

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Collection of blood stem cells from patients with sickle cell anemia

Cited by 17 publications

References 11 publications

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results

Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion

Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease

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Collection of blood stem cells from patients with sickle cell anemia

Cited by 17 publications

References 11 publications

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 + hematopoietic progenitor cells in patients with sickle cell disease: interim results

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 + hematopoietic progenitor cells in patients with sickle cell disease: interim results

Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion

Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease

Contact Info

Product

Resources

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Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 ⁺ hematopoietic progenitor cells in patients with sickle cell disease: interim results