ASCO update on lymphoma.

s concerning indolent and aggressive lymphoma and multiple myeloma with clinical relevance from the ASCO 2017 meeting are discussed.

Oxaliplatin/Irinotecan/Bevacizumab Followed by Docetaxel/Bevacizumab in Inoperable Locally Advanced or Metastatic Gastric Cancer Patients - AGMT_GASTRIC-3.

BACKGROUND/AIM: Although high response rates using the doublet-chemotherapy of oxaliplatin and irinotecan as well as its combination with cetuximab in advanced gastric cancer were shown in previous trials, time to progression was short, suggesting acquired chemotherapy resistance. PATIENTS AND METHODS: Sequential chemotherapy (oxaliplatin and irinotecan followed by docetaxel) combined with bevacizumab was investigated in the GASTRIC-3 trial. Patients achieving at least stable disease were continued on maintenance bevacizumab. RESULTS: Objective response rate was available in 33 patients: Complete response (CR) 12.1%, partial response (PR) 39.4%, stable disease (SD) 27.3%. Median time to progression was 7.0 months (95%CI=5.0-11.0) and median overall survival was 11 months (95%CI=9.0-15.0). Of note, two patients continue to receive bevacizumab maintenance therapy for more than 5 years with ongoing CR. CONCLUSION: Combining sequential chemotherapy with oxaliplatin/irinotecan and docetaxel with bevacizumab followed by bevacizumab maintenance is feasible and clinically active in advanced gastric cancer.

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14).

BACKGROUND: Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. PATIENTS AND METHODS: Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. RESULTS: The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Thirty-six of 40 (90%) patients in the R-COMP arm, but only 24/36 (66.7%) in the R-CHOP arm had all NT-proBNP levels below 400 pg/ml during and at the end of treatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm. INTERPRETATION: In patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP. FUNDING: Cephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper.

Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial.

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.

Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial.

BACKGROUND: Trastuzumab, one important treatment option for HER2-positive metastatic breast cancer (MBC) is limited by its cardiotoxic potential. Lapatinib and pegylated liposomal doxorubicin (PLD) represent a cardiosparing alternative that can cross the blood brain barrier. This is important, because one third of breast cancer patients develop brain metastases. PATIENTS AND METHODS: We included 24 patients with HER2-positive MBC progressing under trastuzumab. They received 1,250 mg lapatinib daily until progression plus PLD (40 mg/m(2)) every 4 weeks for maximal 6 cycles. The primary end-point was the overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), 1-year PFS and 1-year OS rates. RESULTS: ORR was 54%. Median PFS was 5.8 and median OS 23.3 months. The one-year PFS rate was 27% and 1-year OS rate 76%. CONCLUSION: Lapatinib-plus-PLD is active and safe in HER2-positive MBC, especially suitable for patients with cardiological risk or brain metastases.

A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors.

Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

Oxaliplatin, irinotecan and cetuximab in advanced gastric cancer. A multicenter phase II trial (Gastric-2) of the Arbeitsgemeinschaft Medikamentose Tumortherapie (AGMT).

BACKGROUND: Patients suffering from advanced gastric cancer still have a poor prognosis and treatment options are limited. In our previous phase II trial (AGMT-Gastric-1), we showed that the combination of oxaliplatin and irinotecan was well tolerated and effective. The same chemotherapy regimen was now tested in combination with cetuximab in a multicenter phase II trial. PATIENTS AND METHODS: Oxaliplatin at 85 mg/m(2) biweekly and irinotecan at 125 mg/m(2) biweekly were combined with cetuximab at 400 mg/m(2) loading dose and subsequent weekly infusions of 250 mg/m(2). Fifty-one patients with histologically proven unresectable and/or metastatic gastric adenocarcinoma were treated in the first line setting. The median age was 62 years. A single metastatic site was found in 24 patients, 27 patients had multiple metastatic sites. RESULTS: Frequently reported adverse events (in more than 20% of patients) were predominantly grade 1 or 2 and included neutropenia (35%), thrombocytopenia (33%), anemia (73%), nausea (45%), diarrhea (57%), alopecia (22%), and fatigue (37%). Grade 3/4 toxicities included neutropenia in 9/1 patients., thrombocytopenia in 1/0 patients, anemia in 3/1 patients, nausea in 2/0 patients, and diarrhea in 7/2 patients. Sensory neuropathy occurred mostly as grade 1 and 2 in 37% of patients, grade 3 neurotoxicity was observed in 7 patients. Acne-like rash grades 1/2/3/4 were reported in 31%/20%/6%/2% of patients respectively. Thirteen patients discontinued the study due to neutropenia (n=5), nausea/vomiting (n=1), diarrhea (n=1), toxic colon (n=2), and allergic reaction to cetuximab at first (n=2), second (n=1) or third infusion (n=1). Thirty-five patients were assessable for response, with 1 patient (3%) showing a complete response, 21 patients (60%) a partial response, 7 patients (20%) a stable disease, and 6 patients (17%) a progressive disease respectively. The median time to progression was 24.8 weeks, median overall survival was 38.1 weeks. All patients tested had a wild type KRAS status. CONCLUSION: The combination of oxaliplatin and irinotecan with cetuximab is safe and its action established in advanced gastric cancer.

Sentinel node biopsy after primary chemotherapy in breast cancer: a note of caution from results of ABCSG-14.

Over the past years, experience has been increasing with lymphatic mapping and sentinel node biopsy (SNB) after preoperative chemotherapy for breast cancer, with a wide range of results reported in the literature and final conclusions on the diagnostic value and clinical consequences of this sequential approach still missing. Between 1999 and 2002, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) conducted a prospective randomized multicenter trial comparing three versus six preoperative cycles of epirubicin/docetaxel + granulocyte colony-stimulating factor for operable breast cancer. Of the 292 patients recruited to the trial overall, 111 were enrolled in a prospective subprotocol for performing LM and SNB in addition to obligatory axillary lymph node dissection (ALND) after PC. SNB after PC identified at least one sentinel node in 100 of 111 patients (identification rate 90%). In six cases, a false-negative SN was identified, resulting in a false-negative rate of 13% (6 of 47). We only found little correlation between patients and tumor characteristics and the identification rate or false-negative rate. Lymphatic mapping and SNB after primary chemotherapy failed to predict histologic infiltration of the sentinel node with sufficient sensitivity. The routine use of SNB after primary chemotherapy should therefore be discouraged.

Dose-dense therapy improves survival in aggressive non-Hodgkin's lymphoma.

This study aimed to determine whether dose-dense therapy improves 3-year survival over the standard therapy for untreated aggressive lymphoma. One hundred and fifteen patients with untreated aggressive lymphoma were stratified by center, age, and international prognostic index and randomized to one of two treatment arms. One hundred and three were eligible. The experimental dose-dense arm consisted of weekly therapy with cyclophosphamide, epirubicine, vincristine, prednisolone, ifosfamide, etoposide, methotrexate, dexamethasone, and filgrastim (CEOP/IMVP-Dexa). The standard arm consisted of three-weekly cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). The primary endpoint was overall survival after 3 years. Overall survival at 3 years was 0.766 (95% CI 0.6247, 0.8598) in the dose-dense arm and 0.462 (95% CI 0.3200, 0.5925) in the CHOP arm. Overall 5-year survival was 0.746 (95% CI 0.603, 0.843) in the dose dense and 0.406 (95% CI 0.265, 0.543) in the CHOP arm (P = 0.0062). Grade 3 and 4 infections occurred four times more frequently in the dose-dense arm. However, two patients died from toxicity in the dose-dense arm and three in the CHOP arm. Dose-dense therapy with CEOP/IMVP-Dexa is feasible and resulted in an absolute increase of 34% in the survival probability compared to CHOP in untreated patients with aggressive lymphoma.

Long-term results of dose density therapy in patients with aggressive lymphoma.

To evaluate the long-term outcome of dose density chemotherapy in the treatment of aggressive lymphoma, we analyzed 142 patients with untreated aggressive lymphoma. Chemotherapy was an eight-drug regimen given in weekly intervals in two prospective trials. The median observation period was 8 years; the longest follow-up was 13 years. Overall survival at 8 years was 0.583. The 8-year survival of patients < or =60 years was significantly better than that of older patients, namely 0.713 vs 0.304 (p=0.000000697). This excellent survival of patients aged < or =60 years was identical for high-risk and high-intermediate-risk patients compared with low-risk and low-intermediate-risk patients in the age-adjusted international prognostic index (IPI). The excellent long-term results of the CEOP/IMVP-Dexa regimen (cyclophosphamide, epirubicin, vincristine, and prednisone/ifosfamide with systemic mesna, methotrexate, etoposide, and dexamethasone) for patients aged < or =60 years suggest that this regimen might be superior to the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and needs to be tested in comparison to high-dose regimens and novel approaches including antibody treatment.