Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and ...safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
Myelofibrosis (MF) is the most symptomatic of the myeloproliferative neoplasms and is associated with the greatest symptom burden and poorest prognosis. Patient-reported outcomes is an effective way ...to identify patients' needs and risks/benefits of MF treatment. We aimed to study quality of life (QoL) and symptom burden in MF patients in a real-world setting.
44 MF patients - 27 primary MF, 8 post-essential thrombocytopenia, 9 post-polycythemia vera - were enrolled in the multicenter real-world QoL study. Mean age - 60.8±13.3; male/female - 14/30. All the patients received the best available treatment (BAT, n=28) or novel treatment modality ruxolitinib (n=16) for at least 6 months (range 6-160 mths). A high proportion of patients (80%) had intermediate to high prognostic risk scores according to International Prognostic Scoring System. All the patients completed the QoL questionnaire SF-36, symptom assessment questionnaire CSP-MF and Patient Global Impression of Change (PGIC) tool. Integral QoL Index (IQoLI) in MF patients was calculated on the basis of SF-36 and QoL impairment grade was assessed in comparing with QoL population norms (PN). Comparison t-test for independent samples or Mann-Whitney test was applied.
The heterogeneity of MF patients population in terms of QoL impairment was shown: 55% of patients had mild QoL impairment (IQoLI≤25% from PN), 7% - moderate (IQoLI≤25-50% from PN), 38% - severe or critical QoL impairment (IQoLI≤50% from PN). Patients receiving BAT exhibited more pronounced QoL impairment as compared to patients receiving ruxolitinib (p<0.05); they had worse physical functioning, general health, vitality, social functioning, and mental health (p<0.05). All the patients experienced multiple symptoms; the most severe symptoms were fatigue, inactivity and pain in bones/muscles. The symptoms were more expressed in patients on BAT as compared to patients on ruxolitinib (p<0.005). Patient's impression of health changes was better in patients treated with ruxolitinib: the mean PGIC score was higher in patients on BAT on ruxolitinib - 4.4 vs 2.3 (p=0.001).
Quality of life and perceived change in health condition are better and symptom severity is less in MF patients on ruxolitinib therapy than those on BAT. Results of this real-world study demonstrate benefits of ruxolitinib therapy from patient perspective. Patient-reported outcomes are of help to better identify the needs of MF patients.
No relevant conflicts of interest to declare.
Abstract 3822
Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) commonly experience severe thrombocytopenia with a high risk for bleeding. Eltrombopag is an oral ...thrombopoietin receptor agonist indicated for treatment of chronic immune thrombocytopenia. Eltrombopag may reduce platelet transfusions and bleeding, and preclinical data suggest that it may have an anti-leukemic effect (Erickson-Miller 2008; Kalota 2010; Will 2009; Mavroudi 2010; Roth 2012). We present results of the 8-week, open-label part of an ongoing multicenter trial to evaluate the safety and efficacy of eltrombopag in patients with intermediate (int)-2 or high-risk MDS or AML (WHO criteria) with platelets <25,000/μL.
Eltrombopag was administered daily at 3 escalating dose levels, with increases every 2 weeks in patients without a platelet response: Dose Level (DL)1, 100 mg (50 mg for East Asian EA patients); DL2, 200 mg (100 mg for EA patients), and DL3, 300 mg (150 mg for EA patients). Platelet response was defined as on-treatment platelets ≥2x baseline and >20,000/μL for patients with baseline platelets <20,000/μL or ≥2x baseline and ≥50,000/μL for patients with baseline platelets ≥20,000/μL. Treatment with hydroxyurea was permitted.
Seventeen patients with a median age of 72 years (range, 49–91) with int-2 or high-risk MDS (n=12) or AML (n=5) were enrolled. Baseline median platelet count was 12,500/μL (range, 6,000–35,000/μL). Sixteen of 17 patients had received ≥1 prior treatment for their disease. Five, 3, and 9 patients received DL1, DL2, and DL3 as their maximum daily dose. Nine of 17 patients completed 8 weeks of treatment, 6 of whom continued to receive eltrombopag in the extension part of the study. Of the 9 patients who completed all 8 weeks of therapy, 2, 2, and 5 were receiving DL1, DL2, and DL3 at the time they completed their treatment. Ten of 17 (59%) patients had reductions in platelet transfusions during treatment with eltrombopag compared with the 4-week pre-treatment period (Table). Platelet responses were observed in 4/17 (24%) patients. Post-baseline bone marrow examinations 1–3 months after starting eltrombopag (n=11) showed no clinically meaningful changes in blast counts. The most common adverse events (AEs) were pyrexia (n=4), alanine aminotransferase (ALT) increase, diarrhea, epistaxis, headache, and pneumonia (n=3 each). Two of 3 patients with increased ALT met protocol-defined liver-stopping criteria. Both elevations occurred while patients were receiving 300 mg eltrombopag and resolved following discontinuation of eltrombopag. Three deaths were reported (2 patients with fatal AEs of sepsis, considered not related to eltrombopag treatment; 1 patient died of disease progression).
Preliminary data suggest that eltrombopag may reduce platelet transfusion requirements in thrombocytopenic patients with advanced MDS and AML. AEs were as expected for this patient population and for treatment with eltrombopag. Randomized studies assessing the potential benefits and risks of eltrombopag in this setting are ongoing.TableSummary of Clinical Benefit by PatientPatientBaseline DiseasePlatelet TransfusionsPlatelet ResponsecBone Marrow Blasts, %ScreeningaBest ResponsebBaselinePost-treatmentAMDS10Yesc1112BMDS10No1520CAML10 (3m)No2525DAML9Not evaluableNo20No post-baselineEMDS22No105FMDS00Yesc118GMDS20No0No post-baselineHMDS44No0No post-baselineIMDS12 (2m)No18No post-baselineJMDS3Not evaluableNo00KMDS21 (2m)Yesc1621LMDS84No178.6MMDS2Not evaluableNo19.420NAML114Yesc48.8No post-baselineOMDS114No00PAML10No36.2No post-baselineQAML10 (2m)No26.755.4aScreening platelet transfusions are the number of transfusions during the 4 weeks prior to Day 1bBest platelet transfusion response is the minimum number of transfusions received by each patient during any 4-week period during treatment with eltrombopag. In parentheses, is the duration in months (m) for the best transfusion response, if >1 month. Patients with <4 weeks of eltrombopag treatment were not evaluablecPlatelet counts for platelet responders: A: Baseline=12,000/μL, maximum=33,000/μL; F: Baseline=27,500/μL, maximum=114,000/μL; K: Baseline=12,500/μL, maximum=47,000/μL; N: Baseline=11,000/μL, maximum=26,000/μL. Platelet counts assessed within 3 days of a transfusion were not evaluable for a platelet response
Off Label Use: Eltrombopag is an oral TPO agonist indicated for chronic ITP being studied in MDS/AML. Garcia Delgado:Celgene: Consultancy, Speakers Bureau. Mannino:GlaxoSmithKline: Employment. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Messam:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment.
Conventional therapies do not provide satisfactory control of multiple sclerosis (MS) due to their inability to eradicate self-specific T cell clones. During the last decade high-dose ...immunosuppressive therapy (HDIT) with autologous haematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients. We have identified 4 strategies of HDIT+AHSCT depending on the stage in disease process: early, conventional, late, and salvage. In the current study we aimed to study clinical and patient-reported outcomes in MS patients after different strategies of HDIT+AHSCT. One hundred and twenty patients with MS (secondary progressive – 53 patients, primary progressive –21, progressive-relapsing – 9, relapsing-remitting – 37) were included in this study (mean age - 33.0, range: 17–54; male/female – 53/67). Thirty seven patients underwent early transplantation (EDSS 1.0–3.0), 72 patients – conventional transplantation (EDSS 3.5–6.0), 6 patients – late transplantation (EDSS 6.5–7.0), and 5 patients – salvage transplantation (EDSS 7.5–8.5). Median EDSS at baseline was 5.0 (range 1.5 – 8.0). The mean follow-up duration was 18 months (range 6 – 108 months). Neurological and quality of life (QoL) evaluation was performed at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter following AHSCT; MRI examinations - at baseline, at 6, 12 months, and at the end of follow-up. Notably, transplantation procedure was well tolerated by the patients with no transplant-related deaths. The efficacy analysis was performed in 79 patients. At 6 months post transplant the following distribution of patients according to clinical response was observed: 42 patients (53%) achieved an objective improvement of neurological symptoms; 37 patients (47%) had disease stabilization. At long-term follow-up clinical response was classified as improvement in 40 patients (50.6%); stabilization in 34 patients (43.1%); progression in 5 patients (1 patient after early transplantation, 3 patients after conventional transplantation, and 1 patient after late transplantation). No active, new or enlarging lesions were registered in patients without disease progression. Furthermore, out of 44 patients included in QoL analysis 39 exhibited improved QoL 6 months post-transplantation. Further QoL improvement was observed at longer follow-up in patients without disease progression. All the patients without disease progression were off therapy throughout the post-transplant period. Thus, AHSCT appears to be an effective treatment for MS both in terms of clinical and patient-reported outcomes. Further studies should be done to establish the best timing for transplantation and to validate high-dose immunosuppressive therapy with ASCT regimens in patients receiving early, conventional, late and salvage transplantation.
During the last decade immunoablative therapy with ASCT (IT+ASCT) has been used with increasing frequency as a therapeutic option for MS patients. Among a number of unanswered questions is the timing ...of IT+ASCT. We have identified 3 strategies of IT+ASCT depending on the stage in disease process: early, conventional and salvage/late. The goal of our research was to study clinical and patient-reported outcomes in MS patients after early, conventional and salvage/late transplantation. 54 patients with MS (secondary progressive - 26 patients, primary progressive -10, progressive-relapsing - 1, and relapsing-remitting - 17) from 6 medical centers were included in this study (mean age - 32.0, range: 17–51; male/female - 21/33). 13 patients underwent early, 37 patients - conventional, and 4 patients - salvage/late transplantation. Median EDSS at base-line was 6.0 (range 1.5 – 8.0). The median follow-up duration was 18 months (range 6 – 84 months). Neurological and quality of life (QoL) evaluation was performed at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter following IT+ASCT. MRI examinations were conducted at baseline, at 6, 12 months, and at the end of follow-up. FACT-BMT and FAMS were used for QoL evaluation. Notably, no transplant-related deaths or unpredictable severe adverse events were observed. All 42 patients (6 - early transplantation; 32 - conventional transplantation; 4 - salvage/late transplantation) with the follow-up of longer than 9 months experienced clinical stabilization or improvement. More than half of them (27 patients) improved: 8 patients showed significant improvement in EDSS, 9 patients improved by 1.0 point, and 10 - by 0.5 points on EDSS. Notably, all of the patients after early transplantation (mean age - 28.0) improved at least by 0.5 points on EDSS. 15 patients achieved stabilization. 2 patients deteriorated to a worse score after 18 months of stabilization; 2 others progressed after 12 and 30 months of improvement, respectively. All of the patients with clinical stabilization and improvement had negative MRI scans. Out of 24 patients included in QoL analysis 22 exhibited improved QoL 6 months post-transplantation. In conclusion, IT+ASCT appears to be an effective treatment for MS both in terms of clinical and patient-reported outcomes. The data obtained point to feasibility of early, conventional and salvage/late transplantation in MS patients. Our data support the hypothesis that transplantation is more effective in young patients at early stages of rapidly progressing disease. Further studies should be done to establish the best timing for transplantation and to validate IT+ASCT regimens in patients receiving early, conventional and salvage transplantation.
During the last decade HDCT+ASCT is more often used as a therapeutic option for MS patients. The major treatment outcomes for MS patients are disease-progressive free period and improvement of ...patient's quality of life (QoL). We aimed to study treatment outcomes in MS patients after early, conventional and salvage HDCT+ASCT.
Thirty two patients with MS (secondary progressive - 16 patients, primary progressive - 8, progressive-relapsing - 1, relapsing-remitting - 7) from 6 medical centers were included in this study (mean age - 32.0, range: 19–49; male/female - 12/20). Two patients underwent early HDCT +ASCT, 27 patients - conventional HDCT+ASCT and 3 patients - salvage HDCT+ASCT. Median EDSS at base-line was 6.0 (range 2.0 – 8.0). The median follow-up duration was 18 months (range 6 – 78 months). All of the patients had previously undergone conventional treatment. Neurological and QoL evaluation was provided at baseline, at discharge, 3, 6, 9, 12 months, and then every 6 months after HDCT+ASCT. MRI was conducted at baseline, at 6, 12 months, and at the end of follow-up. FACT-BMT and FAMS were used for QoL evaluation. QoL response was evaluated using Integral QoL index.
All 27 patients with the follow-up longer than 1 year, included in the analysis, experienced a clinical stabilization or improvement. More than half of them improved: 6 patients showed significant improvement in EDSS (by more than 1.0 point), 4 patients improved by 1.0 point, and 5 patients - by 0.5 points on EDSS. Twelve patients achieved stabilization. Two patients deteriorated to a worse score after 18 months of stabilization; 2 other patients progressed after 12 and 30 months of improvement, respectively. All the patients with clinical stabilization and improvement exhibited negative MRI scans.
Out of 21 patients included in the analysis of QoL response 19 exhibited improved QoL 6 months post-transplantation. At one year after HDCT+ASCT 1 patient exhibited excellent QoL response; 3 patients - good QoL response; 7 patients - moderate QoL response and 8 patients - minimal QoL response. At 2.5 years post-transplantation 3 more patients had excellent QoL response. Further QoL improvement was observed at longer follow-up. One of the patients who experienced progression after stabilization had no QoL response; another patient who progressed after stabilization had stable QoL during 6 months post-transplant and significantly worsened at 9 months.
In conclusion, clinical response was observed in 100% of MS patients after early, conventional and salvages HDCT+ASCT. The majority of patients with clinical response had a good or moderate QoL response. Further studies should be done to investigate the clinical and patient-reported outcomes of HDCT+ASCT in MS patients to better define treatment success.
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