Multiple myeloma (MM) is a clonal plasma cell malignancy, characterized by the proliferation of antibody-producing plasma cells within the bone marrow and the secretion of monoclonal immunoglobulins into the peripheral blood and/or the urine. In most cases, MM is preceded by an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). Despite the immense progress that has been made in the treatment of MM, the disease still remains uncurable. Interactions between malignant plasma cells and different immune cells support the development and progression of refractory malignant clones. The main immune checkpoint pathways in MM are PD-1/PDL1 and CTLA-4. Despite the enhancement of anti-myeloma immune responses in vitro, checkpoint inhibitors failed to show success in clinical trials in MM. However, combined therapeutic strategies show promising results. LAG3 is another checkpoint that has been recognised mostly on T-cells. The expression of LAG3 was recently discovered on regulatory plasma cells in mice. Micro-environmental cell LAG-3 expression was found to be increased during the progression of smouldering multiple myeloma. Our group showed increased expression of LAG3 on purified plasma cells from patients with plasma cell dyscrasia.

The immunological inhibitory mechanisms in MM play an important role in the development and progression of relapsed-refractory disease and are promising targets in new treatment development.

During this presentation I will conduct an up-to-date review of published studies on the management and treatment of naïve multiple myeloma patients. As indicated by the assigned title of the talk, I will expand on the literature and share my interpretation of published data as well as hands on experience from my clinic. Focus will be on clinical aspects and management for optimized clinical outcomes. Also, I will discuss gaps in the literature and address future directions.

Despite significant advances in the treatment of myeloma in the past two decades, most patients still relapse, and require further treatment lines, eventually developing refractory disease. The landscape of the therapeutic approach to relapsed myeloma is constantly evolving, as potent triplets and quadruplets are being introduced at the upfront setting, which in turn limits treatment options at relapse. Lenalidomide refractory patients pose a major challenge, as LEN-based triplets for relapse therapy are no longer appropriate. Fortunately, novel combinations have been evaluated as well as new agents which are being developed to affect newly discovered targets. We will discuss criteria for initiating therapy at the relapse setting, and considerations  for selection of treatment regimen based on patient and disease factors. Recent outcomes of lenalidomide-free regimens will be reviewed. We will discuss outcomes of recently approved anti-myeloma drugs including selinexor and belantamb. Finally, recent advances in T-cell redirection immunotherapy including BCMA CART and bispecific antibodies will be reviewed.

¹⁸F-Fluorodeoxy-D-Glucose Positron Emission Tomography/Computed Tomography (PET/CT) has become the new paradigm for the overall management of Hodgkin lymphoma (HL). As a matter of fact, it proved to play a definite role in tumor staging and restaging, interim response assessment during 1^st line and 2^nd line chemotherapy, before and after Radiation therapy and before and after Autologous Stem Cell Transplantation (ASCT). Four main aspects will be covered:

Baseline PET for HL staging & prognostication:  A clinical case will be presented along with a literature review on how HL staging has been revolutionized by PET/CT.  Interim-PET adapted strategy for frontline HL treatment: Interim PET has been proposed to down escalating treatment in advanced stage HL starting their treatment with BEACOOPP escalated or in ABVD-treated patients to escalate treatment in patients with a positive PET-2; This second aspect will be mainly addressed as a different number of therapeutic strategies have been proposed in advanced-stage disease based on BVD backbone: interim PET guided treatment strategies, and non-PET adapted ABVD-based strategies incorporating new drugs. A comparison between these two therapeutic strategies, in terms of efficacy, will be presented based on the respective 3-Year Progression-free survival of both. PET imaging to guide consolidation Radiotherapy: Combined modality of treatment (Chemotherapy followed by radiation therapy) has been the mainstay of treatment of HL for more than half a century. Upon introduction of PET/CT for tumor staging and restaging the prognostic meaning of a non-FDG avid residual mass (RM) at the end of chemotherapy, which was first questioned by George Canellos in 1988: “residual mass is not residual disease” has been reassessed. Moving from a evidence-based medicine approach, the speaker will show to the audience that there is no longer any role for consolidation radiotherapy in patients showing a non FDG-avid after ABVD or BEACOPP escalated chemotherapy in advanced-stage HL. PET imaging for response assessment to immune checkpoint inhibitory agents. A clinical case of a primary refractory advanced-stage HL will be presented failing several lines of treatment that ultimately responded to immune checkpoint inhibitors. However, It will be shown how the classic 2014 Lugano criteria for PET/CT-based treatment response assessment do not work in this therapeutic context and new criteria (So-called LYRIC criteria) are needed for a proper response assessment.

Early-stage classical Hodgkin lymphoma (stages I/II; localized) is a highly curable disease. Risk assessment is traditionally based on the GHSG or the EORTC classification schemes taking into account mediastinal bulk, the combination of ESR and B-symptoms, the number of involved sites and extranodal extension (GHSG) or age >50 years (EORTC). Patients are classified as early-stage (EORTC early-favorable) or intermediate-stage (EORTC early-unfavorable) according to the absence or the presence of ≥1 risk factors.

The combination of ABVD and radiotherapy has been the standard of care. More intensive chemotherapy (2xBEACOPP-esc+2xABVD) improves disease control without however any effect on overall survival. The very high cure rates (80-90%) with front-line therapy and the young age of the patients emphasize the importance of the well recognized long-term sequelae of radiotherapy (and/or chemotherapy). During the last 5 years, important data have emerged regarding the application of PET-guided therapy in localized-stage Hodgkin lymphoma. There is now evidence that the omission of radiotherapy may be feasible without clinically meaningful loss in disease control, especially in the early-unfavorable (intermediate) stages, if an interim PET evaluation is strictly negative. On the contrary, there is now randomized evidence for the superiority of a brief BEACOPP-esc treatment over continuing ABVD in case of interim PET positivity. These data need to be reevaluated with longer follow-up. Meanwhile, the definition of PET negativity/positivity in this setting (especially Deauville 3) should be carefully assessed.

Risk-and-response adapted strategies appear very promising over standard combined modality, while novel agents are being tested, albeit mainly in advanced disease.

Dr. Moshe Gatt is the director of the Hematology department at the Hadassah Hebrew University Medical Center, Jerusalem. He is also a senior lecturer of hematology. His interest is in monoclonal gammopathies, multiple myeloma and AL amyloidosis in particular.

Dr. Gatt received his medical degree from the Hebrew University School of Medicine. He then completed his residencies and fellowships at the Hadassah Medical Center, Jerusalem, Israel, and did a research fellowship at the Jerome Lipper center for Multiple Myeloma, Department of Medical Oncology, Dana Farber Medical Center and Harvard Medical school, Boston, MA. USA.

His research interests include plasma cell dyscrasias, multiple myeloma and amyloidosis. Dr. Gatt’s work revolves around improving current diagnostic techniques for AL amyloidosis and in investigating novel methods to study this disease. He has also investigated and reported various treatments outcomes in MM, and is participating in many phase 2 and 3 clinical trials in Multiple Myeloma and Amyloidosis as a Principal Investigator or Sub-Investigator. He is an author of over 50 peer-reviewed publications in international journals.

He has been the secretary (2012-2016) and is currently the chairman of the Israeli Multiple Myeloma Study Group.

Systemic amyloidosis is a protein misfolding and deposition disorder, which leads to progressive organ dysfunction and death. Amyloidosis can be acquired or hereditary. It can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues.

Symptoms are typically insidious and nonspecific. Since various organs can be affected there is no single medical discipline where patients are initially seen. As a result, diagnostic delay is common, which has profound negative impact on the ability to reverse organ damage and prolong survival. Making a  timely and accurate diagnosis is the most important step to improve survival in this disease. This talk will discuss the challenges in making the diagnosis of amyloidosis and will highlight the pathway for accurate diagnosis.

Poems syndrome is a rare plasma cell dyscrasia characterized by the secretion of a monoclonal protein that is lambda light chain type in 90%.  Patients present with a progressive mixed axonal and demyelinating peripheral neuropathy associated with either a sclerotic bone lesion that represents a plasmacytoma or the presence of multicentric Castleman’s disease.  Other clinical manifestations include hepatosplenomegaly, endocrinopathies, skin hyperpigmentation and hirsutism.  Patients may have cardiovascular abnormalities that include pulmonary hypertension, pleural or peritoneal effusions.

May patients present with erythrocytosis and thrombocythemia and these patients can be incorrectly diagnosed with a myeloproliferative disorder.  In addition to a lambda monoclonal gammopathy serologic clues include elevations of vascular endothelial growth factor and interleukin 6. The differential diagnosis includes chronic inflammatory demyelinating polyneuropathy, DADS and amyloid neuropathy.  Although it is a clonal plasma cell disorder poems syndrome rarely transforms into overt multiple myeloma.  When the sclerotic bone lesions are solitary radiotherapy can result in resolution of the syndrome.  The preferred technique for this disease is autologous stem cell transplantation resulting in resolution of the neuropathy and long-term hematologic remission.  However other anti myeloma therapies have been used in this disease including bortezomib lenalidomide and car T therapy.

The major unmet need this disease is failure to recognize the diagnosis in patients have been treated for long periods of time with total plasma exchange and high-dose corticosteroids which have not shown to provide value in the management of the disorder.

Hairy Cell Leukemia variant (HCL-V) is defined as a rare and indolent form of small, mature, B-cell leukemia characterized by a splenomegaly, an elevated white blood cell (WBC) count and hyper-cellular bone marrow. HCL-V is not considered to be biologically related to classical HCL (HCL-C). The WHO classification included HCL-V as a provisional entity among the unclassifiable splenic B-cell leukaemia/lymphoma together with splenic diffuse red pulp small B cell lymphoma (SDRPL). HCL-V constitutes 0.4% of all lymphoid malignancies and incidence rate is 0.2. In comparison to HCL-C, patients with an HCL-V are often older, present with lymphocytosis, and are resistant to common treatments using purine nucleoside analogs. Morphologically, HCL-V cells are similar to HCL-C but with higher nuclear cytoplasmic ratios and no ribosome-lamella complexes. HCL-V cells   express   bright CD20, bright CD22, CD11c and CD103, but absent CD25 and dim to absent CD123. In addition HCL-V cells do not demonstrate reactivity to tartrate–resistant acid phosphatase (TRAP) and BRAF mutation is absent. Differential diagnosis includes splenic lymphoma with villous lymphocytes (SLVL), SRPL, HCL-C, mantle-cell lymphoma and B-cell prolymphocytic leukaemia (B-PLL). The median survival is approximately nine years, with only 15% survival over 15 years.  Treatment options include splenectomy, purine nucleoside analogs interferon-a, monoclonal antibodies and moxetumomab pasudotox. The results of cladribine monotherapy in HCL-V are inferior to those achieved with cladribine in HCL-C. Rituximab combined with cladribine is more effective than cladribine alone or rituximab alone. Novel agents like ibrutinib are also considered for the treatment of this disease. In addition autologous and allogenic hematopoietic stem cell transplantation can be taken into account in relapsed/refactory cases.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course, but poor overall survival (OS). In 2018 the T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria were published in Blood in 2019. They will facilitate the design and conduct of clinical trials in T-PLL, which are necessary for the approval of new therapeutics by healthcare authorities. In addition they will provide a useful resource for clinicians treating this rare disease.

In 2019 we also reviewed results from 174 T-PLL patients who were diagnosed or treated at RMH between 1989-2019. This data was presented at the ASH meeting in December 2019. Mean age at diagnosis was 61 years old (range 32-88) and M: F ratio was ~2:1 (113:61). At diagnosis the median white blood cell count was 74 x 10⁹/L (range 10-918), median haemoglobin 126 g/L (range 59-175) and median platelet count 116 x 10⁹/L (range 7-513). Sufficient immunophenotyping data was available for analysis in 135/174 patients. The results showed predictably high expression of CD2, CD3, CD5, CD7, CD52 and TCRαβ. CD25 was positive in 67/135 (50%) of cases, which is higher than the 18-35% seen in the current literature. CD4+/CD8- cases comprised 83/135 (61%) with CD4-/CD8+ 19/135 (14%), CD4+/CD8+ 32/135 (23%) and CD4-/CD8- 2/135 (2%). We analysed OS by decade of diagnosis covering 3 decades 1990-1999, 2000-2009 and 2010-2019. The median OS for the whole cohort was 20.6 months with median OS of 21 months, 23 months and 19 months for each decade respectively. There was no statistically significant difference between the curves by log-rank analysis.

Alemtuzumab was used in 116 patients, 69/116 (59%) receiving it as frontline treatment and 47/116 (41%) as salvage therapy. In 50/116 (43%) alemtuzumab was used as single agent, the remaining 66/116 (57%) receiving combination therapy, mostly pentostatin.

Mean time from diagnosis to receiving alemtuzumab was 6.8 months (range 0-53 months). Overall response rate (ORR) to alemtuzumab was 94/116 (81%) with complete remission (CR) 69/116 (59%), partial remission (PR) 25/116 (22%) and no response (NR) 20/116 (17%). Alemtuzumab produced better response rates when used as intravenous frontline therapy.

Allogeneic stem cell transplant (allo-SCT) was performed in 34 patients. Relapse rate post allo-SCT was 47%, non-relapse mortality 38% and transplant related mortality 29%. Although relapse rates are high post allo-SCT there is a small cohort of patients who are achieving long-term remission.

Our data shows that outcomes in T-PLL have remained unchanged since the first decade of alemtuzumab usage, with no improvement in OS in the last 20 years. Despite improvements in diagnostic techniques and supportive care median OS is static at approximately 20 months. Notably, in the last decade in particular, referrals to our centre have included a higher proportion of patients with relapsed or refractory disease and this may be contributing to the lack of improved survival in our cohort. Nevertheless, these results highlight the need for novel therapies in T-PLL. Given the rarity of T-PLL, international, multicentre, randomised trials such as the ibrutinib and venetoclax trial are needed to improve outcomes.

An outbreak of SARS-CoV-2, which first emerged in Wuhan in December 2019 and rapidly spread within China and to other countries, made the WHO declare the novel infectious disease COVID-19, caused by SARS-CoV-2, a global pandemic.

As hematologists and hemato-oncologist we are interested to know which are the special challenges that COVID-19 poses on Hem-Onc patients and healthcare providers.

First, Hem-onc patients are at particular risk for severe disease related to COVID-19 viral pneumonia. Second, healthcare resources are limited during the pandemic. Third, special measures to minimize patients’ exposure to COVID-19 are necessary. Thus, efforts should be done to minimize patients’ time in clinical areas. And last but not least, specific decisions regarding therapy of hematological malignancies need to be individualized based on disease risk, the risks of immunosuppression, the rates of transmission of COVID-19 and availability of local healthcare resources.

As a general rule,  treatment options with a clear established benefit in terms of survival outcomes should not be postponed for example in acute leukemias and aggressive lymphomas while in the setting of low grade lymphomas, CLL or low risk myeloma, treatment should be omitted or deferred with curtailment of treatment as much as possible. At the same time patients’ time spent in clinical settings should be reduced by using telemedicine /telehealth as much as possible and by changing IV medications to SC or PO.

In the event of infection with COVID-19 in immunocompromised patients the treatment algorithm should be adapted and decisions regarding the approach to the COVID-19 infection should be taken according to the patient’s immune status and the severity of the infection.

In the event of infection with COVID-19 during chemotherapy, chemotherapy should be continued on a case-by-case basis.

Until a few years ago, we did not realize that a quarter of patients diagnosed with Chronic Lymphocytic Leukemia (CLL) were suffering from infections, and 10% of those even dying within 30 days of infections, prior to any CLL specific treatment. Based on an extensive multidimensional time series of health data through Danish National Health Registries, we have created proof of concept that it is possible to predict risk of infections for patients with CLL. Addressing the necessity of developing models that are usable in the clinic, a modelling approach that is able to make predictions for all patients (irrespective of missing data) and providing uncertainty estimates as well as personalized risk factors for each patient prediction is emphasized. CLL-TIM (Treatment Infection Model) is now being prospectively tested to assign patients for the investigator-initiated, international PreVent-ACall clinical trial (NCT03868722), where we are aiming to improve immune dysfunction for patients with CLL by 12 weeks treatment with acalabrutinib and venetoclax. Going forward, we encourage collaborations on developing predictive models that can be applied at different time points of the CLL disease course, allowing testing of various interventions including immunoglobulin substitution, prophylactic antibiotics and novel targeted treatment approaches to improve the immune dysfunction in CLL and to improve the outcome for patients with CLL.

While minimal residual disease (MRD) analysis was commonly accepted as a surrogate marker for progression-free survival (PFS) in the era of immunochemotherapy (ITT) in chronic lymphocytic leukemia (CLL), the advent of kinase inhibitors such as ibrutinib initially questioned its value. More recently, the development of venetoclax, the first inhibitor of bcl2, as well as the prospect of new combinations put back on the spotlight the interest of the analysis of the MRD, not only to evaluate the effectiveness of these associations, but perhaps also to guide the therapeutic strategy.

In this talk, I will address the following potential roles for MRD measurement in CLL:

• Assess response and predict outcome for clinic patients
• Determine duration of treatment for clinic patients
• Monitor patients in remission after treatment
• Improve drug development in clinical trials

Waldenström’s macroglobulinemia (WM), also defined as lymphoplasmacytic lymphoma (LPL), is a rare, distinct indolent lymphoma with an IgM monoclonal gammopathy. Clinical presentation of WM is variable and may be governed by either lymphoplasmacytes infiltration or the IgM monoclone, often related to its immune attributes.

Differential diagnosis from other indolent lymphomas and correctly identifying symptoms etiology can be challenging.
With current knowledge of disease pathobiology, we can distinguish between disease patterns according to MYD88 and CXCR4 mutations. These are also important in prediction of disease response and thus, choice of therapy.

Fortunately, there is a variety of approved therapeutic option in previously untreated WM patients, based on either an alkylating agent, proteasome inhibitor, bendamustine, rituximab-alone, or ibrutinib. Therefore, choosing the best regimen depends not only on response rate and PFS, but also on disease presentation, and patient comorbidities and preferences.

In this talk, I will discuss current chemo-immunotherapeutic (CIT) regimens versus ibrutinib treatment, as well as second generation BTK-inhibitors. I will also present new data coming from ASH 2020, portraying future directions in the treatment of WM.

PTCL (Peripheral T cell Lymphoma) represent approximately less than 10% of all NHL in the Western world. The most common entities include: PTCL-NOS, angioimmunoblastic T cell lymphoma (AITL) including the new entity of PTCL with follicular helper phenotype, and anaplastic large cell lymphoma (ALCL) ALK positive and negative.

Despite progress during the last years, there is currently no accepted standard of care for newly diagnosed patients with PTCL. CHOP like treatment and consolidation with autoSCT is the common practice.

In the talk, we will discuss the 1^st line treatment for ALCL and other nodal PTCL including the recent studies. We will discuss the role of autoSCT in 1^st remission, for and against, and targeted therapy in relapse and refractory PTCL.

Marginal Zone Lymphoma (MZL) represents 10 -11% of all B-cell non-Hodgkin lymphomas. Three subtypes are recognized in the World Health Organization classification:  extranodal MZL (EMZL) (7-8%), splenic MZL (SMZL) (2%) and nodal MZL (NMZL) (1.5-1.8%).  MZLs typically exhibit and indolent course with longer survival in patients with EMZL compared than those with SMZL and NMZL. In this presentation we will focus on the treatment of EMZL. There is only one randomized trial in EMZL in rituximab era (IELSG-19). Given the paucity of trial data, treatment policies have been based on large institutional experiences, which in turn have been transformed into guidelines by organizations such as National Cancer Center Network (NCCN) and the European Society of Medical Oncology (ESMO).

In this presentation we will discuss treatments of newly diagnosed EMZL presenting with limited stage and disseminated disease. We will assess risk of high grade of transformation and treatment algorithm in these patients. Finally, we will summarize some of the new data presented at ASH 2020 meeting on treatment of relapsed MZL.

The medical profession today is in the midst of a revolution that is changing the face of medicine. This revolution affects every physician, whether they be residents or senior physicians, young or experienced. Among the factors driving this change are; a fast-evolving world of technology that changes the face of the medical profession, heavy regulation, the new Y and Z generations, patients who become more sophisticated and knowledgeable, and a steadily increasing life expectancy, accompanied by rising health care costs. These changes have a significant impact on every aspect of the doctor’s work.

In a world that is changing ever so quickly and becoming ever more complicated, there is no doubt that any physician who wishes to continue to provide each patient with personalized, compassionate, innovative, professional, and high-quality treatment will need to “upskill” themselves and develop a new mindset and set of skills.

The 5-Lands Model is an inclusive conceptual framework for the skills of the New Era of Medicine. This Model is based on cutting-edge theories on the brain’s plasticity, the future of medicine, and leadership in the age of VUCA (Volatility, Uncertainty, Ambiguity, and Complexity). It is also based on interviews with hundreds of hospital CEOs and medical leaders, L&D leaders, and professors from various universities and faculties (including medical faculties), as well as on the writer’s own experience in implementing upskilling and strategic change management processes in multiple healthcare systems and countries.