The prognostic features influencing the OS in a large Italian cohort of CML patients are prospectively analyzed in the data base of the GIMEMA CML Italian registry. Among 1206 patients, 608 of them received frontline IMA and 598 2genTKIs.  In this study Italian hematologists tend to prevalently prescribe IMA to older patients, with more comorbidities, as compared to 2genTKIs. These differences explain a better OS for patients treated with 2genTKIs vs IMA, however, the risk of death for CML related causes is quite similar between the two groups, all the differences being attributable to other causes of death. Prognostic baseline features associated to an increased OS confirmed that, in addition to age, the ELTS score and the comorbidities are the main clinical factors that independently influence the long-term OS.

About 50% of adults with chronic myeloid leukemia (CML) in chronic phase (CP) with prolonged deep molecular response under tyrosine kinase inhibitor (TKI) could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. We identified in the International Registry of Childhood CML 18  patients  less than 18 years of age at diagnosis with  CML in CP exhibiting sustained  molecular response > MR4.0 (BCR-ABL1/ABL1 ratio <0,01%) for ≥ 2 years under imatinib treatment and then  discontinued the TKI. Seven children experienced a molecular relapse (defined as the loss of major molecular response) with a median time of 4 months (range, 1.9-6.4 months) after stopping and restarted imatinib at full dose. Six of these 7 children  re-achieved MR4.0. Eleven children remained in molecular response with a median follow up of 116 months (range, 71-209 months) after discontinuation. The proportion of patients maintaining treatment free remission was 61% (95%CI, 38%-83%), 56% (95%CI, 33%-79%) and 56% (95%CI, 33%-79%)  at 6, 12, and 36 months, respectively. In univariate analysis, age, sex, prognostic scores, imatinib treatment duration before discontinuation and duration of MR4.0 until imatinib discontinuation had no influence on  treatment free remission. Imatinib  could be safely discontinued in children <18   years of age at diagnosis of CML with sustained MR4.0 for at least  2 years under  imatinib. Larger studies in children with CML are needed in order to identify factors predicting TFR.

My talk will highlight the distinct issues relevant for elderly patients with CML, including the aspects of COVID-19, mostly relevant for the elderly.

A significant proportion of CML patients are in fact “elderly” according to the most widely accepted definition of “old person” (namely, age> 65 yrs.). In the past, the aim of therapy in this subset of patients was only to contain the leukemic mass. Nowadays, the aim of therapy is more ambitious. According to the SEER National Cancer Institute, 28.6% of CML patients are 75 years and above. Unfortunately, only 3.8% of these patients are represented in clinical trials (compared to 79% of patients < 65 years old). This poses another difficulty in choosing the best treatment for elderly patients.

All TKIs have shown efficacy in elderly CML patients. However, their use is accompanied by adverse events and toxicity, especially in this population. Various TKIs used for CML will be compared, mainly with respect to their toxicity and the pathogenesis of TKI-induced vascular adverse events.

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. In the last part of my talk I will focus on unique aspects, which are obviously more relevant for elderly CML patients, being a risk group for complications of COVID-19.

Hemophilia is a genetic X-linked severe bleeding disorder. For decades intravenous (IV) factor VIII (FVIII) infusion (namely replacement therapy) was the only treatment given either on demand or as prophylaxis. Non the less, the hallmark of the disease, repeated  hemarthroses, yielded progressive joint damage and hemophilic arthropathy that worsened with aging. The development of a comprehensive approach in specialized hemophilia centers resulted in reduction of the bleeding- related death rate, while hemophilic life expectancy has now become similar to the general population. Thus, physicians must now deal with the issue of age related co-morbidities. In particular, cardiovascular risk factors and their complications should be addressed.

The current lecture will discuss controversies related to anticoagulant care and management of potential thrombotic risks among elderly patients will hemophilia. Special focus will be shed on cases when novel non replacement therapies are applied. The issue of gene therapy  and its promise to younger and older patients will be addressed. Overall, the risk – benefit of new treatment modalities should be evaluated separately in the elderly hemophilia patients paying attention to those with established atherosclerosis or any prothrombotic risk factors.

Anemia is a common disorder considered as a global public health problem.

It may affect up to 25% of the world’s population, especially in preschool-aged children and women.  The prevalence is estimated at 9% in developed countries, and may reach 43% in low income countries. Anemia has been shown in a population based cohort study to be an independent risk factor for all-cause mortality in the general population, as well as cardiovascular and cancer-related mortality.

In general, iron deficiency anemia is the most common cause of anemia. The causes of anemia vary according to age. In this lecture, we will discuss specific clinical settings of anemia.

In the young, we will address anemia of pregnancy and anemia in inflammatory bowel diseases.

In older patients, we will discuss anemia in chronic heart failure and chronic kidney disease.

The main focus of the talk will be iron deficiency in these situations.

There are two forms of iron deficiency: absolute (true) iron deficiency and functional iron deficiency. Absolute iron deficiency is defined by severely reduced or absent iron stores in bone marrow, liver, and spleen. Functional iron deficiency is defined by normal or increased total body iron stores, which are unavailable for incorporation into erythroid precursors for erythropoiesis. Functional iron deficiency is mainly due to increased levels of hepcidin which reduce the ability to recruit iron stores from reticuloendothelial cells and hepatocytes for erythropoiesis.

We will discuss the definitions of absolute and functional iron deficiency in the different settings, the prognostic effect of anemia and iron deficiency on long term outcomes, and treatment. We will review randomized controlled trials and meta-analyses comparing oral iron to intravenous iron, as well as the current guidelines. We will discuss the efficacy outcomes in each of the settings as well as the safety issues of intravenous iron.

Chronic lymphocytic leukemia (CLL) cells proliferate in secondary lymphoid organs, where B cell receptor (BCR) signaling promotes the expansion of the monoclonal B lymphocytes. BCR signaling is targeted by kinase inhibitors, which have transformed CLL therapy during the last decade. Bruton tyrosine kinase (BTK) and isoform-selective PI3K inhibitors disrupt BCR signaling and other circuits between CLL cells and the tissue microenvironment. BCL2, an anti-apoptotic molecule highly expressed in CLL cells, emerged as another important therapeutic target. The transition from chemotherapy-based regimens to these new, molecularly targeted agents is based on a series of randomized clinical trials, demonstrating a survival benefit from BTK inhibitors (ibrutinib, acalabrutinib) and the BCL2 antagonist venetoclax, when compared with older CLL therapies. Before, when chemo-immunotherapy (CIT) was standard-of-care CLL therapy, younger fit patients typically received more intensive therapy, while elderly patients with co-morbidities were treated with low-intensity regimen. Today, use of chemo-immunotherapy has steadily declined, given the better tolerability and improved survival with the novel agents, based on comparisons of BTK inhibitors or venetoclax plus anti-CD20 antibodies with fludarabine, cyclophosphamide, and rituximab (FCR), bendamustine and rituximab (BR), or chlorambucil and obinutuzumab. An exception is the small group of younger fit patients with low-risk CLL, i.e. mutated IGHV, who can stay in remission beyond 10 years after FCR. In such patients, FCR remains an alternative to the newer agents. The new agents work well and generally are well tolerated across all age groups. Therefore, nowadays age-consideration are of minor importance when treating CLL patients.

Median age at diagnosis of multiple myeloma is 70 years.  For some patients multi agent intensive and myeloablative chemotherapy may not be an optimal choice due to safety issues.  In this presentation we will review the criteria that are used to assess comorbidities in the elderly that result in them being classified as fit unfit or frail.  Trials that are specifically designed for elderly patients with an emphasis on oral agents and nontraditional cytotoxics approaches will be reviewed.  Trials of ixazomib lenalidomide dexamethasone, ixazomib cyclophosphamide dexamethasone as all oral regimens will be reviewed.

The criteria and outcomes for stem cell transplantation in patients over the age of 70 and 75 will be reviewed in terms of outcomes and the criteria for safe patient selection.  Utilization of newer agents including ixazomib daratumumab and pomalidomide, ixazomib cyclophosphamide dexamethasone and daratumumab ixazomib dexamethasone in combinations in newly diagnosed and relapse patients will be covered.

Hairy cell leukemia (HCL) is a rare form of leukemia and accounts for only about 2% of all leukemias. This distinctive, lymphoproliferative disorder, is characterized by peripheral blood pancytopenia, splenomegaly, and morphologically by infiltration of the bone marrow and peripheral blood by malignant B-cells showing typical fine hair-like cytoplasmic projections. V600E BRAF mutation is identify in almost all cases of classic Hairy cell leukemia and pathogenesis of this disorder lies in the RAS-RAF-MAPK signaling pathway.

The major advances in treatment of  HCL occurred in the 1980s when the purine analogues: cladribine and pentostatin, were introduced. Both, chemotherapy agents induced high complete response rates of 75-90 %.

Recently the use of novel agents to treat HCL have being introduced including anti CD20 monoclonal antibodies, BRAF inhibitor, Recombinant Immunotoxins, and BTK inhibitors.

We will discuss how the introduction of biological agents as well as the COVID-19 epidemiology affect the approach to elderly HCL patients.

The therapy of younger adults with acute myeloid leukemia has changed with the recent approval of several new agents including midostaurin , gemtuzumab ozagamicin, and liposomal encapsulated daunorubicin/cytarabine. Proper use these drugs requires rapidly available genetic and molecular data both for prognosis and therapeutic selection. If a patient’s blasts harbor a FLT3 mutation in either of the two subtypes (internal tandem duplication or tyrosine kinase domain missense) midostaurin will be added to the classic daunorubicin/cytarabine “3+7” backbone on days 8-22. Core binding factor cytogenetic abnormalities mandate the addition of fractionated gemtuzumab to “3 + 7”. Thirdly, although the drug was tested and shown to be better than “3+7” only in patients between age 60 and 75 with secondary AML, it is common to use liposomal encapsulated daunorubicin/cytarabine even in younger patients with a history of therapy for other cancers, prior MDS, or MDS-related cytogenetics. In the relapsed setting we may consider one of three targeted agents: ivosidenib or enasidenib for patients with IDH1 or IDH2 mutant disease, respectively; or gilteritinib for patients with FLT3 mutant relapsed/refractory disease. The results with single agent therapy in this setting are far from ideal so we need to determine what drugs can or should be combined with these agents. While TP53 mutant AML in a younger adult is currently a dismal situation, the development of drugs such as the ‘refolding agent’ APR-246 and antibodies which obstruct the CD47  ‘don’t eat me’ signal on blasts, thereby allowing macrophage mediated destruction, offer promise.

The recent approval of multiple novel and targeted therapeutics offers new hope and increasingly effective treatment options for patients with acute myeloid leukemia (AML).  Dr. Courtney DiNardo from the MD Anderson Cancer Center will discuss the clinical management of AML in this new era of precision medicine, summarizing available evidence and highlighting optimal strategies for treatment and management.  She will review the importance of a comprehensive genomic assessment, and consider available treatment strategies particularly for patients considered inappropriate or refractory to standard intensive therapies.  A review of key ongoing clinical trials and key areas of ongoing translational research will also be summarized. 

Despite the enormous progress in genetic classification of acute leukemias and the prognostic utility of such genetic markers in determining patient outcome, age still serves as an independent prognostic factor in acute leukemia.

The advent of novel, targeted agents added to low-intensity approaches for older patients with acute myeloid leukemia (AML) on the one hand, and the positive effect of adopting dose-intense, pediatric-like approaches to treat young adults with acute lymphoblastic approaches (ALL) on the other hand are examples of how age-adjusted approaches are impacting care in acute leukemia.

In this talk I will present some of the Israeli experience with age adjusted approaches including prospective observational data on low-intensity approaches in AML and ongoing prospective trials in young adults with ALL.

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.

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.

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 (1st, 2nd, 3rd 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.