Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Clinical characteristics and outcomes of allogeneic hematopoietic stem cell transplantation recipients with coronavirus disease 2019 caused by the Omicron variant: a prospective, observational cohort study.

We aimed to describe the clinical characteristics, particularly the occurrence and risk factors of severe/critical illness, in allogeneic hematopoietic stem cell (allo-HSCT) recipients infected with coronavirus disease 2019 (COVID-19) caused by Omicron variant in an observational prospective study (n = 311). The median time from allo-HSCT to COVID-19 diagnosis was 8.5 months (range 0.8-106.1) months. Four patients (1.3%) were reported to be asymptomatic during Omicron variant infection, and 135 (43.4%) patients showed lower respiratory tract disease. Thirty-four (10.9%) patients were categorized into serious infection (severe illness n = 25; critical illness n = 9) and the median duration from COVID-19 diagnosis to serious infections was 6 days (range, 0-29) days. Thirteen (4.2%) and 6 (1.9%) patients required intensive care unit care and invasive mechanical ventilation, respectively. Receiving more than 1 type of immunosuppressive therapies at COVID-19 diagnosis was associated with severity and persistence of infection. Six patients (1.9%) died after diagnosis of COVID-19 infection. The 4-week probability of overall survival after COVID-19 diagnosis was 98.7%, which was 100% and 88.2% for non-serious and serious infection group (P < 0.001), respectively. Thus, we observed a relatively low serious infection and mortality rate in allo-HSCT recipients infected with COVID-19 caused by Omicron variant.

The outcome and predictive model of allogeneic hematopoietic stem cell transplantation among elderly patients with severe aplastic anemia from the Chinese Blood and Marrow Transplant Registry Group.

Not available.

Mini-dose methotrexate combined with methylprednisolone as a first-line treatment for acute graft-versus-host disease: A phase 2 trial.

Background and Objectives: Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methylprednisolone (MP; 1-2 mg/kg/day) remains the standard first-line therapy for aGvHD, although no response is detected in nearly one-half of the patients with aGvHD. This study aimed to investigate the feasibility of mini-dose methotrexate (MTX) combined with standard-dose MP as a front-line therapy for aGvHD. Materials and Methods: A prospective Phase 2 clinical trial was performed to evaluate the safety and efficacy of 5 mg/m2 MTX combined with 1 mg/kg/day MP as the initial therapy in 31 patients with aGvHD. Moreover, the effects of MTX combined with MP were explored in a humanized xenogeneic murine model of aGvHD. Results: The overall response and complete response rate at 7 days after the initial treatment were 100% and 83%, respectively. The overall response rate on day 28 was 87%. The complete response rates for aGvHD grades I, II, and III were 100% (6/6), 82% (18/22), and 66% (2/3), respectively. Grade 3 toxicities occurred in only three patients presenting with cytopenia. Importantly, MTX and MP demonstrated synergistic effects on ameliorating aGvHD in humanized xenogeneic murine model. Conclusion: The current study suggests that mini-dose MTX combined with standard-dose MP could potentially become a novel first-line therapy for patients with aGvHD.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection.

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules; stronger cytotoxicity against HCMV-infected fibroblasts; and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32-0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18-0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

Low-dose post-transplant cyclophosphamide with G-CSF/ATG based haploidentical protocol provides favorable outcomes for SAA patients.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11-20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen.

Haploidentical transplants with a G-CSF/ATG-based protocol: Experience from China.

Haploidentical donor stem cell transplantation (haplo-SCT) has made great advances in recent decades. The granulocyte colony-stimulating factor (G-CSF)- and antithymocyte globulin (ATG)-based protocol, which is known as the Beijing Protocol, represents one of the current T-cell repletion strategies in haplo-SCT. The key elements of the Beijing Protocol for graft versus host disease (GvHD) prophylaxis include G-CSF inducing T-cell tolerance and altering graft cell components, as well as ATG administration exerting an immunoregulatory effect for intensive prophylaxis. This review will summarize the GvHD incidence, the underlying novel mechanism for GvHD prophylaxis, how to optimize GvHD prophylaxis, and the recent advances of the Beijing Protocol, mainly focusing on the issues of GvHD.

Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease.

Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.

Long-term follow-up of haploidentical transplantation in relapsed/refractory severe aplastic anemia: a multicenter prospective study.

In recent decades, haploidentical stem cell transplantation (haplo-SCT) to treat severe aplastic anemia (SAA) has achieved remarkable progress. However, long-term results are still lacking. We conducted a multicenter prospective study involving SAA patients who underwent haplo-SCT as salvage therapy. Long-term outcomes were assessed, mainly focusing on survival and quality of life (QoL). Longitudinal QoL was prospectively evaluated during pretransplantation and at 3 and 5 years posttransplantation using the SF-36 scale in adults and the PedsQL 4.0 scale in children. A total of 287 SAA patients were enrolled, and the median follow-up was 4.56 years (range, 3.01-9.05 years) among surviving patients. During the long-term follow-up, 268 of 275 evaluable patients (97.5%) obtained sustained full donor chimerism, and 93.4% had complete hematopoietic recovery. The estimated overall survival and failure-free survival for the whole cohort at 9 years were 85.4% ± 2.1% and 84.0% ± 2.2%, respectively. Age (≥18 years) and a poorer performance status (ECOG >1) were identified as risk factors for survival outcomes. For QoL recovery after haplo-SCT, we found that QoL progressively improved from pretransplantation to the 3-year and 5-year time points with statistical significance. The occurrence of chronic graft versus host disease was a risk factor predicting poorer QoL scores in both the child and adult cohorts. At the last follow-up, 74.0% of children and 72.9% of adults returned to normal school or work. These inspiring long-term outcomes suggest that salvage transplantation with haploidentical donors can be routine practice for SAA patients without human leukocyte antigen (HLA)-matched donors.

Comparable clinical outcomes of haploidentical hematopoietic stem cell transplantation in patients with hepatitis-associated aplastic anemia and non-hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia (HAAA), a rare subtype of aplastic anemia (AA), is defined as bone marrow failure occurring after acute hepatitis. Severe HAAA requires immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) as lifesaving treatment. The outcomes of HAAA patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have not been systematically evaluated. We retrospectively compared the characteristics of 15 patients with HAAA and 60 non-hepatitis-associated aplastic anemia (non-HAAA) patients, all 75 of whom underwent haplo-HSCT in our hospital between January 2006 and October 2021. The median ages of the patients were 18 years old (range, 3-36) for HAAA patients and 13 years (range, 2-45) for non-HAAA patients (p = 0.693). The median time for neutrophil engraftment was 14 days (range, 11-22) in the HAAA group and 12 days (range, 10-21) in the non-HAAA group (p = 0.363). At the time of analysis, 15 HAAA patients and 58 non-HAAA patients were alive, and their median follow-up times were 37 (range, 3-87) months and 31 (range, 2-110) months (p = 0.347), respectively. There were no significant differences in the three-year overall survival (OS) rates (100% vs. 96.7 ± 0.33%, P = 0.638) or liver event-free survival (LEFS) (80.0 ± 0.17% vs. 76.7 ± 0.19%, P = 0.747) between the two groups. Despite the small number of HAAA patients due to the rarity of the disease, these results, such as the similar incidence rates of 3-year OS and fewer liver events than expected, suggest that haplo-HSCT is a feasible treatment for HAAA a when there are no human leukocyte antigen (HLA)-matched donors available and has a low risk of transplant-related mortality and complications.

The Incidence, Outcomes, and Risk Factors of Secondary Poor Graft Function in Haploidentical Hematopoietic Stem Cell Transplantation for Acquired Aplastic Anemia.

Secondary poor graft function (sPGF) increases the risk of life-threatening complications after hematopoietic stem cell transplantation (HSCT). The incidence, clinical outcomes, and risk factors of sPGF have not been elucidated in haploidentical (haplo-) HSCT for acquired aplastic anemia (AA) patients. We retrospectively reviewed 423 consecutive AA patients who underwent haplo-HSCT between January 2006 and December 2020 and report a 3-year cumulative incidence of 4.62% (95% confidence interval [CI]: 3.92%-10.23%) of sPGF. While no primary PGF occurred. The median time to sPGF was 121 days (range 30-626 days) after transplantation. To clarify the risk factors for sPGF, 17 sPGF cases and 382 without PGF were further analyzed. Compared to patients without PGF, the 2-year overall survival was significantly poorer for sPGF patients (67.7% vs 90.8%, p =.002). Twelve sPGF patients were alive until the last follow-up, and 7 achieved transfusion independency. The multivariable analyses revealed that later neutrophil engraftment (OR 2.819, p=.049) and a history of refractory cytomegalovirus viremia (OR=7.038, p=.002) post-transplantation were associated with sPGF. There was weak evidence that a history of grade 3-4 acute graft-versus-host disease increased the risk of sPGF (p=.063). We advocated better post-transplantation strategies to balance the risk of immunosuppression and viral reactivation for haplo-HSCT in AA patients.

Comparable long-term outcomes between upfront haploidentical and identical sibling donor transplant in aplastic anemia: a national registry-based study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.

Development and validation of a mortality predicting scoring system for severe aplastic anaemia patients receiving haploidentical allogeneic transplantation.

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

A modified conditioning regimen based on low-dose cyclophosphamide and fludarabine for haploidentical hematopoietic stem cell transplant in severe aplastic anemia patients at risk of severe cardiotoxicity.

Severe cardiotoxicity is a fatal complication during high-dose cyclophosphamide (Cy)-based conditioning in hematopoietic stem cell transplant (HSCT) for severe aplastic anemia (SAA). This study aimed to evaluate the feasibility and efficacy of a modified conditioning regimen in haploidentical HSCT (haplo-HSCT) for severe-cardiotoxic-risk SAA patients. This BuCylow Flu conditioning utilized busulfan (Bu, 3.2 mg/kg for 2 days), low-dose Cy (100 mg/kg), fludarabine (150 mg/m2 ), and rabbit antithymocyte globulin (rATG, 10 mg/kg). Compared to BuCy conditioning using high-dose Cy of 200 mg/kg, Bu of 3.2 mg/kg for 2 days, and rATG of 10 mg/kg, the incidence of severe cardiotoxicity of BuCylow Flu conditioning was significantly decreased (2.17% vs 12.80%, p = .032). The engraftment rates (100% for neutrophil and 84.44% for platelet) were favorable. The probabilities of 100-day transplant-related mortality were similar in the BuCylow Flu and the BuCy group (8.75% vs 10.53%, p = .671). Both 1-year overall survival (88.79% vs 84.66%, p = .357) and 1-year failure-free survival (84.78% vs 81.70%, p = .535) were comparable. The BuCylow Flu group had higher rates of cytomegalovirus and Epstein-Barr virus reactivation. In conclusion, the BuCylow Flu provided reduced severe cardiotoxicity, and achieved favorable engraftment and survival. Our results suggest BuCylow Flu conditioning can be a feasible alternative for haplo-HSCT recipients at risk of severe cardiotoxicity.