Annals of Oncology Advance Access originally published online on December 22, 2005
Annals of Oncology 2006 17(2):281-285; doi:10.1093/annonc/mdj112
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© 2005 European Society for Medical Oncology
Acute myelogenous leukemia in elderly patients not eligible for intensive chemotherapy: the dark side of the moon
1 Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita ‘La Sapienza’ di Roma, 2 Ematologia, Ospedale S. Giovanni, Roma, 3 Ematologia, Istituto Regina Elena, Roma, Italy
* Correspondence to: Dr R. Latagliata, Department of Cellular Biotechnology and Hematology, University ‘La Sapienza’, Via Benevento 6 – 00161 Rome, Italy. E-mail: rob.lati{at}libero.it
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Abstract |
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Background: Acute Myelogenous Leukemia (AML) is a common disease in people aged >60 years. About 50% of the patients are not eligible for aggressive chemotherapy (CT) and are only managed with conservative approaches. Results in this subset of patients have not been reported so far.
Patients and methods: We retrospectively evaluated 244 consecutive elderly AML patients (M/F 143/101, median age 72 years, range 60–90) diagnosed at our institution from January 1989 to December 1998 and not eligible for intensive CT. Eighty-nine patients (36.5%) had evolved from previous myelodysplasia (sAML). Fifty-three out of 192 (26.4%) patients with available bone marrow (BM) analysis had oligoblastic leukaemia (blasts <40% and WBC <15x109/l).
Results: Sixty-seven patients (27.5%) were managed with supportive treatment only. One hundred seventy-seven patients (72.5%), in order to control disease, received conservative CT, consisting of Hydroxyurea (HU) (127 patients, 71.7%), Cytarabine and 6-Thioguanine (39 patients, 22%) or low-dose cytarabine (11 patients, 6.3%). Median overall survival was 179 days (1–3278) with 50 patients (20.5%) surviving >12 months. Older age (>75 years), poor WHO PS (>2), lower PLT levels (<50x109/l) and higher absolute peripheral blast count (>5 x 109/l) showed a negative prognostic impact on survival in multivariate analysis.
Conclusions: Our data outline the great heterogeneity of elderly AML patients not eligible for intensive CT. A simple scoring system including easily evaluable parameters, which could distinguish subjects with different prognosis, is proposed. Moreover, randomized studies in order to establish best conservative approaches are warranted.
Key words: acute myelogenous leukemia, conservative treatment, elderly patients, quality of life
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introduction |
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Acute Myelogenous Leukemia (AML) is a common disease in elderly people, median age at onset being about 65 years [1
]. As for many other diseases, the incidence of AML increases with the progressive ageing of the general population [2]. While the best management of AML is based mainly on intensive chemotherapy (CT) in younger patients, it still remains a matter of controversy in the elderly; in this latter patient population, intensive CT is often poorly tolerated and gives scanty results [3–5], owing to disease intrinsic biologic characteristics, such as presence of dysplastic features, high incidence of MDR and unfavourable karyotypes [6–7]. Moreover, many patients do not undergo intensive CT as they are considered too frail by physicians, for their poor performance status (PS) and/or the presence of co-morbidities. As a matter of fact, less than 50% of newly-diagnosed AML patients aged >60 are included in intensive CT trials [8]. Furthermore, it has to be considered that patients of very old age (over 80 years) or with very poor PS are not referred to haematology departments and are managed in medicine wards by general physicians. All studies relating to this issue are thus focused on those patients who enter intensive CT programs; the remaining casistics comprises patients with heterogeneous features and represents the ‘dark side’ of the matter, which haematologists have only scanty means to highlight.
The aim of the present study is to examine retrospectively 244 consecutive elderly AML patients diagnosed at our department over a 10-year period and not eligible for intensive CT, and point at the possible identification of patients with different disease outcome and survival.
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patients
From January 1989 to December 1998, a total of 374 patients aged >60 years were diagnosed as having AML at the Haematology Department, University ‘La Sapienza’ of Rome. Of these, 86 (23.1%) (median age 65 years, range 60–77) were eligible for intensive CT and were enrolled into protocols of the GIMEMA Cooperative Group, while 288 (median age 72 years, range 60–90) were considered not eligible for an intensive approach. Of these latter patients, 44 (11.7%) were referred to other centers close to their homes immediately after diagnosis, and were excluded from present analysis. The remaining 244 patients (65.2%) were followed at our institution with conservative approaches, and constitute the basis of the present examination.
In 192/244 patients (78.7%), the diagnosis was performed on bone marrow (BM) and peripheral blood (PB) smears, according to FAB criteria (marrow blasts 
30%). In the remaining 52 patients (21.3%), BM aspirate was not performed because of poor clinical conditions or patient refusal; in these cases the diagnosis was only made on the basis of PB blastosis 30%, in the absence of well-established diagnostic criteria.
Clinical and haematological characteristics of the patients at disease onset are presented in Table 1; 53 out of 192 patients with evaluable BM examination (26.4%) (M/F 36/17, median age 71 years, median WBC value 2.3x109/l, median PLTS value 73.0x109/l) had oligoblastic AML, as defined by BM blastosis 30 and <40%.
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As regarding karyotype, 52 patients did not perform marrow aspirate at diagnosis, 107 patients (diagnosed with marrow aspirate elsewhere and revised by us or diagnosed at our institution with a simple morphologic marrow aspirate) did not repeat a second aspirate for bad general conditions, refusal or medical decision, 22 patients performed karyotype but the study failed. As a matter of fact, only 61/242 patients (25.2%) had an evaluable karyotype and they were heavily selected when compared with the whole population: thus, data from karyotype were excluded from this study.
As concerns concomitant diseases present at AML diagnosis, they consisted of a symptomatic heart impairment in 63 patients (25.8%), arterial hypertension in 32 (13.1%), diabetes in 30 (12.2%), chronic pneumopathy in 27 (11%), renal and hepatic failures in eight (3.3%) and seven (2.9%), respectively.
treatment
All patients were managed with a conservative strategy.
supportive therapy
- Red packed cell transfusions for Hb levels <9 g/dl (or <10 g/dl in the presence of cardiac disease);
- anti-haemorrhagic prophylaxis with tranexamic acid and low-dose steroids, for PLT levels <50x109/l;
- PLT transfusions in patients with severe haemorrhages (WHO >2) or PLT levels <10x109/l in the presence of fever;
- broad-spectrum antibiotic treatment with Ceftriaxone + Amikacin in case of neutropenic fever (PMN <1x109/l). Prophylactic antibiotics were not routinely prescribed in neutropenic patients to avoid bacterial selection.
palliative chemotherapy.
Palliative CT was started in the presence of leukocytosis (WBC >15x109/l or with a doubling time shorter than a week). Three different schedules were employed:
- 6-Thioguanine (6-TG) (100 mg/m2 days 1–4) + Cytarabine (AraC) (100 mg/m2 s.c. day 5) every 15 days, according to a palliative GIMEMA protocol (between November 1988 and September 1990);
- Hydroxyurea (HU) (at the initial dose varying according to WBC count), with the addition of 6-Mercaptopurine (6MP) in case of poor disease control (from January 1988 to October 1988 and from October 1990 to December 1998);
- low-dose cytarabine (LoDAC) (20 mg/m2 s.c. for 14 consecutive days, every 28 days) in patients with severe pancytopenia and hypoplastic BM.
Patients were followed until death or until they were sent to other institutions or lost to follow-up. Hospital stay duration was also calculated along the whole period from diagnosis to death or last follow-up. Disease improvement was defined as an increase in Hb and/or PLT levels without transfusional requirement lasting at least 3 months; progressive disease was defined as increasing WBC values unresponsive to CT.
statistical analysis
The Kaplan–Meier method was used to obtain survival curves; differences between survival were tested by Log rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors.
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results |
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exclusion criteria from intensive CT
Of the 244 patients examined in this study, 74 (30.3%) had been excluded from intensive CT because of a concomitant severe disease (heart failure, 40 patients, renal, hepatic or neurological disease, 34 patients). A PS >2 and a previous MDS lasting more than 6 months had led to CT exclusion in 55 (22.5%) and 44 patients (18%), respectively. The remaining 71 patients (29.2%) had been considered not eligible for intensive CT only because of age >75 years.
treatment
Sixty-seven patients (27.5%) were managed with only supportive treatment along all the course of disease, while 177 (72.5%) required palliative CT to control the disease. Median time from diagnosis to start of CT was 10 days (range 0–1719); treatment was initiated within 30 days in 106 patients (60%), between 30 and 60 days in 17 patients (9.5%) and beyond 60 days in 54 patients (30.5%). HU was employed in 127 patients (71.7%), the association AraC + 6-TG in 39 patients (22%); the remaining 11 patients (6.3%) were treated with LoDAC.
haematological and extra-haematological complications
Sixty-nine patients (28.3%) did not have any documented infective episode; one or more episodes of fever of unknown origin (FUO), defined as a fever 38°C lasting at least 48 h without any other clinical, microbiological or radiological sign of infection, were recorded in 52 patients (21.3%). Documented infections were observed in 123 patients (50.4%), 94 (76.4%) had a single episode, and 29 (23.6%) had 2 episodes. Among bacterial infections, 54 were bronco-pneumonias, 45 abscesses, 23 sepsis and 21 local infections (sinusitis, cystitis, colecystitis and phlebitis); a documented fungal infection was recorded only in five patients (four broncopneumoniae and one sepsis).
Haemorrhages (WHO 2) were observed in 96/244 patients (39.3%), with 23 of them presenting 2 episodes in different sites. The most common events were gingival and nasal bleedings (48 patients), followed by gastro-intestinal (33 episodes) and cerebral (26 episodes) haemorrhages.
Cardiac impairment developed during the AML course in 46 patients (18.9%), 22 of whom (48%) did not refer any previous cardiological disease.
Forty-nine patients (20.1%) were never hospitalised during AML, while 195 patients (79.9%) required hospitalisation. Median hospital stay duration was 9 days (range 0–190); 88 patients (36.1%) were hospitalised for 
10 days, 68 (27.9%) for >10 and 30 days and 39 (15.9%) were hospitalised for more than 30 days. As crude hospital stay duration is a rough indicator of quality of life, we calculated the ‘hospital stay ratio’ (days of hospital stay/days of survival x 100) for each patient. This value was 5% in 122 patients (50%), >5% and 10% in 47 (19.2%) and >10% in the remaining 75 (30.8%).
survival and follow-up
Overall median survival was 178 days (range 1–3278); in particular, 120 patients (49.1%) survived more than 6 months, 50 patients (20.5%) more than 12 months and 16 patients (6.5%) more than 24 months (range 25–109). The diagnosis of patients who survived >12 months was revised and was confirmed in all cases.
Median survival of patients with oligoblastic AML was 204 days (range 47–3278), as compared to 156 days (range 1–2305) of patients with non oligoblastic AML (P < 0.01). Patients who received only supportive treatment had a median survival of 201 days (range 29–3278), as compared to 171 days (range 1–2305) of patients who needed the addition of CT; no significant difference in median survival was observed between patients treated with HU (180 days, range 1–2305) or 6-TG + Ara-C (146 days, range 21–972) (P > 0.08).
After a minimum observation period of 5 years from the last included patient, no patient is alive, 12 (4.9%) were lost to follow-up and 232 (95.1%) died; of these, 22 (9.5%) died from unknown causes, 110 (47.4%) died from disease progression and 100 (43.1%) died while in stable disease (from infections 23 patients, from haemorrhages 27 patients, from heart impairment 27 patients, from other organ failures 21 patients and two patients from a second neoplasia).
prognostic parameters
In order to identify possible prognostic subsets of patients, simple clinical parameters at disease onset (age, gender, PB cell counts, PB blasts percentage and absolute number, PS, previous myelodysplasia) were evaluated in 212 patients (124 males and 88 females, median age 72 years, range 60–90) in whom all these parameters were available. Thirty-two patients were excluded from this analysis as referred to our institution by other hospitals after more than a week from diagnosis with a previous supportive treatment and thus a PS better than at onset and not fully evaluable.
Older age (>75 years), poor PS (>2 according WHO), lower PLT count (<50 x 109/l) and higher absolute peripheral blast count (>5.0 x 109/l) displayed a negative impact on survival in multivariate analysis (Table 2). Based on these results, patients were divided by age in two groups: 143 patients aged <75 years (group A) and 69 aged 75 years (group B). In both groups, patients were then scored according to the other risk factors, i.e. PS, PLTS count and PB blast count: score 0 (no risk factor), score 1 (1 risk factor), score 2 (2–3 risk factors). Results are shown in Table 3: within group A, median survival was significantly different in the three score subgroups, while in group B no difference was noted between score 0 and score 1 subgroups, but both these scores were associated with a longer survival as compared to score 2.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Treatment results in elderly patients with AML are disappointing. In the past two decades several trials have been conducted to address the efficacy of intensive CT in this category of patients [3
–5], but recent data did not show any significant impact on disease outcome [9–11]. The question whether an intensive approach might be of benefit was also raised by a recent GIMEMA Group study, in which >1000 elderly patients treated with intensive as well as palliative approaches were evaluated for survival [12]; in this study, multivariate analysis failed to demonstrate a significant benefit in aggressively treated patients. Moreover, the majority of the so far reported studies deals with selected patients, as a relevant number of them were considered not eligible for controlled clinical trials.
Thus, elderly AML patients not eligible for IC represent a frequent problem for haematologists, but only few studies dealing with these patients are described [12–15]; in addition, as compared to elderly patients treated with intensive CT, they are mostly managed in individual manner or are sent to general physicians soon after diagnosis. Furthermore, for these patients, supportive care is probably less accurate and prompt than for patients who are enrolled into controlled trials. As a matter of fact, they constitute ‘the dark side of the moon’ and there is a general feeling that no effort is worthwhile to improve their prognosis and quality of life.
In the present analysis we aimed at providing an accurate and up-to-date picture of this subset of patients, as concerns clinical features, disease related or unrelated complications, therapy requirement, prognostic factors and survival. We are aware that even our cohort suffers from some selection bias, as some patients have never been referred to us for definitive diagnosis. Moreover, karyotype was available only in a small portion of our patients for several reasons: as a consequence, the impact of this important factor was not evaluated in this study and warrants a future insight.
Of course, no comparison with elderly patients submitted to intensive chemotherapy was possible and useful, owing to the obvious differences in clinical parameters of prognostic significance in the two patient categories. On the other hand, a general consensus on features which define patients unfit for intensive CT is still lacking: thus, we cannot exclude that some of the patients described in this study (for example, some of those considered not eligible only because of age >75 years) could have benefited from some form of more intensive CT.
In particular, our observations might be useful to evaluate and compare in the future progress in palliative chemotherapy and supportive care, as well as the efficacy of new biological targeted approaches (i.e. anti CD33, FT inhibitors).
Thus, some considerations may be drawn from present analysis:
- The series of patients we analysed appears heterogeneous as concerns clinical characteristics at diagnosis, disease evolution and survival. More than 25% of patients showed a relatively indolent disease course and could be managed with only supportive care. Their better survival is not surprising, as they probably had a less aggressive disease for unknown biological features. In addition, about one third of the patients who received palliative chemotherapy required to be treated only after a relevant time interval from diagnosis (>2 months).
- Hydroxyurea is the worldwide employed palliative CT for this type of patients, but no comparisons are available with other conservative approaches; in our analysis, there were no differences in survival between patients treated with HU and patients treated with the association of Ara-C + 6-TG.
- As expected, a variety of complications was observed in our patients that were often not directly related to the disease itself: in fact, about one half of the patients died from complications while being in stable leukemic disease. This observation points to the need of better defining the ‘gold standard’ of the supportive care also for this subset of patients; identification of more effective measures to prevent and manage microbiological, haemorrhagic and cardiological complications would possibly lead to a survival advantage.
- Age, WHO-PS, PLTS level and peripheral blastosis showed a significant impact on survival in multivariate analysis and we attempted to build a score system based on these factors. This system appears to be easily applicable, as it is based on simple parameters, which are evaluable also in general medicine wards, where elderly patients are often referred to; moreover, in our hands this score appeared capable of discriminating patients with a more indolent course from patients with more aggressive disease. If reproducible in wider cohorts of patients in a prospective validation study, it could be helpful for better tailored treatments and evaluation of different casistics.
In conclusion, as recently suggested [16], our study indicates that elderly AML patients not eligible for intensive CT are not all the same [16] and different prognostic subgroups can be identified, which could benefit from different treatments. To improve quality of life and dismal outcome of these patients, our simple scoring system could be useful in decision making for individual patient care. Moreover, as several promising molecular-targeted therapies are currently under investigation, the main goal in elderly AML patients should be the characterisation of different molecular defects underlying this clinical heterogeneity, to target them specifically as already happened for elderly patients with acute promyelocytic leukemia [17] and chronic myelogenous leukemia [18].
Received for publication August 15, 2005. Revision received November 12, 2005. Accepted for publication November 18, 2005.
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