Three-Year Mortality of Older Hospitalized Patients with Osteosarcopenia: Data from the OsteoSys Study.

Osteosarcopenia, the concurrent presence of sarcopenia and osteopenia/osteoporosis, poses a significant health risk to older adults, yet its impact on clinical outcomes is not fully understood. The aim of this prospective, longitudinal multicentre study was to examine the impact of osteosarcopenia on 3-year mortality and unplanned hospitalizations among 572 older hospitalized patients (mean age 75.1 ± 10.8 years, 78% female). Sarcopenia and low bone mineral density (BMD) were evaluated using Dual Energy X-ray Absorptiometry and the European Working Group on Sarcopenia in Older People (EWGSOP2) and WHO criteria, respectively. Among participants, 76% had low BMD, 9% were sarcopenic, and 8% had osteosarcopenia. Individuals with osteosarcopenia experienced a significantly higher rate of mortality (46%, p < 001) and unplanned hospitalization (86%, p < 001) compared to those without this condition. Moreover, "healthy" subjects-those without sarcopenia or low BMD-showed markedly lower 3-year mortality (9%, p < 001) and less unplanned hospitalization (53%, p < 001). The presence of osteosarcopenia (p = 0.009) increased the 3-year mortality risk by 30% over sarcopenia alone and by 8% over low BMD alone, underscoring the severe health implications of concurrent muscle and bone deterioration. This study highlights the substantial impact of osteosarcopenia on mortality among older adults, emphasizing the need for targeted diagnostic and therapeutic strategies.

Cellular therapies in older adults with hematological malignancies: A case-based, state-of-the-art review.

Cellular therapies, including autologous stem cell transplant (ASCT), allogeneic hematopoietic cell transplantation (alloHCT), and chimeric antigen receptor- (CAR-) T cell therapies are essential treatment modalities for many hematological malignancies. Although their use in older adults has substantially increased within the past decades, cellular therapies represent intensive treatment approaches that exclude a large percentage of older adults due to comorbidities and frailty. Under- and overtreatment in older adults with hematologic malignancy is a challenge and many treatment decisions are influenced by chronologic age. The advent of efficient and well-tolerated newer treatment approaches for multiple myeloma has challenged the role of ASCT. In the modern era, there are no randomized clinical trials of transplant versus non-transplant strategies for patients ≥65 years. Nonetheless, ASCT is feasible for selected older patients and does not result in long-term compromise in quality of life. AlloHCT is the only curative approach for acute myeloid leukemia of intermediate and unfavourable risk but carries a significant risk for non-relapse mortality depending on comorbidities, general fitness, and transplant-specific characteristics, such as intensity of conditioning and donor choice. However, alloHCT is feasible in appropriately-selected older adults. Early referral for evaluation is strongly encouraged as this is the most obvious barrier. CAR-T cell therapies have shown unprecedented clinical efficacy and durability in relapsed and refractory diffuse large B cell lymphoma. Its use is well tolerated in older adults, although evidence comes from limited case numbers. Whether patients who are deemed unfit for ASCT qualify for CAR-T cell therapy remains elusive, but the tolerability and efficacy of CAR-T cell therapy appears promising, especially for older patients. The evidence from randomized trials is strong in favor of using a comprehensive geriatric assessment (CGA) to reduce treatment-related toxicities and guide treatment intensity in the care for solid tumors; its use for evaluation of cellular therapies is less evidence-based. However, CGA can provide useful information on patients' fitness, resilient mechanisms, and reveal potential optimization strategies for compensating for vulnerabilities. In this narrative review, we will discuss key questions on cellular therapies in older adults based on illustrative patient cases.

Aspirin use and bleeding events during thrombocytopenia after autologous stem-cell transplantation for multiple myeloma.

Background: In patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication. Methods: We assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events. Results: There were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20-50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia < 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age >60 years, a hematopoietic stem-cell transplantation comorbidity index ≥3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT. Conclusions: The intake of ASA until thrombocytopenia with a platelet count of 20-50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia.

Hematopoietic Stimulation During Impella 5.5 Support to Avoid Transfusions in a Jehovah's Witness.

The population presenting with cardiogenic shock is heterogenous. Anemia is common in advanced heart failure and associated with poor outcomes. Microaxial flow pumps may cause ongoing blood trauma and worsen anemia. Treatment with recombinant erythropoietin, iron, vitamin B, and folate is recommended before cardiac surgery to reduce perioperative transfusion requirements but no data exist on the feasibility and safety during support with microaxial flow pumps. This novel strategy was born out of necessity to support a Jehovah's Witness who opposes blood transfusion but required mechanical circulatory support. We present its efficacy over the duration of 19 days of Impella 5.5 support where hemoglobin level remained stable, and platelet count significantly improved despite a brief episode of gastrointestinal bleeding. No thromboembolic complications occurred. We anticipate this strategy could help not only Jehovah's Witnesses, but also patients awaiting cardiac transplantation since transfusions stimulate development of antibodies which may preclude or postpone finding a suitable donor organ. Furthermore, it may minimize or prevent perioperative needs for transfusions for patients being bridged to durable left ventricular assist devices.

Hypomethylating agent-based therapies in older adults with acute myeloid leukemia - A joint review by the Young International Society of Geriatric Oncology and European Society for Blood and Marrow Transplantation Trainee Committee.

Acute myeloid leukemia (AML) is associated with poor outcomes in older adults. A major goal of treatment is to balance quality of life and functional independence with disease control. With the approval of new, more tolerable regimens, more older adults are able to receive AML-directed therapy. Among these options are hypomethylating agents (HMAs), specifically azacitidine and decitabine. HMAs have become an integral part of AML therapy over the last two decades. These agents are used either as monotherapy or nowadays more commonly in combination with other agents such as the Bcl-2 inhibitor venetoclax. Biological AML characteristics, such as molecular and cytogenetic risk factors, play crucial roles in guiding treatment decisions. In patients with high-risk AML, HMAs are increasingly used rather than intensive chemotherapy, although further trials based on a risk-adapted approach using patient- and disease-related factors are needed. Here, we review trials and evidence for the use of HMA monotherapy and combination therapy in the management of older adults with AML. Furthermore, we discuss the use of HMAs and HMA combination therapies in AML, mechanisms of action, their incorporation into hematopoietic stem cell transplantation strategies, and their use in patients with comorbidities and reduced organ function.

Acute myeloid leukemia: negative prognostic impact of early blast persistence can be in part overcome by a later remission prior to post-induction therapy.

In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, eventfree survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases.

Validation of a proxy-reported SARC-F questionnaire for current and retrospective screening of sarcopenia-related functional impairments.

BACKGROUND: The strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) questionnaire is a well-established instrument for screening of sarcopenia and sarcopenia-related functional impairments. As it is based on self-reporting, its use precludes patients who are unable to answer the questionnaire as a consequence of severe acute diseases or cognitive impairment. Therefore, we aimed to validate a proxy-reported version of the SARC-F for both ad-hoc as well as retrospective screening for severe sarcopenia-related functional impairments. METHODS: Patients aged ≥60 years completed the SARC-F and performed the short physical performance battery (SPPB) at baseline (T1). Proxies in Cohort A gave a simultaneous assessment of the patients' functional status with the proxy-reported SARC-F at T1 and again, retrospectively, after 3 months (T2). Proxies in Cohort B only completed the SARC-F retrospectively at T2. The questionnaires' performances were assessed through sensitivity/specificity analyses and receiver operating characteristic (ROC) curves. For non-inferiority analyses, results of both the patient-reported and proxy-reported SARC-F were correlated with the SPPB total score as well as the results of the chair-rise test subcategory; the respective correlation coefficients were tested against each other. RESULTS: One hundred and four patients and 135 proxies participated. Using a SPPB score < 9 points as the reference standard, the proxy-reported SARC-F identified patients at high risk for sarcopenia-related functional impairment with a sensitivity of 0.81 (ad-hoc), 0.88 (retrospective Cohort A), and 0.87 (retrospective Cohort B) as well as a specificity of 0.89 (ad-hoc), 0.78 (retrospective Cohort A), and 0.64 (retrospective Cohort B). Areas under the ROC curves were ≥ 0.9 for the ad-hoc proxy-reported SARC-F and the retrospective proxy-reported SARC-F in both cohorts. The proxy-reported SARC-F showed a non-inferior correlation with the SPPB compared with the patient-reported SARC-F for ad-hoc (P = <0.001) as well as retrospective screening for severe sarcopenia-related functional impairment in both Cohorts A (P = 0.007) and B (P = 0.026). CONCLUSIONS: Proxy-reported SARC-F is a valid instrument for both ad-hoc as well as retrospective screening for sarcopenia-related functional impairment and could become the standard tool for evaluating this risk in older adults with severe acute disease, for example, in patients with quickly evolving haematological conditions.

Frailty assessment in the care of older people with haematological malignancies.

Frailty, defined as an age-related state of increased vulnerability to acute stressors, is a major challenge in the care of older people with haematological malignancies. Growing evidence from multiple studies suggests that a systematic evaluation of frailty in these patients by use of appropriate assessment tools might help clinicians to make appropriate treatment decisions and initiate frailty interventions. Here, we summarise current knowledge on the origin, decision relevance, assessment methods, and possible treatments of frailty in older people with haematological malignancies. Practical advice is provided on how to care for those with frailty and blood cancer.

Clinical outcome of older adults with acute myeloid Leukemia: An analysis of a large tertiary referral Center over two decades.

OBJECTIVE: In older adults with acute myeloid leukemia (AML), the overall outcome is still dismal and long-term data on survival are scarce, particularly outside of clinical trials. Here, we assess characteristics, prognostic factors and long-term survival in patients ≥60 years who were treated for AML at our center over the past 17 years. METHODS: 590 older adults with newly diagnosed AML were characterized according to Eastern Cooperative Oncology Group (ECOG) score, Charlson comorbidity index (CCI), European LeukemiaNet (ELN) risk, type of therapy, serum ferritin (SF) and further baseline characteristics. Survival analysis was performed accordingly. RESULTS: Median age was 68 years and most patients were in good general condition. Median follow-up was 55.8 months. Of all patients, 66% received intensive chemotherapy (IC) +/- allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining cohort received palliative chemotherapy (PC, 26%) or best supportive care only (BSC, 8%). Enrollment rate for interventional clinical trials was 26%. 5-year overall survival (OS) and relapse-free survival (RFS) were 18% (median 12.5 months) and 11,5% (median 10.0 months). Long-term survival was independently influenced by ECOG score, ELN risk group, baseline SF, previous myocardial infarction, and choice of therapy, but not consistently by age or CCI. Considering therapeutic subgroups, the contribution of particular parameters in predicting OS was most compelling in IC patients, but less consistent with PC or BSC. CONCLUSION: Our results provide thorough insights into prognostication within therapeutic subgroups and emphasize the need for more detailed prognostic algorithms and routine geriatric assessment in the treatment of older adults with AML.

Caring for older patients with cancer during the COVID-19 pandemic: A Young International Society of Geriatric Oncology (SIOG) global perspective.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected millions of people in over 180 territories, causing a significant impact on healthcare systems globally. Older adults, as well as people living with cancer, appear to be particularly vulnerable to COVID-19 related morbidity and mortality, which means that older adults with cancer are an especially high-risk population. This has led to significant changes in the way geriatric oncologists provide care to older patients, including the implementation of novel methods for clinical visits, interruptions or delays in procedures, and modification of therapeutic strategies, both in the curative and palliative settings. In this manuscript, we provide a global overview of the perspectives of geriatric oncology providers from countries across Europe, America, and Asia, regarding the adaptive strategies utilized to continue providing high quality care for older patients with cancer during the COVID-19 pandemic. Through these perspectives, we attempt to show that, although each country and setting has specific issues, we all face similar challenges when providing care for our older patients with cancer during these difficult times.

Treatment of acute promyelocytic leukemia in older patients: recommendations of an International Society of Geriatric Oncology (SIOG) task force.

Approximately one third of patients diagnosed with acute promyelocytic leukemia (APL) are above the age of sixty. It is important to ensure older adults receive optimal diagnosis and management since this subtype of acute myeloid leukemia - given appropriate treatment - is highly curable with lower risk of adverse events compared to other types of leukemia. Historically, older age has been a risk factor for early death and poorer overall survival. However, prospects have changed with the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). APL is curable in the majority of patients regardless of age, and the threshold of fitness that makes ATRA/ATO therapy possible is likely to be lower than for cytotoxic chemotherapy. APL frequently presents as a medical emergency and rapid diagnosis and intervention - typically involving referral to a specialist centre - is a major determinant of outcome. After diagnosis, management of APL in older adults presents particular challenges. Geriatric assessment, including evaluation of frailty, comorbidities and polypharmacy can assist in providing optimal supportive care for older adults during remission induction and may help individualize therapy in the post-remission phase. Here, we review the available evidence, highlighting areas of consensus, gaps in evidence and opportunities for research to enhance diagnosis, management and survivorship for older patients.

Anthracycline-related cardiotoxicity in older patients with acute myeloid leukemia: a Young SIOG review paper.

The incidence of acute myeloid leukemia (AML) increases with age. Intensive induction chemotherapy containing cytarabine and an anthracycline has been part of the upfront and salvage treatment of AML for decades. Anthracyclines are associated with a significant risk of cardiotoxicity (especially anthracycline-related left ventricular dysfunction [ARLVD]). In the older adult population, the higher prevalence of cardiac comorbidities and risk factors may further increase the risk of ARLVD. In this article of the Young International Society of Geriatric Oncology group, we review the prevalence of ARLVD in patients with AML and factors predisposing to ARLVD, focusing on older adults when possible. In addition, we review the assessment of cardiac function and management of ARLVD during and after treatment. It is worth noting that only a minority of clinical trials focus on alternative treatment strategies in patients with mildly declined left ventricular ejection fraction or at a high risk for ARLVD. The limited evidence for preventive strategies to ameliorate ARLVD and alternative strategies to anthracycline use in the setting of cardiac comorbidities are discussed. Based on extrapolation of findings from younger adults and nonrandomized trials, we recommend a comprehensive baseline evaluation of cardiac function by imaging, cardiac risk factors, and symptoms to risk stratify for ARLVD. Anthracyclines remain an appropriate choice for induction although careful risk-stratification based on cardiac disease, risk factors, and predicted chemotherapy-response are warranted. In case of declined left ventricular ejection fraction, alternative strategies should be considered.

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL.

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features.

BCR-ABL-positive acute myeloid leukemia (AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. Since a clear distinction between de novo BCR-ABL+ AML and chronic myeloid leukemia (CML) blast crisis is challenging in many cases, the existence of de novo BCR-ABL+ AML has been a matter of debate for a long time. However, there is increasing evidence suggesting that BCR-ABL+ AML is in fact a distinct subgroup of AML. In this study, we analyzed all published cases since 1975 as well as cases from our institution in order to present common clinical and molecular features of this rare disease. Our analysis shows that BCR-ABL predominantly occurs in AML-NOS, CBF leukemia, and AML with myelodysplasia-related changes. The most common BCR-ABL transcripts (p190 and p210) are nearly equally distributed. Based on the analysis of published data, we provide a clinical algorithm for the initial differential diagnosis of BCR-ABL+ AML. The prognosis of BCR-ABL+ AML seems to depend on the cytogenetic and/or molecular background rather than on BCR-ABL itself. A therapy with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib is reasonable, but-due to a lack of systematic clinical data-their use cannot be routinely recommended in first-line therapy. Beyond first-line treatment of AML, the use of TKI remains an individual decision, both in combination with intensive chemotherapy and/or as a bridge to allogeneic stem cell transplantation. In each single case, potential benefits have to be weighed against potential risks.

BCR-ABL1(+) acute myeloid leukemia: clonal selection of a BCR-ABL1(-) subclone as a cause of refractory disease with nilotinib treatment.

The presence of a Philadelphia chromosome with a corresponding BCR-ABL1 rearrangement is the hallmark of chronic myeloid leukemia, but is considered a very rare event in de novo acute myeloid leukemia (AML). Here, we report the first case in which a dominant Philadelphia chromosome-positive subclone was detected upon relapse in a formerly Philadelphia chromosome-negative MLL-AF6(+) AML. Due to refractory disease under salvage chemotherapy, the patient was started on nilotinib treatment. As a result, the Philadelphia chromosome-positive subclone was eradicated within 1 month; however, disease progressed and was again dominated by the Philadelphia chromosome-negative founding clone, demonstrating rapid clonal expansion under nilotinib-induced selection pressure.