Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism.

Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P<0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-γ and tumor necrosis factor-α also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-γ secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity.

Applicability of the EORTC/MSG criteria for IFD in clinical practice.

Invasive fungal disease (IFD) is a feared complication in patients with hematological malignancies. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) published updated criteria for the diagnostic workup within clinical studies for immunosuppressed patients with suspected fungal infection. We applied these criteria in a routine clinical setting with regard to their feasibility for bedside practice at our institution in a 1-year period. One hundred seventy consecutive patients with a recent history of chemotherapy-induced neutropenia (n = 100) or allogeneic stem cell recipients (n = 70) who had received a CT scan of the chest in search of pulmonary IFD were examined. We analyzed all available radiological and microbiological data according to the EORTC/MSG criteria. The quality of images was good in 94.7%, microbiological diagnostics performed in 94.1% patients. Five patients had histopathologic-proven IFD, 18 patients were classified as "probable," 55 patients as "possible" IFD, and 92 patients did not fulfill any criteria ("no IFD"). Microbiology revealed suggestive findings in 29 patients. These were either galactomannan antigen (Gm-AG) in serum (n = 18) and/or broncho-alveolar lavage (BAL) (n = 5). CT scan showed pulmonary infiltrates in 106 patients; 78 were classified as typical for IPA, further discriminated by morphology and number of nodules, as well as additional signs (halo, air crescent, cavity). We observed a better overall survival in patients without infiltrates compared to those with any type of infiltrate (p = 0.042) and a trend toward favorable survival in patients who had micronodular lesions (p = 0.058). We also found a higher probability of Gm-AG positivity in the group of allogeneic stem cell transplantation (allo-SCT) patients (p = 0.001) and a trend toward an association of Gm-AG positivity and positive findings on CT (p = 0.054). The applicability of criteria was good, both with regard to radiological and mycological evidence and sufficient for the categorization of IFD according to EORTC/MSG in the clinical setting. However, our findings suggest that feasibility improves with stringency of mycological workup, which is reflected in the two subgroups. Radiology harvests by far more suggestive findings which can only partly be correlated with mycological evidence. Although feasible, whether the EORTC/MSG criteria are the appropriate tool for early identification of IFD remains open for discussion.

A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma.

BACKGROUND: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. RESULTS: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. CONCLUSIONS: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab.

Multicenter phase II study evaluating docetaxel and cisplatin as neoadjuvant induction regimen prior to surgery or radiochemotherapy with docetaxel, followed by adjuvant docetaxel therapy in chemonaive patients with NSCLC stage II, IIIA and IIIB (TAX-AT 1.203 Trial).

OBJECTIVES: Neoadjuvant therapy with a platinum based doublet is an option in NSCLC patients with upfront resectable disease. However, the role of neoadjuvant induction in stages IIIA and IIIB and in initially not resectable patients is unclear. PATIENTS AND METHODS: In this phase II trial, 78 patients with locally advanced NSCLC, of whom 56 were considered not resectable at initial diagnosis, were treated with three neoadjuvant cycles of docetaxel and cisplatin and subjected to radical surgery if resectable. Definitive radiochemotherapy (RCT) using weekly docetaxel was the prespecified alternative if patients were not resectable at restaging. The primary objective was response to neoadjuvant induction. RESULTS: After induction, 36 (46%) were radically operated and 24 (31%) were treated with RCT. Overall, 32 patients (41%) completed the entire study plan. Partial response to induction therapy was observed in 43 patients (55%); furthermore, 19 of 56 initially not resectable cases (34%) became resectable upon induction. Median progression-free (PFS) and overall survival (OS) were 8.5 and 16.4 months for the whole cohort. Encouragingly, conversion to resectability was predictive for favorable outcome. On the other hand, patients who were not resectable at restaging and received RCT were characterized by a rather unfavorable prognosis (5-year and 10-year OS, whole cohort: 20% and 12%; RCT: 8% and 0%; surgery: 37% and 24%, respectively). CONCLUSION: Neoadjuvant induction with the doublet docetaxel/cisplatin and subsequent radical resection resulted in favorable survival. Of note, conversion to resectability was mandatory for the chance of cure in patients considered initially not resectable.

R-CHOP versus R-COMP: are they really equally effective?

The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed.

Small steps of improvement in small-cell lung cancer (SCLC) within two decades: a comprehensive analysis of 484 patients.

BACKGROUND: It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade. METHODS: All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol. RESULTS: A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age < 70 years and absence of LDH elevation in the palliative setting. CONCLUSIONS: In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.

Overcoming resistance to first generation EGFR TKIs with cetuximab in combination with chemotherapy in an EGFR mutated advanced stage NSCLC patient.

We report the case of a female never-smoking patient with an epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) who received multiple lines of treatment. When she evolved clinical resistance to first generation EGFR tyrosine kinase inhibitors (TKI), she was treated with a fifth-line combination therapy with cetuximab and vinorelbine. This combination was highly active with a treatment response lasting for 9 months supporting the hypothesis that EGFR monoclonal antibodies in combination with chemotherapy may play a role in reversing EGFR-TKI resistance in EGFR mutation-positive NSCLC.

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients.

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG.

Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m(2) bid, days 1-2 and 8-9 (3 g/m(2) for patients ≤ 60 years with refractory AML or ≥ 2nd relapse); idarubicin 10 mg/m(2) daily, days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine, 15 mg/m(2), 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.

Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study).

It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer's Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

[Risk-adapted therapy in acute myeloid leukemia]. / Risikoadaptierte Therapie der akuten myeloischen Leukämie.

The identification and characterization of an increasing number of chromosomal and molecular aberrations has not only increased the understanding of the pathogenesis of acute myeloid leukemia but also provides the means for a better judgment of prognosis and the direction of therapy. Together with patient-specific factors like age, co-morbidity, and performance status, an individualized risk profile can be used to select the most appropriate therapeutic strategy.

Decline of exhaled isoprene in lung cancer patients correlates with immune activation.

Isoprene (2-methylbuta-1,3-diene) represents a precursor molecule of isoprenoids (steroids, terpens), and available data suggest that isoprene is related to cholesterol biosynthesis. Breath concentrations of isoprene have been reported to be altered in a number of clinical conditions. However, the physiological meaning of isoprene changes has not yet been established. Utilizing proton-transfer-mass spectroscopy, we analyzed isoprene concentrations (m/z 69, tentatively identified as isoprene) in breath samples in Tedlar bags collected from 79 lung cancer patients (23 females, 56 males). Results were compared to the concentrations of immune activation marker neopterin (ELISA, BRAHMS, Hennigsdorf, Germany), lipid parameters (routine enzymology) and C-reactive protein (CRP). Isoprene concentrations were median 92.5 ppb (25th-75th percentile: 79-131 ppb). There was no relationship with staging, grading or age, but isoprene concentrations correlated significantly with total cholesterol (rs = 0.281, p < 0.01) and LDL cholesterol (rs = 0.236, p < 0.05). There was no significant relationship between exhaled isoprene concentrations and HDL cholesterol (rs = 0.048), triglycerides (rs = 0.164) and CRP (rs = -0.115; all not significant). A significant inverse correlation existed between isoprene and neopterin concentrations (rs = -0.215, p < 0.05); the latter also correlated with total cholesterol (rs = -0.343, p = 0.001), HDL cholesterol (rs = -0.273, p = 0.01), LDL cholesterol (rs = -0.236, p < 0.05) and CRP (rs = 0.230, p < 0.05) but not with triglycerides (rs = 0.035, not significant). Results suggest that immune activation might play a role in the decline of isoprene which is probably related to lipid metabolic changes. Interestingly, similar relationships between elevated neopterin and decreased lipid concentrations have been reported earlier in other clinical conditions, e.g. in patients with HIV-1 infection.

[Multiple Sister Mary Joseph's nodules in a patient with gastric cancer]. / Multiple "Sister Mary Joseph's nodules" bei einem Patienten mit Magenkarzinom.

HISTORY AND CLINICAL FINDINGS: A 52-year-old patient presented with a 6-months history of painful, progressive erythematous periumbilical papules and nodules. Seven months previously, an advanced stage of an adenocarcinoma of the stomach with peritoneal carcinosis and malignant ascites had been diagnosed. INVESTIGATIONS: Clinical examination showed ten firm, painful, umbilicated, erythematous, polygonal papules and nodules (size up to 7 mm), partly covered with central hemorrhagic crusts or scales. The histological examination revealed epithelial cell clusters infiltrating the dermis and forming tubular structures. The prominent nuclei varied in size, some were vacuolated. Signet ring structures were visible in the tumor. Immunohistochemical staining revealed MNF116 expressing tumor cells, consistent with a moderately differentiated adenocarcinoma. DIAGNOSIS: Multiple Sister Mary Joseph's nodules - periumbilical skin metastases from gastric carcinoma. TREATMENT AND COURSE: The previous palliative chemotherapy with capecitabine will be expanded by irinotecan after completion of local iradiation of an esophageal stenosis. The patient declined additional local therapeutic options such as excision or electric chemotherapy. CONCLUSION: Sister Mary Joseph's nodule is a rare, umbilical cutaneous metastatic tumor originating from advanced metastatic intraabdominal or intrapelvic malignancies. Our case is remarkable because of the number of the umbilical and periumbilical, but otherwise characteristic nodules. Sister Mary Joseph's nodules are associated with a dismal prognosis. As they may precede cancer diagnosis, histological investigation of suspect umbilical nodules should be performed.

Clinical outcome of pretreated B-cell chronic lymphocytic leukemia following alemtuzumab therapy: a retrospective study on various cytogenetic risk categories.

BACKGROUND: Patients with B-cell chronic lymphocytic leukemia (CLL) with 17p deletion respond poorly to chemotherapy. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL in the various cytogenetic subgroups. PATIENTS AND METHODS: Data were collected from 105 consecutive, pretreated, cytogenetically defined patients who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The hierarchic incidence of cytogenetic abnormalities was: 13q deletion (as sole abnormality), 18%; trisomy 12, 13%; 11q deletion, 19%; 17p deletion, 33%; and none of these, 16%. Overall response rate (ORR) was 43% in the total cohort and 49% in the subgroup of 17p-deleted patients (n = 35). From the start of alemtuzumab monotherapy, median PFS in the total cohort and in the subgroup of 17p-deleted patients was 7.0 and 7.1 months, respectively. Median OS in the total cohort and in 17p-deleted patients was 32.8 and 19.1 months, respectively. The poor-risk group of patients with CLL (i.e. fludarabine resistant, 17p deletion; n = 20) showed encouraging ORR, PFS, and OS (35%, 7.0 and 19.2 months, respectively). CONCLUSIONS: Alemtuzumab was effective in treating patients with CLL across the cytogenetic categories evaluated, but there were differences. In patients with CLL with 17p deletion quite favorable ORR, PFS, and OS were achieved.

Infectious complications after allogeneic stem cell transplantation: incidence in matched-related and matched-unrelated transplant settings.

BACKGROUND: Bacterial, viral, and fungal pathogens frequently cause severe, life-threatening infections in immunocompromised patients after allogeneic hematopoietic stem cell transplantation (SCT). OBJECTIVE: To compare the frequency of infections in patients with matched-related (Group A) or with human leukocyte antigen (HLA)-matched-unrelated donors (Group B). PATIENTS AND METHODS: Patients treated at our transplantation unit between April 2004 and April 2005 were enrolled into this analysis. Documentation comprised demographic data, conditioning treatment, stem cell source, clinical course, as well as microbiological and clinical data and mortality. RESULTS: We analyzed 59 patients, 22 in Group A and 37 in Group B. Both groups were well balanced regarding demographic data. Diagnoses were acute myeloid leukemia (30 of 59 patients, 50.8%), multiple myeloma (15.2%), acute lymphoblastic leukemia (11.9%), and chronic myeloid leukemia (10.2%). Patients in Group A developed infections in 95.5% of the cases compared with 97.3% in patients in Group B. Most frequently detected pathogens were Staphylococcus species, human herpesvirus-6, and Epstein-Barr virus. Three proven fungal infections were detected in Group A compared with 9 proven fungal infections in Group B. Lung infiltrations were observed in equivalent incidence in both groups. Two years after transplantation, 55.9% of patients were alive (Group A: 68.2%; Group B: 48.6%, not significant). CONCLUSION: Allogeneic SCT from HLA-matched-unrelated donors does not have a higher infection risk than patients transplanted from matched-related donors.

Pulmonary MRI--a new approach for the evaluation of febrile neutropenic patients with malignancies.

GOALS OF WORK: Immunocompromised patients with malignant diseases often suffer from pulmonary infections. Early detection of these life-threatening infections is crucial to start effective treatment. The gold standard for the diagnosis of these disorders is high-resolution computed tomography (HR-CT) of the chest. This method, however, has limitations, for instance, in the discrimination of early interstitial infiltrates and the use of X-rays. We conducted a study to determine the feasibility and sensitivity of magnetic resonance imaging (MRI) of the lung compared to HR-CT in immunocompromised patients with persistent fever in neutropenia and suspected pneumonia. MATERIALS AND METHODS: Between January 2003 and July 2004, 50 consecutive neutropenic patients with fever of unknown origin and negative chest X-ray were examined with HR-CT of the lungs. Patients with pulmonary infiltrates were further examined with MRI of the chest within 24 h after HR-CT using a specific lung protocol. In addition, microbiological testing was performed for the characterization of the causative pathogen. RESULTS: Of 50 patients, 35 had pulmonary infiltration according to HR-CT; these were examined with MRI of the lungs. MRI showed a high correlation (91%) with the findings in HR-CT. Both HR-CT and MRI were feasible in 94% of the examined patients. In 12 of 35 patients, fungal pathogens were identified in microbiological testing. CONCLUSIONS: MRI of the lungs is feasible in neutropenic patients with suspected pulmonary infection. Compared to HR-CT, MRI displays a high sensitivity in the detection of pulmonary infiltrates. MRI offers the opportunity of follow-up examinations without repeated X-ray exposure to the patient.