Summary Background Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune ...surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. Methods In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov , number NCT02181738. Findings Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4–7). At a median follow-up of 8·9 months (IQR 7·8–9·9), 53 (66·3%, 95% CI 54·8–76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 25% patients), infusion-related reaction (16 20%), and rash (13 16%). The most common drug-related grade 3 or 4 adverse events were neutropenia (four 5% patients) and increased lipase concentrations (four 5%). The most common serious adverse event (any grade) was pyrexia (three 4% patients). Three patients died during the study; none of these deaths were judged to be treatment related. Interpretation Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. Funding Bristol-Myers Squibb.
Summary Background Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated ...donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. Methods We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. Findings Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 95% CI 1·87–9·67; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 34% of 99 patients in the ATG group vs 41 42% of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 one of whom died—the only death due to an adverse event) versus those who did not receive ATG (two no deaths). No deaths were attributable to ATG. Interpretation ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. Funding The Canadian Institutes of Health Research and Sanofi.
Summary Background The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this ...patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00358982. Findings 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients 17% in the 110 mg group, three 11% in the 85 mg group); fatigue (five patients 22% in the 110 mg group, three 11% in the 85 mg group); and pneumonia (four patients 17% in the 110 mg group, two 7% in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
Objectives We sought to prospectively evaluate risk of stroke and impact of transcatheter patent foramen ovale (PFO) closure in patients with permanent right-to left shunt compared with those with ...Valsalva maneuver-induced right-to-left shunt. Background Pathophysiology and properly management of PFO still remain far from being fully clarified: in particular, the contribution of permanent right-to-left shunt remains unknown. Methods Between March 2006 and October 2010, we enrolled 180 (mean age 44 ± 10.9 years, 98 women) of 320 consecutive patients referred to our center for transcatheter PFO closure, who had spontaneous permanent right-to-left shunt on transcranial Doppler and transthoracic/transesophageal echocardiography. All patients fulfilled the standard current indications for transcatheter closure and underwent preoperative transesophageal echocardiography and brain magnetic resonance imaging, with subsequent intracardiac echocardiographic-guided transcatheter PFO closure. We compared the clinical echocardiographic characteristics of these patients (Permanent Group) with the rest of 140 patients with right-to-left shunt only during Valsalva maneuver (Valsalva Group). Results Compared with the Valsalva Group patients, patients of the Permanent Group had increased frequency of multiple ischemic brain lesions on magnetic resonance imaging, previous recurrent stroke, previous peripheral arteries embolism, migraine with aura, and—more frequently—atrial septal aneurysm and prominent Eustachian valve. The presence of permanent shunt confers the highest risk of recurrent stroke (odds ratio: 5.9, 95% confidence interval: 2.0 to 12, p < 0.001). No differences were recorded between the 2 groups with regard to recurrence of ischemic events after the closure procedure. Conclusions Despite its small-sample nature, our study suggests that patients with permanent right-to-left shunt have potentially a higher risk of paradoxical embolism compared with those without.
Objectives Using cardiac magnetic resonance (CMR), we sought to evaluate the relative influences of mechanical, electrical, and scar properties at the left ventricular lead position (LVLP) on cardiac ...resynchronization therapy (CRT) response and clinical events. Background CMR cine displacement encoding with stimulated echoes (DENSE) provides high-quality strain for overall dyssynchrony (circumferential uniformity ratio estimate CURE 0 to 1) and timing of onset of circumferential contraction at the LVLP. CMR DENSE, late gadolinium enhancement, and electrical timing together could improve upon other imaging modalities for evaluating the optimal LVLP. Methods Patients had complete CMR studies and echocardiography before CRT. CRT response was defined as a 15% reduction in left ventricular end-systolic volume. Electrical activation was assessed as the time from QRS onset to LVLP electrogram (QLV). Patients were then followed for clinical events. Results In 75 patients, multivariable logistic modeling accurately identified the 40 patients (53%) with CRT response (area under the curve: 0.95 p < 0.0001) based on CURE (odds ratio OR: 2.59/0.1 decrease), delayed circumferential contraction onset at LVLP (OR: 6.55), absent LVLP scar (OR: 14.9), and QLV (OR: 1.31/10 ms increase). The 33% of patients with CURE <0.70, absence of LVLP scar, and delayed LVLP contraction onset had a 100% response rate, whereas those with CURE ≥0.70 had a 0% CRT response rate and a 12-fold increased risk of death; the remaining patients had a mixed response profile. Conclusions Mechanical, electrical, and scar properties at the LVLP together with CMR mechanical dyssynchrony are strongly associated with echocardiographic CRT response and clinical events after CRT. Modeling these findings holds promise for improving CRT outcomes.
Abstract Hemifacial spasm (HFS) happens because of vascular compression of the facial nerve at the root exit zone. Vertebrobasilar dolichoectasia (VBD) is a very rare cause of HFS. VBD is diagnosed ...by computed tomography angiography and magnetic resonance imaging. Here, we report a case of 65-year-old female patient with HFS due to VBD. We discuss the complications and the treatment options for the case.
To analyze, through chart review, the efficacy of salvage radiation therapy (sRT) for relapsed or progressive Hodgkin lymphoma (HL) patients who failed autologous stem cell transplant (ASCT).
Among ...347 patients with recurrent/refractory HL who received ASCT from 1986-2006, 163 had post-ASCT progression or relapse. Of these, 56 received sRT and form the basis of this report. Median age at sRT was 30 years (range, 17-59 years). Disease was confined to lymph nodes in 27 patients, whereas 24 had both nodal and extranodal disease. Salvage radiation therapy alone was given in 34 patients (61%), and sRT plus chemotherapy was given in 22 (39%). Median interval from ASCT to sRT was 0.8 years (range, 0.1-5.6 years). The median dose was 35 Gy (range, 8-40.3 Gy). The sRT technique was extended-field in 14 patients (25%) and involved-field in 42 (75%).
The median follow-up from sRT was 31.3 months (range, 0.2-205.5 months). Overall response rate was 84% (complete response: 36%; partial response: 48%). The median overall survival was 40.8 months (95% confidence interval, 34.2-56.3 months). The 5-year overall survival was 29% (95% confidence interval, 14%-44%). The 2-year progression-free survival (PFS) was 16%; the 2-year local PFS was 65%, whereas the 2-year systemic PFS was 17%. The 1-year PFS was higher in patients in whom all diseased sites were irradiated (49%) compared with those in whom only the symptomatic site was treated (22%, P=.07). Among 20 alive patients, 5 were disease free (at 6.4, 6.8, 7.4, 7.9, and 17.1 years).
For patients with HL who fail ASCT, a selective use of RT provides a durable local control rate of 65% at 2 years and should be considered as part of the standard management plan for the palliation of incurable HL. Occasionally irradiation of truly localized disease can lead to long-term survival.
Abstract Purpose Recent emphasis on eye care in intensive care unit (ICU) patients has translated to eye assessment being part of routine care. In this setting, we determined the incidence, risk ...factors, and resolution time of exposure keratopathy. Methods In this prospective cohort study, 301 patients were examined within 24 hours of ICU admission and subsequently daily by an ophthalmologist till death or discharge. Eyelid position, conjunctival and corneal changes, treatment, and outcome data were collected. Results Admission diagnoses included febrile illnesses (35.2%) and respiratory failure (32.6%); 84.1% were ventilated. Forty-nine patients had exposure keratopathy (bilateral = 35, unilateral = 14) at admission; 35 patients developed new onset keratopathy (incidence 13.2%) 4.6 ± 2.6 days after ICU admission. In 67 patients, keratopathy was mild (punctate epithelial erosions). Macroepithelial defects (n = 9), stromal whitening with epithelial defect (n = 3), and stromal scar (n = 3) were infrequent. None developed microbial keratitis. On multivariate logistic regression analysis, eyelid position (odds ratio, 2.93; 95% confidence interval, 1.37-6.25), and ventilation duration (odds ratio, 1.11; 95% confidence interval, 1.04-1.19) were strongly associated with the development of keratopathy after ICU admission. Keratopathy resolved in 3.6 ± 4.5 days. Conclusions Severe exposure keratopathy is infrequent in a protocolized ICU setting. Eyelid position and duration of ventilation are associated with exposure keratopathy.
Highlights • RIC is comparable to MAC for AML/MDS • PSM analysis balances pretransplant patient characteristics • Addition of low-dose TBI to allo-SCT conditioning could reduce the risk of relapse
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