Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) associated with high disease burden, reduced quality of life (QOL), and ...shortened survival. To assess how MPNs affect patients, we conducted a global MPN Landmark survey. This online survey of patients with MPNs and physicians was conducted in Australia, Canada, Germany, Japan, Italy, and the United Kingdom. The survey measured MPN-related symptoms and the impact of MPNs on QOL and the ability to work as well as disease-management strategies. Overall, 219 physicians and 699 patients (MF,
n
= 174; PV,
n
= 223; ET,
n
= 302) completed the survey; 90% of patients experienced MPN-related symptoms. The most frequent and severe symptom was fatigue. Most patients experienced a reduction in QOL, including those with low symptom burden or low-risk scores. A substantial proportion of patients reported impairment at work and in overall activity. Interestingly, physician feedback and blood counts were the most important indicators of treatment success among patients, with improvements in symptoms and QOL being less important. Regarding disease management, our study revealed a lack of alignment between physician and patient perceptions relating to communication and disease management, with patients often having different treatment goals than physicians. Overall, our study suggested that therapies that reduce symptom burden and improve QOL in patients with MPNs are crucial in minimizing disease impact on patient daily lives. Additionally, our findings showed a need for improved patient-physician communication, standardized monitoring of symptoms, and agreement on treatment goals.
JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been ...treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis - a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib's mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov.
RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients ...without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.
Ruxolitinib was well tolerated and superior to best available therapy (including interferon IFN) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving ...polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients) and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at
clinicaltrials.gov
.
Abstract Purpose The single-arm OCTAVIA study evaluated front-line bevacizumab plus weekly paclitaxel and q3w carboplatin. Patients and methods Patients with newly diagnosed ovarian cancer ...(International Federation of Gynecology and Obstetrics FIGO stage IIb–IV or grade 3/clear-cell stage I/IIA) received bevacizumab (7.5 mg/kg, day 1), weekly paclitaxel (80 mg/m2 days 1, 8, 15) and carboplatin (area under the curve 6 AUC6, day 1) intravenously q3w for 6–8 cycles, followed by single-agent bevacizumab (total 1 year). The primary objective was to demonstrate median progression-free survival (PFS) > 18 months according to the lower 90% confidence limit. Secondary end-points included objective response rate, overall survival, safety and tolerability. Results Most (74%) of the 189 treated patients had stage IIIC/IV disease, similar to the ICON7 population. Patients received a median of six chemotherapy and 17 bevacizumab cycles. At the predefined cutoff 24 months after last patient enrolment, 99 patients (52%) had progressed and 19 (10%) had died, all from ovarian cancer. Median PFS was 23.7 months (95% confidence interval CI, 19.8–26.4 months), 1-year PFS rate was 85.6%, Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 84.6% and median response duration was 14.7 months. Most patients (⩾90%) completed at least six chemotherapy cycles. Grade ⩾3 peripheral sensory neuropathy occurred in 5% and febrile neutropenia in 0.5%. Grade ⩾3 adverse events typical of bevacizumab were no more common than in phase III bevacizumab ovarian cancer trials. There was one case of gastrointestinal perforation (0.5%) and no treatment-related deaths. Conclusion OCTAVIA met its primary objective, demonstrating median PFS of approximately 2 years. This bevacizumab-containing regimen is active and tolerable.
Few trial-based assessments of ruxolitinib in patients with lower-risk myelofibrosis (MF) have been conducted, and no studies have made such assessments in a real-world population. We assessed ...changes in spleen size and constitutional symptoms during ruxolitinib treatment using a retrospective, observational review of anonymized US medical record data of patients diagnosed with IPSS low-risk (n=25) or intermediate-1-risk (n=83) MF. The majority of patients were male (low risk, 60%; intermediate-1 risk, 69%). Most patients (92% and 77%) were still receiving ruxolitinib at the medical record abstraction date (median observation/exposure time, 8 months). The proportion of patients with moderate or severe palpable splenomegaly (≥10 cm) decreased from diagnosis (56%) to best response (12%). Fatigue was reported in 47% of patients and was the most common constitutional symptom. For most symptoms in both risk groups, shifts in the distribution of severity from more to less severe from diagnosis to best response were observed. Both patients with low-risk and intermediate-1-risk MF experienced a substantial decrease in spleen size with ruxolitinib treatment in real-world settings. For most symptoms examined, there were distinct improvements in the distribution of severity during ruxolitinib treatment. These findings suggest that patients with lower-risk MF may benefit clinically from ruxolitinib treatment.
Introduction: Published trial data shows that ruxolitinib improves both splenomegaly-related and nonsplenomegaly-related constitutional symptoms in patients with intermediate-2 and high risk ...myelofibrosis (MF). However, few trial-based assessments of ruxolitinib in lower-risk MF patients have been conducted and no studies to date have made such assessments in a real-world population. In this study, we assessed changes in spleen size and constitutional symptoms during ruxolitinib treatment for lower-risk MF patients in real-world clinical settings.
Methods: This was a retrospective, observational review of anonymized medical record data collected in January 2014 by 49 hematologists and oncologists in the United States. Patient inclusion criteria were: (1) diagnosed with lower-risk MF (International Prognostic Scoring System score of 0 or 1); (2) first treated with ruxolitinib ≥3 months before the medical record abstraction date; (3) ≥18 years of age at ruxolitinib initiation; (4) complete medical history from MF diagnosis until the medical record abstraction date; and (5) never enrolled in an MF-related interventional trial. Minimum quotas of n=50 and n=25 were set for intermediate-1 and low-risk patients, respectively, with a predetermined maximum of 110 patients in the combined total. Spleen size and constitutional symptoms were retrospectively observed at MF diagnosis, at ruxolitinib initiation, and at best response while on ruxolitinib. Spleen size was captured via predefined categories of no splenomegaly (spleen not palpable), very mild or mild splenomegaly (<10 cm palpated), moderate splenomegaly (10-20 cm palpated), or severe splenomegaly (>20 cm palpated). Symptoms of interest included those captured in the MPN Symptom Assessment Form (MPN-SAF), which were categorized as mild, moderate, or severe based on medical notes recorded at each time point. For this abstract, we present findings on the 7 most commonly observed MPN-SAF symptoms in our sample. This study was exploratory and used only descriptive analyses.
Results: A total of 108 patients were included in the study (25 low-risk and 83 intermediate-1 patients). Ruxolitinib start dates spanned January 2012 – November 2013. All low-risk patients were ≤65 years of age, and nearly 80% of intermediate-1 patients were ≤65 years of age. The majority of patients in both risk groups (60% and 69%, respectively) were male. A higher proportion of intermediate-1 patients were positive for JAK2 V617F mutation (72%) than low-risk patients (56%). Most patients (92% of low-risk, 77% of intermediate-1) were still receiving ruxolitinib treatment at the medical record abstraction date. Median observed ruxolitinib exposure time was approximately 8 months in both risk groups. In low-risk patients, the combined proportion of patients with moderate or severe splenomegaly (≥10 cm palpated spleen) decreased from 64% at MF diagnosis to 16% at best response during ruxolitinib treatment (Figure 1a). Similar findings were observed for intermediate-1 patients: the proportion with moderate or severe splenomegaly decreased from 53% at MF diagnosis to 10% at best response (Figure 1b). General fatigue was the most commonly observed constitutional symptom in both low-risk and intermediate-1 patients (Figures 2a and 2b). Shifts in symptom severity from more severe to less severe were observed in both low-risk and intermediate-1 patients. Among low-risk patients with fatigue, the proportion with moderate or severe fatigue decreased from 90% at MF diagnosis to 37% at best ruxolitinib response; in intermediate-1 patients, the decrease was from 76% at MF diagnosis to 42% at best response. For most other symptoms, similar improvements in severity distribution were observed.
Conclusions: Both low-risk and intermediate-1 MF patients experienced a substantial decrease in spleen size from MF diagnosis through ruxolitinib treatment in real-world clinical settings. Furthermore, for most symptoms examined, there was a distinct improvement in the distribution of symptom severity at the time of best response during ruxolitinib treatment. These findings suggest that lower-risk MF patients may benefit clinically from ruxolitinib treatment. Further studies are needed to assess adverse effects and evaluate the benefit-risk tradeoff of ruxolitinib.
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Davis:Novartis Pharmaceuticals Corporation: Research Funding. Kaye:Novartis Pharmaceuticals Corporation: Research Funding. Cote:Novartis: Employment. Off Label Use: The study discusses use of ruxolitinib in patients with lower-risk (IPSS 0 or 1) myelofibrosis (MF) in real-world practice; currently ruxolitinib is only indicated in higher-risk MF (IPSS >1).. Gao:Novartis: Employment. Ronco:Novartis: Employment. Seifeldin:Novartis: Employment. Mendelson:Novartis: Employment.
Background
Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) whose associated disease burden includes a range of debilitating ...symptoms, thrombosis, hemorrhage, and shortened survival. To enhance patient care, it is important to understand the impact of MPNs in patients' lives; however, little is known regarding how these conditions affect patients' quality of life (QOL), activities of daily living, productivity, and emotional well-being. The US LANDMARK survey (Mesa et al. BMC Cancer 2016) captured data for US patients. Here, we present an interim analysis of results of another MPN LANDMARK survey conducted in the rest of the world.
Methodology
MPN LANDMARK survey is a cross-sectional survey of MPN patients across 6 countries (Australia, Canada, Germany, Japan, Italy, and UK). Patients completed an online questionnaire to measure MPN related symptoms experienced over the past 12 months and the impact of their condition on their QOL and ability to work. Additional questions related to employment productivity and activity impairment (including absenteeism and loss of productivity over the past 7 days). Patients included in this interim analysis had completed the survey by July 18, 2016, with enrollment continuing in all countries.
Results
Patients: Overall, 437 patients had completed the survey (98 MF, 121 PV, 218 ET). For MF and PV, the male to female gender split was relatively even (54% male for each), whereas an expected greater proportion of ET patients was female (70%). Patients with MF were significantly older than PV and ET patients (mean ages, 62, 59, and 55 years, respectively) and more had been diagnosed within 2 years of experiencing their symptoms (83% MF, 67% PV, 71% ET).
MPN Symptoms (Table): Most patients (94%) experienced MPN-related symptoms in the past 12 months. The most commonly reported symptom among all subtypes was fatigue (69% MF, 62% PV, 73% ET), incidence of other common symptoms varied depending on disease subtype (MF: shortness of breath 38%, bruising 36%, night sweats 35%, early satiety 33%; PV: night sweats 36%, trouble concentrating 36%, trouble sleeping 34%, dizziness 34%; ET: trouble sleeping 37%, dizziness 37%, bruising 35%, night sweats 35%). When asked which symptom patients would most like to have resolved, most patients preferred to have feeling of fatigue/tiredness improved across all disease subtypes (31% MF, 30% PV, 33% ET). Patients experienced an average of 6.4 symptoms at diagnosis but this progressed to an average of 7.6 symptoms since diagnosis after a median time of 6 years.
QOL: A majority of patients indicated that they experienced a reduction in QOL due to MPN symptoms (87% MF, 71% PV, 73% ET) with 33% and 26% of MF and ET patients expressing that their condition has caused emotional hardship, and one-third of patients with PV reporting that they have felt worried or anxious about their disease (39%).
MPN Impact on Activity/Employment: Patients reported a high impact on their ability to work, 12% reported voluntarily leaving their job, 10% had taken early retirement, 10% had moved onto disability living allowance, 8% moved to a lower paid job, and 2% experienced involuntary loss of work (Table). Of the patients who were in full-time or part-time employment at the time of the survey (MF n=17), PV n=41, ET n=98), approximately, 40% had been absent from work within the past 7 days; this was the highest in MF patients (41% MF, 38% PV, 33% ET). On an average, over the past 7 days, MF patients had missed 3.1 hours from work, PV patients 2.3 hours and ET patients 2 hours. Across all subgroups, a substantial proportion of patients reported impairment in work (mean: 34% MF, 33% PV, 31% ET) and overall activity (mean: 46% MF, 42% PV, 39% ET).
Conclusions
This interim analysis from the MPN LANDMARK survey indicates that MPN patients experience a high burden of disease, including a high prevalence of symptoms, an increase in the number of symptoms from diagnosis and reduction of their emotional well-being, QOL, and ability to work. These results are consistent with those from the previous US LANDMARK survey with the addition of novel data on how MPNs impact work. When treating MPN patients, care should be taken in trying to manage a patient's disease burden, so as to minimize the impact on a patient's daily life. Further results from additional survey responses will be presented at the congress.
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Harrison:Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koehler:Novartis Inc. (Germany): Consultancy, Other: Training. Komatsu:Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boothroyd:Novartis: Employment, Equity Ownership. Spierer:Novartis: Employment. Ronco:Novartis: Employment. Taylor-Stokes:Adelphi Real World: Employment. Waller:Adelphi Real World: Employment. Mesa:Celgene: Research Funding; Galena: Consultancy; Novartis: Consultancy; CTI: Research Funding; Ariad: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding.
BACKGROUND:
Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and myelofibrosis (MF)-related symptoms. Additionally, ruxolitinib proved superior to ...placebo and best available therapy in the phase 3 COMFORT studies and showed improved survival. In some patients (pts) receiving ruxolitinib, adverse events (AEs) may lead to treatment interruption; in such pts, AE management, dose optimization, and efficacy expectations may be balanced. This analysis provides further information about the efficacy and safety of ruxolitinib in pts who have restarted treatment after treatment interruption (cutoff date, 01 January 2014) in the JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) trial, a large, phase 3b, expanded-access program.
METHODS:
Pts with MF classified as high risk, intermediate-2 risk, or intermediate-1 risk, with a palpable spleen (≥ 5 cm from the costal margin), received starting doses of ruxolitinib based on their platelet counts at baseline (5 mg twice daily bid; ≥ 50 to < 100 × 109/L, 15 mg bid 100 to 200 × 109/L, or 20 mg bid > 200 × 109/L). Endpoints included safety and tolerability, as well as changes in spleen length, symptoms, and laboratory values. This analysis included all pts who started study treatment ≥ 1 year before data cutoff and had ≥ 1 dose interruption of ≥ 7 days.
RESULTS:
This analysis included 207 pts (primary MF, 68.1%; female, 53.1%; median age, 69 years) presenting with baseline medians: spleen length, 13 cm (range, 1.0-35.0 cm); hemoglobin, 99 g/L (50.7% of pts with < 100 g/L); and platelets, 199.5 × 109/L.
At data cutoff, most pts (60.9%) remained on treatment (38.2%) or completed treatment per protocol (22.7%); the main reasons for discontinuation included AEs (18.4%), death (6.8%), disease progression (5.3%), and other (8.7%).
Overall, the median duration of exposure was 12.5 months: 1.9 months from baseline to interruption and 6.5 months after restart. The mean daily dose was 30.5 mg prior to treatment interruption and 19.4 mg after treatment restart. Dose interruptions lasted 7 to 14 days in 41.1% of pts (15 to 21 days, 26.6%; > 21 days, 32.4%) and were mostly due to AEs (92.3%). Most pts (67.1%) had only 1 dose interruption.
At weeks 12, 24, and 48, overall 45%, 53%, and 54% of pts, respectively, achieved a ≥ 50% reduction from baseline in palpable spleen length. In addition, at the same time points, 29%, 23%, and 23% achieved reductions from 25% to 50%. 68.2% (133/195) of pts experienced a ≥ 50% reduction at any time; 77 pts (58%) achieved it before interruption and 56 pts (42%) after restart. From spleen length at restart, 24% of pts achieved a further 50% reduction, 9% experienced a spleen length increase ≥ 50%, and 67% remained stable in between. Clinically meaningful improvements in symptoms (the range for the minimally important difference is 6.5 to 11.2 points), as assessed by the FACT-Lymphoma Total Score, were observed as early as week 4 (mean change from baseline, 9.6), with a trend toward improvement at week 48 (6.1).
The most common hematologic grade 3/4 AEs were anemia (43.5%) and thrombocytopenia (41.1%), leading to permanent discontinuations in 9 (4.4%) and 14 pts (6.8%), respectively. Rates of nonhematologic AEs grade ≥ 3 were low (≤ 2%), except for pneumonia (5.8%), abdominal pain (3.4%), urinary tract infection (3.4%), increased γ-glutamyltransferase (2.4%), asthenia (2.4%), and dyspnea (2.9%), but these rarely led to discontinuations (≤ 1%). Despite > 3-times longer exposure after restart, the rates of AEs before ruxolitinib interruption and after treatment restart were similar overall.
CONCLUSIONS:
In this cohort of pts, ruxolitinib provided reductions in spleen size and symptoms prior to and after treatment interruption. After restart of treatment, pts were able to stay on ruxolitinib at a median dose of ≈ 10 mg bid, and most pts did not require another interruption. Rates of AEs did not increase after treatment restart, with rates of some AEs decreasing; discontinuation rates after restart of treatment are comparable to those observed in the overall study population (Al-Ali et al. EHA 2014). Overall, ruxolitinib is generally safe and well tolerated and provides meaningful reductions in splenomegaly and symptoms in pts who have restarted ruxolitinib after treatment interruption.
Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.
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