Pomalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of the non-interventional study POSEIDON and comparison with the pivotal phase 3 clinical trials.

BACKGROUND: Prognosis of patients with multiple myeloma (MM) who have relapsed on or become refractory to immunomodulators and bortezomib is poor, and treatment options are limited. While pomalidomide plus low-dose dexamethasone (POM/DEX) has demonstrated efficacy in clinical trials, real-world evidence is scarce. PATIENTS AND METHODS: POSEIDON was a prospective non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of POM/DEX in patients with relapsed or refractory MM (R/RMM) pretreated with at least two prior therapy lines including both lenalidomide and bortezomib in real world in Germany. Patients received POM/DEX according to physicians' choice. Data were analyzed descriptively. RESULTS: Between 2014 and 2017, 151 patients were enrolled, 144 patients with a median of three prior therapy lines qualified for effectiveness analysis. Median age was 73.2 years. Median progression-free and overall survival were 6.3 months [95% confidence interval (CI) 5.2, 8.6] and 12.9 months [95% CI 10.6, 15.1]. Most frequent grade 3/4 adverse events were leukopenia (8.2%), pneumonia (7.5%) and anemia (5.5%). QoL was maintained after start of POM/DEX. CONCLUSION: The results of POSEIDON support the effectiveness and safety of POM/DEX in R/RMM patients pretreated with lenalidomide and bortezomib and highlight the clinical value of the POM/DEX regimen in the real-world setting. Registered at clinicaltrials.gov (NCT02075996).

Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients' preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer.

BACKGROUND: The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. METHODS: In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). RESULTS: 61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first-/second-line, Cap+Bev) and 54.1% and 52.9% (first-/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines. CONCLUSIONS: Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians' preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported. TRIAL REGISTRATION: EudraCT No: 2013-005329-22. Registered on 19 August 20.

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.

Significance of Patient-Reported Outcomes for Metastatic Breast Cancer Patients.

BACKGROUND: Breast cancer is still the most common malignancy in women worldwide. Once metastasized, breast cancer treatment primarily aims at reducing symptom burden, thereby trying to maintain and improve a patient's quality of life (QoL), delaying disease progression, and prolonging survival. Curing the disease is not possible in the palliative setting. To better understand metastatic breast cancer patients, their symptoms, and wishes, which are important for treatment decision making and outcome, patient-reported outcomes (PROs) are of great importance, giving an impression of what really matters to and concerns a patient. SUMMARY: Many advances have been made to implicate PROs in clinical trials, non-interventional studies, registries, and clinical routine care of metastatic breast cancer. For example, large phase III trials like PALOMA-3 (NCT01942135), MONALEESA-7 (NCT02278120), HER2CLIMB (NCT02614794), and KEYNOTE-119 (NCT02555657) trials implemented PROs in their trial design to assess the QoL of their trial patients. Also, non-interventional studies on metastatic breast cancer, e.g., the NABUCCO study (IOM-02240), and prospective non-interventional, multicenter registries, e.g., the tumor registry breast cancer (NCT01351584) or the breast cancer registry platform OPAL (NCT03417115), have implemented PROs to assess QoL during the anticancer treatment periods of the patients. KEY MESSAGE: Using PROs in metastatic breast cancer can support shared treatment decision making and management of symptoms, eventually leading to an improvement in QoL. Progressively, regulatory authorities take PROs into consideration for the approval of new drugs. Hence, the implication of PROs in cancer treatment, and especially in MBC, is of significant value.

First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.

Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

Effectiveness and Tolerability of Nab-paclitaxel in Younger versus Elderly Patients With Metastatic HR-positive/HER2-negative Breast Cancer: Results From the Noninterventional, Prospective Study NABUCCO.

BACKGROUND: There are only scarce data on treatment of elderly patients with nab-paclitaxel for metastatic breast cancer, especially from the real-world setting. Here we present data from the noninterventional study NABUCCO with special focus on taxane-induced peripheral neuropathy (TIPN) in younger and elderly patients. PATIENTS AND METHODS: A total of 407 patients with HR-positive/HER2-negative metastatic breast cancer were enrolled between April 2012 and April 2015 into the prospective, multicenter, noninterventional study NABUCCO. Details on effectiveness, tolerability, and safety of nab-paclitaxel were evaluated for younger (<70 years) and elderly (≥70 years) patients. RESULTS: Neither median time to progression (TTP, younger 6.0 months, 95% confidence interval [CI], 5.5-7.1; elderly 6.9 months, 95% CI, 5.5-8.6) nor median overall survival (younger 16.4 months, 95% CI, 14.2-18.1; elderly 14.5 months, 95% CI, 11.9-17.4) differed by age group, also not in view of prior treatments. A multivariate regression model revealed that age did not significantly influence the TTP. TIPN was reported by 49.0% younger (44.3% common terminology criteria for adverse events [CTCAE] grade 1/2, 4.7% grade 3/4) and 45.8% elderly patients (41.1% CTCAE grade 1/2, 4.7% grade 3/4). The cumulative nab-paclitaxel dose did not correlate with the severity/grading of TIPN. CONCLUSION: Treatment with nab-paclitaxel in first- or further-line of metastatic HR-positive/HER2-negative breast cancer resulted in similar effectiveness and safety, irrespective of age. Therefore, nab-paclitaxel is a valid treatment option for elderly and partially heavily pretreated patients. However, incidence of TIPN is high, influencing the patients' quality of life. A close monitoring and awareness for early TIPN symptoms is warranted.

Final Effectiveness and Safety Results of NABUCCO: Real-World Data From a Noninterventional, Prospective, Multicenter Study in 697 Patients With Metastatic Breast Cancer Treated With nab-Paclitaxel.

BACKGROUND: One of the most effective chemotherapies for metastatic breast cancer (MBC) is nab-paclitaxel (nab-P), which is approved for treatment of MBC after failure of first-line therapy and when anthracyclines are not indicated. Randomized clinical trials have shown high efficacy and acceptable toxicity. Real-world data of nab-P in MBC, however, are still limited. PATIENTS AND METHODS: The prospective multicenter noninterventional study NABUCCO collected data on the routine treatment of patients with MBC receiving nab-P in 128 sites across Germany. The primary objective was time to progression. Secondary objectives were overall response rate, overall survival, safety, and quality of life. RESULTS: Between April 2012 and April 2015, a total of 705 patients with MBC at 128 active sites had been enrolled. A total of 697 patients had evaluable data with a median follow-up of 17.7 months. Median time to progression was 5.9 months (95% confidence interval, 5.6-6.4), overall response rate was 37.2%, and median overall survival was 15.6 months (95% confidence interval, 14.2-17.2). The results were similar in patients aged < 65 versus ≥ 65 years as well as in patients who received nab-P on a weekly or a triweekly schedule. The most frequently reported grade 3/4 adverse events were leukopenia (55, 7.9%), peripheral sensory neuropathy (30, 4.3%), and infections (29, 4.2%). Patients reported no apparent treatment-related impact on global quality of life. CONCLUSION: The results of the NABUCCO study confirm the clinical trial outcomes and the favorable safety profile of nab-P in patients with metastatic breast cancer in a real-world setting.

Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group.

PURPOSE: The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome. PATIENTS AND METHODS: One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter. RESULTS: The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased beta2-microglobulin (beta2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, beta2-MG, and TK were independent prognostic factors for OS. CONCLUSION: Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.