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This meta-analysis was to evaluate the outcome of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for aplastic anemia (AA) compared with matched related donor (MRD)-HSCT, matched unrelated donor (MUD)-HSCT, and immunosuppressive therapy (IST). Pubmed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, and VIP databases were searched for relevant studies from inception to 22 June 2022. Relative risk (RR) was used to indicate the effect indicator, with a 95% confidence interval (CI) being applied to express the effect size. A subgroup analysis based on the literature quality (low, fair, and high) was applied. Totally, 25 studies were included in this study, comprising 2252 patients. Our findings demonstrated no difference between Haplo-HSCT and MRD-HSCT in 1-, 2-, and 3-year overall survival (OS), failure-free survival (FFS), and engraftment. However, Haplo-HSCT had higher incidences of II-IV acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), and cytomegalovirus infection. There were no differences in 3- and 5-year OS, 3-year FFS, platelet engraftment, graft failure (GF), II-IV grade of aGVHD, and complication between Haplo-HSCT and MUD-HSCT; however, Haplo-HSCT had a lower incidence of cGVHD. Compared with IST, Haplo-HSCT had a higher 3-year FFS and 3- and 6-month response rate. However, there were no differences in 3- and 5-year OS, and 12-month response rate between Haplo-HSCT and IST. This study suggests that Haplo-HSCT may be a realistic therapeutic option for AA, which may provide a reference for decision-making.

Haploidentical hematopoietic cell transplantation (HCT) offers potent graft-versus-tumor effects but is historically limited by higher non-relapse mortality (NRM) compared to matched unrelated (MUD) or related donors (MRD). To algorithmically decouple the competing risks of NRM and relapse, we analyzed 1,713 adult patients (MD Anderson discovery cohort) and 6,829 patients (registry replication cohorts) using a double machine-learning framework of Causal Survival Forests to estimate individualized treatment effects, while Random Survival Forests defined absolute prognostic risk. We found biological uncoupling of relapse and NRM: relapse was driven by disease biology, while NRM was governed by physiological reserve. Specifically, cardiovascular or cerebrovascular comorbidities acted as selective amplifiers of haploidentical toxicity—a \"vascular penalty\" that doubled mortality risk in the bootstrapped model (sub-distribution hazard ratio 2.09, 95% confidence interval 1.26–3.35). We developed a 3-factor nomogram (recipient age, vascular comorbidity, B-leader matching status) to identify an \"Optimized Haploidentical\" phenotype. Exploratory multivariable modeling suggested MUD consistently maximized predicted disease-free survival across all subgroups. Among haploidentical versus MRD comparisons, B-leader mismatch appeared to favor MRD across ages, while B-leader matched haploidentical donors in older patients (≥ 60 years) modeled near-equivalent DFS to MRD, representing a hypothesis-generating \"zone of equivalence\" requiring prospective validation.

Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT outcomes rely on an optimal balance of effective immune recovery, minimal graft-versus-host disease (GVHD), and lasting control of disease. The quest to attain this balance has proven challenging over the past few decades. The two-step approach to HSCT was conceptualized and pioneered at Thomas Jefferson University in 2005 and remains the main platform for allografting at our institution. Following administration of the transplant conditioning regimen, patients receive a fixed dose of donor CD3+ cells (HSCT step one-DLI) as the lymphoid portion of the graft on day -6 with the aim of optimizing and controlling T cell dosing. Cyclophosphamide (CY) is administered after the DLI (days -3 and -2) to induce donor-recipient bidirectional tolerance. On day 0, a CD34-selected stem cell graft is given as the myeloid portion of the graft (step two). In this two-step approach, the stem cell graft is infused after CY tolerization, which avoids exposure of the stem cells to an alkylating agent, allowing rapid count recovery. Here, the two-step platform is described with a focus on key results from studies over the past two decades. Finally, this review details lessons learned and current strategies to optimize the graft-versus-tumor effect and limit transplant-related toxicities.

This study prospectively compared the efficacy and safety between matched related donor-hematopoietic stem cell transplantation (MRD-HSCT) ( n  = 108) and immunosuppressive therapy (IST) plus eltrombopag (EPAG) (IST + EPAG) ( n  = 104) to determine whether MRD-HSCT was still superior as a front-line treatment for patients with severe aplastic anemia (SAA). Compared with IST + EPAG group, patients in the MRD-HSCT achieved faster transfusion independence, absolute neutrophil count ≥ 1.0 × 10 9 /L ( P  < 0.05), as well as high percentage of normal blood routine at 6-month (86.5% vs. 23.7%, P  < 0.001). In the MRD-HSCT and IST + EPAG groups, 3-year overall survival (OS) was 84.2 ± 3.5% and 89.7 ± 3.1% ( P  = 0.164), whereas 3-year failure-free survival (FFS) was 81.4 ± 4.0% and 59.1 ± 4.9% ( P  = 0.002), respectively. Subgroup analysis indicated that the FFS of the MRD-HSCT was superior to that of the IST + EPAG among patients aged < 40 years old (81.0 ± 4.6% vs. 63.7 ± 6.5%, P  = 0.033), and among patients with vSAA (86.1 ± 5.9% vs. 54.9 ± 7.9%, P  = 0.003), while the 3-year OS of the IST + EPAG was higher than that of the MRD-HSCT among the patient aged ≥ 40 years old (100.0 ± 0.0% vs. 77.8 ± 9.8%, P  = 0.036). Multivariate analysis showed that first-line MRD-HSCT treatment was associated favorably with normal blood results at 6-month and FFS ( P  < 0.05). These outcomes suggest that MRD-HSCT remains the preferred first-line option for SAA patients aged < 40 years old or with vSAA even in the era of EPAG.

Hepatic sinusoidal obstruction syndrome (SOS) has been rarely studied after haploidentical donor (HID) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective multicentre study on patients with SOS after allo-HSCT in China. The incidence, risk factors, and outcomes were compared between HID HSCT and matched related donor (MRD) HSCT. SOS developed in 0.4% of patients (HIDs: 0.4%, MRDs: 0.5%, p = 0.952) at a median time of 21.50 days (range, 1–55) after allo-HSCT (HIDs: 24 days, MRDs: 20 days, p = 0.316). For patients diagnosed with SOS, the 2-year cumulative incidence of relapse was 22.7% and 22.4% in patients receiving HID and MRD transplantation, respectively (p = 0.584). Overall survival (OS) at 2 year was 10.4% and 38.5% in the two groups (p = 0.113). The transplant-related mortality (TRM) at 100 days was 60.9% in the HID group and 38.5% in the MRD group (p = 0.178). According to the multivariate analyses, significant independent risk factors for the occurrence of SOS were delayed platelet engraftment (p = 0.007) and advanced disease status at the time of HSCT (p = 0.009). The outcomes of SOS after HID HSCT are similar to those after MRD HSCT.

Background Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors ( n  = 660) versus unrelated donors ( n  = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.

Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n =62; 9/10, n =29) or MRD ( n =135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89–2.30, P =0.14) for overall mortality, 1.17 (0.66–2.08, P =0.60) for relapse and 1.79 (0.86–3.74, P =0.12) for NRM, respectively, and the adjusted odds ratio for grades 2–4 acute graft-versus-host disease was 1.50 (0.70–3.24, P =0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52–2.61), P =0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

Background The impact of the use of anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation performed with HLA-identical sibling donors following fludarabine and 4 days intravenous busulfan myeloablative conditioning regimen has been poorly explored. Methods We retrospectively analyzed 566 patients who underwent a first HLA-identical allogeneic stem cell transplantation with this conditioning regimen for acute myeloid leukemia in first complete remission between 2006 and 2013 and compared the outcomes of 145 (25.6%) patients who received ATG (ATG group) to 421 (74.4%) who did not (no-ATG group). The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results Patients in the ATG group were older, received more frequently peripheral blood stem cell grafts from older donors, and were transplanted more recently. With a median follow-up of 19 months, patients in the ATG group had reduced 2-year cumulative incidence of chronic graft-versus-host disease (GVHD) (31 vs. 52%, p  = 0.0002) and of its extensive form (8 vs. 26%, p  < 0.0001) but similar relapse incidence (22 vs. 27%, p  = 0.23) leading to improved GVHD and relapse-free survival (GRFS) (60 vs. 40%, p  = 0.0001). In multivariate analyses, the addition of ATG was independently associated with lower chronic GVHD (HR = 0.46, p  = 0.0001), improved leukemia-free survival (HR = 0.67, p  = 0.027), overall survival (HR = 0.65, p  = 0.027), and GRFS (HR = 0.51, p  = 4 × 10 −5 ). Recipient age above 50 years was the only other factor associated with worse survivals. Conclusions These results suggest that the use of ATG with fludarabine and 4 days intravenous busulfan followed by HLA-identical sibling donor allogeneic stem cell transplantation for acute myeloid leukemia improves overall transplant outcomes due to reduced incidence of chronic GVHD without increased relapse risk.

Clinical data of patients with severe aplastic anemia (SAA) were retrospectively analyzed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched related sibling hematopoietic stem cell transplantation (MSD-HSCT) in complications and survivals. Thirty consecutive patients were enrolled in the study with a median follow-up of 50 months (range 4, 141), and the median age of the patients was 21 years (range 3, 49). All the patients achieved myeloid engraftment in the two cohorts. The cumulative incidences of platelet engraftment were 95.5 and 100% in HID cohort and MSD cohort, respectively. The median time for neutrophil and platelet recovery was 11 (range 9, 19) and 15 (range 10, 25) days in HID cohort, and 12 (range 10, 19) and 14 (range 8, 25) days in MSD cohort. The cumulative incidences of grade II–IV and grade III–IV acute graft vs. host disease (aGvHD) in HID cohort and in MSD cohort were 18.9 vs. 14.3% ( p = 0.77) and 10.5 vs. 0% ( p = 0.42), respectively. The cumulative incidences of chronic graft vs. host disease (cGvHD) was 22.7% in HID cohort and 25.5% in MSD cohort ( p = 0.868). The 5-year overall survival (OS) rates and 5-year failure-free survival (FFS) rates in HID cohort and MSD cohort were 85.1 vs. 87.5% ( p = 0.858), 80.3 vs. 87.5% ( p = 0.635), respectively. The median time to achieve engraftment, cumulative incidence of aGvHD and cGvHD, and the 5-year OS and FFS rates were not significantly different between the two cohorts. We suggest that HID-HSCT might be a safety and effective option for SAA patients without a matched donor.