Anja Welt

Serum Free Light Chain Analysis and Urine Immunofixation Electrophoresis in Patients with Multiple Myeloma

Purpose: Retrospective studies have shown that immunoassays measuring free light chains (FLC) in serum are useful for diagnosis and monitoring of multiple myeloma. This study prospectively evaluates the use of FLC assays and, for the first time, investigates the relationship between serum FLC concentrations and the presence and detectability of Bence Jones (BJ) proteins in the urine. Patients and Methods: Three hundred seventy-eight paired samples of serum and urine were tested from 82 patients during the course of their disease. The sensitivities of serum FLC analysis and urine immunofixation electrophoresis (IFE) in detecting monoclonal FLC were compared. Serum FLC concentrations required for producing BJ proteins detected by IFE were determined. Results: Abnormal FLC were present in 54% of serum samples compared with 25% by urine tests. In abnormal serum samples for κ or λ, the sensitivity of IFE to detect the respective BJ proteins in urine were 51% and 35% and the median serum FLC concentrations required to produce detectable BJ proteins were 113 and 278 mg/L. Renal excretions of monoclonal FLC increased with serum concentrations, but excretions significantly decreased at high serum concentrations combined with renal dysfunction. Conclusion: Serum FLC assays are significantly more sensitive for detecting monoclonal FLC than urine IFE analysis. They also have the advantage of FLC quantification and are more reliable for monitoring disease course and response to treatment.

Recombinant human erythropoietin in the treatment of cancer-related anaemia

Abstract:  The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000–10,000 units (U) daily in 60 patients with cancer‐related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions, was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas

High‐dose chemotherapy (HD‐CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high‐grade non‐Hodgkins lymphoma (NHL) and Hodgkins lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD‐CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD‐CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5‐yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event‐free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment‐related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of ≥2 and resistant disease to first‐line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

Bolus vincristine and epirubicin with cyclophosphamide and dexamethasone (VECD) as induction and salvage treatment in multiple myeloma

The VAD regimen (infusional vincristine, doxorubicin and intermittent high-dose dexamethasone) is widely considered the standard salvage chemotherapy for multiple myeloma resistant to alkylating agents and is increasingly used for induction in previously untreated patients prior to high-dose chemotherapy. We investigated the VECD protocol, a VAD-based regimen using bolus injections of vincristine 1.5 mg day 1 and epirubicin 20 mg/m2 days 2 and 3 with 1 h infusions of cyclophosphamide 200 mg/m2 days 1–3 and oral dexamethasone 20 mg/m2 days 1–5 as induction and salvage treatment in multiple myeloma. Fifteen previously untreated and 25 patients with relapsed or refractory myeloma were included. Cycles were repeated every 3 weeks. In the group of previously untreated patients the response rate was 53% and the median survival has not been reached at 59 months. For relapsed and refractory patients the response rate was 44% and the median survival 13 months. In the group of patients with truly refractory disease on prior chemotherapy a response rate of 47% was achieved, which appears superior to the results observed for VAD alone. The main toxicities were leukocytopenia WHO grade IV and infections grade III/IV with both toxicities being significantly more pronounced in pretreated patients. VECD appears to be an effective regimen for induction and salvage therapy in multiple myeloma. Based on the limited number of patients treated the results are comparable to those reported for VAD, with the advantage that the infusional application of vincristine and the anthracycline is omitted.

Second International Consensus Conference on Advanced Breast Cancer (ABC2), Lisbon, 11/09/2013: The German Perspective.

The Advanced Breast Cancer Second International Consensus Conference (ABC2) on diagnosis and treatment of advanced breast cancer took place in Lisbon, Portugal, on November 7-9, 2013. The focus of the conference was inoperable, locally advanced breast cancer. The diagnosis and treatment of metastatic breast cancer had already been discussed 2 years before at the ABC1 Consensus and were only updated regarding special issues as part of this years ABC2 Consensus. Like 2 years ago, a working group of German breast cancer experts commented on the voting results of the ABC panelists, with special consideration of the German guidelines for the diagnosis and treatment of breast cancer (German Gynecological Oncology Working Group (AGO) recommendations, S3 Guideline) in order to adapt them for daily clinical practice in Germany. The goal of both the ABC Consensus and the German comments is to facilitate evidence-based therapy decisions.

RECURRENCE OF HODGKIN'S DISEASE AFTER 10 OR MORE YEARS : LATE RELAPSE OR DE-NOVO MALIGNANCY DUE TO HLA-DPB1*0301-LINKED SUSCEPTIBILITY?

Recurrences of Hodgkins disease (HD) ten or more years after initial therapy are rare and heterogeneous concerning pathological, biological and clinical features. Though usually regarded as relapses of initial disease at least part of these late recurrences may represent de-novo HD due to an increased constitutional risk. Following recent reports genetic risk for HD may be linked to the HLA-DPB1*0301 allele. Therefore, we investigated DPB1 and other HLA class I and II gene loci in three patients with very late recurrences of HD presenting at our institution within the last two years. All patients carry the HD susceptibility allele HLA-DPB1*0301. The expected probability of three patients with HD displaying the HLA-DPB1*0301 phenotype by chance is only p = 0.022. As serologic investigations also revealed Epstein-Barr virus (EBV) activity in all three cases our results support a role of genetic susceptibility possibly leading to impaired immune responses to EBV in very late recurring HD. Additionally, HLA-DPB1*0301 may be valuable for identifying patients with HD who might be candidates for a long term follow-up.

Long-term results of a phase-I/II study of sequential high-dose chemotherapy with autologous stem cell transplantation in the initial treatment of aggressive non-Hodgkin's lymphoma.

AIMS AND BACKGROUND To improve the survival of patients with aggressive non-Hodgkins lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. METHODS Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. RESULTS Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT. The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. CONCLUSIONS The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.

Response of Pseudomyxoma Peritonei to Gemcitabine

The term Pseudomyxoma Peritonei (PMP) describes a rare pathological condition where mucinous ascites is associated with tumor implants disseminated over the serous membranes of the abdominal cavity. Recent studies have revealed that the origin of PMP is usually an appendiceal neoplasm [1]. With regard to prognosis and optimal treatment modalities, three histologically defined categories can be distinguished: disseminated peritoneal adenomucinosis (DPAM); peritoneal mucinous carcinomatosis (PMCA); and an intermediate histology composed of both features of DPAM and PMCA, with DPAM having the best prognosis [2]. A feasible and effective approach to patients with DPAM is extensive tumor debulking with chemotherapy administered as intraoperative intraperitoneal hyperthermic perfusion of the abdominal cavity, leading to a 10-year survival of 68% [2]. On the other hand, patients with PMCA often show invasive peritoneal implants and organ involvement, making it impossible to surgically remove all tumors. Accordingly, the prognosis is fatal, with only 3% surviving 10 years [2]. These patients might benefit from postoperative systemic chemotherapy. We report a case, where intravenously administered gemcitabine induced a marked tumor reduction after prior incomplete cytoreductive surgery. A 74 year-old male patient presented at our hospital with pain in the lower abdomen. Ultrasonography and computed tomography (CT) suggested massive ascites, but a paracentesis was frustrane. A laparotomy revealed a 20 /20 cm gelatinous appearing capsulated tumor mass located in the pelvis. The appendix could not be found intraoperatively. Because there was no history of appendectomy, a ruptured appendix was considered to be the source or PMP. Cytoreductive surgery was carried out, leaving gross residual tumor. Histological examination of the peritoneal lesions showed mucinous masses with associated fibrosis. Where present, the epithelium formed gland-like structures and showed signs of atypia. Laboratory data showed an elevated chromogranin A (CgA, 288 mg/l; normal,B/110). All other tested tumor markers were within the normal range (CEA, CA 19 /9, CA 12 /5, AFP, b-HCG, NSE). Immunohistochemistry of the peritoneal lesions was positive for cytokeratin 20 and negative for cytokeratin 7 and neuroendocrine markers (CgA, synaptophysin, NSE, CD56). After surgery, an intravenous chemotherapy was started with cisplatin and 5-fluorouracil (5-FU) in a 3-week schedule. Three cycles were administered, but two months after the first surgery the patient presented with a distended abdominal wall. A CT scan showed a progredient pelvic tumor and prompted another tumor debulking including a right hemicolectomy and the resection of 30 cm of terminal ileum, again leaving residual tumor (Figure 2). Postoperatively, one cycle of intraperitoneal mitomycin-C (MMC, 20 mg, absolute) and gemcitabine (750 mg, absolute) was administered. Due to the obstruction of the implanted intraabdominal port system, intravenous gemcitabine (1000 mg/m) was initiated, repeated every 2 weeks, and well tolerated. Further CT scans showed a marked tumor reduction (Figure 3). After 11 cycles, chemotherapy was discontinued for two

Abstract PD2-4: Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

BACKGROUND: The open-label randomized phase III TANIA trial demonstrated statistically significantly improved progression-free survival (PFS; primary endpoint) with the addition of BEV to 2nd-line chemotherapy (CT) in patients (pts) with HER2-negative LR/mBC progressing after 1st-line BEV-containing therapy. We describe efficacy in clinically relevant subgroups to assess consistency of the BEV treatment effect. METHODS: Pts whose HER2-negative LR/mBC had progressed during/after 1st-line BEV–CT were randomized 1:1 to investigator’s chosen 2nd-line single-agent CT given either alone or with BEV (15 mg/kg q3w or 10 mg/kg q2w). 2nd-line therapy was continued until disease progression (PD), unacceptable toxicity or consent withdrawal. At PD, BEV was continued with 3rd-line CT (investigator’s choice) in pts initially randomized to BEV–CT but was not permitted in pts randomized to CT alone. The primary endpoint was PFS from randomization to 2nd-line PD/death. Sample size was calculated based on a log-rank test assuming median PFS of 7→9.3 mo with a corresponding hazard ratio (HR) of 0.75. PFS events were required in 384 of 488 pts for 80% power at 2-sided α=0.05. Subgroup analyses of the primary endpoint were prespecified and included subgroups defined by stratification factors. RESULTS: From Jan 2011 to Apr 2013, 494 pts were enrolled. The data cut-off for the primary analysis was Dec 20, 2013 (median follow-up: CT 15.9 mo; BEV–CT 16.1 mo). The PFS benefit seen in the overall population was observed consistently in most subgroups. CONCLUSIONS: PFS was statistically significantly improved with the addition of BEV to 2nd-line CT in BEV-pretreated pts, meeting the primary objective of TANIA. This effect was seen consistently within subgroups based on stratification factors. Within the limitations of exploratory subgroup analyses with small sample sizes, further subgroup analyses may suggest some potential inconsistencies in treatment effect. These hypothesis-generating observations require further exploration of potential differences in disease and pt characteristics in TANIA, which may have influenced physicians’ CT choice. Citation Format: Fabio Puglisi, Javier Cortes, Eduard Vrdoljak, Joseph Gligorov, Norbert Marschner, Christoph Zielinski, Michele de Laurentiis, Etienne Brain, Christelle Levy, Anja Welt, Zsuzsanna Kahan, Moshe Inbar, Sabine de Ducla, Ulrich Freudensprung, Gunter von Minckwitz. Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD2-4.

359PDFINAL EFFICACY AND SAFETY ANALYSIS OF THE CARIN PHASE III TRIAL: CAPECITABINE (CAP) AND BEVACIZUMAB (BEV) WITH OR WITHOUT VINORELBINE (VIN) IN 1ST LINE METASTATIC BREAST CANCER (MBC)

ABSTRACT Aim: Recent 1st line phase III trials in MBC demonstrated improved progression-free survival (PFS) for the combination of Cap/Bev as compared to Cap alone, but inferior efficacy when compared to paclitaxel plus Bev. Frequently used to treat MBC, Vin has few overlapping toxicities with Cap. The CARIN trial aims at further improving efficacy by adding Vin to Cap/Bev for a less toxic alternative to taxane-based 1st line therapy. Methods: CARIN was a prospective, open-label, multicenter, randomized phase III trial. Key eligibility criteria included confirmed measurable or non-measurable HER2 negative, locally advanced or MBC, ECOG ≤2, and no prior palliative chemotherapy. The 600 patients (pts) randomized (1:1) received oral Cap 1000 mg/m2 BID days 1-14 plus Bev 15 mg/kg q3w IV (Arm A) or Cap/Bev regimen combined with Vin 25 mg/m2 IV days 1 + 8 (Arm B) until progression or unacceptable toxicity. Randomization was stratified by prior adjuvant anthracycline and/or taxane therapy (yes/no) and hormone receptor status (ER/PR + /-). The primary endpoint was defined as PFS; secondary endpoints included objective response rate, overall survival (OS) and safety. Results: 297 pts in Arm A and 295 in Arm B with a median age of 62 were included in the efficacy analysis. Median follow-up was 2.4 years. 38% of pts in Arm A and 32% in Arm B were taxane pretreated; 20.8% were triple negative. The median treatment exposure was 28 weeks for both arms. Median PFS was 8.7 and 9.6 months (ms) (p = 0.03). The effect was most pronounced in pts Grade 3 were 60.6% and 76.3% in Arm A vs B, respectively, with neutropenia and leucopenia being more common in Arm B. No unexpected side effects were observed. Results of a multivariate cox regression will be presented. Conclusions: The addition of Vin to Cap/Bev is at least as effective as the combination of taxanes/Bev as reported in the RIBBON-1 trial and seems an option for taxane pretreated and TNBC pts. Disclosure: A. Welt: Advisory boards: Roche, TEVA, Eisai, Novartis Professional fee for oral presentations: P. Fabre N. Marschner: 1. Share holdings and executive employee iOMEDICO AG 2. Advisory board Roche T. Decker: Advisory Board Roche; C. Salat: Professional fee for oral presentations: Roche; S. Busies: Employee iOMEDICO AG; S. Hegewisch-Becker: Advisory Boards: Roche, Lilly, Merck. All other authors have declared no conflicts of interest.