International Prognostic Scoring System Risk Research Articles

A multicenter phase 2 clinical trial of low-dose subcutaneous decitabine in myelofibrosis

AbstractMyelofibrosis (MF) in the chronic phase is a challenging disease to treat, and conventional treatment options are geared toward symptom palliation. In this prospective, multicenter, phase 2 trial, 21 patients with MF (18 chronic phase, 2 accelerated phase, and 1 blast phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg per day. The overall response rate was 33% (95% confidence interval, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high International Prognostic Scoring System risk score, high baseline fetal hemoglobin level, and sustained decrease in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least 1 grade 3/4 cytopenia. Nonhematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in MF with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. This trial was registered at www.ClinicalTrials.gov as #NCT00095784.

A Systematic Literature Review of Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes.

Erythropoiesis-stimulating agents (ESAs) are the first-line treatment option for anemia in patients with lower-risk myelodysplastic syndromes (LR-MDS). A systematic literature review was conducted to identify evidence of the association between prognostic factors and ESA response/failure in LR-MDS. MEDLINE, Embase, and relevant conferences were searched systematically for studies assessing the association between prognostic factors and ESA response/failure in adult patients. Of 1566 citations identified, 38 were included. Patient risk status in studies published from 2000 onwards was commonly assessed using the International Prognostic Scoring System (IPSS) or revised IPSS. ESA response was generally assessed using the International Working Group MDS criteria. Among the included studies, statistically significant relationships were found, in both univariate and multivariate analyses, between ESA response and the following prognostic factors: higher hemoglobin levels, lower serum erythropoietin levels, and transfusion independence. Furthermore, other prognostic factors such as age, bone marrow blasts, serum ferritin level, IPSS risk status, and karyotype status did not demonstrate statistically significant relationships with ESA response. This systematic literature review has confirmed prognostic factors of ESA response/failure. Guidance to correctly identify patients with these characteristics could be helpful for clinicians to provide optimal treatment.

Real-World Outcome and Prognostic Factors in MDS Patients Treated with Azacitidine-A Retrospective Analysis.

Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival and quality of life. Nevertheless, many patients fail to respond to AZA treatment, as prognostic factors still are not identified. The present retrospective analysis included 79 patients with MDS treated with AZA as first-line therapy in a real-life setting. The percentage of patients with good, intermediate, and poor cytogenetics was 46.8%, 11.4%, and 34.2%, respectively. The overall response rate (complete remission [CR], partial remission [PR], and hematological improvement [HI]) was 24%. The CR, PR, and HI rates were 13.9%, 2.5%, and 7.6%, respectively. Stable disease (SD) was documented in 40.5% of patients. The median overall survival (OS) and progression-free survival (PFS) were 17.6 and 14.96 months, respectively. Patients with ORR and SD had a significantly longer median OS (23.8 vs. 5.7 months, p = 0.0005) and PFS (19.8 vs. 3.5 months, p < 0.001) compared to patients who did not respond to AZA. In univariate analysis, only an unfavorable cytogenetic group was a prognostic factor of a lower response rate (p = 0.03). In a multivariate model, older age (p = 0.047), higher IPSS (International Prognostic Scoring System) risk (p = 0.014), and higher IPSS-R cytogenetic risk (p = 0.004) were independent factors of shorter OS. Independent prognostic factors for shorter PFS were age (p = 0.001), IPSS risk (p = 0.02), IPSS cytogenetic risk (p = 0.002), and serum ferritin level (p = 0.008). The safety profile of AZA was predictable and consistent with previous studies. In conclusion, our study confirms the efficacy and safety of AZA in a real-world population and identifies potential biomarkers for response and survival.

Factors affecting prognosis in myelodysplastic syndrome: an 11 years’ experience from a tertiary care center

Aims: Myelodysplastic syndrome (MDS) is a clonal bone marrow neoplasia characterized by morphological findings of dysplasia in hematopoietic cells, peripheral cytopenia(s), ineffective hematopoiesis, recurrent genetic abnormalities, and an increased risk of conversion to acute myeloid leukemia (AML). The International Prognostic Scoring System (IPSS) is the most commonly used prognostic classification system for MDS. Classification was made by a combination of morphology, cytopenia, and genetic studies. In this study, we aimed to examine the parameters that affect prognosis in MDS patients, show their effects on mortality, and evaluate their positive or negative effects on the course of the disease. Methods: Two hundred twenty-nine patients who applied to Erciyes University Faculty of Medicine, Department of Hematology, and were diagnosed with MDS according to WHO classification between 2010 and 2020 were included in this retrospective study. Age, gender, additional disease status, laboratory parameters, bone marrow biopsy materials, and genetic mutation analysis data were available. The bone marrow aspiration and biopsy examinations of each patient were evaluated and categorized according to the WHO classification. The prognosis was evaluated according to the data of the patients, survival-exitus, and survival after MDS-AML conversion. Risk scoring was analyzed with three different scoring systems (IPSS, WPSS, and R-IPSS). Results: Of the 229 MDS patients included in the study, 57% (131) were male. The mean age of the patients was 67 years. Age, MDS-AML conversion times, disease duration, cellularity, and pathology blast rate were found to be statistically significant between the groups (p&lt;0.05). Leukocyte, neutrophil, platelet, hematocrit, lymphocyte, monocyte, CRP, erythropoietin, ferritin, and LDH data were found to be statistically significant regarding survival (p&lt;0.05). Age, IPSS risk status 3, and W-PSS risk status 3 were found to be independent risk factors affecting survival. Conclusion: Age, IPSS high risk, and WPSS high risk status were found to be independent risk factors affecting survival. Although our study revealed important data in the analysis of MDS patients, single-center analysis of patients and retrospective analysis revealed the need for further studies.

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.

VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.

Platelet-to-lymphocyte ratio and absolute monocyte count have prognostic potential in primary myelodysplastic neoplasms.

The platelet-to-lymphocyte ratio (PLR), peripheral blood absolute monocyte count (AMC), and monocyte-to-lymphocyte ratio (MLR) are considered biomarkers of systemic immune and inflammation response. However, their prognostic potential in patients with myelodysplastic neoplasms (MDS) remains unclear. This study aimed to explore the predictive impact of PLR, MLR, and AMC on MDS outcomes. In total, 334 patients with primary MDS were included between January 2016 and December 2021 and were retrospectively followed up until December 31, 2022. The prognostic significance of PLR, MLR, and AMC was assessed using univariate and multivariate analyses, and predictive models were generated to estimate MDS outcomes. The area under their receiver operating curves was computed to compare the predictive power of these models. Fifty-one patients had disease progression, and 103 patients died during follow-up. In multivariate analyses, a higher PLR was an adverse independent factor for overall survival (OS) (p = 0.011), whereas a higher AMC indicated shorter progression-free survival (p = 0.003). The prognostic model incorporating PLR, MLR, and AMC with the Revised International Prognostic Scoring System (IPSS-R) risk categorization showed higher performance in predicting OS than the model that only utilized the IPSS-R category. Elevated PLR and increased AMC had independent prognostic value for adverse outcomes in patients with MDS. PLR, MLR, and AMC enhanced the IPSS-R risk categorization for OS prediction in MDS.

Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)

CONCLUSIONS Imetelstat, an oligonucleotide and a first-in-class telomerase inhibitor, selectively targets malignant hematopoietic stem and progenitor cells with high telomerase activity by direct binding to the RNA template. In patients with MDS the on-target effects of imetelstat are associated with the development of hematologic treatment-emergent adverse events (TEAEs). In the IMerge phase 3 trial, among patients treated with imetelstat, 68% experienced grade 3-4 neutropenia, and 62% had grade 3-4 thrombocytopenia; however, clinical consequences of grade 3-4 infection or bleeding were similar in patients treated with imetelstat and placebo (Platzbecker et al. EHA 2023. Abstr S165). Here, we report additional data on the occurrence and management of cytopenias after treatment with imetelstat. IMerge phase 3 trial (NCT02598661) is a multicenter study involving 178 patients with a median age of 72 years with red blood cell (RBC) transfusion dependency and LR-MDS relapsed/refractory to or ineligible for erythropoiesis-stimulating agents. Patients were randomized 2:1 to receive either imetelstat or placebo and stratified by prior RBC transfusion burden (4-6 or &amp;gt;6 U) and by International Prognostic Scoring System risk group. The safety population included all patients who received ≥1 dose of study drug and comprised 118 patients treated with imetelstat and 59 with placebo. TEAEs of neutropenia and thrombocytopenia with imetelstat treatment were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time: 42.7% and 48.5% in cycles 4-6, 36.8% and 44.7% in cycles 7-12, and 31.3% and 37.5% in cycle 13 and beyond. Based on laboratory assessment, neutrophil and platelet counts decreased from baseline levels in patients treated with imetelstat versus those treated with placebo (91.5% and 95.8% vs 47.5% and 33.9%, respectively). Neutropenia decreased to a maximum of grade 4 and 3 in 55 and 29 of imetelstat-treated patients, respectively, and &amp;gt;80% of cytopenia events stabilized to grade ≤2 within 4 weeks (Figure). The median time to grade 4 neutropenia was 5.0 weeks (range,1.1-90.3 weeks) for the imetelstat group vs 23.0 weeks (range, 23.0-23.0 weeks) for the placebo group. Similarly, median time to grade 4 thrombocytopenia was 5.2 weeks (range, 2.0-29.9 weeks) with imetelstat vs 35.5 weeks (range, 28.0-43.0 weeks) with placebo. It is noteworthy that among 47 patients who achieved the primary end point of 8-week RBC transfusion independence with imetelstat, 34 (72.3%) and 28 patients (59.6%) had grade 3-4 neutropenia and grade 3-4 thrombocytopenia, respectively. In the imetelstat group, 3 patients had grade 3-4 neutropenia concurrent with grade 3-4 infections, and no patients experienced grade 3-4 thrombocytopenia associated with grade 3-4 bleeding events. There were no grade 5 cytopenias for either imetelstat or placebo groups. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 39 patients (33.1%) and 27 patients (22.9%), respectively. Of imetelstat-treated patients, 6 (5.1%) discontinued treatment due to neutropenia (1 case, grade 4; all others, grade 3), and 4 (3.4%) discontinued due to thrombocytopenia (1 case, grade 2; 3 cases, grade 3). In addition to dose reductions and discontinuation of imetelstat, thrombocytopenia and neutropenia were managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Similar patterns of imetelstat dose modifications were seen in a pooled phase 2 and phase 3 safety analysis of IMerge. In the IMerge phase 3 trial, thrombocytopenia and neutropenia were the most common and most frequently reported grade 3-4 AEs during treatment cycles 1-3. However, these AEs were generally transient, reversible, and manageable through treatment delays and dose adjustments, allowing for patients to remain on treatment and continue to experience clinical benefit. Moreover, occurrence of grade 3-4 cytopenias in responders suggests that these TEAEs do not affect the efficacy of imetelstat.

Risk Factors Associated to Severe Episodes of Infection in Myelodysplastic Syndromes

INTRODUCTION. Mortality differs according to the Revised International Prognostic Scoring System (IPSS-R) risk categories in patients afflicted with myelodysplastic syndromes (MDS). Historically, high-risk (HR)-MDS (IPSS-R &amp;gt;3.5 points) is related to death caused by progression to acute myeloid leukemia (AML), while low-risk (LR)-MDS is associated with mortality due to severe infections (Nachtkamp K, et al. 2016), probably caused by neutrophile dysfunction and hindered oxidative burst. Studies of causes of death (COD) in MDS are scarce. A MD Anderson study in LR-MDS patients identified infections as the leading COD, followed by progression (Dayyani F, et al, 2010), while the Düsseldorf registry recognized infections as the main COD across all MDS categories (Neukirchen, J. et al, 2011). Considering that information in low- and medium-income countries is especially limited, this study aims to describe the characteristics and identify the risk factors for severe infectious events in patients afflicted by MDS in a third-level center in Mexico. METHODS. In this single-center retrospective study, we analyzed severe infection episodes, associated risk factors, and the COD in MDS patients.We included patients diagnosed with MDS from January 2000 to December 2021, according to the 2016 WHO criteria. We registered baseline characteristics and described the episodes of severe infection, defined as hospitalization events due to infectious diseases complicated with septic shock and/or respiratory failure requiring orotracheal intubation. We conducted uni- and multivariate analyses based on the following variables: neutropenia (≤0.5x10 9/L), monocytopenia (≤0.2x10 9/L), lymphopenia (≤1.0x10 9/L), ferritin (≥1,000ng/mL), autoimmune disease, MDS comorbidity index, COPD, granulocyte dysplasia, and treatment with azacytidine or pharmacological immunosuppression. RESULTS. We included 156 patients with MDS treated at our institution. Median age at diagnosis was 65 years (IQR; 55-75 years), 53% of which were women. Multilineage dysplasia was the most prevalent MDS type (59%), followed by excess blasts type 2 (11.5%). LR-MDS represented 68% (n=106), while HR-MDS, 32% (n=50). Hypocellularity in bone marrow biopsy was found in 24.4%. Eighty-seven patients developed 156 infectious episodes, 64.7% of which were severe. A median of 1 serious event (IQR: 0.75-1 event) occurred in each patient, with a median time to diagnosis of 13 months (IQR: 3.5-34.5 months). Infection sites and etiologies are described in Figure 1. Of note, we identified 14 fungal infections, 8 of them by Aspergillus, with a 37.5% death rate. Risk factors associated with increased severe infection risk were neutropenia during follow-up (OR 3.2; 95% CI 1.5-6.4; p=0.001), neutrophil hypogranularity at diagnosis (OR 2.1; CI 95% 1.1-4.1; p=0.029), hyperferritinemia (OR 2.46; CI 95% 1.2-4.9; p=0.011), and azacitidine treatment (OR 3.1; CI 95% 1.01-9.6; p=0.047). Fifty patients (32%) died. In both HR-MDS and LR-MDS groups, the main COD was infection (13 in HR group, 48.1%, vs 10 in LR group, 43.5%; p=0.782), followed by progression to AML (3 in HR group, 11.1%, vs 4 in LR group, 21.7%; p=0.444). Median overall survival was lower in patients with severe neutropenia (62 vs. 210 months; p=0.009) and hyperferritinemia (62 months vs. non-reached, p&amp;lt;0.001) (Figure 2). CONCLUSIONS In our MDS population severe infections represent the leading COD, regardless of risk category. More than half developed at least one infectious episode, 64.7% of which were severe. Fungal infections were highly lethal, suggesting antifungal prophylactic interventions could prove helpful. We found neutropenia during follow-up and hypogranularity at diagnosis to be significant risk factors, the latter perhaps reflecting neutrophil disfunction which should be further evaluated. Hyperferritinemia's association with increased infection and mortality urges to further understand its role in MDS pathophysiology, and could potentially prove a therapeutic target in infections disease prevention. Additionally, there is currently no consensus on infectious disease for use of azacitidine, which might add to a worsening risk of infection.

Combination of Venetoclax and Azacitidine in Patients with Treatment-Naive, High-Risk Myelodysplastic Syndromes with Responses Leading to Stem Cell Transplantation

Introduction: The standard of care for patients with high-risk myelodysplastic syndrome (HR-MDS) who are eligible for intensive therapy includes allogeneic stem cell transplantation (SCT), which is potentially curative. Venetoclax (Ven) is a potent, selective, orally bioavailable BCL-2 inhibitor, which has a synergistic effect when combined with hypomethylating agents in preclinical and clinical investigations of myeloid malignancies. Previous results showed that the combination of Ven and azacitidine (Aza) is associated with an acceptable safety profile and leads to rapid and durable responses in patients with treatment-naive HR-MDS. Here, we report the clinical outcomes of patients with HR-MDS who proceeded to SCT following combination Ven+Aza treatment on the M15-531 clinical trial. Methods: M15-531 is a global, open-label, phase 1b clinical trial (NCT02942290) to identify the recommended phase 2 dose and to study the safety and efficacy of Ven+Aza. Eligible patients were aged ≥18 years with the following criteria: de novo treatment-naïve HR-MDS; International Prognostic Scoring System (IPSS) risk categories of Int-2 or High, or Revised IPSS (IPSS-R) categories of Intermediate, High, or Very High; &amp;lt;20% blasts in bone marrow aspirate/biopsy; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2. Aza was administered at 75 mg/m 2 subcutaneously or intravenously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle. Ven was first evaluated at 100 once daily for 14 days of a 28-day cycle, then escalated to 200 and 400 mg in separate cohorts. Clinical outcomes with Ven+Aza treatment for patients who discontinued study treatment to undergo SCT and who did not experience disease progression are reported. Results: At the data cutoff of May 31, 2023, 124 patients were treated with all doses of Ven-based therapy, and 51 (41.1%) proceeded to allogeneic SCT. Key demographics and baseline characteristics for those who received SCT are shown in the Table. Median age was 64 years (range, 26-78), 58% had an ECOG PS of 0, and 25% had poor or very poor cytogenetic risk by IPSS-R. The median number of cycles of Ven+Aza was 3 (range, 1-22). Median time on study drug was 124 days (range, 28-763), and the median time from first dose of study treatment to SCT was 5.6 months (range, 1.4-29.7). Before SCT, 21 of 51 (41.2%) patients achieved complete remission (CR). Marrow CR (mCR) was achieved by 23 of 51 (45.1%) patients, and the composite response rate (mCR with Hematologic Improvement) was 30.4% (7 of 23; 95% CI, 13.2-52.9). The median time to best overall response (time from first dose of study drug to best response of CR, mCR, partial response, or stable disease) for Ven+Aza was 2.0 months (range, 1.0-10.4). The median overall survival was not reached for patients who achieved CR or mCR and proceeded to transplant. Among patients who underwent transplant, 64.7% (33/51) remained alive at the data cut-off date Conclusion: Early responses after Ven+Aza in patients with HR-MDS enabled them to receive allogeneic SCT. After escalating doses of the combination of Ven+Aza, 41% of patients went on to SCT. These results suggest that Ven-based regimens before SCT may provide a path to curative therapy.

Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) across Different Risk Subgroups in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis-Stimulating Agents (ESAs) in IMerge Phase 3 Study

CONCLUSIONS IMerge (NCT02598661) is a phase 2/3 global study of imetelstat, a first-in-class telomerase inhibitor, for patients with RBC transfusion-dependent non-del(5q) LR-MDS R/R to or ineligible for ESAs, a population with unmet needs. Phase 3 results showed that the rate of ≥8-week, ≥24-week and 1-year RBC-TI was higher with imetelstat than placebo (Zeidan et al. ASCO 2023. Abstr 7004; Platzbecker et al. EHA 2023. Abstr S165). Toevaluate clinical efficacy of imetelstat across different International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), IPSS-R cytogenetic, or IPSS-molecular (IPSS-M) risk categories,cytogenetic analysis was performed centrally on bone marrow aspirates by karyotyping, and mutation profile was analyzed using peripheral blood samples by next-generation sequencing on a panel of 36 genes commonly mutated in MDS. Baseline IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk categories were derived for patients in the phase 3 portion of IMerge based on specific classification criteria, and rates of RBC-TI ≥8-week, ≥24-week, ≥1-year were assessed for each risk subgroup. In 105 IPSS-low patients, 95 (90.5%) remained IPSS-M very low/low/moderate low, and 10 patients (9.5%) upstaged to IPSS-M moderate high and high. In 50 IPSS-intermediate-1 patients, 39 (78%) remained IPSS-M very low/low/moderate low, and 11 patients (22%) upstaged to IPSS-M moderate high/high. Among 129 IPSS-R low/very low patients, 118 (91.5%) remained IPSS-M very low/low/moderate low, and 11 (8.5%) patients upstaged to IPSS-moderate high/high. In 25 IPSS-R-intermediate patients, 16 (64%) remained IPSS-M low/moderate low, and 9 patients (36%) upstaged to IPSS-M moderate high/high/very high. One IPSS-R high-risk patient remained IPSS-M high. Overall, significantly higher rates of ≥8-week, ≥24-week, and ≥1-year RBC-TI were achieved in patients receiving imetelstat (39.8%, 28%, and 13.6%) vs those receiving placebo (15%, 3.3%, and 1.7%). Further subgroup analysis demonstrated that imetelstat consistently had higher TI response rates than placebo across different risk subgroups, irrespective of classification system. For IPSS risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 40.0% vs 20.5% ( P = 0.034), 28.8% vs 5.1% ( P = 0.003), and 12.5% vs 2.6% ( P = 0.082), respectively, in patients with low risk and 39.5% vs 4.8% ( P = 0.004), 26.3% vs 0% ( P = 0.009), and 15.8% vs 0% ( P = 0.048), respectively, in patients with intermediate-1 risk. For IPSS-R risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 42.5% vs 19.6%, 29.9% vs 4.3%, and 11.5% vs 2.2%, respectively, in the low-risk subgroup. The TI rates of ≥8-week, ≥24-week, ≥1-year TI with imetelstat were 35%, 25%, and 20%, respectively, in the intermediate-risk subgroup, whereas placebo treatment had no response. The number of patients was too low in both arms of the very low or high IPSS-R subgroups to assess difference in TI response. For IPSS-R cytogenetic risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 37.1% vs 17.0%, 24.7% vs 4.3%, and 10.1% vs 2.1%, respectively, in very good/good risk groups and 54.5% vs 11.1%, 40.9% vs 0%, and 22.7% vs 0%, respectively, in the intermediate-risk group. For IPSS-M risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 47.8% vs 21.2%, 34.8% vs 3%, and 14.5% vs 0%, respectively, in patients with very low/low risk and 20.7% vs 6.3%, 10.3% vs 0%, and 6.9% vs 0%, respectively, in patients with moderate low/moderate high risk. In patients with high/very high risk, ≥8-week TI rates were 40% vs 0% with imetelstat vs placebo, with no ≥24-week or ≥1-year TI observed in either arm. All results are summarized in the Table. Improvement in RBC-TI rates was observed in patients treated with imetelstat vs placebo across different risk subgroups as defined by IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk profiles. Notably, placebo had not achieved durable (≥24-week and ≥1-year) TI response in the higher-risk groups irrespective of the risk classification assessment model used, while TI response rates with imetelstat in higher-risk subgroups with poor prognosis were similar to TI response rates in lower-risk subgroups of heavily transfused R/R ESA LR-MDS, indicating that clinical efficacy of imetelstat is independent of risk categories.

BMS-986158, a Potent BET Inhibitor, in Combination with Ruxolitinib or Fedratinib in Patients (pts) with Intermediate- or High-Risk Myelofibrosis (MF): Updated Results from a Phase 1/2 Study

Introduction Bromodomain and extra-terminal (BET) inhibitors in combination with Janus kinase inhibitors (JAKi) have demonstrated clinical benefits in pts with MF. BMS-986158 is an orally bioavailable, potent, and selective small molecule BET inhibitor with a dose-proportional pharmacokinetic profile with linear increases in exposure, which has shown time- and dose-dependent modulation of BET target gene expression. BMS-986158 in combination with JAKi ruxolitinib (RUX) or fedratinib (FED) is being evaluated in pts with MF in the CA011-023 study (NCT04817007). Previous analyses showed that BMS-986158+RUX in first-line (1L; RUX-naïve) MF and BMS-986158+FED in second-line (2L; relapsed, refractory, or intolerant to prior RUX treatment) MF was well tolerated, with most pts remaining on treatment, and had promising preliminary efficacy (Ayala R et al. EHA 2023. S213). Updated results with longer follow-up will be presented. Methods Eligible pts had primary or secondary MF and were either RUX-naïve (1L) or relapsed, refractory, or intolerant to RUX (2L), with splenomegaly (spleen volume [SV] ≥ 450 cm 3), ECOG PS ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. In dose escalation, pts with 1L MF received BMS-986158 2.0, 3.0, or 3.75 mg QD 5d on/2d off + RUX 15 mg BID; pts with 2L MF received BMS-986158 0.5, 0.75, 1.0, or 1.25 mg QD 5d on/2d off (alternative schedule for 1.0-mg dose: 5d on/2d off, 3 wks on/1 wk off) + FED 400 mg QD. Primary objectives in dose escalation were safety, tolerability, and determination of the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of BMS-986158+RUX and BMS-986158+FED. Secondary objectives included spleen volume reduction (SVR) from baseline and response rate (SVR35) at wk 24. Assessment of JAK2 variant allele frequency (VAF) was an exploratory objective. JAK2V617 VAF was measured longitudinally in peripheral blood CD34+ stem cells using next-generation sequencing. Results As of May 18, 2023, 16 pts with 1L MF received BMS-986158+RUX (median age 66 y [range, 36-81]) and 24 pts with 2L MF received BMS-986158+FED (median age 68 y [range, 34-81]). At baseline, median SV was 1504 cm 3 (range, 524-4379) in pts treated with BMS-986158+RUX and 2222 cm 3 (range, 581-6598) in pts treated with BMS-986158+FED. Any grade (G) treatment-related adverse events (TRAEs) were reported in 15 (94%) pts treated with BMS-986158+RUX; G 3/4 TRAEs were thrombocytopenia (n = 7, 44%), neutropenia (n = 2, 13%), anemia, leukopenia, herpes zoster, hyperbilirubinemia, and hypertension (n = 1 each, 6%). Any G TRAEs were reported in 18 (75%) pts treated with BMS-986158+FED; G 3/4 TRAEs were thrombocytopenia and anemia (n = 6 each, 25%), hyperbilirubinemia (n=2, 8%), leukocytosis, and diarrhea (n = 1 each, 4%). No TRAEs led to discontinuation of BMS-986158+RUX; 2 TRAEs (G4 thrombocytopenia and G3 hyperbilirubinemia) led to discontinuation of BMS-986158+FED. SVR was observed at wk 12 in all evaluable pts in both treatment regimens and continued to deepen at wk 24 (Figure). Median SV at wk 24 was 603 cm 3 (range, 170-2532) and 1826 cm 3 (range, 1079-5288) in evaluable pts with 1L MF and 2L MF, respectively. In pts with 1L MF, 8/11 (73%) treated with BMS-986158 (2.0, 3.0 or 3.75 mg)+RUX met SVR35 at wk 12; 9/10 (90%) pts met SVR35 at wk 24. In pts with 2L MF, 7/12 (58%) pts treated with BMS-986158 (0.5, 0.75, 1.0, or 1.25 mg)+FED met SVR35 at wk 12; 3/7 (43%) pts met SVR35 at wk 24. At the time of reporting, 32/40 (80%) pts remained on treatment: 14/16 (88%) receiving BMS-986158+RUX and 18/24 (75%) receiving BMS-986158+FED. Available analysis of JAK2 VAF showed reductions in the frequency of JAK2V617F with BMS-986158+RUX (52% max. reduction by C10, n = 7) and BMS-986158+FED (29% max. reduction by C4, n = 4). Conclusions These updated analyses of study CA011-023 show that BMS-986158+RUX in 1L MF and BMS-986158+FED in 2L MF continue to be well tolerated, with most patients remaining on treatment. TRAEs were mostly low-grade and transient. Thrombocytopenia, an on-target effect, was manageable and did not result in clinically significant bleeding. Both treatment regimens produced early and deep SVR by wk 12, which continued and deepened at wk 24 and beyond. The reductions observed in JAK2 VAF provide promising preliminary data of potential disease modification. Dose expansion with BMS-986158+RUX in 1L MF has opened and is actively enrolling patients.

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction MDS are genetically heterogenous neoplasms with diverse prognoses. While hypomethylating agents (HMA) can improve outcomes, HSCT remains the only potentially curative therapy. The IPSS-M incorporates clinical and molecular features to improve outcome prediction beyond traditional risk stratification tools. The IPSS-M has been validated in studies that either variably included pts who underwent HSCT, were limited by sample size, or were single-institution analyses. We aimed to validate the performance of the IPSS-M in predicting outcomes among pts with MDS who were treated with HMAs and subsequently underwent HSCT. Methods The VALIDATE database includes MDS pts treated with frontline HMA from 14 specialized centers. Only pts with available molecular data pre-HMA therapy and subsequently underwent HSCT were included. Time-to-event analyses used Kaplan-Meier estimator and the log-rank test. Overall survival (OS) was measured from time of HSCT. Multivariate-adjusted survival analysis used Cox proportional hazards. We compared the different scoring scores by Harrell's c-index. This study was supported by an independent research grant from AbbVie. Results A total of 350 pts met eligibility ( Panel A). Median age was 63 years (IQR: 58-68). MDS with excess blasts 1/2 (66%) was the most common type. Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. The most prevalent mutations were TP53 (29%), ASXL1 (21%), RUNX1 (13%), STAG2 (12%), SRSF2 (12%), and DNMT3A (11%); 53% of pts had disease harboring &amp;gt;1 gene mutation. Only 44% had TP53 CN-LOH and 40% had MLL-PTD testing. The most common donor types were matched unrelated donors (MUD, 46%), haploidentical donors (21%), and matched related donors (MRD, 17%). Myeloablative, non-myeloablative, and reduced-intensity conditioning were used in 38%, 27%, and 27% of the pts, respectively. Only 14% of pts received post-HSCT maintenance therapy. Our cohort was enriched with very high risk (41%) and high risk (30%) IPSS-R groups at time of diagnosis, while very low (1%), low (9%), and intermediate (20%) IPSS-R risk groups accounted for remaining 29% of pts. According to the IPSS-M, pts were classified into very low (2%), low (10%), moderate low (13%), moderate high (14%), high (27%) and very high (34%) risk groups. The IPSS-M re-stratified 198 (57%) pts, of whom 77 (39%) pts were up-staged and 121 (61%) pts were down-staged. More specifically, 35% and 26% of pts with intermediate risk IPSS-R MDS, and 32% and 35% of pts with high risk IPSS-R MDS were up-staged and down-staged, respectively. Importantly, 45% of pts with very high risk IPSS-R MDS were down-staged. Median follow-up time was 20 (IQR:8-36) months (mo). The median OS for the entire cohort was 32 mo (IQR:10-Not reached [NR]). The IPSS-M groups showed significantly different OS (p-value= 0.001, Panel B)withmedian OS (mo, 95%CI) of: very low (NR, 11.5-NR), low (55, 22-NR), moderate low (48, 25-NR), moderate high (35, 22-NR), high (29, 23-NR), and very high (20, 13-28). The 5-year OS (%) were as following: very low (56%), low (47%), moderate low (37%), moderate high (40), high (43%), and very high (17%). IPSS-M risk (HR: 1.3, 95% CI:1.1-1.5) was significantly associated with OS in a multivariable model (HR, 95%CI) adjusted for age (1.01, 1.00-1.03), sex (1.2, 0.9-1.7), type of HMA used before HSCT (1.0, 0.9-1.1), number of HMA cycles (1.0, 0.9-1.05), donor type (1.0, 0.9-1.1), and conditioning regimen used (1.3, 1.1-1.5). For OS, the IPSS-M significantly stratified pts assigned to the very high risk IPSS-R subgroup (p=0.009). However, the IPSS-M showed comparable performance to IPSS-R with c-index (95%CI): 0.597 (0.555-0.640) vs. 0.599 (0.554-0.643), respectively, for OS. When IPSS-M/IPSS-R were analyzed as continuous scores, the c-index (95%CI) for OS were: 0.606 (0.561-0.651) vs. 0.611 (0.559-0.662). When focusing on the higher risk group defined as IPSS ≥.1.5, the IPSS-M (c-index: 0.584) still had performance comparable to the IPSS-R (c-index: 0.606). Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

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 &amp;gt;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 &amp;gt;3 U and 24% received &amp;gt;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 &amp;gt;3 and &amp;gt;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 &amp;lt; .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 &amp;lt; .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.

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Trends in overall mortality among US veterans with primary myelofibrosis

BackgroundPrimary myelofibrosis [PMF] is a myeloproliferative neoplasm associated with reduced overall survival (OS). Management strategies for PMF have evolved over the last two decades, including approval of ruxolitinib as the first Janus kinase 1 (JAK1)/JAK2 inhibitor for patients with intermediate or high-risk myelofibrosis. This study assessed changes in mortality before and after ruxolitinib approval, independent of ruxolitinib treatment.MethodsThis retrospective study investigated mortality trends among US veterans with PMF in 2 time periods, pre-ruxolitinib approval (01/01/2007–12/31/2010) and post-ruxolitinib approval (01/01/2015–09/30/2018). Deidentified patient-level data were extracted from US Veterans Health Administration (VHA) databases using PMF diagnosis codes; index was the first PMF diagnosis date. The analysis included adults with ≥2 PMF claims during the analysis periods who were continuously enrolled in the VHA plan 1 calendar year prior to and 6 months post-index and had ≥1 available International Prognostic Scoring System (IPSS) risk factor (available factors were age > 65, hemoglobin < 10 g/dL, and white blood cell count > 25 × 109/L; each counted as one point). Patients with ≥1 MF diagnosis for 12 months before the index period were excluded. Ruxolitinib treatment was not a requirement to be included in the post-ruxolitinib approval cohort. Mortality rates and OS were estimated using the Kaplan-Meier approach; all-cause mortality hazard ratio was estimated using univariate Cox regression.ResultsThe pre- and post-ruxolitinib approval cohorts included 193 and 974 patients, respectively, of which 80 and 197 had ≥2 IPSS risk factors. Ruxolitinib use in the post-ruxolitinib cohort was 8.5% (83/974). At end of follow-up, median (95% CI) OS was significantly shorter in the pre-ruxolitinib cohort (1.7 [1.2–2.6] years vs not reached [3.4–not reached]; P < 0.001). Overall mortality rates for the pre- versus post-ruxolitinib approval cohorts were 79.8% versus 47.3%, respectively, and overall risk of death was 53% lower in the post-ruxolitinib period (hazard ratio, 0.47; 95% CI, 0.37–0.58; P < 0.001). Mortality rates were lower among patients with < 2 vs ≥2 IPSS risk factors.ConclusionsAlthough veterans with PMF have high overall mortality rates, and results in this population might not be generalizable to the overall population, there was a significant lowering of mortality rate in the post-ruxolitinib period.

BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study

Background Bromodomain and extraterminal (BET) proteins play a role in cancer-cell proliferation, survival, and oncogenic progression, providing a rationale for using inhibitors of BET as anticancer drugs. BET inhibitors (BETi) alone and in combination with Janus kinase (JAK) inhibitors have been demonstrated to reduce inflammatory signals and disease burden in mouse myelofibrosis (MF) models, and combined inhibition of BET-mediated pathways and the JAK-STAT pathway has shown additional benefits for patients (pts) with MF. BMS-986158 is an orally bioavailable, potent, and selective small-molecule BETi that has demonstrated a dose-proportional pharmacokinetic profile with linear increases in exposure, as well as time- and dose-dependent modulation of BET target gene expression (Hilton J et al. Ann Oncol 2018;29(suppl 8):1429). BMS-986158 is being evaluated in pts with MF, alone and in combination with the JAK inhibitors ruxolitinib (RUX) or fedratinib (FED), in the CA011-023 study (NCT04817007). Here, we present initial safety and efficacy data from the dose-escalation parts (1A and 1B) of this study. Methods CA011-023 comprises a dose-escalation phase with BMS-986158 + RUX in RUX-naive pts (Part 1A) or BMS-986158 + FED in pts with previous RUX treatment (Part 1B), and a dose-expansion phase at the Recommended Phase 2 Dose (RP2D) evaluating BMS-986158 + RUX (Part 2A) or BMS-986158 ± FED (Part 2B). Eligible pts had primary or secondary MF, splenomegaly (spleen volume ≥ 450 cm3), ECOG performance status ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. Planned dose levels for pts in Part 1A are BMS-986158 2.0 mg, 3.0 mg, and 4.5 mg once daily (QD) 5 days on/2 days off and RUX 15 mg twice daily. For pts in Part 1B, planned dose levels are BMS-986158 0.5 mg, 0.75 mg, 1.25 mg, and 2.0 mg QD 5 days on/2 days off and FED 400 mg QD. Primary objectives in the dose-escalation phase are assessment of safety and tolerability and determination of the maximum tolerated dose and/or RP2D of BMS-986158 in combination with RUX or FED. Secondary objectives include spleen volume reduction (SVR) from baseline. Assessment of pharmacodynamic markers, such as JAK2 variant allele, is an exploratory objective. Results As of May 31, 2022, 13 pts were treated, 6 with BMS-986158 + RUX (median 66 years [range, 36-81]; 100% male) and 7 with BMS-986158 + FED (median 62 years [range, 37-77]; 57% male). Grade 1/2 treatment-related adverse events (TRAEs) were reported in 3 (50%) pts in the BMS-986158 + RUX group and in 2 (29%) pts in the BMS-986158 + FED group. Grade 3 TRAEs considered to be related to the combination treatment reported in the BMS-986158 + RUX group were thrombocytopenia (2 pts [33%]), and neutropenia and hypertension (1 pt each [17%]). Grade 3 TRAEs considered to be related to the combination treatment in the BMS-986158 + FED group were anemia (2 pts [29%]) and thrombocytopenia (1 pt [14%]). No grade 4/5 TRAEs were reported for either combination. One dose-limiting toxicity (DLT; grade 3 thrombocytopenia leading to dose reduction of BMS-986158) was reported at the 2.0 mg dose level of BMS-986158 + RUX on cycle 1 day 19. No DLTs have been reported in pts treated with BMS-986158 + FED. No serious TRAEs or TRAEs leading to treatment discontinuation have been reported. Importantly, SVR was observed at Week 12 in all evaluable pts across both treatment groups and continued to deepen at Week 24 in evaluable pts. In the BMS-986158 + RUX group, 4/5 (80%) pts met SVR35 at week 12, and 2/2 (100%) pts met SVR35 at week 24. In the BMS-986158 + FED group 0/3 (0%) pts met SVR35 at week 12, and 1/2 (50%) pts met SVR35 at week 24 (Table 1). Pts with post-baseline spleen volume by MRI in Part 1B were treated at lower BMS-986158 dose levels (0.5 mg and 0.75 mg 5 days on/2 days off) compared to Part 1A (2 mg 5 days on/2 days off). Analysis of JAK2 variant allele frequency and determination of RP2D are ongoing. Conclusions Most TRAEs were grade 1/2 in severity, while grade 3 TRAEs were successfully managed with dose delays or modifications without leading to treatment discontinuation. Initial results demonstrate that BMS-986158 in combination with RUX or FED produced robust SVR in pts with MF, with responses that deepened beyond Week 12 under continued treatment. Enrollment is continuing in the dose-escalation cohorts to establish RP2D for both combinations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improvement in Individual Symptoms and Total Symptom Score (TSS) and Matching-Adjusted Indirect Comparison (MAIC) Analysis to Compare TSS As a Continuous Endpoint in Patients with Myelofibrosis Treated with Pelabresib in Combination with Ruxolitinib Versus Janus Kinase Inhibitor Monotherapy

Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients (pts) with intermediate or high-risk MF in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). TSS50 is a standard measure of symptom improvement; however, the 50% response threshold does not capture clinical benefit in pts with TSS reduction <50% or pts who achieve TSS50 but could benefit from further symptom improvement (Dueck A, et al. European Hematology Association 2017. Poster E1331). Here, we present percentage change in TSS and subdomains as a continuous endpoint from Arm 3 of MANIFEST and indirect comparisons with historical double-blind JAKi trials in MF. Aims: To assess clinically meaningful changes in TSS with PELA in combination with RUX. TSS subdomains were analyzed to assess the underlying impact of PELA + RUX on symptom scores. In the absence of head-to-head studies of PELA + RUX vs JAKi monotherapy, naïve and matching-adjusted indirect comparison (MAIC) analysis (correcting for potential imbalances in baseline characteristics) were used to investigate improvement in TSS as a continuous endpoint in pts treated with PELA + RUX in Arm 3 of the MANIFEST study with historical double-blind Phase 3 JAKi trials: COMFORT-I (RUX), SIMPLIFY-1 (RUX, momelotinib [MOM]) and JAKARTA (fedratinib [FED]). Methods: In MANIFEST, percentage change in TSS and subdomains (fatigue, night sweats, itching, abdominal discomfort, pain under ribs, feeling of fullness and bone pain) from BL at Week (Wk) 12, 24, 36 and 48 were calculated. Pts with BL score = 0 were excluded. For the MAIC analysis, individual pt level data were available for MANIFEST Arm 3, and study-level data were extracted from published waterfall plots using WebPlotDigitizer (Rohatgia A. https://automeris.io/) for COMFORT-I, SIMPLIFY-1 and JAKARTA (FED 400 mg arm). Unanchored MAIC was conducted, whereby pts were reweighted to adjust for imbalances in key prognostic BL characteristics: gender, MF subtype, International Prognostic Scoring System risk status (IPSS), previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status; as a result, bias due to potential unmeasured differences is unlikely. The weights were used to calculate the effective sample size. Pts with IPSS intermediate-1 were excluded from the analysis. Weighted and unweighted treatment effects in terms of difference in least square (LS) means with their 95% confidence intervals using robust sandwich estimators for variance are presented. Studies used different TSS questionnaire versions; however, variations are subtle, and so comparisons across versions are valid (Dueck A, et al.Blood 2017;130:2168). Results: Comparable mean BL TSS scores were observed: 16.1 in MANIFEST Arm 3 and 17.5-19.4 across comparator Phase 3 studies. In MANIFEST Arm 3, a median reduction from BL of >50% was observed for TSS and all subdomains, and this reduction remained consistent across Wk 12 to Wk 48. TSS distribution in MANIFEST at Wk 24 showed greater median and mean reductions from BL vs JAKi monotherapy studies (Figure 1 shows comparison with RUX in SIMPLIFY-1). Complete summary level balance was achieved in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. After adjusting for imbalances, >20% greater reduction in LS mean percentage change in TSS from BL at Wk 24 was observed for all comparisons of MANIFEST Arm 3 vs historical studies, as shown in Figure 2. P values for all MAIC analyses were statistically significant. Conclusions: Analyzing TSS as a continuous endpoint in addition to responder analysis overcomes limitations of using TSS50 alone. TSS50 rates in MANIFEST Arm 3 were higher than all comparator MF studies, and clinically relevant improvements in TSS and its subdomains were observed as early as Wk 12 and were durable over time. When indirectly comparing Arm 3 of the Phase 2 MANIFEST study with historical Phase 3 MF studies using MAIC analysis, improved estimates of changes in TSS with PELA + RUX vs RUX, MOM or FED monotherapy were observed. A randomized Phase 3 MANIFEST-2 study of PELA + RUX vs RUX monotherapy in JAKi-naïve pts is ongoing (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes: Systematic Literature Review

Introduction: Patients with lower-risk myelodysplastic syndromes (LR-MDS) commonly experience chronic progressive anemia, which is initially treated with erythropoiesis-stimulating agents (ESAs). However, many patients do not respond to ESAs, thereby putting them at risk of earlier disease progression, which can require invasive and/or costly treatments, including blood transfusions or hypomethylating agents. A systematic literature review (SLR) was conducted to assess quantitative associations between prognostic factors and response to treatment with ESAs in patients with LR-MDS. Methods: An electronic search for relevant literature was conducted on February 25, 2022, across Embase and MEDLINE via OvidSP. Also, proceedings from the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, Academy of Managed Care Pharmacy, and European Society for Medical Oncology meetings from 2019 to 2022 were searched via OvidSP or manually if not indexed in databases. Articles written in languages other than English were excluded. Adult patients with LR-MDS were included in the analysis. Studies reporting measures of effect between prognostic factors and ESA response were included, as were studies reporting quantitative data pertaining to differences in patient characteristics between ESA responders and non-responders. Studies reporting both univariate and multivariate analyses were included. No geographic or temporal limits were applied to the search strategy, except for congress proceedings, which were limited to 2019 onwards. Results: In total, 38 studies were eligible for inclusion in this SLR, and 8 prognostic factors of interest were most frequently reported: baseline serum erythropoietin (EPO), hemoglobin (Hb), transfusion independence, bone marrow blast count, ferritin levels, International Prognostic Scoring System (IPSS) risk status, age, and karyotype status. Regarding study design, most were retrospective cohort studies (N = 15) or single-arm trials (N = 12), and were conducted in Europe (N = 24). Within the identified publications, ESA response was often assessed using the International Working Group (IWG) MDS 2000 or 2006 criteria in publications after 2000. Studies published prior to 2000 did not use a standardized method of refining response, but still classified patients according to changes in Hb levels or transfusion requirements. The literature available in LR-MDS demonstrated statistically significant relationships suggesting that patients with low serum EPO levels (vs higher EPO levels), high Hb levels (vs lower levels), and transfusion independence (vs transfusion dependent) are more likely to respond to ESA treatment (Table). This relationship was consistent across both univariate and multivariate analyses. The evidence for bone marrow blasts and ferritin levels was inconclusive, but could potentially be influenced in the future by the publication of studies with larger patient populations. There was no published evidence that ESA response was related to IPSS risk status, age, and karyotype status. The associated data for these prognostic factors in responders versus non-responders showed similar patterns. Conclusion: All studies assessing quantitative associations between ESA response and prognostic factors were published after 2000, hence ESA response was assessed according to IWG 2000 or 2006 criteria. The studies demonstrate a clear link between response to ESA treatment and lower serum EPO levels, higher Hb levels, and transfusion independence. The other prognostic factors were either not significant or inconclusive, and more research is needed to clarify whether they have a prognostic impact on ESA response in patients with LR-MDS. Some of the studies comparing prognostic factors for responders versus non-responders to ESA treatment were published before 2000 and did not use standardized methods to describe response. Due to changes in ESA treatment response definitions over time, some patients in the included studies may be classified differently with a more recent version of the IWG MDS criteria. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessment of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model in Hypoplastic Myelodysplastic Syndromes

Assessment of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model in Hypoplastic Myelodysplastic Syndromes

Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes. In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.