Stefan Knop

Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkins lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.

Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom).

We conducted a phase 1/2 trial combining lenalidomide (R) with adriamycin (A) and dexamethasone (D) for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, RAD, delivered for six 28-day cycles. A total of 69 intensively pretreated patients with a median age of 65 years (range, 46-77 years) were enrolled. Using pegfilgrastim (G), the maximum tolerated dose (MTD) was formally not reached at the highest dose level (R, 25 mg on days 1-21; A, 9 mg/m(2) intravenously on days 1-4; and D, 40 mg on days 1-4 and 17-20; dose level 5+G), which was then used to determine efficacy. Grades 3/4 neutropenia and thrombocytopenia were seen in 48% and 38% of patients, respectively. Thromboembolic events occurred in 4.5% and severe infections in 10.5% of patients. On an intent-to treat analysis, overall response rate (ORR) was 73% for the whole study and 77% including 74% complete response (CR) plus very good partial response (VGPR) for dose level 5+G. Response rates and progression-free survival did not differ between relapsed and relapsed-refractory patients. Deletion of chromosome 17p and elevated beta(2)-microglobulin were associated with significantly inferior response and shortened time to progression. In conclusion, RAD induces substantial and durable remission with an acceptable toxicity profile in patients with relapsed and relapsed-refractory myeloma. This trial was registered at www.ClinicalTrials.gov as no. NCT00306813.

Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel.

Bendamustine is a novel bifunctional alkylating agent with promising activity in lymphoid malignancies and several solid tumors. Unfortunately, the early development of this agent did not provide sufficient information on which to determine an optimal systematic dose and schedule. As a result, administration of the agent has been inconsistent among studies. The use of this drug has been increasing since it has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia and rituximab-refractory indolent B-cell non-Hodgkin lymphoma, and is expected to increase further following anticipated European regulatory approval. Thus, a consensus meeting was convened to develop recommendations for standardizing the administration of the drug based on the available clinical data. Recommendations were developed including dose and schedule for the various clinical indications, as a single agent and in combination therapy, and to provide guidance for supportive measures. This report, representing the conclusions of that meeting, should provide guidance for the clinician until definitive dose-finding studies have been conducted.

Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study

PURPOSE Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome-negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m(2)/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. RESULTS Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m(2)/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m(2)/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m(2)/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). CONCLUSION In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m(2)/day. Single-agent blinatumomab showed antilymphoma activity.

Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma.

We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.

Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced- intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study

Forty patients were enrolled in this phase 2 study combining radioimmunotherapy (RIT) using yttrium-90-ibritumomab-tiuxetan (15 MBq [0.4 mCi]/kg) with reduced-intensity conditioning (RIC) using fludarabine (90 mg/m(2)) and 2 Gy total body irradiation followed by allogeneic hematopoietic cell transplantation (HCT) from related (n = 13) or unrelated (n = 27) donors for the treatment of advanced non-Hodgkin lymphoma. Diagnoses were follicular lymphoma (n = 17), chronic lymphocytic leukemia (n = 13), mantle cell lymphoma (n = 8), marginal zone lymphoma (n = 1), and lymphoplasmacytic lymphoma (n = 1). Median age was 55 years (range, 34-68 years). All patients were high risk with refractory disease or relapse after preceding autologous HCT. No additional toxicities attributable to RIT were observed. Engraftment was rapid and sustained. Incidences of acute graft-versus-host disease 2-4 and chronic graft-versus-host disease were 43% and 53%, respectively. Kaplan-Meier-estimated nonrelapse mortality was 45% at 2 years. Twenty-two of 40 patients (55%) are alive, resulting in a Kaplan-Meier-estimated 2-year survival of 51% for all, 67% for follicular lymphoma, 49% for chronic lymphocytic leukemia, and 37% for mantle cell lymphoma patients. The combined use of RIT with RIC is feasible with acceptable toxicity, even in elderly and heavily pretreated patients. This study is registered at www.clinicaltrials.gov as #NCT00302757.

In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma

CXCR4 is a G‐protein‐coupled receptor that mediates recruitment of blood cells toward its ligand SDF‐1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [68Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4‐positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [68Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [68Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [18F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [68Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4‐directed therapeutic approaches in MM and other diseases.

A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors

This study evaluates the degree of kidney damageduring cisplatin/ifosfamide-based combinationchemotherapy and its possible prevention byamifostine. Thirty-one patients with solid tumorsstratified according to pretreatment were randomizedto receive VIP- or TIP-chemotherapy with or withoutamifostine (910 mg/m2) given as a short infusion priorto cisplatin. Chemotherapy consisted of cisplatin(50 mg/m2), ifosfamide (4 g/m2) and either etoposide(500 mg/m2) (= VIP) or paclitaxel (175 mg/m2) (= TIP)repeated at 3 weekly intervals. For all patients theglomerular filtration rate (GFR) measured bycreatinine-clearance, serum creatinine, electrolytesand differential urinary protein/enzyme excretion weredetermined prior to, during and after each cycle. Atotal of 62 cycles of chemotherapy were evaluable. Inthe amifostine-group GFR was fully maintained afterapplication of two cycles of chemotherapy, whereas inthe control group a > 30%-reduction of median GFR(108 to 80 ml/min) was observed (p < 0.001). Patientsreceiving amifostine had a lower degree of highmolecular weight proteins excretion indicating lessglomerular damage. In both groups significantincreases of tubular marker profiles peaking at day 3after chemotherapy were observed with a nearlycomplete reversibility of these changes prior to thenext chemotherapy cycle. The number of patients withlow magnesium serum levels during treatment was 17%after amifostine application versus 69% in controlpatients. The results seem to indicate that treatmentwith amifostine can preserve GFR after application oftwo cisplatin/ifosfamide-based chemotherapy cycles.This may be advantageous if repetitive cycles ofchemotherapy or subsequent administration of high dosechemotherapy is planned.

Effect of Combined Systolic and Diastolic Functional Parameter Assessment for Differentiation of Cardiac Amyloidosis From Other Causes of Concentric Left Ventricular Hypertrophy

Background—Differentiation of cardiac amyloidosis (CA) from other causes of concentric left ventricular hypertrophy remains a clinical challenge, especially in patients with preserved ejection fraction at the early disease stages. Methods and Results—Consecutive hypertrophic patients with CA, isolated arterial hypertension, Fabry disease, and Friedreich ataxia (n=25 per group) were investigated; 25 healthy volunteers served as a control group. Standard echocardiography was performed, and segmental longitudinal peak systolic strain (LSsys) in the septum was assessed by 2-dimensional speckle tracking imaging. Indices of left ventricular hypertrophy and ejection fraction were similar among all patient groups. Deceleration time of early filling was significantly lower in patients with CA (147±46 milliseconds) compared with those with isolated arterial hypertension, Fabry disease, or control subjects (all P<0.0125). Septal basal LSsys (−6±2%) was significantly lower in patients with CA compared with those with isolated arterial hypertension (−14±6%), Fabry disease (−12±5%), Friedreich ataxia (−16±2%), or control subjects (−17±3%; all P<0.001), whereas septal apical LSsys was similar among all patient groups and control subjects (all P>0.05). A data-driven cutoff value for the ratio of septal apical to basal LSsys ratio >2.1 differentiated CA from other causes of left ventricular hypertrophy (sensitivity, 88%; specificity, 85%; positive predictive value, 67%; negative predictive value, 96%). The prevalence of septal apical to basal LSsys ratio >2.1 plus deceleration time of early filling <200 milliseconds was 88% in CA but 0% in all other groups. Conclusions—A systolic septal longitudinal base-to-apex strain gradient (septal apical to basal LSsys ratio >2.1), combined with a shortened diastolic deceleration time of early filling (deceleration time of early filling <200 milliseconds), aids in differentiating CA from other causes of concentric left ventricular hypertrophy.

Biodistribution and Radiation Dosimetry for the Chemokine Receptor CXCR4-Targeting Probe 68Ga-Pentixafor

68Ga-pentixafor is a promising PET tracer for imaging the expression of the human chemokine receptor 4 (CXCR4) in vivo. The whole-body distribution and radiation dosimetry of 68Ga-pentixafor were evaluated. Methods: Five multiple-myeloma patients were injected intravenously with 90–158 MBq of 68Ga-pentixafor (mean ± SD, 134 ± 25 MBq), and a series of 3 rapid multiple-bed-position whole-body scans were acquired immediately afterward. Subsequently, 4 static whole-body scans followed at 30 min, 1 h, 2 h, and 4 h after administration of the radiopharmaceutical. Venous blood samples were obtained. Time-integrated activity coefficients were determined from multiexponential regression of organ region-of-interest data normalized to the administered activity, for example, the time-dependent percentages of the injected activity per organ. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Results: The effective dose based on 150 MBq of 68Ga-pentixafor was 2.3 mSv. The highest organ-absorbed doses (for 150 MBq injected) were found in the urinary bladder wall (12.2 mGy), spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Other organ mean absorbed doses were as follows: 2.7 mGy, liver; 2.1 mGy, red marrow; 1.7 mGy, testes; and 1.9 mGy, ovaries. Conclusion: 68Ga-pentixafor exhibits a favorable dosimetry, delivering absorbed doses to organs that are lower than those delivered by 18F-FDG– or 68Ga-labeled somatostatin receptor ligands.