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Revisiting a single day salvage conditioning following graft failure

Bone Marrow Transplantation volume 57, pages 1845–1847 (2022)Cite this article

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Graft failure (GF) is a frequent life-threatening complication of mismatched hematopoietic cell transplantation (HCT). With the increasing application of haploidentical (haplo) HCT, GF has become an even more significant problem occurring in 5–8% of transplants [1,2,3,4]. Various factors contribute to GF, including the degree of HLA-disparity, the presence in the recipient of antibodies against donor specific HLA antigens, use of reduced intensity conditioning (RIC) regimens, suboptimal cell doses of infused CD34+ and donor-recipient relationship [5, 6]. Despite the very high mortality rate of GF, there is no unified approach on the optimal choice of conditioning regimens to salvage patients especially those that have previously received myeloablative conditioning (MAC).

While there is no standard approach to preparing patients with GF for a second HCT, there is a general consensus that additional immunosuppression is necessary for successful sustained trilineage engraftment to occur. Options with regards to intensity are usually limited especially if the first regimen was myeloablative, as organ toxicity may preclude high doses of multiagent chemotherapy. Moreover, reapplication of high dose cyclophosphamide (CY) as used post-transplant (PT-CY), may have underlying risks such as hemorrhagic cystitis, cardiomyopathy or interstitial lung disease. Recent published reports have described a variety of conditioning regimens followed by T-cell replete grafts and PT-CY or T-cell depleted HCT. A retrospective review in patients developing GF after allogeneic HCT showed improved survival with the use of fludarabine (FLU), CY and 2 Gy of total body irradiation (TBI) along with PT-CY, compared to those conditioned with other regimens although details for each regimen were missing [7]. In a smaller case series, five patients that failed to engraft following the Baltimore RIC haplo-BMT with PT-CY subsequently received MAC conditioning. This consisted of busulfan (BU) (110 mg/m2 × 4 days), FLU (25 mg/m2 × 5 days) and CY (14.4 mg/kg × 2 days) or FLU (40 mg/m2 × 4 days), melphalan (MEL) (140 mg/m2) and 2 Gy TBI followed by T-replete peripheral blood stem cell (PBSC) grafts from a different donor and PT-CY [8]. These regimens resulted in significant toxicity as two patients died of sinusoidal obstruction syndrome and one of infection. In a pediatric study, use of a RIC with 7 Gy total nodal irradiation combined with FLU (40 mg/m2 × 3 days), thiotepa (TT) (5–10 mg/kg), CY (60 mg/kg) and thymoglobulin (4.5 mg/kg over 3 days), followed by T cell-depleted PBSC grafts, from mostly a different haploidentical donor, resulted in rescue of two thirds of their patients that had developed GF after a MAC haplo-HCT but with significant grade 3–4 toxicities including mucositis, liver, pulmonary injury and infections [9].

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Fig. 1: Probability of overall survival following single day salvage conditioning.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Pediatrics, University of Arizona, Tucson, AZ, USA

    Emmanuel Katsanis

  2. Department of Immunobiology, University of Arizona, Tucson, AZ, USA

    Emmanuel Katsanis

  3. Department of Medicine, University of Arizona, Tucson, AZ, USA

    Emmanuel Katsanis

  4. Department of Pathology, University of Arizona, Tucson, AZ, USA

    Emmanuel Katsanis

  5. The University of Arizona Cancer Center, Tucson, AZ, USA

    Emmanuel Katsanis

  6. Duke Division of Hematologic Malignancies and Cellular Therapy, Durham, NC, USA

    Therese Hennig, Gwynn Long, Nelson Chao & Mitchell Horwitz

  7. Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Jacob E. Robinson

  8. Novant Health Cancer Institute, Chapel Hill, NC, USA

    David Rizzieri

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Contributions

EK and DR conceived and designed the work. EK, TH, and JER acquired and analyzed the data. EK wrote the paper. All authors interpreted the results, read, edited and approved of the final version of the paper. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Emmanuel Katsanis.

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Katsanis, E., Hennig, T., Robinson, J.E. et al. Revisiting a single day salvage conditioning following graft failure. Bone Marrow Transplant 57, 1845–1847 (2022). https://doi.org/10.1038/s41409-022-01832-1

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