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The effect of iron overload on the mobilization of peripheral blood hematopoietic stem cells in pediatric patients with thalassemia major
Van Timothee, B. M., Du, J., Ren, Y., He, Y., Ruan, Y., Liu, X., Chen, L., Wen, J., Ding, R., Yu, L., et al
Acta haematologica. 2023
Abstract
INTRODUCTION The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with ꞵ-thalassemia major (TM). METHODS We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload measured by magnetic resonance imaging (MRI) T2*. RESULTS The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI, and lower leukapheresis-product WBC count and and CD34+ cell levels (all, P < 0.05). CONCLUSION Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload , in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.
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Optimizing haematopoietic stem and progenitor cell apheresis collection from plerixafor-mobilized patients with sickle cell disease
Sharma, A., Leonard, A., West, K., Gossett, J. M., Uchida, N., Panch, S., Stroncek, D., Poston, L., Akel, S., Hankins, J. S., et al
British journal of haematology. 2022
Abstract
We adjusted haematopoietic stem and progenitor cell (HSPC) apheresis collection from patients with sickle cell disease (SCD) by targeting deep buffy coat collection using medium or low collection preference (CP), and by increasing anticoagulant-citrate-dextrose-solution A dosage. In 43 HSPC collections from plerixafor-mobilized adult patients with SCD, we increased the collection efficiency to 35.79% using medium CP and 82.23% using low CP. Deep buffy coat collection increased red blood cell contamination of the HSPC product, the product haematocrit was 4.7% with medium CP and 6.4% with low CP. These adjustments were well-tolerated and allowed efficient HSPC collection from SCD patients.
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Disease severity impacts plerixafor-mobilized stem cell collection in patients with sickle cell disease
Leonard, A., Sharma, A., Uchida, N., Stroncek, D., Panch, S. R., West, K., Molloy, E., Hughes, T. E., Hauffe, S., Taylor, T., et al
Blood advances. 2021;5(9):2403-2411
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Abstract
Recent studies suggest that plerixafor mobilization and apheresis in patients with sickle cell disease (SCD) is safe and can allow collection of sufficient CD34+ hematopoietic stem cell (HSC) collection for clinical gene therapy applications. However, the quantities of plerixafor-mobilized CD34+ cells vary between different SCD patients for unknown reasons. Twenty-three participants with SCD underwent plerixafor mobilization followed by apheresis, processing, and HSC enrichment under a phase 1 safety and efficacy study conducted at 2 institutions. Linear regression or Spearman's correlation test was used to assess the relationships between various hematologic and clinical parameters with total CD34+ cells/kg collected. Median CD34+ cells/kg after 2 or fewer mobilization and apheresis cycles was 4.0 × 106 (range, 1.5-12.0). Similar to what is observed generally, CD34+ yield correlated negatively with age (P < .001) and positively with baseline (P = .003) and preapheresis blood CD34+ cells/µL (P < .001), and baseline white blood cell (P = .01) and platelet counts (P = .03). Uniquely for SCD, CD34+ cell yields correlated positively with the number of days hydroxyurea was held (for up to 5 weeks, P = .01) and negatively with markers of disease severity, including hospitalization frequency within the preceding year (P = .01) and the number of medications taken for chronic pain (P = .002). Unique SCD-specific technical challenges in apheresis were also associated with reduced CD34+ cell collection efficiency and purification. Here, we describe factors that impact plerixafor mobilization success in patients with SCD, confirming known factors as described in other populations in addition to reporting previously unknown disease specific factors in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03226691.
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Pre-transplant myeloid and immune suppression, upfront plerixafor mobilization and post-transplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease
Kharya, G., Bakane, A., Agarwal, S., Rauthan, A.
Bone marrow transplantation. 2020
Abstract
Allogenic hematopoietic stem cell transplant is the only curative option for symptomatic sickle cell disease (SCD). HLA haploidentical related donor transplants are associated with high graft failure rates. We conceptualized a novel protocol (APOLLO protocol) using pre-transplant immune and myelosuppression (PTIS) using fludarabine, cyclophosphamide, and dexamethasone followed by augmented John Hopkins protocol by adding thiotepa to conditioning. Twenty-five consecutive patients suffering from symptomatic SCD were enrolled into the study. We added upfront plerixafor to granulocyte colony stimulating factor (GCSF) for mobilization of healthy donors. Graft versus host disease (GvHD) prophylaxis was done using post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil. Graft failure was not seen in any of our patients. Five patients developed acute grade II/IV GvHD (4 classical acute, 1 late onset), 3 had limited chronic GvHD. Out of 25 evaluable patients, 22 are alive and disease free, making an overall survival (OS) and disease-free survival (DFS) of 88% with a median follow up of 485 days (range 198-802). T-cell-replete haploidentical transplant with PTIS, augmented John Hopkins conditioning and plerixafor based mobilization is a safe and effective way of treating patients suffering from SCD with minimal or no risk of graft failure and acceptable GvHD rates.
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G-CSF-mobilized blood and bone marrow grafts as the source of stem cells for HLA-identical sibling transplantation in patients with thalassemia major
Li, Q., Luo, J., Zhang, Z., Liu, L., Luo, L., Yang, G., Liu, R., Shi, L., Huang, R., Wu, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
As inherited anemia, thalassemia major (TM) is currently only curable with allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we report an allo-HSCT protocol for TM patients who received a combination of granulocyte-colony-stimulating factor-primed bone marrow and peripheral blood stem cells (G-BM&PBSCs) from their matched sibling donors (MSD). The conditioning regimen consisted of intravenous busulfan, cyclophosphamide, fludarabine, and anti-thymocyte globulin. Chimerism analysis was performed for all patients. Immunosuppressive treatment was terminated if rejection was suspected, and the donor-lymphocyte infusion was given once no response was observed. A total of 184 TM patients were enrolled in this study between July 2007 and July 2018. The cumulative incidence of grade II-IV acute graft versus host disease (GvHD) and moderate or severe chronic GvHD was 13.1% and 5.7%, respectively. The cumulative incidence of graft rejection rate was 0.6%. The 3-year overall survival, thalassemia-free and GvHD-free survival, and relapse-free survival of all patients were 97.8%, 97.3%, and 89.5%, respectively. Collectively, our results indicated that G-BM&PBSCs from MSD could be employed as a good source of stem cells for TM patients undergoing allo-HSCT.
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Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with beta-thalassemia major
Constantinou, V. C., Bouinta, A., Karponi, G., Zervou, F., Papayanni, P. G., Stamatoyannopoulos, G., Anagnostopoulos, A., Yannaki, E.
Transfusion. , 2016 Dec 17. 2016
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Abstract
BACKGROUND Hematopoietic stem cell mobilization and leukapheresis in adult patients with beta-thalassemia have recently been optimized in the context of clinical trials for obtaining hematopoietic stem cells for thalassemia gene therapy. In some patients, however, the yield of cluster of differentiation 34-positive (CD34+) cells was poor despite successful mobilization, and a modification of apheresis settings was mandatory for harvest rescue. STUDY DESIGN AND METHODS Data were analyzed from 20 adult patients with beta-thalassemia who were enrolled in a clinical trial of optimizing mobilization strategies for stem cell gene therapy. The aim of this post-hoc analysis was to assess how certain hematological and/or clinical parameters may correlate with low collection efficiency in the presence of adequate numbers of circulating stem cells after pharmacological mobilization and standard leukapheresis procedures. RESULTS Among 19 patients who achieved optimal mobilization with Plerixafor, four who underwent splenectomy demonstrated disproportionately poor CD34+ cell harvests, as determined by their circulating CD34+ cell counts after mobilization. All four patients who underwent splenectomy presented at baseline and before first apheresis with lymphocytosis resulting in lymphocyte/neutrophil ratios well above 1 and marked reticulocytosis compared with patients who achieved optimal mobilization/CD34+ cell harvest. Such unexpected expansion of specific cell populations disrupted the normal cell layer separation and necessitated modification of the apheresis settings to rescue the harvests. CONCLUSIONS By close examination of certain hematological and/or clinical parameters before leukapheresis, patients who, despite adequate mobilization, are at risk for poor CD34+ cell harvests may be identified, and harvest failure can be prevented by adjusting the apheresis settings. Copyright © 2016 AABB.