Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

BACKGROUND: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PATIENTS: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. RESULTS: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. CONCLUSION: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

Rare lymphomas in routine practice - Treatment and outcome in marginal zone lymphoma in the prospective German Tumour Registry Lymphatic Neoplasms.

Owing to its heterogeneity and rarity, management of disseminated marginal zone B-cell lymphoma (MZL) remains largely understudied. We present prospective data on choice of systemic treatment and survival of patients with MZL treated in German routine practice. Of 175 patients with MZL who had been documented in the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms (NCT00889798) collecting data on systemic treatment, 58 were classified as extranodal MZL of mucosa-associated lymphoid tissue (MALT) and 117 as non-MALT MZL. We analyzed the most commonly used first-line and second-line chemo(immuno)therapies between 2009 and 2016 and examined objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and prognostic factors for survival. Compared to patients with MALT MZL, those with non-MALT MZL more often presented with bone marrow involvement (43% vs. 14%), Ann Arbor stage III/IV (72% vs. 57%) and were slightly less often in good general condition (ECOG = 0; 41% vs. 47%). In German routine practice, rituximab-bendamustine for a median of 6 cycles was the most frequently used first-line (76%) and second-line treatment (36%), with no major differences between MZL subtypes. The ORR for patients encompassing any positive response was 81%. For patients with MALT and non-MALT MZL, respectively, 5-years PFS was 69% (95% CI 52%-81%) and 66% (95% CI 56%-75%), 5-years OS 79% (95% CI 65%-89%) and 75% (95% CI 66%-83%). Cox proportional hazards models showed a significantly increased risk of mortality for higher age in all patient groups. Our prospective real world data give valuable insights into the management and outcome of non-selected patients with MZL requiring systemic treatment and can help optimize therapy recommendations.

Buparlisib in combination with tamoxifen in pretreated patients with hormone receptor-positive, HER2-negative advanced breast cancer molecularly stratified for PIK3CA mutations and loss of PTEN expression.

The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor-positive (HR+ ), HER2-negative advanced breast cancer patients after failure of prior endocrine therapy. In this open-label, single-arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28-day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6-month progression-free survival (PFS) rate. Key secondary endpoints included the 6-month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6-month PFS rate was 33.3% (n/N = 7/21, one-sided 95% CI 16.8-100) and median PFS was 6.1 (CI 2.6-10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA-mutated subgroup consistently showed the highest 6-month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk-benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker-stratified studies with isoform-specific PI3K inhibitors are warranted. EudraCT No: 2014-000599-24.

Rare lymphomas in routine practice-Treatment and outcome in Waldenström's macroglobulinaemia in the prospective German Tumour Registry Lymphatic Neoplasms.

Waldenström's macroglobulinaemia (WM) is a rare indolent B-cell lymphoma for which only little prospective phase III evidence exists. Thus, real world data are important to provide insight into treatment and survival. We present here data on choice and outcome of systemic treatment of patients with WM treated in German routine practice. In total, 139 patients with WM who had been documented in the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms (NCT00889798) were included into this analysis. We analysed the most frequently used first-line and second-line treatments between 2009 and 2017 and examined best response, progression-free survival (PFS) and overall survival (OS). Bendamustine plus rituximab, with a median of six cycles, was by far the most frequently used first-line treatment (81%). Second-line treatment was more heterogenous and mainly based on bendamustine, cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP), fludarabine or ibrutinib, the latter approved in 2014. Three-year PFS from start of first-line treatment was 83% (95% confidence interval [CI] 74%-88%), 3-year OS was 87% (95% CI 80%-92%). These prospective data give valuable insights into the management and outcome of non-selected patients with WM treated in German routine practice. In the lack of prospective phase III clinical trials, real world data can help bridging the gap of evidence.

Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

Similar effectiveness of R-CHOP-14 and -21 in diffuse large B-cell lymphoma-data from the prospective German Tumour Registry Lymphatic Neoplasms.

OBJECTIVES: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard therapy for patients with previously untreated diffuse large B-cell lymphomas (DLBCL). Dose-dense two-weekly 'R-CHOP-14' was not superior over three-weekly 'R-CHOP-21' in randomised clinical trials (RCTs). We present real-world data on effectiveness of R-CHOP-14 and R-CHOP-21 in patients with DLBCL treated in German routine practice. METHODS: We identified 582 patients with DLBCL treated with R-CHOP-14 or R-CHOP-21 in 92 sites from the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms. Patients' schedules were classified by (a) length of the initial first cycle and (b) length of cycles 1-4. RESULTS: About 55% of patients received R-CHOP-21, 45% R-CHOP-14, in median 6 cycles. 51% and 55% of patients, respectively, were able to continue their initial R-CHOP-14 and R-CHOP-21 schedule. While most characteristics between the patient cohorts were similar, patients receiving R-CHOP-21 presented slightly more often with tumour stage I and lower IPI risk. 3-year overall survival of patients with R-CHOP-14 and R-CHOP-21 did not differ: 84% vs 84% (first cycle), 87% vs 89% (cycles 1-4). CONCLUSIONS: Patients with DLBCL in Germany are slightly more likely to receive R-CHOP-21 than R-CHOP-14. Both schedules are similarly effective in routine practice confirming the results from RCTs.

Therapy Landscape in Patients with Metastatic HER2-Positive Breast Cancer: Data from the PRAEGNANT Real-World Breast Cancer Registry.

This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.

Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors - Data from the German PRAEGNANT breast cancer registry.

PURPOSE: This study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). METHODS: The PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed. RESULTS: This analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern. CONCLUSIONS: This analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities.

Preference of elderly patients' to oral or intravenous chemotherapy in heavily pre-treated recurrent ovarian cancer: final results of a prospective multicenter trial.

BACKGROUND: Palliative systemic treatment in elderly gynaecological cancer patients remains a major challenge. In recurrent ovarian cancer (ROC), treosulfan an active alkylating drug showed similar cytotoxicity whether as oral (p.o.) or intravenous (i.v.) application. The aim of this innovative trial was to evaluate the preference of elderly patients (≥65 years) for p.o. or i.v. chemotherapy focusing compliance, outcome, toxicities, and geriatric aspects as secondary endpoints. METHODS: Patients with ROC had the free choice between treosulfan i.v. (7000 mg/m2 d1, q29d) or p.o. (600 mg/m2 daily d1-28, q57d). Only indecisive participants were randomized. RESULTS: Overall 123 patients with 2nd to 5th recurrence were registered and 119 received at least one cycle of chemotherapy. 85.7% preferred treosulfan i.v. and 14.3% oral, where only three patients were randomized. Main reasons for i.v. preference associated with individual expectations of lower rate of gastrointestinal disorders, higher activity and tolerability of treatment. Median of applied chemotherapies was three (range 1-12 cycles), with most common grade 3/4 toxicities thrombopenia (18.7%), leukopenia (15.7%), ascites (7.6%), bowel obstruction (6.7%), and abdominal pain (4.2%). Median time until progression/overall survival was 5.2/7.8 months (i.v.), and 5.6/10.4 months (p.o.), respectively, without significant differences in efficacy. CONCLUSIONS: Elderly patients with recurrent ovarian cancer asked and demonstrated active participation in the decision-making process of their oncological treatment and favoured predominantly the i.v. application. Treosulfan was generally well-tolerated despite comorbidities and heavy pre-treatment. Our study demonstrates that patients' preference did not influence prognosis negatively and remains important in gynaecologic oncology decision practice. EUDRACT NR: 2004-000719-25; NCT 00170690.

Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial.

OBJECTIVE: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies. METHODS: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level. RESULTS: The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment. CONCLUSION: The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL.

Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma.

The place of bevacizumab (BEV) in salvage re-irradiation (Re-RT) settings of malignant glioma is poorly defined. In the current study risk/benefit profiles of two BEV-based Re-RT protocols were analyzed and compared with that of salvage BEV plus irinotecan (BEV/IRI). According to interdisciplinary tumor board recommendations, patients were assigned to one of three BEV-based treatment protocols: (1) BEV/IRI, (2) Re-RT (36 Gy/18 fx) with concomitant BEV (Re-RT/BEV), and (3) Re-RT with concomitant/maintenance BEV (Re-RT/BEV→BEV). Prognostic factors were obtained from proportional hazards models. Adverse events were classified according to the NCI CTCAE, v4.0. 105 consecutive patients were enrolled from 08/2008 to 05/2014. Patients undergoing Re-RT experienced longer time intervals from initial diagnosis to BEV treatment (median: 22.0 months vs. 13.7 months, p = 0.001); those assigned to Re-RT/BEV→BEV rated better on the performance scale (median KPSREC: 90 vs. 70, p = 0.013). Post-recurrence survival after BEV-based treatment (PRS) was longest after Re-RT/BEV→BEV (median: 13.1 months vs. 8 months, p = 0.006). PRS after Re-RT/BEV and BEV/IRI was similar. Multivariately, higher KPSREC and Re-RT/BEV→BEV were associated with longer PRS. Treatment toxicity did not differ among groups. Re-RT/BEV→BEV is safe, feasible and effective and deserves further prospective evaluation.

Routine treatment of patients with chronic lymphocytic leukaemia by office-based haematologists in Germany-data from the Prospective Tumour Registry Lymphatic Neoplasms.

Various treatment options exist for patients with chronic lymphocytic leukaemia (CLL). Clinical registries provide insight into routine treatment and identify changes in treatment over time. The Tumour Registry Lymphatic Neoplasms prospectively collects data on the treatment of patients with lymphoid B-cell neoplasm as administered by office-based haematologists in Germany. Data on patient and tumour characteristics, co-morbidities, systemic treatments, and outcome parameters are recorded. Eight hundred and six patients with CLL were recruited between May 2009 and August 2013. At the start of first-line treatment, median age was 71 years, 64% were male, and 44% had a Binet stage C disease. The most frequently used first-line/second-line regimens were bendamustine + rituximab (BR, 56%/55%), fludarabine + cyclophosphamide + rituximab (FCR, 22%/11%), and bendamustine (B, 5%/9%). Chlorambucil was used in only 7% (first-line) and 6% (second-line) of patients. Patients treated with FCR were younger and healthier than patients treated with BR. Overall, 91% of first-line treatments were successful (40% complete response). Real-life patient populations differ considerably from patients treated in randomized controlled trials. BR and FCR dominate the first-line and second-line treatments of CLL by office-based haematologists in Germany. Future analysis will investigate progression-free and overall survival times.

Treatment of Non-transplant patients with multiple myeloma: routine treatment by office-based haematologists in Germany--data from the prospective Tumour Registry Lymphatic Neoplasms (TLN).

BACKGROUND: Various treatment options exist for patients with multiple myeloma (MM). Clinical registries provide insight into routine treatment and identify changes in treatment over time. PATIENTS AND METHODS: The Tumour Registry Lymphatic Neoplasms (TLN) prospectively collects data on the treatment of patients with lymphoid B cell neoplasms as administered by office-based haematologists in Germany. Data on patient and tumour characteristics, comorbidities, systemic treatments and outcome parameters are recorded. RESULTS: 371 non-transplant patients with MM were recruited between 2009 and 2011. At the start of first-line (second-line) treatment, the median age was 73 (75) years; 67% (74%) of the patients had stage III MM (classification of Durie and Salmon) and 19% (28%) had renal insufficiency. In the first line, 40% of the patients received bortezomib+melphalan+prednisone (VMP), 25% received bortezomib±dexamethasone (V±D) and 8% were treated with melphalan+prednisone+thalidomide (MPT). While use of bortezomib-based regimens increased from 67% (2009) to 85% (2011), use of melphalan-based regimens decreased from 68% to 48%. The overall objective response rate of treatment was 82%. In the second line, 34% of the patients received V±D and 16% lenalidomide+dexamethasone (LD). CONCLUSION: Bortezomib-based regimens dominate the first- and second-line treatment of MM. Future analyses will investigate outcome data, e.g. effectiveness of bortezomib retherapy compared to other second-line treatments.

Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer - results from the HER-OS patient registry.

BACKGROUND: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab. METHODS: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression. RESULTS: Overall, 47.1% of patients (95% confidence interval (CI): 39.9-54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0-6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression. CONCLUSIONS: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.

Metronomic oral cyclophosphamide in patients with advanced solid tumors.

BACKGROUND: Cure is rarely achieved in patients with advanced metastatic solid tumors, and quality of life including times without burdening therapies is an important endpoint. Metronomic oral cyclophosphamide (Cy) has been studied before and is a reasonable option. PATIENTS AND METHODS: 24 patients with a mean age of 64.4 years (range 36-82 years) were studied. 18 patients had breast cancer, 4 prostate cancer, 1 uterine carcinoma, and 1 carcinoma of unknown primary. RESULTS: All patients had advanced disease with a mean of 2 metastatic sites. Cy was given at a mean dosage of 52 mg daily. Time from diagnosis to start of Cy was 108.6 ± 7.6 months, and from occurrence of metastatic disease to Cy 45.8 ± 45.6 months. Patients had received a mean of 4.2 ± 2.1 prior regimens for metastatic disease. The mean time to treatment failure was 6.4 ± 5.4 months, and mean overall survival was 12.7 ± 7.3 months. Patients received 2.1 ± 1.4 further treatments upon progression. Main toxicities were grade 1 and 2 (n = 25); 3 patients had grade 3 nausea, leucopenia, and elevated gamma glutamyl transferase, respectively. CONCLUSION: Low-dose oral Cy is a reasonable, generally well tolerated, and inexpensive option for patients with advanced solid tumors.

Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104--a randomized trial of the German AIO CRC study group.

PURPOSE: The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR). RESULTS: In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe. CONCLUSION: This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.

Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer.

PURPOSE: Previous phase II studies have indicated a greatly reduced hematotoxicity of docetaxel-based regimens administered on weekly schedules. The present trial was initiated to randomly compare the toxicity and efficacy of weekly docetaxel versus its standard 3-weekly application. METHODS: Patients previously untreated with chemotherapy for metastatic disease were recruited. Patients aged >60 years or with a Karnofsky Perfomance Status (KPS) of 60-80% were eligible for the D2 study. Patients were randomized to receive docetaxel either on a 3-weekly [75 mg/m(2) every 3 weeks (q3w)] or on a weekly (30 mg/m(2) on days 1, 8, and 15; q4w) schedule. Treatment was continued until a maximum of 8 cycles, unacceptable toxicity, or disease progression. All patients received standard corticosteroid prophylaxis. RESULTS: Since statistical significance for the primary endpoint (toxicity) was achieved in the interim analysis, the study was closed according to the study protocol (102 of 162 patients). Compared to the standard arm, leukopenia ≥grade 3 was a rare event in the weekly arm of the D2 study (per-patient analysis: 4.2% q1w vs. 51.9% q3w; p < 0.0001). No difference was observed between the 2 schedules regarding the occurrence of anemia or thrombocytopenia. With regard to nonhematological toxicity, there was a higher incidence of skin/nail and hepatological toxicity with the weekly schedule, whereas neurotoxicity was observed more often in the standard arm. The rate of omitted doses was significantly increased in the weekly arm (8.6% q1w vs. 0% q3w). The overall response rate was 22.9% in the weekly arm compared to 42.6% in the standard arm (p = 0.039). Time to progression was 5.4 (q1w) versus 6.3 (q3w) months (p = 0.91), and overall survival was 22.7 (q1w) versus 15.8 (q3w) months (p = 0.24). CONCLUSION: The present data support the feasibility of both weekly and 3-weekly application of docetaxel. As expected, severe leukopenia seems avoidable in weekly scheduled single-agent docetaxel and may serve as an important treatment option, particularly in elderly patients and patients with a reduced performance status.

Prospective multicenter randomized phase III study of weekly versus standard docetaxel plus doxorubicin (D4) for first-line treatment of metastatic breast cancer.

PURPOSE: Previous phase II studies have indicated a greatly reduced hematotoxicity of docetaxel-based regimens administered on weekly schedules. The present trial was initiated to compare the toxicity and efficacy of weekly docetaxel versus its standard 3-weekly application in combination with doxorubicin. METHODS: Patients previously untreated with chemotherapy for metastatic disease were recruited. Inclusion criteria were age <65 years or a Karnofsky Performance Status of 70-100%. All patients in the D4 study received doxorubicin (50 mg/m(2)) on the first day of treatment in addition to docetaxel given either at a 3-weekly dose of 75 mg/m(2) every 3 weeks (q3w) or at a weekly dose of 35 mg/m(2) (days 1, 8, and 15; q4w). Treatment was continued until a maximum of 8 cycles, unacceptable toxicity, or disease progression. All patients received standard corticosteroid prophylaxis. RESULTS: Since interim analysis showed failure to reach a significant difference for the primary endpoint (hematotoxicity, i.e. leukopenia), the study was closed according to the study protocol (85 of 242 patients). A lower-than-expected rate of leukopenia ≥ grade 3 was observed in the standard arm of the D4 study compared to the weekly schedule (per-patient analysis: 61.9% q3w vs. 65.1% q1w; p > 0.05). Grade 3 and grade 4 fever, diarrhea, and infections occurred more frequently in the standard arm, whereas neurotoxicity and skin/nail disorders were observed more frequently in the weekly arm. Except for fever, none of these differences reached a level of significance. Dose delays, dose reductions, and the rate of omitted doses were increased in the weekly arm. The overall response rate was 44.2% in the weekly arm compared to 52.4% in the standard arm (p = 0.52). Time to progression was 6.2 (q1w) versus 10.3 (q3w) months (p = 0.36), and overall survival was 20.5 (q1w) versus 28.7 (q3w) months (p = 0.98). CONCLUSION: The present data support the feasibility of both weekly and 3-weekly application of docetaxel in combination with doxorubicin. Nevertheless, given that leukopenia was similar in both arms and the efficacy parameters were at least numerically inferior with the weekly schedule, standard 3-weekly application seems to be preferable for patients requiring combination chemotherapy.

Mutations in the JAK2 and MPL genes and their correlation to clinical parameters in patients with chronic myeloproliferative disease.

BACKGROUND: The objective of this study was to correlate the V617F mutation of the JAK2gene and the W515 mutation of the MPLgene in patients with chronic myeloproliferative disease (CMPD) with clinical parameters. PATIENTS AND METHODS: 51 patients were analyzed: 31 with essential thrombocythemia (ET), 20 with polycythemia vera (PV) and 2 with primary myelofibrosis (PMF). 1 patient had unclassifiable CMPD (CMPD-U). 3 patients had overlapping features of ET and PV. RESULTS: 31 patients (14 with PV, 19 with ET, 3 with concomitant ET and PV, and 1 with PMF) showed the JAK2mutation, and 2 patients with ET the W515 mutation. There were no significant differences in hematocrit at diagnosis in JAK2-nonmutated versus -mutated patients with PV. Also, patients with ET had comparable platelet counts at diagnosis. The mean time from diagnosis to initiation of first therapy was similar for all patients with non-mutated versus mutated JAK2. Patients with ET and mutated JAK2were significantly older at diagnosis than those with the wildtype gene (65.5 years vs. 54.4 years; p = 0.016). CONCLUSIONS: JAK2V617F or MPLW515 mutations do not seem to correlate with simple clinical parameters. ET patients with wild-type JAK2were significantly younger at diagnosis.