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SummaryThis phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570’s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15 ). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n  = 41) and “cachectic” (CXI <49.8, n  = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p  = 0.044) and OS (HR = 4.05, p  = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.

Background Doxorubicin remains one of the most common causes of cardiotoxicity in patients with lymphoma, leading to significant morbidity and mortality. Early decline in left ventricular (LV) ejection fraction predicts chemotherapy-induced cardiotoxicity and mortality, but limited data exist on doxorubicin-induced subclinical right ventricular (RV) dysfunction. We investigated dose-dependent subclinical doxorubicin-induced RV dysfunction in lymphoma patients. Methods Thirty-five patients with adult lymphoma treated with doxorubicin were studied. All patients had normal baseline LV ejection fraction (LVEF > 55%), and no known cardiopulmonary disease. We studied the dose-dependent effect of doxorubicin on RV strain by 2D speckle-tracking echocardiography (STE) using a vendor-independent software (TomTec). Images were analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Baseline LVEF, RV fractional area change (RV FAC), RV free wall strain (RV FWS), and RV global longitudinal strain (RV GLS) were measured prior to chemotherapy initiation and compared with echo studies obtained at a 6-month follow-up interval. Patients served as their own controls. Comparisons between pre- and post-therapy were achieved using paired Student’s t-tests or Chi-Square test. Results The Interobserver Intraclass Correlation Coefficient for RV GLS, RV FAC and RV FWS, was 0.87, 0.81 and 0.79, respectively. The mean age was 51 ± 13 years, 40% women, 60% white. The mean cumulative doxorubicin dose was 239 ± 104 mg m − 2 . There was there was significant decline in RV FAC (47.3 ± 4.4% vs. 43.7 ± 3.9%), RV FWS (− 24.9 ± 3.3 vs. -22.2 ± 2.9), and RV GLS (− 22.4 ± 4.1 vs. -20.6 ± 3.4) (all p  < 0.01); but no significant decline in LVEF during the 6-month follow up (63.3 ± 6.2% vs. 61.6 ± 11.1%, p  = 0.374). At cumulative doxorubicin dose ≥200 mg m − 2 we found a significant decline in RV FAC (47.0 ± 4.7% vs. 42.2 ± 3.1%, p  < 0.01), RV FWS (− 24.6 ± 3.6 vs. -21.5 ± 2.4, p < 0.01), and RV GLS (− 22.3 ± 4.5 vs. -20.1 ± 2.9, p  = 0.03). Conclusion In this cohort of adult lymphoma patients, doxorubicin-based therapy was associated with subclinical RV dysfunction, but not LV dysfunction, at a cumulative dose ≥200 mg m − 2 . Additional studies evaluating the long-term prognostic implications of RV dysfunction in this population are essential.

Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20–25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16–59) in group A, 10% (2–33) in group B, and 30% (13–54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3–4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Cyclacel Limited.

A 60-year-old woman was diagnosed with isolated mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexa and treated with two years of weekly rituximab for eight doses followed by rituximab maintenance. After nearly two years of maintenance therapy, she developed a tender, indurated mass on the left neck. Biopsy results were consistent with primary cutaneous classical Hodgkin lymphoma (PCCHL).

Background Non-resolving pneumonia poses a significant clinical challenge. It is common to treat non-resolving pneumonia over an extended period of time, without evaluating the cause of failure or eliciting the exact aetiology. Objective To determine the aetiology and clinical-radiological profile of non-resolving pneumonia. Materials and methods Analytical, observational study done among 77 consecutive patients with non-resolving pneumonia, who attended a tertiary care centre over 1 year. Clinical details were obtained using prefixed questionnaires. Necessary diagnostic procedures like bronchoscopy and image guided transthoracic sampling along with histopathological and microbiological investigations were done to obtain final diagnosis. Results The most common aetiology was lung malignancy (44.2%) followed by chronic infections (40.3%) dominated by tuberculosis (14.3%). Adenocarcinoma (32.5%) was the commonest malignancy presenting as non-resolving consolidation. History of smoking ( p value 0.001), chest pain ( p value 0.001), and haemoptysis ( p value 0.006) was associated with a diagnosis of malignancy. Actinomycosis (7%) had a significant association with chest pain ( p value 0.032). Transthoracic image-guided tissue sampling had a high diagnostic yield of 84.8% and bronchoscopy of 66.9%. Conclusion Malignancy needs to be considered promptly once we encounter with non-resolution of consolidation. The clinical pointers like advanced age, smoking history, symptoms more than 8 weeks, symptoms like chest pain, and haemoptysis mandate evaluation for malignancy in non-resolving pneumonia. The labyrinth of diabetes mellitus impedes the timely resolution of infections.

The phase 2, multicohort, ongoing ELM-2 study evaluates odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory (R/R) B cell non-Hodgkin lymphoma after ≥2 lines of therapy. Here primary analysis of the diffuse large B cell lymphoma (DLBCL) cohort is reported. Patients received intravenous odronextamab in 21-day cycles until progression or unacceptable toxicity, with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS) risk. The primary endpoint was objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival (PFS) and overall survival. A total of 127 patients were enrolled. At the 29.9-month efficacy follow-up, the ORR was 52.0% and CR rate was 31.5%. Median durations of response and CR were 10.2 and 17.9 months, respectively. Undetectable minimal residual disease at cycle 4 day 15 was associated with PFS benefit. With a step-up of 0.7 to 4 to 20 mg ( n  = 60), CRS was the most common treatment-emergent adverse event (53.3% (grade ≥3, 1.7%)). No immune effector cell-associated neurotoxicity syndrome was reported. Infections were reported in 82/127 (64.6%) patients (grade ≥3, 38.6%; coronavirus disease 2019, 18.1% (grade ≥3, 12.6%)). In conclusion, odronextamab showed encouraging efficacy in heavily pretreated R/R DLBCL and generally manageable safety with supportive care. Clinical trial registration: NCT03888105 . Kim and colleagues perform a phase 2 clinical trial (ELM-2) of odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma and report on the primary analyses of the efficacy and safety profile.

Breast implant-associated (BIA) anaplastic large-cell lymphoma (ALCL) is a rare disease, comprising a small percentage of all non-Hodgkin lymphomas (NHLs), reportedly 2-3%. There is currently no established standard approach to the treatment of BIA ALCL. The first case on the development of ALCL in the presence of a breast implant was reported in 1997 and the association was first identified by the Food and Drug Administration in 2011. We herein describe a case of BIA ALCL in a patient with a previous history of breast cancer and breast reconstruction who presented with hardening of her breast implant. The patient underwent capsulectomy and the findings of the pathological examination were consistent with ALCL. The patient completed three cycles of combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regimen) followed by radiation consolidation therapy, and has maintained a complete remission ever since. The aim of the present study was to review the treatment options for BIA ALCL and suggest an investigation of the CD30-directed antibody-drug conjugate, brentuximab vedotin, as a potential treatment option for BIA ALCL.

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by [sup.90]Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by [sup.90]Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/[m.sup.2] on day 1 and day 7, 8, or 9, followed by a single injection of [sup.90]Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity. Key words: dose-dense chemotherapy, radioimmunotherapy, consolidation, large B-cell lymphoma, CHOP-R-14

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m on day 1 and day 7, 8, or 9, followed by a single injection of Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.