Assessment of monocytic-myeloid-derived suppressive cells (M-MDSC) before and after allogeneic hematopoietic stem cell transplantation in acute leukemia patients.

In this monocentric prospective study, the influence on long-term outcomes of peripheral blood levels of monocytic-myeloid-derived suppressive cells (M-MDSC) was investigated in 56 patients with acute leukemia (myeloid n = 47; lymphoid n = 9) before and after (Days+60/+90) allogeneic hematopoietic stem cell transplantation (Allo-HSCT). A risk of relapse was found to be associated with a level of pregraft M-MDSC above 1.4% by ROC curve analysis. In multivariate analysis, this threshold retained a strong statistical significance (HR: 5.94 [2.09-16.87], p = 0.001). Considering only the group of patients who were in complete remission prior to Allo-HSCT (n = 44), a significant prediction of relapse was found to be associated, in multivariate analysis, with a level of pregraft M-MDSC above 1.4% (HR: 55.01 [14.95-202.37], p < 0.001) together with pregraft-positive measurable -residual disease (MRD) (HR: 11.04 [1.89-64.67], p = 0.008). A poorer OS (HR: 6.05 [1.24-29.59], p = 0.026) and disease-free survival (HR: 6.52 [1.41-30.19], p = 0.016) were also associated with higher levels of pregraft M-MDSC. Remarkably, no relapse occurred in patients with pregraft-negative MRD and ≤1.4% of M-MDSC (vs. a 3-year relapse rate of 60% for others, p = 0.004). Patients developing grade 3-4 acute graft-versus-host-disease (GVHD, median occurrence: day+30 posttransplant) showed significantly higher levels of M-MDSC% at days +60 and +90, suggesting a possible amplification of these immunosuppressive cells as a reaction to GVHD. In conclusion, this prospective study demonstrates a negative impact of higher proportions of peripheral M-MDSC before Allo-HSCT in leukemic patients. This paves the way to potential therapeutic intervention to decrease M-MDSC levels before Allo-HSCT and thus perhaps the incidence of relapse in such patients.

Post-transplant cyclophosphamide as sole GHVD prophylaxis after matched reduced-intensity conditioning allotransplant.

BACKGROUND: Post-transplant cyclophosphamide (PTCY) alone as graft-versus-host disease (GVHD) prophylaxis may avoid/reduce short- and mid-term toxicities of drugs commonly used for GVHD prophylaxis, accelerate immune reconstitution after the graft to decrease infections and facilitate the early integration of adjunct maintenance therapies to prevent relapse. OBJECTIVE: A prospective phase 2 study was designed in order to assess the feasibility and safety of PTCY as a sole GVHD prophylaxis in adult patients receiving a Baltimore-based reduced-intensity conditioning (RIC) peripheral blood (PB) allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with a matched donor. STUDY DESIGN: Patients were planned to be included stepwise up to 59 evaluable PTCY recipients, in order to be able to stop the protocol in case of excessive corticosteroid resistant grade 3-4 severe acute GVHD (aGVHD). Because a high incidence of grade 2-4 aGVHD was observed after analysis of the first 27 patients, the protocol was amended to test the addition of 1 day of anti-thymoglobulin to PTCY. In spite of this, the trial had to be stopped after 38 treated patients, because of an unacceptable rate of grade 3-4 aGVHD. Donors were matched related to 12 patients and unrelated to 26. RESULTS: With a median follow-up of 29.6 months, 2-year overall, disease-free and GVHD-free relapse-free (GRFS) survivals were respectively 65.4%, 62.1% and 46.9%. Cumulative incidences of grade 2-4 and 3-4 aGVHD at day 100 were 52.6% and 21.1%, respectively, while that of moderate/severe chronic(c) GVHD was 15.7% at 2 years. Addition of ATG to PTCY did influence neither aGVHD, cGVHD nor GRFS. CONCLUSION: Despite paradoxically good survivals, especially GRFS, this study failed to demonstrate that PTCY (± ATG) alone can be used for Baltimore-based RIC PB Allo-HSCT with matched donors. Other combinations should be tested to try and avoid long-term use of immunosuppressive drugs following Allo-HSCT in this setting.

Anti-SARS-CoV-2 vaccines in recipient and/or donor before allotransplant.

The impact of pre-transplant anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine in 20 recipients of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and/or their donors is reported here, showing that the persistence of anti-SARS-CoV-2 antibodies can be detected in almost all patients, whatever the type of vaccine used, and up to 9 months post transplant. Also, an anti-SARS-CoV-2 spike glycoprotein CD3+ T-cell response could be detected in six (35%) of 17 evaluable patients. This study provides a rationale to consider anti-SARS-CoV-2 vaccination of both recipients and donors before Allo-HSCT.

Prophylactic or Preemptive Low-Dose Azacitidine and Donor Lymphocyte Infusion to Prevent Disease Relapse following Allogeneic Transplantation in Patients with High-Risk Acute Myelogenous Leukemia or Myelodysplastic Syndrome.

Because of the persistently high rates of relapse of patients with high-risk acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), post-transplantation maintenance therapy has been proposed. We previously initiated a Phase II trial in which epigenetic therapy was combined with immunotherapy in an attempt to reduce disease relapse. In that study, low-dose azacitidine (AZA) and escalating doses of donor lymphocyte infusion (DLI) were given as post-allo-HSCT maintenance treatment. In the present study, we retrospectively analyze a larger cohort of patients receiving post-transplantation maintenance therapy and provide updates on some patients of the earlier study. The objectives of the present study were to analyze the cumulative incidence of relapse (CIR), overall survival (OS), and progression-free survival (PFS) and the incidence of acute and chronic graft-versus-host disease (GVHD) of patients with high-risk AML or MDS receiving post-transplantation maintenance treatment with AZA with or without DLI. We retrospectively analyzed 77 patients (54 with AML, 23 with MDS) considered at high risk based on either their genomic or clinical status at transplantation. Following allogeneic transplantation, they received at least 1 cycle of prophylactic or preemptive low-dose AZA with or without escalating doses of DLI to prevent disease relapse. Almost one-half of the patients (47%) were able to receive the full 12 cycles of scheduled AZA, and a majority (79%) received at least 1 DLI. With a median follow-up of 24 months, 19 patients (25%; 16 with AML, 3 with MDS) relapsed, at a median of 9.8 months (range, 4 to 58.6 months), giving a 22% CIR at 24 months. OS and PFS at 24 months were 70.8% and 68.3%, respectively. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 27.4% and 45%, respectively. Only a minority of patients (11%) required delayed administration of AZA. These findings confirm that AZA-DLI maintenance is both tolerable and effective in reducing the risk of post-transplantation relapse.

Early Post-Transplantation Serum Ferritin Level Predicts Survival in Recipients of Haploidentical Stem Cell Transplantation Using Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis.

The negative impact of high serum ferritin level (SFL) before and after allogeneic hematopoietic cell transplantation (allo-HSCT) on outcomes is well recognized. However, it is poorly documented in adults undergoing haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PTCY) for hematologic malignancies. The main objective was to assess the impact of pretransplantation and post-transplantation SFL on overall survival (OS), disease-free survival (DFS), and nonrelapse mortality (NRM) in patients undergoing haplo-HSCT with PTCY. The secondary objective was to identify factors associated with outcomes after transplantation by comparing SFL with other parameters related to the status of patients or donors. This multicentric retrospective study included 223 consecutive patients who underwent haplo-HSCT with PTCY in 4 French centers (Nantes, Angers, Besançon, and Brest) between October 2013 and January 2020. The impact of SFL on OS, DFS, and NRM at different time points was assessed based on receiver operating characteristic curves. With a median follow-up of 37.6 months (interquartile range, 23.5 to 51.0 months), 3-year OS, DFS, and NRM were 48.1 ± 4%, 46.3 ± 4%, and 30.0 ± 3%, respectively. Pretransplantation SFL had no impact on outcomes irrespective of the cutoff tested. Considering patients alive at 3 months post-transplantation, an SFL ≥3500 µg/L at 3 months was statistically significantly associated with worse 3-year OS (32.7 ± 8.7% versus 53.4 ± 7.2%; P = .01) and DFS (30.1 ± 8.2% versus 53.1 ± 7.1%; P = .008), with a trend toward higher NRM (33.2 ± 8.6% versus 17.6 ± 5.4%; P = .10). Similarly, high SFL (≥2700 µg/L) at 6 months post-transplantation was associated with worse 3-year OS (56.1 ± 9.1% versus 79.2 ± 6.0%; P = .02) and DFS (53.6 ± 8.7% versus 74.9 ± 6.2%; P = .01), with a trend toward higher NRM (21.4 ± 7.4% versus 8.2 ± 4.0%; P = .10). In multivariate analysis, high 3-month and 6-month FL remained associated with lower OS and DFS, with a trend toward higher NRM. Pretransplantation SFL appears to have no impact on outcomes in haplo-HSCT with PTCY, in contrast to what is documented in the matched allo-HSCT setting. In contrast, in the haplo-HSCT setting, high SFL early post-transplantation is associated with lower survival and a trend toward higher NRM.

Deauville Scores 4 or 5 Assessed by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Early Post-Allotransplant Is Highly Predictive of Relapse in Lymphoma Patients.

The impact of early fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) status on survival after allogeneic transplantation for lymphoma is poorly reported. This retrospective study included all adult Hodgkin lymphoma (HL) or non-Hodgkin lymphoma(NHL) patients (>18 years old) who benefited from FDG PET-CT before (within 1 month) and/or early (+3 months and within +6 to 9 months) after allogeneic stem cell transplantation in our institution between 2005 and 2015 and who were still without documented progression or relapse at the time of the FDG PET-CT. All FDG PET-CT were reviewed by a nuclear medicine expert in hematology and restaged according to the Deauville scale. FDG-PET CT was considered positive when the uptake was higher than liver background (Deauville score ≥ 4). The primary objective was to study the impact of pre- and post-transplant FDG PET-CT on lymphoma-free survival (LFS) and overall survival (OS). Inclusion criteria were fulfilled for 103 patients (69 men; median age, 51.6 years old; range, 22 to 67). Diagnoses were high-grade NHL (n = 47), low-grade NHL (n = 6), T cell lymphoma (n = 34), and HL (n = 16). More than half of the patients were in complete remission at the time of transplant (n = 56). A reduced-intensity conditioning regimen was applied in most cases (n = 90). With a median follow-up of 49.5 months (range, 6 to 140.5) for alive patients, median 3-year OS and LFS were, respectively, 81% (range, 71% to 87%) and 65% (range, 54% to 74%) for the entire cohort. In multivariate analysis, positive FDG PET-CT at 3 months was the strongest independent factor significantly associated with poorer LFS (hazard ratio, 9.22; 95% confidence interval, 1.88 to 645.2; P = .006). FDG PET-CT positivity at 3 months appears to be highly predictive of LFS in patients after allogeneic transplantation and may help to guide strategies to prevent relapse. These results need to be validated prospectively.