Therapeutic Results and Survival of Patients with Myelofibrosis Treated with Ruxolitinib-A Real-Life Longitudinal Study.

The aim of this study was to analyze the therapeutic results and survival of patients with myelofibrosis treated with ruxolitinib in comparison with a group on standard therapy. It is a cross-sectional, retrospective, non-interventional, real-life study that was performed between January 2000 and February 2023. Patients treated between 2000 and 2016, before the introduction of ruxolitinib, constituted the control group (n = 45), while those treated after May 2016, after ruxolitinib inclusion, constituted the active group (n = 66). Demographic characteristics, clinical indicators, the severity of the disease, and survival were explored using Kaplan-Meier survival analyses. Spearman's correlation, linear regression, and other statistical analyses were performed. According to the Kaplan-Meier analysis, there was a 75.33% reduction in the fatality risk in the sample. On a general-population level, the fatality risk in the group treated with ruxolitinib varied between 7.9% and 77.18% compared to that of the risk in the control group. There was a decrease in blood parameters (leukocytes, hemoglobin, and platelets) and spleen size. During the first six months, the spleen size of the patients on ruxolitinib decreased by 6%, and during the second six months, it decreased by another 9%. This study shows that patients in a real-life clinical setting treated with ruxolitinib exhibited improved clinical signs of the disease, had a lower symptom severity, and survived longer than patients on standard therapy before ruxolitinib's entrance into the national market. The improvements correlate with those reported in randomized clinical trials.

Effectiveness and safety of romiplostim among patients with newly diagnosed, persistent and chronic ITP in routine clinical practice in central and Eastern Europe: an analysis of the PLATON study.

OBJECTIVES: The objective of this analysis was to assess the effectiveness and safety of romiplostim in the real-world by duration of primary immune thrombocytopenia (ITP): <3 ('newly diagnosed'), 3-12 ('persistent'), and >12 ('chronic') months. METHODS: This was a post-hoc analysis of the PLATON single-arm, observational cohort study of adults from five Central and Eastern European countries receiving ≥1 romiplostim dose as second-line therapy, or where surgery was contraindicated. Durable (≥75% of measurements with ≥50 × 109 platelets/L during weeks 14-24) and overall platelet response (≥30 or ≥50 × 109 platelets/L at least once), rescue therapy, bleeding, discontinuation of other ITP medications, and adverse drug reactions (ADRs) were assessed. RESULTS: Of 100 participants, 22.0% had newly diagnosed, 17.0% had persistent, and 61.0% had chronic ITP. Prior splenectomy was most frequently reported in chronic ITP (32.8%), prior bleeding was predominant in newly diagnosed patients (68.2%). Durable platelet response was achieved in 50.0% (95% confidence interval [CI]: 28.2-71.8%) of newly diagnosed, 35.3% (95% CI: 14.2-61.7%) of persistent, and 31.1% (95% CI: 19.9-44.3%) of chronic ITP patients. Overall platelet response was achieved in >80% across all strata. Safety was comparable across groups, with a low incidence of thrombotic ADRs and no bone marrow ADRs. DISCUSSION: In this real-world study, platelet response to romiplostim was consistent across all strata of ITP duration. ADRs were infrequent and similar across ITP settings. CONCLUSION: These findings support the utilization of romiplostim in patients with newly diagnosed and persistent ITP in accordance with recent guidelines and the recent romiplostim label extension.

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Real­world multiple myeloma management practice patterns and outcomes in selected Central and Eastern European countries.

Introduction Multiple myeloma (MM) treatment has evolved substantially in recent years. Solid data on the impact of treatment strategies on patient outcomes beyond clinical trials are scarce, especially in budget­restricted environments with limited access to new treatments. Objectives This study investigated treatment practices, patterns, and outcomes in real­world clinical practice in Bulgaria, Croatia, Czech Republic, Poland, Romania, and Slovakia. Patients and methods This was a noninterventional, observational chart review comprising a cross­sectional and a retrospective longitudinal phase observing adult patients with symptomatic MM at all stages of therapy. Results The study revealed structural differences in clinical practice compared with a similarly designed study previously conducted in 7 Western European countries. Stem cell transplantation was performed in less than half of newly diagnosed eligible patients. The most frequently used first­line regimens were bortezomib based, with frequent bortezomib retreatment after the first relapse. Lenalidomide­based regimens were predominant in the third and subsequent lines of therapy. Depth of response decreased with each treatment line, with half of patients achieving at least very good partial response (≥VGPR) in the first line, while only one­fourth achieved ≥VGPR in the third or subsequent lines. Time to progression was longer in patients with better response levels. Conclusions Inadequate access to advanced antimyeloma regimens and-in some countries-stem cell transplantation highlights the challenges of MM treatment in the region. Information on real­world patient management and its outcomes can provide valuable input for decision makers to effectively allocate limited resources.

Calorimetric markers for monitoring of multiple myeloma and Waldenström's macroglobulinemia patients.

The blood proteome has been studied extensively for identification of novel reliable disease biomarkers. In recent years, differential scanning calorimetry has emerged as a new tool for characterization of the thermodynamic properties of the major serum/plasma proteins and for the establishment of calorimetric markers for a variety of diseases. Here we applied calorimetry to monitor the effect of treatment of patients diagnosed with multiple myeloma and Waldenström's macroglobulinemia on the calorimetric profiles of patients' blood sera. The parameters derived from the calorimetric profiles were compared with the primary serum biomarkers, monoclonal immunoglobulin (M protein) concentration, and κ/λ free light chain ratio. For the secretory cases, the calorimetric parameters thermogram's shape similarity and weighted average center strongly depended on the M protein level but had lower sensitivity and specificity. By contrast, for non-secretory cases, the calorimetric parameters did not depend on the κ/λ free light chains ratio and exhibited significantly higher sensitivity and specificity than M protein levels. A combination of the immunological and calorimetric tests was found to greatly improve the sensitivity and specificity of the clinical status evaluation. The pronounced differences in blood sera thermograms before and during monitoring reflected the individual patients' response to treatment received and showed maintenance of heterogeneity during the disease course.

Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukemia treated with nilotinib.

Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1IS at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177).

Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study.

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01080391.

Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma.

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial.

BACKGROUND: In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. METHODS: In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. FINDINGS: Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). INTERPRETATION: Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. FUNDING: Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

Results of a prospective dose intensity and neutropenia prophylaxis evaluation programme (DIEPP) in cancer patients at risk of febrile neutropenia due to myelosuppressive chemotherapy.

OBJECTIVE: To describe the incidence of febrile neutropenia (FN) and use of pegfilgrastim in cancer patients with high overall risk of FN and to investigate the relationship between granulocyte-colony stimulating factor (G-CSF) guideline adherence and chemotherapy delivery in Central and Eastern Europe (CEE) and Austria. METHODS: Dose Intensity Evaluation Program and Prophylaxis (DIEPP) was a multicentre, prospective, and observational study of adult patients with breast cancer, lymphoma, lung cancer, gastric cancer, and ovarian cancer, who received chemotherapy with pegfilgrastim support and who had an overall risk of FN ≥ 20 %. Physicians assessed patient risk factors and reported their reasons for administering pegfilgrastim. RESULTS: Patients were enrolled from 113 centres in CEE and Austria between August 2010 and July 2013, and data were analysed from 1072 patients. The most common tumour types were breast cancer (50 %) and lymphoma (24 %). FN incidence was 5 % overall. FN occurred in 3 % of patients (28/875) who received pegfilgrastim as primary prophylaxis (PP) and 13 % of patients (19/142) who received it as secondary prophylaxis (SP); 79 % of FN events in SP patients occurred in the first cycle before pegfilgrastim was administered. The three most frequently chosen reasons for using pegfilgrastim were planned chemotherapy with high FN risk, female gender, and advanced disease. Overall, 40 % of patients received > 90 % of their planned chemotherapy dose within 3 days of the planned schedule. CONCLUSION: FN incidence was relatively low with pegfilgrastim PP in patients with a physician-assessed overall FN risk of ≥ 20 %. The most important reasons for pegfilgrastim use were consistent with the investigators' risk assessment and international guidelines.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. CONCLUSIONS: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Therapeutic effects of epoetin zeta in the treatment of chemotherapy-induced anaemia.

OBJECTIVE: To perform an open, non-controlled, multiple-dose, international, multicentre, phase III study to evaluate epoetin zeta, a biosimilar epoetin referenced to epoetin alfa, for the treatment of chemotherapy-induced anaemia in patients with cancer. METHODS: Safety, tolerability and efficacy of subcutaneously administered epoetin zeta were assessed in 216 patients with solid tumours or non-myeloid haematological malignancies receiving chemotherapy and at risk of transfusion. RESULTS: A significant (p < 0.0001) increase in mean haemoglobin (Hb) level (1.8 g/dL) was observed between baseline and week 12 (intent-to-treat population); 176/216 (81.5%) patients achieved a response (increase in Hb > or = 1 g/dL or reticulocyte count > or = 40,000 cells/microL) by week 8. Over the treatment period, 231 treatment-emergent adverse events were experienced by 91 patients; 9/216 (4.2%) experienced a clinically significant thrombotic event within the first 12 weeks of epoetin zeta treatment, significantly lower than the assumed 18% baseline incidence (p < 0.0001) based on historical data from epoetin trials. No transfusion was necessary for 175/216 patients (81.0%) and quality of life improved over the study. No patients developed anti-erythropoietin antibodies. Sponsor trial no: CT-830-05-0009. CONCLUSION: This study demonstrates that subcutaneously administered epoetin zeta is well-tolerated and has efficacy in the treatment of anaemia in patients with cancer receiving chemotherapy and at risk of transfusion.