A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck - the RESGEX study.

BACKGROUND: The aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment. PATIENTS AND METHODS: In this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival. RESULTS: Median progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02). CONCLUSIONS: The glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease.

In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

[Treatment of head and neck squamous cell carcinoma recurrences and distant metastases : Highlights of the 2019 ASCO Meeting]. / Therapie der rezidivierten und fernmetastasierten Plattenepithelkarzinome des Kopf-Hals-Bereichs : Highlights des ASCO-Meetings 2019.

BACKGROUND: The contributions presented at this year's ASCO conference on treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) focused on systemic therapies, as in recent years. Two phase III studies-TPExtreme and Keynote-048-are expected to change clinical practice in first-line treatment of R/M-HNSCC. MATERIALS AND METHODS: Abstracts and presentations from this year's ASCO Annual Meeting on R/M-HNSCC were screened and checked for clinical relevance. RESULTS: TPExtreme, a randomized phase III trial, could show less toxicity and similar overall survival in patients treated with docetaxel, cisplatin, and cetuximab (TPEx regimen) compared to standard first-line therapy with the Extreme regimen (cisplatin, 5­fluorouracil [5-FU], cetuximab), albeit failing its endpoint of significantly improved survival. The randomized phase III Keynote-048 study could show a significant survival benefit in all patients treated with pembrolizumab, 5­FU, and cis-/carboplatin compared to Extreme. When selected patients (PD-L1 CPS ≥1 and ≥20) were treated with pembrolizumab monotherapy, they showed increased overall response rates in contrast to patients treated with Extreme. CONCLUSION: Based on the results of Keynote-048, pembrolizumab ± chemotherapy gained FDA approval as first-line treatment for R/M-HNSCC in the USA. Approval in Europe is expected soon and will probably have a strong impact on clinical routine.

Impact of single-room contact precautions on hospital-acquisition and transmission of multidrug-resistant Escherichia coli: a prospective multicentre cohort study in haematological and oncological wards.

OBJECTIVES: Colonization and infection with third-generation cephalosporin-resistant Escherichia coli (3GCR-EC) are frequent in haematological and oncological patients. In this high-risk setting, German guidelines recommend single-room contact precautions (SCP) for patients with 3GCR-EC that are non-susceptible to fluoroquinolones (F3GCR-EC). However, this recommendation is controversial, as evidence is limited. METHODS: We performed a prospective, multicentre cohort study at four haematology and oncology departments assessing the impact of SCP on hospital-acquired colonization or bloodstream infection (BSI) with F3GCR-EC. Two sites performed SCP for F3GCR-EC patients including single rooms, gloves and gowns (SCP sites), and two did not (NCP sites). Active screening for 3GCR-EC was performed and isolates were characterized with molecular typing methods including whole genome sequencing and core genome multiple locus sequence typing to assess patient-to-patient transmission. Potential confounders were assessed by competing-risk regression analysis. RESULTS: Within 12 months, 1386 patients at NCP sites and 1582 patients at SCP sites were included. Hospital-acquisition of F3GCR-EC was observed in 22/1386 (1.59%) and 16/1582 (1.01%) patients, respectively (p 0.191). There were 3/1386 (0.22%) patients with BSI caused by F3GCR-EC at NCP sites and 4/1582 (0.25%) at SCP sites (p 1.000). Patient-to-patient transmission occurred in three cases at NCP and SCP sites each (p 1.000). The number of patients needed to screen in order to prevent one patient-to-patient transmission of F3GCR-EC was determined to be 3729. CONCLUSIONS: Use of SCP had no significant impact on hospital-acquisition or patient-to-patient transmission of F3GCR-EC in this high-risk setting.

Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis.

Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23).

The current role of systemic chemotherapy in the primary treatment of head and neck cancer.

The treatment of patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) is still evolving into the perfect combination of the different multidisciplinary approaches. Induction chemotherapy (ICT) prior to planned definitive local therapy is widely used in this patient population for over 30 years but it is still unclear how to incorporate ICT into multimodality treatment the best. It appears to have a role in selected clinical situations especially for those patients with high risk for distant metastasis. However, since ICT protocols in different studies varies a lot, a comparative and consistent statement of benefits is difficult. We show the recent developments including randomized trials comparing radiochemotherapy (RCT) and ICT followed by definitive RCT here. This review summarizes how ICT has developed over the years, provides critical remarks of recent developments, and discusses how clinical trials including ICT should be conducted in the future.

[Therapy of recurrent or metastatic head and neck squamous cell carcinoma : highlights of the ASCO Meeting 2014]. / Therapie der rezidivierten und fernmetastasierten Plattenepithelkarzinome des Kopf-Hals-Bereichs : Highlights des ASCO-Meetings 2014.

The treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) requires exceptional interdisciplinary cooperation within the treatment team, as many factors need to be taken into account to come to an adequate treatment decision. Most of these patients need to be treated in a palliative concept, as comorbidities and prior oncologic treatment limit the treatment options. Inhibitors of epidermal growth factor receptor (EGFR) in combination with platinum and 5-fluorouracil (5-FU) may be considered as standard. However, survival rates are poor and new therapeutic approaches and substances are therefore tested continuously. At the annual meeting of the American Society of Clinical Oncology (ASCO) in 2014, numerous studies on first- and second-line treatment of R/M-HNSCC were presented. A selection is discussed in this paper, including a report about the combined therapy of cetuximab with established chemotherapies, new results from protocols including small molecules and investigations of mTOR inhibitors.

Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

[The most important study results of primary chemoradiation for head and neck squamous cell carcinoma : highlights of the ASCO Meeting 2013]. / Die wichtigsten Studienergebnisse der primären Radio-Chemo-Therapie von Kopf-Hals-Tumoren : Highlights des ASCO-Meetings 2013.

Primary concomitant and sequential chemoradiation is a commonly used therapeutic strategy for head and neck squamous cell carcinoma. At the annual meeting of the American Society of Clinical Oncology 2013 numerous trial results were presented. A selection of the most important trials will be summarized in this article. This year several results from phase II and III trials in concomitant and sequential therapy were demonstrated.

[Therapy of recurrent and metastatic squamous cell carcinoma of the head and neck : highlights of the ASCO Meeting 2013]. / Therapie der Rezidiv- und Fernmetastasen bei Plattenepithelkarzinomen des Kopf- und Halsbereichs : Highlights des ASCO-Meetings 2013.

In many cases squamous cell carcinoma of the head and neck is already in an advanced stage when initially diagnosed. Despite definitive treatment, loco-regional recurrences and metastases are common and patients ultimately require systemic treatment. Epidermal growth factor receptor (EGFR) inhibitors have proven to significantly prolong survival and have therefore become the first line treatment in recurrent and metastatic squamous cell carcinoma of the head and neck in addition to platinum and 5-FU treatment. Good results have also been reported for EGFR inhibitors in cases where platinum-based treatment has failed. Further strategies, such as salvage surgery, platinum-based chemotherapy, targeted therapy, chemoradiation and reirradiation are currently under investigation to reduce toxicity and improve survival and health-related quality of life.

[The most important results on primary chemoradiation for head and neck squamous cell carcinoma: highlights from the 2012 ASCO meeting]. / Die wichtigsten Studienergebnisse der primären Radiochemotherapie von Kopf-Hals-Tumoren: Highlights vom ASCO-Meeting 2012.

Primary concomitant and sequential chemoradiation is a commonly used therapeutic strategy for head and neck squamous cell carcinoma. At the annual meeting of the 2012 American Society of Clinical Oncology numerous trial results were presented. A selection of the most important trials will be summarized in this article. This year, several important results from phase III trials-including the long awaited comparison of sequential and concomitant chemoradiation-were demonstrated.

Evaluation of BM cytomorphology after allo-SCT in patients with AML.

Estimation of relapse risk in AML after allo-SCT is critical. The negative impact of increased blast count post transplant is widely accepted. Here, we studied cellularity and dysplasia in BM cytomorphology on days 30 and 100 in 112 AML patients who achieved haematological CR after SCT. Overall cellularity on day 30 was normal in 45.3%, reduced in 37.3% and increased in 17.3% of samples (day 100: normal: 54.8%; reduced: 38.7%; and increased: 6.5%). Dysplasia in ≥10% of cells was frequent on day 30 (granulopoiesis: 25.0% of samples; erythropoiesis: 34.6%; and megakaryopoiesis: 47.7%) and also on day 100. Relapses were less frequent in patients with normal BM cellularity on day 30 (7/34; 20.6%) when compared with reduced (9/28; 32.1%) or increased cellularity (10/13; 76.9%; P = 0.001). Estimated 2-year OS was 59.0% for patients with normal overall cellularity, followed by patients with increased (44.0%) and reduced cellularity (31.4%, P = 0.009). In contrast, cellularity at day 100 and dysplasia at days 30 and 100 did not correlate with outcome measures. Thus, in the cohort studied, BM cellularity represents a prognostic parameter for the post-transplant period in AML patients. Dysplasia seems to be an unspecific phenomenon in the cohort analysed.

Lenograstim after autologous peripheral blood progenitor cell transplantation: results of a double-blind, randomized trial.

A phase III, randomized, double-blind, placebo-controlled, multi-center trial was conducted in order to compare the incidence of microbiologically defined infections occurring after high-dose chemotherapy (HDT) and ASCT in 98 patients given lenograstim (Granocyte) and 94 patients given placebo after transplantation. Hematopoietic recovery, the use of i.v. antibiotics, the numbers of red blood cell and platelet transfusions, the days spent in hospital, and the days on parenteral nutrition were also compared. The incidence of infections until neutrophil recovery was significantly less in patients who received lenograstim after HDT and ASCT as compared to patients who received placebo (66 of 98 vs 86 of 94 patients, P<0.001). Lenograstim also significantly reduced the use of i.v. antibiotics (P<0.001) and the median duration of i.v. antibiotic treatment (8 days vs 10 days, P=0.04), improved neutrophil recovery (absolute neutrophil count >0.5 x 10(9)/l: 11 days vs 15 days, P<0.001) and reduced the number of days spent in hospital (15 days vs 17 days, P<0.001). The administration of lenograstim after HDT and ASCT significantly reduces the incidence of microbiologically defined infections until neutrophil recovery. It also leads to less use of antibiotics and earlier discharge from hospital.

Semiquantitative reverse transcription polymerase chain reaction analysis for detection of bcr/abl rearrangement using RNA extracts from bone marrow aspirates compared with glass slide smears after 0, 2 and 4 d of storage.

The polymerase chain reaction (PCR) is an established tool for the detection of specific chromosomal aberrations in different haematological malignancies. Owing to fast degradation of RNA, the immediate processing of samples is thought to have a major influence on the reliability of results. Any delay caused by transport may be an obstacle to reverse transcription PCR (RT-PCR)-based methods in multicentre studies. However, as air-dried bone marrow smears are usually available, we have improved a method to use smears as a source for routine RT-PCR investigations. We studied whether this source of RNA could overcome problems caused by delayed transport of samples. The aim of the present study was (i) to investigate the influence of a storage period of up to 4 d before processing of a specimen by nested bcr/abl RT-PCR, and (ii) to compare bone marrow aspirates with bone marrow smears stored at room temperature in parallel. Bone marrow aspirates and smears were taken from 11 patients with Ph-positive chronic myeloid leukaemia (CML). PCR results were semiquantified using a limiting dilution assay. We observed a loss of sensitivity < 1 log in stored bone marrow aspirates, even after 96 h. Results obtained from air-dried unstained glass slide smears were similar to investigations performed on approximately 1 x 10(5) cells of a bone marrow aspirate. We conclude that a storage period of up to 96 h has little influence on the detection of a bcr/abl fusion transcript in CML at diagnosis. Glass slide smears were equivalent to bone marrow aspirates in 8 out of 11 cases as a source for RT-PCR analysis when nested PCR was performed.

Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment-related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T-cell depletion with anti-thymocyte globulin.

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment-related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T-cell depletion using rabbit anti-thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft-versus-host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV-negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0.001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2.1; CI: 1.2-3.8; P = 0.014), apart from age > 20 years (RR: 2.74; CI: 1.2-3.8; P = 0.004) and late leucocyte engraftment (RR: 2.4; CI: 1.2-4.9; P = 0.015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment-related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5.3; CI: 1.9-14.6; P = 0.002), followed by age > 20 years (RR: 4.8; CI: 1.3-18.1; P = 0.02) and delayed leucocyte engraftment (RR: 3.6; CI: 1.2-11; P = 0.02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T-cell depletion with ATG.