PD-1/PD-L1 inhibitors in haematological malignancies: update 2017.

The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD-1/PD-L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B-cell lymphoma, follicular lymphoma or several T-cell lymphomas. Monotherapy with PD-1/PD-L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti-PD-1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5-azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD-1/PD-L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.

Waldenström's macroglobulinemia: Two malignant clones in a monoclonal disease? Molecular background and clinical reflection.

Waldenström's macroglobulinemia (WM) is a complex disease characterized by apparent morphological heterogeneity within the malignant clonal cells representing a continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. At the molecular level, the neoplastic B cell-derived clone has undergone somatic hypermutation, but not isotype switching, and retains the capability of plasmacytic differentiation. Although by classical definition, WM is formed by monoclonal expansion, long-lived clonal B lymphocytes are of heterogeneous origin. Even more, according to current opinion, plasma cells also conform certain population with pathogenic and clinical significance. In this article, we review the recent advances in the WM clonal architecture, briefly describe B-cell development during which the molecular changes lead to the malignant transformation and mainly focus on differences between two principal B-lineage clones, including analysis of their genome and transcriptome profiles, as well as immunophenotype features. We assume that the correct identification of a number of specific immunophenotypic molecular and expression alterations leading to proper aberrant clone detection can help to guide patient monitoring throughout treatment and successfully implement therapy strategies directed against both B- and plasma cell tumor WM clones.

Diagnostics in Waldenström's macroglobulinemia: a consensus statement of the European Consortium for Waldenström's Macroglobulinemia.

The diagnosis of Waldenström's macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, can be challenging due to the different forms of disease presentation. Furthermore, in recent years, WM has witnessed remarkable progress on the diagnostic front, as well as a deeper understanding of the disease biology, which has affected clinical practice. This, together with the increasing variety of tools and techniques available, makes it necessary to have a practical guidance for clinicians to perform the initial evaluation of patients with WM. In this paper, we present the consensus recommendations and laboratory requirements for the diagnosis of WM developed by the European Consortium of Waldenström's Macroglobulinemia (ECWM), for both clinical practice as well as the research/academical setting. We provide the procedures for multiparametric flow cytometry, fluorescence in situ hybridization and molecular tests, and with this offer guidance for a standardized diagnostic work-up and methodological workflow of patients with IgM monoclonal gammopathy of uncertain significance, asymptomatic and symptomatic WM.

Identifying and treating candidates for checkpoint inhibitor therapies in multiple myeloma and lymphoma.

Introduction: One of the hallmarks of cancerogenesis is the ability of tumor cells to evade the immune system. They can achieve it by abusing inhibitory immune checkpoint pathways, which, under normal circumstances, maintain peripheral tolerance during infection. Immune checkpoint inhibitors, especially anti-PD-1/PD-L1 monoclonal antibodies, currently represent a widely discussed treatment option not only in solid oncology, but in hematology-oncology as well.Areas covered: The manuscript is focused on clinical research concerning PD-1/PD-L1 blockade in lymphoma and multiple myeloma in order to identify the patients who would profit the most from this treatment modality. The authors reviewed articles on the topic on PubMed and relevant clinical trials on clinicaltrials.gov before October 2019.Expert opinion: So far, nivolumab and pembrolizumab have been approved for treating patients with relapsed/refractory classical Hodgkin lymphoma and primary mediastinal B cell lymphoma. Nevertheless, monotherapy alone is not curative and a combinational approach is needed. Modern treatment strategies and combinations are comprehensively summarized in this manuscript. There is no approved immune checkpoint inhibitor for the multiple myeloma indication. Although the combination of PD-1/PD-L1 inhibitors with immunomodulatory agents initially seemed promising, unexpected immune related toxicities have stopped any further development. Novel strategies and more potent combinations in myeloma and lymphoma are further discussed in the manuscript.

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma.

For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

Cytarabine + G-CSF is more effective than cyclophosphamide + G-CSF as a stem cell mobilization regimen in multiple myeloma.

Cyclophosphamide (Cy) plus granulocyte-colony stimulating factor (G-CSF) is currently a standard regimen for hematopoietic stem cell (HSC) mobilization in patients with multiple myeloma (MM). However, cytarabine (AraC) in intermediate doses plus G-CSF seems to have a higher mobilization efficacy. The aim of this study was to retrospectively compare mobilization using AraC and Cy. Thirty consecutive MM patients were mobilized by Cy + G-CSF, and the subsequent 40 patients by AraC + G-CSF. Both groups were comparable. The target yield of 10 × 106 CD34+ cells/kg (for tandem and 2 additional transplantations) was achieved in 98% (AraC) and 57% (Cy) of patients (p < 0.0001) by 1.2 and 2.1 apheresis (means), and by single apheresis in 83 and 17% of patients, respectively. AraC mobilization resulted in higher peak concentration of CD34+ cells in blood (median 238.0 vs. 87.9/µL, p < 0.0001) and higher CD34+ yield (median 28.6 × 106 vs. 10.4 × 106/kg, p < 0.0001) compared to Cy mobilization. Toxicities were comparable except for thrombocytopenia gr. 4, observed in 50% of patients after AraC (Cy 7%). In view of these results, we conclude that mobilization with AraC plus G-CSF is very effective with acceptable toxicity and could be considered in MM patients with planned or expected higher numbers of transplantations.