Achieved Transfusion Independence Research Articles

Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.

An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis. In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes. We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths. In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

Modified lentiviral globin gene therapy for pediatric β0/β0 transfusion-dependent β-thalassemia: A single-center, single-arm pilot trial.

β0/β0 thalassemia is the most severe type of transfusion-dependent β-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a β-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in β0/β0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22months. The treatment extended the lifespan of red blood cells by over 42days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all β-thalassemia.

Luspatercept for the treatment of congenital sideroblastic anemia: Two case reports

Congenital sideroblastic anemia (CSA) is a group of disorders caused by different genetic mutations that result in low iron utilization and ineffective erythropoiesis. Current treatments are limited, and some patients do not respond to vitamin B6 therapy. Luspatercept is a novel erythropoietic maturation agent approved for adult β-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

Clinical Safety and Efficacy of Narsoplimab in Pediatric and Adult Patients with Transplant-Associated Thrombotic Microangiopathy: A Real-World Experience

Introduction Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication occurring after hematopoietic stem cell transplantation (HSCT), often resulting in high morbidity and mortality. There are currently no approved treatments for TA-TMA, but complement inhibition is increasingly recognized as an active treatment option in this setting. Narsoplimab (OMS721) is a fully human IgG4 antibody that binds MASP-2, the effector enzyme of the lectin pathway of the complement system. A recent pivotal trial demonstrated the safety and efficacy of narsoplimab in patients with TA-TMA. We report the results of a real-world experience with narsoplimab in a series of pediatric and adult patients with TA-TMA. Material and methods The diagnosis of TA-TMA was based on the following criteria (Schoettler ML, et al. Transplant Cell Ther. 2023 Mar;29(3):151-163): anemia (failure to achieve transfusion independence, hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence); thrombocytopenia (failure to achieve platelet engraftment, transfusion dependence, or ≥50% reduction in baseline platelet count after full platelet engraftment); elevated lactate dehydrogenase (LDH); decreased serum haptoglobin; schistocytes in the peripheral blood smear; hypertension; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]). A positive direct Coombs test was an exclusion criterion. Narsoplimab was administered intravenously at the dose of 4 mg/kg (max 370 mg) twice weekly for at least eight doses. Response criteria were defined by improvement in both laboratory TMA markers and any clinical benefit (Khaled SK, et al. J Clin Oncol. 2022 Aug;1;40(22):2447-2457). Results Fifteen patients with a median age of 61 years (range, 6 - 71), 11 adults and 4 pediatrics, were treated under a compassionate use program, after ethical committee approval, between January 2018 and April 2023. All patients had previously undergone allogeneic HSCT (Table 1). All patients presented at least 4 of the 6 criteria for TA-TMA diagnosis. Fourteen patients (93%) were defined as high-risk TA-TMA for the presence of the following criteria: LDH > 2 times the ULN, rUPCR ≥ 1 mg/mg, multiorgan dysfunction, concurrent acute GvHD ≥ grade 2, or infection. Time from transplant to TA-TMA was 161 days (range, 30 - 452). Before TA-TMA, all patients had acute GvHD with a median of 116 days (range, 21 - 405) after transplant. Severe infection had been documented in 10 patients (67%) after transplant. CMV reactivation and BK virus hemorrhagic cystitis occurred in 5 and 4 patients, respectively. Twelve patients (80%) were on calcineurin inhibitors at TA-TMA onset. Fourteen patients (93%) were transfusion dependent at baseline. Patients received a median of 11 (range, 8-34) doses of narsoplimab. All infusions were well-tolerated, and no narsoplimab-related adverse events were reported. Eleven patients responded to treatment (73%), based on the achievement of transfusion independence (10 patients) as well as on clinical and laboratory improvement, which occurred in all responders. Before and after narsoplimab, the median hemoglobin values were 9,1 g/dL (range, 7,7 - 12,3) and 10,35 g/dL (range, 9,2 - 12,4); the median platelet count was 25.000/mmc (range, 10.000 - 62.000) and 76.000/mmc (range 32.000 - 367.000); the median LDH values were 497 U/L (range 271 - 1201) and 224 U/L (range 184 - 393), respectively. The median time to response was 50 days (range, 9 - 105). One-hundred-day survival was 80% in the study population and 100% for responders (Figure 1). After treatment completion, TA-TMA never reoccurred. Three of the four patients who failed to respond, eventually died with laboratory and clinical evidence of persisting TA-TMA. Conclusion In this study of high-risk TA-TMA patients, the inhibition of the lectin pathway of complement activation with narsoplimab was shown to be not only an effective but also a remarkably safe treatment option with no evidence of an increased risk of infectious complications in both children and adults.

Durable Transfusion Independence in Lower-Risk Myelodysplastic Syndrome (LR-MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database

CONCLUSIONS Red blood cell (RBC) transfusions are commonly used to treat patients with LR-MDS and anemia. RBC transfusion dependence (TD) is an impairment on patients' quality of life and associated with worsened survival (Lemos et al. Sci Rep. 2021). The few approved therapeutic options for LR-MDS have limited efficacy and durability. In this study, the baseline RBC-TD before first-line (1L) and second-line (2L) of therapy, durability of transfusion independence (TI), and associated survival among patients with LR-MDS treated with current standard-of-care therapies were assessed in a large US health insurance claims database. Optum Clinformatics ®, a large single-payer database of administrative health claims for members of large commercial and Medicare Advantage health plans, includes approximately 17-19 million annual covered lives, for a total of >76 million unique lives over a 9-year period. Patients with LR-MDS were identified through 5 relevant International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes (D46.0, D46.1, D46.9, D46.A, and D46.B) between Oct 2015 and Jun 2022 and were required to have no MDS/acute myeloid leukemia (AML) diagnosis and no use of higher-risk MDS or AML medication before their respective index diagnosis dates. As revised International Prognostic Scoring System or other risk score classification information was not available in the database, ICD-10 diagnosis codes were used as a proxy for the identification of LR-MDS; these codes have been used previously in published studies (Zeidan et al. Leuk Lymphoma. 2019). Lines of treatment were determined based on claims for MDS treatments contained in the database: erythropoietin stimulating agents (ESAs; darbepoetin, epoetin alfa), hypomethylating agents (HMAs; azacitidine, decitabine, decitabine-cedazuridine), lenalidomide, luspatercept, eltrombopag, and cyclosporine. Outcomes of interest included transfusion burden (RBC units [U] in 8 weeks), proportion of patients who were transfusion independent before and after different lines of treatment, time to 8- and 16-week continuous TI, Kaplan-Meier analysis of real-world progression-free survival (starting a next line of treatment, progression to higher-risk MDS or AML, and death were considered events), and overall survival. The analysis included 5662 patients with LR-MDS (median age, 79 years; 57% male; 76% non-Hispanic White, primarily covered by Medicare Advantage) who received ≥1 line of treatment. Overall, 66% and 17% of patients received frontline monotherapy with ESAs and HMAs, respectively. In the 16 weeks before 1L treatment initiation, 35% of patients received ≥1 RBC transfusion. During 1L treatment, 45% of patients received ≥1 RBC transfusion, of whom 49% received >3 U and 24% received >6 U during any 8-week period. 2L treatment consisted of ESA monotherapy (40%), HMA monotherapy (21%), luspatercept (9%), or a combination thereof (19%). In the 16 weeks before 2L treatment initiation, 49% of patients received ≥1 RBC transfusion, and 55% received transfusions during 2L treatment (Table). Among patients receiving ≥1 transfusion during 2L treatment, 61% and 31% had >3 and >6 U/8 weeks, respectively. Transfusion burden was greater for patients with ring sideroblast-positive disease and increased with subsequent lines of therapy. Among 612 patients who received ≥1 transfusion in the 16-week period before 2L, 33% achieved 16-week TI with subsequent therapies. Median real-world progression-free survival from start of 2L was 20.0 months in patients who achieved 16-week TI and 4.1 months in patients who did not ( P < .0001). The median overall survival from start of 2L was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming RBC-TI vs nonresponders, respectively ( P < .0001; Figure). Among patients with LR-MDS, 35% and 49% were RBC-TD before 1L and 2L of therapy, respectively. Achievement of TI was associated with improved survival, suggesting that RBC-TD is a modifiable predictor of clinical outcomes in LR-MDS. Despite the currently available therapies, RBC-TD after any line of therapy is associated with poorer outcomes. Our study results show that novel therapies that provide durable TI are expected to yield decreased progression and improved survival.

Retrospective Analysis of the Relationship between Transfusion Independence and Bone Marrow Fibrosis Reduction in Patients with Myelofibrosis Treated with Pacritinib Versus Ruxolitinib

Background Pacritinib is a JAK1-sparing JAK2/IRAK1/ACVR1 inhibitor for treatment of myelofibrosis (MF). In addition to improving spleen volume and symptoms, pacritinib is associated with anemia benefit in MF patients. Recent in vivo studies have shown that dual JAK2/IRAK1 inhibition is associated with improvement in both cytopenias and bone marrow reticulin fibrosis (BMF) in an inflammation-driven murine MF model ( Cuenca Zamora E, et al. EHA 2023; P987 and P990). Here, we retrospectively analyzed the relationship between achieving transfusion independence and reduction in BMF in MF patients treated with pacritinib 200 mg twice daily (BID) vs ruxolitinib (RUX) on the phase 3 PERSIST-2 study. Methods: PERSIST-2 enrolled patients with platelet counts ≤100 x 10 9/L. This analysis focused on pacritinib 200 mg BID and on patients who received RUX as best available therapy (BAT) who enrolled ≥12 weeks prior to study termination and who required red blood cell (RBC) transfusions at baseline. The proportion of patients who achieved transfusion independence response (TI-R, any 12-week interval with no RBC transfusions) was ascertained for pacritinib vs RUX. The proportion of patients with BMF reduction (≥1 grade decrease in reticulin fibrosis from baseline at week 24) was reported among patients on pacritinib achieving TI-R vs. non-response (NR). Results: The analysis included 41 patients on pacritinib (median dose intensity 100% through week 24) and 18 on RUX (median daily dose 10mg at week 24). Baseline characteristics were similar between the groups, including median platelet count (41 vs 38 x 10 9/L) and median hemoglobin (8.7 vs 8.6 g/dL). All patients required RBC transfusion at baseline. A significantly greater proportion of patients treated with pacritinib vs RUX achieved TI through week 24: 37% (n=15/41) vs 6% (n=1/18), P=0.023. Nominally, this trend held for those with baseline platelets <50 x 10 9/L: 28% vs 8%, P=0.222. In addition, a greater percentage achieved a 50% reduction in RBC transfusions over any 12 weeks (49% vs 6%, P=0.001). Paired bone marrow assessments at baseline and week 24 were available for 18/41 of patients on pacritinib, of whom 44% (8/18) achieved TI-R on study. The proportion of patients who experienced BMF reduction (>=1 grade at any point) was significantly greater among TI-R (62.5%, n=5/8) compared to TI-NR (10%, n=1/10) on pacritinib ( P=0.043). Of the 5 patients who achieved TI-R and BMF reduction, all had grade 2-3 fibrosis at baseline, and 2 experienced a reduction from grade 3 to grade 1 ( Figure 1). By contrast, paired bone marrow biopsies were available for 5 patients on RUX, and there was no association between fibrosis reduction in TI-R (0%, n=0/1) and TI-NR (25%, n=1/4). Conclusions: In cytopenic MF patients from PERSIST-2, TI-R on pacritinib was associated with BMF improvement. Though these results are based on a small sample size, they contrast with recent data suggesting no correlation between BMF reduction and TI-R on the JAK1/2 inhibitors momelotinib and ruxolitinib ( Oh ST, et al. Blood 2022;140 (Supp 1):821-23). While differences in study design could have impacted these results, these findings suggest that distinct inhibitory profiles may further distinguish the clinical impact of these treatments. Further studies are warranted to confirm the relationship between BMF reduction and anemia benefit in patients treated with pacritinib. Study funded by CTI BioPharma Corp., a Sobi company

ASXL1 Mutation and Leukocytosis Undermine Spleen Response to Pacritinib in Myelofibrosis

Background: Non-transplant treatment options in myelofibrosis (MF) are palliative in scope and include JAK2 inhibitors (JAKi): ruxolitinib, fedratinib, pacritinib, and momelotinib. All four JAKi are effective in reducing spleen size and alleviating symptoms. In addition, pacritinib and momelotinib exhibit erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type-I. In the current study, we sought to identify molecular or clinical predictors of response to pacritinib in MF patients treated outside of clinical trials. Methods: The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from patient records (Mayo Clinic, Rochester, MN; Scottsdale, AZ; and Jacksonville, FL). Anemia response assignment was restricted to patients with baseline hemoglobin level of <10 g/dL and required, for transfusion dependent cases, achieving transfusion independence and, for transfusion-independent cases, an increase in hemoglobin of ≥1.5 g/dL, both sustained for a minimum 2 months; spleen response was clinically vetted but was also supported by radiologic imaging when available and required a ≥50% decrease in palpable splenomegaly for spleen size >10 cm or the spleen becoming not palpable for a spleen size 5-10 cm at base line. Symptom response was adjudicated by central review and required a marked or moderate improvement to qualify as response; because of the retrospective nature of the study, symptom burden assessment by formal criteria was not attempted. Leukocyte cutoff level used for response analysis was determined by receiver operating characteristic curve analysis. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA). Results: We identified 36 NGS-annotated patients with MF who received pacritinib therapy between April,2022 and June,2023 (median age 66 years; 56% males). Twenty-five (69%) patients had failed previous JAKi therapy while 11 (31%) were JAKi-naïve. Eighteen (50%) patients were transfusion-dependent while the median (range) counts were 106 x 10(9)/L (14-578) for platelets, 6.6 x 10(9)/L (1.2-112.8) for leukocytes, and 9 x 10(9)/L (5-12.4) for hemoglobin; leukocyte count was ≥15 x 10(9)/L in 11 (31%) patients and hemoglobin <10 g/dL in 29 (81%). Karyotype was unfavorable in 12 (34%) patients. Driver mutation distribution was JAK2 55%, CALR 27%, MPL 11%, and triple-negative 5%. NGS revealed mutations involving ASXL1 36%, U2AF1 13%, IDH1 13%, SF3B1 13%, K/NRAS 5%, SRSF2 8%, and EZH2 5%. Pacritinib was started at 200 mg BID in 9 (25%) patients and at lower doses in the remaining. Median duration of pacritinib therapy was 4 months (range 1-15). Anemia response was documented in 5 (17%) of the 29 patients with baseline hemoglobin <10 g/dL, spleen response in 12 of 28 evaluable (42%) and symptom response in 18 (50%). Improvement in symptoms was always accompanied by both anemia (p=0.008) and spleen (p=0.01) response; by contrast, there was no significant correlation between anemia and spleen responses (p=0.9) (Table 1). Significant correlations with molecular or clinical variables were mostly apparent for spleen response, which was more likely to occur in the absence of ASXL1 mutation (61% vs 10%; p=0.006), with leukocyte count <15 x 10 (9)/L (55% vs 0%; p=0.005), and in JAKi-naïve vs previously-exposed cases (75% vs 30%; p=0.03; Table 1); significance was sustained by all three risk factors during multivariable analysis; the prognostic impact of ASXL1 (p=0.02 vs 0.01) and leukocytosis (p=0.01 vs 0.07) was apparent in both JAKi-naïve vs JAKi-exposed cases. Anemia response was non-significantly (p=0.27) higher in transfusion-independent (27%) vs dependent (11%) cases, at baseline, and was more likely (p=0.04) to occur in patients starting at lower dose levels. Treatment-emergent adverse events included diarrhea 44%, nausea/vomiting 19%, and grade-3/4 thrombocytopenia 38% or neutropenia (11%). Conclusions: ASXL1 mutation and leukocytosis (>15 x 10 9/L) are independently associated with inferior spleen response to pacritinib, in both JAKi-naïve and JAKi-exposed myelofibrosis. These observations are important for individualized treatment selection.

Longitudinal Safety of Luspatercept in the Treatment of Anemia in Patients with Myelofibrosis: Results from the ACE-536-MF-001 Study

Introduction Luspatercept (LUSPA) is approved for the treatment of anemia in some adults with β-thalassemia or myelodysplastic syndrome who require red blood cell transfusion and has a well characterized safety profile for these indications. The primary readout from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated manageable safety and promising efficacy of LUSPA for treatment of myelofibrosis (MF)-related anemia with 19.0%-31.6% of patients (pts) achieving transfusion independence (defined as 84 consecutive days transfusion free), and 18.2%-21.4% of non-transfusion-dependent (NTD) pts achieving anemia response (defined as 84 consecutive days ≥ 1.5 g/dL hemoglobin increase from baseline without transfusion) in the entire treatment period (Gerds ASCO 2023 7016). To characterize further the safety profile of LUSPA in MF and provide data on adverse event (AE) management, we present a detailed longitudinal safety analysis of the MF-001 study. Methods Pts were enrolled into 4 cohorts based on transfusion dependence (TD) and stable ruxolitinib (RUX) treatment - cohort 1: NTD, no RUX; cohort 2: TD, no RUX; cohort 3A: NTD, RUX; cohort 3B: TD, RUX. All pts received LUSPA 1.0 mg/kg subcutaneously with titration up to 1.75 mg/kg in 21-day cycles; the starting dose was 1.33 mg/kg in the cohort 3B expansion group. Response was assessed at day 169 (24 weeks), with treatment extended for pts showing clinical benefit. The primary endpoint was anemia response; AEs alongside LUSPA and RUX dosing were also assessed. On dosing days, seated blood pressure was assessed prior to LUSPA administration. In the case of ≥ grade 3 hypertension (systolic ≥ 160 mmHg, diastolic ≥ 100 mmHg), dosing was delayed until hypertension had resolved to ≤ grade 1 or baseline, followed by dose reduction by 1 dose level. If ≥ 2 dose reductions were implemented due to any suspected treatment-related AE (TRAE), LUSPA was discontinued. Results In the safety population (N = 95; cohort 1, n = 22; cohort 2, n = 14; cohort 3A, n = 21; cohort 3B, n = 38), the most frequently used prior medications for anemia treatment were erythropoiesis-stimulating agents (23.2%, most frequently epoetin alfa [14.7%]), followed by danazol (11.6%), lenalidomide (2.1%), and thalidomide (1.1%). Prior history of hypertension was recorded in 50.5% of pts. Median follow-up duration was 546 days. A total of 47.4% of pts had ≥ 1 TRAE; the most common were hypertension (17.9%), bone pain (7.4%), and diarrhea (6.3%). Incidence of treatment-related grade ≥ 3 diarrhea was low (2.1%). Overall, 13.7% of pts received concomitant antidiarrheals. LUSPA was discontinued in 9 pts due to AEs; 1 event of cerebral toxoplasmosis was considered treatment related by the investigator. Among pts receiving RUX (cohorts 3A/3B), hypertension was the most frequently occurring grade ≥ 3 TRAE ( Table 1) and 5 pts had LUSPA dose modifications related to hypertension events; considered related to LUSPA in 4 pts ( Table 2). In contrast, among pts not receiving RUX (cohorts 1/2), no pts experienced grade ≥ 3 hypertension events. Hypertension was manageable with clinical intervention; during the study the most frequent concomitant medications for hypertension were angiotensin-converting enzyme inhibitors (26.3%), beta-blocking agents (selective, 23.2%; non-selective, 3.2%), and angiotensin II receptor blockers (alone, 20.0%; plus diuretics, 5.3%). Among NTD pts (cohort 3A), there were no changes in RUX dose. Among TD pts (cohort 3B), 25 (65.8%) pts maintained their RUX dose and 6 (15.8%) pts had ≥ 1 dose increase. Overall, 9 deaths occurred during treatment; none were considered treatment related. Causes of death were pneumonia, septic shock, intracranial hemorrhage, ischemic stroke, organ dysfunction, post-procedural hemorrhage, myelofibrosis, renal failure, and pneumonitis (n = 1 each). Conclusions The safety profile of LUSPA in the ACE-536-MF-001 study was consistent with previous studies in other indications, and AEs were mostly low grade. In addition to benefits in anemia, the safety profile of LUSPA allowed most pts receiving RUX to maintain or increase their RUX dose, supporting maintenance of Janus kinase inhibitor therapy for adequate disease control of MF. Study support: Bristol Myers Squibb.

Time without Transfusion Reliance or Anemia Worsening: A Novel Method for Integrating Transfusion Dependence, Anemia, and Survival with Myelofibrosis Therapies Based on the Phase 3 Simplify-1 and Simplify-2 Trials

Introduction: While approved Janus kinase inhibitors (JAKi) have improved overall survival (OS) in myelofibrosis (MF), traditional survival analyses do not consider individual patient (pt) experience, which may be negatively impacted by factors such as persistent symptoms, adverse events (AEs), and red blood cell (RBC) transfusion dependence. In particular, RBC transfusions, an important component of anemia management in MF with currently approved JAKi, are associated with negative quality of life (QOL), increased healthcare resource utilization, and poor prognosis. Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated consistent anemia benefits, including increased transfusion independence and reduced transfusion burden, as well as spleen and symptom improvements across 3 phase 3 trials in MF. In the SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials, achieving transfusion independence with MMB was associated with prolonged OS (Mesa R, et al. Leukemia. 2022). Here we apply time without transfusion reliance (TWiTR) analyses, integrating transfusion-dependent (TD) status and OS, to further characterize the benefits of MMB on survival quality. Methods: Analyses were performed in the safety populations, by treatment arm, over the randomized 24-wk treatment period of SIMPLIFY-1 (n/N=430/432; MMB vs ruxolitinib [RUX], JAKi naive) and SIMPLIFY-2 (N=156; MMB vs best available therapy [BAT; 88.5% RUX], JAKi experienced). TWiTR (Zeidner JF, et al. Haematologica. 2023) was based on the established time without symptoms and toxicity (TWiST) analysis, replacing toxicity with TD status. The analysis partitioned survival duration into 3 health states: (1) TD, defined as the number of days on which pts were TD (defined per protocol in the SIMPLIFY studies as requiring ≥4 units of RBC transfusions or having a hemoglobin level <8 g/dL in the previous 8 weeks) before experiencing a leukemia-free survival (LFS) event (leukemic transformation or death); (2) Post-LFS, defined as the number of days from an LFS event to death or censoring (OS; Post-LFS = OS − LFS); and (3) TWiTR, defined as the number of days without Post-LFS or TD (TWiTR = LFS − TD). An additional analysis incorporated the number of days on which pts had any-grade anemia events in the TD state (TD-Anemia [TD-An]) to define time without transfusion reliance or anemia worsening (TWiTR-An). Health state durations were estimated via Kaplan-Meier curves of the survival distribution function, with mean duration in each state calculated as the area under the curve. Results: In SIMPLIFY-1, pts in the MMB arm spent less time in the TD state and more time in the TWiTR state vs pts in the RUX arm (Figure 1). Mean duration in the TD state was 28.3 vs 62.7 days (difference with MMB, −34.4 days), while mean duration in the TWiTR state was 163.4 vs 131.1 days with MMB vs RUX (difference with MMB, 32.3 days). Fewer pts in the MMB arm had treatment-emergent anemia AEs, and incorporation of anemia events into the analysis increased the mean time spent in the TD-An state compared with the TD state in both treatment arms, although this increase was smaller in the MMB arm, at 32.0 vs 74.8 days in the RUX arm (difference with MMB, −42.8 days). Mean duration in the TWiTR-An state was 159.7 vs 119.0 days with MMB vs RUX (difference with MMB, 40.7 days). Similar results were observed in SIMPLIFY-2, although incorporating anemia events had less impact. Mean duration in the TD state was slightly shorter with MMB vs BAT, at 69.4 vs 89.9 days (difference with MMB, −20.5 days); mean duration in the TD-An state was 69.6 vs 89.9 days (difference with MMB, −20.3 days). Consistently, mean duration in the TWiTR state was slightly longer with MMB vs BAT, at 118.3 vs 95.9 days (difference with MMB, 22.4 days); mean duration in the TWiTR-An state was 118.0 vs 95.9 days (difference with MMB, 22.1 days). Conclusions: Pts treated with MMB spent less time reliant on RBC transfusions and more time free from transfusions and anemia events, without the cost of increased AEs, compared with those treated with RUX or BAT. Given the negative QOL and prognostic impact of RBC transfusion dependence, these analyses suggest that the anemia benefits of MMB lead to improved quality of survival for pts with MF.

Effective and Safe Molecular-Pharmacodynamic Once Weekly Dosing of Decitabine and Venetoclax Is a Highly Effective and Well-Tolerated Induction Therapy for AML: Interim Results of a Phase 2 Trial

Background: Hypomethylating agents (HMAs) (5-azacytidine or decitabine) combined with venetoclax (Ven) have become the new standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, myelosuppression and infectious complications are common adverse events of currently approved HMA/Ven regimens, requiring dose interruptions/delays that often undermine treatment goals. Previous studies have identified the minimum dose of decitabine needed to deplete DNA methyltransferase-1 (DNMT1) without causing cytotoxicity. Administration of a single venetoclax dose synergizes with low dose weekly decitabine by inhibiting de-novo pyrimidine synthesis - a major mechanism of resistance to HMAs. A recently reported retrospective experience has shown proof of concept for a regimen of once weekly low dose decitabine combined with a single weekly dose of venetoclax in MDS and AML. Here, we report the feasibility portion of an ongoing Phase II clinical trial evaluating tolerability and efficacy of a metronomic dosing of decitabine and venetoclax for treatment of older patients with AML. Aims: The primary endpoint of this study is percentage of patients who are able to continue on treatment during the 12-week induction period without dose interruptions or delays. The key secondary endpoints include best overall response, rate of Grade >3 adverse events, infections, and hospitalizations. Correlative studies evaluate DNMT1 depletion in bone marrow at the time of diagnosis and at week 12. Methods: This is a single arm open-label Phase II clinical trial (NCT05184842). Patients >18 years old with a diagnosis of AML, MDS, CMML, MDS/MPN, and MDS/AML not fit for intensive chemotherapy are eligible. Subcutaneous decitabine and oral venetoclax are administered on the same day, once a week at 0.2mg/kg and 400mg, respectively. A bone marrow exam and measurable residual disease (MRD) assessment by multiparametric flow cytometry (MFC) are performed following 12-week induction period. Results: Between June 2022 and April 2023, twenty patients on this study have completed the 12-week induction period, these included AML (n=14), MDS (n=2), MF (n=1), MDS/MPN (n=1), CMML (n=2). Median age was 75 and 50% of patients were minorities (Table 1). Seventeen patients (85%) were able to complete all 12 weeks of induction treatment without dosing interruptions or delays and only one patient (5%) had a dose interruption post-induction. There were no Grade > 3 non-heme therapy-related adverse events. Eight patients (40%) required hospitalization during the induction period and no patient required hospitalization post-induction. Of the 14 AML patients who have completed the 12-week induction period, the median age was 75 years old (63-87). At the end of induction, the ORR was 71% with 8 patients (57%) achieving a CR, 1 CRI and 1 PR; 5/8 CRs were MRD negative by MFC. At a median followup of 10.9 months, 7/14 (50%) responses are ongoing and 11/14 patients (79%) remain alive. Of the six patients with TP53 mutations, four achieved MRD-negative CR with transfusion independence and two with no response (one post-MPN AML and other with erythroid leukemia). During the induction period, four patients (29%) had progression of disease (POD). The primary refractory cases included one patient with post-MPN AML, one patient with FLT3-ITD and two patients with monocytic-M5 AML with RAS mutations. One of two patients with MDS, had an MRD negative CR and achieved transfusion independence while the other transformed to erythroid leukemia. Of the two patients with CMML, one had a CR with transfusion independence, and one with stable disease. The 30 and 60-day mortality was zero. Studies evaluating DNMT1 staining on bone marrow samples from patients treated on this study are ongoing. Summary/Conclusion: In this preliminary analysis we demonstrate safety and efficacy of weekly, low-dose, metronomic dosing of decitabine and venetoclax, by allowing frequent sustained drug exposure often not possible with standard HMA/Ven regimens. The minimal cytotoxic nature of this regimen allowed for blood count recovery without drug interruptions with a high rate of clinical responses. (Figure 1). Additional cohorts are being enrolled in an expansion phase of the study in order to more fully assess the efficacy of this regimen in subsets of AML and MDS patients, including patients with p53 mutations.

Clinical Parameters, Anemia, and Spleen Response in Patients with MF-Related Anemia Treated with Luspatercept: Efficacy Sub-Analysis from the ACE-536-MF-001 Study

Introduction: Approximately 24% of patients with myelofibrosis (MF) have anemia requiring red blood cell (RBC) transfusion at initial diagnosis. For patients with MF, chronic anemia and RBC transfusion dependence (TD) often increase throughout the disease course and are an indicator of poor prognosis. Luspatercept (LUSPA) is an erythroid maturation agent approved to treat anemia in adults with β-thalassemia and myelodysplastic syndrome requiring RBC transfusions. Primary results from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated reductions in MF-related anemia and transfusion dependence (Gerds et al. ASCO 2023 7016). Here we provide an extended analysis of the impact of LUSPA on clinical parameters and transfusion burden over time, and associated management of MF disease symptoms. Methods: Patients were enrolled into cohorts based on TD and ruxolitinib (RUX) treatment. Patients received LUSPA 1.0 mg/kg subcutaneously (with titration up to 1.75 mg/kg), administered on day 1 of each 21-day cycle (starting dose was 1.33 mg/kg for cohort 3B expansion). Patients were defined as TD if receiving an average of 4-12 RBC units/84 days immediately up to cycle 1 day 1 (C1D1). For non-transfusion dependent (NTD) patients, anemia was defined as 3 or more hemoglobin (Hgb) level measurements of ≤ 9.5 g/dL recorded on at least 3 different days in the 84-day period immediately preceding C1D1. The primary endpoint was anemia response, assessed at day 169 (week 24) and defined as 84 consecutive days without RBC transfusion for TD patients, and 84 consecutive days with Hgb increase of ≥ 1.5 g/dL from baseline without transfusion for NTD patients. Treatment was extended if clinical benefit was observed at day 169. Secondary and exploratory endpoints included anemia response for the entire treatment period, transfusion burden, and clinical and laboratory parameters. Results: A total of 95 patients were enrolled: cohort 1 (NTD, no RUX, n = 22), cohort 2 (TD, no RUX, n = 21), cohort 3A (NTD, RUX, n = 14), and cohort 3B (TD, RUX, n = 38). A total of 63 (66.3%) patients continued to the follow-up period. The mean (SD)/median (range) duration of treatment was 42.8 (47.6)/24.0 (2.0-232.0) weeks and mean/median (range) follow-up duration after first dose was 101.1/78.0 (2.1-232.1) weeks. Anemia response was seen across all cohorts. Among transfusion-dependent patients (cohorts 2 and 3B), transfusion independence ≥ 12 weeks was observed in 4 (19.0%, 95% CI 5.45-41.91) and 12 (31.6%, 95% CI 17.5-48.7) patients, respectively, in the entire treatment period. Additionally, approximately half of patients with TD achieved a 50% reduction in transfusion burden; 10 (47.6%) patients in cohort 2 and 20 (52.6%) patients in cohort 3B had ≥ 50% reduction in transfusion burden over any 84-day period in the entire treatment period, including 16 patients from cohorts 2 and 3B who achieved transfusion independence (100% reduction) (Figure). Changes in laboratory parameters of Hgb, serum erythropoietin, serum ferritin, and platelet count at day 169 are summarized in the Table; in addition, patients with clinical benefit continuing LUSPA treatment after day 169 showed ferritin decreases with longer follow-up from cycle 13 (n = 20) to cycle 33 (n = 6). Additionally, there was minimal (~1 cm) to no increase in median spleen size across patients in all cohorts. Of the 3 patients in cohort 3B who increased their RUX dose during LUSPA treatment, spleen size remained stable, with a -4.0 cm, 1.0 cm, and 3.0 cm change from baseline during the entire treatment period, respectively. Conclusions: In the phase 2 ACE-536-MF-001 study, LUSPA demonstrated improvements in anemia and transfusion burden in patients with MF. Further analysis of clinical and laboratory parameters may reveal differences between responders and non-responders. Spleen size stability was observed in all patients; this suggests that LUSPA does not worsen splenomegaly and may support continual use of RUX for MF disease and symptoms. Study support: Bristol Myers Squibb.

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia

Background: Transfusion-dependent β-thalassemia (TDT), an inherited hematological disorder which requires life-long, chronic red blood cell transfusion (RBC) and regular iron chelation therapy, has a substantial negative impact on health-related qualify of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, non-viral, ex vivo CRISPR-Cas9 gene-edited cell therapy in phase 3 clinical trials that has been shown to eliminate the need for RBC transfusions and achieve transfusion independence. Here, we report HRQoL data from a pre-specified interim analysis of the exa-cel CLIMB TDT-111 study. Methods: CLIMB TDT-111 is an ongoing, 24-mo, phase 3 trial of a single dose of exa-cel in patients aged 12-35 years with TDT and a history of ≥100 mL/kg/year or ≥10 U/year of packed RBC transfusions for 2 years prior to screening. Changes in patient-reported outcome (PRO) measures including EuroQol Quality of Life Scale 5 dimensions 5 levels of severity (EQ-5D-5L, including descriptive system and visual analog scale [VAS]) and Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, including FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]) for adults and the EuroQol Quality of Life Scale 5 dimensions youth (EQ-5D-Y) and Pediatric Quality of Life Inventory (PedsQL) for adolescents were assessed through month 24 as a secondary endpoint in the trial. Data are presented as of 16 January 2023 for the 24 adults (aged ≥18-35 years) and 11 adolescents (aged ≥12 to < 18 years) who had been followed for ≥16 months after exa-cel infusion. Results: Clinically meaningful improvements, exceeding the minimal clinically important difference (MCID) thresholds, were observed in all PRO measures in adults. Baseline mean EQ-5D-5L health utility US index score (n=24, mean [SD]: 0.85 [0.18]) was near the general population norm and in line with baseline scores previously reported for adult patients with TDT. By month 24, both EQ-5D-5L health utility US index scores and EQ VAS scores showed substantial improvement (mean [SD] changes at month 24 [n=15]: 0.12 [0.26] and 10.2 [20.9] points; MCIDs 0.078 and 7 to 10, respectively). FACT-G Total Score improved from baseline by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 10.3 [17.0] points; MCID 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, and functional well-being). BMTS score improved by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 6.8 [4.7] points; MCID 2 to 3). For adolescents, EQ VAS scores improved through month 18 (mean [SD] change from baseline 4.8 [6.1] points). Total PedsQL score improved by month 6 and was sustained through month 18 (mean [SD] change from baseline [n=7] 14.1 [9.2] points; MCID 4.36). Physical functioning and psychosocial health scores, sub-components of PedsQL, both showed sustained improvement through month 18 (mean [SD] change [n=7] 19.2 [9.1] and 11.4 [10.9] points; MCID of 6.66 and 5.30 points, respectively). Improvement in psychosocial score was observed in all 3 subscales (social, emotional, and school functioning). Conclusion: Adults and adolescents infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family and functional well-being and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with TDT.

Inducible Knockout of Codanin-1: An Adult Mouse Model of Congenital Dyserythropoietic Anemia Type-I

Congenital dyserythropoietic anemias (CDAs) are a heterogenous group of congenital blood diseases, characterized by ineffective erythropoiesis, hemolysis, and the presence of bi- or multi-nucleated erythroblasts in the bone marrow (BM). Several CDA types exist, originally classified by bone marrow pathology and now more accurately by their causative mutations, when known. Mutations in codanin-1 ( Cdan1) are the major contributor (≈80%) to CDA type-I (CDA-I). Patients with CDA-I frequently require transfusions in utero to survive and present with varying degrees of hemolytic anemia with relative reticulocytopenia suggesting ineffective erythropoiesis, binucleated erythroblasts, and, under transmission electron microscopy (TEM), a “swiss cheese” appearance in the nuclear heterochromatin of erythroblasts. Treatment for patients with CDA-I includes blood transfusions and iron chelation, or IFN-α, which allows most treated patients to achieve transfusion independence. However, the molecular mechanisms of dyserythropoiesis in CDA-I as well as those of the therapeutic effect of IFN-α are unknown. To study the pathogenesis of the disease and the mechanisms of IFN-α action in vivo, we generated an adult mouse model of CDA-I. Previous efforts to produce a CDA-I mouse model were achieved via a constitutional, EpoR Cre+/--driven erythroid-specific deletion of Cdan1; however, this mouse suffered embryonic lethality by E12.5 [Noy-Lotan et al, Frontiers in Physiology, 2021]. We developed a transgenic mouse model in which the most common CDAN1 missense mutation (p.R1042W in humans corresponding to mouse p.R1047W) was introduced using CRISPR-Cas9 editing, and the mice were bred to homozygosity. These mice survived to term but exhibited no significant anemia, altered erythropoiesis, or the characteristic “swiss cheese” appearance in the heterochromatin of the erythroblasts under TEM. They demonstrated no differences from control mice in recovery after induction of stress erythropoiesis by phlebotomy (in agreement to the findings reported in parallel by Noy-Lotan et al, 2021), suggesting that this model is inadequate for studying the CDA-I phenotype. Therefore, we proceeded to generate an inducible Cdan1 knockout mouse model to test the hypothesis that deletion of Cdan1 in the erythroid lineage,mediated by Gata1 creERT2 [Yu et al. Blood. 2021], will recapitulate the CDA-I phenotype in adult mice. This maneuver avoids embryonal lethality during the extreme stress erythropoiesis phase of fetal development. We bred mice with the wildtype (WT) or floxed Cdan1 gene ( Cdan1WT/WT and Cdan1Fl/Fl, respectively) with mice carrying Gata1 creERT2. Cdan1WT/WT; Gata1creERT2+/- mice served as WT controls and Cdan1Fl/Fl; Gata1creERT2+/- mice served as the experimental mice with erythroid-specific Cdan1 deficiency after 10 injections of tamoxifen every other day to activate Cre expression. We evaluated the phenotype of these mice using complete blood counts (CBCs), light microscopy, TEM, and flow cytometry of erythroid progenitors and precursors. The Cdan1-deficient mice became anemic with reduction in RBC count, hemoglobin ( Fig. 1), and hematocrit. Light microscopy of the BM and spleen revealed erythroblasts joined by a thin-interchromatin bridge and binucleated erythroblasts in the Cdan1-deficientcompared to WT mice (z-test of proportions, P < 0.001), appearing at a frequency of ≈13% of all erythroblasts (see Fig. 2). TEM revealed a “swiss cheese” appearance in the heterochromatin of erythroblasts, the pathognomonic finding of CDA-I. Flow cytometry of the BM and spleen revealed decreased late-stage erythroblasts, demonstrating ineffective erythropoiesis. To determine a possible stage in which IFN-α may be directly acting on erythropoiesis, we examined the expression of IFNαR1 in erythroblasts. In all mice, basophilic, polychromatic, and orthochromatic erythroblasts had relatively low expression of IFNαR1. Interestingly, proerythroblasts had relatively high expression of IFNαR1 but only in the spleen. These data provide a starting point for localizing the effect of IFNα in the CDA-I phenotype. In conclusion, erythroid-specific deletion of Cdan1 via Gata1 creERT2 in adult mice recapitulates the CDA-I phenotype and provides a viable mouse model to investigate the disease mechanism and the therapeutic effect of IFN-α on CDA-I.

Patient and Physician Preferences for Acute Myeloid Leukemia Maintenance Treatments Following Hematopoietic Stem Cell Transplantation.

This study assessed and compared preferences for treatment attributes of maintenance therapies post-hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and in physicians who treat these patients. Patients with AML post HSCT and physicians from the United States, United Kingdom, Canada, and Australia (physicians only) completed a web-based discrete choice experiment (DCE). The DCE used inputs identified via a targeted literature review and qualitative interviews to ascertain relevant treatment attributes and associated levels. Six treatment attributes were selected (chance of 2-year relapse-free survival, quality of life [QoL], risk of serious infections, risk of nausea, chance of achieving transfusion independence, and duration of hospitalization annually), each with three or four levels. The experimental design included 36 choice tasks that presented a pair of hypothetical treatment profiles with varying attribute levels; participants chose a preferred treatment for each choice task. Choice tasks were divided into three blocks of 12 tasks each in the patient survey and 4 blocks of 9 tasks each in the physician survey; survey participants were randomly assigned to one of the blocks. Random parameter logit regression models were used to assess the impact of stated attributes on preferences for maintenance treatment post HSCT. Surveys from 84 patients and 149 physicians were assessed. For patients, QoL was the most important attribute, followed by duration of hospitalization and chance of 2-year relapse-free survival. For physicians, chance of 2-year relapse-free survival was the most important attribute, followed by QoL and risk of serious infections. Differences in how patients and physicians valued post-HSCT maintenance treatment attributes were identified. These differences suggest that patient-centered decision-making may help physicians choose maintenance treatments for patients with AML post HSCT that better meet their treatment needs and improve their treatment satisfaction.

Real world practices of luspatercept at an academic medical center.

Introduction: Luspatercept is approved for patients with very low-to intermediate-risk myelodysplastic syndrome (MDS). Dosing is based on pre-dose hemoglobin levels and transfusion requirements. This study aims to evaluate if a site with a pharmacist prospectively reviewing luspatercept doses achieves dose optimization, compared to a site that does not have a pharmacist prospectively reviewing doses. Methods: We performed a retrospective chart review involving patients age ≥18 years or older with MDS at a major academic medical center main campus, which does not have a pharmacist prospectively review luspatercept doses, and a satellite campus infusion center, which has a pharmacist prospectively reviewing doses. Patients included received at least one dose of luspatercept between January 1, 2017 through August 31, 2022. The primary endpoint is the percentage of off-label luspatercept doses not consistent with prescribing information (PI) recommended dose adjustments. Results: The study included 17 patients. Of the 162 doses evaluated, 37 (23%) were off-label. Off-label dosing at the main campus was more common than at a satellite location (29.6% vs. 2.4%; p < 0.003). More patients achieved transfusion independence at the satellite compared to the main campus (83.3% vs. 27.3% p < 0.39). Conclusions: There was a higher percentage of off-label dosing at a center without a pharmacist's prospective review vs. a center with a pharmacist's prospective review. On-label dose optimization may lead to a higher percentage of patients achieving transfusion independence. Enhancements in the current ordering and review process can be improved with the involvement of a pharmacist's prospective involvement at both centers.

A-150 Abo Subgroup Incompatibility Leading to Red Cell Engraftment Failure and Fatal Outcome: A Rare But Preventable Complication in Related Allogeneic HSCT

Abstract Background Pre-allogeneic hematopoietic stem cell transplant (HCST) testing includes, among others, ABO and HLA typing and testing for anti-HLA antibodies. ABO subgroup typing is not routinely performed, as A2 subgroup representes 1% of the total group A population and only 0.4% of A2 individuals have anti-A1 in their serum. ABO antigens are also found on the platelet surface. We describe a case of alloHSCT performed between siblings, the donor A1 and the recipient A2, with a fatal outcome caused by red cell and platelet engraftment failure due to anti-A1 antibodies, and emphasize the need to routinely investigate subgroup incompatibility in the pre-alloHSCT workup. Methods Patient data was collected from hospital and laboratory electronic records. Blood typing and immunohematological investigation was performed at the hospital blood bank using gel cards for ABO typing, DAT and antibody screening panels (Grifols, Barcelona). Tube method was used for A subgroup typing (Fresenius, Germany). Bone marrow analysis and other blood tests were performed at local hospital laboratory. HLA typing and antibody screening (Luminex, USA) were sent to a specialized laboratory. Results A 51 year-old male with Non-Hodgkin lymphoma underwent a full-match ABO compatible allogeneic HSCT, both brother/donor and recipient group A. Pre-transplant anti-HLA or ABO antibodies were negative. WBC recovery was achieved on D + 22. The patient had a catheter infection on D + 15 (Permcath removed), CMV infection on D + 24 (treated with gancyclovir) and received several blood transfusions. On D + 22, he had a hemolytic transfusion reaction with fever (38.5°C), chills and a decline in hemoglobin (7.3 g/dL to 6.6 g/dL in the following day), low haptoglobin and increased indirect bilirrubin levels. Immunohematological investigation revealed a positive DAT with an anti-A antibody in the eluate. Subgroup incompatibility was suspected and the patient was found to be subgroup A2, whereas the donor typed A1. Three days later the DAT became negative and anti-A1 was no longer detected. Other RBC antibodies were also excluded. Only group O RBCs and A / AB platelets were transfused thereafter to prevent further hemolysis. On D + 35 the patient was diagnosed with GI-GVHD, which responded to corticosteroids. He never achieved transfusion independence and received RBC and platelet transfusions on a regular basis. Failure of RBC and platelet engraftment was confirmed by a bone marrow aspirate on D + 45, showing only 20% erythroid lineage and absence of megakaryocytes. Marrow chimerism revealed 83% of donor origin. Sepsis by S. aureus ensued on D + 57 and three days later he had fever (38.2°C) and dyspnea after a platelet transfusion. Despite entubation and mechanical ventilation, he evolved to RCP and died on D + 60. Conclusion ABO subgroup typing is a simple and low-cost technique routinely available in the blood bank. Detection of A subgroup incompatibility impacts on key decisions, such as donor choice (if more than one candidate) and the need for erythrocyte depletion of donor stem cells and recipient plasmapheresis if the anti-A1 titer is high. Since graft failure due to ABO subgroup incompatibility can be hazardous, we recommend routinely ABO subgroup typing in the pre-alloHSCT workup to increase donor safety.

Lenalidomide treatment of Japanese patients with myelodysplastic syndromes with 5q deletion: a post-marketing surveillance study

Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.

Role of Luspatercept in the Management of Lower-Risk Myelodysplastic Syndromes.

Treatment options are limited for patients with anemia associated with lower-risk myelodysplastic syndromes (LR-MDS). The recent approval of luspatercept for the treatment of anemia associated with very low-to intermediate-risk MDS with ring sideroblasts (RS) or with myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis has provided adult patients and practitioners with a much-needed new therapeutic option. Luspatercept is a first-in-class erythroid maturation agent that exerts its effects on later stages of erythropoiesis. In the phase III MEDALIST trial of patients with LR-MDS with RS, luspatercept (starting dose 1 mg/kg) demonstrated substantial clinical benefit (38% of patients treated with luspatercept vs. 13% of those treated with placebo [p < .001] achieved transfusion independence for ≥ 8 weeks during the first 24 weeks of treatment) and a favorable safety profile. The most common adverse events (AEs), including fatigue, asthenia, dizziness, and diarrhea, were more frequent during the first 4 treatment cycles and subsequently declined. This review provides a comprehensive overview of luspatercept treatment administration, including the mechanism of action, efficacy and safety data, management of dosing, and AEs associated with luspatercept treatment of patients with LR-MDS.

Long Term Outcomes of 63 Patients with Transfusion-Dependent β-Thalassemia (TDT) Followed up to 7 Years Post-Treatment with betibeglogene autotemcel (beti-cel) Gene Therapy and Exploratory Analysis of Predictors of Successful Treatment Outcomes in Phase 3 Trials

Background: One-time treatment with beti-cel ex vivo gene therapy (GT) adds functional copies of a modified HBB gene, βA-T87Q, to autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) through transduction with BB305 lentiviral vector (LVV), thereby addressing the underlying genetic cause of Transfusion-Dependent β-Thalassemia (TDT). Here, we evaluate the long-term efficacy and safety profile of beti-cel across phase 1/2, phase 3, and long-term follow-up (LTF) studies. We also present an exploratory analysis of predictors of successful treatment outcomes in patients from phase 3 studies. Methods: Patients with TDT underwent HSPC collection followed by pharmacokinetic-adjusted myeloablative busulfan conditioning and beti-cel infusion. Patients were followed for 2 yrs in the parent phase 1/2 (HGB-204, NCT01745120; HGB-205, NCT02151526) and phase 3 (HGB-207, NCT02906202; HGB-212, NCT03207009) studies; enrollment and all beti-cel infusions have been completed. Patients then entered a 13-yr LTF study, LTF-303 (NCT02633943). Transfusion independence (TI) was defined as weighted average hemoglobin (Hb) ≥ 9 g/dL without packed red blood cell transfusions for ≥ 12 months. An exploratory multivariate analysis was also carried out in patients enrolled in the phase 3 trials to identify predictors of clinical outcomes. Results: As of August 2021, 63 patients had received beti-cel and were followed for a median of 41.4 (9.0-87.5) months across the 4 parent studies and LTF. The median time until neutrophil and platelet engraftment was 23 (13-39) and 45 (19-191) days, respectively, and lymphocyte subsets were generally within normal range after beti-cel infusion. Peripheral blood vector copy number (VCN), levels of GT-derived adult Hb (HbAT87Q), and total Hb were stable and durable across studies and higher in phase 3 vs phase 1/2 studies following optimized beti-cel drug product (DP) manufacturing. HbAT87Q levels were stabilized by Month 6 and contributed to stable levels of total Hb. Total unsupported Hb levels ≥ 9g/dL at Month 6 were significantly associated with achieving TI (p<0.0001) (March 2021 data cut). One-time beti-cel GT was followed by durable TI across ages and genotypes with up to 7 yrs follow-up. A trend towards more patients achieving TI was observed in phase 3 (34/38; 89.5%) (Fig 1A) vs phase 1/2 (15/22; 68.2%). All patients who achieved TI (N=49) continue to remain TI as of last follow-up. Patients who achieved TI had reductions in markers of ineffective erythropoiesis and iron overload. Overall, 21/37 patients who restarted chelation stopped chelation at 24 months; 25% (12/49) of patients who achieved TI utilized phlebotomy for iron removal, including 6 patients who also received iron chelation. Overall, 18% (11/63) of patients experienced ≥1 adverse event (AE) considered related or possibly related to beti-cel; the most common DP-related AEs were abdominal pain (5/63 [8%]) and thrombocytopenia (3/63 [5%]), but none were observed beyond 2 yrs post-infusion, supporting a favorable long-term safety profile. Veno-occlusive liver disease was reported in 11% (7/63) of patients and resolved after appropriate treatment. No malignancies, insertional oncogenesis, vector-derived replication competent lentivirus, or clonal predominance was observed. The safety of the beti-cel treatment regimen largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. An exploratory multivariate analysis in patients from phase 3 studies (n=37; March 2021 data cut) identified that the percentage of DP cells transduced with the BB305 LVV (%LVV+ cells) was the best predictor of clinical outcomes (Fig 1B). DP VCN and %LVV+ cells are current release assays for beti-cel. Summary: beti-cel is a potentially curative GT for patients with TDT across ages and genotypes through the achievement of TI and normal or near normal Hb levels. An exploratory multivariate analysis demonstrated that DP transduction efficiency was the most predictive attribute of TI, a key endpoint for clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal