Distinct autoantibody profiles across checkpoint inhibitor types and toxicities.

Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

Severe insulin resistance in a patient with diabetes after treatment with brentuximab vedotin.

A man in his late 60s with a history of well-controlled type 2 diabetes and hepatic cirrhosis presented to the emergency department due to uncontrollable hyperglycaemia following the initial brentuximab vedotin (BV) infusion. BV was initiated as a treatment for mycosis fungoides, a form of cutaneous T-cell lymphoma. The patient was diagnosed with severe hyperglycaemia with ketosis. Empiric treatment with amoxicillin-clavulanic acid, hydration and intravenous insulin infusion was initiated. Hyperglycaemia persisted despite receiving massive amounts of insulin and was corrected only after treatment with high-dose methylprednisolone for suspected type B insulin resistance. Extremely high and difficult-to-treat hyperglycaemia is a rare side effect of BV. Unfortunately, the patient died of upper gastrointestinal bleeding 22 days after discharge. In patients with obesity and/or diabetes mellitus, the blood glucose levels should be carefully monitored when treated with BV.

Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD). We report the clinical history of a patient with refractory classical HL who underwent two allo-HSCTs (first from matched unrelated and second from haploidentical donor) after relapsing on BV and nivolumab and for whom durable remission was finally obtained using BV-pembrolizumab combination for relapse after haploidentical HSCT. Such treatment was associated with the onset of GVHD after only two cycles which led to treatment discontinuation. However, the side effects were rapidly controlled, and after 2 years of follow-up, the patient is still in remission. Our data support the feasibility and efficacy of combining PD-1 blockade with BV to enhance the graft-versus-lymphoma effect after allo-HSCT.

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

How I Follow Hodgkin Lymphoma in First Complete (Metabolic) Remission?

Hodgkin lymphoma is characterized by a high cure rate in the modern era of medicine regardless of stage, but patients suffer from a high risk of comorbidity associated with the administered therapy. The main aim of this review article is to assess and analyze the various comorbidities associated with Hodgkin lymphoma and address the survivorship of patients, including fertility, secondary cancers due to cardiovascular toxicity, and quality of life. Furthermore, this review explores the optimal strategy for detecting relapse. The treatment paradigm of Hodgkin lymphoma has shifted, with a paradigm shift toward achieving a high cure rate and low toxicity as a standard of care in this patient population. Checkpoint inhibitors, especially nivolumab, in combination with chemotherapy are increasingly being studied in the first line of therapy. However, their long-term toxicity remains to be assessed in longer follow-up. In conclusion, Hodgkin lymphoma survivors, regardless of their treatment, should be followed up individually by a multidisciplinary survivorship team in order to detect and properly treat the long-term side effects of therapy.

Case report: The utilization of crizotinib and brentuximab vedotin as a bridge to autologous stem cell transplantation and followed by CD30-directed CAR-T cell therapy in relapsed/refractory ALK+ ALCL.

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness.

SOHO State-of-the-Art Updates and Next Questions: Treatment for Newly Diagnosed Peripheral T-Cell Lymphomas.

Although a rare subset of non-Hodgkin lymphomas, peripheral T-cell lymphomas (PTCL) account for a disproportionate proportion of patient mortality. Conventional therapies are derived from experience treating aggressive B-cell lymphomas and center around CHOP-based chemotherapy. However, due to the unique biology and diverse subtypes of PTCL, most patients fail to durably respond to this approach and 5-year survival is only 20% to 30%. There have been multiple attempts to improve outcomes for patients with PTCL. Among the more successful strategies are the use of consolidative autologous stem cell transplant, the augmentation of CHOP with etoposide (CHOEP), and the use of brentuximab vedotin in CD30-positive PTCL. Advances in the understanding of histology-specific biology has cultivated enthusiasm to evaluate hypomethylating agents, histone deacetylate inhibitors, and phosphoinositol-3-kinase inhibitors in the frontline setting. Improvements in monitoring disease response and prognostication including the use of cell-free DNA, mutational profiling, and interim PET/CT imaging are also on the horizon. For patients with acute T-cell leukemia/lymphoma, the use of mogamulizumab-based therapy in the frontline setting may lead to advances in care. The true impact of these new-era therapies will only be elucidated as clinical practices incorporate the rapidly changing evidence.

Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy.

ABSTRACT: Older patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Real-world treatment patterns, healthcare resource utilization and costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU) and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using the IQVIA PharMetrics® Plus claims database from 1 April 2011 to 30 November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOT and ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOT and 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-like and brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Peripheral T-cell lymphomas (PTCL) are a rare and fast-growing form of blood cancer. About 8000­12,000 people in the USA are diagnosed with PTCL every year. As it is a rare disease and has many types, and there is a limited understanding of the patients who have PTCL and the treatments they receive in the real world. The purpose of this study was to evaluate how these patients are treated, what are they treated with and what are the costs of these treatments in the USA. The data collected on these patients was divided into three groups based upon the number of lines of treatment/therapy (LOT) they received: 1LOT, 2LOT and ≥3LOT. This study researched different treatments and their duration in each line of therapy. Among 189 PTCL patients included in the study, the average age of patients was 55 years and 62% were male. Among these patients, 62% had 1LOT, 22% had 2LOT and 16% had ≥3LOT. The most common treatments in the 1LOT were traditional chemotherapy regimens followed by targeted therapies: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) or CHOEP-like, and brentuximab vedotin. Treatment regimens with only one drug were most common in the 2LOT and ≥3LOT. The total cost of PTCL treatment in the USA is very high; 70% of this cost is related to their treatment with various drugs. More research is needed to better understand the treatment and cost of this rare cancer.

Optimizing assessment of CD30 expression in Hodgkin lymphoma by controlling for low expression.

Since the approval of brentuximab vedotin (BV), assessment of CD30 status by immunohistochemistry gained increasing importance in the clinical management of patients diagnosed with CD30-expressing lymphomas, including classical Hodgkin lymphoma (CHL). Paradoxically, patients with low or no CD30 expression respond to BV. This discrepancy may be due to lack of standardization in CD30 staining methods. In this study, we examined 29 cases of CHL and 4 cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) for CD30 expression using a staining protocol that was designed to detect low CD30 expression levels, and an evaluation system similar to the Allred scoring system used for breast cancer evaluation. For CHL, 10% of cases had low scores and 3% were CD30 negative, with 3 cases in which the majority of tumor cells showed very weak staining. Unexpectedly, one of four cases of NLPHL was positive. We demonstrate intra-patient heterogeneity in CD30 expression levels and staining patterns in tumor cells. Three CHL cases with weak staining may have been missed without the use of control tissue for low expression. Thus, standardization of CD30 immunohistochemical staining with use of known low-expressing controls may aid in proper CD30 assessment and subsequent therapeutic stratification of patients.

Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity.

Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.

The combination of brentuximab vedotin and chidamide synergistically suppresses the proliferation of T-cell lymphoma cells through the enhancement of apoptosis.

PURPOSE: Peripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL. METHODS: A high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice. RESULTS: Chidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group. CONCLUSION: The use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other.

Real-World Treatment Patterns and Clinical Outcomes With Brentuximab Vedotin or Other Standard Therapies in Patients With Previously Treated Cutaneous T-Cell Lymphoma in the United States.

INTRODUCTION/BACKGROUND: Primary cutaneous anaplastic large-cell lymphomas (pcALCLs) are a type of cutaneous T-cell lymphoma (CTCL) in which CD30 is uniformly expressed. In mycosis fungoides (MF), another CTCL, CD30 is heterogeneously expressed. In ALCANZA, patients with pcALCLs or CD30-positive MF randomized to brentuximab vedotin (BV) vs. physician's choice of methotrexate or bexarotene had significantly improved outcomes, including higher objective response rates (ORR) lasting ≥4 months (ORR4), as well as longer median progression-free survival (PFS) and time to next treatment (TTNT). In this study, we sought to assess the real-world impact of treatment with BV in second or later lines of therapy for CTCL. MATERIALS AND METHODS: This retrospective chart review describes patient characteristics, treatment patterns, clinical outcomes, and healthcare resource use (HRU) in patients with pcALCLs or MF previously treated with ≥1 systemic therapy and subsequently treated with BV (n = 139) or other standard therapy (OST; n = 164). RESULTS: Most patients in the BV cohort (96.4%) received BV as second-line (2L) systemic therapy. The most common OSTs were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies. For 2L BV and OST, median duration of therapy was 8.4 and 5.2 months, real-world ORR was 82.1% and 66.5%, and real-world ORR4 was 42.5% and 25.0%. Real-world 1- and 2-year PFS, TTNT, and OS were significantly longer (all P < .01) and HRU was lower for BV vs. OST. CONCLUSION: These real-world outcomes are consistent with ALCANZA results, demonstrating favorable outcomes with BV vs. OST in patients with CTCL previously treated with ≥1 systemic therapy.

Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the 'standard' treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL.