Platelet Transfusion Requirements Research Articles

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p<0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p=0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p=0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p<0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Necrotising enterocolitis in a middle-income country: Early onset and risk factors for mortality.

There is limited literature available about necrotising enterocolitis (NEC) in low- and middle-income countries. This study sought to determine the proportion, pattern and risk factors for mortality among very low birth weight (VLBW) neonates with NEC in a middle-income setting. A retrospective observational cohort study was conducted on all infants with birth weights less than 1501 g admitted from 2018 to 2020 at Groote Schuur Hospital, Cape Town, South Africa. Data were obtained from the Vermont Oxford Network and hospital folders. A total of 104/1582 (6.6%) neonates were diagnosed with NEC with a median onset of 8 days of life. The mortality rate was 39.0%, compared to the all-cause mortality rate of 18.7% for VLBW neonates. Thirty-two (32.0%) neonates with NEC were transferred for surgery of whom 10 (31.3%) died. Small for gestational age (p = 0.13), NEC stage 2B or above (p = 0,002), a positive blood culture (p = 0.018), a raised C-reactive protein (p = 0.013), hyponatraemia (p = 0.004), anaemia requiring blood transfusion (p = 0.003) and thrombocytopenia requiring platelet transfusion (p = 0.033) were associated with mortality. A positive blood culture was found in 37.0% with a predominance of Klebsiella pneumoniae isolates. NEC has an early onset and a high mortality rate in our setting.

Effect of Recombinant Human Thrombopoietin on Platelet Reconstitution after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.

Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components

AbstractPatients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen–reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of –1.5% (95% confidence interval [CI], –2.7 to –0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, –2.4%; 95% CI, –4.2 to –0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

The Prevalence and Associated Risk Factors for Neonatal Thrombocytopenia Among Newborns Admitted to the Neonatal Intensive Care Unit.

Background Thrombocytopenia is the most prevalent hematological condition in neonates that develops in the neonatal intensive care unit (NICU). This set of illnesses is caused by either decreased platelet production due to placental insufficiency, increased platelet breakdown (consumption), or a combination of the two causes. Based on platelet count, it is defined as mild, moderate, or severe thrombocytopenia, with early and late onset. Purpose The purpose of this study is to determine the prevalence of thrombocytopenia and the factors that contribute to it in newborns hospitalized in the neonatal critical care unit at the Maternity and Children Hospital in Al Ahsa, Saudi Arabia. Methods This descriptive retrospective cross-sectional study was carried out at the NICU of the Maternity and Children Hospital in Al Ahsa, Saudi Arabia, over the span of one year (August 2022 to August 2023) among hospitalized neonates with thrombocytopenia. Thrombocytopenia is defined as a platelet count of 150,000 or less. These patients were monitored until they recovered or died. Results The inclusion criteria were met by a total of 242 newborns with thrombocytopenia. Half of the neonates (57%) were full-term, with Apgar scores greater than 5 at the first (84%) and fifth (93%) minutes, respectively. The great majority of individuals (84%) experienced early-onset thrombocytopenia of mild severity (62%) and were asymptomatic (93%). The majority of the cases resolved spontaneously, with only 21%requiring platelet transfusion. There was a significant relationship discovered between gestational age and the severity of thrombocytopenia, with very preterm infants having moderate to severe thrombocytopenia, as well as birth weight (p=0.001). Furthermore, neonates with severe thrombocytopenia had a considerably higher mortality rate (p=0.001). Conclusion The mortality and morbidity of newborns with perinatal risk for neonatal thrombocytopenia can be reduced with timely detection of the cause and development of thrombocytopenia, as well as adequate and early care.

Clinical Signs and Treatment of New-Onset Bone Marrow Failure Associated SARS-CoV-2 Infection in Children: A Single Institution Prospective Cohort Study.

Viral infections can cause direct and indirect damage to hematopoietic stem cells. The objectives of this study were to identify the frequency and severity of aplastic anemia in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as recognize the response to treatment. 13 children with newly diagnosed severe aplastic anemia were enrolled in this prospective clinical trial. Blood samples were obtained from all patients to detect SARS-CoV-2 antibodies, and nasopharyngeal swabs were collected for reverse-transcription Polymerase Chain Reaction to detect SARS-CoV-2 viruses. According to the laboratory results, patients were classified as having SARS-CoV-2 positive antibodies and SARS-CoV-2 negative antibodies. Both groups received combined cyclosporine (CsA) + Eltrombopag (E-PAG). The hematological response, either complete response (CR) or partial response (PR), no response (NR), and overall response (OR) rates of combined E-PAG + CsA treatment after 6 months were evaluated. Four children were recognized to have aplastic anemia and SARS-CoV-2 positive antibodies. Two patients fulfilled the hematological criteria for CR and no longer required transfusion of packed red blood cells (PRBCs) or platelets, and one had PR and was still PRBC transfusion-dependent but no longer required platelet transfusion. The remaining patient showed NR, and he had died before reaching the top of the HSCT waiting list. Moreover, six patients in the SARS-CoV-2 negative antibodies group had CR, while three patients had PR. The difference in ANC, Hg, and platelet counts between both groups was not significant. The SARS-CoV-2 virus is added to several viral infections known to be implicated in the pathogenesis of aplastic anemia. Studies are needed to establish a definitive association and determine whether the response of bone marrow failure to standard therapy differs from that of idiopathic cases.

Etoposide combined with cytarabine and pegfilgrastim for poorly mobilizing patients with multiple myeloma and lymphoma: A prospective multicentre study.

A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2 /day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106 /kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.

APRI as a predictor of severe dengue fever.

The AST/platelet ratio index (APRI) is a well-researched indicator of liver fibrosis. Some studies have shown that APRI can be used as a predictor of severe dengue, but the data is limited. As dengue epidemics are common in our country with limited healthcare resources, we believe APRI can help emergency physicians/primary physicians in predicting the severity of dengue and plan for the appropriate use of limited healthcare resources. 1) To determine the utility of APRI as a predictor of severe dengue. 2) To determine the association of APRI with length of hospital stay and platelet requirement. A retrospective cross-sectional study was done on patients presented to the Emergency Medicine department at Travancore Medicity Medical College with a positive Dengue NS1 antigen or IgM antibody. We found from the univariate analysis results that ALT > 74.5 IU/L has a sensitivity of 59.6 and a specificity of 76.3 (AUC: 0.696; 95% CI: 0.606-0.786), AST > 160.5 IU/L has a sensitivity of 42.3 and a specificity of 93.7 (AUC: 0.747; 95% CI: 0.665-0.829), and APRI > 3.2 has a sensitivity of 69.2 and a specificity of 84.2 (AUC: 0.806; 95% CI: 0.72-0.884) to predict severe dengue. Patients with an APRI of >3.2 required a mean hospital stay of 5.47 days (P = 0.005); 27 (81.8%) requiring platelet transfusion had an APRI of > 3.2 (P = 0.00). APRI is a straightforward index that can be easily derived from AST and platelet values. APRI values of >3.2 can predict severe dengue with a sensitivity of 69.2 and a specificity of 84.2. APRI values of >3.2 are also associated with the length of hospital stay and requirement of platelet transfusion.

Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients.

Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo-HSCT) had inferior overall survival (OS). This single-center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long-term outcomes after allo-HSCT through multivariate analyses. A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011-2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1-18 units) or PLT (98.2% transfused, median 6, range 1-144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8-60.3%) and 86.1% (95% CI: 83.2-88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow-up among survivors (n = 307) was 7.1 years (range: 2.7-11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5-year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49-2.25), leukemia-free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43-2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45-2.89) (p < .001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p = .34) or PLT (p = .64) transfusion independence. Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non-relapse complications.

Trend towards reduction of transfusion reactions using prestorage leukocyte-reduced and pooled whole blood-derived platelets and cost savings compared with poststorage whole blood-derived random platelets as evidenced by real-time hemovigilance.

Due to chemotherapy-induced neutropenia or hematologic malignancies, immunocompromised cancer patients may have higher incidence of febrile nonhemolytic transfusion reactions compared with the general population and frequently require platelet transfusions. This quality improvement project compared the safety of transfusion using prestorage leukocyte-reduced and pooled whole blood-derived platelets (Acrodose/WBD) with conventionally produced poststorage WBD platelets (RDP) using an active hemovigilance system. Every patient receiving a blood product at the hospital was virtually monitored in real time by trained nurses from a remote hemovigilance unit. These nurses monitor a digital dashboard, which populates a watch list of patients from the time blood product administration is initiated until 12 hours posttransfusion. Over the course of 6 months, 371 patients receiving 792 RDP transfusions and 423 patients receiving 780 Acrodose/WBD platelets transfusions were monitored for transfusion reactions. We identified 26 transfusion reactions in RDP but only 12 transfusion reactions in the Acrodose/WBD platelet group. Acrodose platelet transfusion was associated with fewer transfusion reactions, which resulted in significant cost savings.

Effect of serum panel reactive antibodies on allogeneic hematopoietic stem cell transplantation in pediatric thalassemia patients: A single-center experience.

The aim of this study was to assess the impact of serum panel reactive antibodies (PRA) on the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric thalassemia patients. A total of 73 pediatric patients with thalassemia were included in this single-center study. Pre-transplant PRA levels were evaluated, and the patients were divided into two groups: PRA-negative (group 1; n = 44) and PRA-positive (group 2; n = 29). Patient characteristics, including age, gender, donor type, stem cell source, and HLA compatibility, were analyzed. Transplant outcomes, including engraftment, transfusion requirements, and transplant-related complications, were compared between the two groups. Further subgroup analysis was performed based on MFI values. At the time of transplantation, patients in group 1 were younger than those in group 2 (p = .008). The number of fully matched donors within the family (MSD and MFD) was significantly higher in group 1 (p = .049). Additionally, Rh blood group incompatibility was higher in group 2 (p = .03). There was no statistically significant difference in the engraftment days of neutrophils, platelets, and erythrocytes between the two groups. The frequency of poor graft function and graft failure was higher in the group 2, but there was no statistically significant difference. Post-transplant transfusion requirements for platelets and red blood cells were significantly higher in the group 2 (p < .001). Transplant-related complications such as VOD, PRES, and aGvHD were more common in the group 2, but no statistical significance was detected. Serum PRA in pediatric thalassemia patients may impact the outcomes of HSCT. PRA-positive patients had higher rates of blood product transfusion requirements. Although poor graft function, graft failure, and post-transplant complications were more common in the group 2, statistical significance was not observed. Identifying patients with high PRA levels can assist in optimizing transplant strategies and post-transplant care, leading to improved outcomes for the patients.

Analysis of Influencing Factors of Positive Antiplatelet Antibody in Patients with Diffuse Large B-Cell Lymphoma

Background Diffuse large B-cell lymphoma (DLBCL) is a common malignant tumor of the hematological system. Chemotherapy is the main treatment. As a cytotoxic drug, chemotherapeutic drugs can lead to thrombocytopenia, increase the risk of bleeding and require platelet transfusion if necessary. Since platelet antibody is the main cause of ineffective platelet transfusion, the detection of platelet antibody is of great significance to prevent the inefficacy of platelet transfusion in patients with diffuse large B-cell lymphoma. Objective To analyze the screening results of antiplatelet antibodies in patients with diffuse large B-cell lymphoma and to explore the main factors affecting the production of antiplatelet antibodies so as to provide basis for safe blood transfusion. Methods Patients with diffuse large B-cell lymphoma treated in our department from August 2022 to May 2023 were selected as subjects. Antiplatelet antibodies (GP IX, GP Ⅰ b, GPIIb, GPIIa, GMP140) were detected by flow cytometry. The factors affecting the positive antiplatelet antibodies were analyzed from the aspects of clinical characteristics and laboratory indexes. Results In 155 patients with diffuse large B-cell lymphoma, the positive rate of antiplatelet antibody was 63.23% (98/155). Among them, the positive rate of antiplatelet antibody in male patients was 63.75% (51/80), higher than that in female patients was 62.67%(47/75), and the difference was statistically significant (P&amp;lt;0.05). The positive rate of antiplatelet antibody in patients over 60 years old was 65.18% (43/67), higher than that in patients aged ≤ 60 years old was 62.5%(55/88). The difference was statistically significant (P&amp;lt;0.05). In addition, the positive detection of antiplatelet antibody was related to the abnormal results of large platelet ratio, mean platelet volume, D-dimer and aspartate aminotransferase. In the positive distribution of antiplatelet antibodies, the positive rates of GP IX, GP Ⅰ b, GPIIb, GPIIa and GMP140 autoantibodies were 1.29% (2/155), 29.03% (45/155), 37.42% (58/155), 1.29% (2/155), 49.68% (77/155), respectively. The positive number of antiplatelet antibodies was related to the abnormal results of partial prothrombin time, prothrombin time, prothrombin activity, international standardized ratio, thrombin time, fibrin (prothrombin) degradation products, globulin, alanine aminotransferase and aspartate aminotransferase. Conclusion Patients with diffuse large B-cell lymphoma with abnormal results of large platelet ratio, mean platelet volume, D-dimer and aspartate aminotransferase should pay attention to the detection of antiplatelet antibodies before platelet transfusion to prevent transfusion failure.

Aplastic Anemia: Insight from a Single Center Experience

CONTEXT: Aplastic anemia (AA) is a rare disease with changing treatment modalities over time. Patients often do not respond to first line therapy and require multiple lines of therapy. Treatment has also evolved over time, with the addition of thrombopoietin receptor agonists. Understanding treatment response and outcomes remains imperative. AIMS: To categorize treatments and outcomes of aplastic anemia patients DESIGN: Single center retrospective study of 96 patients who were seen at Moffitt Cancer Center with a diagnosis of Aplastic Anemia between January 2009 and January 2023. RESULTS: Our study included 96 patients (mean age at diagnosis, 54 years) diagnosed with AA. 56 patients (58%) were male, while 41 patients (42%) were female. Seventy-four (74%) were Caucasian, 7 (7%) were African American, 10 (10%) were Hispanic. At diagnosis, mean white blood count was 2.60, with an absolute neutrophil count of 1.02, a hemoglobin of 8.45, and platelet count of 26. At diagnosis, 67/91 (70%) patients had required packed red blood cell transfusion, while 68/91 (71%) had required platelet transfusion. In total, 77/91 (80%) required either a packed red blood cell or platelet transfusion at the time of diagnosis. At diagnosis, 27 patients had infectious complications while 27 also had bleeding complications. Bone marrow cellularity was 10% or less in 59/86 patients (69%), and under 15% in 71 (83%). Forty-two patients were tested for large granular lymphocyte (LGL) clones, and 14 (33%) had clones present. Paroxysmal nocturnal hematuria (PNH) clones were detected in 35 out of the 75 patients tested (47%). The clones progressed in 14 patients. Seven patients had transformation from AA into Myelodysplastic syndrome (MDS), while 3 had transformation into Acute Myeloid Leukemia (AML). Of the 96 patients, 6 patients were managed with observation. The most used frontline therapies were equine ATG (eATG) + cyclosporine (CSA) in 41 patients, followed by eATG + CSA + eltrombopag in 20 patients. In total, 65 patients received eATG based therapy first line (4 patients received eATG alone frontline). Eleven patients received an eltrombopag based therapy without concomitant ATG. Between singlet/doublet eATG based therapy and triplet therapy, the overall response rate to singlet/doublet was 66% (complete response rate (CR) 23%, partial response rate (PR) 43%) and 67% for triplet (CR 28%, PR 39%) (p=.91). There was no difference to date in OS. There was also no difference in response based on the presence on PNH clones or LGL clones. When looking specifically at severe/very severe AA, triplet CR was 30%, while singlet/doublet was 19%, showing a higher trend of CR in those patients receiving triplet therapy and severe/very severe AA. Thirty-eight patients who received eATG based singlet/doublet or triplet therapy upfront also received a second line treatment. The most common treatments were eltrombopag in 8 and Allogenic Hematopoietic Stem Cell Transplant (AHSCT) in 7. Fifteen had no response, 13 had a partial response, and 10 had complete response. Three patients received AHSCT as a first line therapy, while another 19 patients received it second line or greater. AHSCT was second line for 10 patients, third line for 5, and fourth line for 3. Of these 22 patients, 2 had documented relapse (after receiving it as second line therapy) and were retransplanted. One developed MDS after AHSCT. CONCLUSIONS: AA is diagnosed primarily in symptomatic patients requiring transfusions with life threatening cytopenias. Frontline treatment varies, but the most common therapies, which rely on eATG and CSA, as well as more recently thrombopoietin receptor agonists, have shown the most success. Our data showed that triplet therapy, incorporating eATG, CSA, and eltrombopag had a similar overall response rate, but that CR was higher in patients with severe/very severe AA receiving triplet versus singlet/doublet therapy upfront. Patients often require multiple lines of treatment. AHSCT remains a viable treatment option, with great response, but is not without its drawbacks.

Vdpace As Salvage Therapy in Triple Class Relapse/Refractory Multiple Myeloma

Background: Patients that have triple-class relapsed/refractory multiple myeloma (RRMM) have relapsed on each of the following classes: an immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and anti-CD38 monoclonal antibody (MoAb). RRMM poses a significant challenge with poor prognosis due to limited options. We evaluated VDPACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) for efficacy and safety as salvage therapy in heavily pre-treated RRMM. Methods: We retrospectively analyzed 54 patients who had triple-class RRMM and received at least 1 cycle of VDPACE between June 2016 - July 2023 at the University of Kansas Health System in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC). VDPACE consisted of bortezomib 1 mg/m2 subcutaneous on days 1,4,8 and 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, cyclophosphamide 400 mg/m2 CI x 4 days and etoposide 40 mg/m2 CI x 4 days. Descriptive analysis was performed on available data for patient characteristics, disease course, and outcomes differentiating these two groups. Adverse events were graded based on the CTCAE v5.0 criteria. Responses to therapy, including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression-free survival (PFS) and overall survival (OS) assessments. Results: Of the 54 patients in this study, the median age was 62 years (41-75), 81% (n=44) were Caucasian, 48% (n=26) were IgG subtype, 42% of the patients (n=23) had Stage-III disease at treatment, 74% (n=40) had high-risk cytogenetics, and extramedullary disease (EMD) was present in 50% (n=27) of patients. These patients had a median of 5 (2-10) prior lines of therapy;67% (n=36) were penta-drug exposed, 59% (n=32) were penta-RRMM and 19% (n=10) were refractory to BCMA-directory therapy. Patient characteristics are summarized in Table 1. The overall response rate (ORR) for the whole cohort was 54%, 7 (13%) patients achieved ≥ VGPR, median PFS was 4.67 months (95% CI, 2.97 to 8.40), while OS was 7.93 months (95% CI, 6.33 to 14.73), see Figure 1. Regarding efficacy on penta-RRMM (n=32) vs non-penta-RRMM subgroups (n=22), the ORR was 44% vs 68% respectively, while the median PFS was 2.67 months (95% CI, 2-7.6) in the penta-RRMM subgroup compared to 9.28 months(95% CI, 4.67-NA) in the non-penta-refractory subgroup. Treatment post salvage therapy of VDPACE included autologous/allogenic stem cell transplant (SCT), BCMA-directed therapies (CAR-T, T-cell engaging bispecific antibodies and antibody-drug conjugates), other chemotherapies, in addition to enrollment to clinical trials reported at 13%, 26%, 39% and 4%, respectively. 11% patients proceeded to hospice due to progression disease. Most patients experienced hematological adverse events (AEs), including grade III/IV lymphopenia (96%), neutropenia (93%), thrombocytopenia (87%) and anemia (76%). 69% (n=37) required a blood transfusion and 67% (n=36) required platelet transfusion. Neutropenic fever (NF) was reported in 33% (n=18), while the most common cause of infection was bacteremia in 24% of patients, followed by pneumonia in 20% of the patients. Following the initial hospitalization to receive treatment, the readmission rate within 60 days was 50% (n=27), that was mostly due to NF (52%, n=14). Treatment related mortality (TRM) in the first 30 days was reported in 6% (n=3), all due to severe sepsis. See Table 1. Conclusions: Based on our retrospective study, VDPACE is an effective salvage treatment in triple RRMM, and can be used as a bridging therapy prior to CAR-T, prior to enrollment in clinical trials or proceeding to SCT, however, due to TRM secondary to severe infections, careful selection of patients for this intensive therapy must be emphasized.

Efficacy and Safety of Avatrombopag in the Treatment of Chemotherapy-Induced Thrombocytopenia in Children with Acute Lymphoblastic Leukemia: A Retrospective Study

Introduction: Chemotherapy-induced thrombocytopenia (CIT) is one of the most common complications during cancer treatment, increasing the risk of bleeding, medical costs, and potentially affecting treatment outcomes by necessitating chemotherapy dose reductions or delays. Avatrombopag, a thrombopoietin receptor agonist, has been approved as the first-line drug for the treatment of thrombocytopenia in chronic liver diseases. Its efficacy and safety was demonstrated in disorders like aplastic anemia and primary immune thrombocytopenia. However, the research regarding its use in children with CIT is lack. Objective: This retrospective study aimed to analyze the efficacy and safety of avatrombopag in the treatment of chemotherapy-induced thrombocytopenia in children with acute lymphoblastic leukemia, providing a potential new therapeutic option for managing CIT in pediatric cancer patients. Methods: The data of experimental group were collected from 30 pediatric patients with acute lymphoblastic leukemia and CIT who received avatrombopag treatment in the pediatric ward of Southern Hospital from August 2022 to July 2023. Additional data from 250 pediatric patients with acute lymphoblastic leukemia and CIT who did not receive avatrombopag treatment at Southern Hospital from January 2020 to July 2023 were collected as the control group. A propensity score matching method was employed to analyze the two patient groups, resulting in a successful matching of 30 pairs (CAT 21 pairs, CAT+9 pairs). The collected clinical data included age, gender, height, weight, risk stratification, infection status, platelet count changes during each chemotherapy cycle, platelet transfusion frequency, clinical manifestations of bleeding, avatrombopag usage, and complications. All patients were treated with the 2020-CCCG-ALL chemotherapy regimen,diagnosed with CIT,under 18 years of age, and excluded if they had concomitant hematological disorders, chronic liver disease, cardiovascular diseases, severe arterial or venous thrombosis, or splenomegaly. The initial avatrombopag dose was 10mg daily for patients weighing less than 30kg and 20mg daily for patients weighing 30kg or more. Avatrombopag was stopped when PLT≥100×10 9/L or an increase in PLT by ≥50×10 9/L compared to pre-treatment levels. Results: Comparison between the experimental and control groups revealed that the experimental group had a shorter duration of grade 3 or higher thrombocytopenia (3.36±1.77 days vs. 4.7±2.46 days, P=0.019) and a shorter time to platelet recovery (7.9±2.63 days vs. 9.76±2.77 days, P=0.01). Subgroup analysis within the CAT and CAT+ chemotherapy phases indicated that significant platelet value differences (P&amp;lt;0.05) were observed between the two groups at the start of platelet decline (day 10±2) [PLT: (268.13±216.52) ×10 9/L vs. (152.13±89.58) ×10 9/L] and during platelet nadir (day 14±2) [PLT: (435.97±285.83) ×10 9/L vs. (285.07±148.67) ×10 9/L]. Additionally, a statistically significant difference (P&amp;lt;0.05) in PLT change from baseline to day 5 and day 7 was observed in the experimental group [46.5 (20.5, 93) ×10 9/L and 67 (15.5, 180) ×10 9/L, respectively]. During the chemotherapy cycles, only 4 patients (8.3%) experienced bleeding events, and after avatrombopag treatment, 11 patients (22.9%) did not require platelet transfusions. Four adverse events of secondary platelet increase were recorded, and no other adverse events were reported. Conclusion: Avatrombopag, as an alternative treatment for chemotherapy-induced thrombocytopenia in children with acute lymphoblastic leukemia, demonstrated the potential to promote platelet recovery and exhibited good safety. keywords:avatrombopag,Chemotherapy-induced thrombocytopenia,acute lymphoblastic leukemia

Impact of Outpatient Administration of Cytarabine Consolidation Chemotherapy on Hospital Length of Stay in Adults with Acute Myeloid Leukemia

Background: Administration of 3-4 cycles of high/intermediate dose cytarabine (H/IDAC) reduces relapse of acute myeloid leukemia (AML) and bridges patients (pts) to allograft. There is no accepted standard model of safely delivering H/IDAC in these pts. To reduce reliance on inpatient (inpt) chemotherapy administration and safely avoid or forestall hospitalization during cycles, we developed an outpatient (outpt) protocol to deliver H/IDAC. Pts were assigned outpt or inpt treatment at their hematologist's discretion. We aimed to evaluate the benefits and safety of our model in this retrospective observational study. Methods: Pts diagnosed with AML and treated with intensive induction chemotherapy between 2015 and 2020 were identified; included pts received ≥1 consolidation cycle of 1-3g/m² cytarabine over 3 hours BID, dose adjusted for age and renal function, on days 1, 3 &amp; 5 of a planned 28-day cycle. Outpts received H/IDAC via computerized ambulatory delivery device (CADD) pump and central venous access device (CVAD), attended days 1-6, then 3 times a week for blood product support until count recovery; elective readmission was not mandated. Pts were educated to present to hospital if unwell. Inpts were admitted for H/IDAC but could be discharged prior to count recovery. Antimicrobial prophylaxis consisted of antifungal agents and valaciclovir. The primary endpoint was mean duration of hospital admission (LOS) per consolidation cycle. As pts may have been treated on an inpt and/or outpt basis, generalized estimating equations were used to compare LOS clustered by pt. Secondary outcomes included death during H/IDAC; intensive care unit (ICU) admission; time to admission; blood product use; cycle length; bacteremia; time to count recovery; relapse free survival (RFS) and overall survival (OS). Results: Of 109 pts identified, 62 pts were included and 47 pts excluded (not AML=3; induction death=7; refractory leukemia=14; alternative=13; no consolidation=10). Median age was 55.2 years (range 18.2-70.3); 31 (50%) males; ELN 2010 fav=23 (37.1%), Int-2/3 = 30 (48.4%), Adv=8 (12.9%); denovo AML in 60 (96.7%); and therapy related in 2 (3.2%). FLT3-ITD, NPM1 and bi-allelic CEBPA mutations detected in 11 (17.7%), 27 (43.5%) and 2 (3.2%) pts, respectively. Fifty-nine pts (95.1%) received 7+3 idarubicin induction and 7 (11.3%) received midostaurin. A total of 131 cycles of H/IDAC were administered; 81 (61.8%) were commenced as outpt and 50 (38.2%) as inpt. Twenty-seven (43.6%) pts commenced all cycles as an outpt. Those commencing consolidation as an outpt spent, on average, 10.3 fewer days in hospital per cycle. The mean (SD) LOS for outpt and inpt was 11 (8.3) versus 21.3 (8) days (p&amp;lt;0.001), respectively. For each consolidation cycle, outpts spent less time in hospital (mean, [SD]): cycle 1, 12.6 (10.3) vs 20.7 (8.0) days (RR 1.6, p=0.007); cycle 2, 11.6 (7.2) vs 21.4 (8.3) days (RR 1.8, p=0.001); cycle 3, 8.4 (5.8) vs 24.6 (7.4) days (RR 2.9, p&amp;lt;0.001). There were no deaths among inpts and one death in outpts (septic shock). ICU admission occurred in 8/81 (9.9%) cycles in outpts vs 1/50 cycles (2%) in inpts (p=0.12). Mean ICU LOS for outpts vs inpts in cycle 1 was 17.6 days vs 1.6; cycle 2, 5.1 vs 0 days; and cycle 3, 4.2 vs 0 days. Bacteremia was detected in 41 cycles (31.3%), with 38 isolates (gram pos=17, gram neg=21) in 31 outpt cycles (38.2%) and 15 isolates (gram pos=6, gram neg=9) in 10 inpt cycles (20%). Median time to admission in outpts was 14 days (IQR, 3-21); 15 (18.5%) cycles did not result in pt admission. There were no differences in timing of admissions by cycle number nor time-point to prompt elective admission (Fig.1). There was no difference in packed cell or platelet transfusion requirement between inpts and outpts. Time to blood count recovery was similar. No improvement was seen in cycle length. The proportion undergoing allogeneic transplant in first remission was 37.1%, and at any time, 59.7%. Over a median follow up of 3.3 years, median RFS was 2 years and OS, not reached. Conclusion: In selected pts, outpt based AML H/IDAC consolidation therapy significantly reduced hospital length of stay compared with inpts. There was no impact on cycle length. Bacteremia and ICU admission rates were higher in outpts, and strategies such as remote monitoring or pre-emptive hospitalization could be considered. Our findings suggest outpt consolidation should be considered in a supported clinical setting.

Applying the Novel EHA/EBMT Grading System for Icaht Following CAR-T Therapy: Comparative Incidence across Disease Entities and Association with Infections and Mortality

Background: Hematological toxicity is a frequent side effect of CAR-T therapy and predisposes for severe infectious complications. Recently, the EHA/EBMT consensus grading for Immune Effector Cell Associated HematoToxicity (ICAHT) was developed ( Rejeski et al. Blood 2023). In contrast to existing grading systems such as the CTCAE, the novel ICAHT grading integrates both the depth and duration of neutropenia. We hypothesized that ICAHT severity is associated with key clinical sequelae such as transfusion requirements, hospitalization, severe infections, and adverse treatment outcomes. Methods: We applied the novel grading of early ICAHT (day 0-30) to a multicenter retrospective real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR T-cells for relapsed/refractory B-cell malignancies (334 large B-cell lymphoma [LBCL], 112 multiple myeloma [MM], 103 mantle cell lymphoma [MCL]) across twelve international sites (Germany, France, Spain, USA). Hematotoxicity endpoints included the total cumulative duration of severe neutropenia (ANC &amp;lt;500/µL, day 0-60) and phenotypes of neutrophil recovery ( Rejeski et al. Blood 2021). Infections were studied until day +90 after CAR-T and were graded on a 5-grade scale as mild, moderate, severe, life-threatening, or fatal. Non-relapse mortality (NRM) was defined as death following CAR-T without evidence of relapse or progression. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using log-rank test. Results: Our study cohort included 424 patients without severe ICAHT (absent or grade 1-2) and 125 patients with severe ICAHT (grade 3-4). The distribution of mild (1°), moderate (2°), severe (3°) and life-threatening (4°) ICAHT was 36%, 29%, 17%, and 5%. Seventy patients (13%) did not develop ICAHT of any grade. When comparing ICAHT grades across disease entities, we noted a numeric trend towards increased severe ICAHT in MCL compared to LBCL or MM patients (Grade ≥3: 28% vs. 23% vs. 15%). Patients that subsequently developed severe ICAHT displayed elevated serum inflammatory markers and pronounced cytopenia at baseline - reflected by increased CAR-HEMATOTOX scores (median 3 vs. 1, p&amp;lt;0.0001). On multivariate binary logistic regression, co-stimulatory domain (CD28z), low platelet count, low ANC, low hemoglobin, increased serum ferritin, and the presence of bone marrow infiltration were independent risk factors for severe ICAHT. We noted a strong positive correlation between ICAHT severity and the cumulative duration of severe neutropenia (r=0.92, p&amp;lt;0.0001). The aplastic phenotype of neutrophil recovery was enriched in patients with grade 3 (73%) and especially grade 4 ICAHT (100%). Severe ICAHT was also associated with coincident multilineage cytopenias, resulting in increased transfusion requirements for both platelets (85% vs. 21%, p&amp;lt;0.0001) and red blood cells (86% vs. 41%, p&amp;lt;0.0001). In terms of management of hematotoxicity, the severe ICAHT group more commonly received G-CSF (72% vs. 44%, p=0.01), TPO mimetics (12% vs. 2%, p&amp;lt;0.0001) and hematopoietic stem cell boosts (6% vs. 0.2%, p&amp;lt;0.0001). Importantly, patients with severe ICAHT displayed a significantly increased rate of severe infections (49% vs. 13%, p&amp;lt;0.0001, Fig. 1a) and severe bacterial infections (36% vs. 8%, p&amp;lt;0.0001). This translated into a markedly increased 1-year NRM rate (14% vs. 4.5%, logrank p&amp;lt;0.0001, Fig. 1b), which was primarily attributed to fatal infections of fungal or bacterial origin. Of note, the ICAHT grading showed superior discrimination for severe infections (C-index 0.73, 95%CI: 0.67-0.78) compared to CTCAE grading (C-index 0.55, n.s.). Prolonged hospitalization was noted in case of severe ICAHT (median 21 vs. 16 days, p&amp;lt;0.0001) and intensive care admission was more common (23% vs. 4%, p&amp;lt;0.001). Finally, we observed inferior PFS (1-year PFS 35% vs. 51%, median 4 vs. 14 months, p&amp;lt;0.0001) and inferior OS (1-year OS 52% vs. 73%, median 12 months vs. not-reached, p&amp;lt;0.0001) in the patients that developed severe ICAHT. Conclusions: These data highlight the clinical relevance of the novel EHA/EBMT ICAHT grading system. Importantly, ICAHT severity was closely associated with transfusion dependence, increased infection incidence, and adverse treatment outcomes with high NRM. Taken together, these findings argue for reporting ICAHT grades in clinical trials evaluating established and novel CAR constructs.

Avatrombopag for Adults with Early Versus Chronic Immune Thrombocytopenia

Background Avatrombopag (AVA) is a newer thrombopoietin receptor agonist (TPO-RA) with certain advantages over other TPO-RAs. AVA is currently approved to treat adults with immune thrombocytopenia (ITP) in the chronic disease phase (duration &amp;gt;12 months). However, no studies have evaluated the safety and effectiveness of AVA in newly diagnosed ITP (duration &amp;lt;3 months) or persistent ITP (duration 9-12 months), leaving open questions regarding its safety (including thromboembolic risk) and effectiveness in these patients, and also drastically limiting availability of the drug to patients with early ITP, for whom it is off label. We hypothesize that AVA has similar safety and effectiveness in all phases of ITP. Methods We performed a multicenter, observational cohort study of all adult patients with primary or secondary ITP at 4 hospitals treated with AVA to compare outcomes of patients with newly diagnosed or persistent ITP versus patients with chronic ITP. We collected patient and disease characteristics and characteristics and outcomes of AVA treatment, including dosing, platelet counts prior to and during treatment, adverse events, concurrent and rescue therapies for ITP, and platelet transfusions. Platelet outcomes included rates of response (R, the primary outcome, defined as platelet count of ≥50 × 10 9/L) and complete response (CR, platelet count ≥100 × 10 9/L), both on at least one measurement without requirement for rescue therapy. The response fraction (RF) and complete response fraction (CRF), fractions between 0 (representing no instance of response at any timepoint for a patient) and 1 (representing a response at all timepoints for a patient) were calculated for each patient from monthly measurements during the first six months of treatment with avatrombopag. Other outcomes included major bleeding, rescue therapy requirements, thrombocytosis, and adverse events. Results Patient Population. 75 patients were included, 23 patients with newly diagnosed or persistent ITP (17.7 patient-years of AVA exposure) and 52 patients with chronic ITP (65.3 patient-years of AVA exposure). The median (range) age was 55 (18-80) years in the newly diagnosed/persistent ITP group versus 66 (22-90) years in the chronic ITP group; approximately 65% of patients in each group were female. Platelet Outcomes. With regards to the primary outcome, R was achieved in a similar proportion of newly diagnosed/persistent ITP patients (91%) as in chronic ITP patients (96%), P=0.58. Similar proportions also achieved a CR: 86% newly diagnosed/persistent ITP patients versus 81% of chronic ITP patients, P=0.78. Mean RF and CRF were also similar between the two groups ( TABLE). The median platelet count at baseline and over the first six months of treatment by disease phase is illustrated in the FIGURE. Other Outcomes. Incidence of major bleeding and requirement for rescue therapy and platelet transfusion were low in the newly diagnosed/persistent group ( TABLE) and statistically similar to incidences in the chronic group. Safety. The incidence of thrombocytosis (platelet count ≥400 × 10 9/L on ≥1 measurement) was similar (44% in the newly diagnosed/persistent ITP group and 40% in the chronic ITP group). No patient developed an arterial thromboembolic event. No patient in the newly diagnosed/persistent group developed a venous thromboembolism (VTE) and only one patient in the chronic group developed a VTE. No patient in the newly diagnosed/persistent group discontinued AVA due to an adverse event or safety concern. The rate of thromboembolic complications in the entire cohort including 83.0 patient-years of AVA exposure was 1.2 thromboembolic events per 100 patient-years, considerably lower than prior phase 2 and 3 clinical trials of AVA in ITP (which together documented 11 thromboembolic events occurring over 72.4 patient-years of AVA exposure, or 15.2 thromboembolic events per 100 patient-years). Conclusions AVA was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving AVA for chronic ITP. Given its lack of dietary restrictions and hepatotoxicity, access to AVA in early ITP could improve disease outcomes and patient health-related quality of life. Further studies are needed to confirm our findings and evaluate the ability of AVA to induce sustained responses off treatment in patients with early ITP.

One Year Follow-up on the First Patient Treated with Nula-Cel: An Autologous CRISPR/Cas9 Gene Corrected CD34+ Cell Product to Treat Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common serious genetic disease in the world with over 500,000 births per year globally. It is estimated that there are &amp;gt;100,000 patients in the US with SCD and at least 20% have severe disease. Patients with SCD have at least one HBB gene with an adenine to thymidine variant at position 6 of the coding region resulting in a glutamic acid to valine amino acid change ( HbS). The success of allogeneic hematopoietic stem cell transplantation demonstrates that reconstitution of the hematopoietic compartment with HSCs that contain at least one non- HbS allele can cure the disease. Homology directed repair gene editing (HDR-editing) has achieved high frequencies of conversion of the thymidine to the non-pathologic adenine in CD34+ hematopoietic stem and progenitor cells from patients with SCD. Nulabeglogene autogedtemcel (nula-cel) is an investigational drug product in which HDR-editing of plerixafor-mobilized CD34+ HSPCs corrects the underlying variant that causes SCD. This is the first drug to directly correct a disease-causing variant. We report on the 1 year follow up of the first and only patient to receive nula-cel. Results Patient 1 is now a 23 year old female with homozygous SCD. She was consented and enrolled on a Phase I//II trial to test the safety and efficacy of nula-cel. In the 2 years prior to enrollment, the patient averaged 6 VOC's and 4 hospitalizations per year. Two aphereses of plerixafor-mobilized CD34+ cells were performed followed by fresh CD34+ cell purification. The purified CD34+ cells were pooled and cryopreserved. A 5-day manufacturing process starting with 9.3 x 10 6 cells/kg of cryopreserved CD34+ cells resulted in a yield of 8.75 x 10 6 CD34/kg with an on-target allele correction frequency of 33%. In August, 2022 the thawed drug product was infused after the patient received AUC-adjusted busulfan myeloablative conditioning chemotherapy. The initial cell viability was 77% giving a viable infused cell dose of 6.74 x 10 6 CD34/kg. Follow-up exploratory apoptois studies, however, showed the viable CD34+cell dose may have been as low as 3.5 x 10 6 CD34+/kg. Neutrophil engraftment occurred at transplant Day +40. Because of the lack of platelet recovery and continued platelet and RBC transfusion requirements, the patient was started on eltrombopag on day +106 (marrow cellularity of 5%). Since eltrombopag usage was not part of the protocol, its use prompted the reporting of an SAE but the trial was never put on FDA hold. The last dose of GCSF was D+140, the last platelet transfusion was D+181 and the last RBC transfusion was D+263. With rising platelet counts and hemoglobin and a stable ANC &amp;gt;1500, eltrombopag was discontinued on D+322. The blood counts have continued to slowly increase after discontinuation of the eltrombopag. On D+307, with a Hgb of 8.5 g/dl, hemoglobin electrophoresis demonstrated HgbA=12.5%, HgbF &amp;gt;78% and HgbS=4.5%. On D+349 the blood tests show Hgb=9.1 g/dl, Platelet=77,000/ul, ANC=1788/ul with an absolute reticulocyte count of 119,130/ul. There are no signs or symptoms of hemolysis. Table 1 shows the time course of gene marking with stable allele gene correction and INDEL frequencies since D+49. No change in off-target INDEL frequency nor change in on-target INDEL spectrum has occurred and no evidence of oligoclonal or clonal hematopoiesis has been observed. Clinically, the patient has shown marked improvement in quality of life with zero VOE's or other manifestations of SCD. The patient still has not reached a steady state and updated results will be presented. Conclusion We describe the clinical results of the first patient treated with an autologous cell product (nula-cel) in which the pathologic variant was directly corrected. The mechanism of action is fundamentally different than other clinical gene editing and gene therapy programs as the level of the pathologic HgbS is directly decreased thereby removing the dominant negative effect that HgbS has on red blood cells. The high HgbF is an unexpected but potentially effective mechanism of action for the clinical benefit and is being further studied. Longer follow up to assess the durability of the curative clinical impact is underway. Improvements in cell manufacturing are being implemented to shorten the duration of transfusion needs and increase the level of gene correction of engrafted cells. Plans to treat the next patients with an improved nula-cel product are in place.

Impact of Non-Immune Factors on Platelet Transfusion Responses in an Allo-Immunized Cohort

Background: Patients with hematologic malignancies and/or hematopoietic stem cell transplantation (HSCT) recipients often require platelet transfusion support for extended periods. This can result in platelet transfusion refractoriness (PTR) from HLA alloimmunization in up to 30% of individuals. These medically complex patients may also have splenomegaly, fevers and other factors which contribute to PTR. Consequently, they may demonstrate variability in immediate platelet recovery (at 0-2 hours post-transfusion), and in subsequent platelet consumption (at 18-24 hours) despite receiving HLA-selected platelet products. We sought to examine patient and product related factors which impacted platelet transfusion response in a cohort of HLA-alloimmunized platelet transfusion refractory patients. Methods: From April 2021 to June 2023, HLA-alloimmunized (PRA &amp;gt;50%) subjects who required three or more HLA selected platelet units were identified at the Fred Hutchinson Cancer Center/University of Washington. Data were obtained on patient demographics, diagnoses, Panel Reactive Antibodies (PRA %) and factors shown to be associated with poor platelet responses (spleen size, disseminated intravascular coagulation (DIC), bleeding, selected medications, history of hematopoietic stem cell transplant (HSCT) and/or graft versus host disease (GVHD), ABO compatibility, and product age). Platelet corrected count increments (CCI) were calculated for each transfusion. Non-HLA factors potentially contributing to CCIs at 0-2 and 18-24 hours post-transfusion were compared among HLA-compatible (either 4/4 HLA matched without HLA antigen mismatches, or with permissive mismatches (defined as cumulative a mean fluorescent intensity (MFI) &amp;lt;10,000 on the Luminex donor specific HLA antibody testing platform)) and HLA incompatible transfusions (cumulative MFI &amp;gt;10,000 or random donor apheresis products). Results: Of the 420 patients screened, 75 had sufficient records for inclusion. These subjects received 2729 platelet transfusions, an average of 36 transfusions per patient over 5.2 (± 4.1) months. Post transfusion platelet counts were available for 1528 transfusions. All platelet products were leukoreduced, irradiated, single donor apheresis products. Patients were predominantly Caucasian (70.7%; n=53/75), female (82.7%; n=62/75), aged 57 (±14.9) years. The primary diagnosis was Acute myelogenous leukemia or myeloproliferative disorder in most cases (88%; n=66/75). 58.7% (n=44/75) of patients were HSCT recipients (3 auto-; 41 allo-HSCT). Average PRA among patients was 72.4%±22.2%. 25 patients had splenomegaly. Among HLA-compatible transfusions, average CCIs at 0-2 and 18-24 hours were 17,088 and 6,666. In HLA-mismatched/random donor transfusions, average CCIs at 0-2 and 18-24 hours were 11,489 and 2,786; HLA compatible products increased CCIs by 5,599 and 3880 at 0-2 and 18-24 hours. In both groups splenomegaly had the most consistent association with poor CCI at both time intervals (Figures A and B). Conclusions: In this cohort of individuals with HLA-alloimmunization mediated PTR, the administration of HLA-compatible products offset the impact of other detrimental factors generating adequate CCIs at 0-2 and 18-24 hours. Among patients with splenomegaly, CCIs were lower despite HLA compatible product administration. In the same individuals, HLA-incompatible/random donor products negatively impacted CCIs overall and the negative effect of other concomitant non-immune/product-related factors was additive.Our data highlights the need to account for non-HLA related conditions while evaluating CCI response following each HLA-selected product transfusion, and to further explore any interactions among such factors. Next steps include conducting a multivariate analysis and developing a predictive model for platelet transfusion response in HLA-alloimmunized recipients who have concomitant non-immune or product related risk factors.