Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Quantitative MRI reveals heterogeneous impacts of treatment on diseased bone marrow in a mouse model of myelofibrosis.

PURPOSE: Analyzing bone marrow in the hematologic cancer myelofibrosis requires endpoint histology in mouse models and bone marrow biopsies in patients. These methods hinder the ability to monitor therapy over time. Preclinical studies typically begin treatment before mice develop myelofibrosis, unlike patients who begin therapy only after onset of disease. Using clinically relevant, quantitative MRI metrics allowed us to evaluate treatment in mice with established myelofibrosis. METHODS: We used chemical shift-encoded fat imaging, DWI, and magnetization transfer sequences to quantify bone marrow fat, cellularity, and macromolecular components in a mouse model of myelofibrosis. We monitored spleen volume, the established imaging marker for treatment, with anatomic MRI. After confirming bone marrow disease by MRI, we randomized mice to treatment with an approved drug (ruxolitinib or fedratinib) or an investigational agent, navitoclax, for 33 days. We measured the effects of therapy over time with bone marrow and spleen MRI. RESULTS: All treatments produced heterogeneous responses with improvements in bone marrow evident in subsets of individual mice in all treatment groups. Reductions in spleen volume commonly occurred without corresponding improvement in bone marrow. MRI revealed patterns associated with effective and ineffective responses to treatment in bone marrow and identified regional variations in efficacy within a bone. CONCLUSIONS: Quantitative MRI revealed modest, heterogeneous improvements in bone marrow disease when treating mice with established myelofibrosis. These results emphasize the value of bone marrow MRI to assess treatment in preclinical models and the potential to advance clinical trials for patients.

Real-world outcomes with immunosuppressive therapy for aplastic anemia in patients treated at the University of Michigan.

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

Impact of Chemotherapy Educational Videos for Patients with Acute Myeloid Leukemia.

Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education presents an opportunity to supplement traditional patient education and address some of the gaps associated with standard methods. This single-center study sought to assess the potential impact of supplemental video education on patients receiving induction chemotherapy for AML. Participants were consented to be randomized to receive their education with or without a supplemental video designed for their treatment regimen. We then provided a survey to each participant to assess knowledge retention, anxiety, and overall satisfaction with their care. Patients that received video education were found to have significantly improved knowledge retention compared to those that did not. There were no differences detected in anxiety or patient satisfaction. Video education appears to be an effective supplemental method for patient education in AML. Limitations include the single-center nature of the study at an urban academic medical center with a relatively well-educated, primarily Caucasian, younger population. Future research is warranted to assess the video in a diverse set of languages and to explore its broader benefits.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Evaluating the efficacy and toxicity of dose adjusted pegylated L-asparaginase in combination with therapeutic drug monitoring.

The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548-1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282-3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph-) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18-65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16-65 years), and median body mass index (BMI) was 30 kg/m2 (18.3-53.4 kg/m2). The 36-month survival estimate was 62.1% (95% CI 48.1-77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1-89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8-91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.

Oncology stewardship in acute myeloid leukemia.

In recent years, an explosion of novel agents has shifted the treatment paradigm for patients with acute myeloid leukemia. The optimal place in therapy for many of these novel agents remains unknown due to limited guidance from national guidelines and the way these agents were studied prior to entering the market. A critical evaluation of the literature and incorporation of oncology stewardship principles can be helpful in determining an optimal place for these agents while being mindful of the overall cost that is associated with therapies. The purpose of this review is to critically evaluate the efficacy and safety data for five controversial agents and provide examples of the use of stewardship practices in determining their place in the treatment of acute myeloid leukemia.

Real world use of FLT3 inhibitors for treatment of FLT3+ acute myeloid leukemia (AML): A single center, propensity-score matched, retrospective cohort study.

BACKGROUND: Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. METHODS: We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. RESULTS: A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. CONCLUSION: Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML).

BACKGROUND: Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. METHODS: This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. RESULTS: Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. CONCLUSIONS: Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction.

Relapsed/refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, with survival rates of less than a year, even with novel therapies. Patients frequently experience toxicities from induction chemotherapy such as hepatotoxicity, which can limit therapeutic options upon relapse. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, there are limited data on use of this agent in patients with significant organ dysfunction. In this report, we describe the safe and effective use of blinatumomab in an adult patient with refractory Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia in the setting of severe hepatic dysfunction. Blinatumomab may represent a viable option to treat relapsed/refractory acute lymphoblastic leukemia in patients with significant hepatic dysfunction.

The leukemia strikes back: a review of pathogenesis and treatment of secondary AML.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

Tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax and hypomethylating agents with or without dose ramp-up.

Venetoclax with hypomethylating agents (HMAs) is an important treatment for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. However, there is limited data on the safety of venetoclax without a dose ramp-up in patients with AML. A retrospective cohort analysis of patients with AML treated with HMA/venetoclax (HMA/Ven) with or without a dose ramp-up, or HMA alone from 6/30/2014-8/22/2022 was conducted. The primary endpoint was the incidence of laboratory and/or clinical tumor lysis syndrome (TLS) by day 10. Of 225 patients, 111 patients received HMA alone or HMA/Ven with a dose ramp-up and 114 received HMA/Ven with no dose ramp-up. The incidence of TLS was similar between the control and no dose ramp-up groups, with rates of 5.4% and 5.3% respectively (p = 0.962). TLS incidence was comparable in patients with and without a dose ramp-up, suggesting that a dose ramp-up may not be mandatory in patients with AML.

Broad Next-Generation Integrated Sequencing of Myelofibrosis Identifies Disease-Specific and Age-Related Genomic Alterations.

PURPOSE: Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl-ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. EXPERIMENTAL DESIGN: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN. RESULTS: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. CONCLUSIONS: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.

Exploring Adolescent and Young Adult Cancer Survivors' Experience with Cancer Treatment-Related Symptoms: A Qualitative Analysis of Semi-Structured Interviews.

Purpose: Few studies have specifically targeted symptom management interventions for adolescent and young adult (AYA) cancer survivors. A greater understanding of AYA cancer survivors' experiences with cancer treatment-related symptoms would help develop age-appropriate oncology symptom management interventions. The purpose of this qualitative analysis was to explore AYA cancer survivors' experience with cancer treatment-related symptoms. Methods: Nineteen post-treatment AYA cancer survivors (18-39 years old) who self-reported moderate-severe cancer treatment-related symptom severity participated in video conferencing or telephone interviews. The questions in the interview guide queried participants to share their experience with cancer treatment-related symptoms. Inductive content analysis was used to identify themes from the interviews. Results: The themes that emerged from the interviews included (1) cancer treatment-related symptoms negatively affected AYA cancer survivors' quality of life (e.g., symptoms served as a reminder of cancer recurrence possibility); (2) AYA cancer survivors' attitudes and feelings about communicating cancer treatment-related symptom concerns to clinicians (e.g., patient-clinician communication was bolstered when AYAs perceived that symptoms were being taken seriously); (3) AYA cancer survivors are interested in oncology symptom management clinical trials, but logistical challenges are barriers to participation; and (4) AYA cancer survivors are interested in nonpharmacological treatments for symptom management. Conclusion: Results highlight the burden of cancer treatment-related symptoms on day-to-day life among post-treatment AYA cancer survivors. Future work is needed to identify nonpharmacological symptom management interventions, strategies to improve patient-clinician communication about symptoms, and strategies to increase the visibility and accessibility of symptom management clinical trials for AYA cancer survivors.

Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

ABSTRACT: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized clinically by cytopenias, fatigue, and splenomegaly stemming from extramedullary hematopoiesis. MF commonly arises from mutations in JAK2, MPL, and CALR, which manifests as hyperactive Jak/Stat signaling. Triple-negative MF is diagnosed in the absence of JAK2, MPL, and CALR but when clinical, morphologic criteria are met and other mutation(s) is/are present, including ASXL1, EZH2, and SRSF2. While the clinical and classic molecular features of MF are well-established, emerging evidence indicates that additional mutations, specifically within the Ras/MAP Kinase signaling pathway, are present and may play important role in disease pathogenesis and treatment response. KRAS and NRAS mutations alone are reportedly present in up to 15 and 14% of patients with MF (respectively), and other mutations predicted to activate Ras signaling, such as CBL, NF1, BRAF, and PTPN11, collectively exist in as much as 21% of patients. Investigations into the prevalence of RAS and related pathway mutations in MF and the mechanisms by which they contribute to its pathogenesis are critical in better understanding this condition and ultimately in the identification of novel therapeutic targets.

Impact of number of lumens in central-venous catheters on central-line bloodstream infection (CLABSI) and venous thromboembolism (VTE) risk in patients with acute leukemia.

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).

Multicenter evaluation of the addition of eltrombopag to immunosuppressive therapy for adults with severe aplastic anemia.

Eltrombopag has been shown to improve response rates when added to standard therapy in adults with severe aplastic anemia in controlled trial settings. However, outcomes in real-world populations have mostly been examined in small retrospective studies. This robust, multicenter, retrospective cohort study across six academic health systems compared outcomes in patients who received immunosuppressive therapy with or without eltrombopag. The study included 82 patients who received front-line therapy from January 2014 to August 2021. Overall response rates at 6 months did not differ significantly for patients receiving eltrombopag versus immunosuppressive therapy alone (58% v. 65%, p = 0.56). However, complete response rates at 6 and 12 months were over two times higher in the eltrombopag arm (29% v. 12%, p = 0.06 and 48% v. 18%, p = 0.005). Rates of hepatotoxicity were similar across both arms. Eltrombopag addition did not impact overall survival (median not reached in either arm at 2 years, p = 0.86) or disease-free survival (median not reached v. 13.3 months at 2 years, p = 0.20). Eltrombopag may not produce as large of a benefit in real-world settings compared to controlled trial settings but may offer patients deeper responses with similar rates of toxicity to immunosuppressive therapy alone.

A Phase Ib Trial of AVID200, a TGFß 1/3 Trap, in Patients with Myelofibrosis.

PURPOSE: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFß, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFß 1/3 trap, reduced TGFß1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. PATIENTS AND METHODS: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. RESULTS: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFß1 levels and pSMAD2 in MF cells. CONCLUSIONS: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.