Page 119 - Haematologica March 2020

Transfusion dose density in lower-risk MDS
(P<1x10-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.
Introduction
Red blood cell transfusions (RBCT) are the major com- ponent of the supportive care of patients with myelodys- plastic syndromes (MDS). The life expectancy of MDS patients treated with RBCT is usually shorter than that of untransfused patients,1,2 but whether the impaired out- come is a result of intrinsic deterioration of the underlying disease or a result of external factors related to transfusion per se (for example the iron toxicity induced by RBCT) remains an open question. Since 2007, the European MDS (EUMDS) Registry has prospectively collected observa- tional data on patients with MDS classified as low and intermediate-1 risk according to the International Prognostic Scoring System (IPSS),3 collectively defined as lower-risk MDS.4 The majority of lower-risk MDS patients become transfusion dependent (51% in the EUMDS Registry),4 usually within 6 months after diagnosis. With an expected median survival of 2.4 to 11.8 years, these patients might be prone to long-term accumulation of iron due to RBCT.3,5-8 The toxic effects of iron overload in other iron-loading diseases, such as hereditary hemochromato- sis9 and the thalassemia syndromes,10 are well known, but the consequences in MDS patients require further clarifica- tion. MDS patients are generally older than patients with other iron-loading disorders.11 Their exposure to RBCT may not be long enough to develop classical tissue damage due to iron overload, but they may suffer from oxidative stress caused by toxic iron species, including non-transfer- rin bound iron (NTBI) and labile plasma iron (LPI), which have been suggested to serve as early indicators of iron toxicity in iron-loading anemias, such as thalassemia syn- dromes.8,12 Biomarkers of oxidative stress have been found to be increased in patients with MDS and iron overload.4,13- 16 Data from a recently completed study of the EUMDS Registry17 showed that elevated LPI levels - in contrast to elevated NTBI levels and transferrin saturation - are asso- ciated with decreased survival. The risk of dying prema- turely in patients with detectable LPI levels occurred too early in this study to be explained by classical iron over- load with organ toxicity (lungs, liver and heart) after long term transfusions, and this may suggest a direct effect associated with elevated LPI levels.
The aim of this analysis was to assess the effect of RBCT dose density on progression-free survival (PFS) of patients with lower-risk MDS. The hypothesis is that transfusional iron may be toxic and associated with oxida- tive stress, which may lead to bone marrow failure, genet- ic damage, increased risk for progression or premature death. Two countervailing forces may play a role in this analysis: (i) patients with symptomatic anemia are more likely to receive more frequent RBCT; and (ii) higher RBCT doses may lead to faster deterioration of lower-risk MDS or to a higher risk of complications by co-morbidi- ties.
Methods
Patients with lower-risk MDS (IPSS risk: low or intermediate-1)3 from 16 European countries and Israel were included in the EUMDS Registry, after providing signed informed consent, within 100 days of their initial diagnosis of a MDS which was made according to the World Health Organization (WHO) 2001 crite- ria.18 Patients with an IPSS intermediate-2 or high risk, or with therapy-related MDS were excluded, but MDS-specific treatment, started before registration within 100 days after diagnosis, was not a reason for exclusion. Data were collected at baseline and at each 6-monthly outpatient routine follow-up visit. Clinical information was collected on: demographics, anthropometrics, co-morbidities, performance status, quality of life (EQ-5D), concomitant medica- tion, laboratory parameters, diagnostics including information on bone marrow morphology, histology, cytogenetics, RBCT episodes, total number of transfused units and simultaneous ther- apeutic interventions. All subjects were followed prospectively by full reports every 6 months until death, progression to high risk MDS or leukemia, loss to follow-up or withdrawal of informed consent. The Registry was approved by each institution’s ethics committee in accordance with national legislation.
Transfusion data available in the EUMDS Registry consists of the number of units received between each reported visit, usually at 6-month intervals. In order to assess the association between transfusions received and PFS, proportional hazards regression with time-varying covariates was employed, adjusting the effect of transfusions by appropriate baseline and time-varying variables. For the purposes of the time-to-event analyses, time was meas- ured from the date of diagnosis with MDS to the date of disease progression or date of death. Progression is defined as an increase to either refractory anemia with excess blasts-2 or to acute leukemia. Patients without disease progression and still alive at the time of the analyses were censored at the date of their last visit.
In order to avoid problems with simultaneity of cause and effect assumed by the proportional hazards approach to survival analy- sis a “dose density” variable was defined, in the following way, for blood transfusions received. The cumulative total of units of blood received at the end of each inter-visit time interval was calculated. This was then divided by the time since the beginning of the time interval in which the first post-diagnosis transfusion was received, giving a dose-density measurement. This dose-density was then assigned to each time interval. The value of this variable at each point in time represents the average rate at which the patient has been receiving units of blood since they started transfusions.
Adjusted baseline variables included age at diagnosis, number of cytopenias and number of units of blood received before diag- nosis. Adjusted time-varying variables (with the intention of adjusting for the condition of the patient over time) were bone marrow blast count, EQ-5D index, revised IPSS cytogenetic cate- gory, and platelet and neutrophil counts. Additional analyses were adjusted for the effect of treatment with erythropoiesis-stimulat- ing agents (ESA), iron chelation therapy and lenalidomide, taking these treatments to be confounding factors. Finally, a sensitivity
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