(1) Background: Consolidation therapy is an emerging strategy for patients with relapsed/refractory (RR) Hodgkin Lymphoma (HL) at high risk of failing salvage autologous stem cell transplantation ...(ASCT). (2) Objectives: To assess the safety and effectiveness of PD1-blockade consolidation for these high-risk patients. (3) Design: Multi-center retrospective analysis. (4) Methods: We identified 26 patients given anti-PD1 consolidation, from June 2016 to May 2020. (5) Results: Patients displayed the following risk factors: refractory disease (69%), relapse < 12 months from upfront therapy (15%), ≥2 lines of salvage therapy (73%), extranodal disease (65%). Nineteen patients (73%) had ≥3 of these factors. In addition, 16 patients (61%) also displayed PET-positive (Deauville ≥ 4) disease before ASCT. Treatment-related adverse events (TRAEs), never graded > 3, occurred in 12 patients (46.15%) and mainly included skin rashes (41.7%), transaminitis (33.3%), and thyroid hypofunction (25%). Patients completed a median of 13 courses (range 6−30). At a median follow-up of 25.8 months post-ASCT, the median progression-free (PFS) was 42.6 months, with a 2-year PFS and overall survival rates of 79% and 87%, respectively. (6) Conclusions: Post-ASCT consolidation with anti-PD1 is feasible and effective. Further studies are warranted to define the optimal treatment length and patients’ subsets more likely to benefit from this approach.
Patients with non-hodgkin lymphomas (NHL) represent a population of special interest during the current Coronavirus disease-19 (COVID-19) pandemics. NHLs are associated with disease- and ...treatment-related immunodeficiencies which may generate unusual COVID-19 dynamics and pose unique management challenges. We report the unusual clinical course of COVID-19 in a patient with mantle cell lymphoma (MCL) exposed to nine doses of Rituximab shortly before infection with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). He had a prolonged asymptomatic phase, with negative molecular and antibody testing for SARS-CoV-2, followed by a rapidly progressive evolution to severe COVID-19. Despite detection of viral RNA overlapped with first symptoms occurrence, anti-SARS-CoV-2 antibodies displayed an asynchronous pattern, with IgG first appearing 2 days after RNA positivity and IgM never being detected throughout the entire clinical course. While disease-associated immune derangements and/or previous treatments involving anti-CD20 antibodies might have contributed to COVID-19 dynamics in our patient, data suggests that antibody testings, without concurrent molecular assessment for SARS-CoV-2, may turn inadequate for monitoring of MCL patients, and in general NHL patients heavily exposed to anti-CD20 antibodies, during the current pandemics. We suggest that repeated molecular testing of nasopharyngeal swab should be implemented in these subjects despite a negative serology and absence of symptoms of SARS-CoV-2 infection. For the same reasons, a customized strategy needs to be developed for patients exposed to anti-CD20 antibodies, based on different features and mechanism of action of available SARS-CoV-2 vaccines and novel vaccinomics developments.
In emergency veterinary practice, gastrointestinal foreign body (GFB) removal is a common procedure that is performed with different techniques, such as endoscopy or surgery. The aims of this ...retrospective, multicentre, clinical study were to report the common locations and types of objects recovered and to investigate clinical factors and outcomes in dogs after surgical or endoscopic treatment for GFB removal. Records of dogs with a GFB diagnosis referred to the Teaching Veterinary Hospital or treated in three different veterinary hospitals from September 2017 to September 2019 were examined. The data obtained from each case included breed, age, clinical signs at presentation, duration of clinical signs, type and location of the GFB, treatment, length of hospitalisation and outcome. Seventy-two dogs were enrolled in the study. There were 42 males (58%) and 30 females (42%). The median age was 36 months (range: 3 months to 8 years). Endoscopic retrieval was performed in 56% of GFBs (located in the stomach or duodenum), whereas 44% of dogs underwent surgery. The type of FB detected varied greatly: kid toy (14%), metallic object/coin (13%), cloth (13%), sock (8%), ball (8%), plastic material (8%), peach stone (7%), fishhook (6%), sewing needle (4%), hair tie (4%), pacifier (3%), plant materials (3%) and others (9%). Moreover, the FBs were classified as sharp (13%,
= 9), pointed (33%,
= 24), blunt (26%,
= 19), or linear (28%,
= 20). In this study, 68% of FBs were localised in the stomach, 25% in the intestinal tract (50% duodenum, 28% jejunum, and 22% ileum), and 7% in both the stomach and small intestine. The type of GFB was not significantly associated with age, site or breed. There was a significant association between the type of GFB and sex: if the dog was male, there was a 38% probability of ingesting linear GFBs. The dog survival rate was 100% in cases treated by gastric endoscopic or surgical removal, 94% in cases treated with enterotomy and 33% in cases in which enterectomy was necessary. Enterectomy and multiple surgical sites were associated with a poor outcome. The presence of vomiting for more than 24 h was significantly associated with death.
In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus ...thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.
Abstract High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be ...identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m2 ) to high-dose MEL (140 mg/m2 ) before a second ASCT, in a tandem ASCT strategy, in 64 patients with “de novo” MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.
Introduction: T-cell and natural killer (NK)-cell lymphomas encompass a heterogeneous spectrum of malignancies with variable degrees of biological and clinical aggressiveness and different patterns ...of nodal/extra nodal dissemination. Despite advances in understanding of their genetic landscape, treatment options for these tumors are limited and survival remains dismal especially in patients (pts.) who relapse/progress after frontline treatment. Therefore, development of new active agents is a pressing medical need in this setting. The unconventional alkylator BDM and HDACi are clinically effective in pts. with recurring disease and the combination of these agents was suggested as a way to overcome early resistance and improve response and survival rates in T-cell tumors. Since EDO-S101 is a fusion molecule that combines the active structures of BDM and the pan-HDACi vorinostat to simultaneously damage DNA and block damage repair, we investigated its antitumor activity in preclinical models of human T- and NK- lymphomas.
Methods: We assessed the patterns of EDO-S101 cytotoxicity and its regulatory effects on genes involved in DNA-damage/repair, apoptosis and drug resistance on a large panel of cell lines representative of most T-lymphoma subtypes, including precursor T-cell lymphoma/leukemia (pTCL; MOLT-4, KE-37, Jurkat, CCRF-CEM), anaplastic large T-cell lymphoma (ALCL; SR-786, SUDHL1) and cutaneous T-cell lymphoma (CTCL; HUT78, MYLA, HH, PB2B, MAC-2A). As a further model, we exploited an ALCL cell line (SUDHL1-R100) selected for resistance to BDM. SUDHL1-R100 display a growth pattern indistinguishable from parental cells in the presence of BDM (100 μmol/L).
Results: EDO-S101 induced a significant time- and dose-dependent inhibition of growth and survival in all T-cell lines, with a IC50 at 48 hrs (0.33 to 0.68 μmol/L), that was at least 90% and 50% lower than IC50 of BDM (10.5 to 23.67 μmol/L) and vorinostat (0.42 to 1.17 μmol/L) in the same cell lines. No significant differences emerged across various cell lines as to sensitivity to EDO-S101. Notably, growth inhibitory effects of EDO-S101 were 35% to 40% higher than those achieved by the concomitant exposure of tumor cells to BDM and vorinostat at equimolar concentrations. A significant induction of the DNA double strand breaks marker pγH2AX, along with decreased levels of Thr-1989 pATR and Polo-like kinase 1 (PLK1) were consistently observed in pTCL, ALCL and CTCL cell lines, indicating that EDO-S101 triggered inappropriate mitotic entry with unrepaired DNA damage. In addition, qRT-PCR results showed upregulation of the proapototic genes NOXA, p21 and/or p27 in pTCL, CTCL and ALCL cells. Among DNA repair genes, EDO-S101-induced downregulation of ATM, ATR and EXO1 was paralleled by an increase of MGMT transcripts. Most intriguingly, BDM-resistant ALCL cells (SUDHL1-R100) were highly sensitive to EDO-S101, with an IC50 of only 0.72 μmol/L, but less responsive to vorinostat (IC50: 2.17 μmol/L) than parental cells (IC50: 1.46 μmol/L). Exposure to EDO-S101 also resulted in transcriptional regulation of components of the PI3K pathway, mainly the PI3Kα and δ isoforms and mTOR. These findings, prompted experiments showing that EDO-S101 at sublethal concentrations was highly synergic with the predominant PI3Kα/δ inhibitor copanlisib in inducing cell death of tumor T- and NK-cells. Finally, exposure to EDO-S101 (1.0 μmol/L) for 48 hrs resulted in a sustained upregulation of surface PD1 and PD-L1 in most tumor T- and NK-cell lines, as a possible result of its HDACi component.
Conclusions: We have shown for the first time that the BDM/vorinostat fusion molecule EDO-S101 is very active in preclinical models of T/NK cell lymphomas. It shows a superior activity towards different types of tumor T- and NK-cells than its single components administered either individually or in combination by also overcoming acquired resistance to BDM. Data indicate that EDO-S101 simultaneously damages DNA and interferes on its repair pathways in tumor T-cells. We also showed synergy between EDO-S101 and PI3Kα/δ inhibitors possibly due to regulatory effects on specific components of the PI3K pathway as well as a potential for this agent to enhance PD1-blockade strategies. A clinical trial is ongoing to evaluate efficacy and safety of EDO-S101 in pts. with relapsed/refractory hemopoietic malignancies including T-cell lymphomas.
Mehrling:Mundipharma-EDO Gmbh, Basel, CH: Employment. Pinto:Celgene: Honoraria; Merck Sharp Dome: Honoraria; Millenium Takeda: Research Funding; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau.
Summary
High‐dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable ...proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third‐generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR‐HL accrued into a prospective registry‐based study. Application of FEAM resulted in a 2‐year progression‐free survival (PFS) of 73·8% 95% confidence interval (CI), 0·64–0·81 with median PFS, overall survival and time to progression yet to be reached. The 2‐year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12–0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose (18FFDG)‐uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had 18FFDG‐positrin emission tomography‐positive lesions before HDT, the 2‐year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12–0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR‐HL patients typically pre‐exposed to lung‐damaging treatments.
Summary
We explored activity and safety of a dose‐dense/dose‐intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD‐DI) in 82 patients with advanced Hodgkin Lymphoma. Patients ...entered a two‐stage Bryant‐Day Phase II study to receive six cycles of ABVDDD‐DI without consolidation radiotherapy. Cycles were supported with granulocyte colony‐stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co‐primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event‐free (EFS) and disease‐free survival (DFS). All patients received the four doxorubicin‐intensified courses and 96% concluded all six cycles (82·3% within the intended 18 weeks). This translated into a 66·9% increase of received dose‐intensity for doxorubicin and 31·8% for the other agents over standard ABVD. The CR rate was 95·1% (78/82) and 87·8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14·6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five‐year EFS and DFS was 88·3% and 93·7%, respectively. ABVDDD‐DI regimen was well‐tolerated and ensured substantial CR and EFS rates without radiotherapy.
Summary
We explored activity and safety of a dose‐dense/dose‐intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (
ABVD
DD‐DI
) in 82 patients with advanced
H
odgkin
L
ymphoma. ...Patients entered a two‐stage
B
ryant‐
D
ay
P
hase
II
study to receive six cycles of
ABVD
DD‐DI
without consolidation radiotherapy. Cycles were supported with granulocyte colony‐stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard
ABVD
except for doxorubicin (35 mg/m
2
; first four cycles only). Co‐primary endpoints were complete response (
CR
) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event‐free (
EFS
) and disease‐free survival (
DFS
). All patients received the four doxorubicin‐intensified courses and 96% concluded all six cycles (82·3% within the intended 18 weeks). This translated into a 66·9% increase of received dose‐intensity for doxorubicin and 31·8% for the other agents over standard
ABVD
. The
CR
rate was 95·1% (78/82) and 87·8% (72/82) achieved a metabolic
CR
after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14·6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five‐year
EFS
and
DFS
was 88·3% and 93·7%, respectively.
ABVD
DD‐DI
regimen was well‐tolerated and ensured substantial
CR
and
EFS
rates without radiotherapy.
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