Allogeneic Hematopoietic Cell Transplantation Research Articles

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT

AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.

Novel machine learning technique further clarifies unrelated donor selection to optimize transplantation outcomes

AbstractWe investigated the impact of donor characteristics on outcomes in allogeneic hematopoietic cell transplantation (HCT) recipients using a novel machine learning approach, the Nonparametric Failure Time Bayesian Additive Regression Trees (NFT BART). NFT BART models were trained on data from 10 016 patients who underwent a first HLA-A, B, C, and DRB1 matched unrelated donor HCT between 2016 and 2019, reported to the Center for International Blood and Marrow Transplant Research, then validated on an independent cohort of 1802 patients. The NFT BART models were adjusted based on recipient, disease, and transplant variables. We defined a clinically meaningful impact on overall survival (OS) or event-free survival (EFS; survival without relapse, graft failure, or moderate to severe chronic graft-versus-host disease) as >1% difference in predicted outcome at 3 years. Characteristics with <1% impact (within a zone of indifference) were not considered to be clinically relevant. Donor cytomegalovirus, parity, HLA-DQB1, and HLA-DPB1 T-cell epitope matching fell within the zone of indifference. The only significant donor factor that associated with OS was age, in which, compared with 18-year-old donors, donors aged ≥31 years old were associated with lower OS. Both donor age (≤32 years) and use of a male donor, regardless of recipient sex, improved EFS. We, therefore, recommend selecting the earliest available donor within the 18 to 30 years age range for HCT to optimize OS. If several donors in the 18 to 30 years age range are available, a male donor may be chosen to optimize EFS.

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML

AbstractMeasurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.

Toxoplasma qPCR kinetics to guide pre-emptive treatment of toxoplasmosis after allogeneic hematopoietic stem cell transplantation.

Recent ECIL-guidelines recommend a quantitative PCR (qPCR) guided pre-emptive treatment approach to toxoplasmosis in seropositive recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While qPCR might serve as a sensitive tool for early Toxoplasma detection, its role in treatment follow-up remains unknown. We analyzed the qPCR kinetics of allo-HCT recipients experiencing either Toxoplasma infection (TI, n=71) or disease (TD, n=14) in relation to different parameters. We included 85 patients with available qPCR values expressed as quantitative cycle (Cq) from four large hematological centers from 2009 to 2023, and kinetic analysis was performed in a selection of 74 patients screened at least weekly with blood qPCR. Day 0 (D0) was the day of anti-Toxoplasma treatment start or (when untreated) day of diagnosis. Time to qPCR negativity was inversely proportional to the Cq value at D0 (p=0.0063). Not reaching negativity at D10 was associated with a significantly higher mortality at D30 (p=0.023). Patients with a high D0-parasitic load and patients with TD showed slower clearance (p<0.001, p=0.032). Time to negativity was not significantly different for patients started on prophylactic vs curative doses as first-line treatment regimen (p=0.16). This study underscores the predictive value of qPCR kinetics monitoring in allo-HCT patients with toxoplasmosis. With the aforementioned risk factors, clinicians can identify patients at high-risk for worse outcome. Our results support to consider a therapeutic change or reinforcement if the parasitic load does not decrease after 10 days, supplementing existing clinical guidelines.

An international survey to better understand the current incidence, severity, and management of VOD/SOS.

This international questionnaire survey aimed to explore the current incidence, diagnostic policies, management, and outcomes of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) among healthcare providers involved in the management of these patients. A questionnaire was e-mailed to practitioners with an interest in allogeneic hematopoietic cell transplantation (allo-HCT). Of the respondents, 144 of 215 (67.0%) felt that early detection or diagnosis of VOD/SOS was difficult. Regarding diagnostic criteria, 142 (66.1%) already declared using the 2023 EBMT refined criteria. Most respondents (163/215, 75.8%) found these recent refined EBMT criteria useful for diagnosis, and 193 (89.8%) found the severity criteria easy to use. The major risk factors identified for VOD/SOS were a second allo-HCT (41.4%), pre-existing liver disease (54.9%), and prior use of antibody-drug conjugates (49.8%). Preferences for starting VOD/SOS treatment varied, with 61 (28.4%) preferring initiating therapy at a mild stage, and 122 (56.7%) preferring the moderate stage. In summary, this survey provided valuable insight into the challenges and opportunities of the identification and management of VOD/SOS. By improving current knowledge and increasing collaboration among healthcare professionals, early detection, management, and clinical outcomes for patients with this potentially serious complication can also be improved.

Prophylactic Cranial Irradiation prior to HCT for Acute Lymphoblastic Leukemia: To Boost or Not To Boost.

Total body irradiation (TBI) with or without cranial radiation boost (CRB) is an integral component of conditioning prior to allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). The benefit of CRB is not yet established. This is a retrospective single center cohort study. Between January of 2003 and April of 2019, electronic medical records of 166 patients with ALL were retrospectively reviewed. One hundred forty-three patients with ALL and no prior central nervous system (CNS) involvement were included. Patients were divided into two cohorts according to cranial radiation boost (cohort-1: CNS-/CRB+ (110/143, 77%) and cohort-2: CNS-/CRB- (n=33/143; 23%). No patients received post-transplant prophylactic intrathecal chemotherapy. Following alloHCT, 15 patients (10.5%) experienced relapse; 11 relapses (10%) in cohort-1, and 4 (12%) in cohort-2. Four patients (26.6%) experienced systemic medullary relapse with initial central nervous system (CNS) involvement. One patient (6.6%) experienced isolated first central nervous system relapse after allotransplant with no difference between the two cohorts (6.6% vs 0; P-0.59). Age at transplant and phenotypic subtype were predictive of first central nervous system relapse after allotransplant with respective P-values of 0.001 and 0.015.At a median follow-up of 30 months (range: 2.5-128 months), the estimated 3-year overall survival was 61% (95% CI: 53-69), relapse free survival was 60% (95% CI: 52-69) and 3-year central nervous system-relapse-free survival was 99% and 100% in in cohort-1 and cohort-2 respectively, when systemic relapses were censored. There was no statistical significant difference in either survival or relapse free survival between the two cohorts (P > 0.69). Our results suggest that augmenting total body irradiation with cranial radiation boost in patients with ALL with no prior CNS involvement did not improve relapse risk in central nervous system or survival outcomes.

Outcome of adult acute myeloid leukemia patients with extramedullary disease and treatment with venetoclax/hypomethylating agents.

We evaluated response to VEN/HMA in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease (EMD). Median age was 65 (range, 19-81) years. Patients had a median of two EMD sites (range, 1-5) and 35 (76%) patients had concurrent bone marrow involvement. Twenty (43%) patients had highrisk genetic features according to the European Leukemia Net 2022 classification. Twenty-nine (63%) were relapsed or refractory after intensive chemotherapy (CTX) including 13 (28%) with prior allogeneic hematopoietic cell transplantation (allo-HCT). Patients received a median of 2 cycles of VEN/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) after VEN/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allo-HCT (CR/CRi, n=4; PR, n=2). Median follow-up was 49.1 months (95%-CI, 26.1 months - not reached) and median overall survival (OS) 6.4 months (95%-CI, 5.1-11 months). One-year and 2-years OS rates were 29.3% (95%-CI, 18.6-46.2%) and 12.3% (95%-CI, 5.5-27.6%), respectively. Age with a cut-off of 60 years had no impact on OS (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after VEN/HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and 2 (10%) died in CR. In our cohort of patients with AML with EMD with high-risk features, treatment with VEN/HMA resulted in an encouraging ORR of 54% with a CR/CRi rate of 43.5%. However, VEN/HMA alone may not be effective in maintaining disease control.

Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin

AbstractMeasurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos]) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)–based MRD assay with a limit of detection of 10−4 to 10−5, we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the AMLSG16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. Achievement of MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .001) and overall survival (OS) (4y-OS; 70% vs 44%; P = .012). This survival advantage was also seen among patients who underwent allogeneic hematopoietic-cell transplantation during first complete remission (4y-CIR, 14% vs 39%; P = .001; 4y-OS, 71% vs 49%; P = .029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (hazard ratio [HR], 0.29; P = .006) and OS (HR, 0.39; P = .018). An NPM1 co-mutation correlated with a deeper molecular response as reflected by stronger MRD reduction and a higher rate of FLT3-ITD MRDneg after Cy2. During follow-up, conversion from MRDneg to MRDpos was a strong, independent factor for inferior CIR (HR, 16.64; P < .001) and OS (HR, 4.05; P < .001). NGS-based FLT3-ITD MRD monitoring allows for the identification of patients at high risk for relapse and death following treatment with intensive chemotherapy and midostaurin. Using NGS-based technology, FLT3-ITD emerges as a novel, highly clinically relevant target for MRD monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT01477606.

Therapeutic advances for the management of adult T cell leukemia: Where do we stand?

Adult T cell leukemia (ATL) is an aggressive blood malignancy secondary to chronic infection with the human T cell leukemia virus type I (HTLV-1) retrovirus. ATL encompasses four subtypes (acute, lymphoma, chronic, and smoldering), which exhibit different clinical characteristics and respond differently to various treatment strategies. Yet, all four subtypes are characterized by a dismal long-term prognosis and a low survival rate. While antiretroviral therapy improves overall survival outcomes in smoldering and chronic subtypes, survival remains poor in lymphoma subtypes despite their good response to intensive chemotherapy. Nonetheless, acute ATL remains the most aggressive form associated with profound immunosuppression, chemo-resistance and dismal prognosis. Targeted therapies such as monoclonal antibodies, epigenetic therapies, and arsenic/IFN, emerged as promising therapeutic approaches in ATL. Allogeneic hematopoietic cell transplantation is the only potentially curative modality, alas applicable to only a small percentage of patients. The recent findings demonstrating the expression of the viral oncoprotein Tax in primary ATL cells from patients with acute or chronic ATL, albeit at low levels, and their dependence on continuous Tax expression for their survival, position ATL as a virus-addicted leukemia and validates the rationale of anti-viral treatment strategies. This review provides a comprehensive overview on conventional, anti-viral and targeted therapies of ATL, with emphasis on Tax-targeted therapied in the pre-clinical and clinical settings.

Efficacy and safety of hetrombopag in the treatment of recombinant human thrombopoietin–resistant thrombocytopenia after allogeneic hematopoietic stem cell transplantation

BackgroundThrombocytopenia after allogeneic hematopoietic cell transplantation is a challenging clinical problem. Recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists are increasingly used in posttransplant thrombocytopenia. However, the use of hetrombopag in patients with posttransplant thrombocytopenia, especially in patients with resistance to rhTPO, has not yet been reported. ObjectivesThe present study aimed to investigate the efficacy and safety of hetrombopag in patients with rhTPO-resistant posttransplant thrombocytopenia. MethodsThis retrospective study included 21 patients with rhTPO-resistant posttransplant thrombocytopenia who received hetrombopag from August 2021 to July 2022. The primary endpoint was the overall response rate, including partial response and complete response (CR). We also evaluated the predictors of hetrombopag efficacy and adverse events. ResultsThe overall response rate to hetrombopag was 81%, and the CR rate was 62%. The median time from hetrombopag initiation to response and CR were 16 and 31 days, respectively. Decreased megakaryocytes in bone marrow negatively correlated with CR to hetrombopag (P = .027). All the patients tolerated hetrombopag well without any significant increase in adverse events. At the last follow-up, 71% of responders had discontinued hetrombopag and sustained their best response. ConclusionOur results suggested that hetrombopag is an effective treatment option to promote platelet recovery in patients with posttransplant thrombocytopenia, even in patients resistant to rhTPO.

Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Myelodysplastic Syndromes: Considerations and Challenges

Myelodysplastic syndromes/neoplasms (MDS) and related diseases are highly heterogeneous myeloid stem cell cancers that predominantly affect the elderly. The only curative treatment is allogeneic hematopoietic cell transplantation (HCT). Given the prevalence of age-related comorbidities, HCT in patients aged 65 years or older requires a highly personalized approach. This review summarizes disease risk stratification, treatment modalities, and outcomes for patients with MDS and related disorders, and discusses specific considerations and challenges for elderly patients undergoing HCT, including geriatric assessment, timing, conditioning treatment, donor and graft selection, and graft-versus-host disease prophylaxis.

Persistently Low IgG2 Levels in a Subset of Patients Following Hematopoietic Cell Transplantation.

Infectious diseases remain a major cause of morbidity and mortality after hematopoietic cell transplantation (HCT). Secondary hypogammaglobulinemia is a risk factor for infectious diseases. Total immunoglobulin G (IgG) levels and the history of infectious diseases are an integral part of determining the indication for immunoglobulin replacement therapy. The clinical significance of IgG2 levels is not well established. Guidelines recommend using pathogen-specific IgG to evaluate patients with potential secondary immunodeficiency. However, it is difficult in practice to perform such testing. IgG2 may correlate well with pathogen-specific IgG but the clinical significance of IgG2 is not well established. To assess the prevalence of low IgG2 levels with normal IgG after HCT, we cross-sectionally measured the levels of several immunoglobulins, including IgG, IgA, IgM, and IgG2, after HCT, and we assessed the correlation between them. Among 121 patients who underwent cross-sectional measurements of IgG, IgA, IgM, and IgG2 levels after HCT, 114 had normal IgG2 levels (normal IgG2 group, ≥ 100mg/dL) and 7 had low IgG2 levels (low IgG2 group, < 100mg/dL). These 7 patients were allogeneic HCT recipients. All 7 patients with low IgG2 had cGVHD and 4/7 patients had normal total IgG levels. IgG2 levels may be low even in patients with normal IgG levels years after allogeneic HCT. Therefore, our study suggests that when patients develop infectious diseases, especially multiple episodes, it is recommended to measure IgG2 levels to exclude the possibility of secondary hypogammaglobulinemia after allogeneic HCT.

New insights into hematopoietic cell transplantation in ALL: Who should be transplanted, when, and how

Advancements in multi-agent chemotherapy through clinical trials conducted by multi-institutional collaborative groups worldwide, along with risk stratification using molecular genetic features and treatment responses, including minimal residual disease, have significantly improved outcomes for children and adolescents with acute lymphoblastic leukemia (ALL) over the past half-century. However, for a certain number of high-risk patients, including those with relapsed or refractory disease, for whom existing chemotherapy alone is insufficient for cure, allogeneic hematopoietic cell transplantation (HCT) has provided a potential opportunity for leukemia cure. For these patients, the appropriate selection of donor and stem cell source, conditioning regimen, timing of transplantation, and comprehensive supportive care, including effective graft-versus-host disease prophylaxis, are prerequisites for successful HCT. While HCT from a human leukocyte antigen (HLA)-matched sibling has traditionally been the preferred option, less than 25 % of patients currently have such a donor in developed countries. Consequently, alternative donor HCT options, such as those from matched unrelated donors identified through high-resolution HLA typing, unrelated cord blood donors, and more recently, haploidentical donors using post-transplant cyclophosphamide or TCRαβ+/CD19+ cell-depleted grafts, are providing broader access to HCT for patients lacking matched sibling donors. Nonetheless, HCT carries the risk of various acute and late toxicities. In particular, the use of myeloablative conditioning with total body irradiation, a standard in pediatric ALL, is associated with significant long-term sequelae. As our understanding of the pathophysiology of the disease improves and novel molecular targeted therapies and immunotherapies are developed, the indication for HCT in pediatric ALL is becoming more selective, leading to a gradual decrease in the number of transplants performed. However, further optimization and evolution of allogeneic HCT are needed to both maximize its anti-leukemia effects and minimize transplant-related complications, as there remain cases that undoubtedly require HCT for the cure of leukemia.

Safety and efficacy of G-CSF after allogeneic hematopoietic cell transplantation using post-transplant cyclophosphamide: clinical and in vitro examination of endothelial activation.

Since 2021 the use of G-CSF was implemented in allo-HCT with PTCY-based prophylaxis with the aim of shortening the aplastic phase and reducing infectious complications. This study investigates the effectiveness of this change in protocol performed at our institution. One-hundred forty-six adults undergoing allo-HCT with PTCY-based prophylaxis were included, and among them, 58 (40%) received G-CSF. The median of days to neutrophil engraftment was shorter in the G-CSF group (15 vs. 20 days, p < 0.001). Patients receiving G-CSF had a lower incidence of day +30 bacterial bloodstream infections (BSI) than the rest (20.7% vs. 47.7%, p < 0.001). GVHD, SOS, and TA-TMA incidences were comparable between groups, and using G-CSF did not impact on survival. Endothelial activation was investigated using EASIX and by the measurement of soluble biomarkers in cryopreserved plasma samples obtained on days 0, +7, +14 and +21 of 39 consecutive patients (10 received G-CSF) included in the study. EASIX, VWF:Ag, sVCAM-1, sTNFRI, ST2, REG3α, TM and NETs medians values were comparable in patients receiving G-CSF and those who did not. Compared with allo-HCT performed without G-CSF, the addition of G-CSF to PTCY-based allo-HCT accelerated neutrophil engraftment contributing on decreasing BSI incidence, and without inducing additional endothelial activation.

Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia.

Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.

N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial

Maintenance therapy may improve natural killer (NK) cell surveillance after allogeneic donor hematopoietic cell transplant (HCT) for myeloid malignancies and represents a potential approach to improve cure rates. Interleukin-15 (IL-15) enhances lymphocyte proliferation and antitumor activity. In a prior Phase 1 study of an IL-15 superagonist (N-803) in patients with AML who relapsed after HCT, we observed in vivo expansion of NK cells and antitumor responses. The primary objective of this Phase 2 trial was to determine if post-transplant N-803 could reduce relapse. We administered N-803 (n = 20) (dosed 6 mcg/kg subcutaneously [SQ] at day 60 after HCT to patients with myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML] who were in complete remission [CR]). N-803 treatment was planned weekly, biweekly or every 4 weeks in 2 sequential cohorts. The most common adverse events after administration were self-limited injection sites skin rashes (n = 20). One week after an N-803 dose, we observed enhanced NK cell proliferation and improved antitumor cytotoxicity without inducing immune exhaustion. Five patients who developed acute graft versus host disease (aGVHD) after N-803 responded promptly to steroids and 4 patients developed chronic GVHD. Patients receiving >4 doses of N-803 had a 3-fold decrease in relapse at two years (P = .06). These findings support the safety, immune activation, and potential efficacy of N-803 to prevent relapse of AML/MDS after HSCT.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Which allogeneic hematopoietic cell transplant recipients have an increased risk for delayed-onset clinically significant cytomegalovirus infection after letermovir prophylaxis?

Cytomegalovirus (CMV) reactivation is one of the most common complications after allogeneic hematopoietic stem cell transplantation (HSCT). Letermovir is approved for CMV prophylaxis among high-risk recipients. However, delayed-onset post-prophylaxis clinically significant CMV infection (csCMVi) has been observed, suggesting the potential for extending letermovir prophylaxis beyond the first one hundred days post-HSCT. Retrospective multicenter cohort study of allogeneic HSCT patients from August 2018 to March 2023. The primary aim of this study was to identify the risk factors at day 100 associated with delayed onset csCMVi, in patients who received letermovir prophylaxis up to day 100. Competing risk analysis was used to evaluate incidence with specific risk factors, using Gray's Test comparing groups for each event. Among 166 eligible allogeneic HSCT recipients, the most common primary hematological diagnosis was acute myelogenous leukemia (AML) (42.2%). Twenty-six (15.7%) developed a breakthrough csCMVi. Delayed-onset csCMVi occurred in 23.5%, at a median time of 133 days after SCT. On multivariate analysis, having a matched unrelated donor (odds ratio [OR] 2.46) and a CMV donor negative/recipient positive status (OR 3.47) were associated with delayed onset csCMVi. In contrast, AML had a lower odd of having delayed-onset csCMVi (OR 0.23). Having a matched unrelated donor, a CMV donor negative/recipient positive status, and a non-AML underlying disease were associated with delayed onset csCMVi. Prospective studies are needed to evaluate whether extended letermovir prophylaxis is beneficial for these patients.

Evaluation of risk for bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation with myeloablative conditioning regimens.

Bronchiolitis obliterans syndrome (BOS), as chronic manifestation of graft-versus-host disease (GVHD), is a debilitating complication leading to lung function deterioration in patients after allogeneic hematopoietic cell transplantation (allo-HCT). In the present study, we evaluated BOS development risk in patients after receiving myeloablative conditioning (MAC) regimens. We performed a retrospective analysis of patients undergoing allo-HCT, who received MAC with busulfan/cyclophosphamid (BuCy, n = 175) busulfan/fludarabin (FluBu4, n = 29) or thiotepa/busulfan/fludarabine (TBF MAC, n = 37). The prevalence of lung disease prior allo-HCT, smoking status, GvHD prophylaxis, HCT-CI score, EBMT risk score and GvHD incidence varied across the groups. The cumulative incidence of BOS using the NIH diagnosis consensus criteria at 2 years after allo-HCT was 8% in FluBu4, 23% in BuCy and 19% in TBF MAC (p = 0.07). In the multivariate analysis, we identified associated factors for time to BOS such as FEV1<median (99% of predicted) (HR = 2.39, p = 0.004), CMV patient serology positivity (HR = 2.11, p = 0.014), TLC < 80% of predicted (HR = 0.12, p = 0.02) and GvHD prophylaxis with in vivo T-cell depletion (HR = 0.29, p = 0.001) as predictors of BOS. In summary, we identified risk factors for BOS development in patients receiving MAC conditioning. These findings might serve to identify patients at risk, who might benefit from closely monitoring or early therapeutic interventions.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.