Hematologic malignancies, also called blood cancers are tumors that affect cells of the bone marrow, the lymphatic and the immune system. Basically, hematological malignancies originate from the proliferation and the survival of the two major blood cell lineages: myeloid and lymphoid cell lines.

The Division of Hematologic Oncology provides specialized care for subjects aged above 16 yrs., with all types of cancers of the blood, including:

1. I.          Leukemia (cancer of the blood cells)
   1. Acute myeloid leukemia (AML)
   2. Acute lymphoblastic leukemia (ALL)
   3. Chronic myelogenous leukemia (CML)
   4. Chronic lymphocytic leukemia (CLL)

1. II.        Lymphoma (cancer of the lymphatic cells)
   1. Hodgkin’s lymphoma
   2. Non-Hodgkin’s lymphoma

1. III.        Multiple Myeloma (cancer of plasma cells)

1. IV.        Myelodysplastic Syndrome (serious blood abnormalities that can lead to overt cancer)

1. V.        Other hematological disorders

The IEO-OM-2 has at present a 16-bed ward for in-patient hospitalization, with four rooms equipped for the management of patients undergoing hematopoietic stem cell transplant, with either autologous or allogeneic procedures. Indeed, most patients are managed in the outpatient service, the large common area in IEO-Building-2, where patients undergo diagnostic procedures, receive the appropriate treatments or continue the clinical monitoring both at early and late follow-up after therapy. Among various diagnostic procedures, patients with hematological malignancies may undergo some minimally  invasive procedures including, Lumbar Puncture, Bone Marrow aspirate and biopsy, abdominal fat aspiration. The outpatient service for the IEO-OM-2 is coordinated by Dr. Alberto De Crescenzo.

Patients with hematological malignancies require careful medical surveillance, particularly at disease onset and during the period of treatment delivery. In fact, they may experience complications of variable degree of severity as a consequence of both the underlying disease and the treatment received. In order to offer the highest support to our patients, we have recently set up the CARE (continuous assistance for IEO-OM-2 patients) program, including a 24-hr on-call assistance. All OM-2 patients have a direct phone number (number to dial: 02-4379960), where to call and talk to the on-call doctor, if unexpected signs or symptoms have occurred. In case of emergency, the patient can be seen in the two-bed emergency room within the OM-2 ward. The patient will have a full physical examination, along with primary diagnostic procedures and possible therapies, according to the clinical presentation. The patient will be then hospitalized if required. The CARE program has been activated in June 2015. During the initial 6-month activity, 54 patients (51 already known, 3 newly addressed to IEO-OM-2) consulted the CARE, 28 patients were seen and managed in the hematology-emergency room and 13 of them were ultimately hospitalized. Given the favorable experience, the CARE program has been definitely confirmed and it represents now an effective clinical support for the hematology patients managed at IEO-OM-2.      

 The term Outcome Research indicate all studies that are concerned with the effectiveness of any therapeutic intervention and health service, that is, the outcomes of the services. Part of of our studies are devoted to the outcome research, that is to evaluate the overall outcome of the patients managed at our Institution. We collect data on the number of patients treated at our Center and the final aim will be to produce reports showing as possible how many patients benefited from our treatments. In details, main themes of outcomes research include: i. Safety and Effectiveness, with the characteristics of the patients receiving interventions and how patients were adherent to therapy; ii. patient-wellbeing, i.e. how medical interventions will affect physically and psychologically our patients, the adverse effects of medications, and those complications from interventions that may affect the quality and quantity of life. An example of outcome research is reported in Figure 11, summarizing the data recently reported at 2015 ASH Meeting in Orlando, USA, on the long-term outcome of 597 patients with Follicular Lymphoma, managed over the last 30 years in Hematology Centers in Torino and Bergamo

Academic and company sponsored trials

Multicenter clinical trials represent a unique instrument for the advancement in medicine. Basically, the safety and efficacy of novel diagnostic or treatment approaches are evaluated at more than one medical center, with the inclusion of larger number of participants. The possibility to compare results among centers further strengthen the value of multicenter studies, increasing the generalizability of the results obtained. Indeed, the benefits of multicenter trials are well established and the participation to multicenter trials is a distinctive activity of highly qualified Medical Institutions, particularly those dedicated in medical oncology. Our Center participate to several multicenter clinical trials, both “academic” (no-profit) and pharma-driven studies. Most academic studies are promoted by national and international multicenter study groups and the IEO-Hemato-oncology Division is affiliated to the main Italian multicenter study groups, including FIL (Fondazione Italiana Linfomi) for studies on lymphoproliferative neoplasms, NILG (Northern Italy Leukemia Group) for studies on acute leukemia, GIMEMA—Italian Multiple Myeloma Network for studies on multiple myeloma; among international groups, our Hemato-oncology Division participate to multicenter trials conducted within the European PTLD (Post-Transplant Lymphoproliferative Disorders) Network and the IELSG (International Extranodal Lymphoma Study Group). Finally, there are ongoing participations to some multicenter, international trials sponsored by Pharmaceutical Companies. Most of these latter trials are aimed to evaluate novel and promising targeted drugs.

Bone marrow transplant

A non-negligible proportion of our activity is assigned to bone marrow transplantation (BMT), including both autologous and allogeneic transplant. This section is mainly based on the long experience of the Director, Prof. Tarella, in the field of mobilization and clinical use of circulating hematopoietic stem cells, also known as PBSC or Peripheral Blood Stem/progenitor Cells. Prof. Tarella has given seminal contributions, promoting the development of PBSC-based treatments, both in the setting of autologous and allogeneic Hematopoietic Stem Cell Transplantation (HSCT).  The BMT section at IEO is presently coordinated by Dr. Rocco Pastano. In the last few years, besides the well established procedures of autologous HSCT, the OM-2 Division at IEO has developed the allogeneic HSCT approach from haplo-identical donors, exploiting the potent engraftment capacity of PBSC. The haploidentical approach with PBSC has allowed to offer the therapeutic opportunities of the allogeneic HSCT to patients with very low if any chances of survival with conventional therapies. Thus, most clinical and research efforts at IEO-OM-2 are addressed to the BMT activity, both in terms of outcome research and development of novel transplant procedures.

Part of the research activity of the IEO-OM-2 is devoted to basic research. The studies are carried out at the Experimental Hematology Laboratory, directed by Prof. Myriam Alcalay at IEO-Campus. Collaborative studies are also carried out together with the group of Prof. Pier Giuseppe Pelicci. These are the main topics of the research program og the IEO-OM-2.  

Telomere, cell ageing ad cancer

Telomere is a region at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Indeed, telomere is an essential structure in order to prevent genetic instability and ultimately the risk of development of malignant cell clones. Telomere localization at chromosome end and its main biological roles are described in Figure 12. At each cellular division, telomeric DNA is not fully replicated. Consequently, each somatic cell division is associated with a physiologic loss of telomeric DNA. Therefore, a typical feature of telomere is its slow and progressive shortening during the life-span of each cell and analogously during the life-span of each individual. As a consequence, telomere length (TL) represents a reliable biomarker of cell age and mitotic potential, both in vitro and in vivo. Hematopoietic cells are subjected to telomere erosion during their constant commitment and differentiation. Moreover, exposure to cytotoxic agents or a high proliferative stress, including bone marrow regeneration after HSCT, may produce a non-physiological TL shortening.  For these reasons, TL has been extensively analysed with the aim to define the degree of cell ageing in the hematopoietic system. Indeed, part of the biological studies carried out by Prof. Tarella and collaborators over the last years has been addressed to the study of TL of hematopoietic cells both in normal subjects and in patients with hematological malignancies. Some of the initial studies allowed to detail the physiologic shortening of TL in peripheral blood (PB) cells in normal subjects, as shown in Figure 13.  Ongoing studies are investigating the role that various substances may play in the dynamic of TL shortening in hematopoietic cells and the possibe correlation with the onset of malignant cells.

Extracellulare vescicles (EVs) and TRAIL-armed EVs

Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into the extracellular microenvironment and are potent vehicles of intercellular communication. EVs have the capacity to transfer proteins, lipids and nucleic acids, an important mechanism for various physiological and pathological functions of both recipient and parent cells. There is a growing interest in the oncology research field for utilizing EVs as vehicles of genetic materials which may reverse tumor development or as treatment in combination with chemotherapy. The IEO-OM-2 group is running research studies on this filed. Most studies take advantage form the release of EVs from cutured human mesenchymal stromal cells (hMSC). Standardized culture system for the in vitro expansion of hMSC and for the consistent production of EVs  from cultured MSC are well established and are depicted in Figure 14. The goal of our research program is to genetically modify cultured hMSC by Lentiviral transduction to express specific membrane molecules active against tumor cells. The same molecules will be expressed on EVs from genetically engineered hMSC. These EVs will be extraordinarily effective vehicles of tumor-killing molecules. This is a sub-project of the large Research Program on “Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effector”, directed by Prof. Alessandro M. Gianni and supported by the AIRC-5%o  Special Program - Molecular Clinical Oncology MCO-9998

Biological characterization of novel therapeutic targets in lymphoma

Another active line of research in our Hemato-oncology Unit is aimed at the definition and biological characterization of novel molecular targets in lymphoproliferative neoplasms. The goal of our research is the identification of novel therapeutic targets and biological therapies able to overcome resistance to standard chemotherapeutic treatments with decreased toxicity. We are currently testing the efficacy of precision therapy approaches using in vitro and in vivo models of lymphoma and lymphoid leukemia, with the aim of designing clinical trials with novel targeted agents for patients with relapsed-refractory high-risk lymphoma.

Genomic and epigenetic studies

Genomic studies aim to understand the structure and the function of the genome, including the DNA. It allows to examine  the molecular differences between normal and transformed cells, thus ultimately it will identify the molecular abnormalities involved in the mechanism of tumor development and expansion. Several other factors are involved in the mechanisms of gene expression that are not caused by changes in the DNA sequence. These mechanisms are investigated by the epigenetic studies. Again,  abnormalities in factors regulating switching genes on and off are known to be involved in tumor cell growth. In strict collaboration with the other groups of the Hematology Program at IEO, i.e. the groups leaded by Francesco Bertolini, Pier Giuseppe Pelicci and Stefano Pileri, the IEO-OM-2 will expand investigation at both genomic and epigenetic levels, on samples from normal subjects and patients with hematological malignancies.

Novel targeted drugs for lymphomas treatment

 In the last decade, impressive advancements have been obtained in the understanding of normal and pathological lymphocyte generation, with major contributions by some eminent research groups, including the group directed by Riccardo Dalla Favera at the Columbia University in New York. This has lead to the identification of several molecular checkpoints that are crucial for the proliferation of lymphoma cells.

As a consequence, novel lymphoma subtypes have been recognized and the WHO Classification is the unique reference text for the correct pathological diagnosis of any lymphoma entity that can be now identified on the basis of specific cellular and molecular markers. Prof. Stefano Pileri, Director of the Hematophatology Unit at IEO, is among the eight Editors of the WHO Classification. Novel drugs have been developed and others are under development. The present challenge is to define the ideal place of these new drugs, in combination with other effective treatment already available for lymphoma. The accurate and detailed histological diagnosis for any new patient is now mandatory to optimally exploit the novel molecularly-directed drugs.