Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML [Clinical trial]

Highlight(s):
• 131I-Apamistamab-led regimen before allogeneic hematopoietic cell transplantation (allo-HCT) resulted in higher rates of durable complete remission (dCR) when compared to conventional care in patients aged ≥55 years with active relapsed or refractory acute myeloid leukemia (RR AML). 
• There were no significant differences in safety, and overall, 131I-apamistamab was well tolerated without excess toxicity. 

Active disease before alloHCT is the principal prognostic factor for post-transplant relapse in AML. Furthermore, elderly patients tend to have higher rates of toxicity and morbidity to remission induction regimens or intensive myeloablative regimens, resulting in <10% of older patients with active RR AML being offered alloHCT.  

¹³¹I-apmistamab is an anti-CD45 monoclonal antibody conjugated to radioactive isotope iodine-131. CD45 is expressed only on nucleated hematopoietic cells, including 85-90% of AML, thus resulting in delivery of direct radiation to hematopoietic cells with myeloablative effects. This study compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate ¹³¹I-apamistamab with conventional care. SIERRA was a phase 3 open-label trial in which patients aged ≥55 years with active RR AML were randomly assigned 1:1 to either an ¹³¹I-apamistamab–led regimen before alloHCT, or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the ¹³¹I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive ¹³¹I-apamistamab followed by alloHCT. The primary end point was durable CR (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population.

The ITT population included 153 patients (¹³¹I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received ¹³¹I-apamistamab and alloHCT, with six patients (143.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with ¹³¹I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; p < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; p = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring ¹³¹I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the ¹³¹I-apamistamab and conventional care groups, respectively.

The authors conclude that an ¹³¹I–apamistamab–led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. ¹³¹I-apamistamab was well tolerated and could address an unmet need in this population.

Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study [Clinical trial]

Peripheral T cell lymphoma comprises a heterogeneous group of generally aggressive lymphomas, of which the most common is T follicular helper-type lymphoma. Patients with Lugano classification stages II-IV or adverse prognostic indicators are eligible for auto-HCT. Allo-HCT is associated with greater toxicity and transplantation-related mortality than auto-HCT. In this retrospective cohort, 218 patients were evaluated between 1997 and 2023 at the MD Anderson Cancer Center, of which 84 (39%) underwent auto-HCT. Survival analysis was performed with Kaplan-Meier curves and comparisons were made using log-rank tests. Most patients had advanced-stage disease (92% with stage III or IV) and elevated lactate dehydrogenase (LDH) (89%). The most common first-line treatments were CHOP (37%) followed by CHOEP (14%) and a combination of brentuximab with either CHP or CHEP (13%). Interestingly, individuals who underwent auto-HCT exhibited a notably greater overall survival (p < 0.01) in comparison to those who did not receive auto-HCT. The cohort's median PFS following initial treatment was 12.5 months, and its median OS was 40.3 months (see Table 1 of original research).

Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD [Retrospective study]

Highlight(s): 
• The Manhattan score relies on clinical symptoms at onset of acute graft-versus-host disease (aGvHD) to classify patients into three risk strata (low, intermediate, and high) and is more accurate than the existing Minnesota score (0.69 vs. 0.64, p =0.009). 
• A composite score (MAGIC) incorporating clinical features and serum GvHD biomarkers (ST2 and REG3α) with Manhattan risk was created. The resulting score enlarged the low-risk group and more accurately predicted outcomes. resulting in higher accuracy of identifying aGvHD risk when compared to the Manhattan score alone (AUC, 0.76 vs. 0.70, p = 0.010). 

aGvHD remains an important cause of morbidity after allogeneic hematopoietic stem cell transplant as patients often require prolonged courses of steroids due to aGvHD falres. Furthermore, 30% of patients have refractory aGvHD to steroids. The Minnesota risk score is the only validated risk stratification system that uses clinical symptoms at aGvHD onset; however, it classifies patients as high- or standard-risk without a low-risk stratum. 

The authors randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) treated for GvHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar non-relapse mortality (NRM); they used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs. 0.64, p = 0.009) in the validation cohort. The Manhattan score differs in two main aspects from the Minnesota score. First, half of the standard-risk patients in the Minnesota risk classification were re-classified as low-risk. Second, patients with any liver GvHD are classified as high-risk using the Manhattan score (as opposed to the Minnesota score that considers standard-risk for liver GvHD plus skin stage I-III). 
Serum GvHD biomarker scores were integrated with the Manhattan risk using patients with available serum samples and using a CART algorithm to establish MAGIC composite scores that significantly improved the prediction of NRM compared to Manhattan risk (AUC, 0.76 vs. 0.70, p = 0.010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs. 63% vs. 30%, p < 0.001).

The authors conclude that the two new proposed risk systems are more accurate than existing classification systems, with the composite MAGIC score providing the highest accuracy. 

Long-Term Follow-Up of the Prospective Randomized AATT Study (Autologous or Allogeneic Transplantation in Patients With Peripheral T-Cell Lymphoma) [Prospective study]

Primary analysis of the phase III randomized AATT study showed that younger patients with PTCL consolidated with autologous or allogeneic hematopoietic cell transplantation (Auto- or Allo-SCT) had similar EFS and OS.

The authors report the updated follow up. In this trial, the seven-year EFS of patients randomly assigned to Allo-SCT was 38% (95% CI, 25 to 52) compared with 34% (95% CI, 22 to 47) for patients randomly assigned to Auto-SCT; OS was 55% (95% CI, 41 to 69) and 61% (95% CI, 47 to 74), respectively. Among patients undergoing Allo-SCT (n = 26) or Auto-SCT (n = 41) on study, the cumulative progression/relapse rate was 8% (95% CI, 0 to 19) and 55% (95% CI, 35 to 74), respectively. Non-relapse mortality (NRM) was 31% (95% CI, 13 to 49) and 3% (95% CI, 0 to 8) after Allo-SCT and Auto-SCT, respectively. Fifteen of 30 patients with early progression and 11 of 20 patients with progression/relapse after Auto-SCT received Allo-SCT. Seven-year OS after salvage Allo-SCT was 61% (95% CI, 47 to 74); NRM was 23% (95% CI, 6 to 40). Long-term follow-up documents the strong graft versus lymphoma effect of Allo-SCT independent of the timing of transplantation.
 
The outcomes of 26 patients who received Allo-SCT for consolidation or salvage after primary progression (n = 15) or after failing Auto-SCT (n = 11). OS of patients who received Allo-SCT for consolidation or at later stages was identical at 61% (42%-80%; Fig 2I). The cumulative incidence rate of NRM was 31% (13%-49%) for on-study and 23% (6%-40%) for off-study patients. In contrast, the survival of patients unable to undergo transplantation was dismal. 

The author concludes that these results suggest chemotherapy consolidated by Auto-SCT can achieve excellent long-term survival if patients are closely monitored and undergo immediate Allo-SCT after progression or relapse.

Comparison of Thiotepa-based Conditioning Regimens for Older Adults with Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (PCNSL) Undergoing Autologous Hematopoietic Cell Transplantation (Auto-HCT) [Retrospective study]

Highlight(s): 
• In older adults with PCNSL undergoing autologous hematopoietic cell transplantation (auto-HCT), carmustine/thiotepa (BCNU/Thio) is associated with decreased non-relapse mortality (NRM) and improved overall survival (OS) compared to thiotepa, busulfan, cyclophosphamide (TBC) conditioning.
• BCNU/Thio should be the conditioning regimen of choice for older patients with PCNSL undergoing auto-HCT given the lower NRM, and improved OS observed. 

Although outcomes for PCNSL have improved with the adoption of methotrexate-based induction followed by consolidation with thiotepa-based auto-HCT, the outcomes in older adults have remained unchanged, and this subgroup is primarily underrepresented in clinical trials. This subgroup is also at risk of increased toxicity with conditioning, and although BCNU/Thio and TBC have been reported to be similar in patients aged <65 years, it is unclear if there are differences in older adults. 

The authors report here on a dataset made available by the Center for International Blood and Marrow Research (CIBMTR), including patients who were ≥65 years of age with PCNSL and who underwent auto-HCT as consolidation with TBC or BCNU/Thio conditioning. Of 147 patients, 84 received BCNU/Thio and 63 received TBC. The 1-year NRM in the BCNU/Thio group was 10% versus 22% in the TBC group (p =0.05) and the 2-year relapse rate was 5% versus 5%, respectively (p=1.00). The 2-year progression-free survival (PFS) in the BCNU/Thio group was 85% versus 71% in the TBC group (p =0.05) and 2-year OS was 86% versus 74% (p = 0.08). In a multivariable regression model, BCNU/Thio was associated with a lower risk for NRM (hazard ratio [HR], 0.33, p=0.009), improved PFS (HR, 0.41, p=0.008) and OS (HR, 0.37, p =0.007), but there was no association with relapse risk.

Based on these results, the authors conclude that BCNU/Thio should be the conditioning regimen of choice for patients aged ≥65 years with PCNSL, given the improvement in NRM seen with this regimen in comparison to TBC.

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Adults Over 70 Years Old [Review]

The advent of reduced-intensity conditioning regimens, improvements in graft-versus-host disease (GvHD) prophylaxis, and better supportive care have permitted increasing use of allogeneic hematopoietic stem cell transplantation (allo-HCT) in adults age ≥70 years with acute myeloid leukemia (AML). In patients with AML in first remission, the graft-versus-leukemia effects and, possibly, intensification of conditioning reduce leukemia relapses by 60-70% compared to intensive chemotherapy alone. This striking risk reduction is observed independent of AML biology and measurable residual disease. Since post-relapse outcomes are poor, allo-HCT likely benefits patients with predicted relapse risk >40-45% if the non-relapse mortality risk is <20%. 

This interesting article (“Blood Spotlight” in Blood journal) pragmatically reviews the merits of allo-HCT, who should undergo allo-HCT, optimizing donor selection and GvHD prophylaxis, optimal first-line therapies, conditioning regimens, and post-transplant maintenance.

Here are some key clinical considerations summarized in Table 1 and the “Visual Abstract” of the original article: 

• In medically fit patients, HLA typing should be performed at diagnosis, and a donor search initiated
• Medically fit patients should be referred early for allo-HCT consideration
• Suitability for allo-HCT should be comprehensively, multidimensionally assessed (predicted leukemia relapse, fitness/comorbidity burden, donor availability, and caregiver support)
• Patients should be carefully counselled concerning benefits of transplant and attendant toxicities 
• A reduced-intensity conditioning regimen is generally recommended
• GVHD prophylaxis utilizing post-transplant cyclophosphamide or in vivo T cell depletion with antithymoglobulin is preferred
• In patients with high-risk disease features, rapid immunosuppression tapering should be considered
• All patients proceeding to transplant should be enrolled in prospective clinical trials where available
• In patients with FLT3-mutated AML, maintenance therapy with a tyrosine kinase inhibitor should be considered

ASTCT Consensus Recommendations on Testing and Treatment of Patients with Donor-specific Anti-HLA Antibodies [Consensus]

This article aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this potentially serious complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients.

Donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic HSCT using an HLA-mismatched allograft. Patients with a low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with a very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high levels of DSA, desensitization therapy can successfully mitigate DSA level and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade (see Figure 1 in the original paper). Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. 

High-dose chemotherapy with autologous stem cell transplants in adult primary non-seminoma mediastinal germ-cell tumors. A report from the Cellular Therapy and Immunobiology working party of the EBMT [Retrospective study]

Highlight(s): high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may well represent a therapeutic option in patients with primary mediastinal non-seminoma germ-cell tumors (PMNSGCTs) after the first relapse or even as a front-line program.

Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of a carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. The overall survival (OS) was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded.

Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Evidence-Based Guidelines from the American Society for Transplantation and Cellular Therapy [Guidelines]

Table 1 in the original article summarizes the recommendations, the evidence grading and the level of agreement. Figure 2 in the original paper summarizes the therapeutic approach in an algorithm.

Here is a short selection of questions and answers from the consensus:
• Should an age cutoff of 40 years be used for adult patients receiving hematopoietic cell transplantation (HCT) for severe aplastic anemia (SAA)? Due to improvement in supportive care and conditioning regimen, our panel suggests that upfront HCT may be considered up to 50 years of age or beyond for patients with severe cytopenias, in centers with expertise in HCT. 
• Should HCT remain a priority for adults with SAA who lack a matched related donor (MRD)? The panel suggests the use of either a matched unrelated donor (MUD) or haploidentical HCT (Haplo-HCT) in preference to immunosuppressive therapy for patients with SAA lacking an MRD. 
• Should rabbit anti-thymocyte globulin (ATG) or horse ATG be used in conditioning regimens for SAA patients? The panel recommends rabbit ATG over horse ATG as part of the conditioning regimen
• Should fludarabine containing HCT conditioning be prioritized over other regimens for aplastic anemia? The panel recommends cyclophosphamide-ATG conditioning for pediatric and adolescents and young adult patients receiving MRD-HCT. Fludarabine containing conditioning is recommended for adults or those with a high risk of graft failure. All patients receiving MUD-HCT, cord blood transplant or Haplo-HCT should receive fludarabine containing conditioning. 
• What should be the preferred regimen for graft-versus-host disease (GVHD) prophylaxis? The panel suggests either calcineurin inhibitor + methotrexate or post-transplant cyclophosphamide (PTCy)-based prophylaxis for GVHD for recipients of MRD- or MUD-HCT. For patients undergoing Haplo-HCT, the panel recommends PTCy-based prophylaxis. 

Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques

Highlight(s): Late cytomegalovirus (CMV) disease after the first 100 days continues to be a problem. Immunosuppressive drugs e.g., posttransplant cyclophosphamide and glucocorticoids at a dose ≥1 mg/kg, HLA-mismatched related donor status, high-risk level viremia, and inadequate frequency of surveillance are the most important modifiable risk factors in late CMV disease recurrence.

Preemptive therapy remains a widely used approach for CMV disease prevention worldwide. Letermovir given for three months after hematopoietic stem cell transplant (HCT) reduces the risk for clinically significant CMV infection but reactivation is common after withdrawal. A retrospective cohort at Fred Hutchinson Cancer Center investigated the key characteristics of late CMV disease in allogeneic HCT survivors. For this, the authors included patients who survived at least 100 days after HCT between 2001 and 2017 (preemptive therapy; PET cohort) and 2018 and 2021 (letermovir; LET cohort). Clinical manifestations, risk factors, and outcomes of late CMV disease in the first 2 years after transplantation were analyzed. Weekly testing by plasma polymerase chain reaction (PCR) until one year after transplant was performed by protocol for patients who received transplantation from cord blood, recipients of anti-thymocyte globulin or alemtuzumab, those who either received treatment for CMV reactivation or disease before day 100 or who were receiving corticosteroids for treatment of chronic graft-versus-host disease. Since 2018, all CMV seropositive HCT recipients received letermovir prophylaxis for up to 100 days after HCT according to institutional guidelines. Early and late CMV disease was defined as CMV disease diagnosed before or after day 100 post-HCT, respectively. There were 203 episodes of late CMV disease among 2469 survivors (2155 of 2298 [94%] survived up to day 100 after HCT in the PET cohort and 314 of 327 [96%] in the LET cohort). The estimated cumulative incidence of first-onset late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the LET cohort (5.4%; 95% CI, 3.2-8.3). Among the late CMV disease cases in the PET cohort, 142 (78%) occurred by 1 year after transplantation, and 40 (22%) occurred in the second year. In the LET cohort, most CMV disease diagnoses (n = 15 [71%]) occurred within the first year after HCT. In both populations, gastrointestinal tract involvement and pneumonia were the most common manifestations of CMV infection. The greatest risk for late CMV disease in both cohorts was associated with corticosteroid treatment at a dose ≥1 mg/kg and high-risk viremia detected before day 100 (defined as ≥10 antigen-positive cells or viral load ≥1000 IU/mL). Additionally, for the PET cohort, post-transplant cyclophosphamide-based GVHD prophylaxis was a significant independent factor for first-onset late CMV disease by the second year after HCT (adjusted hazard ratio [HR], 2.36; 95% CI, 1.22-4.59). Other risk factors identified in PET and LET cohorts were HLA-mismatched donors, lymphopenia <300 cells per mm3, early CMV disease, and GVHD. The authors concluded that delayed-onset CMV infection is an emerging problem because of different CMV prevention protocols along with the new transplantation techniques and drugs that may affect CMV-specific viral responses.

CMV reactivation during pretransplantation evaluation: a novel risk factor for posttransplantation CMV reactivation [Retrospective study]

Highlight(s): Pre-HCT cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) surveillance can be routinely detected in high-risk hematopoietic stem cell transplant (HCT) candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Clearance of pre-HCT CMV reactivation was associated with reduced risk of post-HCT CMV reactivation.

CMV reactivation after HCT, as detected by CMV DNA PCR, is associated with increased HCT-related mortality as well as an increased risk of CMV disease after HCT. Probably, the detection of CMV DNA during preconditioning increases the post-HCT complications, risk of CMV disease, and mortality after transplant. With this hypothesis in mind, the investigators evaluated the impact of pre-HCT CMV detection and the clearance of CMV DNAemia in the post-HCT outcomes. To do this, they analyzed two cohorts independently: CMV-seropositive recipients who underwent allogeneic HCT (allo-HCT) from 2007 to 2017 during the pre-letermovir era and allo-HCT recipients from 2018 to 2021 who received letermovir prophylaxis after HCT. The main outcome was to assess the influence of pre-HCT CMV on post-HCT CMV in patients who underwent HCT in the current letermovir era. Per institutional protocol, the patients initiated preemptive antiviral treatment when pre-HCT CMV reactivation was detected (≥150 and ≥50 IU/mL in low- and high-risk HCT recipients, respectively). 1536 patients in the first cohort (2007-2017) and 342 patients in the letermovir group (2018 to 2021) were analyzed. Between 2007 and 2017, a total of 155 patients (11%) had a positive CMV DNA PCR test prior to HCT, and 97 patients (7%) began preemptive antiviral medication for CMV. Comparably, before HCT, 37 patients (11%) from the 2018–2021 period had a positive CMV DNA PCR test, and 23 patients (7%) started preemptive antiviral medication. In both cohorts, the median onset period for a positive CMV DNA PCR test prior to HCT was 14 days (interquartile range: 6-23 days). Risk factors for pre-HCT CMV DNAemia included HCT-specific comorbidity (HCT-CI) scores ≥ 3, underlying lymphoid malignancy, and lymphopenia at 0.1-0.3 × 103 /μL within 90 days before HCT. Patients with any level of pre-HCT CMV reactivation had a greater incidence of post-HCT CMV in the first 100 days after HCT (and up to 1 year) than patients without pre-HCT CMV. Initiation of preemptive antiviral therapy for pre-HCT CMV DNA PCR influenced the risk of post-HCT CMV. Patients with pre-HCT CMV and who cleared their DNAemia with preemptive antiviral therapy were at significantly increased risk of post-HCT CMV DNAemia at any level and ≥ 150 IU/mL, compared with patients negative for pre-HCT CMV DNAemia. However, individuals who continued to HCT with pre-HCT CMV without clearing their CMV DNAemia despite preemptive antiviral medication were at an even larger risk of CMV DNAemia at any level, ≥150 IU/mL, and ≥500 IU/mL. Furthermore, there was a higher chance of overall and non-relapse mortality linked to any CMV reactivation. Similar results with post-HCT CMV outcomes were noted in the letermovir cohort. The authors concluded that CMV DNAemia detection before HCT is a strong independent risk factor for post-transplant CMV events, even in letermovir recipients. Strict CMV DNA PCR surveillance is recommended, especially in patients with profound lymphopenia within 90 days before HCT.

CD70 identifies alloreactive T cells and represents a potential target for prevention and treatment of acute graft versus host disease [Basic and clinical research]

Highlight(s): CD70 is an earlier marker of highly activated alloreactive T cells and is enriched in the blood and tissue of patients with acute graft-versus-host disease (aGVHD).

aGVHD is a result of an alloimmune effect, initially comprising tissue damage from the conditioning regimen which in turn leads to activation of host antigen-presenting cells, activation and proliferation of donor T cells (afferent phase), and finally, cytotoxic cell damage and release of inflammatory cytokines (efferent phase). GVHD is a major contributor to morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HST). CD70 is a costimulatory molecule that plays a crucial role in T cell activation in the afferent phase. For this reason, a recent study, published in Blood Advances, investigated the functional relevance of CD70-expressing T cells in patients undergoing allo-HST. Samples of peripheral blood of patients who underwent allo-HST were collected on the day of the transplant before infusion of the stem cells and then every 2 weeks until the first 3 months, at the onset of aGVHD (sampled at diagnosis before the start of the treatment), and monthly for up to 2 years. CD70+ and CD70-T cell subsets were sorted from cryopreserved peripheral blood mononuclear cells of patients with aGVHD sampled within 0 to 7 days before aGVHD diagnosis. Assays for transposase-accessible chromatin with sequencing (ATAC-seq) and total RNA sequencing (RNA-seq) were performed. Enzyme-linked immunosorbent assay was used to quantify the concentration of soluble CD27 (sole receptor of CD70). The frequency of CD27+ and CD70+ T cells after allo-HST was assessed by flow cytometry. Comparative analysis of the expression of these molecules was performed on the donor stem cell bag (SCB) and patient blood samples taken at 2-week intervals up to 14 weeks after cell infusion. A substantial increase in CD70+ T cells at day 14 after transplant exceeded the values observed in autograft transplants (CD70+CD4+T cells in the SCB: 1.1% of T cells that increased to 33% at day 14; CD70+CD8+T cells in the SCB: 0.6% of T cells that increased to 34% at day 14 [p<0.05]). CD70+CD4+T cells lacked FOXP3 expression and showed increased values of the Fas receptor (CD95), lymphocyte-activation gene 3 (LAG-3), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Using ATAC-seq, chromatin regions were relatively more open in CD70+ cells than in the CD70– subset, indicating their increased transcriptional potential (RGS1, implicated in autoimmune conditions, and USP3, which suppresses type I IFN signaling). Additionally, RNA-seq revealed upregulated expression of several MYC target genes associated with cell cycle-related signaling pathways. Also, an oligoclonal TCR repertoire and low repertoire diversity were demonstrated, with an average of 300 to 1220 clonotypes (the top 10 most abundant clones comprised 25% to 50% of the T cell repertoire in most cases). The percentage of CD4+CD70+ and CD8+CD70+ T cells was 9.6-fold and 4.2-fold higher in patients with severe aGVHD (25% and 13%) than in patients with no GVHD (2.6% [p < 0.005] and 3.1% [p< 0.05], respectively). Alloantigen stimulation in T cells isolated from blood at day 14 after HST was reduced, in the presence of CD70 antibodies. The study concluded that CD70 is an early biomarker (peak at around day 14 after allo-HST) of aGVHD and generates the important hypothesis of inhibiting CD27-CD70 costimulation for aGHVD treatment.

Transplant for myelodysplastic neoplasms [Retrospective study]

Highlight(s): Post-transplant cyclophosphamide in unrelated donor transplants for myelodysplastic neoplasms improves overall survival and progression-free survival as compared with anti-lymphocyte globulins.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the treatment of choice for all patients with high-risk myelodysplastic syndrome (MDS) who are fit enough to be considered for transplantation. Administration of post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis improves outcomes after unrelated donor HCT and has challenged the optimal GVHD prophylaxis recently. Alternatively, phase 3 trials have demonstrated the advantage of anti-thymocyte (ATG) or anti-lymphocyte globulins over placebo treatment with a lower incidence of chronic GVHD (cGVHD). The optimal GVHD prophylaxis strategy for patients with MDS who undergo allo-HCT is unclear and controversial. A retrospective cohort from the European Society for Bone Marrow Transplantation (EBMT) database evaluated the patients who underwent a first HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) allo-HCT between 2012 and 2019 to evaluate the outcomes comparing ATG vs. PTCy as GVHD prophylaxis. Study endpoints were overall survival (OS), progression-free survival (PFS), incidence and severity of acute GVHD (aGVHD) and cGVHD, extensive cGVHD-free and relapse-free survival (GRFS), relapse incidence (RI), non-relapse mortality (NRM), and neutrophil and platelet engraftment. Primary endpoints (OS, PFS, and GRFS) were estimated using the Kaplan-Meier product limit estimation method, and differences in subgroups were assessed using the log-rank test. A total of 209 patients received PTCy, and 751 received ATG as GVHD prophylaxis. Risk categorization (IPSS-R) was as follows: 35 (6.6%) were very low, 86 (16.1%) were low, 146 (27.4%) were intermediate, 157 (29.5%) were high, and 109 (20.5%) were very high risk. The results showed that neutrophil engraftment at 28 days was significantly better with ATG (93% vs. 85% in the PTCy group; p < 0.001). Grade 2 to 4 aGVHD incidence was lower using PTCy (23%; 95% confidence interval [CI], 17-29 vs. 30%; 95% CI, 27-33; p = 0.044), but differences in grade 3 to 4 aGHVD and cGHVD were not statically significant. Over a median follow-up of 4.4 years, the 5-year PFS was better with PTCy at 53% (95% CI, 45-60 vs. 44%; 95% CI, 40- 48) with ATG (p = 0.043), and also OS was better with PTCy compared to ATG (PTCy: 58%; [95% CI, 50-65] vs. ATG: 49%; 95% CI, 46-53; p= 0.07); 5-year GRFS, cumulative RI, and 5-year NRM were similar in the two cohorts. The adjusted multivariable model demonstrated a better OS (hazard ratio [HR]  for ATG of 1.32; 95% CI, 1.0-1.74; p = 0.05) and PFS for PTCy (HR for ATG of 1.33; 95% CI, 1.03-1.73; p = 0.03). Similarly, the risk for grade 2 to 4 aGVHD was significantly increased among patients who received ATG (HR 1.61; 95% CI, 1.12-2.33; p = 0.01). In this multicenter retrospective cohort, GVHD prophylaxis with PTCy improved OS and PFS with a decreased incidence of grade 2 to 4 aGHVD compared to ATG. PTCy is a feasible option for the prevention of aGHVD in countries in which ATG is more difficult to obtain.

Allogeneic stem cell transplantation in de novo core-binding factor acute myeloid leukemia in first complete remission [Retrospective study]

Highlight(s): Consolidation in first complete remission after high-dose cytarabine (HiDAC) chemotherapy with allogeneic hematopoietic stem cell transplantation results in worse outcomes than autologous hematopoietic stem cell transplantation

The European LeukemiaNet (ELN) 2022 acute myeloid leukemia (AML) risk classification considered the mutations in core-binding factor (CBF)-AML as favorable prognostic markers. It is characterized by the presence of t(8;21) or inv(16) associated with the molecular abnormalities RUNX1/RUNX1T1 (AML1/ETO) and CBFB/MYH11, respectively. However, the five-years outcomes of both translocations are quite different. After the first remission (CR1) with cytarabine/ anthracycline-based chemotherapy induction followed by high-dose cytarabine (HiDAC) consolidation, the role of transplant as consolidation therapy is not clear. For this reason, a retrospective study using the data from the European Society for Blood and Marrow Transplantation (EBMT) registry investigated the effect of hematopoietic stem cell transplantation (SCT) with either allogeneic-SCT (allo-SCT) or autologous-HCT (ASCT), in patients with CBF-AML in CR1. A total of 1901 patients who received their first transplant between 2010 and 2021 were analyzed. 65.5% harbored t(8;21) associated with the molecular abnormality RUNX1/RUNX1T1 (AML1/ETO)and 34.4% harbored inv(16) associated with CBFB/MYH11. The majority of patients (n = 1470, 77%) received an allo-SCT. Baseline characteristics showed a longer follow-up (41.2 vs. 24 months, p < 0.0001) in patients who received an ASCT; allo-HCT was performed in older aged patients (median age: 49.5 vs. 44.1 years, p < 0.0001), more recently (median year: 2018 vs. 2015, p < 0.0001), and with a longer time between diagnosis and transplantation (5.3 vs. 4.6 months, p < 0.0001). ASCT recipients had the following mutation distributions: 48.3% harboring t(8;21) and 51.7% harboring inv(16), compared to allo-HCT (70.7% harboring t(8;21) and 29.3% harboring inv(16)). Of a total of 1901, measurable residual disease (MRD) data was available for 1203 (63%) patients, 673 (56%) of whom were MRD-negative at the time of transplant. Among MRD-negative patients, non-relapse mortality (NRM) and overall survival (OS) were worse in the allo-SCT group (12.9% vs. 5.2%, p = 0.007 and 75.8% vs. 82%, p= 0.07, respectively). On multivariate analysis, harboring t(8;21) instead of inv(16) was associated with worse OS (hazard ratio [HR]: 1.49, p = 0.003), and receiving an allo-SCT compared to ASCT was associated with worse NRM (HR: 4.26, p < 0.0001) and OS (HR: 1.67, p = 0.003). In conclusion, after induction/consolidation in patients who achieve CR1 with CBF-AML, consolidation with allo-SCT result in poor outcomes compared to ASCT. The latter is the best choice for these patients but their role compared with chemotherapy is uncertain.