Reconstitution of cytomegalovirus-specific T-cell immunity following unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with posttransplant cyclophosphamide

Huntley, Dixie; Giménez, Estela; Pascual, Marı́a; Remigia, María José; Amat, Paula; Vázquez, Lourdes; Hernández, Marta; Hernández‐Boluda, Juan Carlos; Gago, Beatriz; Piñana, José Luís; García, María Inmaculada García; Martínez, Ariadna Pérez; Mateo, Eva M.; Gozalbo-Rovira, Roberto; Albert, Eliseo; Solano, Carlos; Navarro, David

doi:10.1038/s41409-020-0865-x

Cited by 10 publications

(20 citation statements)

References 37 publications

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“…In another retrospective study with thiotepa based conditioning and PBSCs as graft in Haplo setting, pre-transplantation ATG (1 mg/kg from day−6 to day−2) and the PT-Cy were used as GVHD prophylaxis. It showed that the 2-year cumulative incidences of III-IV aGVHD, severe cGVHD, NRM and relapse were 16, 16, 26, and 26%, respectively, which compared favorably with those of other reports using BM as graft (21).…”

Section: Discussionsupporting

confidence: 66%

“…As to the safety of the protocol, we observed a quite high incidence of CMV reactivation particularly in patients transplanted from MUD or Haplo donor (14/16) vs. MSD (2/7, p<0.001). This high incidence of CMV reactivation may attribute to late addition of ATG even with low dose of 2.5 mg/kg due to its direct immune suppression and/or delay of CMV specific immune reconstitution (26). In further clinical study, reducing the dose of ATG or more effective CMV prophylaxis such as use of letermovir after ATG should be considered (27).…”

Section: Discussionmentioning

confidence: 99%

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Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study

et al. 2021

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The PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT 04118075.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study

et al. 2021

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“…Initial studies hypothesized that the high incidence of CMV-I correlated with delayed CD4 + T cell and dendritic cell recovery [ 39 , 40 ]. Also, CMV-I has a strong impact on the integrity and heterogeneity of the T cell repertoire, leading to CD8 + effector memory T cell expansion and contraction of naïve cells [ 41 ]. However, a recent report found that CMV-specific-T-cell reconstitution in T-cell replete haploSCT with PTCy was comparable to other types of alloSCT without PTCy [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Severe infections and infection-related mortality in a large series of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide

Esquirol

Pascual

Kwon

et al. 2021

Bone Marrow Transplant

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Severe infections and their attributable mortality are major complications in recipients of allogeneic hematopoietic stem cell transplantation (alloSCT). We herein report 236 adult patients who received haploSCT with PTCy. The median follow-up for survivors was 37 months. The overall incidence of bloodstream infections by gram-positive and gram-negative bacteria at 37 months was 51% and 46%, respectively. The incidence of cytomegalovirus infection was 69%, while Epstein Barr virus infections occurred in 10% of patients and hemorrhagic cystitis in 35% of cases. Invasive fungal infections occurred in 11% at 17 months. The 3-year incidence of infection-related mortality was 19%. The median interval from transplant to IRM was 3 months (range 1–30), 53% of IRM occurred >100 days post-haploSCT. Risk factors for IRM included age >50 years, lymphoid malignancy, and developing grade III-IV acute GvHD. Bacterial infections were the most common causes of IRM (51%), mainly due to gram-negative bacilli BSI. In conclusion, severe infections are the most common causes of NRM after haploSCT with PTCy, with a reemergence of gram-negative bacilli as the most lethal pathogens. More studies focusing on the severe infections after haploSCT with PTCy and differences with other types of alloSCT in adults are clearly warranted.

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“…Huntley et al . reported >1 and >1.2 counts/mL of IFN-γ + CMV-specific CD8 + and CD4 + T cells, respectively, to protect against reactivation following haplo-HSCT with pt-cy, 13 but other studies, predominantly on HLAmatched HSCT recipients, reported that multifunctional responses have a stronger predictive value. 14 , 15 We did not detect a significant difference in the total count of CMV-specific CD8 + or CD4 + T cells in the first 6 months post-transplant between patients with subclinical versus clinical CMV viremia, although CMV-specific CD4 + T cells tended to be present in higher amounts among patients with subclinical CMV ( Figure 3A ).…”

mentioning

confidence: 97%

Single-cell profiling reveals the dynamics of cytomegalovirus-specific T cells in haploidentical hematopoietic stem cell transplantation

et al. 2021

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Reconstitution of cytomegalovirus-specific T-cell immunity following unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with posttransplant cyclophosphamide

Cited by 10 publications

References 37 publications

Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study

Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study

Severe infections and infection-related mortality in a large series of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide

Single-cell profiling reveals the dynamics of cytomegalovirus-specific T cells in haploidentical hematopoietic stem cell transplantation

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