Contents
9.1 Introduction . . . 95 9.2 Co-morbidity and Causes of Death . . . 95 9.3 Quality of Life . . . 96 9.4 Red Blood Cell Transfusions . . . 96 9.5 Iron Chelation Therapy . . . 97 9.6 Thrombocytopenia and Bleeding . . . . 97 9.7Neutropenia and Infection . . . 98 References . . . 98
9.1 Introduction
Although active therapeutic interventions are available for patients with myelodysplastic syndrome (MDS), many patients may be suitable for supportive care only.
This is a consequence of both a lack of effective thera- peutic strategies, and the relatively high co-morbidity in this predominantly older patient cohort. Supportive care usually refers to the replacement of deficient blood components (red blood cells and platelets) in sympto- matic patients, treatment of infection, and iron chela- tion therapy for transfusional iron overload. These in- terventions will not alter the natural history of the dis- ease, though there is some evidence that iron chelation therapy may have a disease-modifying effect. High- quality evidence for the effectiveness of supportive care in terms of outcome measures such as quality of life and
survival is lacking and has not been systematically stud- ied. It is paradoxical that supportive care, which is dif- ficult to standardize, has remained the standard of care against which new therapeutic interventions are com- pared. Nevertheless, the goal of supportive care is to im- prove quality of life, and where possible, prolong surviv- al.
9.2 Co-morbidity and Causes of Death
Transformation to acute myeloid leukemia (AML) and overall survival are the endpoints most widely reported for large cohort studies of unselected patients with MDS. AML transformation is easy to recognize and al- most always contributes directly to the cause of death in the affected patients, predominantly in the high-risk MDS subtypes (refractory anemia with excess blasts (RAEB)-2 by the World Health Organization (WHO), INT-2/high-risk groups by International Prognostic Scoring System (IPSS)). However, causes of death among patients who do not transform to AML may be directly related to their MDS, including therapy-related complications such as iron overload, or alternatively to co-morbid conditions. Analysis of the largest cohort of MDS patients, including all categories, in whom the causes of death were reported, identified 28% of deaths due to AML transformation, 60% due to hemorrhage/
infection, 12% due to apparently MDS-unrelated causes, and 1% (3/216 deaths) due to secondary hemosiderosis (Table 9.1) (Sanz et al. 1989). In low-risk MDS, death due to unrelated causes occurred in up to 45% of pa- tients with the low-risk WHO subtype refractory ane- mia with ringed sideroblasts (RARS), and in approxi-
Supportive Care
David T. Bowen
mately 15±20% of patients with multilineage dysplasia (Germing et al. 2000; Matsuda et al. 1999; Mufti et al.
1985).
9.3 Quality of Life
Parameters of physical quality of life (QOL) are im- paired in MDS patients compared with healthy age and sex-matched subjects. These physical parameters include physical functioning and vitality (Short Form- 36 tool) and the physical component of fatigue (Euro- QOL-5D Visual Analogue Scale instrument). Each of these physical parameters was correlated to hemoglobin concentrations in a cohort of regularly transfused MDS patients (Jansen et al. 2003). Mental components of the QOL instruments were not influenced by hemoglobin concentrations in this small study. In separate cohorts of patients with cancer-related anemia treated with re- combinant Epo, a similar improvement in physical QOL parameters has been observed, correlating well with an improvement in hemoglobin concentration (Boogaerts et al. 2003; Fallowfield et al. 2002).
Options and indications for supportive care are listed in Table 9.2.
9.4 Red Blood Cell Transfusions
Chronic anemia, though seldom life threatening, can produce significant morbidity and is, therefore, impor- tant in relation to QOL and to co-morbid conditions.
The influence of chronic anemia on cardiac complica- tions in MDS patients remains unknown. Chronic ane- mia increases cardiac pre-load, which leads to left ven- tricular hypertrophy and an increased cardiac output.
In well-chelated patients with b-thalassaemia, asympto- matic abnormalities of cardiac function have been documented, including both an increase in left ventri- cular mass, and reduced contractility (Bosi et al.
2003). Left ventricular ejection fraction was reduced in patients with greater iron load but was also abnormal in some patients who were well chelated.
96 Chapter 9 ´ Supportive Care
Table 9.1. Causes of death in MDS patients
Study Subtype Hemor-
rhage (%)
Infection (%)
AML trans- formation (%)
Cardiac failure (%)
Unrelated to MDS (%)
Unknown (%)
Total
Sanz et al.
(1989)
All MDS 129 (45) 60 (21) 3 (1) 24 (8) 72 (25) 288
RA (high risk)
Matsuda et 2 (22) 4 (44) 3 (33) 0 0 0 9
l
al. (1999) RA (int. risk) 6 (25) 8 (33) 5 (21) 3 (13) 0 2 (8) 24
RA (low risk) 1 (11) 4 (44) 2 (22) 0 2 (22) 0 9
Germing et PSA 0 9 (24) 0 6 (16) 11 (29) 12 (31) 38
l
al. (2000) RARS* 6 (8) 24 (32) 9 (12) 5 (7) 12 (16) 18 (25) 74
RA refractory anemia (FAB), PSA pure sideroblastic anemia (WHO=RARS)
* RARS now reclassified as RCMD-RS by WHO
Table 9.2. Supportive care: options and indications Red cell transfusion
Symptomatic anemia Platelet transfusion
Chronic thrombocytopenia with clinical bleeding Planned surgical intervention
Granulocyte-colony stimulating factor Infectious episodes
Chronic neutropenia with recurrent infections Antibiotic therapy
Infectious episodes Iron chelation therapy
Patients with longer life expectancy (e.g., 5q± syndrome, WHO subtypes RA, RARS)
Initiate after 25 units transfused (500 mg iron)
Red cell transfusions should be considered in any patient symptomatic of anemia, irrespective of hemo- globin concentration and after exclusion of other causes. Patients with MDS may, however, compensate well for their anemia and the hemoglobin trigger for the introduction of red cell transfusions will vary be- tween individuals. The frequency of red cell transfusion is variable, and anecdotal evidence would suggest that the intertransfusion interval decreases with time. For patients with short transfusion intervals, bleeding and hemolysis must be considered, but the high transfusion requirement usually simply reflects profound erythroid failure (severe reticulocytopenia) with or without pe- ripheral consumptive processes such as hypersplenism.
Although most physicians and patients accept the ªup- downº cyclical symptoms of a conventional transfusion program, evidence from cancer patients treated with re- combinant Epo would indicate the greatest incremental benefit in QOL to occur at hemoglobin concentrations
>12 g/dl (Cella 1997; Demetri et al. 1998). Most regularly transfused MDS patients rarely achieve this level, even transiently.
The risks associated with red cell transfusions are considerable, and many may not have been recognized.
Increasing recognition of transfusion-transmitted infec- tion drives the search for alternative strategies for the management of anemia. Recent infectious agents con- sidered or proven to be associated with red cell transfu- sions include hepatitis C, TT virus, and new variant Creutzfeldt-Jakob disease. Although these infections with long incubation times, if transmitted, appear of lit- tle relevance to the majority of MDS patients whose life expectancy is <6 years, there are long-term transfused patients for whom the concern for infections is a major issue. Further, red cell alloimmunization is common and the frequency increases with increasing numbers of blood units transfused. Allosensitization may be of particular concern in patients who are candidates for hemopoietic cell transplantation. Of note, reactions to red cell transfusion are equally frequent in patients with and without red cell antibodies, presumably because of sensitization to antigens expressed on leukocytes (Fluit et al. 1990).
9.5 Iron Chelation Therapy
There are no data on which to base recommendations for iron chelation therapy in patients with MDS. Anec-
dotally, all Hematologists will recall patients with trans- fusional iron overload who have died of cardiac failure.
For most of these patients, it is difficult to exclude at least a contribution from co-existent cardiac disease or the cardiac effects of chronic anemia. For practical purposes, the UK Guidelines for the Diagnosis and Management of MDS have recommended instituting iron chelation therapy for those transfusion-dependent patients who have a good prognosis (e.g., 5q± syn- drome, WHO category RARS), commencing after ap- proximately 25 units of packed red blood cells trans- fused (Bowen et al. 2003). Desferrioxamine remains the iron chelator of choice, usually administered subcu- taneously by prolonged infusion or twice daily bolus.
The support of an active multidisciplinary team is es- sential to maximize compliance with this cumbersome and invasive therapy. Desferrioxamine, given as a regu- lar subcutaneous infusion, can reduce serum ferritin and liver iron concentration in MDS patients (Jensen et al. 1995). Addition of Vitamin C, 100±200 mg daily, taken about 1 h prior to desferrioxamine infusion, in- creases the proportional iron excretion but should not be started until approximately 4 weeks after desferriox- amine therapy is initiated. The use of twice daily subcu- taneous bolus injections of desferrioxamine (Franchini et al. 2000) may be considered where infusions are not tolerated, but there is even less information about their potential value in MDS than for the prolonged in- fusions. Observational studies have also suggested that desferrioxamine therapy may be associated with im- proved marrow function, and reduced transfusion re- quirements (Haines and Wainscoat 1991; Jensen et al.
1996). The oral iron chelator Deferiprone is increasingly used, although large studies demonstrating efficacy and safety in MDS patients are lacking. The availability of new oral iron chelators will catalyze research and hope- fully lead to a more rational approach to iron chelation in MDS patients (Nisbet-Brown et al. 2003).
The main challenges are to clearly link transfusional iron overload to life-threatening complications such as cardiac failure, and to develop reliable methods for monitoring iron status in relevant end organs such as the liver and heart (Jensen et al. 2003).
9.6 Thrombocytopenia and Bleeding
Bleeding occurs usually coincident with severe thrombo- cytopenia due to bone marrow failure, but may rarely
a 9.6 ´ Thrombocytopenia and Bleeding 97
also be a manifestation of MDS-associated functional de- fects of platelets. Prophylactic platelet transfusions are not indicated in asymptomatic thrombocytopenic pa- tients and should be reserved to cover symptomatic bleeding or planned interventional procedures such as surgery or dental extraction. The efficacy of danazol in transiently improving platelet counts in MDS patients is controversial (Chabannon et al. 1994; Chan et al. 2002).
9.7 Neutropenia and Infection
Neutropenia is common in MDS patients, and infection is one of the major causes of death (Table 9.1). Most MDS patients treated with granulocyte-colony stimulat- ing factor (G-CSF) increase their blood neutrophil counts, indicating reasonable marrow reserve. No ran- domized studies have yet demonstrated a clear benefit for routine use of G-CSF, although in one cohort study, patients with neutrophil counts maintained at >1.5 ´ 109/ L had fewer infections than those with lower values (Ne- grin et al. 1992). Prophylactic G-CSF therapy may have some role in patients with severe chronic neutropenia and recurrent infections. There is no evidence for pro- phylactic antibiotic therapy in this context.
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