Additional Supporting Information may be found in the online version of this article: Fig S1. Western blot analysis for KAT8 expression and H4K16 acetylation level in three leukemia cell lines. (B) Realtime PCR analysis for KAT8 mRNA expression during U937 cell line PMA-induced differentiation. (C) Vector control (Vec) and shKAT8 cells were incubated with PMA (10 ng/ ml) for 0 and 48 h, and adherent cells were photographed following PBS washing. (D) Real-time PCR analysis for KAT8 knockdown in U937 cell line. (E) Real-time PCR analysis for MN1 mRNA expression in vector control (Vec) and shKAT8 U937 cell line. (F) Vector control (Vec), shKAT8 and and shKAT8 + siMN1 cells lines were incubated with PMA (10 ng/ml) for 0 and 48 h, and adherent cells were photographed following PBS washing. Table SI. Clinical characteristics of the patients with AML.

Polycythemia vera (PV) is characterized by erythropoiesis and JAK2-activating mutations, with increased risks of morbidity and mortality. Most patients with PV are iron deficient, and treatment often includes hematocrit control with phlebotomy, which may exacerbate iron deficiency-associated complications. The phase 3 RESPONSE trial evaluated the JAK1/JAK2 inhibitor ruxolitinib (n=110) versus best available therapy (BAT; n=112) in patients with PV who were hydroxyurea-resistant/intolerant. Ruxolitinib was superior to BAT for hematocrit control, reduction in splenomegaly, and blood count normalization. This exploratory analysis, the first to evaluate iron status in a prospective study of patients with PV, investigated ruxolitinib effects on 7 serum iron markers and iron deficiency-related patient-reported outcomes (PRO). Among patients with evidence of baseline iron deficiency, ruxolitinib was associated with normalization of iron marker levels, compared with lesser improvement with BAT. Iron levels remained stable in ruxolitinib patients with normal iron levels at baseline. Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with baseline iron deficiency. The improvements in iron deficiency markers and PROs observed with ruxolitinib are suggestive of clinical benefits that warrant further exploration.

7087 Background: The RESPONSE trial is a multicenter, open-label phase 3 study evaluating the efficacy and safety of ruxolitinib (Rux) compared with best available therapy (BAT) in patients (pts) with polycythemia vera resistant to or intolerant of hydroxyurea. Results from the primary analysis, 48 wks from last pt first treatment (LPFT), were published (Vannucchi, NEJM 2015). Methods: This was a second preplanned analysis 80 wks after LPFT. The primary response was defined as achieving both hematocrit (HCT) control without phlebotomy (PBT) through wk 32 and a ≥ 35% reduction in spleen volume (SV) by imaging at wk 32. Durability of the primary response, HCT control, spleen volume reduction, and complete hematologic remission (CHR), as well as long-term safety, were evaluated. Results: At data cutoff, 91 (82.7%) pts randomized to Rux (Rux arm) were receiving treatment (median exposure, 111 wks), compared to 93 (84.5%) at the wk 48 analysis (median exposure, 81 wks). No pts remained on BAT, compared to 3 pts at the wk 48 analysis. Of the 23 (21%) pts in the Rux arm who achieved the primary response at wk 32, only 1 lost this response. For the 60% of pts in the Rux arm who achieved HCT control at wk 32, the probability of maintaining this response for 80 wks from time of initial response was 89%. Of the 98 pts on Rux at wk 32, 90% did not have a PBT from wk 32 to 80. A ≥ 35% SV reduction at wk 32 was achieved in 38% of Rux pts; all maintained their response. CHR at wk 32 was achieved in 24% of Rux pts; the probability of maintaining CHR for 80 wks was 69%. The Pruritus Symptoms Impact Scale was "very much improved" for 5 of 10 pts in the Rux arm at their end of study visit. The most common nonhematologic adverse events in the Rux arm were headache (21.8% at the wk 80 analysis [ie, entire follow-up] vs 20.9% at the wk 48 analysis), diarrhea (20.0% vs 19.1%), pruritus (20.0% vs 17.3%), and fatigue (17.3% vs 17.3%); most were grade 1 or 2. Grade 3 or 4 anemia and thrombocytopenia occurred in 1.8% and 5.5% of pts, respectively (no increase from wk 48 analysis). The rate of treatment discontinuation in the Rux arm due to adverse events remained low (4.5%). Conclusions: In RESPONSE, Rux responses were durable and treatment remained generally well tolerated, with 83% still receiving Rux at a median exposure of 111 wks. Clinical trial information: NCT01243944.

OBJECTIVES:Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. METHODS:In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). RESULTS:Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. CONCLUSIONS:Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant.

Summary The randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera ( PV )‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV ‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID ( n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster ( TSS ‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS ‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV ‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

2551 Background: Patients (pts) with ovarian cancer (OC) often develop resistance to standard medical treatment (Rx) with platinum-taxane chemotherapy. Preclinical studies have shown that intra-nuclear activation of AKT by DNA-dependent protein kinase inhibits cisplatin-mediated DNA damage in OC cell lines, which is reversible through AKT inhibition. The following study investigates whether the oral pan-AKT inhibitor afuresertib can restore sensitivity to platinum Rx and reverse acquired resistance to standard Rx in recurrent OC. Methods: In phase I, the maximum tolerated dose (MTD) was investigated; pts with recurrent OC were treated with afuresertib (orally qd) at doses escalating from 50 to 150 mg combined with paclitaxel (IV 175 mg/m2) and carboplatin (AUC 5) q3w for ≤ 6 cycles followed by afuresertib maintenance until progression/toxicity. Phase II investigated efficacy and safety of afuresertib at MTD plus paclitaxel and carboplatin followed by afuresertib maintenance. Pts were split into two cohorts: platinum resistant (PTR) or platinum refractory pts. Results: Phase I enrolled 29 pts; dose-limiting toxicities (DLTs) were reported in 1 pt from the 125 mg cohort (G3 rash [n = 1]) and 2 pts from the 150 mg cohort (G3 rash in both pts with concurrent G2 febrile neutropenia and G2 lip swelling in 1 pt). The MTD of afuresertib was established as 125 mg. Phase II enrolled 30 heavily pre-treated pts (median time since diagnosis = 2.1 y; median prior Rx lines = 3); 28 were PTR and 2 were platinum refractory. Tolerability of Rx was consistent with findings in phase I; G3/4 AEs included diarrhea (20%), fatigue (10%), rash (10%), vomiting (7%), and nausea (3%). Overall response rate (ORR) per RECIST v1.1 for pts in the platinum-resistant cohort was 32.1% (95% CI: 15.9–52.4) and median PFS was 7.1 months (95% CI: 6.3–9.0). ORR per GCIG CA125 in evaluable pts was 52.0% (n = 25; 95% CI: 31.3–72.2). Ad hoc analyses showed ORR to correlate with duration of sensitivity to prior platinum Rx and platinum-free intervals. Conclusions: An MTD of 125 mg afuresertib was established for the Rx of pts in combination with paclitaxel and carboplatin. Combination Rx was well tolerated and showed promising activity in pts with PTR OC. Clinical trial information: NCT01653912.

e18082 Background: Polycythemia vera (PV) is associated with over-activation of the JAK/STAT pathway and characterized by erythrocytosis and an increased risk of thrombosis. Some patients (pts) may require chronic therapy to control their blood counts and symptoms. The purpose of this analysis was to evaluate the long-term safety of ruxolitinib (Rux), a JAK1/JAK2 inhibitor, in a PV clinical trial program. Methods: This safety analysis included pts from the following studies: 1) a phase 2, single-arm, open-label study in pts resistant to or intolerant of hydroxyurea (HU) (NCT00726232); 2) the phase 3, randomized, open-label RESPONSE trial (NCT01243944) comparing Rux with best available therapy (BAT) in HU resistant/intolerant pts; and 3) the phase 3b, randomized, blinded RELIEF study (NCT01632904) comparing Rux with HU in pts generally well controlled on HU but reporting symptoms. Safety data were pooled for Rux across the two studies in HU resistant/intolerant pts (phase 2 study and RESPONSE), including pts in RESPONSE receiving Rux after crossover from BAT. Results: Median Rux exposure was 19.5 months (range, 0.3–66.7 months) in the HU resistant/intolerant group (N = 241), representing 457 pt-yrs of exposure. The most common adverse events (reported as rate per 100 pt-yrs of exposure) in this group were diarrhea (8.7), headache (8.5), and pruritus (7.4); most were grade 1 or 2. Anemia and thrombocytopenia of grade 3 or 4 occurred in 3.7% and 3.7% of pts, respectively, over the duration of follow-up. The rate of non-melanoma skin cancer was 2.8 per 100 pt-yrs. Herpes zoster occurred at a rate of 5.0 per 100 pt-yrs. The rate of thromboembolic events was 2.2 per 100 pt-yrs (vs 8.2 per 100 pt-yrs in the RESPONSE BAT group). In RELIEF, median exposure was 21.6 weeks in the Rux arm (N = 54). During the blinded phase, the adverse event profile was generally consistent with that observed in studies of HU resistant/intolerant pts. Conclusions: Overall, this long-term follow-up of the PV clinical trial program provides evidence supporting the safety and tolerability of Rux in pts who have an inadequate response to or are intolerant of HU. Clinical trial information: NCT00726232, NCT01243944, and NCT01632904.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis and debilitating symptoms. Patients (pts) often have elevated white blood cell (WBC) and platelet (PLT) counts. Ruxolitinib is a JAK1/JAK2 inhibitor that proved superior to best available therapy (BAT) in controlling hematocrit (HCT) and improving splenomegaly and symptoms in pts with PV who have an inadequate response to or unacceptable side effects from hydroxyurea (HU). In the phase 3 RESPONSE study, HCT control was achieved by wk 32 in 60% of pts in the ruxolitinib arm and 20% of pts in the BAT arm; 40% of pts in the ruxolitinib arm achieved ≥ 35% reductions in spleen volume from baseline at wk 32 (spleen response) vs 1% in the BAT arm. Although not all pts randomized to ruxolitinib achieved protocol-defined HCT control or a spleen response at the time of the primary analysis, 85% remained on treatment, suggesting that most pts were deriving a therapeutic benefit from ruxolitinib therapy beyond HCT and spleen responses. This was supported by a higher proportion of HCT non-responders (ie, pts who did not achieve protocol-defined HCT control) achieving a symptom response (≥ 50% reduction in MPN-SAF total score) at wk 32 compared with all pts in the BAT arm (38% vs 4%; Verstovsek et al, ASH 2014). Additionally, HCT non-responders in the ruxolitinib arm had a greater median duration of time to subsequent phlebotomy (PBT) eligibility (52 wk) compared with HCT non-responders in the BAT arm (21 wk; Verstovsek et al, ASH 2014). Here, we explore whether pts randomized to ruxolitinib who did not achieve HCT control or a spleen volume response at the time of the primary analysis were able to subsequently achieve a response with continued ruxolitinib treatment.

ObjectivesThe randomized comparison of deferasirox to deferoxamine for myocardial iron removal in patients with transfusion-dependent anemias (CORDELIA) gave the opportunity to assess relative prevalence and body distribution of iron overload in screened patients.MethodsPatients aged 10yr with transfusion-dependent anemias from 11 countries were screened. Data were summarized descriptively, overall and across regions.ResultsAmong 925patients (99.1% with -thalassemia major; 98.5% receiving prior chelation; mean age 19.2yr), 36.7% had myocardial iron overload (myocardial T2* 20ms), 12.1% had low left ventricular ejection fraction. Liver iron concentration (LIC) (mean 25.8mg Fe/g dw) and serum ferritin (median 3702ng/mL) were high. Fewer patients in the Middle East (ME; 28.5%) had myocardial T2* 20ms vs. patients in the West (45.9%) and Far East (FE, 40.9%). Patients in the West had highest myocardial iron burden, but lowest LIC (26.9% with LIC <7mg Fe/g dw) and serum ferritin. Among patients with normal myocardial iron, a higher proportion of patients from the ME and FE had LIC 15 than <7mg Fe/g dw (ME, 56.7% vs. 17.2%; FE, 78.6% vs. 7.8%, respectively), a trend which was less evident in the West (44.6% vs. 33.9%, respectively). Transfusion and chelation practices differed between regions.ConclusionsEvidence of substantial myocardial and liver iron burden across regions revealed a need for optimization of effective, convenient iron chelation regimens. Significant regional variation exists in myocardial and liver iron loading that are not well explained; improved understanding of factors contributing to differences in body iron distribution may be of clinical benefit.

SummarySome patients with β thalassaemia experience non‐progressive creatinine increases with deferasirox, mostly within normal limits; the mechanisms involved are not fully elucidated. The effects of deferasirox on renal haemodynamics, including glomerular filtration rate (GFR) and renal plasma flow (RPF), were investigated in a Phase I, open‐label study in β thalassaemia major patients with iron overload. Patients received deferasirox 30 mg/kg/d up to Week 8, followed by a 2‐week washout period, and extended treatment up to Week 104 with a 4‐week washout period. In the short‐term study (n = 11), mean GFR and RPF declined from baseline to Week 8 (mean [%] change:−9·2 [−9·5%] and −105·7 ml/min [−17·8%], respectively). A similar pattern was observed during the long‐term study (n = 5); mean GFR and RPF decreased up to Week 52 (−19·1 [−17·7%] and −155·6 ml/min [−26·1%]), with similar change at Week 104 (−18·4 [−17·2%] and −115·9 ml/min [−19·6%]). Measures returned to baseline values after each washout. Serum creatinine and creatinine clearance followed a similar pattern. Effects of deferasirox on renal haemodynamics were mild and reversible for up to 2 years of treatment, with no progressive worsening of renal function over time. www.clinicaltrials.gov: NCT00560820.

Objective Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC Methods THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6months before reaching LIC<3 (Period 1), and the 6months immediately before achieving LIC<3 (Period 2). Results Mean +/- SD deferasirox treatment duration up to reaching LIC<3 was 476 +/- 207d, and deferasirox dose was 9.7 +/- 3.0mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LICLIC assessment. Conclusions The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation.

Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK/STAT activation and is associated with erythrocytosis and a broad symptom burden that may negatively impact patient quality of life (QoL). Hydroxyurea (HU) is often used as first-line therapy for high-risk patients but may not effectively control or reduce symptom burden. RESPONSE is a phase III trial comparing ruxolitinib (RUX) with best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU according to modified European LeukemiaNet (ELN) criteria. The primary study endpoint (a composite of hematocrit control and ≥35% spleen volume reduction at Week 32) was achieved by 21% of patients in the RUX arm vs 1% in the BAT arm (P<0.0001); 77% of patients in the RUX arm achieved at least one component of the primary endpoint. The current analysis was conducted to evaluate the effect of RUX on PV-related symptoms and QoL measures in the RESPONSE trial.

Long‐term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion‐dependent beta thalassemia patients. In a 1‐year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long‐term safety profile of deferasirox or DFO was consistent with previous reports; serious drug‐related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron‐overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938). Am. J. Hematol. 90:91–96, 2015. © 2014 Wiley Periodicals, Inc.

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.

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.

Introduction: Ruxolitinib is a JAK 1/2 inhibitor approved in patients with myelofibrosis (MF). The safety profile is well characterized with anemia being a common adverse event. The aim of this mathematical modeling analysis is to characterize individual hemoglobin (Hb) dynamics during ruxolitinib treatment, and to establish a dose-response relationship between treatment and occurrence of an anemic event as defined by an on-treatment reduction in Hb to < 8g/dL.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume.

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).