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CD34-selected stem cell boost as therapy for late graft rejection following allogeneic transplantation for sickle cell disease

Bone Marrow Transplantation volume 57, pages 1592–1594 (2022)Cite this article

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A Correction to this article was published on 19 October 2022

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Allogeneic hematopoietic stem cell transplantation (HCT) is a curative option for patients with sickle cell disease (SCD). While initial transplant approaches utilized predominantly myeloablative conditioning (MAC), more recently, conditioning regimens have expanded to include lower intensity combinations to offset organ toxicities [1, 2]. Due to robust host immune competence, full donor chimerism (DC) is not achieved post-HCT in all recipients and mixed chimerism (MC) is observed. Rates of MC in SCD patients following MAC and reduced intensity conditioning (RIC) regimens range from 27% to 44% [2, 3], while MC is universal following non-myeloablative (NMA) conditioning [1]. In the setting of MC, donor cell engraftment in the myeloid/erythroid compartment as low as 20–25% has been demonstrated to be sufficient for abrogation of SCD symptoms [4]. However, unstable/declining MC can result in eventual graft loss presumably mediated by recipient immune system recovery. While donor lymphocyte infusions (DLI) have been used in patients with declining DC to prevent graft loss, this intervention comes with a risk of graft-versus-host disease (GVHD) which is unacceptable in non-malignant disorders (NMD) [5, 6]. A stem cell boost (SCB), if successful, can avoid this risk and achieve the same goal [7, 8]. We report a successful strategy of lymphodepletion followed by a SCB in three children with SCD and declining DC following a RIC HCT.

There is no consensus on interventions for declining DC following allogeneic HCT, especially in SCD patients. In a registry based retrospective analysis of 996 SCD patients who underwent allogeneic HCT, GR rates were 7%, 17%, 21% and 44% following MSD, matched unrelated donor, MMUD and haploidentical donor HCT respectively [9]. Rescue interventions that include a second HCT, DLI or SCB are indicated in the setting of recurrence or progression of SCD manifestations, decline in donor myeloid or erythroid chimerism to <20%, rising Hb S levels or an absolute Hb S level of >50% when donors have sickle cell trait. A second HCT is associated with increased risk of toxicity [10, 11]. DLI is associated with a 40–60% risk of acute GVHD and 33–61% risk of chronic GVHD [5, 6]. In contrast, with a CD34 selected SCB, rates of GVHD have ranged from 0–13% for both acute and chronic GVHD [7, 8]. Therefore a CD34 SCB is a more desirable strategy for patients with NMD. Following NMA transplants, intensification of immunosuppression can help stabilize /improve DC [1]. However, this strategy did not benefit P3. Similar to MAC, we have noted that withdrawal of immunosuppression is more conducive to stabilizing donor engraftment following this immune-ablative regimen in NMD transplants. Here we demonstrate the achievement of donor engraftment stability and successful mitigation of SCD symptoms/ radiographic vasculopathy progression following SCB and was used due to imminent or overt disease progression. Ngwube et al. [12] employed a single dose of r-ATG (2.5 mg/kg) pre-SCB and a short course of sirolimus in three SCD patients with declining DC following a RIC MSD HCT. In contrast to the appreciable stable improvement in both donor myeloid and lymphoid chimerism noted in our patients this strategy had a modest increase in donor myeloid chimerism (when available) and donor lymphoid chimerism was relatively unaffected leaving the long-term durability of this strategy in question. P1 and P2 both MSD recipients, received the intervention outpatient and in the presence of CD3 depletion received no additional GVHD prophylaxis. P3 (MMUD recipient) was treated inpatient through neutrophil recovery and received 3 months of immunosuppression. Post-SCB no patient developed GVHD and immune reconstitution was robust. In summary, a SCB following lymphodepletion was able to rescue and stabilize engraftment in patients with gradual decline in DC levels following initial engraftment and persistent donor CD3 engraftment at varying levels. The efficacy of this strategy in patients with early primary GR is untested. Based on this experience, we recommend SCB based interventions over other options in patients with NMD and declining DC where stabilization of engraftment achieves long-term disease control.

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Fig. 1: Trends in Donor Chimerism and Sickle Cell Hemoglobin (HbS) percentage before and after Stem Cell Boost (SCB).

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Authors and Affiliations

  1. Department of Pediatric Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH, USA

    Hemalatha G. Rangarajan & Sara A. Crowell

  2. Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA

    Alison S. Towerman & Shalini S. Shenoy

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  1. Hemalatha G. Rangarajan
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  2. Sara A. Crowell
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  4. Shalini S. Shenoy
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HGR and SSS conceptualized the report, wrote and edited the manuscript. SAC and AST collected the data and edited the manuscript.

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Correspondence to Hemalatha G. Rangarajan.

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The original online version of this article was revised: In the original article we state “Following informed consent, all three patients received fludarabine 100 mg/m2 on days −6 to −3, cyclophosphamide 60 mg/kg on days −3 and −2, and rabbit anti-thymocyte globulin (r-ATG) 10 mg/kg on days −5 to −2.”. It should be read: Following informed consent, all three patients received fludarabine 25 mg/m2 on days −6 to −2 (total dose 125 mg/m2, cyclophosphamide 60 mg/kg on days −3 and −2 (total dose 120 mg/kg) and rabbit anti-thymocyte globulin (r-ATG) 2.5 mg/kg on days −5 to −2 (total dose 10 mg/kg).

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Rangarajan, H.G., Crowell, S.A., Towerman, A.S. et al. CD34-selected stem cell boost as therapy for late graft rejection following allogeneic transplantation for sickle cell disease. Bone Marrow Transplant 57, 1592–1594 (2022). https://doi.org/10.1038/s41409-022-01749-9

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