Search

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p .001), HR of 0.66 (95% CI 0.64-0.67, p .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVRREFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVRBetween Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVRThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy.AbbVie.

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

Key Points Somatic UBA1 mutations define VEXAS in men with late-onset systemic inflammatory disease and cytopenia.Features summarizing VEXAS include cytopenia, hypercellularity, lack of hematogones, and vacuoles in myeloid and erythroid precursors., VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This condition affects unrelated men with adultonset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. Although bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in patients with VEXAS, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular bone marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially underrecognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management may prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

Background Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors acquired somatic gene mutations in JAK2, CALR, or MPL. In the Phase 3 COMFORT-1 trial, which enrolled 309 patients (pts) with JAK inhibitor-naïve MF, ruxolitinib (RUX) showed spleen volume reduction of ≥35% (SVR35) and an improvement of 50% or more in the total symptom score (TSS50) in 42% and 46%, respectively compared to placebo. Activity has been shown with the combination of selinexor (SEL) plus RUX in preclinical studies. Methods XPORT-MF-034 is an open-label, Phase 1/2 study (NCT04562389) to evaluate the safety and efficacy of SEL plus RUX in treatment-naïve MF pts. SEL is evaluated at 2 dose levels, 40mg and 60mg once-weekly plus twice daily RUX in 28-day cycles. For nausea, all pts receive prophylaxis with a 5-HT3 antagonist prior to each SEL dose and as needed. Primary endpoints are to determine maximum tolerated dose, recommended Phase 2 dose (RP2D), and safety. Secondary endpoints include spleen and symptom response, and hemoglobin stabilization and improvement. The efficacy population for spleen and symptom evaluable pts included those who had a spleen assessment or at least one symptom score available, respectively, at baseline and the W12 or W24 timepoint. Results As of Oct 21, 2022, 24 pts have received at least one dose of 40mg or 60mg weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77) and 11 pts had primary MF, 6 had post-ET MF, and 7 had post-PV MF. DIPSS risk category was int-1, int-2, and high risk for 7, 11, and 6, respectively. The median daily dose of ruxolitinib received was 20 mg. In efficacy evaluable pts, 63% (12/19) and 92% (11/12) achieved SVR35 at W12 and W24, and 83% (10/12) and 67% (4/6) achieved TSS50 at W12 and W24. Among the 11 pts who had a baseline hemoglobin level Conclusions To date, in pts with treatment-naïve MF, the novel combination of SEL and RUX has been reasonably well-tolerated with a generally manageable safety profile and has shown encouraging activity in spleen and symptom responses, in addition to hemoglobin stabilization. Updated safety and efficacy, including symptom data amongst those pts non evaluable for TSS50 at the time of the Oct data cutoff, as well as RP2D, will be available for presentation at AACR 2023. Citation Format: Haris Ali, Ashwin Kishtagari, Keri Maher, Sanjay Mohan, Karen Ansaldo, Xulong Wang, Kamal Chamoun, Josef T. Prchal, Srinivas K. Tantravahi. A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT261.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm of older individuals characterized by persistent monocytosis. Somatic mutations in CMML are heterogeneous and only partially explain the variability in clinical outcomes. Recent data suggest that cardiovascular morbidity is increased in CMML and contributes to reduced survival. Clonal hematopoiesis of indeterminate potential (CHIP), the presence of mutated blood cells in hematologically normal individuals, is a precursor of age-related myeloid neoplasms and associated with increased cardiovascular risk. To isolate CMML-specific alterations from those related to aging, we performed RNA sequencing and DNA methylation profiling on purified monocytes from CMML patients and from age-matched (old) and young healthy controls. We found that the transcriptional signature of CMML monocytes is highly proinflammatory, with upregulation of multiple inflammatory pathways, including tumor necrosis factor and interleukin (IL)-6 and -17 signaling, whereas age per se does not significantly contribute to this pattern. We observed no consistent correlations between aberrant gene expression and CpG island methylation, suggesting that proinflammatory signaling in CMML monocytes is governed by multiple and complex regulatory mechanisms. We propose that proinflammatory monocytes contribute to cardiovascular morbidity in CMML patients and promote progression by selection of mutated cell clones. Our data raise questions of whether asymptomatic patients with CMML benefit from monocyte-depleting or anti-inflammatory therapies.

Purpose: Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis. Experimental Design: A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear–cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor). Results: JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo. Conclusions: Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.

Myelodysplastic Syndrome (MDS) with an isolated deletion of chromosome 5q [del(5q)] is a relatively rare MDS variant (5%) characterized by a moderate to severe anemia and normal or elevated platelet count with modest neutropenia [1-3]. These latter features, in addition to its excellent response to lenalidomide, are likely what contribute for its favorable prognosis [3-5]. The somatic gain of function mutation in JAK2 V617F is a driving mutation in Myeloproliferative Neoplasms (MPN), occurring in 97% of polycythemia vera (PV), 50-60% of essential thrombocytosis (ET) and primary myelofibrosis (PMF) [6]. This mutation results in constitutive activation of the JAK-STAT signaling pathway leading to increased proliferation and hypersensitivity to cytokines erythropoietin, IL-3, thrombopoietin, and GCSF. An allelic burden of JAK2 V617F mutation correlates with an increased risk of thrombosis and hemorrhage, as well as secondary fibrosis in MPN patients [7].

Although ruxolitinib (RUX) is effective in alleviating splenomegaly and constitutional symptoms for patients with myelofibrosis (MF), it does not appear to modify underlying disease biology. RUX discontinuation rate within 5 years is approximately 40%, and patients have poor prognosis after discontinuing RUX [1]. The definition of disease modification in MF is evolving. Reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as evidence of disease modification; however, clinical benefits derived from achieving these responses have not been fully elucidated. Ultimately, benefits in patient survival are requisite to claim true clinically meaningful disease modification. There is also an unmet need of effective therapies for patients with MF with high molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157). REFINE (NCT03222609) is a phase 2 trial evaluating navitoclax (NAV), a BCL-XL/BCL-2 inhibitor, combined with RUX, in patients with MF who progressed on or had a suboptimal response to RUX monotherapy. Here, we report the exploratory analyses assessing BMF, VAF, and HMR with respect to outcomes. As BMF improvements were often observed in patients who achieved ≥35% reduction in spleen volume (SVR35), we explored if the survival benefit observed was due to this potentially disease modification-related response. All statistics were descriptive. As of May 6, 2021, 34 patients were enrolled in Cohort 1a and received ≥1 dose of NAV plus RUX. Of these, 32 were evaluable for BMF and 12 (38%) had ≥1 grade improvement during anytime on study, 4 of whom improved by 2 grades. For driver gene VAF reductions, 26 patients (JAK2, n=19; CALR, n=7) were evaluable and 6 (23%) achieved ≥20% reduction at Week 24. Five patients achieved both BMF and VAF responses. Median overall survival (OS) for patients who had ≥1 grade improvement in BMF was not reached compared with 28.5 months for those without improvement (P Reference 1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 2020; 126(6): 1243-52 Citation Format: Naveen Pemmaraju, Jacqueline Garcia, Jalaja Potluri, Yan Sun, Jason Harb, Srinivas K. Tantravahi, Srdan Verstovsek, Claire Harrison. Addition of navitoclax to ruxolitinib mediates responses suggestive of disease modification in patients with myelofibrosis previously treated with ruxolitinib monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB108.

Context: Chronic myelomonocytic leukemia (CMML) is a rare hematopoietic stem cell disorder that predominantly affects the elderly. Previous genetic analysis supports the presence of mutations including ASXL1, TET2, spliceosome components (SF3B1, SRSF2, U2AF1, and ZRSR2), and the oncogenic RAS pathway (NRAS, KRAS, CBL, PTPN11, and NF1). Objective: As part of a precision cancer surveillance to increase our basic, translational, and clinical understanding of rare diseases at the Huntsman Cancer Institute, we identified a cohort of patients with CMML treated at our institution. This report reports their clinical and molecular characteristics based on standard of care molecular profiling with myeloid next-generation sequencing. We also describe the overall survival of patients with molecular profiles of interest. Design: We extracted data from 57 CMML patients from the Huntsman Cancer Institute electronic health record system. We categorized the patients using their first bone marrow myeloid malignancy panel diagnosis between October 2009 and September 2020. We reviewed their charts for the following information elements: date of birth, sex, vital status, bone marrow biopsy, CMML diagnosis, and date of death or last follow-up. Our analysis was performed by producing Kaplan-Meier survival curves. Results: We identified a total of 34 gene mutationstal Saint-Louis, Paris, France

The discovery of the Philadelphia chromosome (Ph) and BCR-ABL1 fusion gene in chronic myeloid leukaemia (CML) was a first step in understanding the genetic basis of myeloproliferative neoplasms (MPN), but it took more than 20 years until the molecular basis of Ph– MPN was unravelled with the identification of mutually exclusive mutations in JAK2, MPL, and CALR. The common effect of these mutations, activation of JAK/STAT signalling, informed the therapeutic development of JAK kinase inhibitors. Additional mutations in epigenetic modifier, mRNA splicing, and transcriptional regulator genes are present in many MPN cases. Elucidating the prognostic and functional significance of these mutations is the focus of intense ongoing studies. Given that JAK kinase inhibitors have limited impact on the mutant allele burden these additional pathways may offer much needed additional therapeutic targets. In this chapter, we discuss in detail the genetic landscape of MPN in the context of prognostication and therapy.

Background Treatment at academic cancer centers (ACs) has been associated with improved outcomes across hematologic malignancies, including acute myeloid leukemia and non-Hodgkin lymphoma. ACs offer the benefit of high treatment volume in addition to enrollment in clinical trials, involvement in post-graduate education, and expanded access to diagnostic and treatment related services. Though studies on multiple myeloma (MM) have demonstrated a survival benefit with treatment at both high-volume centers and at NCCN designated cancer centers, this is the largest study to date examining the benefit of academic centers. Methods The National Cancer Database was utilized to obtain data on patients diagnosed with MM between 2004-2017 for which data on treatment facility type was available. Using the Commission on Cancer facility categories, patients treated at ACs were compared to those treated at non-academic centers (NACs), including small and large volume community cancer centers. Demographic and treatment characteristics were compared between centers, with median overall survival (OS) assessed by Kaplan Meier. Cox regression analysis was used to asses the HR for OS by facility type, and adjusted on multivariate analysis for age, sex, race, insurance, time to treatment, and use of autologous transplant. Results Of the 179,769 MM patients available, 42.4% were treated at ACs (p 75 years of age were more often treated at NACs (35.6% vs. 20.3%, p The time from diagnosis to treatment was longer at ACs, at 32.4 vs. 26.5 days (p Median OS at ACs was significantly longer than at NACs, with median OS of 67.8 months (95% CI 66.89-68.79 months) compared to 38.6 months (95% CI 38.15-39.13 months) at NACs, p Conclusion Patients with MM had significantly improved survival when treated at academic centers compared to all other facility types. The improvement in OS remained when controlled for available treatment and demographic features. Multiple factors, including specialized care, trial enrollment, and early access to autologous stem cell transplant may contribute to these improvements. Further investigations into the factors contributing to such disparities are required to standardize care and improve overall outcomes. Figure 1 Figure 1. Disclosures Tantravahi: CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy.

Background: Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model. Methods: An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets > 30 K/μL and neutrophils > 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment. Results: Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment. Conclusions: Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. Figure 1 Figure 1. Disclosures Tantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

Introduction: Germline pathogenic variants in DDX41 represent the most common predisposition to myeloid neoplasms accounting for 1-4% of patients (pts). Myeloid neoplasm with germ line DDX41 mutation is included as a separate entity in the revised 2016 World Health Organization classification of myeloid neoplasms and acute leukemia. The risk to develop any myeloid neoplasm in individuals with pathogenic germline DDX41 variants is modest, estimated to be about 20-30%. The recent inclusion of DDX41 on next generation sequencing panel (NGS) for myeloid neoplasms has led to increase in identification of DDX41 variants. Identification of germline DDX41 variants in MDS/AML pts will inform on donor selection and genetic testing of family members who are potential hematopoietic stem cell transplant (HSCT) donors is critical to eliminate the risk for transmission of a donor derived leukemia. Herein, we describe 10 pts with acute myeloid leukemia who were identified to have a DDX41 variantsince January 2020. Methods Among the pts diagnosed with acute myeloid leukemia in Utah between January 2020 and April 2021, 10 pts were identified to have a DDX41 variant on myeloid NGS panel (peripheral blood or bone marrow) performed at the time of diagnosis (9 pts) or through genetic testing performed on cultured skin fibroblasts (1 pt). When possible, pts with met a genetic counselor and germline genetic testing was performed utilizing DNA obtained from cultured skin fibroblasts through GeneDX Laboratory and Prevention Genetics. DDX41 variants are classified (Table 1) as per the ACMG criteria. Results Of the 10 pts with a DDX41 variant on myeloid NGS panel, 9 (90%) were diagnosed with AML. One pt (10%, Pt 9)) was initially diagnosed as AML and subsequently classified as mixed phenotype T/myeloid leukemia on repeat marrow evaluation after failure of initial induction based on blasts co-expressing cytoplasmic CD3 and MPO. The DDX41 variant was classified as pathogenic and variant of uncertain significance (VUS) in 6 (60%) and 4 (40%) pts, respectively. The variant allele frequency (VAF) of DDX41 variants was above 35% in all pts (Table1). Seven pts had germline testing performed from cultured skin fibroblasts, all were found to have germline DDX41 variants. Three pts did not undergo germline genetic testing, but the VAFs were highly suggestive of germline origin. Baseline demographics and the AML disease characteristics are outlined in Table 1. ELN risk category was unknown in 1 pt (10%), favorable in 1 pt (10%), intermediate in 3 pts (30%) and adverse in 5 pts (50%). Karyotype was normal in6 pts (60%), 20 q deletion in one pt and a complex in 2 pts (20%). Other somatic variants identified on the myeloid NGS panel are outlined in Table 1. First line treatment included intensive chemotherapy in 6 pts (60%) and 4 pts (40%) received hypomethylating agent based (HMA) therapy. Seven pts achieved a complete remission (CR), after first line treatment, of whom 5 received intensive chemo and 2 received HMA based treatment. One pt who received HMA therapy failed to achieve CR or CRi (pt 5), achieved CR after receiving intensive chemo for salvage. One pt failed initial induction with idarubicin and cytarabine (7+3 regimen) and achieved CR after reinduction with cycle 1 A of HyperCVAD. 5 pts relapsed after first line treatment (2 after intensive chemo and 3 after HMA based treatment). At the time of this report, 2 pts received allogeneic stem cell transplant (allo-SCT) both from unrelated donors and 3 pts died. Conclusion: In our experience, AML pts with germline DDX41 variant presented after fifth decade similarly to sporadic AML. Most pts had pathogenic variants in DDX41 (per ACMG), though 3 pts were classified as uncertain variants which represent an area of further knowledge. The majority of the pts had a normal karyotype at diagnosis. A second somatic DDX41 variant was observed in 2 pts. ASXL1 mutations were observed in 3 pts. Inclusion of the DDX41 gene in a myeloid NGS panel is necessary to identify this subset of pts and in addition germline testing should also be considered for all MDS/AML pts with age Figure 1 Figure 1. Disclosures Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Shami: JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; Aptevo: Research Funding. Kovacsovics: Stemline: Honoraria; Novartis: Research Funding; Amgen Inc.: Research Funding; Janssen Pharmaceuticals: Research Funding; AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria. Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tantravahi: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding; Abbvie Inc.: Research Funding; CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding.

Context: IPSS-R is used to classify risk of disease progression and guide treatment decisions for patients with MDS. Recent data shows mutational profiling may improve the prognostic stratification of MDS. Minimal real-world evidence exists for this population. Objective: Assess treatment patterns and clinical outcomes in patients with MDS by IPSS-R risk scores. Design: A retrospective cohort study assessed real-world, patient-level data from adults diagnosed with MDS between 2010–2019 at HCI. All data were obtained from electronic medical records via chart review. Patients with intermediate to very-high IPSS-R scores comprised the higher-risk cohort. Results: Of 259 patients with MDS, 90 had an IPSS-R score at diagnosis, 65 patients who were not clinical trial participants were included. IPSS-R score distribution: 10/65 (15%) very low; 18/65 (28%) low, 14/65 (22%) intermediate, 15/65 (23%) high, and 8/65 (12%) very high. Average patient age was 68 years, 52% (n=34) of patients were female, 91% (n=59) were White, 8% (n=5) had autoimmune disorders, and 5% (n=3) had cerebrovascular disease. In the higher-risk cohort, hypomethylating agents (HMAs) were used to treat 62% (n=23) of patients (median 2 cycles), while 27% (n=10) received no MDS-directed therapy and 11% (n=4) received other MDS-related medications. Stem-cell transplant (SCT) was received more frequently (n=13, 35%) and sooner (median 4.8 months from diagnosis) by higher-risk patients compared with lower-risk patients (18%, n=5; median 15.0 months from diagnosis). Complete (CR) or partial response was achieved by 17% (n=4) of higher-risk patients treated with HMAs versus 7% (n=1) of lower-risk patients. Transfusion independence was achieved by 60% (n=3) of higher-risk and 100% (n=4) of lower-risk patients who received PLT or pRBC prior to treatment initiation. Disease progression or death occurred in 82% (n=53) of patients during the study period, with a median progression-free survival of 8.3 months and 25.3 months for higher-risk and lower-risk patients, respectively. Conclusions: These results show that higher-risk patients have a low likelihood of achieving and maintaining CR. Limited treatment options for patients with higher-risk MDS reveals a large unmet need. Specific genetic profiles may indicate the need for more aggressive treatments and management of relevant comorbidities.

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.

FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.

e19034 Background: IPSS-R is used to classify risk of disease progression and guide treatment decisions for patients with MDS. Recent data shows mutational profiling may improve the prognostic stratification of MDS. Minimal real-world evidence exists for this population. Methods: A retrospective cohort study assessed real-world, patient-level data from adults diagnosed with MDS between 2010-2019 at HCI. All data were obtained from electronic medical records via chart review. IPSS-R scores were manually calculated from lab and cytogenetic data within 30 days of diagnosis. Patients with an intermediate to very-high IPSS-R score comprised the higher risk (HR) cohort. Primary objectives were to assess treatment patterns & clinical outcomes in the HR cohort. Results: Of the 259 MDS patients at HCI, 90 had an available IPSS-R score at diagnosis (ANC results were missing for 64% of cohort). After excluding clinical trial participants, 65 patients were included. Distribution of IPSS-R scores was: 15% very low (n = 10), 28% low (n = 18), 22% intermediate (n = 14), 23% high (n = 15), & 12% very high (n = 8). The average age of HR subjects was 67 years. 57% of HR patients were female (n = 21), 92% were white (n = 34), 8% (n = 3) had autoimmune disorders, & 8% (n = 3) had cerebrovascular disease. 14% (n = 5) of NGS-tested HR patients had TP53 alterations, while the most frequently altered gene was DNMT3A at 17% (n = 6). In the HR cohort, HMA was used to treat 62% of patients (n = 23) (median 2 cycles), while 27% (n = 10) received no MDS-related medication, and 11% (n = 4) received other MDS-related medications (lenalidomide, ruxolitinib, hydroxyurea). Second-line treatment was received by 9% of HR patients (n = 3). 35% of HR patients (n = 13) underwent stem-cell transplantation. Complete or partial response was achieved by 21% of HR patients treated with a HMA (n = 5); the remaining patients had stable disease (39%, n = 9), disease progression (26%, n = 6), or died (4%, n = 1). Transfusion independence was achieved by 60% of HMA-treated HR patients (n = 3) (median duration = 151 days from treatment initiation). Disease progression or death occurred in 89% of HR patients (n = 33) during the study period with a median progression free survival (PFS) of 8.3 months. PFS was significantly shorter for HR patients with TP53 alterations compared to wild-type (HR: 5.75, 95% CI (1.34-24.64)), using cox regression. Median overall survival for HR patients was 18.8 months. Conclusions: These results show HR patients have a low likelihood of achieving & maintaining complete remission. In addition, limited treatment options for HR patients further reveals a large unmet need. Specific genetic profiles may indicate the need for more aggressive treatments and management of relevant comorbidities. Updated results will be presented, including LR patients & economic outcomes.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life threatening disorder characterized by excessive immune activation with resulting tissue injury [1]. Ibrutinib is an irreversible inhibito...

Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy

Background Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. Materials and Methods We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. Results A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). Conclusion Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

BackgroundImatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy.MethodsWe developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed.ResultsThe lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY.ConclusionsAlthough the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

Background Invasive fungal infection (IFI) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is also associated with excess healthcare costs. Current approaches include universal antifungal prophylaxis, preemptive therapy based on biomarker surveillance, and empiric treatment initiated in response to clinical signs/symptoms. However, no study has directly compared the cost-effectiveness of these treatment strategies for an allogeneic HSCT patient population. Methods We developed a state transition model to study the impact of treatment strategies on outcomes associated with IFIs in the first 100 days following myeloablative allogeneic HSCT. We compared three treatment strategies: empiric voriconazole, preemptive voriconazole (200 mg), or prophylactic posaconazole (300 mg) for the management of IFIs. Preemptive treatment was guided by scheduled laboratory surveillance with galactomannan (GM) testing. Endpoints were cost and survival at 100 days post-HSCT. Results Empiric treatment was the least costly ($147 482) and was equally effective (85.2% survival at 100 days) as the preemptive treatment strategies. Preemptive treatments were slightly more costly than empiric treatment (GM cutoff ≥ 1.0 $147 910 and GM cutoff ≥ 0.5 $148 108). Preemptive therapy with GM cutoff ≥ 1.0 reduced anti-mold therapy by 5% when compared to empiric therapy. Posaconazole prophylaxis was the most effective (86.6% survival at 100 days) and costly ($152 240) treatment strategy with a cost of $352 415 per life saved when compared to empiric therapy. Conclusions One preemptive treatment strategy reduced overall anti-mold drug exposure but did not reduce overall costs. Prevention of IFI using posaconazole prophylaxis was the most effective treatment strategy and may be cost-effective, depending upon the willingness to pay per life saved.

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾ 10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾ 2 ARCH genes and 52% had ⩾ 7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Background Hypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR-TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. Patients and Methods A retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. Results Of 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of ≤ 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. Conclusion The severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic phase chronic myeloid leukemia (CP-CML) to an extent that survival is largely determined by non-CML mortality. Monitoring for minimal residual disease by measuring BCR-ABL1 messenger RNA is a key component of CML management. CP-CML patients who achieve a stable deep molecular response may discontinue (TKIs) with an ~ 50% chance of entering treatment-free remission (TFR). So far discontinuation of TKIs has largely been limited to clinical trials, but is on the verge of becoming a part of wider clinical practice. Careful patient selection, dense molecular monitoring, and prompt reinstitution of treatment in the event of relapse are all vital to reproduce the same level of success. Much effort has been dedicated to identifying therapeutic strategies to eliminate CML stem cells and enable to TFR in more patients. Unfortunately, despite promising preclinical data, as yet, none of the various approaches have entered clinical practice.

INTRODUCTION/BACKGROUND: Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.PATIENTS AND METHODS: We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).RESULTS: We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.CONCLUSION: Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.

Systemic mastocytosis (SM) is a rare chronic myeloproliferative neoplasm characterized by the accumulation of morphologically and phenotypically abnormal mast cells in affected organs. The clinical...

INTRODUCTION: The prognosis of multiple myeloma (MM) has improved drastically in the last 20 years with the advent of novel agents, specifically with the introduction of bortezomib in late 2003. Novel agents in combination with autologous stem cell transplant (ASCT), have led to the achievement of high response rates in many patients. ASCT is now considered standard of care for all eligible patients, and previous studies have found increasing rates of ASCT in all age groups since the introduction of novel agents. Studies have also revealed disparities with decreased ASCT utilization in racial and socioeconomic minorities. This study utilizes the National Cancer Database (NCDB) to determine how the use of ASCT has changed for MM in the bortezomib era. METHODS:The NCDB was used to identify 157,443 patients diagnosed between 2004-2016 with Multiple Myeloma. Only patients with information on ASCT were included, and demographic characteristics between those patients that received and did not receive ASCT were compared. Race, insurance type, facility type, average income, education, and Charleson-Deyo comorbidity score, among other factors, were included in this analysis (Table 1). To determine the trends in ASCT over the era of novel agents, the proportion of patients receiving ASCT within these groups was trended over each year, and linear models to determine the rate of change in each group was compared. Bivariate and Multivariate regression analysis for each characteristic was used to determines odds ratios (OR) for receiving ASCT by demographic factors. RESULTS: Between 2004 to 2016 the proportion of all patients receiving ASCT as part of initial therapy more than doubled from 10.1% to 22.0%; increasing by approximately 1.06% per year on a linear regression model (R20.98) (Table 2). The greatest proportional increases were seen in Blacks, Hispanics, patients over 65 years of age, patients with higher comorbidity scores, Medicare, and patients treated at community centers. On multivariate analysis the patients that were most likely to receive ASCT (p DISCUSSION: In the era of novel agents, the rate of ASCT has rapidly increased each year, with the greatest increases seen in elderly patients, those with higher comorbidity indexes, and in patients who are racially and socioeconomically disadvantaged. However, significant racial and socioeconomic disparities still exist in the treatment of MM, and must be considered as treatment continues to advance. Disclosures No relevant conflicts of interest to declare.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient’s prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988–2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35–0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10–0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00–9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

Chronic myelomonocytic leukemia (CMML) is a hematopoietic stem cell neoplasm with features of both myelodysplasia and myeloproliferation.[1] Cytopenias and progression to acute myeloid leukemia (AM...

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered.

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen–deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.