Summary
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded‐access ...study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109/l) and patients without splenomegaly – populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low‐platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low‐platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non‐haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50–100 × 109/l. (ClinicalTrials.gov identifier NCT01493414).
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.
Summary
Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life (HRQoL). Here, we report post‐hoc analyses of the ...impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT‐II study (N = 219). During the follow‐up period of 48 weeks, HRQoL and MF‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy (BAT)‐treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ‐C30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT‐General, FACT‐Lym trial outcome index, and FACT‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.
Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged ≥18 ...years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low‐, intermediate (Int)‐1‐, Int‐2‐, and high‐risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse‐event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade ≥3 events in high‐risk patients. Approximately, 73% of patients experienced ≥50% reductions in palpable spleen length at any point in the ≤24‐month treatment period, with highest rates in lower‐risk categories (low, 82.1%; Int‐1, 79.3%; Int‐2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower‐risk patients. Across measures, 40%–57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int‐2‐risk than high‐risk patients (253.6 vs. 147.3 weeks), but not evaluable in low‐/Int‐1‐risk patients. By Week 240, progression‐free survival (PFS) and leukemia‐free survival (LFS) rates were higher in lower‐risk patients (PFS: low, 90%; Int‐1, 82%; Int‐2, 46%; high risk, 15%; LFS: low, 92%; Int‐1, 86%; Int‐2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower‐risk DIPSS patients in addition to higher risk.
Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically ...accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies.
Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up ...to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms.
This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects.
The sample comprised 182 patients (68% female, 61 ± 12 years). The prevalence of moderate-to-severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports-inactive patients preferred a frequency of 1-2 times/week and session durations of 15-45 min, whereas sports-active patients preferred 3-4 times/week and 30-60 min (p < 0.001). Higher sport-inactiveness was observed in patients with lower educational level compared to patients with higher educational level (69% vs. 50%, p = 0.021). For beginners, combined resistance-endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen.
PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations.
Purpose
Despite evidence for clinical benefits, recommendations in guidelines, and options for electronic data collection, routine assessment of patient-reported outcomes (PROs) is mostly not ...implemented in clinical practice. This study aimed to plan, conduct and evaluate the implementation of electronic PRO (e-PRO) assessment in the clinical routine of an inpatient radiation oncology clinic.
Methods
The guideline- and evidence-based, stepwise approach of this single-center implementation study comprised preparatory analyses of current practice, selection of assessment instruments and times, development of staff training, and evidence-based recommendations regarding the use of the e-PRO assessment, as well as on-site support of the implementation. Process evaluation focused on potential clinical benefit (number of documented symptoms and supportive measures), feasibility and acceptance (patient contacts resulting in completion/non-completion of the e-PRO assessment, reasons for non-completion, preconditions, facilitators and barriers of implementation), and required resources (duration of patient contacts to explain/support the completion).
Results
Selection of instruments and assessment times resulted in initial assessment at admission (EORTC QLQ-C30, QSR 10), daily symptom monitoring (EORTC single items), and assessment at discharge (EORTC QLQ-C30). Recommendations for PRO-based clinical action and self-management advice for patients concerning nine core symptoms were developed. Staff training comprised group and face-to-face meetings and an additional e-learning course was developed. Analyses of clinical records showed that e-PRO assessment identified more symptoms followed by a higher number of supportive measures compared to records of patients without e-PRO assessment. Analysis of n = 1597 patient contacts resulted in n = 1355 (84.9%) completed e-PROs (initial assessment: n = 355, monitoring: n = 967, final assessment: n = 44) and n = 242 (15.2%) non-completions. Instructions or support to complete e-PROs took on average 5.5 ± 5.3 min per patient contact. The most challenging issue was the integration of the results in clinical practice.
Conclusion
E-PRO assessment in oncologic inpatient settings is acceptable for patients and can support symptom identification and the initiation of supportive measures. The challenge of making the “data actionable” within the clinical workflow and motivating clinical staff to use the results became evident.
Plain English summary
Cancer patients’ perceptions regarding their symptoms and functioning are important as they can differ from a professional assessment. Patients’ perceptions and self-assessment can be collected via electronic devices. Thus, the clinical staff can see a graphic overview of individual disease-related burden. Despite studies indicating the benefit of this assessment for care and symptom management, it is not integrated into routine care so far. The aim of our study was, to plan, conduct and evaluate the implementation of electronic patient-reported assessment in a radio-oncology inpatient clinic under “real-life” clinical conditions instead of study conditions. Patients could complete an electronic assessment at the beginning/end and during their treatment. Results indicate that electronic self-assessment can identify more symptoms than the assessment of physicians and nurses. Patients completing a self-assessment are more likely to receive supportive measures. The majority of 80–90% of patients were willing to complete a self-assessment. On average 5–6 min were needed to explain or support the completion. While the intervention was feasible and acceptable for patients, motivating clinical staff using its results was most challenging. The importance of technical support became evident.
Sequential genotyping for phenotype‐driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2‐ and ...MPL‐mutations were described in some triple‐negative patients. Whether noncanonical and/or concomitant JAK2‐ and MPL‐mutations exist in myelofibrosis (MF) regardless of phenotype‐driver mutations is not yet elucidated. For this, next‐generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post‐ET–MF, n = 18; post‐PV–MF, n = 17). While no atypical JAK2‐ or MPL‐mutations were seen in 24 CALR‐positive samples, two JAK2‐mutations c.3323A > G, p.N1108S; c.3188G > A, p.R1063H were detected in two of the 21 (9.5%) triple‐negative patients. Twelve of the 82 (14.6%) JAK2V617F‐positive cases had coexisting germline JAK2‐mutations JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1 or at least one somatic MPL‐mutation MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1. Overall, MPL‐mutations always coexisted with JAK2V617F and/or other MPL‐mutations. None of the JAK2V617F plus a second JAK2‐mutation carried a TET2‐mutation but all patients with JAK2V617F plus an MPL‐mutation harbored a somatic TET2‐mutation. Four genomic clusters could be identified in the JAK2V617F‐positive cohort. Cluster‐I (10%) (noncanonical JAK2mutated (mut) + TET2wildtype (wt)) were younger and had less proliferative disease compared with cluster‐IV (5%) (TET2mut + MPLmut). In conclusion, recurrent concomitant classical and/or noncanonical JAK2‐ and MPL‐mutations could be detected by NGS in 15.7% of JAK2V617F‐ and MPLW515‐positive MF patients with genotype‐phenotype associations. Many of the germline and/or somatic mutations might act as “Significantly Mutated Genes” contributing to the pathogenesis and phenotypic heterogeneity. A cost‐effective NGS‐based approach might be an important step towards patient‐tailored medicine.
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