Novel Therapies and Approaches to Relapsed/Refractory HL Beyond Chemotherapy

Although Hodgkin lymphoma (HL) is highly curable with first-line therapy, relapses occur in approximately 10–20% of patients with early stage disease and 30–40% of patients with advanced stage disease. The standard approach for relapsed or refractory disease is salvage therapy, followed by consolidation with high dose therapy and autologous stem cell transplant (ASCT). Patients who achieve a complete response to salvage therapy prior to ASCT have better outcomes, thus recent studies have focused on incorporating newer agents in this setting. Major challenges in the management of relapsed patients remain how to choose and sequence the many salvage therapies that are currently available and how to best incorporate novel agents in the current treatment paradigms. In this article, we will summarize the most recent advances in the management of patients with recurrent HL and will mainly focus on the role of new agents approved and under investigation. Aside from brentuximab vedotin and checkpoint inhibitors, other novel agents and therapies are showing promising early results. However, at least with some of the newest targeted strategies, it is important to recognize that we are facing new challenges in terms of toxicities, which require very close monitoring and education of both the patient and treating physician.

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Novel agents and strategies in transplant-eligible patients with relapsed and refractory Hodgkin lymphoma

Hematology ◽

10.1182/asheducation-2016.1.331 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 331-338 ◽

Cited By ~ 8

Author(s):

Craig Moskowitz

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Brentuximab Vedotin ◽

Novel Agents ◽

Cell Transplant ◽

Antibody Drug Conjugate ◽

Early Stage Disease ◽

Treatment Paradigm

Abstract The majority of patients with Hodgkin lymphoma are cured with frontline therapy; however, 10% to 15% with early-stage disease and 20% to 30% with advanced stage require second-line therapy that includes a potentially curative transplant, of which an additional 50% to 55% are cured. Those with multiply relapsed disease traditionally would receive novel agents on a clinical trial or combination chemotherapy as a potential bridge to an allogeneic stem cell transplant. This treatment paradigm has changed with the availability of brentuximab vedotin, an antibody drug conjugate used pre- and post-ASCT, as well as for palliation. With the availability of the checkpoint inhibitors, nivolumab and pembrolizumab, there will be another shift in treatment, with these agents being used for palliation and potentially replacing allogeneic stem cell transplantation in certain patient populations. Finally, up-front management is also changing and this will have an impact on how patients in the relapsed and refractory setting will be treated.

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Systemic light chain amyloidosis: an update for treating physicians

Blood ◽

10.1182/blood-2013-01-453001 ◽

2013 ◽

Vol 121 (26) ◽

pp. 5124-5130 ◽

Cited By ~ 142

Author(s):

Giampaolo Merlini ◽

Ashutosh D. Wechalekar ◽

Giovanni Palladini

Keyword(s):

Light Chain ◽

Cell Clone ◽

Proteasome Inhibitors ◽

Organ Damage ◽

Cardiac Biomarkers ◽

Novel Agents ◽

High Dose ◽

Cell Transplant ◽

Close Monitoring ◽

Light Chain Amyloidosis

Abstract In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of “red-flags” before advanced cardiomyopathy ensues, is essential for improving outcomes. Differentiation from other systemic amyloidoses may require advanced technologies. Prognosis depends on the extent of cardiac involvement, and cardiac biomarkers guide the choice of therapy. The protean clinical presentation requires individualized treatment. Close monitoring of clonal and organ response guides therapy changes and duration. Conventional or high-dose alkylator-based chemotherapy is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylators achieve high response rates, although controlled studies are needed. Risk-adapted stem cell transplant and consolidation with novel agents may be considered in selected patients. Immune-modulatory drugs are good options for refractory/relapsed patients. Novel agents and therapeutic targets are expected to be exploited, in an integrated, more effective and less toxic treatment strategy.

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Current strategies for salvage treatment for relapsed classical Hodgkin lymphoma

Therapeutic Advances in Hematology ◽

10.1177/2040620717728000 ◽

2017 ◽

Vol 8 (10) ◽

pp. 293-302 ◽

Cited By ~ 11

Author(s):

Liana Nikolaenko ◽

Robert Chen ◽

Alex F. Herrera

Keyword(s):

Hodgkin Lymphoma ◽

Early Stage ◽

Complete Response ◽

High Dose Chemotherapy ◽

Autologous Stem Cell Transplant ◽

Salvage Chemotherapy ◽

High Dose ◽

Cell Transplant ◽

Early Stage Disease ◽

First Line Therapy

Hodgkin lymphoma (HL) is curable in 70–80% of patients with first-line therapy. However, relapses occur in a minority of patients with favorable early stage disease and are more frequent in patients with advanced HL. Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) for patients with chemotherapy-sensitive disease is a standard treatment sequence for relapsed or refractory (rel/ref) HL. Patients who achieve complete response prior to ASCT have better survival outcomes. The choice of salvage chemotherapy therapy is becoming increasingly difficult in the era of novel agents, as there are no randomized studies to guide the choice of a second-line regimen. In this article, we will review current salvage therapy options, including combination chemotherapy and novel-agent-based salvage regimens for rel/ref HL.

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How I treat nodular lymphocyte-predominant Hodgkin lymphoma

Blood ◽

10.1182/blood.2019004044 ◽

2020 ◽

Vol 136 (26) ◽

pp. 2987-2993

Author(s):

Dennis A. Eichenauer ◽

Andreas Engert

Keyword(s):

Hodgkin Lymphoma ◽

Early Stage ◽

Treatment Options ◽

Relative Survival ◽

Treatment Modalities ◽

High Dose ◽

Combined Modality Treatment ◽

Early Stage Disease ◽

Stage Disease ◽

Stage Ia

Abstract Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with distinct pathologic and clinical characteristics. Unlike the malignant cells in classical Hodgkin lymphoma, the disease-defining lymphocyte-predominant cells in NLPHL are consistently positive for CD20, but do not express CD30. The clinical course of NLPHL is indolent in the majority of cases. Most patients present with early-stage disease at the initial diagnosis. First-line treatment of stage IA NLPHL usually consists of limited-field radiotherapy alone. Patients with early-stage NLPHL other than stage IA and intermediate-stage disease mostly receive combined-modality treatment, whereas individuals with advanced NLPHL are treated with chemotherapy alone. In relapsed NLPHL, conventional chemotherapy, anti-CD20 antibodies, and radiotherapy represent active treatment modalities. Only patients with poor-risk characteristics such as early disease recurrence are candidates for aggressive salvage treatment with high-dose chemotherapy and autologous stem cell transplantation. The overall and relative survival of patients with NLPHL is excellent as indicated by a low excess mortality compared with the general population. This article discusses treatment options for patients with NLPHL and factors that influence the choice of therapy on the basis of the available data and 2 clinical cases.

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Cisplatin contributes to programmed death-ligand 1 expression in bladder cancer through ERK1/2-AP-1 signaling pathway

Bioscience Reports ◽

10.1042/bsr20190362 ◽

2019 ◽

Vol 39 (9) ◽

Cited By ~ 7

Author(s):

Te-Fu Tsai ◽

Ji-Fan Lin ◽

Yi-Chia Lin ◽

Kuang-Yu Chou ◽

Hung-En Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Western Blot ◽

Cell Lines ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Expression Level ◽

Dependent Manner ◽

Activator Protein 1 ◽

Early Stage Disease ◽

Stage Disease

Abstract Bladder cancer (BC) is the second most common urologic malignancy and the ninth most common malignancy worldwide. Surgical resection is the mainstay of treatment for patients with early-stage disease, whereas therapeutic options are limited for patients with advanced-stage or residual BC. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in BC; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced BC is ongoing. In the present study, we used Western blot and quantitative real-time PCR (qPCR) to define the expression level of PD-L1 after cisplatin treatment in BC-derived cell lines. The signal activation was also evaluated by Western blot in BC-derived cell lines. We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC-derived cell lines. Furthermore, the expression level of PD-L1 was increased in a dose- and time-dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK1/2 but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor activator protein-1 (AP-1) to regulate PD-L1 expression. The chemotherapy drug such as cisplatin may trigger resistance of BC through PD-L1 up-regulation. The present study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC.

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New Frontiers in the Medical Therapy of Hepatocellular Carcinoma

Chemotherapy ◽

10.1159/000521837 ◽

2022 ◽

Author(s):

Claudia Angela Maria Fulgenzi ◽

Antonio D'Alessio ◽

Thomas Talbot ◽

Alessandra Gennari ◽

Mark R. Openshaw ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Phase Iii ◽

Early Stage Disease ◽

Primary Liver Tumor ◽

Phase Iii Clinical Trials ◽

Stage Disease ◽

Major Treatment

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with anti-angiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPIs-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first line treatment, the second line scenario relies mainly on tyrosine kinase inhibitors, which however, have not been formally trialed after ICPIs. Key messages: In this review we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

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Response-adapted frontline therapy for Hodgkin lymphoma: are we there yet?

Hematology ◽

10.1182/asheducation-2016.1.316 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 316-322 ◽

Cited By ~ 10

Author(s):

Peter W. M. Johnson

Keyword(s):

Disease Control ◽

Hodgkin Lymphoma ◽

Early Stage ◽

Advanced Stage ◽

Early Stage Disease ◽

Interim Pet ◽

Early Results ◽

Stage Disease ◽

Consolidation Radiotherapy ◽

Pet Scans

Abstract Treating Hodgkin lymphoma by using chemotherapy with or without radiotherapy is highly successful, with substantially fewer deaths from lymphoma than from other causes in recent studies of both early-stage and advanced-stage disease. Long-term toxicity is a major consideration in this context, and recent trials have used functional imaging with [18F]fluorodeoxyglucose (FDG) positron emission tomography early in the course of treatment (interim PET) to assess response and modulate subsequent therapy. In early-stage disease, this has allowed omission of consolidation radiotherapy after a good response to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, and trials have shown that this can be done without detriment to overall survival, despite a small increase in rates of recurrence of ∼5%. Conversely, escalation to more intensive chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) for those with positive interim PET scans seems to be an effective strategy with improved disease control. In advanced-stage disease, several groups have elected to start treatment with ABVD and escalate to BEACOPP or myeloablative therapy for patients who remain PET positive after 2 cycles, which gives rates of disease control of ∼65%. De-escalation by omission of bleomycin and consolidation radiotherapy after a negative interim PET scan seems safe with no increase in recurrence rate, but the performance of interim PET after ABVD is suboptimal, especially for those with very advanced disease at presentation; recurrence rates after a negative scan are ∼15%. The negative predictive value of PET is higher after escalated BEACOPP chemotherapy, and the approach of initially treating with BEACOPP and de-escalating to ABVD for those with negative interim PET scans shows promising early results. Response-adapted therapy has yielded important results for patients with Hodgkin lymphoma and is becoming established as a standard approach.

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Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events

ESMO Open ◽

10.1136/esmoopen-2018-000472 ◽

2019 ◽

Vol 4 (4) ◽

pp. e000472 ◽

Cited By ~ 10

Author(s):

Esmée P. Hoefsmit ◽

Elisa A. Rozeman ◽

John B. A. G. Haanen ◽

Christian U. Blank

Keyword(s):

Adverse Events ◽

Autoimmune Diseases ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Future Research ◽

Early Stage Disease ◽

Stage Disease ◽

Cell Death Protein

Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.

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