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ABSTRACTIntroductionPeripheral T cell lymphomas (PTCL) are a group of heterogenous hematologic malignancies derived from post-thymic T lymphocytes and mature NK cells. Conventional chemotherapy does not guarantee a good outcome.Areas coveredThe article summarizes recent investigational therapies and their mechanism of action, as well as the pharmacological properties, clinical activity, and toxicity of new agents in the treatment of primary nodal PTCLs. The review scrutinized papers included in the MEDLINE (PubMed) database between 2010 and October 2020. These were supplemented with a manual search of conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology. Further relevant publications were obtained by reviewing the references from the chosen articles.Expert opinionPTCLs have proved difficult to treat and investigate because of their rarity. Studies of aggressive lymphoma, including a small proportion of T-cell lymphomas, found that any benefit from intensified traditional chemotherapy in patients with PTCL is accompanied by increased toxicity. However, the management of PTCL is beginning to change dramatically, thanks to the use of more sophisticated agents targeting the mechanisms of disease development.

Der Einsatz neuartiger, zielgerichteter Wirkstoffe ist dabei, die Behandlungsparadigmen der chronischen lymphatischen Leukämie (CLL) von Grund auf zu verändern. Verschiedene Wirkstoffe für das Management der rezidivierenden/refraktären (R/R)-CLL haben große Verbesserungen bei den Überlebensraten der R/R-CLL-Patienten bewirkt, insbesondere Inhibitoren der Bruton-Tyrosinkinase (Ibrutinib und Acalabrutinib), der Phosphatidylinositol-3-Kinase (Idelalisib und Duvelisib) und von B-Zell-Lymphoma-2 (Venetoclax) sowie neuartige monoklonale Antikörper gegen CD20. Patienten mit rezidivierender, aber asymptomatischer CLL bedürfen jedoch keiner sofortigen alternativen Behandlung, sondern sollten bis zu manifesten Anzeichen einer Progression beobachtet werden. Von den bereits zugelassenen Therapien wird Venetoclax plus Rituximab für 24 Monate oder Ibrutinib als Dauertherapie empfohlen. Eine weitere, weniger empfohlene, Option ist Idelalisib in Kombination mit Rituximab. Die Wahl der passenden Behandlungsoption richtet sich danach, welche Therapie vorher angewendet wurde, wie der Patient darauf ansprach und welche Nebenwirkungen aufgetreten sind, welche Komorbiditäten vorliegen und welches Toxizitätsrisiko besteht. Allogene hämatopoetische Stammzelltransplantationen und experimentelle Therapien wie z. B. chimäre Antigenrezeptor-T-Zell-Therapien stellen vielversprechende Optionen für Hochrisikopatienten dar, einschließlich derer mit Krankheitsprogression nach einer oder mehreren zielgerichteten Therapien. In der vorliegenden Übersichtsarbeit werden die aktuellen Behandlungsstrategien für Patienten mit R/R CLL besprochen.

Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.

ABSTRACTIntroductionThe outcome of patients with lymphoid malignancies has markedly improved in recent years due to the implementation of new therapeutic options. Chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas (NHL) are characterized by the activation of the phosphatidylinositol 3-kinase (PI3 K) pathway viaB-cell receptor signaling. The PI3 K delta (PI3 Kδ) p110δ isoform inhibitor, idelalisib, showed high anti-tumor activity in this group of tumors. It was the first agent from a new class of isoform-specific inhibitors to receive regulatory approvals for the treatment of refractory/relapsed CLL, as well as small lymphocytic lymphoma and follicular lymphoma.Areas coveredIn this paper, the authors provide a comprehensive overview of the activity and safety profile of idelalisib and other, newly developed PI3 K inhibitors in patients with indolent B-cell malignancies.Expert opinionIdelalisib is a very potent anti-lymphoma agent in CLL and other NHL. However, there are some limitations of its broad clinical use according to some important side effects observed during treatment. Consequently, the development of new PI3 K inhibitors, which will be highly active and possess better safety profiles are warranted.

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2−patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.govas #NCT01712490 (EudraCT no. 2011-005450-60).

ABSTRACTIntroduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.

Acute myeloid leukemia (AML) is a heterogeneous, highly malignant neoplasm. Apoptosis is a complex process executed by caspases and suppressed by the inhibitor of apoptosis (IAP) family. Neuronal apoptosis inhibitory protein (NAIP), IAP’s member, may play an exceptional role in the mechanisms of tumors’ resistance to chemotherapy. The aims of the study were to assess the expression of NAIP in leukemic blasts of AML patients using flow cytometry and to evaluate its influence on disease outcome. NAIP expression was found in 106 out of 108 patients. A higher complete response rate was associated with a low expression of NAIP, age < 60 yo, and white blood cell count < 20 G/L (p= 0.009, p= 0.033, and p= 0.076, respectively) in univariate analyses and a low NAIP expression and age < 60 yo (p= 0.025 and p= 0.013, respectively) in multivariate analyses. Longer overall survival (OS) in the univariate analysis was influenced by a low NAIP expression, age < 60 yo, and intensive chemotherapy (p= 0.033, p< 0.001, and p< 0.001, respectively). In the intensively treated group, better OS was observed in patients with age < 60 yo, de novoAML, and a low NAIP expression (p= 0.03, p= 0.024, and p= 0.07, respectively). In multivariate analysis, longer OS was associated with age < 60 yo (p= 0.009) and de novoAML (p= 0.007). In conclusion, we suggest that NAIP might play an adverse role in response to chemotherapy.

ABSTRACTIntroduction: Ixazomib is a new, orally administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia (WM).Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone; (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly diagnosed MM following induction therapy and autologous stem cell transplantation; (iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis. Finally, we explore early phase clinical studies of this agent in Waldenström macroglobulinemia.Expert opinion: A key advantage of ixazomib is that it could allow an efficacious treatment approach to MM and other lymphoproliferative disorders through a convenient oral administration route. Ixazomib could soon be used in combination treatment regimens, but more work is necessary to define the place of this agent going forward.Trial registration:ClinicalTrials.gov identifier: NCT02420847.Trial registration:ClinicalTrials.gov identifier: NCT00932698.Trial registration:ClinicalTrials.gov identifier: NCT00963820.Trial registration:ClinicalTrials.gov identifier: NCT00963820.Trial registration:ClinicalTrials.gov identifier: NCT01383928.Trial registration:ClinicalTrials.gov identifier: NCT01939899.Trial registration:ClinicalTrials.gov identifier: NCT02898259.Trial registration:ClinicalTrials.gov identifier: NCT03323151.Trial registration:ClinicalTrials.gov identifier: NCT02632396.Trial registration:ClinicalTrials.gov identifier: NCT03547700.Trial registration:ClinicalTrials.gov identifier: NCT00893464.Trial registration:ClinicalTrials.gov identifier: NCT02158975.Trial registration:ClinicalTrials.gov identifier: NCT02481310.Trial registration:ClinicalTrials.gov identifier: NCT02339922.Trial registration:ClinicalTrials.gov identifier: NCT01318902.Trial registration:ClinicalTrials.gov identifier: NCT01659658.Trial registration:ClinicalTrials.gov identifier: NCT02400437.

Introduction

ABSTRACTIntroduction: While chemotherapy still remains a cornerstone of oncologic therapy, immunotherapy with monoclonal antibodies has steadily improved the treatment strategy for several hematologic malignancies. New treatment options need to be developed for relapsed and refractory non-Hodgkin lymphoma (NHL) patients. Currently, novel agents targeting specific molecules on the surface of lymphoma cells, such as anti-CD37 antibodies, are under considerable investigation. Here we report on anti-CD37 targeting for the treatment of patients with B-cell NHL.Areas covered: CD37 seems to be the perfect therapeutic target in patients with NHL. The CD37 antigen is abundantly expressed in B-cells, but is absent on normal stem cells and plasma cells. It is hoped that anti-CD37 monoclonal antibodies will increase the efficacy and reduce toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics.Expert opinion: The development of new therapeutic options might help to avoid cytotoxic chemotherapy entirely in some clinical settings. This article presents the latest state of the art on the new treatment strategies in NHL patients. It also discusses recently approved agents and available clinical trial data.

ABSTRACTIntroduction: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34–35% and 25–38%, with complete response (CR) rates of 6% and 15–18%, respectively.Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma.Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It’s also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.

ABSTRACTIntroduction: Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects.Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.

Background: Chronic lymphocytic leukaemia (CLL) cells are characterized by failures in the apoptosis pathway and increased proliferation, resulting in the progressive accumulation of B-lymphocytes in blood. Despite the wide range of antileukaemic drugs, CLL remains an incurable disease. However, a breakthrough is expected which will allow more effective treatment. Objective: The study investigates the influence of poly(propyleneimine) (PPI) dendrimer with peripheral amino groups, 30% of which were coated with maltotriose (PPI-G4-OS-Mal-III), on CLL cells, and demonstrates that it acts through the induction of the apoptotic mechanism. It is important to note that the dendrimer was used as a drug itself and not as a drug carrier. Method: CLL and normal lymphocytes were treated in vitro with the dendrimer, either alone or in combination with fludarabine (FA). The percentages of apoptotic and necrotic cells, and the protein expression, were checked using a flow cytometer. Gene expression was screened using a two-colour microarray with 60-mer probes. Results: The results confirm that PPI-G4-OS-Mal-III influences the viability of CLL cells in vitro and does not exert any significant harmful effect on normal lymphocytes. The dendrimer appears to significantly influence gene and protein expression in CLL cells. Conclusion: Since dendrimers can be specifically targeted, they may be very effective in CLL therapy, especially since in vitro PPI-G4-OS-Mal-III has been found to have stronger effect than fludarabine.

ABSTRACTIntroduction:A new generation of anticancer agents called target drugs has been recently developed for the treatment of non-Hodgkin lymphomas. Current recovery rates in these diseases are up to 70% with immunotherapy based on the anti-CD20 monoclonal antibody combined with standard chemotherapeutics. However, there are still refractory or relapsed patients. Recently, several novel anti-lymphoma agents have been developed. Choosing the most effective personalized therapy still remains a crucial challenge in hematology.Areas covered:New drugs can specifically target malignant cells and inhibit cancer cell growth, proliferation and survival by specific interactions with one or more target proteins. Recent clinical studies have illustrated promising outcomes for novel drugs used as single agents and in combination with traditional therapeutics. In this article, the authors discuss novel targeted therapies with a promising outcome in NHL patients that are becoming integrated into treatment paradigms.Expert opinion:The development of new treatment options may help to avoid cytotoxic chemotherapy entirely in some clinical settings. Multicenter studies should be continued to investigate small agents and pathways inhibitors as this will enable us to enhance not only the duration of the treatment response but also the quality of the extended survival.

The management of patients with chronic lymphocytic leukaemia (CLL) is currently undergoing improvements, particularly because of novel therapies. Purine analogs based immuno-chemotherapy, especially fludarabine combined with cyclophosphamide and rituximab (FCR), is still the current standard of care for first line therapy in younger, fit patients. However, its use in older, co-morbid patients is limited, particularly due to high toxicity. In fit patients older than 65 years or/and with previous infections bendamustine and rituximab (BR) should be considered instead of FCR. Recently, in patients with relevant comorbidities chlorambucil and anti CD20 monoclonal antibodies (rituximab, obinutuzumab or ofatumumab) are recommended as the first-line treatment. In addition, in 2014, two novel agents targeting the B cell receptor (BCR) signaling pathway, ibrutinib and idelalisib, were approved for patients with 17p deletion and/or p53 mutations and in the relapsed situation because of high efficacy and a favorable toxicity. Subsequently, ibrutinib has been approved to treat CLL patients regardless of their treatment history. Thus far it is recommended to treat patients with these agents until progression or unacceptable toxicity. The BCL-2 antagonist venetoclax is another oral drug with very promising preliminary data in patients refractory to immunochemotherapy as well as patients harboring del 17p. In 2014, the PTHiT and PALG-CLL group defined guidelines for the diagnosis, prognosis and treatment of CLL. In this article, we present updated recommendations for therapy of CLL.

For decades, the available anticancer therapies were mostly based on nonspecific cytotoxic regimens. These cytostatic combinations, while effective in some subpopulations of patients, are often limited by extensive toxicity and/or development of tumor resistance. Although standard chemotherapy still remains a common therapeutic tool in the fight with cancer, immunotherapy increasingly revolutionizes treatment strategy for several hematologic malignancies. For a subset of patients with B-cell lymphoproliferative disease, the introduction of subsequently developed classes of anti-CD20 monoclonal antibodies (mAbs) has resulted in improved overall response rates and, to some extent, patient overall survival. Rituximab, the most thoroughly-explored chimeric mouse anti-human anti-CD20 mAb, has been widely and successfully introduced to oncohematology, but also to other fields of medicine, such as transfusiology or rheumatology. Currently, several new generation anti-CD20 mAbs are undergoing different stages of preclinical and clinical studies of assessment to further improve the outcome and overcome mechanisms of resistance. The nature of the direct mechanisms responsible for the anticancer properties of different classes of anti-CD20 mAbs is still not fully understood. This is reflected in different approaches during the investigation of novel anti-CD20 agents. So far, three classes of anti- CD20 mAb have been described. In this review, we focus on CD20 antigen-targeting therapies both currently available and undergoing preclinical or clinical investigation for B-cell lymphoproliferative malignancies.

Despite of great progress in anti-neoplastic treatment the several solid tumors and hematologic malignancies still remain incurable. Immune system remains under control of several controlling mechanism. Genetic or epigenetic changes in neoplastic cells provide antigen-derived diversity; however, these cells do not initiate immune response. The main mechanism of development of immune resistance by tumor cells seems to be a change in expression of proteins engaged in the immune control point. Immunotherapy with immune checkpoint inhibitors has emerged as promising modality of tumors showing response to several antigens, e.g. anti-CTLA-4 or PD1-PDL1 monoclonal antibodies. In this review we demonstrate the state in the field on this modality of anti-neoplastic treatment.

Introduction:Over the last few years, several new immunological drugs, particularly monoclonal antibodies (mAbs), immunomodulatory drugs and B-cell receptor (BCR) pathway inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). This article summarizes recent discoveries regarding their mechanism of action, pharmacological properties, clinical activity and toxicity, as well as the emerging role of these agents in CLL.Areas covered:A literature review of mAbs, BCR pathway inhibitors and immunomodulating drugs was conducted of the MEDLINE database via PubMed for articles in English. Publications from 2000 through February 2015 were scrutinized. The search terms used were alemtuzumab, BI 836826, duvelisib ibrutinib, idelalisib, lenalidomide, monoclonal antibodies, MEDI-551, MOR208, obinutuzumab, ocaratuzumab, ofatumumab, ONO-4059, otlertuzumab, spebrutinib, veltuzumab and XmAb5574 in conjunction with CLL. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.Expert opinion:The use of mAbs, BCR inhibitors and immunomodulating drugs is a promising new strategy for chemotherapy-free treatment of CLL. However, definitive data from ongoing and future clinical trials will aid in better defining the status of immunological drugs in the treatment of this disease.

Introduction:Monoclonal antibodies (MoAbs) were developed in the 1980s in order to treat malignancies. An important target for MoAbs was the CD20 B-cell lineage antigen. Rituximab (RTX) is a chimeric mouse anti-human MoAb that targets the CD20 antigen on the surface of malignant and normal B lymphocytes, and has rapidly become the widest used immunotherapeutic drug. RTX has had a significant impact on how B-cell non-Hodgkin’s lymphomas (NHLs) and chronic lymphocytic leukemia is now treated.Areas covered:In this review, the authors demonstrate the mechanisms of action of RTX, and the preclinical data that have led to clinical trials and its final approval for the treatment of B-cell NHLs.Expert opinion:The discovery of RTX opened a new era for treatment of B-cell malignancies and became the starting point for the development of new, more active classes of anti-CD20 agents. Furthermore, it has contributed to the construction of a number of MoAbs specific for other antigens that target different types of neoplastic cells.

Introduction:As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months.

Dlugosz-Danecka: Roche: Consultancy; Servier: Consultancy. Jurczak:Nordic Nanovector: Research Funding; Epizyme: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Merck: Research Funding; Servier: Consultancy, Honoraria, Research Funding; European Medicines Agency: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Roche: Research Funding; Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; TG therapeutics: Research Funding. Zaucha:Roche: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria.