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outcomes for patients that underwent allogeneic stem cell transplantation in the retrospective and prospective study
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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 p...
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Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (1...
Background:
Clofarabine has been proved to have higher anti-leukemic myeloid activity compared to fludarabine, a drug extensively used as part of reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT).
Results:
Eighty-four patients were included. The majority of patients had acute myeloid leukemia (AML, n = 63)....
Background:
Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial.
Methods:
We retrospectively c...
Background:
Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods:...
Stem cell transplantation (SCT) is an attractive post-remission treatment option for patients with intermediate-risk acute myeloid leukemia (AML) and for some favorable-risk AML patients with additional non-genetic risk factors. Autologous SCT (auto-SCT) and haplo-identical donor SCT (haplo-SCT) are the widely used alternatives in case of a lack of...
Citations
... Haplo-HCT is considered to have potent GVL effects accompanied by increased risk of graftversus-host disease (GVHD) and treatment-related mortality. 5,6 It is reported that younger, male, non-inherited maternal antigen (NIMA)-mismatched donors are potential factors associated with reduced risk of GVHD. 7,8 Beyond refining donor selection criteria, advancements in understanding hematopoietic cell sources (such as bone marrow grafts) and GVHD prophylaxis (such as the use of anti-thymocyte globulin [ATG] and posttransplant cyclophosphamide) have effectively mitigated the risk of GVHD. ...
Abstracts
Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18–60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT ( n = 134) or haplo-HCT ( n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75–46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7–87.9 vs. 67.8% 95% CI 60.0–76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6–78.8 vs. 57.6%, 95% CI 49.6–67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0–12.2 vs. 30.3%, 95% CI 30.1–30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3–4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery ( p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.
... A single-centre study reported that the 3-year OS and event-free survival (EFS) of paediatric patients with FLT3-ITD AML treated with allogeneic HSCT (allo-HSCT) were remarkably better than those of patients treated without allo-HSCT [10]. For the past few years, T-cell-replete haploidentical HSCT (haplo-HSCT), especially unmanipulated haplo-HSCT with anti-thymocyte globulin, has been a viable alternative for patients without human leucocyte antigen (HLA)-identical donors, and several high-risk paediatric patients with AML have benefited from it [11,12]. The reports on the use of haplo-HSCT in the treatment of FLT3-ITD AML in children are limited. ...
The presence of internal tandem duplication mutations in the FMS-like tyrosine kinase 3 receptor (FLT3-ITD) is a poor prognostic predictor in paediatric patients with acute myeloid leukaemia (AML). We evaluated the treatment outcomes and prognostic factors of 45 paediatric patients with FLT3-ITD AML who achieved complete remission before haploidentical haematopoietic stem cell transplantation (haplo-HSCT) at our institution from 2012 to 2021. Among the 45 patients, the overall survival (OS), event‑free survival (EFS), and cumulative incidence of relapse (CIR) rates were 74.9% ± 6.6%, 64.1% ± 7.2%, and 31.4% ± 7.1%, respectively, with 48.8 months of median follow-up. Univariate and multivariate analyses associated positive minimal residual disease (MRD) at pre-HSCT and non-remission (NR) after introduce 1 with inferior long-term survival. The 100-day cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) was 35.6% ± 5.2%, and that of grade III–IV aGVHD was 15.6% ± 3.0% The overall 4-year cumulative incidence of chronic graft-versus-host disease after transplantation was 35.7% ± 9.8%, respectively. In conclusion, haplo-HSCT may be a feasible strategy for paediatric patients with FLT3-ITD AML, and pre‐HSCT MRD status and NR after introduce 1 significantly affected the outcomes.
... Thus, some investigators suggested that factors reflecting underlying disease biology may be more important for predicting relapse compared with MFC positivity [13]. However, there were some limitations for these studies, for example, the MRD was performed by 4-color MFC analysis [19], the cut-off values for MFC positivity were relatively low (0.001%-0.01%) [16][17][18], or the ratios of patients with adverse-risk AML were low (~10%) [12,16]. We firstly identified the prognostic value of MFC MRD detected at three critical timepoints before allo-HSCT in a disease-specific population of adults with adverse-risk AML, and our results provided a valuable experience for exploring the upto-date undefined role of pre-HSCT MFC status in these patients. ...
... The target mononuclear cell count (MNC) of BM + PB or PB alone were more than 6 × 10 8 per kilogram of recipient weight, and all patients received G-CSF (5 μg per kilogram of body weight) from day +6 to neutrophil engraftment. The protocol of multiparameter flow cytometry (MFC) using for MRD monitoring was summarized in Supplementary Method [25]. Patients who showed MRD positive after HSCT could receive preemptive immunotherapy such as donor lymphocyte infusion (DLI) [26] and interferon-α treatment (Supplementary Method) [27,28]. ...
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most important curative method for intermediate- and high-risk adult acute myeloid leukemia (AML) patients. We aimed to identify the clinical outcomes of haploidentical related donor (HID) peripheral blood stem cell transplantation (PBSCT) who receiving peripheral blood (G-PB) harvest, and the patients receiving bone marrow (BM) plus G-PB harvest (BM + PB) as grafts were enrolled as control. The engraftments of neutrophil and platelet in G-PB group were both faster than those in BM + PB group. The cumulative incidences of grade II–IV acute graft-versus-host disease (aGVHD), and moderate to severe chronic GVHD (cGVHD) were all comparable between G-PB and BM + PB groups. The cumulative incidence of relapse and non-relapse mortality at 3 years after HID HSCT was 12.6% versus 13.7% (p = 0.899) and 3.6% versus 7.3% (p = 0.295), respectively, in G-PB and BM + PB group. While the probabilities of GVHD-free/relapse-free survival, leukemia-free survival, and overall survival at 3 years after HID HSCT were 60.6% versus 53.4% (p = 0.333), 83.8% versus 79.0% (p = 0.603), and were 87.3% versus 82.9% (p = 0.670), respectively. We confirmed the safety and efficacy of HID PBSCT in intermediate- and high-risk AML patients in a large cohort.
... 32 However, the impact of MRD status on haplo-HSCT outcomes is complicated. 33,34 While a recent analysis by the EBMT suggested that MRD status pre-HSCT is an independent predictor of relapse, 34 Chang et al. 33 did not find any association between MRD status and relapse. Instead, they suggested superior outcomes with haplo-HSCT versus MSD-HSCT in MRD+ patients. ...
... 32 However, the impact of MRD status on haplo-HSCT outcomes is complicated. 33,34 While a recent analysis by the EBMT suggested that MRD status pre-HSCT is an independent predictor of relapse, 34 Chang et al. 33 did not find any association between MRD status and relapse. Instead, they suggested superior outcomes with haplo-HSCT versus MSD-HSCT in MRD+ patients. ...
Data from 200 children with high‐risk acute myeloid leukaemia who underwent their first haploidentical haematopoietic stem cell transplantation (haplo‐HSCT) between 2015 and 2021 at our institution were analysed. The 4‐year overall survival (OS), event‐free survival (EFS) and cumulative incidence of relapse (CIR) were 71.9%, 62.3% and 32.4% respectively. The 100‐day cumulative incidences of grade II–IV and III–IV acute graft‐versus‐host disease (aGVHD) were 41.1% and 9.5% respectively. The 4‐year cumulative incidence of chronic GVHD (cGVHD) was 56.1%, and that of moderate‐to‐severe cGVHD was 27.3%. Minimal residual disease (MRD)‐positive (MRD+) status pre‐HSCT was significantly associated with lower survival and a higher risk of relapse. The 4‐year OS, EFS and CIR differed significantly between patients with MRD+ pre‐HSCT (n = 97; 63.4%, 51.4% and 41.0% respectively) and those with MRD‐negative (MRD‐) pre‐HSCT (n = 103; 80.5%, 73.3% and 23.8% respectively). Multivariate analysis also revealed that acute megakaryoblastic leukaemia without Down syndrome (non‐DS‐AMKL) was associated with extremely poor outcomes (hazard ratios and 95% CIs for OS, EFS and CIR: 3.110 (1.430–6.763), 3.145 (1.628–6.074) and 3.250 (1.529–6.910) respectively; p‐values were 0.004, 0.001 and 0.002 respectively). Thus, haplo‐HSCT can be a therapy option for these patients, and MRD status pre‐HSCT significantly affects the outcomes. As patients with non‐DS‐AMKL have extremely poor outcomes, even with haplo‐HSCT, a combination of novel therapies is urgently needed.
... In addition, the 100day cumulative incidence of grade 3-4 aGVHD in our study was less CAR-T chimeric antigen receptor T cell, LFS leukemia-free survival, OS overall survival, RI relapse incidence, NRM non-relapse mortality, HSCT hematopoietic stem cell transplantation, Allo allogeneic, Auto autologous, ATG-F ATG-Fresenius, ATG-T ATG-thymoglobulin, ATG-P ATG-porcine, 95%CI 95% confidence interval. than 10%, which is similar to other previously reported rates in first allo-HSCT without receiving CAR-T therapy (32,33). However, the grade 3 to 4 aGVHD was lower than our previously reported in second transplant for hematological malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML)(8.4% vs 15.1%) (28). ...
Background
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival.
Methods
A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy.
Results
The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021).
Conclusions
Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
... [24][25][26][27] MRD after HID HSCT was detectable by multiparameter flow cytometry (Supplementary Method). 28 For patient who showed MRD occurrence after HID HSCT, they could receive pre-emptive immunotherapy including donor lymphocyte infusion (DLI) 29 or interferon-α treatment (Supplementary Method). 30,31 Definition AML risk category was assessed by the European Leukemia Net (ELN) genetic risk. ...
We aimed to identify the efficacy of haploidentical related donor (HID) haematopoietic stem cell transplantation (HSCT) in adolescent and young adults (AYAs) with acute myeloid leukaemia (AML) in a large cohort. Consecutive AML AYAs (15–39 years old, n = 599) receiving HID HSCT in complete remission (CR) were included. The 3‐year cumulative incidence of measurable residual disease occurrence, relapse and non‐relapse mortality after HID HSCT was 28.6% (95% CI: 25.0–32.2), 11.6% (95% CI: 9.0–14.2) and 6.7% (95% CI: 4.7–8.7) respectively. The 3‐year probability of event‐free survival, leukaemia‐free survival (LFS) and overall survival (OS) after HID HSCT was 60.7% (95% CI: 56.9–64.8), 81.7% (95% CI: 78.7–84.9) and 85.6% (95% CI: 82.8–88.4) respectively. In multivariable analysis, AML risk category at diagnosis and comorbidity burdens before HID HSCT were independently associated with LFS and OS. Compared to the older adults (≥ 40 years, n = 355) with AML receiving HID HSCT in CR during the same time period, AYAs have a lower incidence of non‐relapse mortality and higher probabilities of LFS and OS. Thus, we firstly confirmed the safety and efficacy of HID HSCT in AYAs with AML‐CR.
... (P = 0.408) in CR1 and CR2 groups, respectively. In CR1 group, patients achieved myeloid recovery at a median of 13 (range, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] days. In CR2 cohort, patients achieved myeloid recovery at a median of 13 (range, 10-21) days. ...
... Over the past decade, great progress has been made in the use of haplo-HSCT which has led to improvements in patients' survival, haplo-HSCT has become an attractive immediate option for many patients [21][22][23][24][25][26]. It was reported that receiving haplo-HSCT in stage CR1 had better prognosis than those in stage CR2 in our center for acute lymphoblastic leukemia [27]. ...
There was no consensus on whether prognostic advantages existed when transplant conducted at first complete remission (CR1) stage than at second complete remission (CR2) stage for patients with AML who received haploidentical hematological stem cell transplantation (haplo-HSCT). In 768 consecutive AML patients who received haplo-HSCT from January 2014 to December 2017, a 1:2 ratio matched-pair analysis was performed, 69 patients who in CR2 group and 138 CR1 patients were enrolled. Hematopoietic recovery, graft versus host disease (GVHD), relapse, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) were compared in two groups, and further evaluated in low-, intermediate-, and high-risk subgroups. The cumulative incidences of 30-day myeloid recovery and 90-day platelet recovery were comparable in CR1 and CR2 groups. The cumulative incidences of grade II–IV and grade III–IV aGVHD were not significantly different. The cumulative incidences of relapse at 3-year and 5-year in these two groups were 12.4% versus 11.6% (P = 0.880) and 12.4% versus 17.5% (P = 0.322). The cumulative incidences of TRM at 3-year and 5-year were both 10.9% versus 23.2% (P = 0.019). The probability of DFS at 3-year and 5-year were 76.7% versus 65.2% (P = 0.029) and 76.7% versus 59.3% (P = 0.009). The probability of OS at 3-year and 5-year were 81.8% versus 68.1% (P = 0.026) and 76.7% versus 59.3% (P = 0.026). In the intermediate-risk group, TRM was lower in CR1 group, DFS and OS of CR1 group were superior to CR2 group. In conclusion, haplo-HSCT at CR1 stage was of better prognosis for intermediate-risk AML patients than at CR2 stage.
... This also suggested that HID HSCT is safe and effective for these patients. On the other hand, HID HSCT may show a stronger GVL effect than matched sibling donor (MSD) HSCT 43 , and several studies showed that HID HSCT could achieve a lower relapse rate and a better survival rate compared with MSD HSCT in high-risk AML including those with MRD positive before HSCT [44][45][46] . Because only 2 patients received non-HID HSCT, we could not further compare the clinical outcomes among different donor types. ...
... The incidences of total aGVHD and cGVHD were 58.0% and 47.5%, respectively, in our study, which seemed to be comparable with other studies enrolled HID HSCT recipients 45,47 . However, the incidences of grade III to IV aGVHD and severe cGVHD were only 11.5% and 27.2%, respectively. ...
Nucleoporin 98 ( NUP98 ) gene rearrangements comprise a family of rare recurrent alterations in acute myeloid leukemia (AML), and conferred dismal outcomes. The efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) were still unclear. In this retrospective, multicenter, real-world study, we enrolled 26 de novo adult AML patients with NUP98 rearrangements who received first allo-HSCT. The 100-day cumulative incidence of grade II–IV acute graft-versus-host disease (GVHD) after allo-HSCT was 19.2% (95% CI, 3.8–34.7%) and the 2-year cumulative incidences of moderate to severe chronic GVHD after allo-HSCT was 47.5% (95% CI, 17.0–77.9%). Ten (38.5%) patient received maintenance therapies after allo-HSCT. Among the 24 patients with MRD monitoring regularly, all of them achieved MRD negative after allo-HSCT, and 21 (87.5%) achieved persistent MRD negative until the last follow-up. The 2-year cumulative incidence of relapse and non-relapse mortality after allo-HSCT was 17.2% (95% CI, 1.4–33.1%) and 4.6% (95% CI, 0–13.7%), respectively. The 2-year probabilities of leukemia-free survival and overall survival after allo-HSCT were 78.2% (95%CI, 62.8–97.2%) and 86.3% (95%CI, 73.0–100%), respectively. In summary, we firstly identify the efficacy and safety of allo-HSCT in adult AML patients with NUP98 rearrangement, which should be further confirmed in prospective cohorts with a longer follow-up.
... Furthermore, the Haplo procedure may be associated with enhanced anti-leukemic efficacy as was recently nicely proved by Professor Huang Xia June in a mice model which carried the human AML-ETO or MLL-AF9 fusion gene showing that cytotoxic T lymphocytes from the haploSCT group had higher cytotoxicity than those from the MSD group [38]. Although controversial, the GVL effect may be stronger with non-T cell-depleted Haplo donors with faster clearance of post-transplant measurable residual disease, reduced post-transplant disease progression, and relapse, and better results in positive MRD pre-transplantation high-risk leukemia as compared to sibling transplantation [19,20,[38][39][40][41][42]. Furthermore, it is conceivable that the GVL effect is not the only mechanism that protects from disease relapse when using PTCy. ...
We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.
