Achieved Transfusion Independence Research Articles

Clinical outcomes and healthcare resource utilization (HCRU) in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) reinitiating erythropoiesis-stimulating agents (ESAs) following previous ESA treatment.

e19067 Background: The median survival for pts with LR-MDS is estimated to be 5–10 years. ESAs are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and HCRU for pts with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Methods: This was a retrospective study of pts with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Pts were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of pts who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 pts with confirmed LR-MDS who initiated ESA-based therapy. Pts had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 pts who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of pts were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most pts (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Conclusions: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these pts, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for pts with LR-MDS.

Results of a phase 1 trial of azacitidine with venetoclax in relapsed/refractory higher-risk myelodysplastic syndrome (MDS).

e19068 Background: The prognosis of patients with higher-risk (HR) MDS after hypomethylating agent (HMA) failure is poor with a survival of 4-6 months (Garcia-Manero et al, Lancet Oncology 2016). The combination of azacitidine (Aza) with venetoclax (Ven) in frontline HR MDS is very active (Garcia JS et al, ASH 2021). Methods: This is a phase 1 study evaluating patients ≥ 18 years old after HMA failure with adequate organ function and performance status were enrolled. HMA failure was defined as relapse or progression after ≥ 4 cycles of HMA. Patients with prior Ven exposure were excluded. All patients received Aza 75mg/m2 IV/SC on D1-5. A 3+3 Ven dose escalation was utilized; patients at dose level 0 (DL0), 1 (DL1), and 2 (DL2) received 100 mg, 200 mg, and 400 mg respectively on D1-14. The IWG2006 criteria was utilized to assess response. Results: To date, 12 patients have been enrolled (3 in DL0, 3 in DL1, and 6 in DL2) with a median age of 78 years (range: 67-82). The median bone marrow blasts at enrollment was 9% (range: 6 – 17%) with a median ANC, Hgb, and PLT of 1.15 K/µL, 7.5 mg/dL, and 33 K/µL respectively. When stratified based on cytogenetics, 6 (50%) patients had intermediate risk, 2 (17%) had poor risk, and 4 (33%) had very poor risk cytogenetic alterations. When stratified based on IPSS-R criteria, 2 (16%) had intermediate, 5 (42%) had high, and 5 (42%) had very high risk disease. ASXL1 (50%) and TP53 (42%) mutations were most the common mutations on next generation sequencing. The most frequently observed grade 3-4 adverse events(AE) were cytopenias, occurring in all patients. Four (33%) patients had grade 3-4 cytopenias, either thrombocytopenia or neutropenia, that were attributed to the drug combination, with 3 patients consequently requiring dose reductions. At the time of data cut-off, response was seen in 8 patients with an overall response rate of 75%. The median number of cycles to response was 1 (range: 1-4). One patient achieved a CR. Seven patients achieved a marrow response with 2 having neutrophil recovery and 2 with platelet recovery. Three patients achieved transfusion independence. One patient underwent allogeneic stem cell transplantation after receiving 7 cycles. Four patients had no response with 3 of those having TP53 mutations. With a median follow-up of 13.6 months, the mOS is 8.5 months with a 30-day and 60-day mortality of 8% and 17% respectively. Early mortality was related to infection in 1 patient and disease progression in the other. Conclusions: This phase 1 study in patients with relapsed/refractory HR MDS suggests potential benefit with the addition of Ven to HMA with a 75% overall response and a mOS of 8.5 months. TP53 mutations and complex karyotypes still confer poor prognosis despite the addition of Venetoclax. Overall, this combination was well-tolerated with treatment-related AEs primarily consisting of thrombocytopenia and neutropenia. The study continues to accrue. Clinical trial information: NCT04550442.

Safety and Efficacy of Thalidomide and Hydroxyurea Combination in Beta Thalassemia Patients.

Beta thalassemia results from imbalance in alpha and beta globin chains causing severe anemia, transfusion dependency, and iron overload. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Patients without the option of HSCT may benefit from Hemoglobin F (HbF) inducing agents like thalidomide and hydroxyurea (HU). We conducted a retrospective analysis on 87 beta thalassemia patients who received a combination of low dose thalidomide and HU from January 2017 to December 2020. Patients received combination of HU 500mg everyday (> 30kg) or every alternate day (< 30kg) and thalidomide 100mg (> 30kg) or 50mg (< 30kg) once daily. Parameters such as transfusion requirement, anthropometry, Hb levels, ferritin, drug side effects etc. were monitored and evaluated at the end of one year of therapy. Sixty-three patients (72%) achieved transfusion independence and were eligible for the study. Median time to transfusion independence was 6months (range 3-11months). At the end of 1year, overall response rate was 72%. There was significant improvement in the Hb levels, ferritin values and height at the end of 1year of follow up. No grade 3 or 4 toxicities were noted. We document improvement of Hb levels, transfusion independence, reduction in iron overload, and improvement in growth parameters with minimal side effects at the end of 1year of follow up.

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria

BackgroundAzacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria. MethodsWe retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FindingsThe overall response rate at cycle 4–6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype. InterpretationIn our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.

New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents

Several novel myelodysplastic syndromes (MDS) treatment drugs are being developed, and luspatercept and oral hypomethylating medicines have already been licensed in the United States and other countries. Luspatercept is a ligand trap that inhibits SMAD2/3 signals by combining the extracellular domain of the activin type IIA receptor with the human immunoglobulin G1 Fc domain. In the phase 2 study for low-risk MDS, the hematological improvement-erythroid (HI-E) was found in 63% of patients, and in the phase 3 study for transfusion-dependent low-risk MDS with ring sideroblasts, 38% of patients achieved transfusion independence. A combination of oral decitabine with oral cedazuridine, an inhibitor of cytidine deaminase, which metabolizes decitabine, demonstrated pharmacological equivalence with intravenous decitabine and has overall response rates of 60% and 43% for high-risk MDS in phase 2 and 3 trials, respectively. Furthermore, oral azacitidine and its combination with oral cedazuridine have been under development.

Improvement in Health-Related Quality of Life Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent β-Thalassemia Enrolled in Phase 3 Studies

Improvement in Health-Related Quality of Life Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent β-Thalassemia Enrolled in Phase 3 Studies

Final Results of a Phase 2 Study of Sotatercept (ACE-011) for Anemia of MPN-Associated Myelofibrosis

Final Results of a Phase 2 Study of Sotatercept (ACE-011) for Anemia of MPN-Associated Myelofibrosis

Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine: A Phase 1 / 2 Study in Patients with Myelodysplastic Syndrome (ASPEN-02)

Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine: A Phase 1 / 2 Study in Patients with Myelodysplastic Syndrome (ASPEN-02)

Real World Use of Narsoplimab in a Case of Severe HSCT-TMA

Introduction: Hematopoietic stem cell transplantation (HSCT) offers a curative approach for hematologic malignancies. However, endothelial injury from HSCT activates the lectin pathway of complement, resulting in complications such as thrombotic microangiopathy (TMA). HSCT-TMA causes significant mortality. Incidence is reported up to 39%, although lack of consensus on diagnostic criteria results in under-recognition. Risk factors for HSCT-TMA include calcineurin inhibitors (CNI), conditioning, and infection. There is currently no approved treatment for HSCT-TMA.Narsoplimab is a monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway. We report a patient with late-onset HSCT-TMA who was successfully treated with narsoplimab via a compassionate use program.Methods and Results: A 60-year-old woman with de novo acute myeloid leukemia t (9;11) (p22; q23) who achieved first complete remission (CR1) with minimal residual disease positivity confirmed by flow cytometry (0.04%) underwent matched related allogeneic HSCT from her sister. Patient was cytomegalovirus (CMV) seropositive and blood group O, whereas donor was CMV seronegative and blood group B. Patient received induction with 7+3 and HiDAC consolidation, achieving CR1. Conditioning regimen was Bu4Flu with graft versus host disease (GVHD) prophylaxis of mini methotrexate and tacrolimus.Letermovir was used for CMV reactivation prophylaxis until Day +100. Post-transplant maintenance therapy with azacitidine 36 mg/m 2 was administered by four 5-day cycles (de Lima Cancer 2010). Patient achieved completed donor myeloid CD33 chimerism at Day +30, but donor lymphoid CD3 chimerism was not complete until Day +239. Tacrolimus was discontinued at Day +180. Patient initially had red cell aplasia but achieved transfusion independence by 6 months post-transplant.Circa achieving complete donor CD3 chimerism, patient developed extensive skin and gastrointestinal-overlap GVHD requiring admission for high-dose steroid therapy and resumption of tacrolimus. Onset of GVHD precluded stopping CNI. Patient became steroid refractory and ruxolitinib was added for immunosuppression with resolution of symptoms.Four weeks later, patient developed CMV reactivation and started induction therapy with valganciclovir, during which time she became red cell-transfusion dependent. Patient required 3 weeks induction and 10 days maintenance to clear CMV viremia.Subsequently, she reported dark red urine with evidence for hemoglobinuria without viruria, bilateral leg edema unresponsive to diuretic therapy, and rising serum lactate dehydrogenase (LDH). Evaluation revealed negative direct antiglobulin test, schistocytes on peripheral blood smear (~5/hpf), elevated sC5b-9 levels of 334 ng/mL (72-244 ng/mL), and elevated random urine protein of 124 mg/dL indicative of end organ damage. LDH was modestly elevated 302 IU/L (84-246 IU/L) and haptoglobin was elevated. Based on clinical symptoms and lab results, she was diagnosed with late-onset HSCT-TMA on Day +282 (9 months) using published diagnostic criteria proposed by Cho (2010) and Jodele (2014).The patient's clinical symptoms worsened with severe leg edema - which impeded her ability to walk - and red cell and platelet transfusion dependency. With no approved therapies, compassionate use of narsoplimab was requested for this clinical course of HSCT-TMA. Treatment commenced on Day +309.Patient received a total of 21 doses of narsoplimab 370 mg administered twice weekly on an outpatient basis. All infusions were well tolerated. No adverse events were noted with narsoplimab. Peripheral counts, LDH, anemia, thrombocytopenia and sC5b-9 normalized with reduction in proteinuria, reflecting resolution of HSCT-TMA by dose 19 (10 weeks of treatment); two additional doses were administered (Figure 1). Narsoplimab was given concomitantly with tacrolimus. Patient became transfusion independent and leg edema resolved.Conclusions: This report presents a real-world case study of HSCT-TMA treated with narsoplimab via compassionate use. HSCT-TMA resolved after 10 weeks of treatment, as evidenced by peripheral counts, normalization of LDH and sC5b-9, reduction in urinary protein reflecting improvement in renal function, and improvement in clinical symptoms. Narsoplimab was effective in this complicated case despite several risk factors for poor outcomes. [Display omitted] DisclosuresPantin: Omeros Corporation: Honoraria. Billy: Omeros Corporation: Current Employment. OffLabel Disclosure:Off-label use of azacitidine for post-transplant maintenance therapy

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

Evaluation of the Long-Term Safety and Efficacy of Pegcetacoplan Treatment for Paroxysmal Nocturnal Hemoglobinuria Patients: An Extension Study

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening disease characterized by complement mediated hemolysis and thrombosis. Current C5-inhibitors, such as eculizumab and ravulizumab, are able to partially treat these symptoms by controlling intravascular but not extravascular hemolysis, manifesting as persistent anemia in up to 72% of treated patients and transfusion dependence in up to 36% of patients.Pegcetacoplan (PEG) is a Food and Drug Administration (FDA)-approved C3-inhibitor that controls both intravascular and extravascular hemolysis (IVH and EVH). In the PEGASUS phase 3, multi- center, active-comparator controlled, randomized trial (NCT03500549), improvements in hemoglobin levels from baseline to Week 16 demonstrated the superiority of PEG over eculizumab; 85% of the patients receiving PEG achieved transfusion independence when compared with the 15% of patients on eculizumab. The extension study will evaluate the long-term safety and efficacy of PEG in patients with PNH.Acute hemolytic (AH) events occurred during the PEG clinical development program. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with PEGAims: Determine the long-term safety and efficacy of PEG for PNH treatment, as well as evaluate a treatment regimen to address acute hemolytic (AH) events in these patients.Study Design: The PEG extension study (NCT03531255) is an active, multi-center, open-label, non-randomized trial with an estimated enrollment of up to160 adult PNH patients (≥18 years), who have completed prior PEG trials - phase 1b PADDOCK (NCT02588833) and PHAROAH (NCT02264639), phase 2a PALOMINO (NCT03593200), and the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) trials. The main study will determine long-term safety and efficacy of PEG dosing on complement-mediated hemolytic activity, hemoglobin levels, and transfusion independence in PNH patients. For enrolled subjects experiencing AH episodes, a substudy to evaluate safety and efficacy of intensive SC or IV dosing of PEG acute treatments will be offered. Dose adjustments will be offered for AH subjects declining to enter the substudy, but continuing to participate in the main study.Inclusion criteria for the management of AH substudy specify that lactate dehydrogenase (LDH) levels in patients must be >2 times the upper limit of normal, accompanied by new or worsening clinical signs of hemolysis (hemoglobinuria, fatigue, decreased hemoglobin, etc.). Notable exclusion criteria include subjects who have withdrawn from a previous PEG trial, co-morbidities and infections that can enhance risk profiles for adverse events or confound study interpretation, and complement deficiency.The safety population consisting of patients that will receive at least one dose of the drug will be used for all efficacy analyses. Descriptive statistics will be used in documenting changes from baseline, along with qualitative descriptors (improved, maintained, or worsened).Intervention: Patients in the long-term extension study receive subcutaneous (SC) administration of 1080 mg PEG twice weekly, every 3 days, or 3 times weekly. For AH events substudy, patients with steady-state PEG dose of 1080 mg SC twice weekly will receive a loading dose of 1080 mg IV once, or 1080 mg SC every 24 hours for 3 doses, followed by increase in maintenance dose to 1080 mg SC every 3 days; for those receiving 1080 mg SC every 3 days, identical loading dose will be followed by subsequent maintenance dose of 1080 mg SC 3 times weekly.Primary and Secondary Outcome Measures: The study will monitor safety outcomes such as occurrence and severity of adverse events within a 2-year timeframe from baseline. Additional biomarkers include recurrent acute hemolysis, thromboembolism, laboratory and electrocardiogram (ECG) parameters. Efficacy endpoint measurements over a 48-week timeframe include mean change from baseline levels of hemoglobin, LDH, and indirect bilirubin, absolute reticulocyte counts, RBC transfusions, and functional assessment of fatigue scale scores.Results: Trial results are anticipated in 2022, upon study completion. DisclosuresHoffman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Machaidze: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weitz: Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Novartis Corporation: Consultancy, Honoraria; Sanofi Genxyme: Consultancy, Honoraria. OffLabel Disclosure:Pegcetacoplan is a Food and Drug Administration approved C3-inhibitor that controls both intravascular and extravascular hemolysis. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with pegcetacoplan.

Patient and Physician Preferences for Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) in Patients Not Candidates for Intensive Chemotherapy

BackgroundThe number of targeted antileukemic therapies for the treatment of AML has increased over the past decade. However, for patients who are not candidates for high intensive chemotherapy (HIC), a better understanding is needed of what treatment attributes patients and physicians value and how their preferences differ to potentially improve treatment satisfaction.ObjectiveTo understand the impact of treatment attributes on treatment selection, we quantified the preferences of: a) patients newly diagnosed with AML who are not candidates for HIC; and, b) the physicians who treat them.MethodsA discrete choice experiment (DCE) was performed to quantify the extent to which treatment attributes impact patients' and physicians' treatment decisions in various scenarios. A literature review was conducted to identify treatment attributes important to patients with AML. Following the review, one-on-one phone interviews were conducted with patients (United States [US], n=3; United Kingdom [UK], n=3) and physicians (US, n=2; UK, n=2) to finalize the attributes and levels included in the DCE. Patients who were eligible to participate in the online survey were adults with a self-confirmed AML diagnosis, who had not relapsed or been refractory to treatment, had not received a stem cell transplant, and had not received HIC or met one of the following criteria: aged ≥75 years, diagnosis of congestive heart failure, chronic kidney disease, or other types of cancer, or ECOG score of 3 or 4. Physicians included hematologists/ oncologists treating >5 patients with AML over the past year. The web-based DCE included choice cards showing 2 hypothetical treatment profiles with 6 attributes (chance of 2-year overall survival [OS], average quality of life [QoL], risk of serious infections, risk of grade 3/4 nausea, chance of achieving transfusion independence, and duration of hospitalization per year) at varying levels. Participants chose a preferred treatment for each choice card. Conditional logit regression models were used to estimate preference weights and to analyze the impact of treatment attributes on participants' choices.ResultsThe DCE was completed by 77 patients newly diagnosed with AML who had not received HIC (US, n=47; UK, n=30) and 145 physicians (US, n=48; UK, n=52; Canada, n=29; Australia, n=16). Mean patient age was 71.4 years; 51.9% were female. Mean (SD) time since AML diagnosis was 8.3 (8.2) months. Most physicians were hematologists (81.4%) and saw a median of 30 AML patients yearly. For patients, duration of hospitalization (decrease from 6 to 2 weeks/year) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point QoL scale) and chance of 2-year OS (increase from 15% to 40%; Figure). Based on these findings, we estimated that patients were willing to accept a decrease in 2-year OS (from 40% to 15%) or an increase in risk of serious infections (from 5% to 20%) to decrease time spent hospitalized (from 6 to 2 weeks per year). For physicians, chance of 2-year OS (from 15% to 40%) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point scale), risk of serious infections (from 20% to 5%), and risk of grade 3/4 nausea and vomiting (from 20% to 1%; Figure). Based on these findings, we estimated that physicians were willing to accept an increased risk of grade 3/4 nausea and vomiting (from 10% to 20%) in exchange for decreased time in hospital (from 6 to 2 weeks per year) and increased chance of achieving transfusion independence (from 35% to 55%) when other treatment attributes remained stable.ConclusionSignificant differences in treatment attribute importance for patients with newly diagnosed AML who had not received HIC were observed between patients and physicians. Patients most valued treatments that reduced hospitalization duration while physicians most valued treatments that improved chance of 2-year OS. These differences highlight the importance of a shared decision-making process when choosing treatments for patients with AML ineligible for HIC. However, given the variability among individual patients, it may be particularly worthwhile for physicians to initiate a discussion with patients prior to treatment selection to determine what treatment attributes each patient values most. Treatment selection could then be tailored based on attributes most valued by the patient and likely lead to improved treatment satisfaction. [Display omitted] DisclosuresZhou: Astellas Pharma, Inc.: Consultancy. Yang: Astellas Pharma, Inc.: Consultancy. Song: Astellas Pharma, Inc.: Consultancy. Marshall: Astellas Pharma, Inc.: Consultancy; Arthur JE Child Chair: Other: Indirectly related salary support. Griffin: Novartis: Patents & Royalties: Post marketing royalties from midostaurin; Astellas Pharma, Inc.: Consultancy. Saini: Astellas Pharma, Inc.: Consultancy, Honoraria. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect.

MPN-328: Pelabresib (CPI-0610) Improved Anemia Associated with Myelofibrosis: Interim Results from the Ongoing MANIFEST Phase 2 Study

Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. Many patients (pts) with MF treated with ruxolitinib (rux) develop worsening anemia and may become RBC transfusion-dependent (TD). Objective: Evaluation of pelabresib monotherapy or as add-on to rux in advanced MF pts. Design: In Arm 1, pts refractory, intolerant, or ineligible for JAKi were treated with pelabresib monotherapy. In Arm 2, pts receiving rux but not deriving adequate benefit were treated with add-on pelabresib. The primary endpoint was achievement of transfusion independence (TI) ≥12 wks in TD cohorts and ≥35% spleen volume reduction at wk 24 in non-TD cohorts. Results: As of 29 Sept. 2020, 19 TD pts and 27 non-TD pts were treated in Arm 1. Seventy-six percent of pts had baseline Hgb Conclusions: Pelabresib monotherapy was associated with a mean increase in Hgb ≥1.5 g/dL in majority of non-TD pts and conversion of one-fifth of TD pts to TI in Arm 1. Pelabresib add-on to rux in Arm 2 resulted in mean increase in Hgb ≥1.5 g/dL in 17% of non-TD pts and conversion to TI in more than one-third of TD pts.

The European Medicines Agency Review of Luspatercept for the Treatment of Adult Patients With Transfusion-dependent Anemia Caused by Low-risk Myelodysplastic Syndromes With Ring Sideroblasts or Beta-thalassemia.

Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta superfamily, resulting in erythroid maturation and differentiation. On June 25, 2020, a marketing authorization valid through the European Union (EU) was issued for luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, or those with transfusion-dependent beta thalassemia (BT). Luspatercept was evaluated in 2 separate phase 3, double-blind, placebo-controlled multicentre trials. The primary endpoints of these trials were the percentage of patients achieving transfusion independence over ≥8 weeks or longer for patients with MDS, and the percentage of patients achieving a ≥33% reduction in transfusion burden from baseline to week 13–24 for patients with BT. In the MDS trial, the percentage of responders was 37.91% versus 13.16%, P < 0.0001, for patients receiving luspatercept versus placebo, respectively. In the BT trial, the percentage of responders was 21.4% versus 4.5% (P < 0.0001) for luspatercept versus placebo, respectively. Treatment with luspatercept led to similar incidences of adverse events (AEs), but higher incidences of grade ≥3 AEs and serious AEs compared to placebo. The most frequently reported treatment-emergent AEs (≥15%) in the pooled luspatercept group were headache; back pain, bone pain, and arthralgia; diarrhea; fatigue; pyrexia; and cough. The aim of this article is to summarize the scientific review of the application, which led to the regulatory approval in the EU.

Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25–300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6–5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11–6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10456-021-09807-4.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Short Course of Bortezomib in Anemic Patients with Refractory or Relapsed Cold Agglutinin Disease. a Phase II Prospective Study By the Gimema Group

Background: Cold agglutinin disease (CAD) is a chronic hemolytic disorder caused by the presence of an IgM autoantibody with specificity towards red cell antigens. The autoantibody is produced by a B-cell clone, which can often be detectable with standard diagnostic work-up. Some patients with CAD require transfusions to compensate for the chronic red cell destruction. There are few therapeutic modalities of proven efficacy which include alkylating agents, rituximab alone or in combination with fludarabine or bendamustine. Bortezomib is a proteasome inhibitor which has been successfully used in Ig-producing diseases, like amyloidosis and Waldenstrom macroglobulinemia (WM). Protein metabolism is a tightly regulated process, and inhibition of its turnover using proteasome inhibitors may lead to apoptosis in protein secreting B-cell malignancies, including multiple myeloma (MM) and WM. Aim: We have conducted a prospective multicenter, phase II, open label study (ClinicalTrials.gov NCT01696474) to evaluate the potential efficacy of a short course of bortezomib in anemic patients with CAD requiring transfusion or with a hemoglobin concentration below 100 g/L determined at least monthly during the two months before entering the trial. Patients and Methods: Patients had to be refractory to at least one previous treatment. The primary endpoint was the achievement of transfusion independence or a significant rise (>20 g/L) of hemoglobin concentration. A single course of bortezomib was given at the dose of 1,3 mg/sqm iv on days 1, 4, 8, 11. Safety evaluation, duration of transfusion independence, and the effects of treatment on the underlying clonal B-cell disorder were secondary objectives of the trial. Patients with a concomitant lymphoproliferative disorder requiring specific treatment for reasons other than CAD or with preexisting peripheral neuropathy were excluded. Results: Between 12-04-2012 and 03-14-2016, 21 patients have been enrolled by 6 Gimema italian centers. Their characteristics were as follows: median age 70 years (range 53 to 85); M/F ratio: 1/2; 6 patients had concomitant or previous clonal B-cell disorder (3 CLL, 3 B-cell lymphoma) not requiring specific therapy. Previous treatments included corticosteroids, rituximab, cyclophosphamide, azathioprine or combinations of them. Median Hb concentration at study entry was 87 g/dL (range 78-102). Ten patients were transfusion-dependent. Treatment response was evaluated at three months. Two patients stopped treatment early, one at day 4 because of pulmonary embolism and the other at day 8 because of headache, respectively, and were excluded from efficacy analysis. One of them actually achieved transfusion independence in spite of treatment stop. Of 19 evaluable patients, 3 achieved complete remission, defined as normalization of hemoglobin levels and absence of symptoms or signs of hemolysis and 3 partial remission, defined as the achievement of transfusion independence or of a stable increase of > 20g/L of hemoglobin concentration in untransfused patients, for an overall response rate of 31,6%. Four of the 6 responding patients achieved transfusion independence. The small number of patients studied precluded an analysis of factors associated with response. Five grade 3 adverse events, including headache, diarrhea, increased bilirubin levels, anemia and upper respiratory tract infection (URTI) in one patient each, and one grade 4 pulmonary embolism. They were considered not related to study drug, except for URTI. Four of 6 responding patients maintained the response after 12 months from study entry (66,7%; 95% CI: 37.9-100). All patients were alive at last follow up except for one who died of septic shock during off treatment follow up, 10 months after study entry. The effects of bortezomib on underlying B-cell lymphoproliferative disorder are being evaluated. Conclusions: The data demonstrate that a short course of bortezomib may be effective in a subset of patients with symptomatic CAD failing previous treatments, with acceptable toxicity. Responses seem to be long-lasting in the majority of responding patients. These data provide a rational for further investigating the potential benefits of bortezomib either by using a more prolonged treatment schedule or in combination with other active agents. The study has been supported by JANSSEN-CILAG Spa which provided bortezomib and a grant for study monitoring. DisclosuresRossi:Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Zaja:Celgene: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria, Research Funding; Janssem: Honoraria; Abbvie: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria. Mauro:Janssen: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Gilead: Honoraria. Barcellini:Alexion: Honoraria; Agios: Honoraria, Research Funding; Novartis: Honoraria.

Response Rates, Non-Relapse Mortality, and Financial Implications of Transplant-Associated Thrombotic Microangiopathy Treated with Eculizumab

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality (NRM). Recently, complement activation has been associated with TA-TMA leading to utilization of complement blockade in TMA. Eculizumab is a humanized monoclonal antibody that binds to C5 and prevents the formation of the membrane attack complex (C5b-9) or the terminal complement pathway. Eculizumab may be an effective treatment for pediatric TA-TMA patients; however, there are limited data regarding its use in adult TA-TMA patients. Furthermore, eculizumab is an expensive medication and there are no published data regarding the financial implications of TA-TMA treated with eculizumab. The purpose of this study was to examine the response rates, NRM, and financial implications of TA-TMA treated with eculizumab.Methods: We performed a retrospective cohort study of patients with TA-TMA who received eculizumab at our institution between January 1, 2012, and April 9, 2017. TA-TMA was defined according to the BMT-CTN criteria with evidence of hemolysis, elevated LDH, renal dysfunction and negative Coombs' test. Serum complement biomarkers (C5b-9) were used to support the diagnosis when platelet or red blood cell transfusion dependence occurred with organ dysfunction or tissue evidence of microangiopathy. Patients were vaccinated against Neisseria meningitides and received appropriate antibiotic prophylaxis. Eculizumab therapy was initiated at the Food and Drug Administration-approved dosing schedule for aHUS: 900 mg intravenously weekly for the first 4 weeks followed by 1200 mg intravenously every other week beginning on week 5 for a total of 8 weeks, with some patients requiring longer than an 8 week course. The primary outcome was complete response to eculizumab therapy and responders were defined by achievement of transfusion independence and improvement in creatinine. Secondary outcomes included non-relapse mortality (NRM), inpatient cost, number of comorbidities, number of infections, number of hospitalizations, and hospital length of stay (LOS). Comorbidities were defined as any documented medical problem other than the reason for transplant and TA-TMA.Results: Twenty patients were included in the study (Table 1). The median (range) time from transplant to diagnosis of TA-TMA was 139 (14-388) days. The median (range) time from diagnosis of TA-TMA to first dose of eculizumab was 2 (0-272) days. The complete response rate was 55%. The median (range) number of doses of eculizumab was 6.5 (2-17) for responders compared to 3 (1-7) for non-responders including both inpatient and outpatient doses (p= 0.01). There were no significant differences between the number of hospitalizations for responders and non-responders. However, responders had shorter LOS and lower inpatient costs than non-responders. The median (range) LOS was 9 days (0-92) for responders compared to 61 days (26-94) for non-responders (p= 0.03). The median (range) total inpatient cost was $259,734 (0-1,670,070) for responders compared to $1,525,758 (385,092-1,948,190) for non-responders (p= 0.003). The itemized inpatient costs are shown in Figure 1. Patients who responded to eculizumab tended to be younger with less comorbidities. In fact, patients were 33% less likely to respond to eculizumab for every additional documented comorbidity at the time of TA-TMA diagnosis (HR=0.67 [95% CI 0.49-0.92]). The NRM was 1/11 (9%) for responders and 9/9 (100%) for non-responders (HR=0.07 [95% CI: 0.007-0.66]).Conclusions: TA-TMA is an important complication of HCT that is associated with high NRM and financial toxicity. Our data suggests that patients who respond to eculizumab have lower NRM, LOS, and financial costs than non-responders. There was a statistically non-significant trend in incidence of steroid-refractory GVHD in the non-responder group; additionally non-responders received significantly fewer doses than responders, which may explain partly the lower response rates compared to the 80% response rates in aHUS. Patient age and the number of comorbidities at the time of diagnosis of TA-TMA may be important predictive factors for response to eculizumab. [Display omitted] DisclosuresMims:Novartis: Honoraria. Hofmeister:Janssen: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

PNH-Phenotype Cells and HLA Class I Allele-Lacking Leukocytes Shared By Family Members Who Developed Acquire Aplastic Anemia: Studies on Six Pairs of Patients in Different Families

[Background] Aplastic anemia (AA) is a syndrome characterized by pancytopenia and bone marrow hypoplasia caused by various factors. When AA occurs in family members, congenital AA is usually suspected. However, some anecdotal reports have described the occurrence of AA in family members who did not show any signs or laboratory findings compatible with congenital AA and instead represented an acquired feature, such as a good response to immunosuppressive therapy. Studying such familial AA without evident congenital features may help to clarify the genetic or environmental factors that are closely associated with susceptibility to AA. [Objectives/Methods] To characterize non-congenital AA that occurred in family members, we reviewed the clinical records of about 3000 AA patients who were referred to our clinic for the examination of glycosylphosphatidylinositol-anchored protein-deficient (PNH-type) blood cells from 1999 to 2017 and found 6 pairs of AA patients in 6 different families (Table). Three pairs were parents and children, and the other three pairs were siblings. None of the families had malformations or family histories except for the affected pairs. All patients' samples were subjected to high-sensitivity flow cytometry for detecting PNH-type cells and HLA genotyping. Two pairs of patients (Cases 7 and 8, and Cases 9 and 10) who were diagnosed after 2015 were also examined for the presence of HLA class I-lacking leukocytes using monoclonal antibodies specific to class I HLA alleles, and for the presence of myeloid malignancy-related gene abnormalities using a next-generation sequencer. [Results] PNH-type granulocytes were detected in 9 of 12 cases at frequencies of 0.016% to 30.381%. Five pairs shared HLA-DRB1*15:01, which is known to be associated with PNH, while three pairs shared HLA-B*40:02, an HLA class I allele most frequently lost as a result of 6pLOH or allelic mutations. HLA-A allele-lacking leukocytes were detected in one of the two pairs studied (Figure). Unexpectedly, the lacked HLA alleles in the pair (Cases 7 and 8) were not B*40:02but A*02:06. No somatic mutations were found in 61 myeloid malignancy-related genes of the granulocytes from the 2 cases. All of 12 patients responded to immunosuppressive therapy (IST, 6 with cyclosporine alone and 4 with ALG/ATG+/-cyclosporine) and achieved transfusion independence. [Conclusions] The high prevalence of markers for immune pathophysiology, including PNH-type cells and HLA allele-lacking cells, the high frequency of DRB*15:01 and B*40:02, and a good response to IST in the 6 family pairs suggests that non-congenital familial AA is a typical type of immune-mediated bone marrow failure affected by the genetic background. The lack of the same HLA class I allele (A*02:06) in the mother (Case 7) and her daughter (Case 8) in their granulocytes suggests the involvement of a common environmental factor that induces the generation of cytotoxic T lymphocytes specific to common antigens presented by the HLA-A allele. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.