The Virtual Congress on

Hematology

Age before Beauty – An Age Adjusted Approach towards Hematological Disorders

The landscape for allogeneic transplantation has changed dramatically over the past five decades.  The upper age for transplant has almost doubled, from close to 40 years to mid- to late 70 years.  There are multiple reasons that have led to this substantial change.  First and foremost are improvements in supportive care.  Milestones in this area have included the ability to store platelets and thus the free availability of platelet transfusions in 1975, the insertion of central venous catheters in 1979, and the dramatic effect of ganciclovir in preemptive therapy of cytomegalovirus (CMV) infection in 1991.  The development of new anti-fungal agents in the 1990s and early 2000s have further facilitated the safer conduct through the peri-transplant period as well as the immunosuppressive months post-transplantation.  Another important area in facilitating transplants for older people has been the understanding of the importance of graft-versus-leukemia (GvL) in the conduct of allogeneic transplant, enabling far less myeloablative, or reduced intensity, conditioning regimens for transplantation.  This in and of itself is a major milestone allowing for older individuals as well as those with co-morbidities.  Finally, the more rapid time to identify a donor as well as the rapidly growing adoption of haploidentical transplants ensured that almost everyone has a donor without a lengthy period of preparation.  Thus, a combination of factors has led to the widespread use of allogeneic transplantation also for individuals well into their eighth decade.

The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell diseases, characterized by abnormal bone marrow differentiation and maturation, as well as impaired apoptosis. The basis is genetic, and the median age is 65–70 years. Anemia occurs in 90% of the patients and pancytopenia in 50% of them. About 20-60% of MDS patients transform into acute leukemia.

MDS treatment depends on the status of the disease, i.e. lower or higher-risk according to the IPSS/R classification, as well as patient individual factors, including age, co-morbidities and functional capacity. As a general rule of thumb, one can conclude that most therapies are effective in about 50% of the patients and response duration is about 2 years, leaving some challenges for the future.

Treatment in LR-MDS: RBC transfusions remain the common approach for anemia. Given the little evidence, the ELN-EU MDS guidelines suggest individualized approach. After 3 decades of successful use, erythroid stimulating agents (ESA) have become the standard 1st line agents, with 50% response rate. Lenalidomide was found to be effective (56%) and safe in del(5q) patients, while only 27% of MDS patients with non-del(5q) benefit from this agent.

Several promising agents are tested as possible treatments after ESA failure, or maybe together with ESA. Here, we will mention luspatercept (activing analogue), low dose or oral hypomethylating agents, roxadustat (HIF inhibitor) and imetelstat (telomerase inhibitor).

Treatment of thrombocytopenia: Surprisingly, there is no evidence to support platelet transfusions, thus the ELN-EU MDS guidelines recommend such an approach only in active bleeding events. Both thrombomimetics, romiplostim and eltrombopag, have been proven to be effective, but safety concerns inhibit their development into clinical practice.

Treatment of HR MDS: It has been more than a decade that hypomethylating agents (HMA) have become the standard 1st line treatment in HR MDS. However, we are still struggling to overcome the barrier of 50% response rate for 2 years. Attempts to improve have included, HMA switch, different dosing, new derivatives, identification of responding subgroups, and a better supportive care, with limited success. Several HMA-based combinations with lenalidomde, vorinostat and other agents have yielded higher response rate but with no survival advantage. Venetoclax might become the best partner to Aza, but it is still too early to conclude. Among the novel agents under trials we will discuss rigosertib (Ras inhibitor), pevonedistat (NEDD8 inhibitoe), glasdegib (Hedgehog inhibitor), selinexor (EXPO inhibitor), and MBG 453 (anti TIM 3).

All these agents and clinical trials, together with new approaches such as immunotherapy, will hopefully, improve the outcome of MDS patients in the coming years.

Cardio-oncology represents the intersection of cardiology and oncology and has emerged as a new clinical discipline. This field which initially emerged from the inevitable need to treat anthracycline-based toxicities is now situated at the frontline aiming to prevent or to at least ameliorate the cardiovascular side-effects of contemporary novel ant-cancer treatments. Moreover, over the past decades, there has been a profound improvement in the survival rates of many oncological diseases, and thus a steady increase in the number of cancer patients and cancer survivors with a parallel increase in their age. Whether due to ageing and associated comorbidities or due to cancer-treatment cardiotoxicities, cardiovascular complications are not uncommonly encountered in these patients with potentially profound impact on morbidity and mortality. Unfortunately, this population of elderly patients has been consistently under-represented both in oncological and in cardiovascular clinical trials. In this session we will discuss cardiovascular dilemmas in the treatment of hemato-oncological patients and present contemporary evidence-based data.

Increasing age is an important risk factor for arterial and venous thromboembolic disease.

The estimated prevalence of atrial fibrillation (AF) in patients aged ≥80 years is 9–10% and the increased stroke risk of 1.45-fold per decade in aging. Unfortunately, older age is also associated with increased risk of major bleeding with oral anticoagulant (OAC) therapy.

Before the era of the direct oral anticoagulants (DOACs) surveys from Europe and North-America consistently showed that Vitamin K Antagonists (VKAs) were used in only 50–60% of patients with AF, and in only 35% of those 85 years or older. Underuse of OAC was mainly due to the risk of bleeding. In the pivotal studies of AF, DOACs consistently reduced the risk of intracranial bleeding compared to VKAs, however the mean age of the patients included in clinical trials was 5–10 years lower than the mean age of real-life patients with AF and only 4-7% of patients were above the age of 85 years.

The lecture will review the literature on safety and efficacy of DOACs in the elderly population.

Mantle cell lymphoma (MCL) represent approximately 5%–7% of all NHL in the Western world. The annual incidence of this disease has increased during recent decades to 1–2/100 000.

MCL is more common in males than in women with a 3: 1 ratio.

Age range at presentation is 35-85 years, with a median of 68 years.

MCL classically has been recognized as an aggressive but incurable small B-cell lymphoma, which can develop in two molecular pathways. The first one is the classical MCL composed of mature B cells, not entering the germinal center with no or minimally mutated IG and express SOX11. The second pathway involve the leukemic non nodal MCL whose cells go through the germinal center with hypermuted IG and do not express SOX11.

We will discuss the difference between indolent vs. non-indolent and the option to observe in a subset of patients with MCL.

We will also discuss the first line treatment in the young vs. the elderly patients, and targeted therapy in relapse and refractory MCL.

Waldenström’s macroglobulinemia (WM), also defined as lymphoplasmacytic lymphoma (LPL), is a distinct indolent lymphoma with an IgM monoclonal gammopathy. Patients symptomatology may be governed by either lymphoplasmacytes infiltration in tissues or IgM monoclone itself. IgM-related neuropathy, for example, continues to pose a clinical and therapeutic challenge, especially in older adults with competing etiology.

WM is a rare disorder with an age-adjusted incidence of ~3.4 per million per year for males and 1.7 for females. The median age at diagnosis is more than 70 years in Caucasians and less than 10% of patients are under 50.

Most cases of WM are preceded by IgM-MGUS or smoldering WM. Although age does not play a role in their progression, it still has a profound impact on survival; WM patients of age 80 or greater have a HR for death of 6.99, compared with a reference group less than age 50. Fortunately, WM median OS has considerably improved over the last decades and currently exceeds 10 years from diagnosis.

WM treatment has been rapidly evolving. Employment of more effective CIT regimens, i.e., BR has improved median PFS to 69 months, compared with 2-3 years with CRd or similar. The advent of BTK-inhibitors portrays a new era in the treatment of WM, with possibly greater efficacy and manageable toxicity, particularly with second generation BTKi.

We will discuss some unique aspects of WM with relation to age and will focus on current therapeutic strategies as we consider an age-adjusted approach to WM therapy in 2020.

Recent years witnessed vast improvement in clinical results of treatment of lymphoproliferative diseases.

However, the results of therapy and clinical outcomes of elderly people lag behind.  Even in biologically similar lymphomas, elderly fare much worse than younger patients. Currently more than 60% of patients with lymphoproliferative disease are over age of 65 and due to the demographic trends this percentage will be much higher in the coming years.

Importantly, elderly people who receive full dose intensity chemotherapy fare as well as younger patients.

What are the causes of the inferior results in elderly and how can we improve upon the current situation?

Elderly people comprise a unique group physiologically, pathophysiologically, clinically and existentially. Therefore, we need to develop a conceptual and strategic approach to this sector of population.

This section of population harbors more comorbidities (affecting outcome and tolerance) and receive multiple medications (drug interactions). These are essential factors to take into account in therapeutic planning.

The physiology of aging is fundamentally different (for example; inflammaging, renal function, drug distribution and decreased physiologic reserve in apparently healthy people etc.).

In contrast to younger population, which is relatively homogenous, the elderly patients with lymphoproliferative disease are very heterogeneous group and therefore, the decisions concerning them should be individualized and based on sufficient data.

In addition, life expectancy and quality of life of elderly people should be essential part of the decision process.

In this presentation we will discuss the pertinent aspects physiology, clinical situation and decision analysis in senior adult lymphoma patients. We will suggest the appropriate hematological-geriatric assessment and propose a detailed approach to decision making in this population group.

Irina St. Louis, Hesham Mohei
Medicine, University of Minnesota, USA

Background. The frequencies of reactivation of latent viral infections in umbilical cord blood recipients (UCB) higher than in matched sibling donor (MSD) after hematopoietic stem cell transplantation treatment for leukemias. It is accompanied by a significant delay in quantitative recovery of T cell subsets, however, faster quantitative recovery of B and natural killer subpopulations in the UCB group, throughout a year of post-transplantation.
Methods. We used Interferon-gamma (INFG) and Granzyme B (GZMB) ELISpot assays to quantify the frequencies of immune cells that secrete cytotoxic molecules in response to stimulation with ten peptides, from five most commonly reactivated viral infections, at four time points after transplantation. Half of the patients in each group were CMV seronegative and another half were CMV seropositive. Half of UCB CMV+ patients developed CMV reactivation, as detected by CMV DNAemia, and none of CMV+ MSD recipients reactivated.
Results. The quantities of the IFNG producing cells increased during a year of observation in all CMV+ groups, however, there was a significant delay in recovery of the response toward antigens in CMV+ reactivated UCB subgroup. Conversely, the secretion of the Granzyme B, in CMV+ subgroup was significantly higher at all time points. A strong positive correlation was observed between low ratios of effector T cells/NK cells, and IFNG/GZMB, in UCB recipients who exhibit viral reactivation.
Conclusion. This comparative analysis revealed delayed kinetics of quantitative immune recovery and viral-specific immune cell responses in UCB patients that were associated with the increased incidence of reactivation of latent viral infections.

Ilaria Elena Palamà, Barbara Cortese, Stefania D’Amone, Giuseppe Gigli
NANOTEC, CNR- Istituto di Nanotecnologia, Italy

Packaging small-molecule drugs into biodegradable polymeric nanoparticles could impact cancer therapy, by increasing drug bio-availability. We focused on chronic myeloid leukaemia (CML) which represents the first clonal malignancy effectively treated with a tyrosine kinase inhibitor (Iimatinib, IM). IM induces complete cytogenetic responses in more than 85% of patients. However, over 20% of initial responders discontinue treatment due to lack of efficacy or other adverse effects. Second- and third-generation inhibitors may address TKI resistance. However, whilst TKIs are highly effective on leukemic myeloid progenitor cells, they are unable to eradicate Leukemic Stem Cells (LSCs), which are BCR‑ABL1‑ independent. This eventually causes disease progression and has stimulated the search for additional LSC-specific therapeutic targets. This therefore prompted us to validate whether polymeric nanoparticles could overcome inherent resistance of CML stem cells to IM, also representing efficient tools for ex vivo purging of malignant progenitors from patient autografts. In the last few years, we have validated different types of polymeric nanoparticles (NPs) for IM and Nilotinib delivery to CML cells. To sum up, our pilot studies showing the clinical application of biodegradable NPs as feasible, specific, safe and effective ex vivo purging agents to target resistant leukemic stem cells, thereby optimizing transplant outcome of CML patients or reducing IM dose escalation.

Median age at diagnosis of light chain amyloidosis is 64 years. Elderly patients have more comorbidities, making early diagnosis challenging. In the elderly, ATTR is becoming more frequent and determining the protein type is imperative before specific therapy can be implemented.

Cardiac involvement is the main driver of prognosis in AL amyloidosis and age is not considered a risk factor in the various staging systems.

The approach to the elderly AL amyloid patient should be multidisciplinary. Comorbidities and performance status should be considered while tailoring the appropriate treatment. Autologous stem cell transplantation has been utilized in AL amyloidosis for over two decades and although early experience was marred by high rates of early mortality, advances in supportive care and careful patient’s selection are improving outcomes. Selection criteria for autologous stem cell transplant in specialized centers usually do not include an age cutoff and performance status and comorbidity should be used to drive the decision of transplant eligibility.

In this presentation we will review the criteria that are used to classify elderly patients as fit, unfit or frail. Trials that are evaluating the efficacy and safety of oral agents will be reviewed.  The selection criteria and outcomes for stem cell transplantation in patients over the age of 70 will be reviewed. Daratumumab as an emerging game changer will be discussed.

Older patients with classical Hodgkin lymphoma (cHL) face unique challenges not only due to less favorable presentations (higher rates of subdiaphragmatic presentation, B symptoms, mixed cellularity subtype) but also due to higher rates of treatment-related toxicity.  In particular, in the North American Intergroup study that evaluated ABVD versus Stanford V (Evens, et al. BJH 2013), 43% of patients age 60 and older treated with ABVD experienced bleomycin-related lung toxicity and 9% experienced treatment-related death.  Recent studies have focused on incorporating novel agents to improve treatment efficacy and modifying treatment to improve tolerability.  These include the phase II study of brentuximab vedotin (BV) and BV-doublets in patients ineligible for standard chemotherapy (Forero-Torres A, et al. Blood 2015; Friedberg JW, et al. Blood 2017; Yasenchak, et al. ASH 2019), as well as the phase II study evaluating sequential therapy with BV and AVD for more fit patients (Evens AM, et al. JCO 2018).  Overall, studies that incorporate novel agents have shown promising outcomes, suggesting improved disease control rates and treatment-related toxicity for this patient population.

Important advancements have occurred in the management of adult ALL over the last years. Ph+ ALL is an illuminating example of targeted treatment applied to ALL. The results obtained with TKIs used upfront have changed our approach to this condition in patients of all ages. It is mandatory that Ph+ ALL is rapidly identified at presentation. Within the GIMEMA network, the BCR-ABL fusion is tested centrally during the one week-steroid pre-phase. TKIs – alone or combined with chemotherapy – have markedly improved the response rates and overall survival of adult Ph+ ALL. Over the years, in the GIMEMA protocols the induction has been based on the use of a TKI (1^st, 2^nd, 3^rd generation) plus steroids and CNS prophylaxis, with no systemic chemotherapy. This has led to hematologic CRs in 94-100% of patients (with no upper age limit) and virtually no deaths in induction. A proportion of patients obtain a molecular response. Some elderly patients treated only with TKIs are alive and well after many years. Other groups have used TKIs and de-intensified chemotherapy, in order to reduce the toxicities (and deaths) associated with conventional chemotherapy plus TKIs. A molecular response should be today the primary endpoint of treatment. New strategies are under active investigation to increase molecular responses. In the GIMEMA LAL2116 front-line trial, dasatinib was used in induction followed by at least two cycles of the bispecific MoAb blinatumumab. This chemo-free induction-consolidation approach is associated with very high rates of molecular response (Chiaretti et al, ASH 2019) and may change our overall approach to Ph+ ALL.

During the past decade, survival rates for all adults with Acute Lymphoblastic Leukemia (ALL) have been improving.  In younger adults (AYA), this had been due largely to the adoption of muti-agent pediatric ALL regimens that incorporate intensive use of glucocorticoids, vincristine and asparaginase with prolonged CNS directed therapy.  Current studies to further improve outcomes now focus on the introduction of the new targeted BiTEs and antibody conjugates, approved for relapsed ALL, into the frontline setting to try to eradicate low level resistant disease (minimal/measurable residual disease) MRD. Treatment improvements in older patients have also focused on introduction of these new immune targeting strategies in frontline treatment; however, in contrast to treatment intensification approaches successful for AYAs, the older adult regimens are utilizing these new agents in combination and/or with minimal chemotherapy to reduce toxicity and enhance response and duration of responses.  Similarly in the relapsed setting, new immune modulatory approaches including the testing of novel CAR-T constructs and targets of the apoptotic machinery are resulting in much higher rates of subsequent remission, allowing more patients an opportunity to proceed with potentially life-saving hematopoietic cell transplants.

Leukemia is the most common cancer in children. Unlike adults the most common leukemia is ALL. It has been convincingly shown that at least 1:20 children carry a pre-leukemic clone initiated in-utero. Hence, similarly, but different, to adults “clonal hematopoiesis” is extremely common in children. These preleukemic clones are created by genomic lesions due to the enhanced V(D)J activity during the intensive lymphopoiesis occurring in-utero. At least for the most common childhood ALL, that is rare to nonexistent in adults, characterized by ETV6-RUNX1 (TEL-AML1) fusion there is a specific human fetal lymphoid progenitor that is sensitive for transformation. Why pediatric specific preleukemic clone do not persist into adulthood is unknown. Transformation to frank leukemia is rare, requires additional somatic genomic events that may be accelerated by infection and microbiome alterations. AML is also different in children than adults. The AML in children with Down Syndrome and recent research of the pathogenesis of pediatric AMKL also suggest a developmental model involving fetal progenitors.