T-Cell Replete Myeloablative Haploidentical Bone Marrow Transplantation Is an Effective Option for Pediatric and Young Adult Patients With High-Risk Hematologic Malignancies

Katsanis, Emmanuel; Sapp, Lauren N.; Reid, Susie Cienfuegos; Reddivalla, Naresh; Stea, Baldassarre

doi:10.3389/fped.2020.00282

Cited by 25 publications

(38 citation statements)

References 45 publications

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“…The subsequent cohorts, currently enrolling, involve Day +3 progressive substitution of BEN for CY, resulting in complete substitution on both days in Cohort 6, with patients receiving 90 mg/m 2 each day. Some of the patients in our early cohorts of the trial were included in two broad haplo-HCT publications from our institution [63,82] and the interim analysis of our Phase I trial was recently published, including the first three cohorts of our study [83]. In this interim analysis of the first three cohorts, Katsanis et al demonstrated that patients achieved trilineage engraftment earlier as PT-BEN escalated, consistent with other murine and clinical data indicating reduced myelosuppression with BEN.…”

Section: Clinical Application Of Ben Post-transplantsupporting

confidence: 67%

“…This is especially challenging for minority patients [ 59 , 60 , 61 ]. As such, more and more institutions have begun implementing haploidentical (haplo) HCT [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. This both increases donor availability and decreases delays involved in finding and collecting stem cells from an unrelated donor.…”

Section: Post-transplant Ben In Murine Modelsmentioning

confidence: 99%

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Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation

Stokes

Molina

Hoffman

et al. 2021

Cancers

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Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.

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Section: Clinical Application Of Ben Post-transplantsupporting

confidence: 67%

Section: Post-transplant Ben In Murine Modelsmentioning

confidence: 99%

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation

Stokes

Molina

Hoffman

et al. 2021

Cancers

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“…Previous work from our laboratory has resulted in an ongoing phase I clinical trial investigating the use of bendamustine (BEN) following haploidentical transplant (2)(3)(4)(5). The most widely used conditioning regimen in alloHCT for acute lymphoblastic leukemia (ALL) is cyclophosphamide (CY) with total body irradiation (TBI) (6).…”

Section: Introductionmentioning

confidence: 99%

Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3

et al. 2020

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Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.

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“…The donor uneventfully underwent a bone marrow harvest, and her brother received a non-cryopreserved T-replete haploidentical bone marrow transplant (haplo-BMT) following conditioning with fractionated total body irradiation (200 cGy × 6) and fludarabine. 4,5 Post-transplant cyclophosphamide was given on days +3 and +4. The patient is now 45 days following his haplo-BMT and remains in remission with no evidence of infection while interestingly his serology remained positive for SARS-CoV-2 IgG on day +32.…”

Section: To the Editormentioning

confidence: 99%