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Background This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts. Methods A retrospective study ( n  = 339) and a prospective study ( n  = 340) were performed. MRD was determined using multiparameter flow cytometry. Results Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings ( P  < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos ( P  = 0.866 and 0.161, respectively). In either the retrospective ( n  = 65) or the prospective study ( n  = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT ( P  < 0.001 and p  = 0.017, respectively). Of the patients with pre-MRDpos in either the total ( n  = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n  = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT ( P  < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI. Conclusions The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.

To define the efficacy of a single dose of 375 mg/m2 rituximab for DSA-positive patients with 2000 ≤ MFI < 10,000, we enrolled a prospective clinical cohort including patients with positive DSA treated with rituximab (n = 55, cohort A), a matched-pair cohort including cases with negative DSA (n = 110, cohort B) and a historical cohort including subjects with 2000 ≤ MFI < 10,000 without receiving any treatment for DSA (n = 22, cohort C). The incidences of primary poor graft function (PGF) in cohort A and cohort B were 5% and 1% (P = 0.076), respectively, both of which were lower than that in cohort C (27%, P < 0.001, for all). Rituximab was associated with a reduced incidence of primary PGF (HR 0.200, P = 0.023). The 3-year nonrelapse mortality of patients in cohort A and cohort B were 23% and 24%, respectively, both of which were lower than that in the cohort C (37%), although no statistical significance was observed. These results led to a low 3-year overall survival in patients in the cohort C (58%) compared with those in the cohort A (71%) and the cohort B (73%). We suggest that a single dose of rituximab could be effectively used to prevent the onset of primary PGF. The prospective cohort of this study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672.

Background Previous reports suggest a benefit associated with haploidentical donor transplantation (HIDT) compared to matched sibling donor transplantation (MSDT) in certain contexts, and the choice of optimal candidates warrants further investigation. Methods We designed a prospective genetically randomized study to evaluate donor options between acute lymphoblastic leukemia (ALL) patients positive for measurable residual disease (MRD) pre-transplantation who underwent HIDT ( n = 169) or MSDT ( n = 39). Results The cumulative incidence of positive MRD post-transplantation was 26% (95% CI, 19–33%) and 44% (95% CI, 28–60%) for HIDT and MSDT, respectively ( P = 0.043). Compared to the HIDT cohort, the MSDT cohort had a higher 3-year cumulative incidence of relapse (CIR; 47%, 95% CI, 31–63% vs. 23%, 95% CI, 17–29%; P = 0.006) and lower 3-year probability of leukemia-free survival (LFS; 43%, 95% CI, 27–59% vs. 65%, 95% CI, 58–72%; P = 0.023) and overall survival (OS; 46%, 95% CI, 30–62% vs. 68%, 95% CI, 61–75%; P = 0.039), without a difference in non-relapse-mortality (10%, 95% CI, 1–19% vs. 11%, 95% CI, 6–16%; P = 0.845). Multivariate analysis showed that HIDT is associated with a low CIR (HR = 0.364; 95% CI, 0.202–0.655; P = 0.001) and better LFS (HR = 0.414; 95% CI, 0.246–0.695; P = 0.001) and OS (HR = 0.380; 95% CI, 0.220–0.656; P = 0.001). Conclusions HIDT is better than MSDT in view of favorable anti-leukemia activity for patients with pre-transplantation MRD positive ALL. The current study paves the way to determine that haploidentical donors are the preferred choice regardless of available matched sibling donors in a subgroup population. Trial registration ClinicalTrials.gov Identifier: NCT02185261. Registered July 9, 2014. https://clinicaltrials.gov/ct2/show/NCT02185261?term=NCT02185261&draw=2&rank=1 .

Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosa-associated invariant T (MAIT) cells are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT cells in the occurrence of gut aGVHD in humans. In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyze the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAIT cells. The number and distribution of MAIT cells in intestinal tissues were analyzed by immunofluorescence technology. Our study showed that the number and frequency of MAIT cells in infused grafts in gut aGVHD patients were lower than those in no-gut aGVHD patients. Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early posttransplantation period (+14 days). At the onset of gut aGVHD, the number of MAIT cells decreased in peripheral blood, and the activation marker CD69, chemokine receptors CXCR3 and CXCR4, and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAIT cells secreted more granzyme B, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ under the interleukin (IL)-12/IL-18 stimulation [non-T-cell receptor (TCR) signal] and secreted most of the IL-17 under the cluster of differentiation (CD)3/CD28 stimulation (TCR signal). MAIT cells inhibited the proliferation of CD4+ T cells in vitro . In conclusion, the lower number of MAIT cells in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAIT cells in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAIT cells and promoted the expression of intestinal protective factors to affect the occurrence of gut aGVHD in humans.

For allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, preemptive interferon-α (IFN-α) therapy is considered as a useful method to eliminate the minimal residual disease (MRD). Our purpose is to assess the long-term efficacy of preemptive IFN-α therapy in acute myeloid leukemia (AML) patients following allo-HSCT based on two registry studies (#NCT02185261 and #NCT02027064). We would present the final data and unpublished results of long-term clinical outcomes with extended follow-up. We adopted polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) to monitor MRD, and a positive result of bone marrow specimen examined by either of them would be identified as the MRD-positive status. Subcutaneous injections of recombinant human IFN-α-2b were performed for 6 cycles, and prolonged IFN-α therapy could be permitted at the request of patients. The median cycles were 3.5 (range, 0.5–30.5) cycles. A total of 9 patients suffered from grade ≥3 toxicities (i.e., infectious: n = 6; hematologic: n = 3). The 6-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 13.0% (95% confidence interval [CI], 5.4–20.6%) and 3.9% (95%CI, 0.0–17.6%), respectively. The probability of disease-free survival at 6 years following IFN-α therapy was 83.1% (95%CI, 75.2–91.9%). The probability of overall survival at 6 years following IFN-α therapy was 88.3% (95%CI, 81.4–95.8%). The cumulative incidences of total chronic graft-versus-host disease (cGVHD) and severe cGVHD at 6 years following IFN-α therapy were 66.2% (95%CI, 55.5–77.0%) and 10.4% (95%CI, 3.6–17.2%), respectively. Multivariable analysis showed that an alternative donor was associated with a lower risk of relapse and the better disease-free survival. Thus, preemptive IFN-α therapy could clear MRD persistently, prevent relapse truly, and improve long-term survival in AML patients following allo-HSCT.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III–IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67–3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%–72.2%) and 55.4% (95% CI = 44.3%–69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%–29.5%) and 33.8% (95% CI = 21.8%–45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

This study investigated the epidemiological characteristics of cytomegalovirus retinitis (CMVR) after haploidentical hematopoietic stem cell transplantation (HSCT). We studied a cohort of 1466 consecutive patients who had undergone haploidentical HSCT between 2013 and 2017. We documented 34 episodes of CMVR in 31 patients, with a median onset of 167 days after the transplant. The cumulative incidence of CMVR was 2.3% 1 year after the transplant. Multivariate analysis suggested that platelet engraft failure at 100 days, EBV DNAemia, refractory or recurrent CMV DNAemia, and acute graft-versus-host disease were related to the development of CMVR in patients with CMV DNAemia. Patients with ≥3 risk factors (high risk) had a higher 1-year incidence of CMVR than patients with ≤2 risk factors (low risk) (26.2% vs. 0.6%, P < 0.001). In patients with CMVR, visual acuity (VA) improved in 16 episodes, remained stable in 10 episodes, and worsened in 8 episodes. The variable related to the improvement of VA was VA ≥ 0.1 at time of CMVR diagnosis. Our study showed that CMVR was a rare complication after haploidentical HSCT but that the risk was greater in patients with multiple risk factors.

Background Acute graft-versus-host disease (aGVHD) remains the major cause of early mortality after haploidentical related donor (HID) hematopoietic stem cell transplantation (HSCT). We aimed to establish a comprehensive model which could predict severe aGVHD after HID HSCT. Methods Consecutive 470 acute leukemia patients receiving HID HSCT according to the protocol registered at https://clinicaltrials.gov (NCT03756675) were enrolled, 70% of them (n = 335) were randomly selected as training cohort and the remains 30% (n = 135) were used as validation cohort. Results The equation was as follows: Probability (grade III–IV aGVHD) =  1 1 + exp - Y , where Y = –0.0288 × (age) + 0.7965 × (gender) + 0.8371 × (CD3 + /CD14 + cells ratio in graft) + 0.5829 × (donor/recipient relation) − 0.0089 × (CD8 + cell counts in graft) − 2.9046. The threshold of probability was 0.057392 which helped separate patients into high- and low-risk groups. The 100-day cumulative incidence of grade III–IV aGVHD in the low- and high-risk groups was 4.1% (95% CI 1.9–6.3%) versus 12.8% (95% CI 7.4–18.2%) ( P  = 0.001), 3.2% (95% CI 1.2–5.1%) versus 10.6% (95% CI 4.7–16.5%) ( P  = 0.006), and 6.1% (95% CI 1.3–10.9%) versus 19.4% (95% CI 6.3–32.5%) ( P  = 0.017), respectively, in total, training, and validation cohort. The rates of grade III–IV skin and gut aGVHD in high-risk group were both significantly higher than those of low-risk group. This model could also predict grade II–IV and grade I–IV aGVHD. Conclusions We established a model which could predict the development of severe aGVHD in HID HSCT recipients.

Background Small studies suggest an association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with primary graft failure (GF) following haploidentical stem cell transplantation, but primary graft rejection (GR) was not discriminated from primary poor graft function (PGF). In this study, we aimed to determine the association of DSAs with primary GF, including GR and PGF, in patients who underwent unmanipulated haploidentical blood and marrow transplantation. Methods A total of 345 subjects were prospectively recruited and randomly selected as training group ( n  = 173) and validation group ( n  = 172). Patient plasma/serum was screened. For HLA antibody positive samples with a median fluorescent intensity (MFI) >500, DSAs were further tested using a LABScreen Single Antigen Kit (One Lambda). Results A total of 342 patients (99.1 %) achieved sustained myeloid engraftment. The median times to neutrophil engraftment and platelet engraftment were 13 days (range, 8–28 days) and 18 days (range, 6–330 days), respectively. The cumulative incidence of primary GF was 6.4 ± 1.3 % and included GR (0.9 ± 0.5 %) and PGF (5.5 ± 1.2 %). Of the 345 cases tested, 39 (11.3 %) were DSA positive. Multivariate models showed that DSAs (MFI ≥ 10,000) were correlated to primary GR ( P  < 0.001) and that DSAs (MFI ≥ 2000) were strongly associated with primary PGF ( P  = 0.005). All patients were classified into three groups for analysis. Group A included cases that were DSA negative and those with a DSA MFI <2000 ( n  = 316), group B included cases with a 2000 ≤ MFI < 10,000 ( n  = 19), and group C included cases with a MFI ≥10,000 ( n  = 10). The DSAs were associated with an increased incidence of the primary GF (3.2 vs. 31.6 vs. 60 %, for groups A, B, and C, respectively, P  < 0.001), transplant-related mortality (TRM) rate (17.2 vs. 14.7 vs. 33.3 %, for groups A, B, and C, respectively, P  = 0.022), and inferior overall survival (OS, 77.3 vs. 85.3 vs. 44.4 %, for groups A, B, and C, respectively, P  = 0.015). The primary GF was independently associated with a higher incidence of TRM ( P  < 0.001), inferior disease-free survival ( P  < 0.001), and OS ( P  < 0.001). Conclusions The findings confirmed the effect of DSAs on primary GF, including GR and PGF, and survival. Our results suggest incorporating DSAs in the algorithm for haploidentical donor selection.

Background The optimal monitoring schedules and cutoff minimal residual disease (MRD) levels for the accurate prediction of relapse at all time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with t(8;21) acute myeloid leukemia (AML). Methods RUNX1-RUNX1T1 transcript levels were measured in bone marrow samples collected from 208 patients at scheduled time points after transplantation (1530 samples in total). Results A total of 92.3% of the requested samples were collected, and 74.0% of patients had complete sample collection. The 1-, 3-, and 6-month RUNX1-RUNX1T1 transcript levels could significantly discriminate between continuous complete remission and a hematologic relapse at 1.5–3, 4–6, and 7–12 months but not at >3, >6, and >12 months, respectively. Over 90% of the 175 patients who were in continuous complete remission had a ≥3-log reduction in RUNX1-RUNX1T1 transcript levels from the time of diagnosis at each time point after transplantation and a ≥4-log reduction at ≥12 months. A <3-log reduction within 12 months and/or a <4-log reduction at ≥12 months was significantly related to a higher 3-year cumulative incidence of relapse (CIR) rate in both the entire cohort and the patients with no intervention after HSCT (58.4 vs. 2.2%, 76.5 vs. 2.0%; all P  < 0.0001). Patients who had received a preemptive donor lymphocyte infusion when the increase in RUNX1-RUNX1T1 transcripts was ≤1-log according to the above dual cutoff values had significantly lower 1-year CIR rate after intervention than the patients who had received an infusion when the increase was >1-log (0 vs. 55.0%, P  = 0.015). Conclusions RUNX1-RUNX1T1 transcripts with a <3-log reduction from diagnosis within 12 months and/or a <4-log reduction at ≥12 months after allo-HSCT could accurately predict relapse and may prompt a timely intervention in patients with t(8;21) AML.