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Background Mycosis fungoides with large-cell transformation (MF-LCT) is associated with an aggressive clinical course, yet data comparing treatment outcomes in MF-LCT are sparse. Objective To compare treatment outcomes and to determine disease prevalence and characteristics associated with survival in MF-LCT. Methods A retrospective review was conducted of mycosis fungoides patients from 2012 to 2020 treated at Thomas Jefferson University. Patients with histopathologic diagnosis of MF-LCT were included. Treatment outcomes were assessed by mean changes in the modified Severity Weighted Assessment Tool (mSWAT) and stage. Results Of 171 patients with mycosis fungoides, 23 (13.4%) had histologic diagnosis of MF-LCT. The overall 5-year survival rate for MF-LCT was 74% and was not significantly associated with sex, age, or initial stage at the time of MF-LCT diagnosis. Brentuximab vedotin showed the greatest mean decrease in mSWAT (−20.53) and stage progression (change in Δ stage: –0.4) in MF-LCT compared to oral bexarotene (ΔmSWAT: +4.51; Δstage: +0.27), skin-directed therapy (ΔmSWAT: −5.93; Δstage: −0.08), and chemotherapy (ΔmSWAT: +4.97; Δstage: +0.85). Limitations Single-center retrospective design, and patients often on multiple treatment modalities. Conclusions We report superior treatment outcomes for brentuximab vedotin compared to oral bexarotene, skin-directed therapy, and chemotherapy in MF-LCT in both early and advanced disease.

Background Patients with relapsed or refractory classical Hodgkin lymphoma (R/RcHL) have limited opportunities for a curative therapy. High-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) produces cure rates of 50-60%. Patients relapsing after, or ineligible for HDT-ASCT have limited therapeutic options and long-term remission is uncommon. Furthermore, few patients are candidate to allogeneic stem cell transplantation (AlSCT), a potentially curative approach. The combination of brentuximab-vedotin and bendamustine (BVB) is a promising treatment for patients with R/RcHL, regardless of SCT eligibility. Patients and methods We report a real-life experience with BVB in 41 patients with R/RcHL after failure of ≥1 therapy including ASCT, AlSCT, or BV. Results Among 40 patients evaluable for efficacy, the overall response rate and complete response (CR) rate was 75% and 50%, respectively. No significant differences were observed between primary refractory and relapsed disease, previously treated with ≤2 and ≥3 lines of therapy, or BV-exposed and BV-naive. After a median follow-up of 38 months, the median progression free survival (PFS) for the entire population is 26 months; PFS is not reached, 10.5 months and 4 months for patients achieving CR, partial response and no response, respectively (p Conclusion Our experience supports the efficacy and tolerability of the BVB combination in R/RcHL as a bridge to SCT or as a definitive therapy for SCT-ineligible patients. Larger comparative studies testing BVB against standards of care are warranted in both settings. MICROABSTRACT In the real-life setting, the combination of brentuximab vedotin and bendamustine was well tolerated and produced an ORR of 75%, CR 50% and a median PFS of 26 months. A significant proportion of heavily pretreated cHL patients may be cured with this approach.

Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.

Background Brentuximab-vedotin (BV) monotherapy has shown high efficacy in heavily pre-treated patients with relapsed or refractory Hodgkin lymphoma (HL) after high-dose chemotherapy or autologous stem cell transplantation (ASCT). We retrospectively analyzed the outcomes of treatment with BV of HL patients and examined the predictive ability of PET-CT for response in this setting. Patients and methods Records of 49 HL patients (median age, 39 years, 55% male) treated with BV for relapse (71.4%) or consolidation (28.6%) post-ASCT were analyzed. Patients who did not reach complete response (CR) on PET/CT after 4 cycles (non-responders) discontinued BV and received the next treatment line. Overall survival (OS) and progression-free survival (PFS) were compared between responders and non-responders. Results After a median follow-up of 19.1 months, all consolidation patients were alive and none progressed. Median OS in 23 relapsed patients that did not achieve CR after 4 cycles and continued to the next treatment was 55.0 months, while all those in CR (n = 24) were alive (P = .0120). No statistically significant differences in OS were observed between responders and non-responders with relapsed HL (P = .1072). Median PFS evaluated after 4 BV cycles was significantly longer in responders compared to non-responders (47.9 vs. 1.5 months, P Conclusions HL patients treated with BV for relapse or consolidation who achieved CR by PET-CT after 4 cycles showed improved PFS and OS compared to non-responders. Non-responders treated for relapsed HL who proceeded to the next treatment line demonstrated comparable OS to responders.

Summary Background Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. Methods We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0–1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1–3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1–3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. Findings Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28–45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7–4·1), 32 (74%; 95% CI 58·8–86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3–4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3–4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. Interpretation Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young ( Funding Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

The cutaneous lymphomas are malignancies of T-cell and B-cell lymphocytes in which the skin is the primary organ of involvement. The cutaneous T-cell lymphomas include variants that can mimic the presentation of common skin diseases or arthropod bites. Mycosis fungoides, the most common cutaneous T-cell lymphoma, usually presents as fixed asymptomatic patches or plaques in sun-protected areas. The cutaneous B-cell lymphomas have fewer variants that often present as papules or nodules that can mimic nonmelanoma skin cancers. Some therapies for cutaneous lymphoma have unique side effects such as central hypothyroidism, hyperlipidemia, and peripheral neuropathy.

Summary Background PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. Methods In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Findings Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Interpretation Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Funding Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA). Translation For the Portuguese translation of the Article see Supplementary Materials section.

Antibody drug conjugates (ADCs) normally compose of a humanized antibody and small molecular drug via a chemical linker. After decades of preclinical and clinical studies, a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin (Adcetris®) for relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, gemtuzumab ozogamicin (Mylotarg®) for acute myeloid leukemia, ado-trastuzumab emtansine (Kadcyla®) for HER2-positive metastatic breast cancer, inotuzumab ozogamicin (Besponsa®) and most recently polatuzumab vedotin-piiq (Polivy®) for B cell malignancies. More than eighty ADCs have been investigated in different clinical stages from approximately six hundred clinical trials to date. This review summarizes the key elements of ADCs and highlights recent advances of ADCs, as well as important lessons learned from clinical data, and future directions., Graphical abstract Antibody drug conjugates (ADCs), normally composed of a humanized antibody and small molecular drugs via chemical linkers, represent a rapidly growing field for cancer therapy. In this review, we provide an overview of ADCs in preclinical and clinical development, as well as future directions of ADCs.Image 1

Mature lymphoproliferative diseases are a heterogeneous group of neoplasms arising from different stages of B-cell and T-cell development. With improved understanding of the molecular processes in lymphoma and novel treatment options, arises a growing need for the molecular characterisation of tumours. Molecular imaging with single-photon-emission CT and PET using specific radionuclide tracers can provide whole-body information to investigate cancer biology, to evaluate phenotypic heterogeneity, to identify resistance to targeted therapy, and to assess the biodistribution of drugs in patients. In this Review, we evaluate the existing literature on molecular imaging in lymphoma, other than 18F-fluordeoxyglucose molecular imaging. The aim is to examine the contribution of molecular imaging to the understanding of the biology of lymphoma and to discuss potential implications for the diagnostics and therapy of this disease. Finally, we discuss possible applications for molecular imaging of patients with lymphoma in the clinical context.

Resume Introduction Le brentuximab-vedotin (BV), agent anti-CD30 couple a un agent antineoplasique, a recemment obtenu des resultats prometteurs dans le traitement des lymphomes T cutanes tels que le syndrome de Sezary. Ces resultats sont etonnamment observes quel que soit le niveau d’expression du CD30 par les cellules tumorales. Observation Nous rapportons le cas d’un homme âge de 52 ans atteint d’un syndrome de Sezary (SS) avec atteintes cutanee et ganglionnaire dont les cellules tumorales, au moment d’une progression de la maladie, n’exprimaient pas le CD30. Sa maladie etait refractaire a plusieurs lignes de traitements, et une reponse partielle a ete obtenue lors du traitement par BV, avec une ulceration secondaire des lesions cutanees specifiques du SS. Discussion L’ulceration des lesions cutanees de notre patient a ete concomitante d’une amelioration clinique et la semiologie etait identique aux cas d’ulcerations cutanees sous methotrexate chez les patients psoriasiques ou atteints de mycosis fongoide. Le mecanisme d’action semble etre lie a une interruption brutale du cycle cellulaire dans un contexte de renouvellement cellulaire rapide, bien que la facon dont l’anticorps pourrait agir sur les keratinocytes ne soit pas parfaitement elucidee.

Salvage therapy with high-dose chemotherapy and hematopoietic stem cell transplant (HDC/SCT) is recommended for patients with relapsed/refractory (R/R) PTCL. We evaluated the outcomes of R/R PTCL from the time of first relapse/progression in patients intended for SCT (ITT).The BC Cancer Lymphoid Cancer Database was reviewed, and patients ≥18 years with R/R PTCLs, such as systemic anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), and PTCL-not otherwise specified (PTCL-NOS), were included. Outcomes were assessed from the time of first relapse/progression and from the time of SCT.Of 114 included patients with ITT R/R PTCL, 60% had refractory disease and were more likely to have a high secondary IPI score, poor performance status, or advanced-stage disease. For second-line therapy, the majority received multi-agent chemotherapy (n = 83, 73%) with GDP, (gemcitabine, dexamethasone, and cisplatin) the most used regimen (n = 59, 52%), whereas 15 patients (13%) received novel agents (brentuximab vedotin [BV] = 12; romidepsin=2; pralatrexate=1). The overall response rate (ORR) to second-line therapy was 61% (24% complete response [CR]; 37% partial response [PR]). The ORR to GDP was 61% (17% CR; 44% PR), with higher responses observed in relapsed patients (81% vs. 41%, p=0.002). Seventy-three patients (63%) received HDC/SCT. Those who underwent allo-SCT were younger and more likely to have refractory disease (50% vs. 16%, p=0.001). Third-line therapy was required in 17/67 (25%), including novel agents in 9 cases. The median follow-up for living patients was 6.8 years. The 5-year progression-free survival (PFS) and overall survival (OS) from the time of first relapse/progression were 28% and 38%, respectively. The 5-year PFS from auto and allo-SCT were 34% and 52% (p = 0.3), and 5-year OS were 44% and 67% (p=0.5), respectively.Overall, outcomes for patients with ITT R/R PTCL remain suboptimal, with long-term survival in only one-third of patients; however, over half remained alive at 5 years if they were able to receive an SCT. A third line of therapy may serve as a successful bridge to SCT, and novel agents should be considered. Despite a higher proportion of refractory patients, results are encouraging with allo-SCT.

Summary Background Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma. Methods A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPPescalated. The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years. Findings Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7–15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2–14·4]), and the lowest direct costs ($53 129 [95% CI 31 914–94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP. Interpretation Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians. Funding None.

Neutropenia, specifically febrile neutropenia (FN), can have profound sequelae (infection, hospitalization, mortality), and the risk of its development differs across chemotherapy regimens/according to patient characteristics. We conducted a comprehensive literature review regarding neutropenia in frontline treatment of adults with advanced Hodgkin lymphoma. Guidelines state primary prophylaxis (PP) with colony-stimulating factors (CSFs) should be implemented when the risk of FN is ≥20%; CSF PP is given with standard-of-care escalated BEACOPP, but the risk of FN with standard-of-care ABVD does not necessitate routine PP. Notably, the risk of neutropenia (including FN) is higher in clinical practice versus clinical studies, and physicians overestimate their adherence to CSF guidelines. ECHELON-1 demonstrated higher FN rates with brentuximab vedotin plus AVD (A + AVD) compared with ABVD (19% vs 8%) and led to the recommendation of PP with granulocyte-CSF (G-CSF) for all A + AVD patients, highlighting the importance of readjusting our risk-assessment thinking as standard backbone regimens are modified.

Hodgkin lymphoma is a highly curable malignancy involving lymph nodes and the lymphatic system. Even at late stage disease, about 70% of patients will be cured with standard first line therapy. For patients who experience relapse or refractory classical Hodgkin lymphoma, the standard treatment option is high-dose chemotherapy followed by autologous stem cell rescue or transplant. However about 50% of patients will have recurrence after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and have worse prognosis with median overall survival of 32% at 5 years. The anti-PD1 checkpoints inhibitors pembrolizumab and nivolumab have remarkably improved outcomes of patients with relapse of refractory classical Hodgkin lymphoma after high-dose chemotherapy followed by autologous stem cell rescue or transplantation. On the other hand, radiotherapy is an entire component of salvage therapy and its efficacy is now well established in term of local disease control in sites of relapsed or refractory Hodkin lymphoma. Defining the optimal modality and timing of radiotherapy as these new agents arrive is a challenge. An interesting approach is the combination of radiotherapy with checkpoint inhibitor and the possibility of stopping the treatment when complete response is achieved. We add to the literature two new cases of combination of radiotherapy with immunotherapy in patients who relapsed after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and consolidation with brentuximab vedotin, resulting in excellent outcomes.

PURPOSE: To report a case of bilateral Vogt-Koyanagi-Harada (VKH)-like granulomatous pan uveitis secondary to brentuximab vedotin (BV) administration to treat for classical Hodgkin lymphoma (CHL). OBSERVATIONS: A case of bilateral pan uveitis is described, following administration of BV, with features of VKH-like uveitis: presence of inflammatory cells in the anterior and posterior segment, multiple small serous detachments around the optic disc and retinal pigment epithelium (RPE) folds confirmed by optical coherence tomography (OCT) as well as hypocyanesent dark dots, disc hyperfluorescence and fuzzy vascular patterns seen on indocyanine green and fluorescein angiography. There were no systemic features of VKH disease. Further etiological investigation showed no clear infectious or inflammatory cause. The uveitis responded well to treatment with corticosteroids and cessation of BV. A relapse occurred a few months later when BV treatment was reinitiated, suggesting a probable adverse event to this drug, according to the Naranjo algorithm. CONCLUSIONS: We hypothesize that administration of BV can induce a VKH-like uveitis, caused by loss of function of protective CD30+ cells present in the uveal tract, possibly aggravated by collateral damage to surrounding CD30-cells and melanocytes, leading to a uveal immune reaction. It is therefore important for the clinicians using BV to be aware of this adverse event. Growing experience with immunotherapy will provide more clinical insights in these complex immune mechanisms in the future. ispartof: Am J Ophthalmol Case Rep vol:26 pages:101440- ispartof: location:United States status: Published online

Cutaneous PTCL-NOS is a rare and aggressive variant of cutaneous T-cell lymphoma with unfavourable prognosis. First line treatment includes anthracycline based regimens. However, the disease tends to be refractory to chemotherapy and patients relapse very quickly. We present a case of cutaneous PTCL-NOS, follicular T-helper phenotype, CD30+, successfully treated with brentuximab vedotin after rapid progression under two standard chemotherapy regimens and TSEBT. The baseline PET/CT in May 2020 (prior to cycle 1 of brentuximab) showed metabolically active subcutaneous nodules throughout the body, with muscle involvement in both legs. The patient already had 2 lines of chemotherapy (CHOP) with progressive multiple focal lesions following cycle 4. The treatment was switched to GCVP – 4 cycles completed 15.08.19 – after which she had further progression. The only available treatment options were either gemcitabine/oxaliplatin containing chemotherapy or CEPP regimen (cyclophosphamide, etoposide, procarbazine, prednisolone). Both treatments had a low chance to be beneficial, considering the rapid progression on the previous two chemotherapy lines. In view of the CD30 positivity (more than 30%) we considered treatment with brentuximab vedotin, which we obtained as compassionate use supply. We started treatment in September 2020 and a restaging PET/CT showed partial response after cycle 4 and complete metabolic response after cycle 8. The patient was still free from recurrence after cycle 13. The treatment tolerance was excellent with only G1–G2 peripheral neuropathy. There was one episode of G3 peripheral neuropathy post cycle 10, which improved back to G1 after giving 2 weeks break from treatment. PTCL NOS is characterised by poor overall survival (20–30% at 5 years) and rapid progression. The treatment with brentuximab vedotin has proven to be safe and effective in our patient, with maintained response at 10 months after treatment initiation.

Context PD-1 immune checkpoint inhibitors, including nivolumab, have shown strong activity in patients with R/R cHL. The CheckMate 205 study demonstrated an objective response rate (ORR) of 69%, a median duration of response (DOR) of 17 months, and median progression-free survival (PFS) of 15 months, at a median follow-up of 18 months. Objective Assess the longer-term outcomes of CheckMate 205 with a median follow-up of 58 months. Design CheckMate 205 (NCT02181738) enrolled patients with R/R cHL after auto-HCT failure into three cohorts by treatment history: (A) brentuximab vedotin (BV)-naive, (B) BV after auto-HCT, and (C) BV before and/or after auto-HCT. Interventions Nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients in cohort C discontinued nivolumab after 1 year in complete remission (CR) with the option to resume within 2 years if relapsed. Outcome Measures Primary: ORR. Others: CR, DOR, PFS, overall survival (OS), and safety. Results Overall, 243 patients were treated. Median duration of treatment was 14 months. ORR was 71% (95% CI, 65%–77%), and CR rate was 21%. Median PFS was 15 months (95% CI, 11–19), and median DOR was 18 months (95% CI, 15–26). The 2-year and 5-year OS rates (95% CI) were 87% (82%–91%) and 71% (65%–77%), and PFS rates were 37% (30%–44%) and 18% (12%–25%), respectively. Patients with CR had improved OS; failure to achieve disease control was a poor prognostic factor for OS. Per protocol, 12 patients in cohort C stopped treatment after ≥1 year of CR. After median of 48 months (range, 36–55) from last treatment, 6 patients were still in response; 3 were re-treated with nivolumab after disease progression (2 re-achieved CR; 1 partial response). The safety profile is similar to previous reports, and no new toxicities were observed. There were no treatment-related deaths. Conclusions This 5-year analysis of CheckMate 205 demonstrated favorable OS and confirmed the efficacy and safety of nivolumab for patients with R/R cHL after auto-HCT. It appears feasible to stop nivolumab after 1 year of CR and re-initiate treatment upon disease progression. Funding BMS. Previous presentation ICML 2021

Context The AETHERA trial reported an increased progression-free survival (PFS) when brentuximab vedotin (BV) was used as maintenance therapy in high-risk Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). Objective To determine the impact and safety of BV as maintenance after ASCT in real-world patients. Design Patients with relapsed/refractory HL started on BV consolidation therapy after ASCT due to high risk of relapse, between January 2016 and July 2019, from 25 institutions, were retrospectively analyzed. Setting All patients were followed by the bone marrow transplantation team of their hospital. Patients or Other Participants Seventy-five patients were included in the study. The median follow-up time was 26 months. The most common high-risk features were primary refractory or relapsed disease Interventions BV consolidation was initiated within 6 months of ASCT and administered at a dose of 1.8 mg/kg intravenous infusion over 30 min every 3 weeks for up to 16 cycles in an outpatient setting. Main Outcome Features The primary endpoint of the study was PFS; secondary endpoints were safety and overall survival (OS). Results At the time of analysis, 42 patients completed consolidation courses, and BV was discontinued in 33 patients. Fifty patients had an ongoing response (CR in 41, PR in six, and SD in three patients), 25 had progressed. Ten died in the follow-up, eight with progressive disease and two due to infection while in CR. The 2-years PFS and OS rates were 67.75% (95% CI:0.55–0.77) and 87.61% (95% CI:0.76–0.94), respectively. Seventeen patients (23%) received BV in the pre-ASCT treatment lines, and there was no survival difference between the BV naive and BV exposed groups. The most common adverse events were neutropenia (27%) and peripheral neuropathy (21%). Sixteen patients (21.3%) experienced grade 3 or 4 toxicity. BV was discontinued due to AE in 12 patients. Conclusions Consolidation with BV after ASCT can achieve a 2-year PFS of 67.75% (95% CI: 0.55–0.75) with an acceptable toxicity profile.

Context R/R PMBL has limited treatment options. CheckMate 436 (NCT02581631), an open-label phase 1/2 study, assessed combination nivolumab (anti–PD-1) and brentuximab vedotin (anti-CD30) in patients with R/R PMBL; the primary analysis (median follow-up 11.1 months) showed an objective response rate (ORR) of 73% and complete remission (CR) rate of 37%. Objective Report extended follow-up data from CheckMate 436. Patients Cohort of patients with R/R PMBL after autologous hematopoietic cell transplantation (auto-HCT) or ≥2 prior multi-agent chemotherapy regimens if ineligible for auto-HCT. Interventions Nivolumab (240 mg IV) + BV (1.8 mg/kg IV) every 3 weeks until disease progression or unacceptable toxicity. Outcome Measure(s) Primary: investigator-assessed ORR (Lugano 2014) and safety. Secondary: duration of response (DOR), CR rate and duration, progression-free survival (PFS), and overall survival (OS). Results Among 30 patients with a median follow-up of 33.7 months, ORR was 73% (95% CI, 54–88; CR, 37%). Median DOR was 31.6 months (95% CI, 23.3–not estimable [NE]), and median duration of CR was not reached. Estimated median PFS was 26.0 months (95% CI, 2.6–NE). Among patients censored in the PFS analysis, 13/17 received consolidation therapy, including auto-HCT (n=6) or allogeneic HCT (n=6) +/- radiotherapy, and radiotherapy alone (n=1). Four patients remained progression free in follow-up for 5+, 9+, 12+, and 20+ months after discontinuation of nivolumab + BV (maximum clinical benefit, n=3; study drug toxicity, n=1) without subsequent therapy. OS was 79% (95% CI, 59–90) at 12 months and 76% (95% CI, 55–88) at 24 months; median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 83% of patients, most frequently neutropenia (30%; all grade 3/4) and peripheral neuropathy (27%; 10% grade 3/4). Six patients discontinued due to TRAEs. Eight patients died, 5 due to disease progression, and none was considered related to treatment. Conclusions Nivolumab + BV demonstrated durable responses and long-term survival benefits; 4 patients remained progression-free without consolidation after nivolumab + BV. Safety was consistent with prior findings. These results further support nivolumab + BV as a treatment option for patients with R/R PMBL. Funding BMS. Previous Presentation: ICML 2021

Introduction Brentuximab vedotin (BV) and the PD-1 inhibitors, pembrolizumab and nivolumab, have dramatically improved therapeutic options in relapsed and refractory classic Hodgkin. More recently, BV-plus doxorubicin, vinblastine and dacarbazine (AVD) has emerged as a standard upfront regimen in patients with advanced stage disease. In addition, recent phase 2 trials have demonstrated promising results combining these novel agents with chemotherapy in the upfront setting.

Targeted therapy has become an effective strategy of precision medicine for improving cancer treatment. Selectivity improvement is always popular in modern oncology because of decreased side effects in conventional cancer chemotherapy. The use of antibody-drug conjugates (ADC), a robust strategy for targeted therapy, applies antibodies to selectively deliver a potent cytotoxic compound to tumor cells and thus improve the therapeutic efficacy of the chemotherapeutic agents. Three ADC products (trastuzumab emtansine, brentuximab vedotin and inotuzumab ozogamicin) are already on the market, and several compounds are in clinical trials. Compared with ADCs, small molecule-drug conjugates (SMDCs) provide a new, less established perspective for targeted delivery. Nevertheless, SMDCs have several strengths: they have 1) a non-immunogenic nature, 2) much more manageable synthesis, 3) lower molecular weights, which confer a high potential for good cell penetration in solid tumors. SMDCs might therefore be a promising alternative with similar efficacy to ADCs. In this article, we highlight the medicinal chemistry aspects of SMDC design. SMDC targeting ligands, linkers and small-molecule payloads will be discussed. Successful cases of SMDCs used as therapeutic agents and other applications of SMDC will also be included.

Cutaneous T-cell lymphoma is a malignant non-Hodgkin T-cell lymphoma, with mycosis fungoides (MF) and Sezary syndrome being the most common subtypes. In patients with MF, transformation to large cell histology is associated with worse prognosis. Paraneoplastic scleroderma has been reported arising within the context of lung, breast, and hematologic malignancies,1 but its association with T-cell lymphomas is exceedingly rare.2, 3, 4, 5 We present the case of a woman with MF with CD30+ large cell transformation who also had the progressive sclerodermoid skin changes of paraneoplastic scleroderma.

Most cutaneous lymphomas are cutaneous T-cell lymphomas, and the most common form is mycosis fungoides. Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma which is characterized by erythroderma and the presence of blood tumor cells. The only potential cure of cutaneous T-cell lymphomas remains allogeneic stem cell transplantation. However, monoclonal antibodies have led to a substantial progress in the treatment of advanced-stage cutaneous T-cell lymphomas. Some of them, such as mogamulizumab (anti-CCR4 monoclobal antibody) or brentuximab vedotin (anti-CD30 coupled to monomethylauristatin E, antibody drug conjugate) have shown efficacy in international randomized controlled studies. Lacutamab, an anti-KIR3DL2 monoclonal antibody, is currently tested in an international, prospective phase 2 trial in cutaneous T-cell lymphomas and peripheral T-cell lymphomas. Finally, immune checkpoint inhibitors have shown clinical benefit in open-label phase 2 studies in cutaneous T-cell lymphomas. This review focuses on the new biotherapies currently used in cutaneous T-cell lymphomas.

We conducted a phase I study of brentuximab vedotin (BV), an antibody–drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3 + 3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with .6 mg/kg every 3 weeks (dose level 0) and increasing by .3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n = 9), patient decision (n = 3), lack of response (n = 2), and death (n = 1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5 ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed.

The unique biological features of primary mediastinal large B-cell lymphoma are offering suggestions for the development and application of innovative drugs in patients who do not respond to first-line regimens or relapse. This lymphoma, in fact, is characterised by high rates of curability with standard anthracycline-containing chemoimmunotherapy regimens, but still displays a severe prognosis if adequate responses are not rapidly achieved or if the disease recurs. Radiotherapy has proved to be effective to consolidate responses after induction, but it may be safely avoided in certain cases, especially when a metabolic complete response is obtained, as to reduce the incidence of radiation-induced long-term sequelae. The current management of this lymphoma, both at diagnosis and at relapse, is reviewed in this paper, along with the description of its peculiar biological panorama.

The European Society for Medical Oncology (ESMO) consensus conference onmalignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

Antibody drug conjugates (ADCs)are one of the most recently developed chemotherapeutics to treat some types of tumor cells. They consist of monoclonal antibodies (mAbs), linkers, and potent cytotoxic drugs. Unlike common chemotherapies, ADCs combine selectively with a target at the surface of the tumor cell, and a potent cytotoxic drug (payload) effectively prevents microtubule polymerization. In this work, we construct an ADC model that considers both the target of antibodies and the receptor (tubulin) of the cytotoxic payloads. The model is simulated with brentuximab vedotin, one of ADCs, and used to investigate the pharmacokinetic (PK) characteristics of ADCs in vivo. It also predicts area under the curve (AUC) of ADCs and the payloads by identifying the half-life. The results show that dynamical behaviors fairly coincide with the observed data and half-life and capture AUC. Thus, the model can be used for estimating some parameters, fitting experimental observations, predicting AUC, and exploring various dynamical behaviors of the target and the receptor.

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.

Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments.

PURPOSE/OBJECTIVE(S) Brentuximab vedotin (BV) and polatuzumab vedotin (PV) are antibody-drug conjugates targeting CD30 and CD79B, respectively, approved for the treatment of select T- and B-cell lymphomas. Safety data to inform the use of concurrent radiation therapy (CRT) with BV or PV is lacking. MATERIALS/METHODS We retrospectively reviewed 31 patients (pts) who received CRT with BV or PV from 5/2018 to 1/2021. We defined CRT as infusion within 3 weeks prior to or concurrent with RT. Timing of toxicity (CTCAE v5.0) was classified as pre-RT (within 1 month prior to RT), acute (start to 1 month post-RT), and subacute (2-3 months following RT), censored at subsequent systemic therapy. Statistics were performed using Mann-Whitney U and Chi-squared tests. RESULTS Of 31 pts, 20 (65%) received BV and 11 (35%) received PV. Median age at CRT was 55 (range 27-88), and 14 pts were female (45%). 26 pts (84%) had stage III-IV disease at the time of CRT. The most common diagnoses were mycosis fungoides (12 pts, 39%; 7 with large cell transformation) and diffuse large B cell lymphoma (10 pts, 32%). Pts received a median of 4 lines of prior systemic therapy (range 0-8). 22 pts received prior RT courses (median 1, range 1-6). Fourteen pts received combination regimens with BV or PV: bendamustine and rituximab (R) (5, 16%); cyclophosphamide (C) (± R) (3, 10%); R alone (5, 16%); and C with doxorubicin (1, 3%). Eleven pts (35%) were treated with electrons targeting skin, with a median dose of 12 Gy (range 4-32). Twenty pts (65%) were treated with photons to 32 sites, with a median dose of 25 Gy (range 9-44); treatment sites included the spine (14 pts, 45%), abdomen/pelvis (9 pts, 29%), and brain (3 pts, 10%). Median percent bone marrow (BM) treated was 6.6 (range 0-18.3). The rate of grade 2 or higher (G2+) hematologic toxicity (HT) was 45% (14/31) pre-CRT vs. 79% (23/29) in the acute setting (P = 0.044) and 71% (10/14) in the subacute setting (P = 0.29). There was no significant change in acute or subacute pain, fatigue, diarrhea, neuropathy, or hepatotoxicity following CRT. Acute G2+ HT was associated with pre-RT G2+ HT (P = 0.019) and more lines of prior systemic therapy (P = 0.011). Percentage of BM irradiated was not significantly associated with acute G2+ HT (P = 0.09). Age, concurrent chemotherapy with BV or PV, prior RT courses, RT dose, and RT modality were not associated with G2+ HT. Six pts (19%) were bridged to stem cell transplant at a median of 26 days (IQR 16-52). 12 patients (39%) received subsequent systemic therapy for progression at a median of 81 days (IQR 25-87). Median time to progression or last follow-up was 72 days (IQR 20-113). At last follow-up, 18 pts (58%) were deceased; median overall survival from CRT was 177 days (95% CI 92-263). CONCLUSION CRT with BV or PV was overall well tolerated. We observed HT, particularly in patients with cytopenias prior to RT. Care should be taken during RT planning to reduce this risk if possible.

PURPOSE/OBJECTIVE(S) Most patients (pts) with relapsed/refractory (RR) cHL undergo salvage chemotherapy (CT) followed by curative-intent autologous stem cell transplant (ASCT). For failure post-ASCT, allogeneic stem cell transplant is considered in select cases. Given the morbidity of transplants, it is beneficial to assess if RT-based regimens can offer potential cure in RR cHL with less toxicity and without consolidative transplant. MATERIALS/METHODS We reviewed medical records of RR cHL pts salvaged between 2009 and 2019 with either RT alone or in combination with systemic therapy (ST) for 2nd line therapy and beyond (i.e., post-ASCT). We defined relapse as recurrence after complete response (CR) and refractory as failure to achieve CR after frontline/salvage therapy. Response and toxicity were assessed by Lugano criteria and CTCAEv.5, respectively. Kaplan Meier survival and univariate Cox regression analyses were performed. RESULTS We identified 26 pts (10 in RT vs. 16 in RT + ST) of which 88% had localized disease prior to RT-based salvage. All relapsed pts (n = 12) had localized relapse (stage I/II), and 50% had relapse > 1 yr after finishing frontline therapy. Relapsed pts who received frontline RT (n = 2) failed outside of prior fields. Reasons to forgo 2nd line therapy of ST followed by ASCT (n = 13) were localized disease/pt preference (92%) and comorbidities (8%). Most relapsed (67%) and refractory (64%) pts got RT + ST with 81% receiving brentuximab vedotin and 19% receiving pembrolizumab. Five pts received cytotoxic CT and then RT-based salvage, forgoing intended ASCT primarily due to refractory disease. After RT-based salvage (median dose 36 Gy (30-45)), 85% of pts achieved CR (70% in RT vs. 94% RT + ST) and 15% had progressive disease (30% in RT vs. 6% in RT + ST). 86% of pts with CR remained disease-free at 5 yrs. With a median follow up of 4.9 yrs, 5 yr PFS and OS for the entire cohort was 72% (95% CI: 56-92) and 92% (95% CI: 82-100), respectively. No significant difference in PFS was found between relapsed vs. refractory disease (HR = 0.7; 95% CI: 0.2-2.9; P = 0.6) or RT vs. RT + ST (HR = 1.8, 95% CI: 0.4-7.1; P = 0.4). Failures (n = 8) were categorized as isolated locoregional (outside of RT field) (38%), isolated distant (25%), combined local/locoregional/distant (25%); and local/locoregional (13%). Three grade (G) 3 and 0 ≥G4 events were reported. G2-3 ST-related toxicities included cytopenias (n = 2, 13%) and neuropathy (5, 31%), resulting in discontinuation/dose-reduction in 5 pts and hospitalization in 1. G2 RT-related toxicities included radiation pneumonitis (2, 8%), dermatitis (6, 23%), esophagitis (9, 35%), and hypothyroidism (5, 19%). CONCLUSION In this retrospective study, most RR cHL pts with localized disease achieved CR after RT-based salvage with low toxicity and without consolidative transplant. With a 5 yr PFS of 72%, RT-based salvage regimens appear effective and well-tolerated options for select RR cHL pts.

Objective: Cutaneous T-cell lymphoma (CTCL) is a malignant manifestation in the skin. The most popular subtype is mycosis fungoides (MF). The straight focus on the molecular background of the malignancy in the last decades lead into new therapeutic possibilities. The subtype CD30+ MF can be nowadays treated with the CD30 antibody conjugate brentuximab vedotin. Diagnostic methods are based on Immunohistochemistry (IHC) followed by manual assessment from pathologists or specialized histologists. Since the manual estimated proportion of CD30+ T cells in the skin is always a subjective calculation, there is a need for objective approaches. QuPath, an open-source software for digital pathology image analysis can meet this need. Methods: In this study, 10 samples from CD30+ diagnosed MF patients with different stages of progression were used for CD3 and CD30 IHC staining. For each patient, the CD30/CD3 ratio was assessed independently by three different histologists and QuPath, a computer-assisted image analysis software with included quantitative statement. Results: The individual estimates for CD30+/CD3+ ratios varied between individual histologists (mean coefficient of variation 0.46; range 0–0.78). QuPath analysis shows excellent separation between the positive stained cells for CD3 and CD30 IHC and other cells and structures. The QuPath data for CD30+/CD3+ ratios correlate strongly with the mean estimates of the three histologists (Pearson R 0.93). Conclusion: In summary, it has been shown that the individual subjective histologist estimates can often be far apart, with the mean of these estimates resembling the QuPath analysis. It can therefore be seen that QuPath image analysis is a good alternative to conventional manual estimation.

Objective Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years of treatment (Radford et al., BMJ 1997;314:346). In ECHELON-1, brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III/IV cHL (Connors et al., NEJM 2018;378:331). We report updated efficacy and safety results; median follow-up was 60.9 months. Design This phase 3, open-label study (NCT01712490) randomized patients with previously untreated stage III/IV cHL to receive 6 cycles of A+AVD or ABVD. Patients underwent an interim positron emission tomography scan after cycle 2 (PET2). An exploratory analysis of PFS per investigator was conducted. Results There were 664 and 670 patients randomized to receive A+AVD and ABVD, respectively. 64%, 62%, and 58% of patients had stage IV disease, extranodal involvement at diagnosis, and B symptoms, respectively. Five-year PFS was 82.2% (95% confidence interval [CI]: 79.0–85.0) with A+AVD and 75.3% (95% CI: 71.7–78.5) with ABVD. Overall, PFS favored A+AVD (hazard ratio [HR]: 0.681; 95% CI: 0.534–0.867; P=0.002). PFS benefits were observed regardless of PET2 status and International Prognostic Score. Estimated 5-year PFS with A+AVD versus ABVD was 84.9% versus 78.9% in PET2-negative patients (HR: 0.663; 95% CI: 0.502–0.876; P=0.004), and 60.6% versus 45.9% in PET2-positive patients (HR: 0.702; 95% CI: 0.393–1.255; P=0.229). Treatment-emergent peripheral neuropathy (PN) resolved or improved in 85% (n=375/443) and 86% (n=245/286) of the patients with PN on A+AVD and ABVD, respectively. Secondary malignancies occurred in 19 and 29 patients with A+AVD and ABVD, respectively. A total of 131 female patients or partners of male patients reported a pregnancy; both arms showed similar proportions of ongoing pregnancies or live births. Conclusions At 5 years, A+AVD still demonstrates clinically meaningful improvement in PFS versus ABVD, independent of PET2 status, with a manageable safety profile, including resolution or improvement of PN. The PFS benefit observed with A+AVD at this important milestone suggests that A+AVD is an attractive treatment option for all patients with previously untreated stage III/IV cHL. Funding Millennium Pharmaceuticals and Seagen

Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

Summary Background A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy. Methods We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18–60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m 2 on days 2–4, doxorubicin 35 mg/m 2 on day 2, cyclophosphamide 1250 mg/m 2 on day 2, procarbazine 100 mg/m 2 on days 2–8, and prednisone 40 mg/m 2 on days 2–15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m 2 on days 2–4, doxorubicin 40 mg/m 2 on day 2, cyclophosphamide 1250 mg/m 2 on day 2, dacarbazine 250 mg/m 2 on days 3–4, and dexamethasone 40 mg on days 2–5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2–21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204. Findings Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73–94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83–99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77–96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3–4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3–4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1–2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period. Interpretation Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity. Funding Takeda Pharmaceuticals.

WOS: 000411827200025, PubMed ID: 28961828, Background: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. Patients and methods: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. Results: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. Conclusions: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/mBetween Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Background CD30 (Ki-1) is a cell membrane protein derived from the tumor necrosis factor (TNF) receptor family. The CD30 antigen has been associated primarily with Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Brentuximab vedotin (BV) is an antibody-drug conjugate targeting the CD30 antigen. FDA approval for BV includes relapsed and refractory HL and sALCL. The CD30 antigen also has been identified in many solid tumors, predominantly of germ cell origins and early clinical data is promising. Objective Perform a focus literature review evaluating the prevalence of the CD30 antigen among nonlymphomatous tumors with a potential correlate for CD30 targeted therapy. Eligibility criteria Inclusion criteria: all retrospective reviews and case reports citing CD30 positivity or negativity in non-lymphomatous malignancies in which data were presented based on location. Exclusion criteria: studies with hematopoetic malignancies, cutaneous malignancies, non-human populations, and non-english publications. Included studies A total of 119 articles met these criteria and are summarized in this manuscript. Conclusion The CD30 antigen has shown variable prevalence among non-hematopoetic tumors, most notably among germ cell tumors and mesothelioma. With additional, preclinical and properly powered clinical studies, CD30 targeted therapy such as that of BV, alone or in combination with other agents may prove to be a strong candidate in the treatment of various CD30+ malignancies.

Anaplastic large cell lymphoma (ALCL) is one of the most common peripheral T-cell lymphomas, and the incidence is higher in blacks than non-Hispanic whites. ALK-positive and ALK-negative ALCL are distinct subtypes that have different characteristics and clinical outcomes. Breast implant-associated ALCL is a rare lymphoma that has a good survival outcome, and a recent study showed that total capsulectomy is essential for treatment. Brentuximab vedotin (BV) is a standard treatment for relapsed/refractory ALCL. The response rate is high at 80-90%; however, once the disease progresses in patients on BV, survival outcome is very poor, with a median overall survival of less than two months.