University of Bologna, Italy
University of Modena and Reggio Emelia, Italy
ASST Grande Ospedale Metropolitano Niguarda, Italy
Waldenstrom’s Macroglobulinemia (MW) is an indolent lymphoproliferative disorder characterized by the histologic evidence of bone marrow involvement by lymphoplasmacytic lymphoma and the presence of an IgM monoclonal component. Importantly the mutation of the myeloid differentiation primary-response gene 88 (MYD88), in about 90% of patients, and the CXCR4 mutation that can be found in about 30-45% of cases, may play a role on the therapeutic decision. Patients carrying CXCR4 mutation have longer time to responses, less deep responses and shorter progression free survival when treated with ibrutinib. The asymptomatic patient only needs regular follow-up. Treatment depends on patients characteristics, type of symptoms, presence or not of bulky disease and above all on the speed with which control of the disease is required. Patients presenting with hyperviscosity syndrome should undergo immediate plasmapheresis and initiate systemic therapy immediately. Immuno-chemotherapy, bendamustine based (BendaR), cyclophospamide based (DRC) or bortezomib in combination with rituximab are the recommended fixed duration treatments in first line. Ibrutinib exerts favourable results in first line and should be considered in patients unfit for immuno-chemotherapy and in those without CXCR4 mutation. The administration of a continuous treatment should be carefully weighed. In unfit very elderly patients monotherapy with chlorambucil, fludarabine and rituximab monotherapy may still have a role. In relapsed disease, if the response to first line has been prolonged, it may be considered to repeat the same therapy. The best results in the salvage setting are certainly obtained with the BTKis. In a phase 2 study a 54% 5-year disease-free survival has been obtained with ibrutinib in heavily pretreated. The randomized Innovate trial, which compared rituximab plus placebo versus rituximab plus ibrutinib confirmed the efficacy in patients treated with a BTK inhibitor, importantly the addition of rituximab resulted in a better outcome independent from CXCR4 mutation. Second generation BTKis, acalabruitnib and zanubrutinib, have shown non inferior efficacy with a more favourable toxic prophile. Several agents are under development in WM, second generation proteasome inhibitors, carfilzomib and ixazomib, are effective leading to good quality of responses with better toxic profile when compared to bortezomib. Trials are ongoing to evaluate chemo-free treatments with fixed duration regimens.
University of Verona, Italy
University of Toronto, Canada
IRCCS San Raffaele Scientific Institute, Italy
University Hospital of Salamanca, Spain
University of Texas MD Anderson Cancer Center, USA
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Italy
University of Pisa, Italy
Minimal Residual Disease (MRD) is today a hot topic also in lymphomas (NHL). Indeed, the availability of new drugs and more sensitive techniques allows now to achieve a good clearance of MRD. In 2018, FDA stated that MRD had to be included in the results necessary for approving new drugs, but, differently from other hematological malignancies, MRD did not still entered into the clinical practice in the context of NHLs. Nevertheless, many pivotal trials put MRD among their research goals. In follicular lymphoma, several studies, including FOLL05, PRIMA, GALLIUM, ZEUS etc…, clearly demonstrated that MRD condition PFS, across different treatment schedules. In mantle cell lymphoma, it has been reported a significant impact of MRD, especially in the high-dose therapy where some gene polymorphisms are able to condition the results from lenalidomide maintenance. In Waldenstrom’s Macroglobulinemia, MYD88 is a good marker of MRD, especially when assessed on plasma circulating cell-free DNA. In DLBCL, MRD has been shown to be predictive of response and survival, especially when applied to the “liquid biopsy” (cf-DNA, extracellular vesicles).
In the last years, also the improvement of molecular techniques helped to put attention to MRD: indeed, in addition to quantitative PCR (ASO-PCR), clonality of IGH, TCR and light chains can be assessed by NGS, that represents an “unsupervised” technique, able to identify also clones absent at diagnosis but that might sustain relapse. NGS has got a sensitivity of 1-3% and is useful also for identifying the mutational background of NHLs. Digital PCR is another new technique that is a quantitative PCR that does not need a reference external curve, with a high sensitivity (1×10-5) and accuracy. This method is able to quantitate about 25% of samples defined “positive but not quantifiable” by the “classic” real-time PCR.
The integration of all these techniques probably will significantly increase the role of MRD detection in NHLs.
Clinica Universidad de Navarra (CUN), Spain
The landscape of multiple myeloma (MM) has changed considerably in the past two decades regarding new treatments, insight into disease biology and innovation in the techniques available to assess measurable residual disease (MRD) as the most accurate method to evaluate treatment efficacy. The sensitivity and standardization achieved by these techniques together with unprecedented rates of complete remission (CR) induced by new regimens, raised enormous interest in MRD as a surrogate biomarker of patients’ outcome and endpoint in clinical trials. By contrast, there is reluctance and general lack of consensus on how to use MRD outside clinical trials. I will discuss critical aspects related with the implementation of MRD in clinical practice.
Hematology and Stem Cell Transplant Center, AORMN Hospital, Italy
Natural killer (NK) cells are lymphocytes belonging to the innate immune system. Their cytotoxic activity is tightly regulated by the balanced expression of a wide and complicated pattern of activating and inhibitory receptors, among which inhibitory receptors called killer-immunoglobulin like receptors (KIRs) have been extensively characterized. In cancer immunology, especially in leukemias, NK cells have been shown to mediate antitumor immune-surveillance both in solid tumours and haematological malignancies. Indeed, NK cells are potent effectors which can target and kill leukemia cells without prior exposure to those cells. Particularly, NK cells have a major role in the eradication of residual acute myeloid leukemia (AML) cells after haploidentical stem cell transplantation (SCT), boosting graft-versus-leukemia (GVL) effects without exacerbating graft-versus-host disease (GVHD). Several groups have sought to translate this notion to the non-transplantation setting by using infusion of NK cells as a means of adoptive immunotherapy for patients with cancers. Based on their crucial role, several strategies of NK cell-based immunotherapy, i.e. freshly isolated, in vitro expanded and/or activated, gene-modified by using the CAR-based approach, have been investigated at the preclinical level with important and promising early clinical results. Our group reported the feasibility and early clinical efficacy of selecting and infusing highly purified, T cell-depleted, KIR-mismatched NK cells to consolidate remission in high-risk patients with AML. The percentage of donor-derived alloreactive NK cell clones before infusion was significantly correlated with relapse occurrence, indicating that a functional dose of 2 x105/kg alloreactive NK cells may be predictive of response. Based on these data, a multicentre clinical trial of adoptive immunotherapy with haplodentical KIR-L mismatched alloreactive NK cells to consolidate remission in AML patients not eligible for allogeneic SCT is currently on-going (NCT03955848).
My talk will summarize the most relevant evidence supporting the translational use of of NK cells as a mean of adoptive immunotherapy against hematological malignancies with a special focus on AML.
University Hospital Leipzig, Germany
MD Anderson Cancer Center Madrid, Spain
MD Anderson Cancer Center, USA
Princess Margaret Cancer Centre, University of Toronto, Canada
University of Insubria of Varese, Italy
UT Health San Antonio MD Anderson Cancer Center, USA
New York Blood Center, USA
Increasing evidence from pre-clinical studies in mouse models suggests that free heme and iron exert vasculo-toxic and proinflammatory effects due to their ability to trigger endothelial and immune cell activation and thus cause vasculopathy and sterile inflammation. These mechanisms are of major relevance for vascular and inflammatory abnormalities that develop in patients with ß-thalassemia major and intermedia, sickle cell disease and spherocytosis.
Hemolysis, transfusions and ineffective erythropoiesis with high erythropoietin and inappropriately low hepcidin account for heme and iron overload, whereby ß-thalassemia major and spherocytosis patients show the most and less severe iron burden, respectively. Increased systemic heme and iron levels are associated with a severe drop in haptoglobin, hemopexin and transferrin, the plasma scavengers for hemoglobin, heme and iron, respectively, leading to the appearance of toxic ‘free’ species. Hemolytic patients show endothelial activation and dysfunction, indicated by increased soluble adhesion molecule and reduced nitric oxide levels. Oxidative stress is highly elevated in these patients as suggested by increased lipid peroxidation and oxidized low-density lipoproteins and proteins, as well as enhanced levels of pro-inflammatory mediators. All markers correlate with increased heme/iron indices as well as scavenger saturation.
Observations made along the last two decades support the involvement of serum hemoglobin, heme and iron in the pathogenesis of vascular dysfunction and chronic inflammation in hemolytic diseases and suggest a vasculo-toxic, pro-atherosclerotic and inflammatory action for these molecules. Overall these findings highlight the key protective role of heme/iron scavengers and the potential therapeutic benefit of iron chelation and scavenger replacement treatment to counteract Hb-/heme-/iron-driven vasculo-toxicity and inflammation in hemolytic and iron-overload conditions.
University of Verona, Italy
Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD.
New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) agents which reduce sickling or prevent sickle red cell dehydration; b) agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) anti-oxidant molecules.
Design of long-term clinical studies is required to fully understand the clinical impact of these new therapeutic agents on natural history of SCD. Furthermore, building-up global collaboration on SCD will represent an added value to progress on clinical management of SCD and to design the primary outcomes of future clinical trials.
Children’s Hospital of Philadelphia and University of Pennsylvania, USA