Comprehensive geriatric assessment predicts azacitidine treatment duration and survival in older patients with myelodysplastic syndromes.

BACKGROUND: Treatment of older patients with myelodysplastic syndrome (MDS) is based on disease biology and performance status. Performance status, however, does not reflect increasing co-morbidities, functional dependence or psychosocial issues in older patients. PATIENTS AND METHODS: This prospective study evaluated the burden of geriatric related health issues, assessed feasibility of "tailored" Comprehensive Geriatric Assessment (CGA), and compared treatment duration and survival in older patients with MDS and oligoblastic acute myeloid leukemia with and without deficits in CGA domains (n = 98). RESULTS: Although only 27 (28%) patients had an Eastern Cooperative Oncology Group score ≥2, 78% (n = 77) patients had deficits in at least one CGA domain. Deficits were spread across all CGA domains, including dependence for instrumental activity of daily living (iADL; n = 33, 34%). Importantly, patients who were dependent for iADL (3.7 ±â€¯2.6 vs 12.1 ±â€¯7.9; p = .009), had cognitive impairment (3.5 ±â€¯2.1 vs. 10.9 ±â€¯7.9; p = .034) or impaired mobility (3.8 ±â€¯2.5 vs. 13.2 ±â€¯7.6; p = .001) completed significantly less azacitidine cycles as compared to those without these deficits. Cox-proportional regression showed that iADL dependency (hazard ratio 3.37; p = .008) and higher comorbidities (hazard ratio 4.7; p < .001) were associated with poor prognosis independent of disease related factors. Poor survival of iADL dependent patients was seen in both azacitidine (6 vs 19 months; p < .001) and supportive care cohorts (26 vs 48 months; p = .01). CONCLUSION: CGA detected geriatric related health issues, predicted poor survival and identified patients less likely to continue and benefit from azacitidine. Hence, CGA should be included in the treatment decision algorithm of older patients with MDS.

Interaction of increasing ICU survival and admittance policies in patients with hematologic neoplasms: A single center experience with 304 patients.

OBJECTIVE: We evaluated the development of ICU survival of patients with hematopoietic malignancies and discussed changes in admittance policies. METHOD: We compared 166 patients treated between 2009 and 2012 with 138 patients treated between 2013 and 2016. Patient characteristics and outcome were analyzed. RESULTS: ICU survival was 45.2% in the first group and 66.7% in the second (P < 0.0005). Infection (P = 0.033), invasive ventilation (IMV) (P = 0.014) and SOFA score at day 3 (SOFA-48h) (P = 0.007) independently indicated worse ICU survival in the first group, IMV (P = 0.013) and SOFA-48h (P = 0.019) in the second group. The second group showed lower frequencies of infection (P = 0.003), IMV (P < 0.0005), need for vasopressors (P < 0.0005) and RRT (P = 0.021) at ICU admittance than the first. Further, the accumulation of hyperkaliemia, acidosis, low bicarbonate, high lactate and hypotension showed worse ICU survival in both groups and was lower in second group. CONCLUSION: ICU survival increased distinctly between 2009 and 2016. At ICU admittance, parameters showing severity of illness were less frequent in the second group. Our findings indicate general treatment improvements especially of infections and changes of admittance policies toward early ICU admittance during time.

Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients.

RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.

Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.

Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.

Cost of transfusion-dependent myelodysplastic syndrome (MDS) from a German payer's perspective.

No curative treatment exists for patients with myelodysplastic syndrome (MDS) besides allogeneic stem cell transplantation. Hence, palliative treatment is provided for a life time accruing high health care cost. As no study in cost of MDS exists in Germany, the objective of this study was to assess and analyze costs of transfusion-dependent low/intermediate-1-risk MDS in Germany from a payers' perspective. From seven centers, 116 low/intermediate-1-risk transfusion-dependent MDS patients with and without isolated 5q-deletion were identified. Claims data and patient records of the previous 5 years were used to collect health care utilization data retrospectively. Publicly available tariff books and remuneration schemes were applied to evaluate mean costs per year in Euro with 2007 as base year. The annual cost of MDS patients was estimated at 14,883. Subgroup analyses showed differences in patient's characteristics and outcomes among patients treated at a hospital-based vs. an office-based setting. Patients treated at the hospital-based registry show higher cost, whereas the reasons for that still need to be detected. Overall, per annum direct costs range from 12,543 (SD 12,967) to 24,957 (SD 36,399) in different subgroups of patients. In both groups, patients with 5q-deletion use more medication than those without deletion. Mean costs for medication in the office-based setting are 5,902 for patients with isolated 5q-deletion vs. 3,932 for patients with no deletion, respectively. MDS leads to a high health care utilization and resulting costs for the health care system which requires a detailed analysis of underlying services.

[Paradigm change in the assessment of myeloid and lymphoid neoplasms associated with occupational benzene exposure]. / Paradigmenwechsel in der Beurteilung myeloischer und lymphatischer Neoplasien bei beruflicher Benzolexposition (BK-Ziffer 1303).

Benzene-caused hematologic neoplasms may be recognized as an occupational disease (OD) according to the German ordinance on ODs. At present, the OD No. 1303 covers heterogeneous diseases and various chemical agents triggering these diseases. The members of the medical advisory board specializing in ODs within the Ministry of Employment and Social Affairs recently proposed excluding "diseases of the blood, the hematopoietic and lymphatic system caused by benzene" from OD No. 1303 and classifying them as a separate OD. Benzene is generally acknowledged as a cause of acute myeloid leukemia, proven by numerous epidemiologic studies. However, there is less epidemiologic evidence of its association with other hematologic neoplasms, notably non-Hodgkin's lymphoma (NHL). To clarify this issue, the experts evaluated international literature and concluded that all kinds of myeloid and lymphoid malignancies including their prestages can be caused by occupational benzene exposure. Hence, physicians should ask patients about occupational benzene exposure and report any kind of diagnosed hematologic neoplasms, including their prestages, as suspected OD. The advisory board considered that a dose range starting from 10 ppm-years (cumulative benzene exposure) is sufficient for a > 50% probability of causing leukemias according to the WHO classification, including chronic lymphatic leukemia, and the potential preleukemias aplastic anemia and myelodysplastic syndrome, but excluding chronic myeloid leukemia (CML). For NHL and myeloproliferative diseases (including CML) the present epidemiologic evidence is considered not to be sufficient to describe a precise dose-effect relationship.

The sepsis-related Organ Failure Assessment (SOFA) score is predictive for survival of patients admitted to the intensive care unit following allogeneic blood stem cell transplantation.

Intensive care unit (ICU) support following allogeneic peripheral blood stem cell transplantation (PBSCT) is controversial due to the limited prognosis of these patients in case of secondary critical illness. In this retrospective single centre study, we looked for factors predicting survival in patients who needed ICU support after myeloablative (MAC) or non-myeloablative conditioning (non-MAC) therapy and allogeneic PBSCT. Between 1999 and 2006, 64 out of 319 patients following allogeneic PBSCT were admitted to the ICU (24 female and 40 male patients, median age 47 years, range 17-65 years; MAC 49 patients, non-MAC 15 patients). All 64 patients required mechanical ventilation. We looked for variables defining the Sepsis-related Organ Failure Assessment (SOFA) score as well as for baseline characteristics and transplant-associated parameters on the day of ICU admission possibly predictive for poor or good survival prognosis. Nineteen of 49 patients who had received MAC therapy survived the ICU stay for a median time of 9 months (range 2-29 months) and three of 15 patients who had received non-MAC therapy could be discharged from the ICU with a survival time of 4, 5 and 12 months. After univariate and multivariate analysis the SOFA score discriminated survivors and non-survivors of the ICU stay. We conclude that the SOFA score is predictive for survival when applied on the day of ICU admission.