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PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment
Abstract
Introduction: The PD-1 pathway provides an important mechanism of immune evasion and an actionable therapeutic target for many tumors. Classical Hodgkin lymphoma (cHL) frequently contains genetic amplification at the 9p24.1 locus, resulting in the overexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumor cell surface. cHL may therefore have a unique sensitivity to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands and can restore antitumor immune activity in several solid tumors. Based on its possible genetically driven dependence on PD-1, cHL was included as an independent expansion cohort in the KEYNOTE-013 study (NCT01953692), a phase 1b multicenter multicohort trial of pembrolizumab in patients with hematologic malignancies. Updated results of the cHL cohort are presented.
Methods: This cohort enrolled patients with relapsed or refractory cHL. Patients had to have relapsed after, be ineligible for, or refused autologous stem cell transplantation (ASCT). In addition, patients were required to have relapsed after or be refractory to brentuximab vedotin (BV) treatment. Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by computed tomography and positron emission tomography scans after 12 weeks of treatment and every 8 weeks thereafter, using International Harmonization Project 2007 criteria. The primary objectives were safety and complete remission (CR) rate; secondary objectives were progression-free survival, overall survival, overall response rate (ORR), duration of response (DOR), and biomarker assessments. Biomarkers included PD-L1/PD-L2 expression in formalin-fixed, paraffin-embedded tissue; flow cytometry evaluating absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString platform.
Results: At the time of data cutoff on May 26, 2015, 31 patients were evaluable for analysis. Median (range) age was 32 (20-67) years. 68% of patients had received ≥4 prior lines of therapy, 71% had failed prior ASCT, and by design 100% had failed prior BV. The most common treatment-related AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%). Five patients had grade 3 related AEs; no grade 4 AEs or treatment-related deaths occurred. ORR among the 31 patients was 65% (90% CI, 48-79). Five patients (16%) achieved CR, 15 (48%) partial remission, and 7 (23%) stable disease as their best response. With a median follow-up of 9.7 (1.3-17.5) months, the median DOR had not been reached (0+ to 13.4+ months). As of the data cutoff, 14 patients (45%) remained on treatment; 2 (6%) patients discontinued for toxicity, 12 (39%) for progression, and 3 (10%) for other reasons. Of the 20 responses, 14 are ongoing.
Eleven patients had evaluable pretreatment tumor tissue (archival or obtained for study). Among them, 10 (91%) were PD-L1+ by immunohistochemistry (IHC). Among 6 available tumor samples obtained at week 13, 4 (57%) were PD-L1+. Additionally, 10/10 patients assessed for PD-L2 expression by IHC showed high levels of PD-L2 staining. Based on flow cytometry analyses, a significant increase was observed at the 13-week time point in the absolute number of circulating total lymphocytes, T cells (CD4 and CD8 subsets), as well as NK cells. NanoString RNA profiling of pre- and posttreatment blood samples showed that several prespecified gene expression signatures were significantly upregulated with treatment, including the 10-gene IFN-γ-induced signature, the 18-gene expanded immune signature, and the 13-gene TCR signature.
Conclusion: PD-1 blockade with pembrolizumab was associated with a favorable safety profile and a high response rate in a very heavily pretreated cohort of patients with cHL. Responses appear durable with ongoing follow-up. Biomarker analyses confirm the frequent presence of PD-L1 and PD-L2 in tumors and further suggest that pembrolizumab results in an expansion of circulating T- and NK-cell populations, as well as in activation of IFN-γ and other pathways involved in regulation and differentiation of immune cells. Those biomarkers may be tested in larger ongoing studies for their relationship with treatment outcomes.
Disclosures
Armand: Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Shipp:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zinzani:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Snyder:Merck: Employment, Equity Ownership. Ricart:Merck: Employment; Pfizer Inc.: Equity Ownership. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Moskowitz:Seattle Genetics: Honoraria, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.
... A multicohort open-label phase Ib clinical trial (KEYNOTE-013) is ongoing to assess the safety and efficacy of pembrolizumab in patients with hematologic malignancies. Results already were reported from a cohort of patients with HL in whom brentuximab vedotin treatment had failed [35,36]. ...
... Seventy-one percent of the patients had a sustained response of more than 24 weeks. With a median follow-up of nearly 18 months for survivors, the PFS at 24 weeks was 69 % [36]. ...
... A patient subset was evaluated for biomarkers [36]. Fifteen patient samples (94 %) were positive for PD-L1 and nine (90 %) for PD-L2. ...
Opinion statement:
Treatment for relapsed/refractory (R/R) Hodgkin and non-Hodgkin lymphoma remains challenging. The introduction of rituximab to B cell non-Hodgkin lymphoma (B-NHL) treatment significantly improved patients' response rate and survival; however, approximately one third of patients with diffuse large B cell lymphoma, the most common B-NHL subtype, still have a relapse or become refractory after first-line therapy. More recently, antibody therapies and small-molecule inhibitors were approved for treating R/R lymphomas; these agents include brentuximab vedotin, ibrutinib, and idelalisib. Immune checkpoint inhibitors and other immune therapies are emerging treatments currently being evaluated in various clinical trials for their efficacy against lymphoid malignancies. Striking results from these treatment modalities have been observed in solid tumors, and evidence is accumulating to support their use in various lymphomas. The most exciting results from immune checkpoint inhibitor therapy have been seen in patients with R/R Hodgkin lymphoma, in whom the overall response rate has reached 60-80 %. Results in NHL are more similar to those seen in other solid malignancies, ranging between 20 and 40 %, depending on the histology. Formal approval of these drugs is being awaited, as are the results of combination therapy with checkpoint inhibitors and other treatment modalities, including conventional chemotherapy, small-molecule inhibitors, and other immune therapies. Although response rates have been promising, attention must be paid to the management of unique immune-related adverse events, which warrant close monitoring in some cases. Identification of biomarkers that predict response or severe adverse events using either the tumor specimen or peripheral blood would aid in selecting patients suited for these types of treatment as well as determining the ideal sequence of treatment within the realm of immune therapies.
... Therapeutic strategies targeting immune checkpoints have shown significant clinical activity in solid tumors and hematologic malignancies by enhancing T-cell activation and inducing T-cell-mediated antitumor response (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). In cHL, 2 monoclonal antibodies directed against PD-1, nivolumab and pembrolizumab, are the most promising thus far (34,(45)(46)(47)(48)(49)(50). Herein, we describe the rationale for utilizing immune checkpoint inhibitors in patients with relapsed/refractory cHL focusing on the novel monoclonal antibody pembrolizumab and how the development of these new agents is reshaping the care of this patient population. ...
... Given the responses in solid tumors and the emerging clinical data in cHL, patients with relapsed/refractory cHL were included as a cohort of an ongoing, multicenter, phase Ib trial of pembrolizumab in hematologic malignancies (NCT01953692, KEYNOTE-013). Thirty-one patients were evaluable for analysis at the most recent update (48). Median age was 32, 21 patients (68%) received greater than three lines of chemotherapy, by design all the patients had failed prior treatment with BV and 22 patients (71%) had failed prior ASCT, 10 patients (32%) received prior radiation therapy. ...
... At the time data were presented, the median duration of response was not reached. Two patients (6%) discontinued for toxicity, 12 (39%) for disease progression, and 3 (10%) for reasons that were not reported (47,48). ...
Pembrolizumab is a humanized monoclonal antibody directed against programmed cell death protein 1 (PD-1), a key immune-inhibitory molecule expressed on T cells and implicated in CD4+ T-cell exhaustion and tumor immune-escape mechanisms. Classical Hodgkin's lymphoma (cHL) is a unique B-cell malignancy in the sense that malignant Reed-Sternberg (RS) cells represent a small percentage of cells within an extensive immune-cell infiltrate. PD-1 ligands are up-regulated on RS cells as a consequence of both chromosome 9p24.1 amplification as well as Epstein-Barr virus infection and by interacting with PD-1 promote an immune suppressive effect. By augmenting anti-tumor immune response, pembrolizumab and nivolumab, another monoclonal antibody against PD-1, have shown significant activity in relapsed/refractory cHL patients as well as an acceptable toxicity profile with immune-related adverse events that are generally manageable. In this review, we explore the rationale for targeting PD-1 in cHL, review the clinical trial results supporting the use of checkpoint inhibitors in this disease, and present future directions for investigation in which this approach may be used. This article is protected by copyright. All rights reserved.
... (Image was realized by Francesco B. Tocci, Scientific High School G. Bruno, Rome (Italy)). Leukemia Research 67 (2018) [45][46][47][48][49][50][51][52][53][54][55] showed a strong PD-L1 expression in HL samples compared with other aggressive types of Non-Hodgkin Lymphomas, with the higher levels in nodular sclerosis and mixed cellularity cHL (82% of cases had at least 90% of RS cells positive for PD-L1). Another recent study by Menter et al. [32], examined a large cohort of HL (n = 280) and B-cell lymphomas (n = 619), for PD-L1 expression. ...
... An ongoing trial on the use of pembrolizumab in hematologic malignancies has included a separate cohort of 31 patients with relapsed/refractory cHL [45]. These patients were treated with single agent pembrolizumab every 2 week until disease progression or for a maximum of 2 years or unacceptable toxicity. ...
Programmed cell death protein 1 (PD-1), is a cell surface receptor with an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1/PDL1 axis represents a checkpoint to control immune responses and it is often used as a mechanism of immune escaping by cancers and infectious diseases. Many data demonstrate its important role in solid tumors and report emerging evidences in lymphoproliferative disorders. In this review, we summarized the available data on the role of PD-1/PD-L1 checkpoint in lymphoproliferative diseases and the therapeutics use of monoclonal blocking antibodies.
... Similar to results with nivolumab, pembrolizumab induced responses in 65% of patients who were brentuximab refractory with an acceptable safety profile. 13 The median progression-free survival for both trials has not yet been reached. On available tumor samples, the RS cells in both trials showed upregulated expression of PD-L1 and PD-L2 as potential biomarkers of response. ...
... Published trials using checkpoint inhibitors in lymphomaPresented at the 57th annual meeting of the American Society of Hematology, Orlando, FL, 5-8 December, 2015.13 allo or auto-HSCT, allogeneic or autologous hematopoietic stem cell transplant; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; GI, gastrointestinal toxicity; HL, Hodgkin lymphoma; IAEs, grade 3 or higher immune-related adverse events; N, number of patients affected; MM, multiple myeloma; NHLs, non-Hodgkin lymphomas; ORR, overall response rate; PR, partial remission. ...
Hodgkin and non-Hodgkin lymphoma are both good targets for immunotherapy, as they are accessible to antibodies and cell-based immunotherapy, express costimulatory molecules, and express lineage-restricted, viral, and unique tumor antigens. Blockade of the programmed-death 1 (PD-1) immune checkpoint has produced very encouraging response rates in patients with Hodgkin lymphoma, whereas adoptive transfer of Epstein-Barr Virus (EBV)-specific T cells has shown clinical activity in patients with posttransplant lymphoma and other EBV-associated lymphomas. T cells can also be genetically modified with chimeric antigen receptors (CARs) to confer specificity for surface antigens, and studies of CD19 CARs in lymphoma also have had encouraging response rates. Future directions include combination of checkpoint blockade and adoptive T-cell studies.
... Our approach is to offer BV as initial therapy for patients with nodal-only disease. 29 At ASH in 2015, 2 very different chemo-immunotherapy ST programs were presented. The first, an outpatient regimen, combined BV with bendamustine. ...
... In HL, as well as primary mediastinal B-cell lymphoma, amplification of chromosome 9p23-4 is the most common genetic abnormality reported and the genes encoding PDL1 and 2 reside there; therefore, these 2 diseases are primed to respond to CPI. 34 Both nivolumab and pembrolizumab are highly active, and phase 1 data were presented at ASH in 2014 and 2015. 29,35 Results are quite similar with both agents, and treatment was administered for up to 2 years provided that the HL remained stable and/or the patient continued to have clinical benefit. These are unusual response criteria, and much different compared with traditional agents, when any time progression is documented, the study drug is discontinued. ...
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. © 2016 by The American Society of Hematology. All rights reserved.
... The ORR was 87% (CR 26%) and the median OS was not reached; in results that were recently updated, with a median of 86 weeks of observation, responses have allowed five patients to pursue alloSCT and 7 of 10 patients electing not to pursue transplant benefited from remission duration >1 year [19]. Another humanized PD-1 monoclonal antibody, pembrolizumab, was explored in the phase Ib KEYNOTE-013 study that pre-specified prior treatment with BV as an inclusion criterion [20]. Among the 31 patients enrolled, 68% had received >4 prior lines of therapy and 71% had received prior ASCT. ...
... Among the 31 patients enrolled, 68% had received >4 prior lines of therapy and 71% had received prior ASCT. In updated results, the ORR was 65% (CR 16%) and after a median follow-up of 9.7 months, the median DOR had not been reached [20]. It is apparent that both of these agents will substantially alter the prognosis of patients who are resistant to BV. ...
Background:
Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described.
Patients and methods:
We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome.
Results:
100 patients met inclusion criteria, with median age 32 years (range 18-84) at progression after BV. The median number of treatments prior to BV was 3 (range 0-9); 71 had prior autologous stem-cell-transplant. The objective-response-rate (ORR) to BV was 57%, and the median duration-of-BV-therapy was 3 months (range 1-25). After disease progression post-BV, the most common treatment strategies were investigational agents (n=30), gemcitabine (n=15) and bendamustine (n=12). The cumulative ORR to therapy was 33% (CR 15%). After a median follow-up of 25 months (range 1-74) the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months respectively. By multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40g/L at disease progression was associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P=0.11).
Conclusions:
Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.
... Overexpression of PD-L1 and PD-L2 in Hodgkin Reed-Sternberg cells as well as the immunosuppressive tumor microenvironment make HL sensitive to PD-1/PD-L1 inhibition. Nivolumab and pembrolizumab, both monoclonal antibodies to PD-1 have demonstrated clinical activity in relapsed/refractory HL and both are FDA approved as monotherapy for relapsed/refractory disease [35][36][37][38][39]. The SWOG S1826 trial is an ongoing phase III intergroup trial investigating the use of nivolumab with AVD compared to brentuximab vedotin with AVD for newly diagnosed advanced stage cHL in patients 12 years of age or older. ...
Purpose of Review
Lymphoma is the one of the most common cancer diagnoses among adolescents and young adults (AYAs) aged 15–39. Despite significant advances in outcomes observed in older adults and younger children, improvements in AYAs have lagged behind. The reasons for this are likely multifactorial including disparities in access to health insurance, low rates of enrollment to clinical trials, potential differences in disease biology, and unique psychosocial challenges. Here we will review Hodgkin lymphoma (HL) and primary mediastinal B cell lymphoma (PMBCL), two of the most common aggressive lymphomas that occur in AYAs. We will discuss the current knowledge about disease biology in AYAs, adult and pediatric treatment strategies, novel targeted therapies, and ongoing AYA clinical trials in these lymphoma subtypes. We also will review unique considerations for treatment-related toxicities in AYAs and psychosocial issues relevant to this population.
Recent Findings
Pediatric and adult trials in HL and PMBCL have demonstrated that treatment with dose-intense chemotherapeutic regimens with or without radiation results in high cure rates but can also be associated with long-term toxicity which must be considered in this young population. Novel targeted agents such as the antibody-drug conjugate brentuximab vedotin and/or antibodies targeted against PD-1/PD-L1 have demonstrated activity in the relapsed setting and are currently being evaluated in the upfront setting, which may reduce our reliance on therapies associated with long-term toxicity. AYA-focused clinical trials are currently underway to better elucidate the optimal therapy for lymphomas in this age group.
Summary
There is an urgent need for clinical trials including AYAs in order to increase the knowledge of age-specific outcomes, toxicities, disease biology, and the need to develop comprehensive AYA care models that meet the unique and complex care needs of this patient population.
... Pembrolizumab was studied in the KEYNOTE-013 trial in R/R HL in patients who have failed AHSCT and brentuximab vedotin. The ORR was 65% with 16% achieving CR and the median duration of response was not yet reached [19]. ...
Objective
The objective of this study was to identify the emerging role of immune checkpoint inhibitors in lymphomas.
Materials and methods:
Medline databases (Google Scholar, PubMed, http://www.ekb.eg) and all materials available on the Internet from 2008 till 2015. The initial search presented 10 articles of which seven have met the inclusion criteria. These articles studied the emerging role of immune checkpoint inhibitors in lymphoma. Studies that did not fulfill were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures have been undertaken. Comparisons were made by a structured review with the results tabulated.
Results:
Antibodies blocking immune checkpoints (programmed death 1 ligand, programmed death 1,
and cytotoxic T‑lymphocyte‑associated protein 4) have shown promising results in relapsed/refractory lymphoma. Formal approval of these drugs is being awaited, and the results of combination therapy of checkpoint inhibitors with other treatment modalities, including chemotherapy, small‑molecule inhibitors, and other immune therapies.
Conclusion:
Immune therapy with checkpoint inhibitors shows promising results against relapsed/refractory Hodgkin’s lymphoma (HL) and non‑HL. The efficacy of checkpoint inhibitors against HL is questionable compared with that against non‑HL and other solid tumors. Despite these treatment modalities are effective in relapsed/refractory lymphoma, caution is needed due to serious immune‑related adverse effects. Results from currently ongoing studies are awaited and
will hopefully provide us with better understanding of treatment efficacy as well as increased information about biomarkers of response that will guide in patient selection.
... Pembrolizumab was studied in the KEYNOTE-013 trial in R/R HL in patients who have failed AHSCT and brentuximab vedotin. The ORR was 65% with 16% achieving CR and the median duration of response was not yet reached [19]. ...
... in treatment relapse/refractory cHL patients. [5][6][7] CTLA-4 has long been recognized for its regulatory function, potentially decreasing antitumor immune response. Improvement of the immune response via CTLA-4 blockade significantly increases the survival of patients with metastatic melanoma. ...
Classical Hodgkin lymphoma (cHL) is a unique neoplasia characterized by only 1% of malignant Reed-Sternberg (RS) cells surrounded by a reactive cellular background. Recent evidence has shown that interaction of ligands is expressed by RS cells with immune checkpoint receptors expressed by T cells in the tumor microenvironment, thereby promoting T cell exhaustion and is thus an ineffective immune response. 1 PD-1 is an inhibitory receptor expressed on activated T cells found in tumor microenvironment. Immune checkpoint inhibition targeting programmed death-1/programmed death ligand-1 (PD-1/ PD-L1) and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) pathways reveal a new therapeutic approach focused on tumor micro-environment interactions, promoting an effective T cell mediated anti-tumor response. 2 Overexpression of PD-L1 on RS cells is related with downregulation of effector T cell function and represents a potent mechanism of tumor evasion. Furthermore, higher expression of PD-L1 on RS cells is associated to an advanced stage and worse prognosis. 3,4 PD-L1 and PD-1 inhibitors have shown excellent results in treatment relapse/refractory cHL patients. 5-7 CTLA-4 has long been recognized for its regulatory function, potentially decreasing antitu-mor immune response. Improvement of the immune response via CTLA-4 blockade significantly increases the survival of patients with metastatic melanoma. 8 The circulating immunological checkpoints, in a soluble form, have appeared as potential biomarkers. As such, for the first time, we detected these immune checkpoint molecules in the blood of patients with cHL treated according to international guidelines. 9
... Identification of novel biomarkers that provide additional value in identifying patients most likely to benefit from pembrolizumab therapy, beyond that already achieved by PD-L1 expression, is another area for further research. Examples of biomarkers that could be further investigated for their potential to predict response to therapy or to be prognostic for survival might include total mutation burden, T-cell inflamed gene expression profile and PD-L2 expression [40,41]. The optimal treatment duration for pembrolizumab and outcomes for patients who are retreated with pembrolizumab after previously discontinuing therapy with this agent should be explored as well. ...
This review describes trials evaluating the monoclonal antibody pembrolizumab (an immunotherapy that blocks the interaction between programmed death-1 and programmed death-ligand 1 and 2 [PD-L1/PD-L2]) as first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the Phase III KEYNOTE-024 study, pembrolizumab monotherapy significantly improved progression-free survival (primary end point) and overall survival, and was associated with fewer adverse events compared with platinum-based chemotherapy in patients with NSCLC with PD-L1 expression on ≥50% of tumor cells. In cohort G of the Phase I/II KEYNOTE-021 study, pembrolizumab plus pemetrexed and carboplatin significantly improved objective response rate (primary end point) and progression-free survival versus pemetrexed and carboplatin alone, and had manageable toxicity in patients with nonsquamous NSCLC. These results have changed first-line management of advanced NSCLC.
... Similar data were reported for PD-1 inhibitor pembrolizumab at the 2014 American Society of Hematology (ASH) Annual Meeting in a similar population of relapsed HL patients, with an ORR of 53% in 15 patients (CR ¼ 20%, PR ¼ 33, 95% CIs were not reported) (60). The data for both agents was updated at ASH 2015 and demonstrates that with longer follow-up (86 weeks and 9.7 months, respectively, durable responses persist in approximately 50% of patients) (61,62). A preliminary report of the phase II studies for both checkpoint inhibitors was reported at the 2016 American Society of Clinical Oncology Annual Meeting. ...
The National Clinical Trials Network lymphoid malignancies Clinical Trials Planning Meeting (CTPM) occurred in November of 2014. The scope of the CTPM was to prioritize across the lymphoid tumors clinically significant questions and to foster strategies leading to biologically informed and potentially practice changing clinical trials. This review from the Hodgkin lymphoma (HL) subcommittee of the CTPM discusses the ongoing clinical challenges in HL, outlines the current standard of care for HL patients from early to advanced stage, and surveys the current science with respect to biomarkers and the landscape of ongoing clinical trials. Finally, we suggest areas of unmet need in HL and elucidate promising therapeutic strategies to guide future HL clinical trials planning across the NCTN. © The Author 2017. Published by Oxford University Press. All rights reserved.
... A subsequent trial using pidilizumab in combination with rituximab in patients with FL revealed an ORR of 65% and a complete response rate of 52%, suggesting that treatment with this combination resulted in a greater level of clinical activity than would be expected with use of rituximab alone 64 . The efficacy of the anti-PD-1 antibodies, nivolumab and pembrolizumab, was evaluated in patients with relapsed B-cell lymphoma, cell lymphoma, or HL (TABLE 1) [65][66][67] . In patients with relapsed HL that received treatment as part of these phase I trials, both antibodies produced response rates >60%, although the complete response rates were more modest (TABLE 1). ...
The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.
... In addition, the analytical run of the mixed mAbs also demonstrated nSMOL proteolysis coupled with LCMS analysis robustness by the QC precision and accuracy. Recently, mAb-based cancer treatments are diversifying the therapeutic applications of mAbs, indicating combined administration therapy of mAbs and other types of mAbs treatment after pretreated mAb [12,13]. Thus, the demand for multiplexing mAbs bioanalysis increases in both preclinical and clinical PK studies. ...
Background: Recently, monoclonal antibody (mAb) bioanalysis using mass spectrometry has begun to be recognized as useful technology for mAbs measurement other than ELISA. We have recently exploited a high-precision method for bioanalysis of monoclonal antibody (mAb) using mass spectrometry. The method is nano-surface and molecular-orientation limited (nSMOL) proteolysis, which is useful for LCMS bioanalysis of many kinds of antibody drugs. Methods: nSMOL is Fab-selective limited proteolysis which consists of the difference of protease nanoparticle diameter (200 nm) and antibody resin pore diameter (100 nm). For limited proteolysis of antibody, Protein A resin (pore: 100 nm) slurry was added to plasma including monoclonal antibody, and the antibody Fc region was immobilized to the resin at 25°C for 10 min with gentle vortexing. Antibody-immobilized resin was washed with PBS, and limited proteolysis was performed with trypsin-conjugated FG beads (diameter: 200 nm). Limited proteolysis of Fab region on antibody was achieved by these two diameter difference. After nSMOL proteolysis, the generated peptides were collected by only simple filtration. Results: In this study, we have demonstrated that the first full validation dataset for bioanalysis using nSMOL of antibody-drug conjugate (ADC), Brentuximab vedotin, in human plasma using nSMOL proteolysis. Full validation using nSMOL proteolysis fulfilled criteria of guideline on bioanalytical method validation in pharmaceutical development for small molecule drug compounds. Conclusions: These results indicate that nSMOL is also significant method for precise quantification of ADC in plasma, such as Brentuximab vedotin. Furthermore, we report that nSMOL proteolysis is able to apply for not only single-analyte but also multi-analyte bioanalysis of each mAbs in plasma, so that, nSMOL proteolysis is feasible multiplex bioanalysis for many clinical pharmacokinetic study and therapeutic drug monitoring.
... 21 More recently, trials using blocking antibodies to PD-1 showed a more promising clinical activity in patients with relapsed Hodgkin lymphoma. [22][23][24] The experience in patients with relapsed DLBCL remains limited to a small number of patients treated in a phase I study, demonstrating a 40% response rate. Other studies are currently evaluating the efficacy of various antibodies targeting PD-L1, such as MPDL3280A, but the results are still pending. ...
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in the western world. Current treatment regimens result in curing approximately 50% to 60% of patients with DLBCL. In 2006, the Food and Drug Administration approved rituximab for use in the first-line treatment of patients with DLBCL in combination with anthracycline-based chemotherapy regimens. Since then, no other agents have been approved for the treatment of DLBCL. This article reviews recent data on the most promising agents in development for the treatment of DLBCL.
... Similar efficacy and safety results were reported for KEYNOTE-013, a phase Ib multicenter, multicohort trial that evaluated the anti-PD-1 humanized monoclonal antibody pembrolizumab. [36] In this study, 31 patients with classical Hodgkin lymphoma unresponsive to treatment with BV (100%) and ASCT (71%) received 10 mg/kg of pembrolizumab every 2 weeks for up to 2 years. At the time this trial was presented at the 2015 ASH Annual Meeting, the ORR was 65%, with a CR rate of 16%. ...
Hodgkin lymphoma is a unique disease entity characterized by a low number of neoplastic tumor cells surrounded by an inflammatory microenvironment composed of dysfunctional immune cells. Recent molecular and genetic studies have revealed that upregulation of the immune checkpoint pathway programmed death 1/programmed death ligand 1 is a key oncogenic driver of Hodgkin lymphoma. Corroborating these mechanistic studies, early-phase clinical trials using the checkpoint inhibitors nivolumab and pembrolizumab in treatment regimens for relapsed and/or refractory Hodgkin lymphoma have demonstrated impressive response rates, a promising durability of response, and a favorable side-effect profile. Given its targeted mechanism of action, acceptable safety, and clinically meaningful activity, the checkpoint inhibitor nivolumab was recently approved by the US Food and Drug Administration as therapy for classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-ASCT consolidation therapy with brentuximab vedotin. In this article we review the scientific rationale, preclinical evidence, and most recent clinical data for the use of checkpoint inhibitor therapy in patients with relapsed Hodgkin lymphoma. © 2016, UBM Medica Healthcare Publications. All rights reserved.
... 7 There is an ongoing, early phase pediatric trial of nivolumab to determine safety and efficacy in a range of pediatric cancers (NCT02304458). Pembrolizumab, another checkpoint inhibitor of PD-1, has also been shown to induce responses in adults with cHL after failure of BV. 8,12 Our patient with chemorefractory cHL, who had failed both ASCT and BV, demonstrated a rapid clinical and radiographic response to a single dose of nivolumab. Adult experience, although predominantly in different diseases, indicates that this agent is typically well tolerated. ...
The programmed death-1 (PD-1) pathway of immune evasion is exploited by many malignancies to limit host T-cell-mediated immune responses. Nivolumab is a PD-1-blocking monoclonal antibody that disrupts this pathway and is FDA approved for the treatment of metastatic melanoma, renal cell carcinoma, and squamous non-small cell lung cancer. In this case report, we describe the first published pediatric experience of nivolumab in refractory classic Hodgkin lymphoma. In this patient with primary refractory disease and high disease burden, cytokine release syndrome requiring inotropic support developed following the first infusion of nivolumab. The patient subsequently demonstrated a dramatic clinical response with resolution of fevers, transfusion independence, improvement in functional status, and very good partial response on PET/CT following a single dose. Nivolumab was continued with corticosteroid and antihistamine premedication without further adverse events and clinical benefit was sustained at 11 months after therapy initiation, despite evidence of slow radiographic disease progression.
... Inhibition of PD-1 by nivolumab or pembrolizumab is blocking this deleterious interaction between the HRS cells and T-cells and restores immune responses against the neoplastic cells. In phase I trials these drugs have shown high response rates in heavily pretreated patients with an acceptable safety profile [28,29]. In one of the four arms of the CHECKMATE-205 phase II study, 80 patients with ECOG performance status 0-1 in whom both ASCT and BV had failed and had received a median of 4 prior lines of therapy (range; 3-15), nivolumab was administered intravenously at a dose of 3mg/kg every 2 weeks up to disease progression or unacceptable toxicity [30]. ...
... ORR among the 31 evaluable patients was 65%. Five patients (16%) achieved CR, 15 (48%) had PR, and seven (23%) had SD as their best response (72). ...
Hanahan and Weinberg described six distinct biological properties of cancer cells that enable tumor growth and metastasis. These properties were referred to as the traditional hallmarks of cancer. Recent discoveries further elucidated hallmarks including evasion of immune destruction by tumor cells that disrupt anticancer response pathways. This review discusses cancer immunology and new treatment strategies aimed at restoration of antitumor immune responses.
... patients with advanced HL. In the HL cohort of the KEYNOTE-013 study, 31 patients with RR-HL, who had progressed after BV and 67 % of whom had also failed ASCT, received pembrolizumab (10 mg/kg every 2 weeks) [58, 59]. The ORR was 65 % with a CR rate of 16 %. ...
Treatment strategies that target the immune system provide the opportunity for antitumor activity across multiple cancer types, regardless of mutational status or tumor histology. While many of the initial advances in immunotherapy have been in melanoma, the focus has now broadened to include many other solid as well as hematological cancers. Different immunotherapeutic approaches are being evaluated across tumor types and their various novel mechanisms of action and safety profiles offer the potential for a variety of combination regimens. Ongoing and planned investigation of these immunotherapies, alone and in combination, represents the start of a new chapter in our treatment of cancer and offers the hope of better outcomes for patients with a wide range of cancers. Recent advances in the use of immune-based approaches to treat non-small-cell lung cancer, breast cancer, ovarian cancer, gastrointestinal cancer, hepatocellular carcinoma, head and neck cancer and lymphoma were discussed at the 2015 Spring and Winter meetings of the Campania Society of Oncology Immunotherapy (SCITO) and are reported here.
... In a phase 2 study, 60 31 patients with relapsed or refractory classical Hodgkin lymphoma not responding to or relapsing from previous brentuximab vedotin therapy, and who had relapsed after or were ineligible for autologous hematopoietic stem cell transplantation (ASCT), received pembrolizumab at 10 mg/kg every 2 weeks. Response was first assessed after 12 weeks (6 courses) of treatment, and then every 8 weeks thereafter. ...
The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50% could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.
... Cancer immunotherapies that target the PD-L1:PD-1 axis of immune regulation have demonstrated remarkable efficacy in a wide range of cancers. In addition to clinical activity in historically immunogenic cancers such as melanoma [13][14][15][16][17][18][19]and renal cell carcinoma [20][21][22][23], anti-PD-L1 and anti-PD-1 agents can produce anticancer responses in a growing list of malignancies, including nonsmall cell lung cancer (NSCLC) [9,[24][25][26][27][28][29], urothelial carcinoma [30][31][32] , triplenegative breast cancer [33, 34], lymphoma [35][36][37], and head and neck cancer [38, 39]. Although these results highlight a key role for PD-L1:PD-1 in suppressing anticancer immunity in multiple cancers, only a subset of patients with each cancer type respond to treatment and not all responders continue to respond indefinitely. ...
The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)-targeted therapy has demonstrated the importance
of the PD-L1:PD-1 interaction in inhibiting anticancer T-cell immunity in multiple human cancers, generating durable responses
and extended overall survival. However, not all patients treated with PD-L1/PD-1 targeted therapy experience tumor shrinkage,
durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why
some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all
cancer cells. Understanding immune escape from PD-L1/PD-1 targeted therapy will be important to the development of rational
immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely
relate to immune escape include lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific
T cells, poor infiltration of T cells into tumors, downregulation of major histocompatibility complex on cancer cells, and
immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms
of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and
combination immunotherapy is chosen based on the presence of specific immune biology. This approach may enable treatment with
immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.
... Patients were treated with 10 mg/kg of pembrolizumab every 2 weeks. An updated report on the first 31 patients was presented at the most recent ASH annual meeting 27 . At a median follow-up of 9.7 months, an objective response was observed in 20 (65%) patients including five (16%) achieving CR. ...
Hodgkin lymphoma (HL) is a rare cancer of the immune system that typically affects lymph nodes and sometimes other organs. Although the majority of patients can be potentially cured with the use of multi-agent chemotherapy and radiotherapy, a proportion of them will relapse or develop resistant disease for which treatment options are limited. In recent years, new agents have been developed and tested in HL with encouraging results. Two classes of drugs stand out as highly active in advanced HL based on recent study results: antibody-drug conjugates and programmed death 1 inhibitors. Clinical trials in HL with these agents have been completed in the past several years and the results have recently become available. In this review, we discuss the recent advances in the management of HL with a focus on strategies to decrease toxicity and a review of the two drug classes that have the potential to change the landscape of treatment of this disease.
Hodgkin lymphoma (HL), which in the past was called Hodgkin disease, has always been one of the front runners of research in lymphomas. It usually arises from germinal centre or post-germinal centre B cells. Composition of HL is commonly defined as having predominantly inflammatory cells having minor population of neoplastic cells which were named as Reed–Sternberg cells.
Purpose of the Review
The ligation of PD-1 with PD-L1 activates a critical immune checkpoint leading to T cell dysfunction, exhaustion, and tolerance. Anti-PD-1 or anti-PD-L1 monoclonal antibodies can reverse the immune checkpoint, releasing the brake on T cell responses. We provide a comprehensive review of the literature on the activity of checkpoint inhibitors in lymphoma.
Recent Findings
We discuss the latest findings with checkpoint inhibitors in lymphoma and new promising studies incorporating these agents.
Summary
Classical Hodgkin lymphoma is very sensitive to PD1/PL1 blockade due to genetic alterations in 9p21.1 leading to the high expression of PDL1. Although majority of NHLs have a much lower sensitivity to PD1/PDL1 blockade, a few subtypes such as primary CNS lymphoma, primary testicular lymphoma, primary mediastinal lymphoma harbor 9p21.1 alterations making them vulnerable to PD1 blockade. EBV-associated lymphomas have a virally mediated increased expression of PDL1 making them sensitive to PD1 blockade.
RESULTS:
Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months).
CONCLUSIONS AND RELEVANCE:
The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.
Importance
Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.
Objectives
To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors.
Design, Setting, and Participants
This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors.
Interventions
Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade.
Main Outcomes and Measures
The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS).
Results
Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months).
Conclusions and Relevance
The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.
CD30 and programmed cell death protein 1 (PD-1) are two ideal therapeutic targets in classical Hodgkin lymphoma (cHL). The CD30 antibody-drug conjugate (ADC) brentuximab vedotin and the PD-1 antibodies nivolumab and pembrolizumab are highly efficacious in treating relapsed and/or refractory cHL. Ongoing studies are evaluating their efficacy in earlier lines of therapy and have demonstrated encouraging results. These agents are expected to further change the landscape of cHL management. Increased cure rates and reduced long-term toxicity from traditional chemotherapy and radiotherapy are likely with the emergence of these novel targeted therapies.
Metastatic basal cell cancer (BCC) is an ultra-rare malignancy with no approved therapies beyond Hedgehog inhibitors. We characterized the genomics, tumor mutational burden (TMB), and anti-PD-1 therapy responses in patients with locally advanced or metastatic BCC. Overall, 2,039 diverse cancer samples that had undergone comprehensive genomic profiling (CGP) were reviewed. Eight patients with locally advanced/metastatic BCC were identified (two had two CGP analyses; total, 10 biopsies). Two tumors demonstrated PD-L1 amplification. Seven patients had >1 actionable alteration. The TMB (mutations/mb) (median (range)) was 90 (3-103) for the BCCs versus 4 (1-860) for 1637 cancers other than BCC (P < 0.0001). Median progression-free survival (PFS) for all four patients treated with PD-1 blockade was 10.7 months (range, 3.8 to 17.6+ months); three patients had an objective response. In conclusion, advanced/metastatic BCC often has biological features (high TMB; PD-L1 amplification) predictive of immunotherapy benefit, and patients frequently respond to PD-1 blockade.
Introduction: Hodgkin lymphoma (HL) is a B-cell-derived malignancy mostly affecting young adults. More than 80% of patients are cured after stage-adapted first-line treatment with chemotherapy and/or radiotherapy. About 50% of patients with disease recurrence achieve long-term remission with second-line treatment consisting of high-dose chemotherapy and autologous stem cell transplantation. However, HL treatment is often associated with acute toxicity and in part life-threatening late effects. Implementing targeted drugs may reduce toxicity and potentially further optimize efficacy. In recent years, CD30-directed antibody-drug conjugate brentuximab vedotin (BV) and anti-PD-1 antibodies, nivolumab and pembrolizumab, underwent especially extensive evaluation in HL. They have exhibited encouraging single agent activity and a favorable toxicity profile in patients with multiple relapses. Therefore, they are currently under investigation in different additional indications.
Areas covered: This article gives an overview over clinical trials evaluating targeted drugs either as single agent or as part of combination therapies in HL patients.
Expert commentary: A multitude of targeted drugs are investigated in HL. Promising data has particularly emerged from studies with BV and anti-PD-1 antibodies. However, mature data needed for final conclusions to be drawn is still pending.
Die medikamentöse Onkologie steht am Beginn eines bedeutenden Umbruchs mit einer Vielzahl von neuen Wirkstoffen und veränderten Behandlungsalgorithmen. Die Behandlung metastasierter Tumoren stellt weiterhin eine große Herausforderung dar, jedoch zeigt der kontinuierliche Erkenntnisgewinn in der Molekularpathologie und Immunbiologie therapeutische Ansatzpunkte auf, deren Umsetzung beim Patienten angekommen ist. Abseits der konventionellen Chemotherapie führten diese einerseits zur Entwicklung von molekular zielgerichteten Hemmstoffen des Tumorwachstums und andererseits zum Prinzip der sog. Checkpointinhibitoren, welche körpereigene, immunologische Tumorabwehrreaktionen nutzen.
Background:
The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study.
Patients and methods:
We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg twice daily; an increase to 300 mg twice daily was permitted at the time of disease progression.
Results:
The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with 1 complete remission and 4 partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event (AE) was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in 3 patients and was grade 1-2. There was 1 AE leading to death (hypoxia).
Conclusions:
Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response.
Immunotherapy has led to promising results in the treatment of malignancies in recent decades. In view of the suboptimal results obtained by applying other treatment modalities in the treatment of Hodgkin lymphoma (HL), attention has been drawn to immunotherapy as an efficient alternative or complement therapy. This chapter seeks to discuss a wide spectrum of immunotherapeutic approaches, from initial monoclonal antibodies to novel techniques developed in recent years, which are still at their infancy. Since correct understanding of the underlying immunopathology seems inevitable in efficient immunotherapy and development of future techniques, a brief description with the emphasis on suitable targets for immunotherapy is given before discussing various immunotherapies.
ANTI-PD-1 ANTIBODIES THERAPEUTIC USE IN LYMPHOID NEOPLASMS: Immune checkpoints blockade is under investigation in oncology, and has demonstrated its clinical efficacy. In hematology, immune checkpoints blockade is in earlier stages of development, but there are strong evidences of PD-1 blockade anti-tumor efficacy in some lymphoid malignancies. In this review, we will discuss the main clinical results of PD-1 inhibitors in lymphoid neoplasms and the main perspectives of development.
© 2016 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.
Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1-PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1-PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed-Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). This Review is focused on the role of PD-1-PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.
Hodgkin lymphoma (HL) is a highly curable hematologic malignancy, and ~70% of cases can be cured with combination chemotherapy with or without radiation. However, patients with primary resistant disease have a cure rate of <30%. For such patients, high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered to be the standard treatment. If patients fail to respond to ASCT or relapse soon thereafter, they usually receive another ASCT, allogeneic stem cell transplantation or treatment with novel agents. This case report presents the case of a 54-year-old patient with primary resistant HL who received single-agent treatment, brentuximab vedotin, after ASCT relapse. Despite treatment with brentuximab vedotin, the disease continued to progress. In patients with such highly resistant disease, the treatment options are limited. Depending on the physical condition and the willingness of the patient, pembrolizumab, a programmed cell death protein-1 inhibitor, can be given as salvage therapy. But, out of our expectation, the patient achieved a very good partial response after four cycles of pembrolizumab. No serious adverse events were observed with pembrolizumab treatment. This case provides support for a new and effective strategy for treating primary resistant Hodgkin lymphoma.
Purpose of review:
After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an overview on recently published clinical trials in this setting. Furthermore, the potential influence of current trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into treatment protocols will be discussed.
Recent findings:
Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-scans have been disappointing so far, but results of some large trials employing this strategy are still awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally, biomarker-based treatment de-escalation might be a possible route for future improvements.
Summary:
The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the majority of patients with first-line treatment while reducing long-term toxicity. New strategies to achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin lymphoma.
Classical Hodgkin lymphoma is curable in the majority of cases with chemotherapy and/or radiation. However, 15-20% of patients ultimately relapse and succumb to their disease. Pathologically, classical Hodgkin lymphoma is characterized by rare tumor-initiating Reed-Sternberg cells surrounded by a dense immune microenvironment. However, the role of the immune microenvironment, particularly T and B cells, in either promoting or restricting Classical Hodgkin lymphoma growth remains undefined. Recent dramatic clinical responses seen using monoclonal antibodies against PD-1, a cell surface receptor whose primary function is to restrict T cell activation, have reignited questions regarding the function of the adaptive immune system in classical Hodgkin lymphoma. This review summarizes what is known regarding T cells, B cells, and immune checkpoints in classical Hodgkin lymphoma.
Checkpoint inhibitors have demonstrated remarkable efficacy in patients with chemotherapy resistant Hodgkin lymphoma. However, it remains unclear if these impressive agents have curative potential, or if relapse and death will eventually occur. In this review, we discuss the options for a therapeutic dilemma which is likely to occur with increasing frequency, what to do for a Hodgkin lymphoma patient who is responding the checkpoint inhibitors? We discuss the four most likely considered options: continuation of checkpoint blockade, cessation of therapy with potential re-treatment, transplantation, and chimeric antigen receptor T-cell therapy. These options will require evaluation in future clinical trials, however we propose a decision strategy which could be of use to practicing clinicians until robust data is available.
Hodgkin lymphoma (HL) has become a highly curable malignancy even in advanced stages when treated adequately. However, relapsed or refractory disease and treatment-related toxicity constitute a significant clinical challenge. Innovative approaches are thus needed to improve treatment of these mainly young patients. In HL lesions, very few malignant Hodgkin and Reed-Sternberg (HRS) cells are embedded in an immunosuppressive microenvironment of reactive cells. Novel approaches such as bispecific antibodies, antibody-drug conjugates, immune-checkpoint inhibitors or adoptive cellular therapies are currently being investigated with promising results in relapsed or refractory patients. Encouraging response rates and a favorable toxicity profile have recently been reported in early phase clinical trials with antibodies blocking the programed-death receptor 1 (PD1). This review will summarize the current clinical knowledge on mechanism, safety and efficacy of the different agents and discuss potential future strategies, which are partly already investigated within clinical trials.
Disease overview: Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,050 new patients annually and representing approximately 11.2% of all lymphomas in the United States. Diagnosis: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. Risk stratification: An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography (PET) scan, are used to optimize therapy. Risk-Adapted Therapy: Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, nonmyeloablative allogeneic transplant or participation in a clinical trial should be considered. Am. J. Hematol. 91:435-442, 2016.
Hodgkin lymphoma's (HL) tumor composition is characterized by a paucity of malignant cells and a preponderance of immune and stromal cells. Despite the rich immune milieu within the tumor microenvironment, malignant cells are able to effectively evade the immune system and use immune support to promote lymphoma cell growth and proliferation. Recognizing this has led to the identification of checkpoint inhibitory signals that enable immune evasion and to opening the door to therapeutic strategies on how to exploit the immune system in targeting tumor cells. We discuss herein some of the tumor evasion mechanisms in HL with a particular focus on the immune checkpoint pathways and focus on recent clinical data of checkpoint blockade in HL treatment.
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