Intensity Conditioning Regimen Research Articles

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.

Impact of spliceosome mutation on outcomes of myelodysplastic syndrome and chronic myelomonocytic leukemia patients undergoing allogeneic hematopoietic cell transplantation

IntroductionAllogeneic Hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The impact of spliceosome mutations on allo-HCT outcome is unclear and further understanding is needed to assess the implications of this class of mutations on risk of relapse, overall survival (OS) and non-relapse mortality (NRM) in order to make decision regarding timing of allo-HCT. We examined the allo-HCT outcomes of MDS/CMML patients based on their spliceosome mutation profile to understand the impact of these mutations on transplant outcomes. ObjectiveTo compare outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT. MethodsThis is a single institution, retrospective study of MDS/CMML patients who underwent allo-HCT with myeloablative or reduced intensity conditioning (RIC) regimen at City of Hope from January 2016 to December 2021. Among them, patients who underwent molecular mutation profiling by NGS (Next Generation Sequencing) for a set of genes known to be mutated in myeloid neoplasms are included in this analysis. We compared OS, relapse free survival, NRM and acute/chronic graft versus host disease (GVHD) incidence between the spliceosome-mutated and unmutated groups. ResultsWe identified 258 consecutive MDS/CMML patients who underwent allo-HCT. Of these, 126 (48.8 %) patients had molecular profiling done among whom 57 (45.2 %) patients carried a spliceosome mutation. 84.9 % of patients had MDS and 55.6 % underwent a matched unrelated donor transplant. The median age for the whole cohort was 66 years (range 12–77).78.6 % and 73.7 % received RIC in the spliceosome and non-spliceosome groups, respectively. The 2-year OS for the whole cohort was 66.5 % (95 %CI 0.55–0.75) with a day 100 NRM of 7.1 % and 2-year cumulative incidence of relapse of 20 %. Grade II-IV acute GVHD at day 100 was 36.3 % (95 % CI 0.27–0.44) and any chronic GVHD at 2-years was 48.4 % (95 % CI 0.37–0.58). Patients who carried a spliceosome mutation had a significantly better 2-year survival of 83.8 % vs 55.9 % in the non-spliceosome group (P=0.002) and a better PFS of 73.7 % vs 50.0 % (P=0.007). There was no difference in the cumulative incidence of relapse at 2-years 15.9 % vs 18.5 % (P=0.59) between two groups but the spliceosome group had a significantly lower NRM at 2-years 10.4 % vs 31.5 % (P=0.009). There was no difference in incidence of acute or chronic GVHD between the two groups. ConclusionsAmong patients with MDS or CMML who underwent allo-HCT, our study shows better OS for patients who have spliceosome mutations due to lower NRM compared to those carrying non- spliceosome mutations. This favorable outcome of the spliceosome-mutated patients could have implications for timing of allo-HCT, particularly for patients in the intermediate MDS prognostic risk groups.

Fludarabine, busulfan, and melphalan conditioning regimen in allogeneic hematopoietic stem cell transplantation for adult patients with myeloid malignancies: A multicenter retrospective study.

Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo-HSCT following fludarabine(≥100mg/m2), busulfan (≥3.2mg/kg) and melphalan (≥100mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n=171, MDS-IB-1 or 2 n=44, CMML n=6) with median age of 46 were enrolled in this study. The median follow-up was 507 days for survivors. The 2-year NRM, CIR, OS and DFS were 10.6%±2.2%, 14.8%±3.3%, 79.4%±3.7% and 74.6%±3.7%, respectively. In multivariate analyses, high HCT-CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p=0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p=0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p=0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR=7.92, 95%CI 1.05-60.03, p=0.045; HR=3.64, 95%CI 1.40-9.44, p=0.008; respectively), while post-transplantation cyclophosphamide based graft-versus-host disease prophylaxis was associated with lower CIR (HR=0.24 95%CI 0.11-0.54, p=0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.

Fludarabine-induced bradycardia in allogeneic hematopoietic stem cell transplantation: A retrospective study.

Fludarabine, a purine analog, is getting more attention with the increasing use of reduced intensive conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The side effect of bradycardia was observed in only a few cases reported in the literature. In clinical practice, bradycardia can be asymptomatic or cause syncope and cardiac arrest. This study aimed to evaluate the bradycardia side effect of fludarabine used in the conditioning regimen in allo-HSCT recipients and to increase awareness of this issue. This retrospective study included 73 patients who received fludarabine in the allo-HSCT conditioning regimen between January 2015 and January 2021. Patients with and without bradycardia were compared regarding demographic data, allo-HSCT characteristics, electrolyte values, fludarabine administration dose and duration, and survival. Univariate and multivariate analyzes were performed to evaluate independent predictors for fludarabine-induced bradycardia. Fludarabine administration doses and days were higher in the bradycardia group, but no statistically significant difference was observed. In the multivariate analysis, age was the only independent predictor of fludarabine-induced bradycardia (odds ratio (OR) 0.93, 95% confidence interval (CI): 0.89-0.98, p = 0.007). The median age in the group with bradycardia was 19 years younger than those without bradycardia (34 (19-49) vs 53 (19-69), p = 0.005). In 11 (84.6%) of the patients who had bradycardia, bradycardia improved with the discontinuation of fludarabine alone, but atropine was administered in 2 (15.4%) patients. Age was the only independent predictor of fludarabine-induced bradycardia; therefore, close heart rate monitoring is recommended during fludarabine administration, especially in younger patients.

On the Way to Curing Advanced-Stage Mycosis Fungoides/Sézary Syndrome

Advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) have poor prognosis with median survivals of less than 5 years. Although a variety of treatments are approved for MF/SS patients, durable complete remissions (CR) are rare. Advanced-stage MF or SS patients who achieved CR and maintained in CR or stage IA for more than 10 years were identified by a retrospective search of the principal investigator's database. Of 2266 patients diagnosed with MF or SS, 23 patients with advanced-stage MF/SS (6 IIB, 1 IIIB, 5 IVA1, 3 IVA2, 8 IVB) who achieved CR and maintained in CR or stage IA for ≥ 10 years were identified. As final/curative treatment, 11 patients underwent allogeneic stem cell transplantation (SCT). Most patients presented at young age, underwent SCT with reduced intensity conditioning regimen, had matched related donors, and controllable post-transplant graft versus host disease. Eleven patients were treated with TSEB as part of combined modality protocol in 2 patients and debulking therapy before allogeneic SCT in 9 patients. Five stage IIB patients achieved CR with radiotherapy. Four patients with blood involvement were treated with extracorporeal photopheresis (ECP) in combination with long-term antibiotics and immunomodulatory agents. Long-term antibiotics were given to 14 patients. TSEB followed by allogeneic SCT, radiotherapy, ECP plus long-term antibiotics and immunomodulatory agents were the most common curative/final treatments found in our patients. We are reporting the details of our long-term complete responders' treatment course in the hopes of obtaining more cure responses in the future.

Efficacy and safety of outpatient fludarabine, cyclophosphamide, and rituximab based allogeneic hematopoietic cell transplantation in adults with severe aplastic anemia

The age effect in severe aplastic anemia (SAA) following allogeneic hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning (RIC) regimens in older adults. We implemented a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) to improve HCT outcomes in SAA. Patients who underwent first HCT for SAA utilizing an FCR regimen between January 2016 and May 2022 were included. Outcomes analyzed included time to engraftment, incidence of graft failure, GVHD, viral reactivation, disease recurrence, and GVHD-free, relapse-free survival (GRFS). Among 24 patients included, median age was 43.5 years (22–62) and a variety of donor types and stem cell sources were represented. At median follow-up of 26.9 months (2.4–72.7), no cases of grade III-IV acute (aGVHD) or severe chronic GVHD (cGVHD) were recorded. Viral reactivation was minimal, and there were no cases of graft failure or PTLD, with 100% disease-free and overall survival at last follow up. The estimate of 1-year GRFS was 86.3% (95% CI: 72.8–100%), with moderate cGVHD accounting for all events. The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates. These encouraging findings should be validated in larger prospective trials.

Allogeneic stem cell transplantation in multiple myeloma: is there still a place?

The introduction of novel agents dramatically improved response and outcomes of multiple myeloma (MM) and led to a sharp decline in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Thus, recent guidelines do not recommend anymore allo-HSCT as consolidation in the first-line treatment of newly diagnosed MM, even in high-risk patients. In a relapsed/refractory setting, allo-HSCT is not routinely recommended but should only be performed within clinical trials in young and high-risk patients. Nonetheless, allo-HSCT still represents a potential curative approach that has been used for decades in the treatment of MM and plasma cell neoplasms with favorable results and may still represent a treatment option for carefully selected patients. Despite that promising results were obtained with CAR T-cell therapies and bispecific antibodies in triple- and penta-exposed/refractory MM, these patients will inevitably relapse. To date, less is known about outcomes of allo-HSCT in patients exposed to novel immunotherapeutic drugs. Therefore, allo-HSCT could represent a reasonable treatment choice for younger and high-risk patients who have relapsed after CAR T-cell therapies and bispecific antibodies as well as an alternative for patients not eligible to these treatments and in those countries where immunotherapies are not yet available. In the choice of conditioning, reduced intensity conditioning regimens are currently recommended for the lower toxicity and mortality. Moreover, the use of alternative donors, particularly haploidentical, has progressively increased in last years with results comparable to full matched donors. Finally, post-transplantation maintenance strategies are encouraged whenever feasible.

Reduced intensity conditioning regimen of fludarabine, busulfan, ATG based haploidentical stem cell transplantation for older or unfit patients.

Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30mg/m²/kg 6 days combined with busulfan 3.2mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2group was significantly higher than Bu3group(P = 0.045). However, the2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.

The effects of substituting cladribine for fludarabine on outcomes of a reduced intensity conditioning regimen.

e18518 Background: Drug shortages may be encountered especially in times of pandemics and war. The extrapolation of data focusing on different diseases may provide clinical clues for substituting two chemotherapeutic drugs of the same class. The substitution of cladribine for fludarabine in a reduced intensity conditioning (RIC) regimen composed of fludarabine, melphalan and total body irradiation (TBI) may yield similar side effect profile and outcomes. Methods: Consecutive patients undergoing an allogeneic stem cell transplant in our center between November 2019 to December 2022 were included. Within this period cladribine had to be substituted for fludarabine during a drug shortage. All patients received intravenous melphalan 75 mg/m2/day on day -2, and 200 cGy TBI on day -1. The regimen included either subcutaneous cladribine 10 mg/m2/day on days -5 to -2, or intravenous fludarabine 40 mg/m2/day on days -5 to -2. Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor (CNI) + mycophenolate mofetil (MMF) for matched related donor transplants; and post-transplant cyclophosphamide + CNI + MMF for matched unrelated (MUD) and haploidentical donors. The distributions and medians of studied parameters in two cohorts were compared with non-parametric methods. Overall survival (OS), progression-free survival (PFS) and transplant-related mortality (TRM) were estimated by the Kaplan-Meier Method. The cut-off for statistical significance was defined as p<0.05. Results: A total of 70 patients (27 in cladribine and 43 in fludarabine cohort) were included. Median age was 59 (22 to 76) and 64.3% constituted males. Median follow-up was 10.2 months (0.1 to 44.7). Acute leukemia diagnosis, intermediate to high disease risk index (DRI) and intermediate to high Charlson comorbidity index (CCI) constituted 45.7%, 60.0% and 58.1% respectively. Haploidentical donors were used in 28.6%. The distribution of gender, diagnosis, DRI and CCI scores, donor type, total CD34 dose given, panel reactive antibody (PRA) positivity were similar. Median days to neutrophil engraftment was shorter with fludarabine (19 vs 16, p=0.01), however, median duration of in-unit stay was similar (27 vs 28 days, p=0.73). TRM, nausea and acute GvHD frequency was lower with cladribine (p=0.35, p=0.001 and p=0.02, respectively). Typhilitis and perianal infections were more common with cladribine (p=0.07 and p=0.04, respectively). OS and PFS were similar (p=0.81 and p=0.66, respectively). When cladribine was compared to fludarabine on day +90, OS was 78,0% (95% CI: 62.3-93.7) vs 65,0% (95% CI: 51.3-78.7); PFS was 70.0% (95% CI: 52.4-87.6) vs 65.0% (95% CI: 51.3-78.7); TRM was 19.0% (95% CI: 3.3-34.7) vs 24.0% (95% CI: 10.3-37.7). Conclusions: Cladribine may be safely constituted for cladribine in a RIC regimen and may yield similar, even some favorable, outcomes when compared to fludarabine.

Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis following mismatched unrelated donor peripheral blood stem cell (PBSC) transplantation.

6503 Background: Our prior prospective multi-center clinical trial (15-MMUD; NCT02793544) estimated 79% overall survival (OS) at one year in adult patients with hematological malignancies undergoing reduced intensity conditioning (RIC), receiving bone marrow (BM) grafts from HLA-mismatched unrelated donors (MMUD), and post-transplant cyclophosphamide (PTCy)-based graft- versus-host disease (GVHD) prophylaxis (Shaw et al, J Clin Oncol 2021). We sought to determine whether OS in adults receiving mobilized PBSC from MMUD would be comparable. Methods: We conducted a prospective, multi-center Phase II study (ACCESS; NCT04904588) to assess the impact of PTCy-based GVHD prophylaxis on OS following MMUD transplantation in adults and children with advanced hematological malignancies. The study included three strata: two for adults based on conditioning regimen intensity [myeloablative (MAC) or RIC] using PBSC, and one pediatric cohort using MAC and BM. Eligible donors were matched at 4-7/8 HLA-loci (HLA -A, -B, -C, and -DRB1) and < 35 years. The primary endpoint was OS at one year following transplantation. We report the results of a planned interim analysis of the first 70 adult patients enrolled on the RIC PBSC stratum. Results: Thirteen sites enrolled 70 patients with the following demographics: median age of 65 years (range 24-77); 50% male; diagnoses: AML (53%), MDS (26%), ALL (7%), other heme malignancies (14%); and patient race/ethnicity: non-Hispanic white (48%). Donor characteristics included: median age 25y (range 18-35); male (44%); and HLA match level: 7/8: 67%; 6/8: 27%; 5/8: 6%. Conditioning regimens included fludarabine (flu) and melphalan (63%), flu/busulfan (20%), other (17%). OS at one year post HCT was 79% (95% confidence interval (CI): 68-87%). Secondary endpoints are provided in the table. Conclusions: Encouraging OS was observed at one year following MMUD PBSC in patients receiving RIC and PTCy. Notably, half of enrolled patients were people of color. OS was similar to our prior study using BM grafts. Rates of GVHD and other complications appear comparable to those in HLA-matched donor recipients, suggesting MMUD HCT could expand access to a potentially life-saving therapy. Accrual to both adult strata of ACCESS is complete, with over 200 patients in follow-up. Accrual to the pediatric stratum continues. Clinical trial information: NCT04904588 . [Table: see text]

Effect of pre-transplant functional status on length of hospital stay in patients undergoing allogeneic hematopoietic stem cell transplant in an outpatient transplant program.

6560 Background: The use of reduced intensity conditioning regimens including non-myeloablative regimens in allogeneic hematopoietic stem cell transplant (allo SCT), has expanded the pool of transplant candidates in the United States. Nonetheless, allo SCT, is associated with significant morbidity and mortality especially in patients 65 and older. In our outpatient transplant program, allo SCT patients undergo a comprehensive physical and occupational therapy (PT/OT) evaluation pre-transplant. Methods: We retrospectively reviewed all patients undergoing an allo SCT between January 2019 and December 2022 who had a PT/OT evaluation pre-transplant. We analyzed lower extremity functional scale (LEFS) and fatigue score (FACIT). The FACIT score is a patient reported outcome tool where the lower the score, the less fatigue impacts a patient’s performance. Results: We identified 218 patients who had at least one variable reported. Eighty-one patients were 65 years of age or older. All patients in the 65 and older group had a RIC or NMA conditioning regimen. In the 65 and older group, 72.8% had an HCTCI score of 3 or more compared to 59.1% in the group younger than 65. In patients younger than 65, those who had a lower LEFS (ie less lower extremity strength), had a statistically significant longer hospital stay of 15.5 days compared to 9 days (p=0.003). In patients 65 and older, lower FACIT scores (ie less patient reported fatigue), resulted in a statistically significant shorter hospital stay of 7.5 days compared to 13 days (p=0.019). In addition, there was a trend towards shorter hospital stays in patient 65 and older who had a higher LEFS of 5 days compared to 12.5 days (p=0.07). There was no difference in survival outcomes but there was a trend towards better overall survival in patients 65 and older with high LEFS (p=0.08) and a trend towards better NRM in this group (p=0.11). Conclusions: Our study highlights the need for comprehensive assessments in patients undergoing allo SCT. Geriatric functional status assessments are necessary to determine patients at risk for complications and to optimize such patients with exercise and cognitive rehabilitation programs prior to allo SCT. [Table: see text]

Impact of spleen volume on post-allogenic hematopoietic transplant outcomes in myelofibrosis: Utility of 3D volumetrics in splenomegaly.

6558 Background: Splenomegaly is a hallmark of myelofibrosis, thought to be correlated with graft failure and worsened overall survival in transplant patients. Past studies have utilized manual spleen measurement, potentially affecting accuracy. Using 3D volume can more precisely measure spleen size. Hence, the true impact of splenomegaly on transplant outcomes remains unclear. In this retrospective study, we examined myelofibrosis patients who underwent HCT and, using 3D volumetrics, analyzed the impact of splenomegaly and volume reduction over time on post HCT outcomes. Methods: This retrospective study included 130 City of Hope myelofibrosis patients with pre HCT imaging (2004–2023). Patients were divided into pre HCT spleen volume of >3000 cc and <3000 cc, with >3000 cc considered massive splenomegaly. Spleen volume was measured using Vitrea 3D volumetric software. For each patient, depending on imaging available, volume was measured 0-3 months pre HCT, 3-6 months, 6-9 months, and 9-12 months post HCT with corresponding volume reduction calculations. Pre HCT spleen volume was also temporally correlated with several post HCT outcomes. Results: Median age at HCT was 60 (17-75), and 95% of patients received the Fludarabine/Melphalan conditioning regimen. Median spleen volume pre HCT was 1150 cc (41-6695 cc). Sixteen patients measured >3000cc, and 114 patients measured <3000cc. Median spleen volume 3-6 months post HCT was 661 cc (80-1731 cc) with a median 48% volume reduction. The data suggests that majority of volume reduction occurred during this time (table). Five-year overall survival (OS) was 72.8%. Relapse was 11.0% at 1 year and 14.7% at 5 years. NRM at 5 years was 17.3%. ANC engraftment peaked at 28 days at 92.3%. Pre HCT spleen volume (<1000 cc, 1000-2000 cc, >2000 cc) did not have a significant impact on OS (P = 0.992), disease free survival (P = 0.783), relapse (P = 0.187), NRM (P = 0.627), or ANC Engraftment (P = 0.526). There was a statistically insignificant downward trend for platelet engraftment (P = 0.162). For patients with or without massive splenomegaly (>3000cc), there was no significant effect with any of the analyzed post HCT outcomes. Conclusions: This retrospective study includes an analysis of spleen volume by 3D volumetrics, a more accurate measurement of spleen size, and whether it significantly impacts post HCT outcomes. Our data analysis demonstrates that splenomegaly, massive or not, does not significantly impact transplant outcomes for patients receiving a reduced intensity conditioning regimen.[Table: see text]

Allogeneic haematopoietic cell transplantation for chronic myeloid leukaemia in Switzerland in the face of rapid development of effective drugs.

Until the year 2000, allogeneic haematopoietic cell transplantation (HCT) was the standard treatment for young and fit chronic myeloid leukaemia (CML) patients. CML was the main indication for allogeneic HCT. The introduction of tyrosine kinase inhibitors changed the treatment of CML patients dramatically. Allogeneic HCT was rapidly replaced by tyrosine kinase inhibitors as first-line treatment for CML, and the indication shifted to the treatment of non-responders, patients intolerant to tyrosine kinase inhibitors and patients whose CML is transforming to the accelerated phase and blast crisis. This paper describes changes in the use of transplantation technology for CML patients in the face of rapid drug development. All patients receiving a transplant for CML between 1997 and 2021 in Switzerland were included in the study. For the purpose of this analysis, time periods were analysed in quinquennia, 1997-2001 (Q1), 2002-2006 (Q2), 2007-2011 (Q3), 2012-2016 (Q4) and 2017-2021 (Q5), as the observation period spanned 25 years. Overall, 239 patients received a transplant. These included 96 in Q1, 56 in Q2, 25 in Q3, 34 in Q4 and 28 in Q5. Patient characteristics changed over time: recent patients were older and had a longer interval from diagnosis to transplantation because of tyrosine kinase inhibitor treatment. However, the proportions of patients receiving transplants during an early versus advanced disease stage differed little. Transplant technology changed, as well. Patients received intensive conditioning regimens less often due to higher age and more commonly had peripheral blood as opposed to bone marrow transplants. However, the type of stem cell donor selected did not differ. In a univariable analysis, there were no significant differences in survival, progression-free survival, non-relapse mortality, relapse incidence or incidences of acute and chronic graft-versus-host disease among the five quinquennia. In a multivariable analysis, older age, donors other than HLA-identical siblings and more advanced disease stage, but not the quinquennium, were associated with higher risk of death. Since the introduction of tyrosine kinase inhibitors haematopoietic cell transplantation has been used less frequently to treat CML. Patients in recent cohorts received transplants at an older age and later in the disease course; despite these higher risks, the outcome of allogeneic HCT has not worsened over time but has not improved, either. As the outcome is worse in advanced phases, it is important to conduct transplants before disease progression. Therefore, patients with advanced disease should be monitored closely and receive transplants in time.

Clinical outcomes of patients receiving three versus four doses of methotrexate with concomitant antithymocyte globulin in match unrelated donor allogeneic stem cell transplant: A single-center experience.

Methotrexate (MTX) doses on days +1, +3, +6, and +11 after match unrelated donor allogeneic stem cell transplant (MUD HSCT) is a common graft-versus-host disease (GVHD) prophylaxis regimen. However, the overlapping toxicity of MTX with conditioning chemotherapy sometimes warrants the omission of the fourth dose of MTX. Prior single-institution studies showed conflicting results comparing the outcomes of patients who received three versus four doses of MTX, but to our knowledge, the effect of concomitant antithymocyte globulin (ATG) has not been reported. Charts of patients who underwent MUD HSCT between 2009 and 2023 were reviewed. Patients received rabbit ATG (Thymoglobulin), given at 0.5mg/kg on day -3, 2mg/kg on day -2, and 2.5mg/kg on day -1. MTX is given at 15mg/m2 on day +1 and 10mg/m2 on days +3, +6, and +11. Severe mucositis was the most common indication for day +11 MTX omission (82%). We identified 292 patients (116 in 3 dose cohort and 176 in 4 dose cohort). Median follow-up was 23 months (range 1-151). Patients in the 4 doses cohort were more frequently male (68% vs. 50%, p<0.01), received a reduced intensity conditioning regimen (38.0% vs. 22%, p<0.01), were older (median 58 vs. 54 years, p=0.02), and received a transplant in the earlier era (median HSCT year 2014 vs. 2018, p<0.01). A statistically significant difference was not evidenced between the cohorts for the following outcomes: acute GVHD (aGVHD) (HR 1.1, 95% CI 0.9-1.5), chronic GVHD (cGVHD) (HR 1.3, 95% CI 0.8-1.6), relapse-free survival (RFS) (HR 1.0, 95% CI 0.6-1.5), non-relapse mortality (NRM) (HR 1.4, 95% CI 0.9-2.2), and overall survival (OS) (HR 1.2, 95% CI 0.9-1.7). Both cohorts had similar median time to neutrophil engraftment at 14 days. When ATG is incorporated, omission of day +11 MTX does not significantly impact the rate of engraftment or cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS.

Long-Term Ovarian Function Assessment After Haematopoietic Stem Cell Transplantation in Female Sickle Cell Anaemia Survivors.

Haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for sickle cell anaemia (SCA). While HSCT offers the possibility of disease remission, it can also lead to long-term complications, including gonadal dysfunction and premature menopause. We conducted a retrospective cohort study of female survivors who had hydroxyurea therapy and those who underwent post-HSCT follow-up for SCA at a teaching hospital in Lagos, Nigeria, between January 2019 and December 2022. Participants were eligible if they were at least five years post-HSCT or hydroxyurea treatment and had available serum samples for markers of ovarian function measurement. Demographic and clinical data were collected from the hospital register and patients' medical records. Serum levels of oestradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) were measured using the Abbott Architect i1000SR chemiluminescent immunoassay analyzer (Abbott Diagnostics, Abbott Park, IL). Descriptive statistics and inferential analyses were used to assess the relationship between markers of ovarian function (FSH and AMH) and clinical parameters. There were statistically significant differences in the median serum levels of all the assessed endocrine hormones between the HSCT and non-HSCT (hydroxyurea) groups of SCA survivors. Up to 82.6% of the SCA survivors experienced ovarian dysfunction after HSCT treatment. Impaired ovarian function in SCA survivors was associated with a longer median follow-up duration than in SCA survivors who had normal ovarian function (12.0 vs. 7.5 years, p = 0.048). There were higher odds of impaired ovarian function in the SCA survivors who had myeloablative regimens than in those who had reduced intensity conditioning regimens (94.1% vs. 50.0%, p = 0.040). Our study highlights the significant impact of HSCT on long-term ovarian function in female SCA survivors. However, further prospective studies with larger sample sizes and longer follow-up periods are required to confirm our findings and elucidate the factors influencing ovarian function in SCA survivors of HSCT. In addition, studies are also needed to further elucidate the optimal transplant protocols and fertility preservation strategies to minimize gonadal toxicity and preserve reproductive potential in female SCA patients undergoing HSCT.

Good engraftment after reduced intensity targeted busulfan-based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies.

Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18years of age. The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3years (range: 3.7-18.8years). The median administered busulfan AUC was 67.4mg/L×h (range: 60.7-80mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1years (range: 2.0-11.1years), whereas T-cell donor chimerism was frequently mixed. This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.

Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

Efficacy and safety of cladribine in combination with busulfan and cyclophosphamide as an intensive conditioning regimen preceding allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute myeloid leukemia

BackgroundCladribine, an analogue of deoxyadenosine, is used for therapy of hematological malignancies. Cladribine-containing regimen has been recommended as a rescue therapy for relapsed or refractory (R/R) acute myeloid leukemia (AML). Its combination with busulfan plus cyclophosphamide (BuCy), as an intensive conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT), requires more clinical evidence. This study aimed to explore the efficacy and safety of cladribine plus BuCy administered as an intensive conditioning regimen before allo-HSCT in R/R AML patients. MethodsTwenty-three R/R AML patients, who underwent cladribine plus BuCy intensive conditioning regimen before allo-HSCT, were retrospectively analyzed. The median (range) follow-up duration time of observation was 0.73 (0.08–2.69) years. ResultsThe median (range) returned levels of mononuclear cells were 11.5 (6.1–18.5) x 108/kg and CD34+ cells were 5.5 (3.5–9.3) x 106/kg. The median (range) time of platelet reconstitution was 13.0 (9.0–21.0) days and neutrophil reconstitution was 14.0 (11.0–26.0) days. The incidence of conditioning regimen related toxicity (CRRT) affected 69.6% of patients; all CRRT-affected patients had grade I-II symptoms, including gastrointestinal tract (39.1%), oral cavity (26.1%), liver (8.7%), and kidney (4.3%) CRRTs. The incidence of acute graft-versus-host disease (GVDH) included 30.4% among all patients with 4.3% of grade III-IV acute GVHD, and 34.8% of chronic GVHD. During the follow-up period, 4 (17.4%) patients relapsed, and 6 (26.1%) patients died (cause of death: disease relapse, n = 3; infection, n = 2; GVHD, n = 1). The 1-year and 2-year accumulating event-free survival rates were 66.3% and 53.1%, respectively. The 1-year accumulating overall survival rate was 74.7% and 2-year survival rate was 64.0%. ConclusionCladribine plus BuCy intensive conditioning regimen before allo-HSCT exhibits favorable treatment efficacy with acceptable toxicity in R/R AML patients.

Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor

Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III–IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed.

Risk Factors of Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation

The clinical data of 300 patients who underwent allo-HSCT at the First Affiliated Hospital of Chongqing Medical University from January 2015 to December 2021 were retrospectively analyzed. The relevant clinical parameters that may affect the occurance of LOHC after allo-HSCT were selected for univariate and multivariate analysis. Then, the differences in overall survival (OS) and progression-free survival (PFS) between different groups were analyzed. The results of multivariate analysis showed that the independent risk factors for LOHC after allo-HSCT were as follows: age≤45 years old (P =0.039), intensified conditioning regimen with fludarabine/cladribine and cytarabine (P =0.002), albumin≤30 g/L on d30 after transplantation (P =0.007), CMV-DNA positive (P =0.028), fungal infection before transplantation (P =0.026), and the occurrence of grade Ⅱ - Ⅳ aGVHD (P =0.006). In the transplant patients who have already developed LOHC, the occurance of LOHC within 32 days after transplantation (P =0.008) and albumin≤30 g/L on d30 after transplantation (P =0.032) were independent risk factors for the progression to severe LOHC. The OS rate of patients with severe LOHC was significantly lower than that of patients without LOHC (P =0.041). For the patients aged≤45 years old and with intensified conditioning regimen, it is necessary to be vigilant about the occurrence of LOHC; For the patients with earlier occurrence of LOHC, it is necessary to be vigilant that it develops into severe LOHC. Early prevention and treatment of LOHC are essential. Regular monitoring of CMV-DNA and albumin levels, highly effective antiviral and antifungal therapies, and prevention of aGVHD are effective measures to prevent the occurrence and development of LOHC.