Acute Graft-versus-host Disease Research Articles

Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM).

Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18-70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution's records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan-Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy.

Haploidentical hematopoietic stem cell transplantation for hematologic malignancies: a novel conditioning regimen with anti-T lymphocyte immunoglobulin instead of anti-thymocyte globulin for in vivo T cell depletion.

We evaluated the safety and efficacy of a novel protocol for haploidentical stem cell transplantation (haplo-SCT) in 312 patients with hematologic malignancies. The protocol evolved from the Beijing platform replacing ATG with ATLG; adding Fludarabine and removing cytarabine and Simustine. GVHD prophylaxis combined Basiliximab and low-dose cyclophosphamide post-transplant; overall, the conditioning duration was shortened. Median times to neutrophil and platelet recovery were both 11 days. Graft rejection occurred in 0.96% of patients. Cumulative incidences of grades II-IV and III-IV acute GVHD by day 200 were 35.3% and 8.9%, respectively. Probabilities of total and extensive chronic GVHD at 2 years were 40.7% and 14.7%. CMV viremia was observed in 35.6% of patients, with a 1.9% 100-day CMV pneumonia incidence and no CMV-related mortality. Cumulative incidences of non-relapse mortality at 100 days, 1 year, and 2 years were 2.9, 4.4, and 6.6%. The 4-year OS, RFS, and GRFS rates were 78.9, 70.7, and 47.3%. Older recipient age was associated with higher NRM, while positive pre-transplant MRD predicted worse OS, RFS, and higher relapse incidence. Our novel protocol for haplo-SCT is associated with low infection rates and acceptable risks of graft failure, severe GVHD, and mortality, representing a safe and effective haploidentical transplantation strategy.

BK virus associated hemorrhagic cystitis in pediatric patients undergoing hematopoietic stem cell transplantation

Abstract Background BK virus (BKV) is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT). Methods Descriptive and retrospective study that included patients from 0-18 years old undergoing HSCT with a diagnosis of HC, admitted from 1/1/2018 to 11/30/2023 in a tertiary care pediatric hospital. Patients with HC were tested for BKV by quantitative polymerase chain reaction (PCR) in urine samples, if positive, plasma viral load was also requested. BKV-HC grading was defined by the European Conference on Infections in Leukemia (ECIL) consensus document. Asymptomatic patients did not undergo standardized screening for BKV. Results During this period 86 HSCT were performed for either malignant (75,6%) or non-malignant disorders (24,4%). Overall, 16 (18,6%) were autologous and 70 (81.4%) were allogeneic: 40 human leukocyte antigen (HLA) matched unrelated donor, 26 HLA-matched related donor and 4 haploidentical. Six patients (7%) suffered HC, all associated with BKV as the cause. These six patients underwent allogeneic HSCT, and 4 of them had HLA-matched unrelated donors. All patients were over 5 years old. Male sex predominated (n:5). All of the patients had hematologic malignancies as the underlying diagnosis (5 with acute lymphoblastic leukemia - ALL). The stem cell source was bone marrow in 3 patients and peripheral blood in the other 3. All patients received myeloablative conditioning regimen and 4 underwent total body irradiation. Only one patient received post-transplant cyclophosphamide. Symptoms (dysuria, abdominal pain, macroscopic hematuria, clots) began more than 14 days after HSCT in 100% of the cases. Hematuria was categorized as grade III in 5 patients and grade IV (severe) only in one. All patients tested positive for BKV PCR in urine samples. High-level BK viruria (>107 copies/mL) was found in 66,6%. BK viremia was detected in 4 patients. All of the patients had another concomitant viral infection, with cytomegalovirus reactivation being the most frequent (n:4). Two patients also had detectable adenovirus (ADV) PCR in urine samples. Acute graft versus host disease (GVHD) was diagnosed in 5 patients, all with skin involvement. All patients were hospitalized and prolonged the length of stay. Regarding treatment, they all received hyperhydration and Cidofovir (more than 3 doses). Dose of immunosuppressive treatment was reduced in 5 cases. Acute kidney failure (AKF) was found in 3 patients. One patient developed chronic kidney failure. The patient with no GVHD was the one who improved the fastest. The patient with severe hematuria required bladder irrigation, had dialysis indication and presented a related death. Conclusion The development of BKV-HC in HSCT patients results in suffering and pain, prolonged hospitalizations and significant morbidity (AKF). Literature shows that male sex, older age and acute GVHD are important risk factors, and this is what we also found in our case series. BKV-HC is considered a difficult and severe condition to manage, remaining troublesome so we should overcome this deficiency with new approaches, particularly emphasizing in preemptive or prophylaxis measures for the benefit of our patients.

Infection-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplants at a Referral Center in Mexico

Abstract Background Infections constitute a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, infection-associated mortality rate ranging from 7% to 17% has been reported, depending on the type of HSCT, being lower in autologous transplants and higher in cases involving unrelated donors. Other factors related to HSCT that influence the clinical outcomes of these patients include the intensity of the conditioning regimen, the development of graft-versus-host disease (GVHD), cytotoxic and immunosuppressive effects of the medications used, the presence of disease activity prior to HSCT, length of hospital stay, and the use of intravascular devices, among many others. Methods All pediatric patients (under 16 years old) undergoing HSCT at the ‘Dr. José Eleuterio González’ University Hospital over a 55-month period (March 2019 – October 2023) were included. Clinical and epidemiological characteristics of the patients, mortality rate, and risk factors related to transplantation and infectious events (IEs) in these patients were recorded. Results A total of 75 patients who received HSCT were included, among them, 52 patients (69%) presented IEs. The mortality associated with IEs among these patients was 6% at day 30 and 12% at day 100, compared to 0% and 1.3% respectively in the non-IEs related deaths. The epidemiological characteristics, baseline diagnosis, donors and graft source are described in table 1. The average number of IEs in the associated mortality cases was 2.8 compared to 1.6 in the survival group. Among the mortality group (8 cases), 67% presented multiple infections and 33% single infections, with a 75% of them caused by viral infections. Regarding HSCT characteristics, in the group with IE-associated mortality, a higher proportion of haploidentical transplants, myeloablative conditioning regimens, lower use of total body irradiation, and a higher proportion of patients with detectable disease by flow cytometry prior to HSCT were observed compared to the survival group. Among non-infectious complications related to HSCT a lower frequency of acute GVHD grade I-II, a higher frequency of acute GVHD grade III-IV in the IE-associated mortality group was identified. Among the risk factors associated with hospital care, the IE-associated mortality group showed a higher use of central venous catheters, mucositis, systemic steroids, and pediatric intensive care unit stay compared to the survival group. Conclusion Pediatric patients undergoing HSCT present multiple risk factors that increase the incidence of infectious events and contribute to higher mortality rates. It is crucial to identify those factors related to adverse events and death to implement strategies that reduce exposure to these factors and improve the clinical outcomes.

Implementing a standardized workflow for early detection of steroid-induced hyperglycemia in allogeneic stem cell transplant recipients: A quality improvement project

BackgroundSteroid-induced hyperglycemia (SIH) worsens overall outcomes in the allo-SCT population. Currently, there is no standardized workflow for monitoring SIH. To address this need, a quality improvement (QI) initiative was implemented, as part of a Doctor of Nursing Practice project for the University of Kansas School of Nursing, to standardize glucose monitoring after the initiation of glucocorticoids (CGs) for the treatment of acute or chronic graft-versus-host-disease (GVHD). ObjectiveThis QI initiative aimed to decrease the median time to identification of SIH and the initiation of treatment in allo-SCT recipients on GCs for GVHD. Study DesignThe study took place at a large Midwestern blood and marrow transplant program. Patients diagnosed with acute or chronic GVHD and prescribed ≥0.5 mg kg-1/day prednisone equivalent (PE) steroids were requested to monitor postprandial blood glucose values for 14 days. A control group (retrospective chart review) was used for comparison. Time to the identification of SIH was compared between the two groups, as well as the time to treatment of hyperglycemia. ResultsOver 9 weeks, 19 patients enrolled in the QI initiative. The control group consisted of 21 patients. The median PE steroid dose was 1 mg kg-1/day in both groups (p = 0.8100). Eighteen of the 19 patients (95 %) had at least 1 blood glucose (BG) > 180 mg/dL and only 6 of 21 patients (29 %) had at least 1 BG > 180 mg/dL (p < 0.0001). The median time to a BG > 180 mg/dL was 1.5 days in the QI group and 7 days in the control group (p = 0.0232). The median time to insulin was 2 days in the QI group and 10 days in the control group (p = 0.0355). ConclusionThis project demonstrated that daily postprandial blood glucose monitoring is superior for the earlier identification and treatment of SIH when compared to monitoring at routine clinic visits alone.

Outcomes of haploidentical transplants with PT-CY vs 10/10 MUD transplants with ATG in Germany

AbstractAllogeneic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors (Haplo-Tx) are the most important sources of stem cells. However, multicenter real-life data that compare 10/10 MUD transplantations with Haplo-Tx are still limited. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs Haplo-Tx using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard models and competing risks regression models were formed to compare the outcomes of the groups. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P < .001]). The risk of acute GVHD (aGVHD) grade 2 to 4, aGVHD grade 3 to 4, and chronic GVHD (cGVHD) was higher in the PT-CY Haplo group than the 10/10 MUD group (aGVHD grade 2-4 [HR, 1.46; CI, 1.25-1.71; P < .001]; aGVHD grade 3-4 [HR, 1.74; CI, 1.37- 2.20; P < .001]; cGVHD [HR, 1.30; CI, 1.11-1.51; P = .001]). A lower incidence of relapse was observed in the PT-CY Haplo group (relapse: HR, 0.83; CI, 0.69-0.99; P = .038). Unrelated 10/10 matched transplantation with ATG treatment leads to lower GVHD rates and improved survival rates compared with PT-CY Haplo transplantation in Germany.

A Case Report of Acute CNS Graft Versus Host Disease (GvHD) with Concurrent Infections

A Case Report of Acute CNS Graft Versus Host Disease (GvHD) with Concurrent Infections

Umbilical Cord Blood Platelet Lysate Eyedrops for the Treatment of Severe Ocular Surface Disorders in Graft vs. Host Disease Patients: Clinical Study

Background: Graft-versus-host disease (GvHD) is an overactive systemic inflammatory response that can arise following allogeneic hematopoietic stem cell transplantation (HSCT). This condition occurs when the transplanted donor immune cells recognize the recipient’s tissues as foreign and trigger an immune response against them. The ocular surface (eyelids, conjunctiva, meibomian glands, lacrimal glands, and cornea) is particularly involved in GvHD, and its response to existing treatments, including potent immunosuppressants and new targeted therapies, is undesirable, with such treatments often being ineffective. Human allogeneic umbilical cord blood platelet lysate stands out as a potent adjunct to conventional therapies for ocular surface disorders related to severe Dry Eye Disease. This study aimed to evaluate the safety and efficacy of umbilical cord blood platelet lysate eyedrops for the treatment of severe ocular surface disorders in graft-versus-host disease patients who have received previous unsuccessful treatments. Methods: This study was a prospective, non-comparative, interventional case series study involving 22 patients (10 females and 12 males) aged 25–46 years with severe ocular surface disorders that were unresponsive to standard treatments. The GvHD patients were categorized based on the severity of their ocular surface disorders into three groups: Group I: five patients with severe Dry Eye Disease and filamentary keratitis; Group II: eight patients suffering from severe blepharo-kerato-epitheliopathy; Group III: nine patients with corneal ulcers. Fresh umbilical cord blood (UCB) was obtained from healthy donors and subjected to centrifugation using a novel PRP preparation kit provided by Sciacca (AG) Cord blood bank, Italy in a one-step process. In all groups, the outcomes before and after treatment were evaluated by means of the OSDI (Ocular Surface Disease Index), SANDE (Symptom Assessment in Dry Eye) questionnaire, VAS (Visual Analogue Scale), slit lamp examination, Esthesiometry, Lissamine Green Staining, the NIBUT (Non-Invasive Break-Up Time) and BUT, fluorescein staining with digital photography and Oxford classification, the Schirmer Test, the Best Corrected Visual Acuity (BCVA), and Meibography. In Group III at each evaluation time, the size of the ulcer and its relative reduction compared to the baseline size were recorded. Clinical variables, such as corneal inflammation, conjunctivalization, corneal neovascularization, or pain, were also considered individually. Results: We observed a significant improvement in the SANDE, VAS, and OSDI scores; Schirmer Test; BUT; BCVA; and Oxford classification after treatment with allogeneic cord blood serum eyedrops. Nevertheless, pain and inflammation reduced markedly over time until complete healing in all cases. The mean reduction in the ulcer surface area (compared to baseline values) was significantly higher at all assessment points (p = 0.001 for day 7 and p &lt; 0.001 for subsequent time points every 30 days for 90 days). At the last check-up (after 90 days of treatment), the number of ulcers (Group III, nine patients) with a reduction in size of greater than 50% was eight (88.8%), of which seven ulcers were completely healed. None of the patients experienced treatment-related local or systemic adverse events. In this study, using a relatively large number of cases, we demonstrated that the use of umbilical cord blood platelet lysate eyedrops is a safe, feasible, and effective curative approach for severe ocular surface disease in patients with GvHD. Conclusions: Our pilot study highlights the remarkable effectiveness of allogeneic cord blood serum eyedrops in patients with severe ocular surface disorders following GvHD who have shown an inadequate response to the usual treatments. It is mandatory to design future studies on the efficacy of this therapeutic approach for acute ocular, mucosal, and cutaneous GvHD.

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.

Institutional insights into engraftment syndrome: A cohort study on allogeneic transplantation outcomes

BackgroundEngraftment syndrome (ES) is a clinical condition that may occur during neutrophil recovery after hematopoietic stem cell transplantation (HSCT). Diagnosis is challenging because of the varying diagnostic criteria and the controversial relationship between ES and graft-versus-host disease (GVHD). ObjectiveTo investigate the incidence of ES and its relationship with GVHD in patients undergoing allogeneic HSCT at our institution. Study designThis retrospective cohort study included patients who underwent allogeneic HSCT (alloHSCT) at a Brazilian tertiary hospital between January 2015 and December 2016. ES was diagnosed based on the Spitzer or Maiolino criteria. ResultsOf the 79 patients who underwent alloHSCT, three presented with graft failure and were excluded from the analysis. The incidence of ES, according to both Spitzer's and Maiolino's criteria, was 16.5 % and 9.8 % in patients older than 14 years and 28.6 % in children, respectively, with a significant correlation (P < 0.05, Pearson's chi-squared test). ES was associated with prolonged hospitalization (P = 0.01; Student's t-test). No correlation was observed between acute GVHD and ES. There was a positive correlation between the use of broad-spectrum antibiotics against multidrug-resistant bacteria and ES development (P < 0.05, Pearson's chi-squared test). ConclusionsThe general incidence of ES in this cohort was consistent with that reported in the literature. Remarkably, ES was associated with prolonged hospitalization (14 days longer than in patients without ES). Moreover, patients who used antibiotics against multidrug-resistant bacteria had a higher incidence of ES.

Sequential Conditioning With FLAMSA Does Not Improve Outcomes of Allogeneic Stem Cell Transplantation in Chronic Myelomonocytic Leukemia Patients

As with myelodysplastic syndromes (MDS), effective treatment options for Chronic myelomonocytic leukemia (CMML) are limited, and the optimal treatment approach remains undefined. Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for patients with CMML. Sequential conditioning with FLAMSA was initially developed for refractory acute myeloid leukemia (AML) and has since been applied in the treatment of MDS and CMML. Data on optimal allo-SCT conditioning in CMML Patients is scarce. This retrospective study from the Department of Stem Cell Transplantation at the University Medical Center Hamburg, Germany, compared allo-SCT outcomes in CMML patients across three conditioning regimes: Thiotepa-Busulfan (TB), Sequential FLAMSA-Busulfan Fludarabine (FLAMSA-FB), and Treosulfan-Fludarabine (Treo-Flu). Sixty-nine consecutive patients with CMML who underwent allo-SCT between the years 2006-2022 were included in the study. Twenty-two received TB, 27 received FLAMSA-FB, and 20 received Treo-Flu conditioning. Transplant sources included matched related donors (MRD, 8 patients), mismatched related donors (MMRD, 8 all in the TB group), matched unrelated donors (MUD, 31), and mismatched unrelated donors (MMUD, 22) with significant group variations (p<0.001). Most patients received anti-T lymphocyte Globulin (ATLG) for graft versus host disease (GVHD) prophylaxis (TB 68%, FLAMSA-FB 93%, Treo-Flu 85%, p=0.08). CPSS-Molecular score was comparable between the groups. One TB patient experienced primary graft failure, but engraftment times were comparable across the groups. Although not statistically significant, the TB group showed a trend towards improved 3-year OS rates (80%) compared to FLAMSA-FB (37%) and Treo-Flu (55%) (p=0.05). The TB group also displayed significantly higher 3-year PFS rates (80%) compared to FLAMSA-FB (33%) and Treo-Flu (both 39%), (p=0.02). No significant differences were observed in 3-year non-relapse mortality (NRM) across the TB (20%), FLAMSA-FB (30%), and Treo-Flu (26%) groups (p=0.8). Interestingly, no TB patients relapsed at 3 years, contrasting with the FLAMSA-FB (41%) and Treo-Flu groups (30%, p=0.02). Lastly, cumulative incidences of acute and chronic GVHD were similar across groups. Our analysis suggests FLAMSA-FB does not improve transplant outcomes, however TB represents the preferred conditioning regimen for CMML patients undergoing allo-SCT. It demonstrates notable advantages in relapse prevention and leads to improved OS and PFS compared to FLAMSA-FB and Treo-Flu protocols.

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

Total Marrow and Lymphoid Irradiation (TMLI) Is Associated with Good Early Outcomes in Patients Undergoing Matched Sibling Donor and Haplo-identical Transplants for Acute Lymphoblastic Leukemia

Total marrow and lymphoid irradiation [TMLI] can deliver higher doses of irradiation without increased toxicity. This study evaluated TMLI and Cyclophosphamide in patients undergoing stem cell transplantation for acute lymphoblastic leukemia [ALL] . Fifty-eight patients underwent matched related, unrelated or haplo-identical donor transplant using TMLI. The graft source was PBSC in all while GVHD prophylaxis consisted of cyclosporine with methotrexate or post-transplant cyclophosphamide. The median age was 20 years [range: 5 - 49] and included 20 children. Engraftment occurred in 56 [96.5%] at median of 15 days [range: 12 - 23] with 2 early deaths. Sinusoidal obstruction syndrome [SOS] was seen in 10 patients while hemorrhagic cystitis and cardiac dysfunction occurred in 2 patients each. Cumulative incidence of grade II - IV acute GVHD was 23.6% while grade III - IV was 10.9%. Chronic GVHD was seen in 46.9% while relapse was seen in 10 patients [17.2%]. The 2-year overall survival [OS] was 65.9 ± 6.8% and 2-year disease free survival [DFS] was 59 ± 6.7%. Outcomes were compared with 52 patients who received either Cy/TBI or Flu/Bu4 for conditioning during the same period. Engraftment rates and time to engraftment were similar. Acute GVHD [p = 0.002], regimen related toxicity [p = 0.043] and Day 100 non-relapse mortality [p = 0.020] were significantly lower with TMLI. TMLI was associated with better OS [p = 0.004] and DFS [p = 0.005] for haplo-identical transplants. Better DFS was seen with TMLI in patients with high-risk disease [p = 0.007] and disease status > CR1 [p = 0.041]. The use of TMLI and cyclophosphamide is associated with good outcomes in patients undergoing HSCT for ALL especially with haploidentical stem cell transplants.

Outcome of donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation in relapsed myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) improves outcomes for myelodysplastic syndrome (MDS) patients, but relapse rates remain high, and post-relapse treatment options are limited. Therefore, this study aimed to identify the factors contributing to the response to donor lymphocyte infusion (DLI) in relapsed MDS patients post-HSCT. This study included 107 patients with relapsed and DLI-treated MDS who underwent their first HSCT between 2002 and 2022 and were registered in the Transplant Registry Unified Program. Univariate and multivariate survival analyses were conducted using log-rank tests and Cox proportional hazards models. Overall survival (OS) and response rates to DLI were also analyzed. The 1-year OS was 30.0% and univariate analysis identified poor prognostic factors: age ≥58 years (P = 0.003), complex karyotype (P = 0.026), hematologic relapse (P = 0.026), and early relapse (P = 0.004). Azacitidine plus DLI also improved prognosis (P < 0.001). Multivariate analysis confirmed age ≥58 years, hematologic relapse, and early relapse as poor prognostic factors. The adjusted OS for patients aged ≥ 58 years who relapsed <110 days post-transplant showed that the 1-year OS in patients with cytogenetic/molecular relapse was 43.6%, compared to 9.4% for those with hematologic relapse. Acute GVHD occurred in 62.3% of patients, and chronic GVHD in 30.8%, with manageable outcomes. DLI may improve OS in younger patients, those with cytogenetic/molecular relapse, and those with late relapse. Despite the risk of GVHD, its impact on prognosis is minimal. Given the limited treatment options, DLI should be considered for relapsed MDS patients post-HSCT.

High activity of the new myeloablative regimen of gemcitabine/clofarabine/busulfan for allogeneic transplant for aggressive lymphomas.

Refractory aggressive lymphomas can be treated with allo-SCT, pursuing a graft-vs-lymphoma effect. While reduced intensity conditioning is safe, tumors often progress rapidly, indicating the need for more active conditioning regimens. The preclinical synergy we saw between gemcitabine (Gem), clofarabine (Clo) and busulfan (Bu) against lymphoma cell lines led us to study Gem/Clo/Bu clinically. Eligibility: age 12-65, refractory aggressive B-NHL, T-NHL or Hodgkin, with a matched donor. Infusional Gem was dose-escalated on days (d) -6 and -4 (475-975 mg/m2/day), followed by Clo (40 mg/m2/day) and Bu (target AUC, 4000 μMol min/day) (d -6 to -3). CD20+ tumors received rituximab. GVHD prophylaxis included ATG (MUD), tacrolimus and MMF. We compared their outcomes to matched-pair concurrent controls receiving Flu/Mel + matched allo-SCT. We enrolled 64 patients, median age 46 (17-63), 31 B-NHL/22 T-NHL/11 Hodgkin, 36 MSD/28 MUD (all PBPC), median 4 (2-10) prior therapies; 18 prior auto-SCT, 42 active diseases at allo-SCT (12 PD). Toxicities (mucositis and transaminitis) were manageable. Gem/Clo/Bu was myeloablative yielding early full donor chimerism. Grades II-IV/III-IV acute GVHD rates of 37% and 18%; chronic GVHD of 33% (13% severe); NRM at D100/1 year was 7% and 18%. ORR/CR rates: 78%/71% (B-NHL), 93%/93% (T-NHL), 67%/67% (Hodgkin). At a median follow-up of 60 (12-110) months, EFS/OS rates: 36%/47%. Gem/Clo/Bu patients had better median EFS (12 vs. 3 months, P = 0.001) and OS (25 vs. 7 months, P = 0.003) than 113 Flu/Mel matched-pair controls. The new myeloablative regimen Gem/Clo/Bu has limited toxicity and high activity in allo-SCT for aggressive lymphomas, yielding better outcomes than concurrent matched-pair controls receiving Flu/Mel.

Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-versus-Host Disease.

Background/Objectives: Despite novel biological agents, steroid-dependent or -refractory graft-versus-host disease (GvHD) remains a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT). Extracorporeal photopheresis (ECP) is an alternative, non-immunosuppressive treatment for patients with acute (aGvHD) or chronic (cGvHD) GvHD. The aim of this study was to investigate the safety and efficacy of ECP in the treatment of acute and chronic GvHD; Methods: We prospectively studied 112 patients with cGvHD who received one or more previous lines of treatment and 28 patients with steroid-dependent or refractory grade II-IV aGvHD post-alloHSCT. Results: In terms of severe aGvHD, most of the patients (19/28) responded to ECP treatment, while the five-year overall survival (OS) was 34%. After adjustment for several confounder factors, the reduction in immunosuppression (p = 0.026) and number of ECP sessions (p < 0.001) were associated with improved OS. Regarding chronic GvHD, only 19 patients failed to respond to ECP treatment; though significantly lower rates of response were presented in patients with visceral involvement (p = 0.037) and earlier post-transplant GVHD diagnosis (p = 0.001). Over a follow-up period of 45.2 [interquartile range (IQR): 5.6-345.1] months, the 5-year cumulative incidence (CI) of cGvHD-related mortality was 21.2% and was significantly reduced in patients with ECP response (p < 0.001), while the 5-year OS was 65.3%. Conclusions: Our results confirm the safety and efficacy of ECP in patients with GvHD and provide sufficient data for further investigation and the best combination drugs needed such that GvHD will not be the major barrier of allo-HCT in the near future.

Soluble MICA concentrations and genetic variability of MICA and its NKG2D receptor as factors affecting Graft-versus-Host Disease development after allogeneic haematopoietic stem cell transplantation

Despite new treatment strategies, graft-versus-host disease (GvHD) remains a formidable complication after allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the impact of polymorphisms and expression of MICA and NKG2D receptor on the development of GvHD in allogeneic HSCT recipients. Soluble MICA (sMICA) concentration was measured in serum collected 30 days after transplantation and the genetic variability of MICA and NKG2D genes was evaluated. The frequency of NKG2D+NK cells was determined by flow cytometry before and (21, 30, 60 and 90 days) after transplantation. Recipients with acute GvHD grades II-IV carried the NKG2D rs1049174 C allele more frequently than controls or patients with no or mild disease. Patients with chronic GvHD had higher frequency of NKG2D expressing NK cells posttransplant, reflecting increased activity of their NK cells. Although no direct relationship between MICA SNPs and GvHD were observed, the presence of MICA rs1051792 GG genotype correlated with elevated sMICA levels and increased serum level of sMICA was associated with higher risk of chronic GvHD. Our findings suggest that sMICA concentration may serve as a potential biomarker for chronic GvHD and emphasize the impact of genetic variability of NKG2D and its surface expression on the HSCT outcome.

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

Characterization of Chronic Graft-versus-host Disease After Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide: A Study on Behalf of GETH-TC.

Chronic graft-versus-host disease (cGVHD) is a cause of late morbidity and nonrelapse mortality (NRM) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Although studies evaluating haploidentical allo-HSCT (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) demonstrate lower cGVHD rates, comprehensive data describing the clinical profile, risk factors, or outcomes of cGVHD within this platform are scarce. We conducted a retrospective multicenter analysis of 389 consecutive patients who underwent haplo-HSCT PTCy in 7 transplant centers of the Spanish Group Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) between 2008 and 2020 describing incidence, clinical profile, risk factors, and cGVHD outcomes. Ninety-five patients of 389 developed cGVHD. Our data revealed that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis and that the strongest predictor for cGVHD was previous acute GVHD ( P = 0.031). Also, recipient age ≥60 y ( P = 0.044) was protective against cGVHD. Moreover, patients with moderate cGVHD had longer event-free survival at 3 y than other patients ( P = 0.016) and a lower relapse rate at 3 y ( P = 0.036). Our results support the fact that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis. In this series, patients who develop moderate cGVHD after haplo-HSCT PTCy had a higher overall survival and event-free survival, and lower relapse, suggesting higher graft-versus-leukemia effect. Although this is the largest series focused on characterizing cGVHD in haplo-HSCT PTCy, further prospective studies are needed to confirm the findings.