Best Available Therapy In Patients Research Articles

Systematic Review and Meta-Analysis of Clinical Efficacy and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections.

Antimicrobial resistance is increasingly concerning, causing millions of deaths and a high cost burden. Given that carbapenemase-producing Enterobacterales are particularly concerning due to their ability to develop structural modifications and produce antibiotic-degrading enzymes, leading to high resistance levels, we sought to summarize the available data on the efficacy and safety regarding the combination of meropenem-vaborbactam (MV) versus the best available therapy (BAT). Articles related to our objective were searched in the PubMed and Scopus databases inception to July 2024. To assess the quality of the studies, we used the Cochrane risk-of-bias tool, RoB2. The outcomes were pooled as a risk ratio (RR) and a 95% confidence interval (95%CI). A total of four published studies were involved: one retrospective cohort study and three phase 3 trials, including 432 patients treated with MV and 426 patients treated with BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, colistin, and tigecycline; or ceftazidime-avibactam; or piperacillin-tazobactam). No significant difference in the clinical response rate was observed between MV and the comparators at the TOC (RR = 1.29, 95%CI [0.92, 1.80], p = 0.14) and EOT (RR = 1.66, 95%CI [0.58, 4.76], p = 0.34) visits. MV was associated with a similar microbiological response as the comparators at TOC (RR = 1.63, 95%CI [0.85, 3.11], p = 0.14) and EOT assessment (RR = 1.16, 95%CI [0.88, 1.54], p = 0.14). In the pooled analysis of the four studies, 28-day all-cause mortality was lower for MV than the control groups (RR = 0.47, 95%CI [0.24, 0.92], p = 0.03). MV was associated with a similar risk of adverse events (AEs) as comparators (RR = 0.79, 95%CI [0.53, 1.17], p = 0.23). Additionally, MV was associated with fewer renal-related AEs than the comparators (RR = 0.32, 95%CI [0.15, 0.66], p = 0.002). MV was associated with a similar risk of treatment discontinuation due to AEs (RR = 0.76, 95%CI [0.38, 1.49], p = 0.42) or drug-related AEs (RR = 0.56, 95%CI [0.28, 1.10], p = 0.09) as the comparators. In conclusion, MV presents a promising therapeutic option for treating CRE infections, demonstrating similar clinical and microbiological responses as other comparators, with potential advantages in mortality outcomes and renal-related AEs.

Firstline Treatment with Ruxolitinib Versus Best Available Therapy in Patients with Polycythemia Vera: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Introduction: Polycythemia vera (PV) is characterized by trilineage blood cell expansion, PV-associated symptoms, and the risk of thromboembolic complications, progression to post-PV myelofibrosis, and acute leukemia. Cytoreductive treatment with hydroxyurea (HU) or ropeginterferon-alpha is approved in EU for the treatment of high-risk patients (pts) with PV. In addition, ruxolitinib (RUX) is approved for HU-intolerant/-resistant PV. However, RUX vs. best available therapy (BAT) has not been investigated as first-line treatment of pts with untreated PV. We hypothesized that RUX may have higher efficacy in such early-line PV pts. Methods: The clinical trial entitled “Ruxolitinib versus Best Available Therapy in pts with high-risk PV or high-risk ET” (RuxoBEAT; NCT02577926) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 190 pts in each stratum. Crossover from BAT to RUX is possible in eligible pts after 6 months. Pts with PV in the RUX arm received a starting dose of 10 mg BID and may increase their dose up to 20 mg BID. The primary endpoint is the clinicohematologic complete response (CR) rate at month 6, as defined by Barosi et al (Blood 2009), using a strict score of zero for the four symptoms by patient-reported outcome measures (PROM, Table 2) and an adjusted level alpha = 0.005 at a power of 80%. Secondary endpoints include overall response rate (CR+PR), freedom from phlebotomy, changes in blood counts, spleen size, and PROM, using p values descriptively. The interim trial data were recently reviewed by the DMC, and, due to the low likelihood of reaching the primary endpoint (CR rate improvement), the DMC has recommended that the trial should continue without recruitment of new pts. Therefore, this pre-specified interim analysis was performed after 78 (instead of 95) PV pts were randomized 1:1 to RUX vs. BAT. A maximum of 6 weeks of previous PV-directed therapy was allowed. Differences between RUX and BAT at month 6 and between baseline and end of month 6 data for each treatment were calculated using Fisher´s exact test/ McNemar Test (for unpaired/ paired binary variables) or the Mann-Whitney-U test/ Wilcoxon signed-rank test (for unpaired/ paired ordered or continuous variables). Results: 78 first-line pts (33% were pre-treated for a median of 22 days [range 1-42]) were included in the intention-to-treat set (n=44 vs 34 randomized to RUX vs. BAT, resp.) and analyzed at the 6-month time point. Baseline characteristics are listed in Table 1. In pts on RUX or BAT, CR rates at 6 months were comparable (2.3% and 2.9%, p=1.0), while overall response (CR+PR) rates were 77.3% with RUX and 55.9% with BAT (p=0.054). Also, at month 6 (Table 2), pts on RUX showed significantly lower hematocrit (40.8% vs 42.1%, p=0.046), and PROM symptom points for pruritus (1 vs 4, p=0.001) and fatigue (2.5 vs 5, p=0.031), and a trend towards less headache, abdominal discomfort, and weight loss, while the number of platelets was lower with BAT vs. RUX (254/nl vs 386/nl, p=0.013). There was no difference between RUX and BAT in the number of white blood cells (WBC), spleen size, or other symptoms at this time point. When each treatment arm was analyzed separately for changes between baseline and month 6, RUX treatment significantly reduced platelet counts, WBC, hemoglobin and hematocrit, phlebotomy rates, spleen size and fraction of pts with splenomegaly (Table 2), and significantly improved PROMs for pruritus, early satiety, and quality of life. During the same time period, BAT significantly reduced platelet counts, WBC, hematocrit, and phlebotomy rates, but failed to impact on hemoglobin, spleen size, fraction of pts with splenomegaly, or any of the symptoms (Table 2). Safety analysis revealed 301 adverse events (AE) in both assigned treatment groups, including 153 AE in the RUX and 148 AE in the BAT group (11.8% and 8.1% grade ≥3, resp.). There was no significant difference in the percentage of grade ≥3 AE between both groups (p=0.358), and there were no consistent patterns of grade ≥3 AE in either of the two arms. Conclusion: In this interim analysis, first-line treatment with ruxolitinib for 6 months in high-risk pts with PV led to clinically meaningful improvements in overall response, hemoglobin and hematocrit, phlebotomy rates, splenomegaly, and patient-reported pruritus and fatigue severity, while BAT only improved platelet counts, WBC, hematocrit, and phlebotomy rates, without having an impact on symptoms.

Clinical Effectiveness and Safety of Momelotinib Compared with Continued Ruxolitinib or Best Available Therapy in Patients with Myelofibrosis Who Required RBC Transfusions: Subgroup Analysis of the Phase 3 Simplify-2 Study

Introduction: Splenomegaly, constitutional symptoms, and anemia are key clinical features of myelofibrosis (MF); approximately one-third of patients (pts) are anemic at diagnosis, and most develop anemia over time. While Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) and fedratinib (FED) may address symptoms and splenomegaly, they do not manage and may exacerbate anemia. Treatments for anemia include erythropoiesis-stimulating agents (ESAs), often in combination with RUX or FED, and androgens such as danazol; however, these have shown limited efficacy. Red blood cell (RBC) transfusions are the mainstay of anemia management in MF, but transfusion dependency is associated with diminished quality of life and is a negative prognostic factor for survival. Treatments that address anemia as well as spleen volume and symptoms are needed. Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms in pts with MF across 3 phase 3 trials. To evaluate outcomes in pts who switched to MMB vs continuing RUX or best available therapy (BAT) despite transfusion requirement, we present a descriptive subgroup analysis of pts enrolled in SIMPLIFY-2 (NCT02101268) who were considered transfusion dependent (TD; ≥4 units of RBC transfusions in the previous 8 wk or hemoglobin [Hb] level <8 g/dL) or transfusion requiring (TR; receiving transfusions but not meeting TD criteria) at baseline (BL). Methods: SIMPLIFY-2 was an international, multicenter, open-label, phase 3 clinical trial investigating the efficacy and safety of MMB vs BAT in pts with MF who had suboptimal responses or hematologic toxicities while receiving RUX. Pts (N=156) were randomized 2:1 to receive open-label MMB or BAT, which was RUX in 88.5% of pts. Treatment washout from prior RUX was not permitted before study enrollment. The primary endpoint was spleen volume reduction ≥35% (SVR35). Total Symptom Score (TSS) response rate (≥50% reduction; TSS50) and transfusion independence response (TI-R; no RBC transfusions for ≥12 wk immediately before the end of wk 24, with all Hb levels ≥8 g/dL) were key secondary endpoints. This post hoc, descriptive analysis focused on pts treated with either MMB or BAT, who were considered non-transfusion-independent (non-TI), defined as either TD or TR, at BL. Results: In SIMPLIFY-2, 72 of 104 pts (69%) in the MMB arm and 33 of 52 pts (63%) in the BAT arm were non-TI at BL, and BL characteristics were balanced between both patient groups. Mean duration of prior treatment with RUX was 64.6 and 59.5 wk in non-TI pts in the MMB and RUX arms, respectively. Average BL TSS for this subpopulation was 18.6. All pts randomized to the MMB arm received a starting dose of 200 mg daily. In the BAT arm, 29 of 33 pts (88%) were treated with RUX, with 59% receiving a BL dose of ≤20 mg daily. ESAs were administered to 5 pts in the BAT arm. At wk 24, SVR35 was observed in 7 of 72 pts (10%) treated with MMB and 1 of 33 pts (3%) treated with BAT. TSS50 was achieved in 21 of 72 pts (29%) treated with MMB, but there were no responses in the BAT arm. Additionally, TI-R was achieved in 25 of 72 pts (35%) treated with MMB compared with only 1 of 33 (3%) treated in the BAT arm on RUX. Many responders with MMB achieved 2 or all 3 endpoints (16 of 36 responders [44%]) (Figure); there were no dual or triple responses in the BAT arm. Of the 5 pts in the BAT arm who received ESAs, only 1 pt each (different pts per response) achieved SVR35, TSS50, or TI. Safety outcomes were consistent with those previously reported for the intent-to-treat (ITT) population. Conclusions: In RUX/BAT-treated pts with MF who required RBC transfusions, continued treatment with RUX/BAT in most pts resulted in poor treatment outcomes compared with MMB. Specifically, treatment with MMB demonstrated an ability to deliver higher SVR, TI, and TSS response rates. The lower SVR35 rate in both arms, similar to the overall ITT population, was likely a result of lack of washout from prior JAK inhibitor treatment. While pt numbers were limited, similar findings were observed compared with pts who received ESAs. Overall, these data support MMB as a potential alternative treatment option for pts with MF who require RBC transfusions. Figure. Responses at Week 24 for Non-TI Patients at Baseline

A randomized, open-label study of the efficacy and safety of galinpepimut-S (GPS) maintenance monotherapy compared to investigator's choice of best available therapy (BAT) in patients with acute myeloid leukemia (AML) who have achieved complete remission (CR) after second-line salvage therapy.

TPS7074 Background: Patients with relapse/refractory (r/r) AML have poor outcomes. Allogeneic stem cell transplantation (allo-SCT) can potentially cure some patients with r/r AML who achieve second CR (CR2). However, barriers to transplantation such as advanced age, poor functional status/comorbidities or lack of donor exist and not all patients are able to proceed to allo-SCT. Therefore, novel strategies to decrease relapse risk in these patients are urgently needed. A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. WT1 has emerged as an encouraging vaccine target in AML due to its overexpression in leukemic blasts. Maintenance therapy with Galinpepimut-S (GPS), a multivalent heteroclitic WT1 peptide vaccine, has shown promising activity in patients with AML by inducing a strong innate immune response (CD4+/CD8+) against the WT1 antigen and across a broad range of HLA types. Methods: This is an open-label, multicenter, randomized, phase III study of GPS vs. BAT in patients with AML in CR2/CRp2 (CR2 with incomplete platelet recovery). BAT may include observation, low dose cytarabine and hypomethylating agents +/- venetoclax. The primary endpoint of the study is overall survival (OS). Secondary endpoints include safety and tolerability of GPS and leukemia-free survival. Exploratory endpoints include WT1-specific immune response dynamics in blood and bone marrow. Approximately 125 - 140 patients will enroll, in a 1:1 ratio, to provide at least 90% power under an assumed hazard ratio of 0.52, based on median OS of 8.0 m (BAT) and 15.4m (GPS). Randomization will be stratified by duration of CR1 ( < 12m vs. ≥12m), Cytogenetics (poor-risk vs. all other), CR2 vs. CRp2 and measurable residual disease (MRD) after CR2 (MRD- vs. MRD+). Inclusion criteria consists of willing subjects ≥18y with AML within 6m of achieving CR2/CRp2, ineligible for allo-SCT due to any reason, with ≥300 lymphocytes/ul and with adequate renal and hepatic function. Subjects with central nervous involvement, having received a live vaccine 30d prior to first dose of study drug, having a diagnosis of immunodeficiency, receiving ≥10mg daily of prednisone equivalent (or any other systemic immunosuppressant) for any indication 7d prior to first dose of study drug, hypersensitivity to study agent and with a history of solid organ transplant would be excluded. The clinical trial is actively enrolling, and the registry number is NCT04229979 . Clinical trial information: NCT04229979 .

Ruxolitinib Versus Best Available Therapy in Patients with Essential Thrombocythemia: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Ruxolitinib Versus Best Available Therapy in Patients with Essential Thrombocythemia: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Evaluation of Ruxolitinib versus Best Available Therapy in Treating Primary Myelofibrosis.

ObjectivesThis study aimed to evaluate the effectiveness of ruxolitinib and compare it with the best available therapy in patients with primary myelofibrosis. Ruxolitinib is a Janus kinase inhibitor that is approved for the treatment of myelofibrosis. The therapeutic protocol has changed after the introduction of ruxolitinib.MethodsIn this retrospective study, 72 patients with primary myelofibrosis were scrutinised from January 2012 to January 2018 at Nanakali Hemato-Oncology Teaching Centre in Erbil, Iraqi Kurdistan. The patients were divided into two cohorts: 26 of them were treated with ruxolitinib and 46 received the best available therapy. The patients’ characteristics, their response to the treatment and the outcomes were evaluated. The efficacy of the treatment in both groups was compared.ResultsMost patients (n = 46; 63.9%) were in the high and intermediate-2 risk groups according to the international prognostic scoring system. At the time of diagnosis, no noticeable differences in the clinical characteristics and laboratory data were observed among the ruxolitinib and best available treatment groups. Ruxolitinib was found to be effective in reducing the size of the spleen and improving the overall survival rate when compared to the best available treatment group (P <0.001 and P = 0.008, respectively). The patients’ performance status had a significant effect on the overall survival in both treatment groups (P = 0.003).ConclusionRuxolitinib appears to have a significant role in reducing the spleen size and potentially affect the survival outcomes in patients with myelofibrosis.

A Randomized, Phase 3 Trial of Fedratinib Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Previously Treated with Ruxolitinib (FREEDOM2)

A Randomized, Phase 3 Trial of Fedratinib Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Previously Treated with Ruxolitinib (FREEDOM2)

Results from the 208-Week (4-Year) Follow-up of RESPONSE Trial, a Phase 3 Study Comparing Ruxolitinib (Rux) with Best Available Therapy (BAT) for the Treatment of Polycythemia Vera (PV)

Results from the 208-Week (4-Year) Follow-up of RESPONSE Trial, a Phase 3 Study Comparing Ruxolitinib (Rux) with Best Available Therapy (BAT) for the Treatment of Polycythemia Vera (PV)

1271. Efficacy and Safety of Cefiderocol and Best Available Therapy in Patients with Serious Infections Caused by Carbapenem-Resistant Gram-Negative Infections: Results of the Pathogen-Focused Phase 3 CREDIBLE-CR Study

BackgroundThe CREDIBLE-CR study assessed the efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, in the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative (GN) bacteria.MethodsCREDIBLE-CR was an open-label, prospective, randomized 2:1, Phase 3 study (NCT02714595) in patients with nosocomial pneumonia (NP), bloodstream infections/sepsis (BSI/Sepsis), or complicated urinary tract infections (cUTI) with evidence of CR GN pathogens. Adults received intravenous CFDC 2 g, q8h, 3-h infusion or best available therapy (BAT; up to 3 drugs) for 7–14 days (extendable to 21 days). The primary endpoint at test of cure in the CR microbiological intent-to-treat (CR-MITT) population was clinical cure (NP, BSI/Sepsis) or microbiological eradication (cUTI). Secondary endpoints were clinical and microbiological outcomes, all-cause mortality (ACM) and safety. Only descriptive statistics were pre-specified.ResultsA total of 101 patients received CFDC and 49 received BAT (CR-MITT: CFDC n=80, BAT n=38): 50% had pneumonia, 31.4% BSI/Sepsis, and 18.6% cUTI (Table 1). Most frequent CR pathogens were Acinetobacter baumannii (45.8%), Klebsiella pneumoniae (37.3%), and Pseudomonas aeruginosa (23.7%). CFDC monotherapy was given to 83% of patients, while BAT monotherapy to 29% of patients. Primary outcome in the CFDC and BAT arms was achieved in 50.0% and 52.6% in NP, 43.5% and 42.9% in BSI/Sepsis, and 52.9% and 20.0% in cUTI patients (Figure). CFDC was highly efficacious vs CREs and NDM-producing pathogens. Day 28 ACM was 24.8% (25/101) with CFDC and 18.4% (9/49) with BAT. Rescue therapy was given more frequently in the BAT than CFDC arm. Mortality results by pathogen showed an imbalance in Acinetobacter spp. infections (Table 2) with a higher rate in the CFDC arm than BAT arm. ICU and shock at randomization were more frequent in the CFDC arm than in the BAT arm in Acinetobacter spp. infections (Table 2). No safety concerns related to CFDC emerged.Table 1. Baseline demographics and characteristics (CR-MITT population) Figure. CREDIBLE-CR study primary efficacy endpoints and secondary outcomes at test-of-cure visit in CR-MITT population. Table 2. All-cause mortality by baseline pathogen inpatients with or without Acinetobacter spp. infection (safety population) ConclusionEfficacy of CFDC was demonstrated in this descriptive pathogen-focused study, including CREs, metallo-NDM producers and CR non-fermenters. Baseline imbalances of ICU and shock in the subset of infections with Acinetobacter spp. may have contributed to the mortality difference between CFDC and BAT arms.DisclosuresMatteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Roger Echols, MD, Shionogi Inc. (Consultant) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden

AbstractMyelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F− disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F− disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F− disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.

Cefiderocol effective for carbapenem-resistant Gram-negative infections

The clinical and microbiological outcomes of cefiderocol, a new antibiotic, were similar to the best available therapy for patients with life-threatening carbapenem-resistant infections, a phase III study has suggested.

Ruxolitinib Shows Efficacy in Patients with Newly-Diagnosed Polycythemia Vera: Futility Analysis of the Randomized Ruxo-BEAT Clinical Trial of the German Study Group for Myeloproliferative Neoplasms

Ruxolitinib Shows Efficacy in Patients with Newly-Diagnosed Polycythemia Vera: Futility Analysis of the Randomized Ruxo-BEAT Clinical Trial of the German Study Group for Myeloproliferative Neoplasms

Delafloxacin IV and OS Administration Compared to Best Available Therapy in Patients With Surgical Site Infections

Delafloxacin IV and OS Administration Compared to Best Available Therapy in Patients With Surgical Site Infections

Myelofibrosis Drug Development through the Decade: Novel JAK Inhibitors

IntroductionMyelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet.MethodsA comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review.ResultsJAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported.JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities.JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia.ConclusionNovel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. DisclosuresNo relevant conflicts of interest to declare.

270 - Reach-2 Trial Design: A Phase 3, Randomized, Open-Label, Multicenter Study to Evaluate Ruxolitinib Compared to Best Available Therapy in Patients with Corticosteroid-Refractory Acute Graft vs Host Disease after Allogeneic Stem Cell Transplantation

270 - Reach-2 Trial Design: A Phase 3, Randomized, Open-Label, Multicenter Study to Evaluate Ruxolitinib Compared to Best Available Therapy in Patients with Corticosteroid-Refractory Acute Graft vs Host Disease after Allogeneic Stem Cell Transplantation

Neurologic Complications After Cardiac Transplant.

Cardiac transplant is the best available therapy for patients with end-stage heart failure. Neurologic complications occur at a rate of 30% to 70% in patients undergoing cardiac transplant, and they affect mortality and morbidity of these patients. Risk factors for neurologic complications include immunosuppressive medication toxicity, infections, brain lesions, and metabolic disorders. The aim of our study was to determine the incidence of neurologic complications in adult patients undergoing cardiac transplant. We retrospectively evaluated the medical records of 70 patients who underwent cardiac transplant between 2004 and April 2016. We recorded the demographic data, neurologic symptoms, neurologic examination findings, laboratory test results, brain imaging study results, and treatments received of the patients. Of the 70 patients enrolled, 55 were male and 15 were female patients. The age range was 18 to 63 years, and the mean age was 42.4 years. Twelve patients had encephalopathy, 4 had neuropathic pain, 3 had tremor, 2 had ischemic cerebrovascular accident, 7 had posterior reversible encephalopathy syndrome, and 1 had drop foot. Encephalopathy usually developed secondary to other neurologic disorders. The incidence of neurologic complications in adult patients undergoing cardiac transplant was 30%. Neurologic complications are common after cardiac transplant. We observed an incidence of 30% for neurologic complications in our clinic, with encephalopathy being the most common complication. Encephalopathy most commonly developed secondary to posterior reversible encephalopathy syndrome.

Ruxolitinib: a targeted treatment option for patients with polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis and the presence of Janus kinase (JAK) 2V617F or similar mutations. This review summarizes the pathophysiology of PV, the challenges associated with traditional treatment options, and the scientific rationale and supportive clinical evidence for targeted therapy with ruxolitinib. Accumulating evidence indicates that activating mutations in JAK2 drive the PV disease state. Traditional PV treatment strategies, including aspirin, phlebotomy, and cytoreduc­tive agents such as hydroxyurea, provide clinical benefits for some but not all patients and may not adequately treat PV-related symptoms. Furthermore, traditional treatment approaches are associated with potential side effects that may limit their usage and lead some patients to discon­tinue the treatment. Ruxolitinib is an orally available small-molecule tyrosine kinase inhibitor that is a potent and selective inhibitor of JAK1/JAK2. Ruxolitinib is approved in the US for patients with PV with an inadequate response or intolerance to hydroxyurea and in Europe for adults with PV who are resistant to or intolerant of hydroxyurea. In the Phase III RESPONSE registration trial, ruxolitinib was superior to the best available therapy in patients with PV who were resistant to or intolerant of hydroxyurea in controlling hematocrit levels, reducing spleen volume, and improving PV-related symptoms and quality-of-life measures. The most common nonhematologic adverse events in ruxolitinib-treated patients were headache, diarrhea, pruritus, and fatigue in the RESPONSE trial; hematologic adverse events were primarily grade 1 or 2. In the Phase IIIb nonregistration RELIEF trial, there were nonsignificant trends toward an improved symptom control in patients with PV on a stable hydroxyurea dose who were generally well controlled but reported disease-associated symptoms and switched to ruxolitinib vs those who continued hydroxyurea therapy. Updated treatment guidelines will be important for educating physicians about the role of ruxolitinib in the treatment of patients with PV.

The Effect of Ruxolitinib on White Blood Cell Counts in Patients with Polycythemia Vera: Results from the RESPONSE Trial

Background: Age, prior thrombotic events, and an elevated hematocrit are established risk factors for increased risk of thrombosis in patients with polycythemia vera (PV). Evidence also suggests that elevated white blood cell (WBC) counts ≥ 11×109/L are a significant independent risk factor for thrombosis in patients with PV (P =0.02; Barbui T, et al. Blood. 2015; 126:560-561). Therefore, this analysis was conducted to evaluate the impact of ruxolitinib (Rux) and best available therapy (BAT) treatment on WBC counts among patients with Baseline WBC counts ≥ 11×109/L in the RESPONSE trial. RESPONSE is a global, multicenter, open-label phase 3 trial investigating Rux and BAT in patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the RESPONSE trial, Rux was associated with durable improvements in hematocrit control without phlebotomy compared with BAT as well as reductions in WBC counts.Methods: Changes from Baseline in WBC counts in the Rux arm (n=110), BAT arm (n=112), and HU subgroup of the BAT arm (n=66) were evaluated as part of an exploratory analysis using the RESPONSE 80-Week analysis dataset. Patient subgroups with Baseline WBC counts ≥ 11×109/L and < 11×109/L were analyzed for changes in WBC counts at Weeks 12, 32, and 80. For patients with Baseline WBC counts ≥ 11×109/L, the proportion of patients who achieved a decrease in WBC counts to ≤ 10×109/L or a ≥50% reduction at Week 12 and Week 32, respectively, was summarized; time to achieve the decrease was analyzed by Kaplan-Meier method.Results: Baseline mean WBC counts were generally similar among patients in the Rux arm, BAT arm, and HU subgroup (17.6×109/L, 19.0×109/L, and 17.4×109/L, respectively). The proportion of patients with Baseline WBC counts ≥ 11×109/L was also similar among the Rux arm, BAT arm, and HU subgroup (75%, 71%, and 70%, respectively). In patients with Baseline WBC counts ≥ 11×109/L, patients treated with Rux had greater mean reductions in WBC counts compared with the BAT arm and HU subgroups, and these reductions were maintained over time; mean changes from Baseline in WBC values at Week 12/Week 32 (×109/L) were -7.7/-7.2 for Rux, -3.2/-4.2 for BAT, and -1.2/-2.2 for HU. In patients with lower Baseline WBC counts, mean values remained stable over time. The change from Baseline to Week 12 for individual patients with Baseline WBC counts ≥ 11×109/L is shown in Figure 1. In patients with Baseline WBC counts ≥ 11×109/L, worsening WBC counts were observed in 10.8% of patients in the Rux arm vs 35.4% in the BAT arm (P =0.0002) and 47.8% in the HU subgroup (P <0.0001). In this same subgroup with elevated WBC counts, a greater proportion of patients in the Rux arm achieved WBC counts ≤ 10×109/L or a ≥50% reduction compared with the BAT arm or HU subgroup (Week 12: Rux, 41% vs BAT, 19% vs HU, 13%; Week 32: Rux, 45% vs BAT, 22% vs HU, 9%); median time to this reduction was 8 weeks in the Rux arm and was not reached in the BAT arm or HU subgroup.Conclusion: Rux treatment resulted in better control of WBC counts compared to BAT in patients with PV. These changes in the Rux arm occurred early after study initiation (within a median of 8 weeks) and were durable over time. Although RESPONSE was not powered to assess the impact of Rux on thromboembolic events, the lower rate of thromboembolic events observed in the Rux arm vs the BAT arm (1.8 vs 8.2 per 100 patient-years of exposure) is consistent with the observed effects of Rux on hematocrit, WBC counts, and C-reactive protein levels, which are all associated with thromboembolic risk. [Display omitted] DisclosuresMiller:Incyte Corporation: Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy; Novartis: Consultancy. Naim:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Gadbaw:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau.

Evaluation of Infectious Complications in the First Year After Kidney Transplantation

Kidney transplantation (KT) is the best available therapy for patients with end-stage renal disease. Infectious complications are a common cause of morbidity and mortality. In this study, we evaluated the risk factors and outcomes of infectious complications in the first year after transplantation. This is a retrospective and observational study of kidney transplant recipients at Ankara University's Ibni Sina Hospital between January 2009 and August 2013. A total of 206 kidney transplant recipients were evaluated. In 129 patients, 298 infectious episodes occurred: 55 (26.7%) had 1; 33 (16%) 2; 19 (9.2%) 3; 7 (3.4%) 4; and 15 (7.3%) had 5 or more infectious episodes. The most common bacterial infection was urinary tract infection (128, 42.9%). Only 4 urinary tract infection episodes (3.1%) were associated with bacteriemia. Seventeen patients (5.7%) had bacteremia. Viral infections after transplantation were CMV infection (10.1%), BK virus infection (5.7%), and zona zoster (1.1%). Deceased donor kidney transplantation was the independent risk factor. Mean follow-up period was 66 months and was the same for the patients with and without infections. There was no significant difference in 5-year survival and creatinine levels at the last follow-up (logrank P = .409). Infections are the second most common cause of mortality in KT patients. The successful treatment of these complications and effective prophylaxis may decrease these complications.

Clinical Benefit of Ruxolitinib Treatment after Crossover from Best Available Therapy in Patients with Polycythemia Vera: Analysis of the RESPONSE Trial

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX.Methods: Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group.Results: A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment.Conclusion: Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. DisclosuresKiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.