Received Stem Cell Transplantation Research Articles

Sensitivity and Specificity of Chimerism Tests in Predicting Leukemia Relapse Using Increasing Mixed Chimerism

Chimerism test was evaluated to predict leukemia relapse. Increasing mixed chimerism (IMC), defined as recipient increase ≥0.1% in peripheral blood total cell chimerism, was used as a surrogate of disease activity. Combination of quantitative PCR and short-tandem repeat method was applied to achieve high assay sensitivity. Total of 184 patients received stem cell transplant for acute myeloid leukemia (N = 110), acute lymphocytic leukemia (N = 41), myelodysplastic syndrome (N = 30), and 2389 chimerism tests (median follow-up, 1054 days). Sixty-six patients relapsed, and 118 patients did not. Cumulative incidence of relapse increased after 1 IMC or ≥2 consecutive IMCs (hazard ratios, 9.9 and 44.4, respectively). Predicted percentage relapse by day 30 after IMC was 0% (0 IMC), 10% (1 IMC), and 40% (≥2 IMCs). The last chimerism results before relapse detected IMC in 57 of 66 relapsed patients (sensitivity, 86.4%). Nine patients had no IMC before relapse (false negative) because of rapidly evolving relapse (N = 4) or extramural relapse (N = 5). In 118 patients without relapse, 158 of 1873 tests detected IMC (false positive, 8.4%; specificity, 91.6%). The false-positive rates increased with higher percentage recipient T-cell chimerism levels, indicating T-cell contamination as a cause. Chimerism monitoring predicts relapse. However, caution must be taken for false-positive or false-negative IMCs. T-cell removal can improve chimerism test specificity in patients with mixed T-cell chimerism.

Characteristics and Treatment Patterns of Long-surviving Patients With Multiple Myeloma: Over 13 Years of Follow-up in the ConnectⓇ MM Registry

BackgroundOver the last 15 years, improvements in patient management and treatments have been associated with longer survival in patients with multiple myeloma (MM). The Connect MM Registry is a long-running, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM (NDMM). We assessed the demographics, clinical characteristics, and treatment patterns of long-term survivors (LTS) enrolled in this registry. MethodsAdults with NDMM (n = 3,011) were enrolled from 250 community, academic, and government sites across the US from 2009-2016. Baseline characteristics, treatment patterns, quality of life (QoL), and overall survival (OS) were examined among LTS, defined as patients with follow-up of ≥ 8 years after enrollment. ResultsAs of February 7, 2023, 518 patients were LTS and 2,493 were non-LTS. LTS were generally younger and had better performance status at enrollment compared with non-LTS. Most (65%) LTS received stem cell transplants and few (2%) experienced disease progression within 6 months of starting first line of therapy. At data cutoff, 63% of LTS were still on treatment at their most recent visit. QoL scores and QoL questionnaire completion rates were consistently higher among LTS than non-LTS. The estimated 8-year OS rate of all patients enrolled in the registry was 40%, comparable to an observed 8-year survival of 39% from the Surveillance, Epidemiology, and End Results (SEER) database. ConclusionThis analysis provides insights on long-surviving patients with MM using real-world data and therefore presents generalizability beyond data obtained in long-term follow-up of clinical trials, underscoring the need for longitudinal follow-up through registries.

Real-Life Management of FLT3-Mutated AML: Single-Centre Experience over 24 Years.

We analyzed 140 patients with a median age of 51 years; 21% had WBC ≥ 100 × 109/L, and 52% had an NPM1 co-mutation. Until 2018, 101 patients received chemotherapy; thereafter, 39 received 3+7+midostaurin. The overall CR rate was 64%, higher in NPM1 mutant patients (73%). Univariate analysis showed that NPM1 mutation (p = 0.032) and WBC < 100 × 109/L (p = 0.013) positively influenced the response, with a trend for FLT3i administration (p = 0.052). Multivariate analysis confirmed WBC count as an independent prognostic factor (p = 0.017). In CR1, 41/90 patients underwent allogeneic and 18 autologous transplantation. The median EFS was 1.1 vs. 1.6 years in autografted and allografted patients, respectively (p = 0.9). The one-year non-relapse mortality was 0.00% for autologous and 28% for allogeneic transplants (p = 0.007); CIR at 1 and 3 years was higher in autologous transplants (39% vs. 15% and 57% vs. 21%, p = 0.004). The median survival was not reached in the FLT3i group. Overall, 69 patients received stem cell transplantation (18 autologous, 51 allogeneic). Post-transplant FLT3i was resumed in eight patients, all alive after a median of 65 months. Allogeneic transplantation is crucial in FLT3-mutated AML, but the next challenge will be to identify which patients can benefit from transplants in CR1 and in which to intensify post-transplant therapy.

Vaginal complications of graft-versus-host disease after hematopoietic stem cell transplantation: a cross-sectional study.

Stem cell transplantation is a clinical approach used to treat certain types of cancers, such as hematologic malignancies. Graft-versus-host disease (GVHD) occurs in 30-70% of cases and often diminishes the quality of life of transplant patients. This study aimed to determine the prevalence of vaginal complications of GVHD following hematopoietic stem cell transplantation. This study employed an analytical cross-sectional design. All patients referred to Shariati Hospital in Tehran between 2019 and 2020 who underwent hematopoietic stem cell transplantation were considered for inclusion in this study if they met the inclusion criteria. Inclusion criteria encompassed nonnot sexually active women aged 18-70 who received stem cell transplantation more than 100 days prior. Exclusion criteria comprised patients who experienced GVHD during the first 100 days posttransplantation. Additionally, individuals over 75 and patients with metastatic cancer were excluded. A total of 55 patients were recruited, with ages averaging 40±9.9 years for recipients and 38.5±12.8 years for donors. Notably, 63.3 and 58.2% of patients exhibited oral and ocular symptoms, respectively. Regarding genital involvement, 49.1% experienced vaginal symptoms, while 25.5% had vulvar involvement. Among the 27 patients with vaginal involvement, two (7.4%) were categorized as mild, 17 (63%) as moderate, and eight (29.6%) as severe. Univariate analysis identified reduced vaginal discharge [odds ratio (OR=6.56)], vaginal tightness (OR=6.23), pelvic pain (OR=5.50), and vaginal involvement (OR=3.81) as significant predictors of other organ symptoms. Moreover, vaginal involvement (OR=3.68) emerged as the sole significant predictor of the cooccurrence of oral, ocular, and other organ symptoms. In the multivariate analysis, reduced vaginal discharge (OR=8.24) and vaginal tightness (OR=3.92) significantly predicted other organ symptoms (P=0.009). Reduced vaginal discharge and vaginal tightness remained significant predictors of other organ symptoms.

Epidemiology and Real-World Treatment of Incident Diffuse Large B-cell Lymphoma (DLBCL): A German Claims Data Analysis.

The objective of this study was to investigate the prevalence, incidence, and treatment patterns (treatment regimens, switches, duration) for diffuse large B-cell lymphoma (DLBCL) in a real-world setting. This was a retrospective German claims data analysis of patients with DLBCL diagnosed between January 1, 2012, and December 31, 2020. The prevalence and cumulative incidence of DLBCL were found for 2019/2020. Line of treatment (LOT) and treatment setting from first DLBCL diagnosis to end of follow-up were described. Kaplan-Meier overall survival (OS) estimates since DLBCL diagnosis and start of treatment lines were calculated. Overall, 2633 incident DLBCL cases were identified (median age 75years, 51% male). Of these, 2119 patients received at least one DLBCL-related treatment (LOT1), and 1567 patients died during follow-up. In 2019/2020, the prevalence and cumulative incidence of DLBCL was 34.8/36.7 per 100,000 patients and 14.0/12.7 per 100,000 patients, respectively. For LOT1, 1922 patients were given a chemotherapy-based regimen (1530 with CD20 antibodies). A total of 403 patients were administered a second line (LOT2), of which 183 patients received a CD20 antibody-containing chemotherapy regimen and 100 patients received stem cell transplantation or chimeric antigen receptor (CAR)-T therapy. Of the 136 LOT3+ treatments, 74 were chemotherapy regimens (54 with CD20 antibodies) and 18 were kinase inhibitors. The median time between treatment lines was less than 6 months. Among patients with at least LOT2, approximately 50% received more than one LOT during the first year after diagnosis. Approximately 25% of treated patients died within 6months of treatment initiation. Of the 2633 included patients, the median OS from diagnosis was 31.0months (treated patients: 46.8months, untreated patients: 3.0months). Despite advances in the field, high unmet medical need in DLBCL remains. The treatment landscape is very heterogeneous, particularly in second- or later-line treatments, with few patients receiving potentially curative treatment beyond the first line. Treatment for DLBCL, particularly for transplant-ineligible patients, remains challenging.

A Systematic Literature Review on Risk Factors for and Timing of Clostridioides difficile Infection in the United States.

Clostridioides difficile infection (CDI) is a major public health threat. Up to 40% of patients with CDI experience recurrent CDI (rCDI), which is associated with increased morbidity. This study aimed to define an at-risk population by obtaining a detailed understanding of the different factors leading to CDI, rCDI, and CDI-related morbidity and of time to CDI. We conducted a systematic literature review (SLR) of MEDLINE (using PubMed) and EMBASE for relevant articles published between January1, 2016, and November11, 2022, covering the US population. Of the 1324 articles identified, 151 met prespecified inclusion criteria. Advanced patient age was a likely risk factor for primary CDI within a general population, with significant risk estimates identified in nine of 10 studies. Older age was less important in specific populations with comorbidities usually diagnosed at earlier age, such as bowel disease and cancer. In terms of comorbidities, the established factors of infection, kidney disease, liver disease, cardiovascular disease, and bowel disease along with several new factors (including anemia, fluid and electrolyte disorders, and coagulation disorders) were likely risk factors for primary CDI. Data on diabetes, cancer, and obesity were mixed. Other primary CDI risk factors were antibiotics, proton pump inhibitors, female sex, prior hospitalization, and the length of stay in hospital. Similar factors were identified for rCDI, but evidence was limited. Older age was a likely risk factor for mortality. Timing of primary CDI varied depending on the population: 2-3weeks in patients receiving stem cell transplants, within 3weeks for patients undergoing surgery, and generally more than 3weeks following solid organ transplant. This SLR uses recent evidence to define the most important factors associated with CDI, confirming those that are well established and highlighting new ones that could help to identify patient populations at high risk.

Use of Aromatherapy to Reduce Symptom Burden in Patients Receiving Stem Cell Transplantation

Use of Aromatherapy to Reduce Symptom Burden in Patients Receiving Stem Cell Transplantation

Improvement of survival after hematopoietic stem cell transplantation and trends at a pediatric transplantation center; a three-decade journey.

Advances in stem cell transplantation have resulted in improved outcomes. This is a retrospective study aimed to analyze changes in patient profile, transplantation, graft characteristics, and outcome among 241 pediatric patients who received stem cell transplantation in a single center between 1993 and 2019. In the 2010-2019, compared with the 1993-2009 period, a significantly higher 5-year overall survival (60% vs. 44%, p = .022) and an event-free survival (53% vs. 34%, p = .025) were observed. Cumulative incidence of deaths due to relapse or progression between the 1993-2009 and 2010-2019 periods were 33% and 26% respectively (p = .66). Cumulative incidence of non-relapse mortality was significantly higher during the 1993-2009 period compared with the 2010-2019 period for malignant diseases (57.7% vs. 28.3%, p = .007). The overall survival from acute graft-versus-host disease between 1993 and 2009 was 11% versus 46% between 2010 and 2019 (p = .0001). The overall survival from infection in both eras did not show any difference (p = .41). Development in transplantation technology has led to a decrease in non-relapse mortality and better control of graft-versus-host disease. However, relapse and infection remained as major causes of death. Studies evaluating institutional trends in patients undergoing HSCT and analyzing their mortality profile, can improve the management of patients, leading to a reduction in transplant-related problems.

Multiple imputation strategies for missing event times in a multi-state model analysis.

In clinical studies, multi-state model (MSM) analysis is often used to describe the sequence of events that patients experience, enabling better understanding of disease progression. A complicating factor in many MSM studies is that the exact event times may not be known. Motivated by a real dataset of patients who received stem cell transplants, we considered the setting in which some event times were exactly observed and some were missing. In our setting, there was little information about the time intervals in which the missing event times occurred and missingness depended on the event type, given the analysis model covariates. These additional challenges limited the usefulness of some missing data methods (maximum likelihood, complete case analysis, and inverse probability weighting). We show that multiple imputation (MI) of event times can perform well in this setting. MI is a flexible method that can be used with any complete data analysis model. Through an extensive simulation study, we show that MI by predictive mean matching (PMM), in which sampling is from a set of observed times without reliance on a specific parametric distribution, has little bias when event times are missing at random, conditional on the observed data. Applying PMM separately for each sub-group of patients with a different pathway through the MSM tends to further reduce bias and improve precision. We recommend MI using PMM methods when performing MSM analysis with Markov models and partially observed event times.

Treatment patterns and costs among US patients with diffuse large B-cell lymphoma not treated with 2L stem cell transplantation.

Aim: To assess treatment patterns, healthcare resource utilization (HCRU), and costs for patients with diffuse large B-cell lymphoma (DLBCL)who did not receive stem cell transplantation in second-line. Patients & methods: An administrative MarketScan® database study to assess DLBCL claims from 01/01/2009-30/09/2020. Results: Most patients (n=750) received rituximab plus cyclophosphamide, doxorubicin, vincristineand prednisone in first-line (86.8%) and rituximab (39.5%) or bendamustine±rituximab±other (16.3%) in second-line. Over half were hospitalized (mean duration: 16.5 (standard deviation [SD]: 25.8) days per patient per year). Mean medical/pharmacy costs were US$141,532 per patient per year (SD: $189,579), driven by DLBCL-related claims. Conclusion: Healthcare resource utilization and costs for DLBCL-related claims were due to hospitalizations and outpatient visits. Novel therapies to reduce clinical and economic burdens are needed.

Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation.

The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies.

Analysis of bacteremia at first-line antibiotic treatment for febrile neutropenia in children and adolescents: A retrospective, single-center analysis

BackgroundControl of bacterial and fungal infections is critical to improving outcomes in hematological neoplastic diseases of children and adolescents. In this study, a retrospective analysis of our previous studies on febrile neutropenia was performed to investigate bacteremia. ProcedureFrom August 2008 to December 2023, five antibiotic studies were performed for febrile and neutropenic pediatric patients who had been treated with chemotherapy, immunosuppressive therapy, or had received stem cell transplantation in the pediatric unit at Sapporo Hokuyu Hospital. The rate of positive blood culture, detected bacteria, and susceptibility of several types of antibiotics in febrile episodes were investigated. ResultsBlood culture was positive in 133 of 1604 febrile episodes of 329 patients. Detected bacteria were Gram-positive cocci (61.2 %), Gram-negative bacilli (27.6 %), Gram-negative cocci (0.7 %), and Gram-positive bacilli (10.4 %). The incidence of bacteremia over time showed a decreasing trend with each passing year. In particular, the incidence of bacteremia was around 10 % in 2008–2013, whereas it was often below 5 % after 2020; this decrease was statistically significant. Although almost all detected bacteria and their susceptibilities to antibiotics (piperacillin/tazobactam, meropenem, ceftazidime, and cefozopran) did not change over time, all Escherichia coli detected after 2014 were extended-spectrum β-lactamase-producing bacteria.

Clinical Observation of Camrelizumab (CAM) Combined with Bendamustine and Gemcitabine (BeGe) in Relapsed/Refractory Classical Hodgkin Lymphoma (cHL): A Phase II Trial

Background The cure rate of classical Hodgkin's lymphoma (cHL) is more than 80%. However, 20% or so of cHL patients have refractory or recurring disease, making clinical treatment complex and challenging. Currently, the standard treatment for patients with r/r-cHL is high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDCT/ASCT). However, the complete response rate of traditional salvage chemotherapy is not ideal, which prevents some patients from receiving stem cell transplantation. In recent years, with the application of new drugs such as PD1 inhibitors, the efficacy of R/R cHL has been further improved. we designed a prospective, single-arm, multi-center trial to evaluate the efficacy and safety of PD-1 antibody camrelizumab combined with bendamustine and gemcitabine（BeGe）in patients with relapsed or refractory (r/r) classical Hodgkin Lymphoma (cHL). Methods This research is a phase 2 exploratory, open-label, multi-center study. Key inclusion criteria include age≥18 and ≤75, ECOG&amp;lt;2, R/R cHL who had received at least first-line chemotherapy, at least one measurable lesion per Lugano criteria 2014, and preparing to receive autologous stem cell transplantation (ASCT). Patients were treated with camrelizumab (CAM, 200 mg IV, day 1 q3w) combined with bendamustine （90mg/m 2, IV, day 2 and Day3) and gemcitabine (1000 mg/m 2 day 1 and day4) for 2 cycles. Patients with complete response (CR) underwent autologous hematopoietic stem cell transplantation after high-dose chemotherapy (HDT/ASCT). Patients who did not achieve CR underwent HDT/ASCT if CR was attained after two additional cycles of CAM plus BeGe. 1-2 cycles of CAM monotherapy were permitted for individuals who were waiting more than 4 weeks for ASCT. The primary endpoint was the proport ion of patients who achieved PET-CT-confirmed complete response (CR) according to Lugano 2014 criteria. Results 17 individuals were enrolled between February 2022 and May 2023, including 5 relapsed and 12 refractory patients. 14 (82.4%) of the enrolled patients were younger than 60 years old, with a median age of 37 years (range: 20-62) and 76.5% male. 12 patients had received first-line prior therapy, and 5 patients had received second-line therapy or more. After 2 cycles CAM plus BeGe, Overall response rate (ORR) was 94.0% (16/17) with CR rate of 64.7% (11/17) and PR rate of 29.4% (5/17). Only one patient withdrew from the study because to progressive disease (PD). 4 patients who achieved PR received 2 additional cycles of CAM plus BeGe, and 2 patients achieved CR. Up to now, autologous hematopoietic stem cell transplantation has been carried out in 7 patients, with stem cell being collected from 5 patients after 2 cycles and 2 patients after 4 cycles. With a cutoff date of June 10, 2023, the 1-year (progression-free survival) PFS rate was 86.3% and the 1-year (overall survival) OS rate was 94.1%. One patient experienced grade 3 pancreatitis. Grade 1-2 AE occurred in 9 patients, and common AEs included pruritus(4/17), pyrexia(4/17), bone marrow suppression(2/17), nausea(1/17), diarrhea(1/17), mild reactive cutaneous capillary endothelial proliferation(RCCEP, 1/17). No grade 4 or above AEs occurred. Conclusion It is well known that refractory cases are more difficult to treat and have a worse prognosis than relapsed cases. Despite the preponderance of refractory cases in this study, the response was excellent. Therefore, Camrelizumab combined with BeGe chemotherapy patients shows encouraging clinical efficacy and safety in R/R HL, and has no significant effect on stem cell collection, which is worthy of further study.

TP53 Y220C Mutations in Patients with Myeloid Malignancies

Background: TP53 gene mutations lead to inactivation of the protein p53, causing genome instability, oncogenesis, and treatment resistance conferring an unfavorable prognosis. TP53 Y220C missense mutations in exon 6 (p.659A&amp;gt;G) are described as a frequent ‘hot spot’ mutation in solid tumors. A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022). No data has been reported about TP53 Y220C in hematologic malignancies to date. We set out to evaluate the clinicopathologic characteristics of TP53 Y220C in hematologic malignancies and particularly, myeloid neoplasms. Methods: We identified all patients with hematologic neoplasms with TP53 Y220C mutations at University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, detected by standard next generation sequencing assays, and focused on patients with myeloid malignancies; summarizing the patient characteristics, disease features and outcomes for patients with this specific TP53 mutation. Overall survival (OS) was assessed by the Kaplan-Meier method from date of diagnosis to date of death from any cause or date of last follow-up. Leukemia-free survival (LFS) was calculated from time to diagnosis of TP53 Y220C mutated myelodysplastic syndrome (MDS) to date of transformation to acute myeloid leukemia (AML) or death. Survival analysis was conducted only for newly diagnosed patients with available follow-up data. Results: We identified 143 patients (pts) with hematologic malignancies harboring a TP53 Y220C mutation. MDS and AML were the most frequent diagnoses (MDS, n=66; AML, n=48). Median age was 69 years (range, 32-92) and 56% of patients were male (Table 1). We then analyzed in more detail patients with MNs, including CHIP/CCUS, MDS, AML and MDS/MPN. Among those, in 76 (64%) pts the TP53 Y220C mutation was detected at initial diagnosis and in 43 (36%) pts, TP53 Y220C was identified in the relapsed/refractory setting. Therapy-related myeloid neoplasms (MNs) accounted for 51 of 119 pts (41%). Complex karyotype was frequent (n=88/119, 74%) in the setting of TP53 Y220C. Median TP53 Y220C variant allele frequency (VAF) was 32% (range, 1%-96%). Eighty-two patients (69%) had additional co-mutations: 24 (20%) pts had additional (non-Y220C) TP53 mutations only; 34 (29%) pts had only non- TP53 co-mutations (most frequently DNMT3A and TET2) and 24 (20%) pts had additional TP53 mutations in the setting of other co-mutations. With a median follow-up of 9 months, median OS for patients with newly diagnosed TP53 Y220C MDS (n=39) and AML (n=23) was 13.1 months (95% CI, 7.6 to 18.7) and 8 months (95% CI, 5.6 to 13.4), respectively ( p=0.06) (Figure 2). For the TP53 Y220C MDS cohort, AML transformation occurred in 13 (33%) patients, after a median of 14.3 months. Median LFS for these patients was 12.2 months (95% CI, 7.9 to 16.5). Modest and non-statistically significant differences in median LFS for MDS patients who did and did not receive stem cell transplant (SCT) were identified; MDS+SCT (n=12) 14.5 months (95% CI, 4 to 25) vs MDS+no-SCT (n=27) 9.3 months (95% CI, 4.6 to 14), p=0.18. Interestingly, four patients diagnosed with TP53 Y220C mutated CHIP/CCUS with a median VAF of 2% were identified, and with a median follow-up of 34.6 months, none have developed dysplastic changes or progression to MDS or AML at the time of cut off. Additional outcomes data will be forthcoming in the analysis of this cohort of patients with TP53 Y220C mutated myeloid neoplasms. Conclusions: TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.

Real World Outcomes of Black Americans with Mantle Cell Lymphoma

Introduction Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 6-8% of all NHL cases. MCL generally affects older, White, male patients, having a significantly lower incidence in Black patients. Thus, clinical outcomes of Black Americans with MCL are poorly characterized, though multiple sources have reported relatively poor survival outcomes when compared to their White counterparts. We aimed to evaluate the overall survival outcomes and explore potential factors contributing to poor survival outcomes for Black patients with MCL in the United States. Methods The National Cancer Database was used to identify MCL patients diagnosed from 2004-2020. Demographic and treatment characteristics were compared between White and Black MCL patients, by self-identified race. Patients of other races were excluded. Kaplan Meier and adjusted Cox regression survival analysis were used to compare overall survival (OS) by race, and stratified for age ≤ 65 or age &amp;gt; 65 years old. Finally, a propensity matched analysis was performed to compare OS in Black and White Americans matched by age, comorbidity burden, insurance status, and zip code income. Results A total of 34,872 patients with MCL were identified, of which 93.1% (N=32,407) were White, 4.2% (N=1,465) were Black, and 1.7% (N=942) identified as another race and were excluded from the dataset. Black patients were more likely to be female (34% Black vs. 29% White), have a younger age at diagnosis (mean age 65 years [SD ± 13] vs. 68 years [SD ± 12], p&amp;lt;0.001), more likely to have ≥1 co-morbidity (30% vs. 23%), and more likely to be uninsured (4% vs. 2%) when compared to White patients. Both Black and White patients had equal rates of stage IV disease (68% vs. 68%) and receipt of systemic therapy at diagnosis (84% vs. 84%), however White patients were more likely to receive stem cell transplant compared to Black patients (13% vs.11%). With a median follow-up of 40 months, the median OS for all MCL patients was 70 months (95% CI 66-71). Compared to White patients of the same age, Black patients age ≤ 65 years had worse median OS (116 months [95% CI 92-139] vs. 140 [95% CI 134-146] months for White patients) along with decreased 1-year (87% vs. 90%), 5-year (62% vs. 70%) and 10-year OS (38% vs. 55%), (all p &amp;lt;0.001). For MCL patients age &amp;gt; 65 years old, Black MCL patients had shorter median OS compared to their White counterparts (36 months [95% CI 28-43] vs. 43 months [95% CI 41-44]), and decreased 1-year (70% vs. 75%) and 5-year OS (40% vs. 41%) (all p=0.030), though by ten years there was no survival disparity. On age-adjusted cox regression, Black race was associated with increased hazard for all-cause death for MCL patients (hazard ratio [HR] 1.17, CI 1.08-1.26; p&amp;lt;0.001). However, when Black and White patients were 1:1 propensity score matched by age, co-morbidity score, insurance status, and income quartile of zip code, there was no significant difference in risk of death by race alone (HR 0.99, CI 0.91-1.08; p=0.61). Conclusion This is the largest study to-date evaluating outcomes among Black patients with MCL. Patients who are Black with MCL are more likely to present at a younger age, have female predominance, and have worse overall survival outcomes than White patients of similar age. Notably, we found that this survival difference was lost when controlling for surrogate markers of healthcare access, such as insurance and income. This study highlights existing disparities for Black patients with MCL, which appear to be related to socioeconomic disparities that may impact access to treatment, supportive care, and other vital aspects of care for MCL. Future studies may seek to evaluate the role of known high risk features for MCL such as TP53 status or blastoid/pleomorphic morphology in these populations. Interventions aimed at improving healthcare access for underserved populations, including racial minorities, are essential.

Real-World Patient Characteristics, Treatment Patterns, and Outcomes in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia in China: A Retrospective Analysis Using a Real-World Database

Background: Innovation in chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) has yield tremendous progresses and new treatment options recently. However, real-world treatment patterns, healthcare utilization and costs associated with CLL/SLL are not well studies in middle-income countries such as China. Because CLL/SLL predominantly affects older adults, this study aimed to evaluate baseline characteristics, treatment patterns, healthcare resource utilization (HCRU), costs, and survival in a representative sample of patients from Tianjin city who newly diagnosed with CLL/SLL. Methods: This retrospective study used integrated regional electronic healthcare records from 2004 to 2022. The sample included patients newly diagnosed with CLL/SLL with continuous healthcare encounters (index date = first CLL/SLL diagnosis date). Outcomes included treatment patterns, all-cause and CLL/SLL-related HRU and costs, and overall survival in the frontline and relapsed/refractory settings. Results: We identified 3665 patients meeting the inclusion/exclusion criteria. Overall, patients with CLL/SLL were 62 years of age at index date, 1409 (38.5%) were female, and 910 (24.8%) had insurance coverage. Patients had an average CCI of 1.6 (SD:2.0) during baseline, and the most common comorbid conditions were hypertension (8.9%), pulmonary infection (7.8%) and diabetes (5.9%). 1500 (41.0%) of patients had been exposed to CLL/SLL-directed treatment, with 856(57.0%), 343(22.9%) and 301(20.0%) of patients exposed to chemotherapy, immunochemotherapy and targeted therapy in first-line treatment, respectively. Among the subgroup of patients received targeted therapy, 335 (74.4%), 98 (21.8%) ,5 (1.1%) ,4 (0.9%) and 8 (1.8%) used ibrutinib, zanubrutinib, orelabrutinib, venetoclax, and lenalidomide. 15 (0.4%) and 2 (0.05%) patients received stem cell transplantation and CAR-T, respectively. In terms of HCRU, 2434of patients (66.4%) had a hospitalization due to any cause, 1769 (48.4%) of which were CLL/SLL-related. Emergency department and outpatient service use increased over the study period. Mean per person per month (PPPM) use for inpatient, outpatient and ED visits were 0.53, 0.30 and 0.59, respectively. Mean total PPPM healthcare costs were $ 3125.0 (inpatient), $ 488.1 (outpatient), $ 87.6 (ED), and $ 1085.8 (medication). Median OS from initial diagnosis or 1L treatment initiation were not achieved. The 1-year and 3-year survival rate was 95.1% and 88.5 % from 1L treatment initiation, 97.6 % and 92.8% from the initial diagnosis. Conclusions: In this real-world study using regional healthcare data, we observed distinct demographic, clinical and tumor-related characteristics. Patients were diverse in terms of age, insurance status and healthcare resource utilization. As newer therapies continue to accumulate, future studies should examine how unmet needs in patients with CLL/SLL can be addressed to ensure better access to novel treatment.

Real-World Treatment Patterns, Outcomes, Health Care Resource Utilization and Cost Burden of Multiple Myeloma in South Korea Using the National Claims Data

Introduction As multiple myeloma (MM) treatments are rapidly evolving, treatment outcomes significantly have improved over the last decade while the disease burden is inevitably rising. Understanding the real-world treatment patterns and health care resource utilization (HCRU) and costs associated with the novel agents is important in evaluating the value of novel treatments. This study aimed to describe the trends of treatment patterns, outcomes, HCRU and cost burden of MM in real-world practice between 2010 and 2020. Methods A retrospective observational study was conducted using the national insurance claims database provided by the Heath Insurance Review and Assessment, which covers the entire South Korean population. MM patients newly diagnosed from January 2010 to December 2019 were followed up from their first MM diagnosis to the earliest of death or the end of study period. An algorithm was developed to identify MM regimens and lines of therapy (LOT); MM drugs prescribed within the first 21 days of LOT initiation were considered to constitute the same LOT, and MM drugs that were not part of the LOT or prescribed after 180 days from the last observed prescription were considered to initiate the next LOT. Time to next treatment (TTNT), treatment duration (TD), and 5-year survival rate were assessed descriptively. Overall survival (OS) was estimated using the Kaplan-Meier method with log-rank test for significance. HCRU and costs were assessed during the TTNT and TD of each LOT. MM-related HCRU and costs included MM and MM-related comorbidities. Results Among 11,450 eligible patients, 3,080 (26.9%) patients received stem cell transplant (SCT) and 9,825 (85.8%) patients received the 1st LOT (1L). Of these patients, 5,346 (46.7%) patients advanced to 2L, 2,759 (24.1%) patients to 3L, 1,431 (12.5%) patients to 4L, and 709 (6.2%) patients to 5+L. In SCT patients, after the novel agent introduction, the most common regimens changed to VT (bortezomib/thalidomide) from T in 1L, KR (carfilzomib/lenalidomide) from V in 2L, P (pomalidomide) from R in 3L, and D (daratumumab) from R in 4L. In non-SCT patients, the most common regimens in 1L (VM) and 2L (R) did not change after the novel agent introduction while P and D became most common from R in 3L and 4L, respectively. Similarly, the most common treatment sequence changed after the novel agent introduction. Most patients received 1L (39.1%) only or up to 2L (22.6%) during the follow-up period; in SCT patients, the most common sequences changed to VT-based (48.1%) and VT-based with subsequent KR-based (12.1%) from T-based (11.7%) and T-based with subsequent V-based; in non-SCT patients, the most common sequence changed to VM-based (30.0%) and R-based from VM-based (24.8%) and chemo-based (11.4%). TTNT decreased as LOT advanced from 571.5 days (time to 2L) to 289.1 days (time to 5+L), and TD of LOT ranged from 200.0 days to 283.7 days. SCT patients showed longer TTNT and TD than non-SCT patients, except for 1L where SCT patients showed shorter TD. The median OS of all patients was 5.49 years, and SCT patients showed significantly longer OS (10.1 yrs) than non-SCT patients (4.0 yrs). The 5-year survival rate of all patients was 50.5%, and the rate decreased as LOT advanced from 36.5% (1L) to 21.1% (5+ L). SCT patients (47.7%) showed higher rate than non-SCT patients (33.8%), and the rate in SCT patients increased from 65.7% in 2010 to 76.5% in 2015. All-cause HCRU was higher in the advanced LOTs compared to 1L, and healthcare cost increased with the LOT advancement after 1L initiation regardless of SCT status or novel agent introduction. The average length of hospital stay per admission was 22.4 days during the follow-up period, and the length of stay also increased as LOT advanced. The overall all-cause HCRU and cost were higher in non-SCT patients and after novel agent introduction. Similar trends were observed in MM-related HCRU and cost (Table 1). Conclusion This large population-based study found that the novel agent introduction has led to the increase of HCRU and costs of MM but was also associated with better treatment outcomes in terms of survival. The HCRU and costs increased with the advancement of LOT. These findings suggest that a comprehensive understanding of economic burden and treatment outcomes would be required for evaluating the value of novel agent and selecting the optimal treatment options.

Real-World Treatment Patterns and Outcomes of Patients (Pts) with Follicular Lymphoma (FL) Who Experienced Progression of Disease within 24 Months (POD24)

Introduction: Follicular lymphoma (FL) accounts for about 35% of all non-Hodgkin lymphomas and 70% of indolent lymphomas in the United States. Despite relatively high 1L remission rates, a clinically high-risk subgroup experiences early disease progression within 24 months of 1L initiation (POD24). As the understanding of this population evolves, a treatment paradigm is yet to be established. This study aimed to describe the characteristics of patients who experienced POD24 to 1L therapy and their outcomes following receipt of select 2L treatment sequences using a contemporary real-world (rw) dataset. Methods: Pts meeting the study criteria were identified in the COTA rw database. Eligible pts were aged ≥ 18 years at diagnosis (dx) with grade I-IIIA FL and had no documented grade IIIB or transformation anytime from dx until index date. Pts were treated with 1L CD20+chemotherapy (CHOP/CVP or Benda) and initiated 2L therapy with one of the following treatment categories between January 1, 2010 and December 31, 2019: Benda-CD20, CHOP/CVP-CD20, chemosalvage (e.g., R-ICE), or other novel therapy (e.g., lenalidomide-CD20). Pts were excluded if they were not treated with the specified 1L or 2L therapies, had missing or imprecise key study dates, multiple concurrent primary malignancies at dx, evidence of histologic transformation prior to 2L,1L or 2L clinical trial participation, or documentation of 1L maintenance therapy that did not contain CD20. Characteristics, treatment patterns, and outcomes were analyzed among pts who experienced POD24, defined as documented progression/relapse event within 24 months of 1L initiation. The index date was the date of 2L therapy initiation, and the observation period was defined as the duration of time from index date to the date of death or last visit date (if date of death was not available). Characteristics and treatment patterns were summarized as appropriate using means, medians, and/or counts and percentages. The following rw time to event outcomes were evaluated using the Kaplan-Meier method: time to next treatment (rwTTNT), progression-free survival (rwPFS), and overall survival (rwOS). Rw complete response rate (rwCRR) was calculated as the proportion of pts who achieved a complete response (CR) as the best response to 2L among all POD24 pts. Results: The study included 149 pts who experienced POD24 and met the remaining study criteria. An additional 170 pts (53.3%) qualified for the study but did not experience POD24. The median age at dx for POD24 pts was 61 years. This population was mostly male (57.0%), White (87.9%), and treated in the community practice setting (86.6%). More than 85% of pts had low grade FL at their last assessment at index. Following 1L therapy, 47.0%, 1.3%, 39.6%, and 0.7% of pts had a documented CR, near CR, partial response, or stable disease, respectively. About 11% of pts had progression as their best documented response to 1L. The most common 2L treatment category was Benda+CD20 (47.0%), followed by CHOP/CVP-CD20 (25.5%), chemosalvage (17.4%), and other novel therapies (10.0%). The CD20 received most commonly in 2L was rituximab (87.2%). Of 68 pts who received 3L, 11 (16.2%) received stem cell transplant. Median rwOS from 2L initiation overall was 64.8 months (95% CI: 54.0, 99.6). For pts who received Benda-CD20, CHOP/CVP-CD20, chemosalvage, and other novel therapies in 2L, 5-year rwOS rate from 2L initiation was 49.9%, 52.3%, 57.2%, and 86.2%, respectively. (Table 1) Median rwPFS from 2L initiation overall was 11.3 months, and pts who received Benda-CD20 or other novel therapies in 2L experienced median rwPFS of 25.6 and 18.0 months, respectively, while pts who received CHOP/CVP-CD20 or chemosalvage in 2L experienced median rwPFS of 8.3 and 4.6 months, respectively. (Figure 1) A similar trend was seen in rwTTNT from 2L initiation (overall: 19.6, Benda-CD20: 38.0, CHOP/CVP-CD20: 12.0, chemosalvage: 5.4, and other novel therapies: 19.6 months) and rwCRR for pts who received 2L (overall: 47.7%, Benda-CD20: 57.1%, CHOP/CVP-CD20: 34.2%, chemosalvage: 34.6%, and other novel therapies: 60.0%). Conclusions: Among pts who experienced POD24 and received qualified therapies, 2L outcomes highlight continued unmet need despite recent improvements. Future research is required to identify this subset of high-risk pts at diagnosis and to investigate prospectively the effect of novel therapeutic approaches on their treatment outcomes.

Combining Low-Dose Post-Transplant Cyclophosphamide(PTCY) with Anti-Thymocyte Globulin(ATG) for Prophylaxis of Graft-Versus-Host Disease in Alternative-Donor Hematopoietic Stem Cell Transplantation for β-Thalassemia Major

Background ： The 5-year overall survival rate (OS) for children with thalassemia major who undergo allogeneic stem cell transplantation is 90% and the event-free survival (EFS) rate is 86%. Due to the limited availability of matched sibling donors, the proportion of transplantations from alternative donors is increasing, particularly from haplo-identical donors. Post-transplant infections and graft-versus-host disease (GVHD) remain the major causes of mortality, especially in those who receive transplantation from alternative donors. Post-transplant cyclophosphamide (PTCY) has shown outstanding results of GVHD prophylaxis in haploidentical matched related donors transplantation with hematological malignancies. However, there is insufficient clinical evidence for its application in pediatric patients who received transplantation from haplo-identical donors with non-malignant hematological disease. Here, we retrospectively analyzed the results of 40 cases that underwent allogeneic stem cell transplantation from haploidentical matched related donors (Haplo-RD) and unrelated donors (UD) to evaluate the safety and efficacy of the novel regimen in GVHD prophylaxis. Method A total of 40 patients with β-thalassemia major received stem cell transplantation, 10 haploid donors (Group Haplo-RD), and 30 unrelated donors (Group UD). Among Group UD, 15 donors were 1 or 2 HLA locus mismatched, remaining 15 were identically matched. The median age of the patients was 5.5 years, ranging from 2 to 12. The Conditioning regimen mainly consisted of fludarabine, busulfan, cyclophosphamide, and thiotepa. GVHD prophylaxis included ATG 1.5mg/kg×3d, cyclophosphamide (CTX) 25mg/kg×2d, cyclosporin A (CsA), and mycophenolate mofetil (MMF). We analyzed the engraftment rate, GVHD incidence, survival rate, and virus reactivation rate for each group. Results Engraftment rate was 100%, with a median time of 11 (10-15) days for neutrophil implantation and 12 (6-31) days for platelet implantation. All patients achieved complete chimerism on day 30 after transplantation. Three cases (7.5%) suffered from Ⅲ-Ⅳ aGVHD, with one being in the Group Haplo-RD group and two in the Group UD. Four cases (10.0%) of cGVHD were recorded. The overall survival (OS) rate and thalassemia-free survival rate were both 92.5%. In Group Haplo-RD, both the OS and thalassemia-free survival rates were 100%. Eight cases reported cytomegaloviremia but no one developed to CMV disease. The total activation rate for CMV was 20%. Nine cases suffered from BK virus urinary tract infection, resulting in a total activation rate of 22.5%. Detailed results are shown in Table 1 and Figure 1. Discussion Due to the high risk of GVHD and infection, stem cell transplantation from haploidentical and unrelated donors cannot be routine therapy for children with thalassemia major. Standard-dose PTCY regimen significantly increases the risk of CMV and BK infection after transplantation and is not suitable for non-malignant disease. The results have been reported that low-dose PTCY/ ATG can reduce the risk of GVHD as compared with standard-dose ATG in haploidentical donor stem cell transplantation. In our study, the novel GVHD prophylaxis regimen, semi-dose PTCY (25mg/kg×2d) combined with low-dose ATG (1.5mg/kg×3d), was used for stem cell transplantation from haploidentical and unrelated mismatched donors. The incidence of III-IV aGVHD was 7.5% and cGVHD was 10.0%, and there was no rejection of the transplant. The activation rate of CMV and BKV was significantly lower than reported in the literature, and the non-relapse mortality (NRM) after transplantation was significantly reduced. There was no statistical difference in the rate of OS, EFS, aGVHD, and cGVHD between Group Haplo-RD and Group UD. The results provide an effective approach for preventing GVHD and infectious diseases in thalassemia patients who underwent allo-HSCT with high-risk GVHD.

Komet-008: A Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-Rearranged or NPM1-Mutant Relapsed/Refractory Acute Myeloid Leukemia

Background and Significance: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) remain a high unmet need. Ziftomenib is a potent and selective inhibitor of the interaction between menin and mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A), which drives leukemogenesis in these subtypes. Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. An ongoing Phase 1/2 study (KOMET-001) in R/R AML has demonstrated that ziftomenib monotherapy is safe and well tolerated and that the clinical activity at the recommended phase 2 dose (RP2D) is robust, as the rates of response were not affected by the presence of downstream co-mutations, such as FLT3 and IDH1 or IDH2. Given the monotherapy activity seen to date, the development of ziftomenib in combination with standard-of-care (SOC) chemotherapies or FLT3 inhibitors may provide increased clinical benefit for R/R AML patients with KMT2A-r or with NPM1-m with or without concurrent FLT3-mutations ( FLT3-m) and warrants further investigation. Study Design and Methods: KOMET-008 (NCT# 05735184) is an open-label, dose escalation and expansion study to determine the safety, tolerability, and preliminary efficacy of ziftomenib when combined with SOC regimens for the treatment of either NPM1-m (Arm A) or KMT2A-r (Arm B) R/R AML. Each genetically defined arm will evaluate ziftomenib in combination with various SOC treatments in separate and independent cohorts, as outlined below: Arm A:NPM1-m R/R AML Cohort A-1: Ziftomenib plus FLAG-IDACohort A-2: Ziftomenib plus LDACCohort A-3: Ziftomenib plus gilteritinib (for NPM1-m + FLT3-m R/R AML) Arm B: KMT2A-r R/R AML Cohort B-1: Ziftomenib plus FLAG-IDACohort B-2: Ziftomenib plus LDAC The Part 1a dose escalation uses a i3+3 design, followed by dose expansion/validation in Part 1b. Key eligibility criteria include adults (≥18 years) with documented NPM1-m (±co-occurring FLT3-m) or KMT2A-r R/R AML, ECOG ≤2, prior hematopoietic stem cell transplant (HSCT) allowed, if recovered and prior gilteritinib allowed. Patients who receive an HSCT during study participation will be allowed to receive ziftomenib maintenance therapy upon recovery. The primary objectives are to establish the safety and tolerability of ziftomenib when combined with SOC therapies (ie, dose limiting toxicities, AEs per CTCAE v5.0) and to identify the RP2D of ziftomenib for each SOC combination in each genetically defined cohort. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.