Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies.

Highlight(s): Haploidentical hematopoietic stem cell transplantation had excellent long-term survival outcomes for patients who were disease-free at two years after transplant.

Previously, the failure of haploidentical hematopoietic stem cell transplantation (haplo-SCT) was mainly attributed to increased risk of graft-versus-host disease (GVHD), graft failure, and infections. Haplo-SCT outcomes have improved over the past decade. However, limited data remains on the long-term outcomes for patients with high-risk hematologic malignancies. The long-term outcomes of these patients were evaluated in a retrospective study of adult patients with high-risk hematologic malignancies who underwent their first haplo-SCT with posttransplant cyclophosphamide (PTCy)-based GVHD prophylaxis between 2009 and 2019. The primary endpoints included progression-free survival (PFS) and overall survival (OS) for the long-term survivors (patients who were alive and disease-free at two years after transplant). Secondary endpoints included cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and GVHD-free, relapse-free survival (GRFS). The Kaplan-Meier method was used to estimate time-to-event data, including PFS and OS. The median age of the study population (n=335) at transplantation was 48 years (range 18-72). Of these, 142 patients were disease-free and alive two years after transplant. There were no notable differences in baseline characteristics between all study patients and the long term survivors, but a higher proportion of patients with low/intermediate disease risk index (DRI) were noted in the long-term survivor group. For the long-term survivors, with a median follow-up of 52 months (range, 24-133), the 4-year PFS and OS rates were 94% and 96%, respectively. Age ≥55 years was the only predictive factor in univariate and multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; p = 0.020) and OS (HR, 3.31; 95% CI, 1.08-10.18; p = 0.037). Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). This study reinforces the effectiveness of haplo-SCT. Probably, the use of PTCy-based GVHD prophylaxis, type of conditioning therapy (reduced intensity and non-myeloablative conditioning), and improvements in the management of cardiovascular disease have the highest impact on long-term survival.

Post-transplant cyclophosphamide compared to sirolimus/ tacrolimus in reduced intensity conditioning transplants.

Highlight(s): In reduced intensity conditioning hematopoietic stem cell transplantation, post-transplantation cyclophosphamide lowers  cGVHD compared with SIR/TAC.

In non-haploidentical transplants, phase 3 randomized clinical trials demonstrated the superiority of a post-transplant cyclophosphamide (PTCY) prophylaxis with cyclosporine/mycophenolate regimen as compared to cyclosporine/methotrexate after reduced intensity conditioning (RIC). In contrast, PTCY alone failed to demonstrate superiority after myeloablative conditioning. In a Spanish retrospective cohort, the investigators evaluated the safety and efficacy of PTCY compared to sirolimus with tacrolimus (SIR/TAC) in RIC-transplants. Between January 2012 to December 2020, 171 consecutive patients with Hodgkin, non-Hodgkin lymphoma, or multiple myeloma were recruited from eight centers and underwent RIC hematopoietic stem cell transplantation (HSCT). Haploidentical and umbilical cord HSCTs were excluded. The primary endpoint was to compare grade III-IV acute GVHD (aGVHD), severe chronic GVHD (cGHVD), and GHVD-free, relapse-free survival (GRFS) between PTCY (82 patients) vs. SIR/TAC (89 patients). There were no significant differences between these patient groups with respect to median patient age, baseline diagnosis, or disease status at the time of HSCT. Conditioning regimens were categorized into two subgroups: high toxicity (thiotepa, fludarabine, plus busulfan [TBF] or thiotepa, fludarabine, plus melphalan [TMF]) and low toxicity (fludarabine, cyclophosphamide, plus total body irradiation [FCyTBI]); fludarabine plus busulfan [FB] or fludarabine plus melphalan [FM]). The choice of conditioning regimens varied, with the TBF/ TMF regimen being most common (37.8%) in the PTCY group, while FB (64.7%) was preferred in the SIR/TAC cohort. Grade III-IV aGVHD incidence was similar between groups (PTCY:12.3% [95% confidence interval -CI-, 6.3 to 20.4] vs. SIR/TAC: 11.3% [95% CI, 5.8 to 19], p = 0.85). The 2-year incidence of moderate-severe cGVHD differed significantly (5.8% [95% CI, 1.8 to 13.1] vs. 39.6% [95% CI, 29.3 to 49.7], p < 0.001). The 2-year GRFS was similar between PTCY (45.9% [95% CI, 35.8–58.7]) and SIR/TAC groups (36.8% [95% CI, 28–48.4]), p = 0.72. In summary, PTCY reduced cGVHD incidence in RIC HSCT without impact on other HSCT outcomes.

Cyclophosphamide and thiotepa increases risk of transplant-associated thrombotic microangiopathy.

Highlight(s): Pre-transplant conditioning with cyclophosphamide (CY) or thiotepa (TT) alone or in combination increases the risk of transplant-associated thrombotic microangiopathy in allogeneic hematopoietic stem cell transplantation (HSCT)

Transplant-associated thrombotic microangiopathy (TA-TMA) is a heterogeneous, frequently fatal disease that occurs within 100 days after HSCT. Risk factors include exposure to calcineurin inhibitors, high-dose chemotherapy, myeloablative conditioning, age, infections, female sex, and graft-versus-host disease (GVHD). Specific causative agents have not been identified. At UCSF Benioff Children’s Hospital, San Francisco, the authors conducted a retrospective review of pediatric and young adult patients who received cyclophosphamide (CY) or thiotepa (TT) alone or in combination as part of pre-transplant conditioning autologous and allogeneic HSCT between 2012 and 2023. High-dose N-acetylcysteine prophylaxis (70mg/kg every 8 hours) was given per institutional standard of care. Prophylactic defibrotide was administered if patients were considered to be at high risk for sinusoidal obstruction syndrome. A total of 558 transplants were carried out, and 43 (7.7%) experienced TA-TMA. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA for allogeneic and autologous HSCT, which was 8.6% (95% interval confidence [CI], 5.9-11.3%) and 7.2% (95% CI, 2.9-11.5%), respectively (p=0.62). The use of CY or TT (hazard ratio [HR]=10.14; p=0.002) or CY+TT (HR=35.93; p <0.001), viral infections (HR=4.3; p =0.017), and fungal infections (HR=2.98; p =0.027) were found to be significant factors associated with an increased risk of developing TA-TMA for allogeneic transplants. In autologous patients, TA-TMA was not observed in patients receiving either CY or TT alone. However, in patients receiving CY+TT, the incidence of TA-TMA was 6.7% (95% CI, 0.1-15.7%) in cytomegalovirus (CMV) seronegative patients at the time of HSCT, compared to 38.1% (95% CI, 35-41.2%) in CMV seropositive patients (p=0.007). The authors hypothesize that alternative conditioning will help to prevent or reduce the severity of TA-TMA. The combination of CY+TT has the highest risk in the allogeneic setting. Risk groups such as CMV seropositivity (in autologous HSCT recipients) and non-White race patients probably need alternative pre-transplant conditioning excluding the combination of CY+TT.

Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma.

Highlight(s): Autologous hematopoietic stem cell transplantation (HSCT) remains an option for consolidation therapy in patients with early disease relapse within 2 years of receiving front line chemoimmunotherapy and achieve a complete/partial response to salvage second line therapies. In settings of  late first relapse, second relapse and beyond, allogeneic HSCT can be a treatment strategy.

A consensus of the American Society of Transplantation and Cellular Therapy (ASTCT) and the European Society of Blood and Marrow Transplantation (EBMT) Committee on Practice Guidelines generated 15 consensus recommendations about role, optimal timing, and sequencing of HSCT (autologous [auto-HSCT] or allogeneic [allo-HSCT]) and cellular therapies in follicular lymphoma (FL). Bispecific antibodies were not in the scope of this project. The guideline recommendations were based on advice from the GRADE (Grading of Recommendations Development, Assessment and Evaluation) working group accompanied by the proper levels of evidence (LOE) and grades of recommendation (GOR), that incorporates both the quality of evidence as well as the clinical significance/magnitude of benefit or harm given by following the recommendation according to the adapted grading system. Here is a summary of some of the most relevant key points about transplant in FL:

Front-Line setting:

·       The panel recommend against auto-HSCT or allo-HSCT as consolidation therapy in FL patients who achieve complete remission (CR) or partial remission (PR) after first line therapies.

Early first relapse/progression:

·       The panel recommends auto-HSCT as an option for consolidation therapy in patients with early disease relapse within 24 months  of receiving treatment front line chemoimmunotherapy (POD24), who do not have evidence of histological transformation and achieve a CR or a PR to salvage second line therapies.

·       The panel does not recommend allo-HSCT as consolidation in patients with POD24 who have achieved CR or PR to salvage second line therapies.

·       The panel does not recommend auto-HSCT as consolidation therapy in relapsed FL patients with POD24 who do not achieve CR or PR after second or subsequent line therapies.

Late first relapse, second relapse and beyond:

·       The panel does not recommend auto-HSCT as consolidation in relapsed FL patients who did not achieve CR or PR after second or subsequent line therapies.

·       The panel does not recommend auto-HSCT as consolidation in FL patients who have relapsed post chimeric antigen receptor (CAR) T-cell therapy and did not achieve CR or PR to most recent anti-lymphoma treatment.

·       The panel recommends considering allo-HSCT as consolidation in relapsed FL patients who have received 3 or more lines of systemic therapy and are in one the following  three clinical scenarios:

a)    Develop disease relapse early post autologous transplant and do not have access to CAR T-cell therapy

b)    post (CAR) T-cell therapy failure

c)     develop therapy related myeloid neoplasms or bone marrow failure syndrome

·       The panel recommends that allo-HSCT should be considered as a salvage/consolidation therapy only in patients who have achieved CR or PR to the most recent anti-lymphoma treatment and maintain adequate performance status and organ function

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

Highlight(s): Haploidentical transplant is a viable option for adult and pediatric patients with severe hemoglobinopathies

Haploidentical hematopoietic stem cell transplantation (HSCT), gene therapy, and gene editing trials for sickle cell disease (SCD) and transfusion-dependent thalassemia are ongoing with promising results. Concerns for increased treatment-related mortality of HSCT have prohibited the widespread adoption of allogeneic HSCT in SCD.  For this reason, investigators of the multicenter Vanderbilt Global Haploidentical BMT Learning Collaborative developed an international multicenter phase 2 clinical trial of nonmyeloablative–related haploidentical HSCT with thiotepa and posttransplant cyclophosphamide (PTCy) in pediatric and adult patients with SCD. The authors tested the hypothesis that HSCT will result in 2-year event-free survival (no graft failure or death) of at least 80%. The protocol evaluated was thiotepa (10 mg/kg) added to the regimen which consisted of rabbit anti-thymocyte globulin (ATG), fludarabine, cyclophosphamide, and total body irradiation (200 cGy) with PTCy as graft-versus-host disease (GVHD) prophylaxis. A total of 70 participants were evaluated. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier–based probability of event-free survival was 82.6% (95% confidence interval [CI], 71.4-89.7). The event-free survival probabilities at 2 years for children and adults were 68.4% (95% CI, 49.1-81.6) and 94.7% (95% CI, 80.6-98.7), respectively. The 2-year overall survival was 94.1%, with no difference between children and adult participants. The 1-year grade 3 to 4 acute GVHD rate was 10% (95% CI, 4.6-18.6), and the 2-year moderate-severe chronic GVHD rate was 10% (95% CI, 4.6-18.6), which was significantly higher in children than in adults (18.8% [95% CI, 8.2-34.6] vs. 2.6% [95% CI, 0.3-11.6], respectively; p = 0.025). Five participants (7.1%) died from infectious complications. This trial demonstrates the potential for a haploidentical transplant to be a viable option for patients with severe hemoglobinopathies. Additional modifications in the conditioning regimens are required in children to decrease graft failure.

Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms (t-MN) After Autologous Transplant for Hodgkin Lymphoma (HL).   

Highlight(s): The presence of TP53 and/or PPM1D mutations in the peripheral blood stem cell transplantation (PBSCT) product increases the risk of post-autologous PBSCT t-MN and non-relapse mortality (NRM) among patients with HL.

A retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71) was evaluated by targeted DNA sequencing of PBSCT products performed for  clonal hematopoiesis (CH)-associated or myeloid malignancy-associated genes. The study identified pathogenic mutations in these patients. CH was identified in the PBSCT product of 46 patients (14.3%) with most prominent representation of DNMT3A (n=25), PPM1D (n=7), TET2 (n=7), and TP53 (n=5) mutations. Presence of CH in the PBSCT product was an independent predictor of therapy-related myeloid neoplasm (t-MN) (adjusted hazard ratio, 4.50 [95% confidence interval (CI), 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSCT product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without cooccurring TP53 or PPM1D mutations) did so. Presence of TP53 and/or PPM1D mutations were associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of NRM (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality.

Clonal relapse dynamics in acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (alloHCT).

Highlight(s): next-generation sequencing-measurable residual disease (NGS-MDR) monitoring from peripheral blood (PB) after alloHCT detects up to 38% and 64% of relapses with a monitoring interval of every 3 or 1 months.

This study elucidates the molecular architecture and kinetics preceding AML relapse by using error-corrected NGS (panel of 46 genes/hot spots with an estimated limit of detection of ~0.01%)  in 74 patients with AML relapsing after alloHCT, evaluating 140 samples from PB collected 0.6 to 14 months before relapse. At least 1 MRD marker became detectable in 10%, 38%, and 64% of patients at 6, 3, and 1 month before relapse, respectively. By translating these proportions into monitoring intervals, 38% of relapses would have been detected through MRD monitoring every 3 months, whereas 64% of relapses would have been detected with monthly intervals. The relapse kinetics after alloHCT are influenced by the functional class of mutations and their stability during molecular progression. Notably, mutations in epigenetic modifier genes exhibited a higher prevalence of MRD positivity and greater stability before relapse, whereas mutations in signaling genes demonstrated a shorter lead time to relapse. Both DTA (DNMT3A, TET2, and ASXL1) and non-DTA mutations displayed similar relapse kinetics during the follow-up period after alloHCT.  Approximately 80% of all MRD mutations found at relapse were present at diagnosis.

Alternative donor transplantation for severe aplastic anemia (SAA): a comparative study of the SAAWP EBMT.   

Highlight(s): For patients with SAA lacking a myelodysplastic syndrome, a matched unrelated donor (MUD) is the preferable alternative donor option. However, selecting between a mismatched unrelated donor (MMUD) and a haploidentical donor (Haplo) remains uncertain and requires further exploration.

Patients with SAA undergoing stem cell transplantation (SCT) from MUD (n = 1106), MMUD (n=340), and Haplo (n=206) registered in the European Society for Blood and Marrow Transplantation (EBMT) database (2012-2021) were evaluated. For Haplo-SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years (the data reported to the European Transplant registry did not include anyone aged >40 years), and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo grafts (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure.  MUD recipients had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; p < 0.001; grade 3-4: 5%, 9%, and 7%, respectively; p= 0.028). The 3-year non-relapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (p< 0.001), whereas overall survival and GVHD-free and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (p< 0.001).

Continuously improving outcome over time after second allogeneic stem cell transplantation (alloSCT2) in relapsed acute myeloid leukemia (AML): an EBMT registry analysis of 1540 patients.  

Highlight(s): outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. Decreased relapse incidence (RI) did not come at the cost of increased toxicity. Half of the patients relapse again and only one third are cured by alloSCT2.

Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT. Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and  higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative RI decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors, and older age were associated with higher NRM and inferior OS. Half of the patients relapse again and only one third are cured by alloSCT2.

Combination of anti-thymocyte globulin (ATG) with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT): systematic review and meta-analysis.  

Highlight(s): Combination of ATG with PTCy (ATG/PTCy) in adjusted dosage for GVHD prevention in haplo-HSCT is associated with significantly lower risk of grade II-IV acute GVHD compared with ATG or PTCy alone. ATG/PTCy is associated with significantly improved overall survival and GVHD-free/relapse-free survival compared with ATG or PTCy alone but may increase the risk of viral reactivation.

This study aims to perform a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT. A literature search of databases including Ovid Medline, Embase, Cochrane Library and Chinese biomedical databases was performed. The search and study selection identified 14 eligible studies including 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied, the total dose was 2.5–10 mg/kg for ATG and 29–100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grade II-IV acute GVHD compared with ATG (relative risk [RR] 0.52; 95% confidence interval [CI]: 0.41–0.65; p < 0.00001) or PTCy (RR 0.53; 95% CI: 0.34–0.83; p= 0.005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly improved overall survival and GVHD-free/relapse-free survival compared with ATG or PTCy alone, but the risks of cytomegalovirus (RR 1.42; 95% CI: 1.03–1.95; p = 0.03) and Epstein-Barr virus (RR 3.17; 95% CI: 1.61–6.23; p = 0.0008) reactivation are higher when compared with PTCy.

Tandem Autologous Stem Cell Transplantation Does Not Benefit High-Risk Myeloma Patients In The Maintenance Era: Real-world Results From The Canadian Myeloma Research Group Database.

Highlight(s): In patients with high-risk cytogenetics, consolidation with tandem autologous stem cell transplant was not associated with improved response, progression-free survival, or overall survival compared to single autologous stem cell transplant.

The presence of high-risk cytogenetics (HRCG), defined as presence of deletion 17p (del17p), t(4;14), or t(14;16), is associated with worse progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) and is not abrogated by the upfront use of autologous stem cell transplant (AutoSCT) and current induction regimens. Tandem AutoSCT has been used to deepen response and has been suggested to be helpful in patients with high-risk diseases based on STaMINA and EMN02/HO95 trial results.

The authors used data from the Canada Myeloma Research Group database, a disease-specific national registry of retrospectively collected information from over 10000 patients.  Patients with HRCG and who received tandem AutoSCT, defined as a second AutoSCT without relapse or progression of disease between the two AutoSCTs were identified. Patients requiring re-induction before the initial AutoSCT were included. Patients receiving allogeneic SCTs or with disease progression within three months of the initial transplant were excluded. The authors compared baseline characteristics and outcomes (overall response rate (ORR), PFS and OS) in patients with HRCG who received single vs. tandem AutoSCT. 381 patients were identified, including 139 patients who received tandem AutoSCT. There were no differences in baseline characteristics. The most common HRCG was del17p (53%), followed by t(4;14) (46%), and t(14;16) (12%). 8% of patients had >1 HRCG alteration. Most patients (87%) received cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as an induction regimen, and 10.8% of patients required reinduction before the initial AutoSCT. The ORR at any time was similar (98.4%) in single and tandem AutoSCT groups. However, the complete response rate was higher in the single AutoSCT cohort (48.8% vs. 28.8%, p < 0.01). The ORR to the first AutoSCT was also similar for both cohorts. There were no differences in median PFS (35.2 vs. 35.3 months) or OS (92.6 vs. 88.9 months) between single and tandem AutoSCT, respectively. Importantly, in multivariable analysis, only t(4;14) and t(4;14), and del17p were associated with worse PFS and OS, respectively. There were no significant associations between tandem AutoSCT use or type of maintenance with either PFS or OS. Based on these findings, the authors conclude that tandem AutoSCT does not seem to improve outcomes in patients with HRCG.

Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?

Highlight(s): Limited utility of revised International Prognostic Scoring System (IPSS-R) “Downstaging” or reduced bone marrow blast percentage before allogeneic stem cell transplant in myelodysplastic syndrome (MDS).

In MDS, a higher IPSS-R before allogeneic stem cell transplant (Allo-SCT) is associated with worse outcomes. However, it is unclear if therapeutic interventions aimed at lowering the IPSS-R before transplant can mitigate such risk. There is a lack of data from prospective randomized trials in this area, and current recommendations suggest induction in those with >10% blasts based on previous retrospective studies. 1482 patients with MDS from the European Society for Blood and Marrow Transplantation (EBMT) registry with sufficient data to calculate the R-IPSS score at diagnosis, and pre-transplant between 2005 and 2018 were selected. Pre-transplant treatment for each patient was classified as induction chemotherapy, hypomethylating agents (HMA), none, or one or the other for each patient, and patients were classified as “progressive” or “improving” depending on changes in IPSS-R or “same” if stable. Donor type, stem cell source, age at Allo-SCT, sex, use of total body conditioning (TBI), and conditioning (standard vs. reduced) were also included. Although both IPSS-R at diagnosis and pre-transplant had an impact of both overall survival (OS) and progression-free survival (PFS), changes in IPSS-R was not associated with either PFS or OS in univariate analysis. There was a significant interaction of pre-transplant treatment modality and IPSS-R changes for both PFS and OS. Transplant outcome was unaffected by change in IPSS-R score in untreated patients and was moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after HMA or other therapies showed no beneficial effect. However, stable or worse IPSS-R after therapy (chemotherapy, HMA or other therapies) correlated with worst transplant outcome than without any prior treatment. Similarly, although higher bone marrow blast percentage at diagnosis was associated with worse PFS and OS, there was no clear association of treatment and reduction in blast percentage with improved outcomes, regardless of initial blast percentage, and often with worse OS/PFS for certain treatment subgroups.

The authors conclude that this large retrospective study suggests there is limited benefit of IPSS-R or bone marrow blast reduction using chemotherapy, while there was no benefit for HMA or other therapies. Additionally, the authors provide mode-based survival estimates that may be helpful for discussion and decision making until prospective randomized data is available.

Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation (HCT).

Highlight(s): Survival benefits of abatacept combined with calcineurin inhibitor and methotrexate (CNI/MTX) in patients with hematologic malignancies undergoing HCT. The addition of abatacept may provide an approach for alternative donor pool expansion when human leukocyte antigen (HLA)-identical sibling donors are unavailable.

Abatacept, a CTLA-4 agonist, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX) represents the first approved acute graft-vs-host disease (GvHD) prophylaxis regimen in mismatched unrelated donor (MMUD) allogeneic stem cell transplant (AlloSCT). The authors explored the impact of abatacept, CNI, MTX in 7-8/8 HLA unrelated donor-AlloSCT using a retrospective cohort for the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Patients who received 7/8 MMUD or 8/8 MUD-AlloSCT between 2011-2018 were included. Overall survival (OS) and relapse-free survival (RFS) at 180 days, 1, and 2 years were compared across different GvHD prophylaxis regimens (abatacept+CNI/MTX, CNI/MTX, CNI/MTX + anti thymocyte globulin [ATG], and post-transplant cyclophosphamide [PTCy]). For 7/8 MMUDs, day-180 OS was higher for abatacept+CNI/MTX vs. CNI/MTX (98% vs. 75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs. CNI/MTX (83% vs. 55%; p=0.0036), CNI/MTX+ATG (83% vs. 46%; p<0.001) and similar to PTCy (80% vs. 68%; p=0.23). Two-year RFS was significantly higher for abatacept+CNI/MTX vs. CNI/MTX (74% vs. 49%; p<0.01) and CNI/MTX+ATG (77% vs. 35%; p<0.01), and similar vs. PTCy (72% vs. 56%; p=0.1). For 8/8 MUD patients, 2-year OS was similar with abatacept+CNI/MTX vs. CNI/MTX (70% vs. 62%; p=0.2), CNI/MTX+ATG (75% vs. 64%; p=0.1), and PTCy (74% vs. 69%; p=0.5). Two-year RFS for abatacept+CNI/MTX was higher but this was not statistically significant vs. CNI/MTX (63% vs 52%; p=0.14),  with an improved hazard ratio (HR): 0.46, 95% confidence interval (95% CI) 0.25-0.86, and vs. CNI/MTX+ATG (66% vs. 55%; p=0.1; HR: 0.39, 95% CI 0.21-0.73). Two-year RFS was similar vs. PTCy (68% vs. 57%; p=0.2; HR: 0.5, 95% CI: 0.26-1.11).  The authors conclude that abatacept+CNI/MTX improved survival outcomes for both 7/8 MMUD and 8/8 MUD recipients, when compared to CNI/MTX and CNI/MTX+ATG, while outcomes were similar to PTCy-based regimens. This is in line with previous data that led to FDA approval and supports the use of abatacept+CNI/MTX as a GvHD prophylaxis strategy in this population.

Assessing the efficacy of allogeneic hematopoietic cell transplantation (Allo-HCT) in VEXAS syndrome: results of a systematic review and meta-analysis.

Highlight(s): Allo-HCT is an effective treatment for VEXAS syndrome.

VEXAS syndrome is an X-linked monogenic disease characterized by adult-onset myeloid dysplasia. VEXAS stands for vacuoles in myeloid and erythroid progenitors, E1 enzyme (more commonly referred to as UBA1) X-linked leading to autoinflammatory syndrome due to somatic mutations in UBA1. VEXAS is a relatively new entity with a significant burden of symptoms with no established treatment, with the use of several agents, including hypomethylating agents, ruxolitinib, and corticosteroids. AlloSCT has been used in VEXAS. However, there are no randomized or prospective data.   The authors performed a systemic review and meta-analysis on the benefit (overall response rate [ORR], complete remission [CR], event-free survival [EFS], and overall survival [OS]) of AlloSCT in VEXAS. The search identified 88 studies. Four studies (39 patients) met the inclusion criteria. Only one study, including 6 patients, reported an ORR of 100%, and it was the only study that reported CR in 5/5 evaluable patients. Median follow-up time after allo-HCT ranged from 8 to 18.5 months. Pooled EFS and OS rates were 56% and 86%, respectively. With respect to outcomes based on harms, pooled non-relapse mortality rate was 14% and pooled rates of acute and chronic graft-versus-host disease (GVHD) were 42% and 13%, respectively.  The authors conclude that AlloSCT is an effective treatment for VEXAS syndrome, with the caveat of the small number of patients and short follow up.