Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials.

The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for "hematological improvement" criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between "procedures" and "criteria" for hematologic improvement-erythroid assessment and a new categorization of transfusion-burden subgroups.

Fatigue at baseline is associated with geriatric impairments and represents an adverse prognostic factor in older patients with a hematological malignancy.

Prospective data on fatigue in elderly persons with a hematological malignancy are rare. We aimed to determine the prevalence of fatigue and its association with clinical outcome and geriatric impairments in older individuals newly diagnosed with blood cancer. The EORTC QLQ-C30 and a multidimensional geriatric assessment (MGA) were performed in parallel in 149 consecutive patients aged > 67 years (median 77.8 years) at Innsbruck Medical University between January 2009 and April 2016. Fatigue as defined by EORTC QLQ-C30 was the most prevalent symptom (84%) and was significantly associated with self-reported role and physical functioning, global health status and insomnia, dyspnea, and loss of appetite (p < 0.001). Remarkably, pronounced fatigue was associated with impaired performance status and objective functional capacities in MGA, with altered depression scoring, G8 screening, and elevation of serum inflammation markers (p < 0.001). Patients with minor fatigue had a median overall survival (OS) of 26.4 months, whereas those with marked fatigue displayed an OS of 7.0 months (p < 0.001). The association between fatigue and shortened OS was supported in multivariate analyses (HR 1.74, CI 1.09-2.76; p = 0.021). Fatigue is seen to have a high prevalence and to be an adverse prognostic factor in elderly patients with a hematological malignancy. The strong impact of fatigue on clinical performance and OS emphasizes the relevance of patient-reported outcomes in individualized treatment algorithms. Patients will benefit from identification of fatigue, allowing timely interventions. The correlation between fatigue, impaired performance, nutritional status, and inflammation might suggest an underlying common pathway.

ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts.

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome.

BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force.

Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.

Clinical judgement and geriatric assessment for predicting prognosis and chemotherapy completion in older patients with a hematological malignancy.

Prior research has focused on comparing clinical judgment with geriatric assessments in identifying potentially unfit patients or the prognostic value of geriatric impairments. In this study, we set out to compare and combine geriatric impairments with clinical judgment in predicting mortality and non-completion of chemotherapy in older patients with a hematological malignancy. Between March 2004 and August 2014, a multi-dimensional geriatric assessment was performed in consecutive patients aged ≥65 years diagnosed with a hematological malignancy at the Innsbruck university hospital. Associations between geriatric assessment, clinical judgment (derived from initial treatment decision) and outcome (mortality, non-completion) were analyzed. Patient sample consisted of 157 patients, of which 37% was 80 + years of age. Aggressive non-Hodgkin lymphoma (29%), acute myeloid leukemia (27%) and myelodysplastic syndromes (20%) were most common diagnoses. Prevalence of an impaired geriatric assessment (i.e. impairments in ≥2 of eight assessed domains) was 71% and similar for patients receiving standard (71%) or attenuated treatment (72%). Clinical judgment was the strongest predictor of mortality (p = 0.003); addition of geriatric assessment allowed for further stratification of patients with a good (>75% one year survival), intermediate (50-60%) and poor prognosis (<30%). Cumulative burden of geriatric impairments further increased risk of mortality. Clinical judgment was greatly superior to geriatric assessment in identifying patients at risk for non-completion. The combination of clinical judgment and geriatric assessment allows for better prognostic stratification of patients compared to clinical judgment alone.

Accuracy of physician assessment of treatment preferences and health status in elderly patients with higher-risk myelodysplastic syndromes.

Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Control Preference Scale. Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring an active or collaborative role. Absence of the patient's request for prognostic information (P=0.001) and judging the patient as having a poor health status (P=0.036) were factors independently associated with the physicians' attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate health status of patients who reported low-level health status. The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care.

Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM).

A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

Azacitidine frontline therapy for unfit acute myeloid leukemia patients: clinical use and outcome prediction.

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.

The G8 screening tool detects relevant geriatric impairments and predicts survival in elderly patients with a haematological malignancy.

The G8 screening tool was developed to separate fit older cancer patients who were able to receive standard treatment from those that should undergo a geriatric assessment to guide tailoring of therapy. We set out to determine the discriminative power and prognostic value of the G8 in older patients with a haematological malignancy. Between September 2009 and May 2013, a multi-dimensional geriatric assessment was performed in consecutive patients aged ≥67 years diagnosed with blood cancer at the Innsbruck University Hospital. The assessment included (instrumental) activities of daily living, cognition, mood, nutritional status, mobility, polypharmacy and social support. In parallel, the G8 was also administered (cut-off ≤ 14). Using a cut-off of ≥2 impaired domains, 70 % of the 108 included patients were considered as having an impaired geriatric assessment while 61 % had an impaired G8. The G8 lacked discriminative power for impairments on full geriatric assessment: sensitivity 69, specificity 79, positive predictive value 89 and negative predictive value 50 %. However, G8 was an independent predictor of mortality within the first year after inclusion (hazard ratio 3.93; 95 % confidence interval 1.67-9.22, p < 0.001). Remarkably, patients with impaired G8 fared poorly, irrespective of treatment choices (p < 0.001). This is the first report on the clinical and prognostic relevance of G8 in elderly patients with haematological malignancies. Although the G8 lacked discriminative power for outcome of multi-dimensional geriatric assessment, this score appears to be a powerful prognosticator and could potentially represent a useful tool in treatment decisions. This novel finding certainly deserves further exploration.

Preference for involvement in treatment decisions and request for prognostic information in newly diagnosed patients with higher-risk myelodysplastic syndromes.

BACKGROUND: The main objective of this study was to assess preferences for involvement in treatment decisions and requests for prognostic information in newly diagnosed higher-risk myelodysplastic syndrome (MDS) patients. PATIENT AND METHODS: This was a prospective cohort observational study that consecutively enrolled MDS patients with an international prognostic scoring system (IPSS) risk category of intermediate-2 or high risk (summarized as 'higher risk'). The control preference scale was used to assess patient preferences for involvement in treatment decisions, and whether a request by patients for prognostic information during consultation was made, was also recorded. All of the patients were surveyed at the time of diagnosis before receiving treatment. Univariate and multivariate analyses were carried out to assess how sociodemographic, clinical and laboratory data related to decision-making preferences and requests for prognostic information. Relationship with the health-related quality of life (HRQOL) profile was also examined. RESULTS: A total of 280 patients were enrolled, 74% with intermediate-2 and 26% with high-risk IPSS. The mean age of patients was 70-year old (range: 32-89 years). One hundred thirty-two patients (47%) favored a passive role in treatment decision-making, whereas only 14% favored an active role. The remaining 39% of patients favored a shared decision-making approach. Patients with lower hemoglobin levels were more likely to prefer a passive role (P=0.037). HRQOL was generally better in patients preferring an active role versus those preferring a passive one. Overall, 61% (N=171) of patients requested prognostic information on survival during consultation. The likelihood of not requesting prognostic information was higher for older patients (P = 0.003) and for those with lower education (P=0.010). CONCLUSION: Decision-making preferences vary among patients with newly diagnosed higher-risk MDS. Current findings suggest that patients with worse underlying health conditions are more likely to prefer less involvement in treatment decisions.

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?

BACKGROUND: Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. METHOD: The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. RESULTS: In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. CONCLUSION: Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population.

The relevance of a geriatric assessment for elderly patients with a haematological malignancy--a systematic review.

BACKGROUND: Geriatric assessment is increasingly used to assess the health status of older cancer patients. We set out to assemble all available evidence on the relevance of a geriatric assessment in the treatment of older patients with haematological malignancies. METHODS: A systematic Medline and Embase search for studies in which a geriatric assessment was used to detect health issues or to address the association between baseline geriatric assessment and outcome. RESULTS: 18 publications from 15 studies were included. The median age of patients was 73 years (range 58-86). Despite generally good performance status, the prevalence of geriatric impairments was high. Geriatric impairments were associated with a shorter overall survival in a relevant proportion of studies (instrumental activities 55%, nutritional status 67%, cognitive capacities 83%, objectively measured physical capacity 100%). Comorbidity, physical capacity and nutritional status retained their significance even in multivariate analyses in 50%, 75%, and 67% of analyses respectively, whereas age and performance status lost their predictive value in most studies. One study found an association between comorbidity and chemotherapy-related non-haematological toxicity. In another study a pronounced association between summarised outcome of geriatric assessment and chemotherapy-related toxicity as well as response to treatment was described. CONCLUSION: This review demonstrates that a geriatric assessment can detect multiple health issues, even in patients with good performance status. Impairments in geriatric domains have predictive value for mortality and also appear to be associated with toxicity and other outcome measures and should thus be integrated in individualised treatment algorithms.