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Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2- negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Method(s): PROMETEO (NCT03802604) is a singlearm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 >= 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter >= 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Result(s): Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (>=10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 - 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusion(s): Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the presurgical radiological imaging and the actual surgical pathological report. Pre-operative window-ofopportunity trials in this context might provide important clues regarding the activity of novel treatment strategies.
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Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1-10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses >=1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Method(s): The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/ kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received >=1 dose and had >=1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a >=50% (PSA50) or>=90% (PSA90) PSA decline from baseline with confirmation>=3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Result(s): At data cutoff (9/10/22), 127 pts with AST received >=1 dose of lorigerlimab 6 mg/ kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy;36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in>=15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade >=3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes;88% had visceral (liver, 26%;lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable;35 were RECIST evaluable. ORR was 25.7% (9/35;9 confirmed PRs). Median duration of response was 16.1 weeks (range 6-25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6%(12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusion(s): Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted.
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We aim aim to compare immunophenotypic charac-teritics of atypical epithelium (AE) with COVID-19-induced diffuse alveolar damage (DAD) and pulmonary lepidic-growth adenocarcinoma, accounting for cell cycle control, proliferation and differentiation]. Methods. We examined pulmonary tissue specimens from twenty-four fatal cases of CO VID-19-induced acute respiratory damage syndrome confirmed by autopsy (Group 1) and four cases of pulmonary lepidic-growth adenocarcinoma (Group 2). Perpendicular dimensions of 10 nuclei were measured on the H&E slides, means of their sums of products (SPNM) were calculated. We have used p53, Ki67, pi6, p63 antibodies for immunohistochemical staining in each case. We evaluate colour intensity, rate of stained cells of AE and the product of these parameters. We evaluated separately Nuclear and cyto-plasmic staining (couple) and only cytoplasmic staining (cyt) for pi6 expression. We measured proliferative index only at KI-67 stained slides. U-test and Spearman rank correlation test were used for statistical analysis. Results. Expression of p63 was higher in group 1 (p=0.001), while pi6 was more frequently expressed in group 2 (p=0.002). We have found no statistically significant differences (p>0.1) in the p53 and Ki67 expression. Group 1 showed There was negative correlation between the number of days from onset of symptoms and the following variables: Ki67 (r=M).587, p=0.003);SPNM (r 0.406, p=0.049). Conclusion. The present study has shown heterogeneity in levels of cell cycle control expression, proliferation and differentiation of atypical epithelium in the pulmonary lep-idic-growth adenocarcinoma and CO VID-19-induced diffuse alveolar damage.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.
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The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers. © 2022 The Authors
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Spitzoid melanoma is very rare tumour in the pediatric population, with clinical and non-uniform behaviour, different from adult melanoma [1]. It can be difficult to differentiate an atypical Spitz nevus from a Spitzoid melanoma, resulting in diagnostic problems. In addition, in our clinical case, the COVID-19pandemiccaused significant delays both in the diagnosis and in the surgical treatment of our patient. We present the clinical case of a 4-year-old child suffering from a localized polypoid cutaneous neoformation on the dorsum of the left hand, which started immediately before the lockdown and steadily increased during the COVID-19 pandemic. After a general clinical framing, the child underwent an excisional biopsy at our Department of Plastic and Reconstructive Surgery, at the Policlinico of Foggia. Subsequently, two independent anatomic pathology groups examined the specimen. Definitive diagnosis was made only after careful genetic analysis in combination with supporting histological and immunohistochemical examinations. This clinical case shows how during the pandemic we have been facing advanced forms of tumours, compared to the previous period and highlight show an interdisciplinary and multicenter collaboration allowed a quick diagnosis of certainty, demonstrating the utility of molecular pathology as a fundamental aid in clinical/surgical practice. © 2022 The Authors
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Intracranial cystic lesions are common findings in cerebral imaging and might represent a broad spectrum of conditions. These entities can be divided into nonneoplastic lesions, comprising Rathke cleft cyst, arachnoid cyst, and colloid cyst, as well as neoplastic lesions, including benign and malignant components of neoplasms such as pilocytic astrocytoma, hemangioblastoma, and ganglioglioma. Surgical resection and histological evaluation are currently the most effective methods to classify cysts of the central nervous system. The authors report two uncommon cases presenting as cystic lesions of the encephalic parenchyma-a enterogenous cyst and a glioblastoma-and discuss typical histological findings and differential diagnosis.
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Objective: The SARS-CoV-2 virus, which emerged in December 2019 in Wuhan, China, spread very quickly in a short time and was declared a pandemic by the World Health Organization in March 2020. Physiological and immunological changes during pregnancy cause complications in respiratory tract infections. Complications by COVID-19 lead to a systemic effect that causes maternal and fetal mortality and morbidity. In this study, we aimed to investigate histopathological changes and Ki-67 expression in placentas of women with positive COVID-19 infection. Study Design: Placentas of 10 samples COVID-19 positive and 10 samples Covid-19 negative pregnant patients who were hospitalized in the Gynecology and Obstetrics Clinic of Dicle University Faculty of Medicine were included in the study. Placental tissues were fixed in 10% formaldehyde (24 hours) and processed for routine paraffin wax tissue staining. Hematoxylin Eosin dye and Ki-67 immunohistochemical staining were performed.
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Introduction: Diffuse Large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, which accounts for approximately 30% of all non-Hodgkin lymphoma cases. Spontaneous remission of DLBCL is exceedingly rare, with only a handful of case reports that describe the phenomenon present in the literature. Specialists are investigating similar cases to find out whether the SARS-CoV-2 infection triggered an antitumor immune response, as has been described with other infections in the context of high-grade non-Hodgkin lymphoma. We report one case of an elderly woman with EBV positive DLBCL diagnosed with PCR-positive SARS-CoV-2 pneumonia in the course of the disease and their outcomes. Case report: A 81 years-old woman, was referred to the consult ambulatory of intern medicine with progressive cervical, axillary and inguinal lymphadenopathy with local pain, fever and weight loss. The biopsy of an axillary lymph node demonstrated diffuse atypical lymphoid infiltrate. Immunohistochemistry stains showed positive CD20, CD30, Bcl-2 and MUM-1. It was negative for CD3, CD10, Bcl-6, c-Myc and CMV. The Ki-67 proliferation index was 80%. Epstein-Barr virus (EBV) stain were positive. These findings were consistent with DLBCL, EBV positive, clinical Stage IIIB and R-IPI 4 (poor prognosis and high risk). Since PET-CT was unavailable, thorax and abdomen computed tomographies were performed and revealed enlarged lymph node on pulmonary hilum, pathological lymph node enlargement in the axillary and supraclavicular chains bilaterally and peri aortocaval adenomegaly, extending along the bilateral femoral iliac vessels (larger lymph nodes of 2.5cm). She was treated with 4 cycles of R-CVP (rituximab with cyclophosphamide, vincristine and prednisone). When an interim PET-CT was performed, disease progression was revealed (Lugano score 5). Therefore, considering patient age and clinical status, treatment scheme was changed to R-mini-CHOP (rituximab with reduced doses of cyclophosphamide, doxorubicin, vincristine and prednisone), achieving partial response after 4 cycles (Lugano score 4). A month after this evaluation, she was admitted to the Emergency Department with diarrhea, fever and was diagnosed with PCR-positive SARS-CoV-2 pneumonia. After 6-days hospitalization with no significant ventilatory impairment, she was discharged. No corticosteroid or immunochemotherapy was administered. Two months later, she had no palpable lymphadenopathy and a PET/CT scan revealed widespread resolution of the lymphadenopathy and reduced metabolic uptake throughout (Lugano score 1). After a 7-months follow-up, the patient still has no clinical relapse. Discussion: The putative mechanisms of action include cross-reactivity of pathogen-specic T cells with tumour antigens and natural killer cell activation by inammatory cytokines produced in response to infection. It is important to consider that the more cases of SARS-CoV-2 infection in patients with non-Hodgkin lymphoma, the more likely it is to analyze lymphoma remissions and demonstrate the exact mechanism of pathogen-specific T cells with tumor antigens. Conclusion: Because spontaneous remission of DLBCL associated with SARS-CoV-2 infection is a new event, careful investigation of these cases is important, because the information gained may lead to new therapeutic targets or treatment strategies for future patients.
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Background: Neoadjuvant endocrine therapy (NET) is used to treat estrogen receptor (ER) positive invasive breast cancer (IBC). Tumors with Ki67 >10% after 2-4 weeks of NET are considered resistant to endocrine therapy (ET). Although high baseline Ki67 >30% is associated with higher level of ET resistance, many of these patients will still respond to NET. During the COVID- 19 pandemic NET is increasingly being used to defer surgery, hence better and more easily accessible biomarkers are needed to predict likelihood of response to NET. EZH2 is a oncoprotein which can be easily evaluated by immunohistochemistry and overexpression of EZH2 in ER+ IBC has been linked to resistance to ET. We examined the potential utility of EZH2 to predict response to NET . Design: We identified 34 pts with ER+ IBC of ductal or lobular type who received NET. Ki67 IHC was evaluated on pretherapy biopsies and post-therapy resections and scored according to guidelines of the International Ki67 Working Group with a global weighted score. We quantified EZH2 nuclear expression in pretherapy biopsies using a score which multiplied intensity (0=negative,1=weak,2=moderate,3=strong) by % of cells staining at each intensity X100 . Ki67 post therapy <=10% was considered endocrine responsive. Pretherapy Ki67 was dichotomized into >30% and <=30%. Results: The pt age range was 48 to 85 yrs (mean 64 yrs and median 65 yrs). All IBCs had ER expression levels >=80% and aromatase inhibitor was the most frequent NET (76%). Duration of NET ranged from 2-24 months (median 6 months and mean 6.5 months). Twenty pts had a pretherapy Ki67 < or =30 % and 14 had a pretherapy Ki67 >30%. Amongst the 20 pts with pretherapy Ki67<=30%, 11 were endocrine responsive and had a mean pretherapy EZH2 of 88 and median of 85 ( range 2-150) whereas 9 were resistant with a median pretherapy EZH2 of 108 and a median of 104 ( range 42-130). There was no significant difference in mean EZH2 score between groups ( t test p=.0.3971). Amongst the 14 pts with pretherapy Ki67>30% 5 were endocrine responsive and had a mean pretherapy EZH2 of 91 and median EZH2 of 93 (range 45-130) whereas 9 were resistant and had a mean pretherapy EZH2 of 186 and median of 178 ( range 120-240) There was a significant difference in mean EZH2 score between groups ( t test p=.0006). There was a significant association between pretherapy EZH2 score >130 and resistance to NET in pts with Ki67>30% pretherapy (p=.0030). Conclusions: In our pilot study EZH2 protein expression levels were significantly associated with response to NET in pts with high risk (Ki67>30%) ER+ IBC ;high EZH2 expression (>130) in IDC in pretherapy core biopsies was associated with resistance to NET in these pts. During the Covid-19 Pandemic , or in other situations where surgery might be deferred, our results suggest that EZH2 might be useful to predict tumor response to NET in high risk (Ki67>30%) ER+ IBC. (Table Presented).
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Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).
ABSTRACT
Background: First-line conventional chemoimmunotherapy in MCL can be improved. Promising results have been seen with Bruton tyrosine kinase inhibitors (BTKis) in combination with venetoclax (V) and an anti-CD20 monoclonal antibody in patients (pts) with relapsed/refractory or TN MCL. Acalabrutinib (A) is a next-generation, highly selective, covalent BTKi currently approved for relapsed/refractory MCL. We report initial safety and efficacy results of the ongoing, multicenter, open-label phase 1b study of A, V, and rituximab (R) (AVR) in TN MCL. Methods: TN MCL pts aged ≥18 y with ECOG PS ≤2 were eligible. Starting on cycle 1 day 1, A was administered at 100 mg BID until disease progression or discontinuation for other reasons. R was administered at 375 mg/m 2 on day 1 of each 28-day cycle for 6 cycles, followed by maintenance every other cycle for pts achieving complete response (CR) or partial response (PR), through cycle 24. Starting on cycle 2 day 1, V was administered via an initial 5-wk ramp-up schedule (20, 50, 100, 200, and 400 mg/d) to 400 mg/d, through cycle 25. Dose-limiting toxicity (DLT) was assessed from cycle 2 day 1 to cycle 3 day 28. Primary endpoint was AVR safety. Secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) per Lugano criteria. Positron-emission tomography (PET)/computed tomography (CT) scans were performed after 3 and 6 cycles and to confirm CR at any time. CT scans were performed after 3, 6, 9, and 12 cycles, and then every 6 cycles. Longitudinal minimal residual disease (MRD) was assessed using the clonoSEQ assay in peripheral blood at PR, CR, every 6 cycles post-CR, and treatment end. Results: 21 pts were enrolled (median age 66 y [range 51-85];ECOG PS ≤1 20 [95%];Ann Arbor stage IV disease 19 [90%];bulky disease >5 cm 7 [33%];intermediate- and high-risk simplified MCL International Prognostic Index scores 11 [52%] and 4 [19%], respectively;blastoid variant 1 [5%];and Ki-67 proliferation index ≥50% 3 [14%]). Fifteen (71%) pts had bone marrow (BM) involvement at baseline. As of March 19, 2021, median time on study was 16 mo (range 8-26.2). Median (range) number of cycles administered was 15 (7-27) for A, 13.5 (5-23) for 400 mg daily V, and 12 (6-15) for R. Seventeen (81%) pts remain on study treatment and 4 (19%) have discontinued (progressive disease: n=1;COVID-19 infection: n=3). No DLTs were observed;V 400 mg daily after ramp-up was the dose chosen for triple therapy. Most common any-grade AEs in ≥20% of pts were diarrhea (13 [62%]), headache (11 [52%]), fatigue (10 [48%]), neutropenia (6 [29%]), paresthesia (6 [29%]), cough (6 [29%]), dyspnea (6 [29%]), myalgia (5 [24%]), dizziness (5 [24%]), and hypoesthesia (5 [24%]). Grade 3/4 AEs in ≥2 pts were neutropenia (5 [24%]) and pneumonia (2 [10%]). Serious any-grade AEs in ≥2 pts were COVID-19 infection (4 [19%]) and pneumonia (2 [10%]). In the 4 pts with COVID-19 infection, the events led to triple-drug discontinuation and death in 3 pts and to dose holds of A and V and event resolution in 1 pt (all considered unrelated to study treatment). Diarrhea led to V dose reduction in 1 pt. AEs led to dose holds in 12 (57%) pts and were associated with A, V, and R in 52%, 48%, and 14%, respectively. Events of clinical interest are shown in Table 1. At the end of cycle 6, ORR was 100%, with CR/PR in 90%/10% by PET/CT alone (11 of the 13 CRs by PET/CT lacked BM confirmation);the CR/PR rate by Lugano criteria with BM confirmation was 38%/62% (Table 2). Median DOR was 19 mo (95% CI 17-not estimable [NE]) overall, and not reached when the 3 pts with COVID-19 deaths were censored. Median PFS and OS were not reached. The 1-y PFS and OS rates were 89% (95% CI 62-97) and 95% (95% CI 71-99), respectively. Treating the 3 COVID-19 deaths as censored, the 1-y PFS rate was 93.8% (95% CI 63.2-99.1). Median time to initial response and best response was 2.8 mo. Twelve of 16 (75%) pts with available MRD results at cycle 6 achieved MRD negativity (10 -6), including 6 pts with
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Introduction:Plasmablastic lymphoma (PBL) is a rare and aggressive lymphoma most commonly seen in the setting of chronic immunosuppression, such as HIV infection and organ transplantation, or in patients with pre-existing lymphoproliferative or autoimmune disorders. PBL commonly presents at extranodal sites and carries a poor prognosis with a global overall survival of 9-15 months after initial diagnosis. Despite poor prognosis for patients with PBL, therapeutic strategies to target this disease are limited, as CHOP-like regimens have failed to produce durable remission, and no standard of care has been established. The cell of origin for PBL is believed to be the plasmablast, as PBL cells possess immunoblastic morphology and contain an immunohistochemical profile positive for plasmablast markers, such as CD38, CD138, and MUM1/IRF4, and negative for B cell markers, such as CD20, CD19, and PAX5. The similarities between PBL cells and multiple myeloma (MM) cells, a plasma cell neoplasm, have led to investigations of the efficacy of MM therapeutics for the treatment of PBL. Daratumumab is a first-in-class monoclonal antibody directed against CD38 that has shown efficacy in treating relapsed/refractory and newly diagnosed MM. Here, we describe the treatment of four patients with advanced-stage PBL in the context of varying degrees of immunosuppression using combination treatment with daratumumab and EPOCH. Methods:Four consecutive patients were treated with daratumumab plus chemotherapy. Three of the four patients were treated in the frontline setting and received low-dose EPOCH (vincristine, doxorubicin, etoposide daily for 4 days;cyclophosphamide day 5) with 16mg/kg daratumumab dosed on days 1 and 8 for 6 cycles. Patient #4 showed partial CD20 positivity, prompting Rituximab co-administration (R-EPOCH). Patient #3 was treated in the relapsed setting with 16mg/kg daratumumab in combination with lenalidomide, dexamethasone, and doxorubicin. She was treated for 12 months. Responses were followed by PET/CT imaging. Results:The four consecutive patients (2 female, 2 male) ranged in age from 26-88 and all had advanced-stage PBL (Table 1). Three of the four patients had some degree of immunosuppression (Patient #1- post-transplantation lymphoproliferative disorder (PTLD), Patient #2- HIV/AIDS, Patient #3- Chron's disease, Patient #4- no history of immunosuppression). All patients had a Ki67 proliferation index over 70% and demonstrated extranodal involvement of disease (bone n=3, intestine n=2, liver n=2;kidney n=1;adrenal n=1). The three patients that received daratumumab in combination with EPOCH demonstrated a complete response at their first disease assessment by PET/CT scan after cycle 2 (Patient #1) or cycle 4 (Patients #2,4) (Fig1). Patient #3, who demonstrated a mixed response to previous therapy, achieved a complete response 5 months after starting treatment with daratumumab in combination with chemotherapy. As of July 2021, three of the four patients continued to have no evidence of disease for a median of 17 months (range 15-19 months). Patient #4 relapsed in July 2021, 3 months after demonstrating a complete response. Adverse events that required hospitalization were rarely noted following daratumumab treatment but included neutropenic fever (n=2, one event following treatment cycle 4 and the other event 2 months after completion of daratumumab administration), COVID-19 infection (n=1), and a PICC line-associated thrombus (n=1). Minor events were also noted and included self-limiting bradycardia (n=1), neuropathy (n=1), and rigor (n=1). Conclusions:We describe four patients with varying degrees of immunosuppression and HIV-status with aggressive-stage PBL that achieved complete response following treatment with daratumumab in combination with low-dose EPOCH or other chemotherapy. Three of four patients obtained durable responses. At the time of this writing, three additional HIV +patients have initiated treatment with daratumumab but have not yet reached their first disease assessment. Disease progression for these patients will be monitored and presented as part of this study. Our findings suggest a potential efficacy and warrant further investigation of using daratumumab for the treatment of HIV +and HIV - PBLs. [Formula presented] Disclosures: Amengual: Epizyme, Inc.: Speakers Bureau;Appia Pharmaceuticals: Research Funding;Daiichi Sankyo, Inc: Consultancy;Seagen: Consultancy. OffLabel Disclosure: our work uses daratumumab, a first-in-class monoclonal antibody against CD38 for the treatment of plasmablastic lymphoma