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Management of Acute Myeloid Leukemia in Elderly Patients

From the Department of Medicine III, University Hospital Großhadern, Munich, and Departments of Medicine A and Medical Informatics and Biomathematics, University of Münster, Münster, Germany, and Department of Medical Biology, University of Vienna, Vienna, Austria.

Address reprint requests to Wolfgang Hiddemann, MD, PhD, Univ.-Klinikum Großhadern, Medizinische Klinik III, Abt Hämatologie/Onkologie, Marchioninistrasse 15, 81377 München, Germany.

	ABSTRACT

TOP ABSTRACT INTRODUCTION BIOLOGY TREATMENT PROGNOSTIC DETERMINANTS AND... REFERENCES

 
ABSTRACT: Acute myeloid leukemia (AML) at older age is associated with several biologic and clinical characteristics. Hence, it may arise from an early level of hematopoietic stem cells and has a high frequency of blast cells with multidrug resistance glycoprotein MDR1 expression and particularly a high incidence of poor prognostic karyotypes. These factors, rather than age per se, underlie the poorer outcome as compared with younger cases. Prospective randomized studies clearly demonstrate, however, that elderly patients benefit from more intensive induction therapy and particularly from full-dose application of anthracyclines and possibly also cytarabine. Hematopoietic growth factors accelerate the recovery from treatment-induced neutropenia and may improve the remission rate, remission duration, and even overall survival. New treatment strategies need to be developed, however, for poor-prognosis AML subtypes in order to further improve the therapeutic perspectives for elderly patients with AML.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION BIOLOGY TREATMENT PROGNOSTIC DETERMINANTS AND... REFERENCES

 
ACUTE MYELOID LEUKEMIA (AML) occurs predominantly in adults, and its incidence increases with rising age. Epidemiologic surveys indicate that the median age of affected patients is in the range of approximately 65 to 70 years.^1,2 For patients who are treated in clinical studies, however, the median age is approximately 15 to 20 years lower and the proportion of patients older than 60 years of age amounts to roughly only one third of the total study population (Table 1). These data indicate that a considerable number of elderly patients with AML are obviously not entered onto these trials.^3-11 This absence may be explained in part by medical contraindications against the study concept, but it could also reflect a reluctance by both patients and physicians to expose elderly patients to the toxicities of antileukemic therapy. Thus, controlled clinical studies in elderly patients most probably reflect a selection of cases, and their results may not necessarily be representative for AML at an older age in general.

View this table: [in this window] [in a new window]   Table 1. Proportion of Patients 60 Years Old in Multicenter Studies

These facts warn against the unreflected generalization of study results. At the same time, however, they strongly argue for the appropriate design of clinical trials to encourage a higher accrual of elderly patients and to address the most pending questions in a controlled and representative fashion.

With these limitations in mind, a comparison of remission rates achieved in multicenter trials that included patients above and below the age of 60 years consistently indicates that older age is associated with a poorer response to initial chemotherapy and shorter disease-free and overall survival (Table 2).^3-12 With the exception of two studies, complete remissions are obtained in less than half of older patients. These results must be considered as disappointing, particularly in view of the fact that patients included in these studies reflect a positive selection. Hence, the question must be posed as to whether outcome of AML in elderly patients is only impaired by age-associated secondary diseases and a lower tolerance to chemotherapy-induced side effects or whether the inferior results reflect a different biology as compared with AML at younger age.

View this table: [in this window] [in a new window]   Table 2. Results of Induction Therapy in Patients 60 and < 60 Years Old

	BIOLOGY

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When compared with AML at younger age, elderly cases more often emerge from an antecedent hematologic disorder or after treatment for another previous malignancy.^13,14 More frequently, morphologic signs of dysplastic features of one or more cell lineages are observed as well.^15,16 Independent of these findings, other factors that are known to be associated with a poor clinical outcome are more often detected in elderly patients. These include karyotype changes, such as abnormalities or partial losses of chromosomes 5 and 7 or complex chromosomal aberrations, but also a higher proportion of patients with high expression of multidrug resistance glycoprotein MDR1.^17-21 Some data also suggest that AML in elderly patients may arise from an earlier level of pluripotent hematopoietic stem cells and may thus involve more than one hematopoietic cell lineage. This might not only explain the different clinical and biologic behavior of the disease but also the observation of some investigators that neutropenia after chemotherapy may be prolonged.^22,23

Hence, as compared with younger patients, AML in elderly cases may arise from an earlier stem-cell level, may have a higher inherent drug resistance, is associated with a higher frequency of poor-prognosis karyotypes, and may have an impaired capacity for hematopoietic recovery after chemotherapy.

	TREATMENT

TOP ABSTRACT INTRODUCTION BIOLOGY TREATMENT PROGNOSTIC DETERMINANTS AND... REFERENCES

 
The different biology and clinical behaviors of AML at older age pose some crucial questions about the most appropriate clinical management of this disease. First, should AML in elderly patients be treated with antileukemic therapy at all? Second, should it be treated with intensive or less intensive therapy? Third, can the side effects of treatment be diminished by hematopoietic growth factors?

Supportive Care Versus Antileukemic Chemotherapy
Considering the relatively high mortality of antileukemic treatment in elderly patients and the substantial toxicity that is associated with this approach, the potential benefits of antileukemic therapy have been questioned repeatedly. In fact, the high rate of elderly patients who are not included in clinical studies may reflect a reluctance against specific antileukemic therapy or even an active decision against it.

The approach to withhold or even "protect" elderly patients from antileukemic treatment is not supported by the published data. Although the majority of previously reported trials were not performed in a randomized fashion, they consistently show a more favorable outcome after specific antileukemic therapy.^24-30 The only available prospective randomized comparison of intensive remission induction therapy versus a primary watch-and-wait strategy followed by mild palliative treatment with hydroxyurea and cytarabine clearly demonstrated a significantly longer median survival of 21 weeks versus 11 weeks after intensive chemotherapy and a 2-year survival rate of 17% versus 0%. Even when considering the requirement for hospital admission and the duration of hospital stay, no advantage for the palliative strategy could be demonstrated.³¹ Hence, cytostatic chemotherapy is the treatment of choice and may offer the chance for longer survival for a considerable proportion of elderly patients.

Intensive Versus Less Intensive Chemotherapy
Although cytoreductive chemotherapy is considered to be the treatment of choice in elderly patients with AML, the question still remains as to at what intensity this approach should be followed and whether elderly patients should even be treated in a similar way as younger patients. Two major questions were addressed by a series of randomized clinical trials.

In one series, intensive versus less intensive therapy was compared using the following methods: by adding etoposide (Eto) to the combination of cytarabine (AraC) and daunorubicin (DNR); by using different doses of AraC within an AraC/DNR regimen; by applying low-dose AraC versus a full-dose protocol of AraC plus rubidazone; and by evaluating the oral combination of Eto plus thioguanine (6-TG) and idarubicin versus a DNR/AraC/6-TG regimen (Table 3). Although the addition of Eto and the higher dose of AraC seemed not to be beneficial, the poor overall outcome, particularly in the study by Dillman et al,⁶ with more than 40% early death and the short overall survival of 2.5 and 3 months raise a note of caution in the interpretation of these results. This reservation must also be emphasized for the study by Ruutu et al,³⁴ in which the results of the control group receiving an attenuated 6-TG/AraC/DNR (TAD) regimen were extremely poor.

As part of the comparison of intensive versus less intensive therapy, the dose of DNR has been given special attention. In Table 4, the results of four major studies are summarized in which different doses of DNR were randomly compared on the basis of AraC-containing combination regimens. The two investigations that were carried out during the early 1980s revealed a better outcome for the study arms that used lower doses of DNR.^35,36 As mentioned before, in both trials, a high early mortality rate was observed in all treatment groups. In contrast, the two recent studies by the British Medical Research Council and the German AML Cooperative Group (AMLCG) both reported a significant improvement of initial response and/or survival from full-dose versus attenuated-dose DNR combinations.^9,10,12 In both studies, early death rates were in the range of 30% overall. In the AMLCG trial, early deaths were even significantly reduced by using full-dose DNR, most probably by a more rapid achievement of a complete remission, as indicated by a higher proportion of patients obtaining remission after only one course of a 9-day TAD 9 regimen.⁹

The studies summarized in Tables 3 and 4 cover a long period of time during which substantial improvements in supportive care were made. These improvements led to a general reduction in treatment-associated mortality during induction therapy for elderly patients with AML, as exemplified by the results of the AMLCG. In the sequence of multicenter trials that were carried out by this group, a reduction in the early mortality rate from 41% in 1985 to 20% in 1995 was observed using the identical TAD 9 regimen for remission induction.^3,9 Hence, the interpretation of Tables 3 and 4 must take these developments into account, and a recommendation for today's practice must rely on more recent analyses with sufficient numbers of cases, such as the Medical Research Council and AMLCG studies.^9,10 Both multicenter studies are in favor of more intensive therapy, demonstrate a higher initial response rate and/or an improved long-term outcome, and indicate that this effect is not reached at the expense of an increased mortality rate.

This conclusion is also supported by a survey of nonrandomized studies using different doses of DNR (Table 5). When these trials are grouped according to a DNR dose-per-induction course less than 90 mg/m² or more than 90 mg/m², it becomes obvious that the higher dose of DNR not only results in a higher rate of complete remissions but also in a higher proportion of patients experiencing long-term disease-free survival (Table 6).

Similar to the development of AML therapy in younger patients, the strategy of more intensive treatment may also be followed for older patients. This general approach may, however, be hampered by the reduced tolerance of intensified treatment in older patients. Hence, the prospective randomized comparison of conventional versus intermediate versus high-dose AraC for post remission therapy that was carried out by the Cancer and Leukemia Group B showed a significant increase in long-lasting remissions with high-dose AraC only in patients younger than 60 years of age.⁸ Older patients experienced no beneficial effect, most probably because of the fact that only 29% of patients older than 60 years of age could tolerate high-dose AraC, compared with 62% of younger patients.

One conclusion from these data are that contraindications against and poor tolerance of intensive treatment, rather than age, determine the choice of treatment in elderly patients with AML.

Hematopoietic Growth Factors
Attempts to improve the tolerance of intensive therapy for elderly patients with AML are particularly directed against the reduction of treatment-associated mortality and morbidity. As indicated by Table 2, patients older than 60 years of age have a high risk of dying during the course of induction therapy. The majority of lethal events emerge from uncontrolled infections whose frequency and severity is closely related to the duration of neutropenia. The shortening of this critical period by the application of hematopoietic growth factors, such as granulocyte and granulocyte-macrophage colony-stimulating factors, might therefore provide a promising approach.

The first encouraging report by the AMLCG was soon followed by a series of phase II studies.^40-45 Recently, data from prospective randomized trials with particular emphasis on elderly patients have become available (Table 7).

Despite differences in the type and timing of growth factor administration, as well as in the requirement for blast cell clearance from the bone marrow, all studies indicate that the application of granulocyte or granulocyte-macrophage colony-stimulating factor shortens the period of critical neutropenia significantly. This beneficial effect translates in two of five studies into an increased remission rate and in two trials into a prolonged remission duration or overall survival. Only the study by Stone et al³⁸ demonstrates no major advantage. On the other hand, no study reported any harmful effects, such as an increased proportion of patients with persistent leukemia or early relapses. The currently available data, therefore, support the prophylactic administration of hematopoietic growth factors after intensive cytoreductive chemotherapy in elderly patients, but they indicate that the conditions of application need to be defined more precisely by future trials.⁴⁸

	PROGNOSTIC DETERMINANTS AND THERAPEUTIC STRATEGIES

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Besides the development of AML after a preceding hematologic disorder or prior chemotherapy, the karyotype of leukemic blasts and possibly the degree of MDR1 expression are of major prognostic significance for treatment outcome. As mentioned before, high expression of MDR1 and chromosomal abnormalities that are associated with a poor prognosis occur more frequently at older ages. As an example, Table 8 depicts the frequency of the three major cytogenetic subgroups for patients below and above the age of 60 years within the AMLCG trials.

A subsequently performed comparison of treatment outcome for the respective cytogenetic subgroups suggests an age-independent effect of cytogenetics on both response to initial therapy and overall survival (Table 9, Figs 1 and 2). These data must be regarded with caution, however, because they are based on small numbers of patients, particularly of patients with favorable cytogenetics in the older age group.

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival of 111 patients with t(8;21) or inv(16).

View larger version (12K): [in this window] [in a new window]   Fig 2. Overall survival of 90 patients with complex aberrant karyotype.

Still, these results suggest that the choice of therapy in elderly patients with AML is directed by the underlying biology of the disease as predominantly reflected by karyotype and by contraindications against intensive therapy. On the basis of these prerequisites, a therapeutic algorithm can be designed, as depicted in Fig 3. This strategy implies that patients without unfavorable cytogenetics and no contraindications against intensive therapy should undergo such treatment. Patients with unfavorable karyotypes and particularly with complex chromosome abnormalities have low expectations for current treatment modalities. They are therefore primary candidates for novel therapeutic strategies. Outside clinical studies, the argument can even be made to withhold antileukemic therapy from such patients and to provide best supportive care only.

View larger version (14K): [in this window] [in a new window]   Fig 3. AML therapy in patients 60 years old.

In general, more intensive therapy for AML at older age seems not only justified but must even be recommended as the treatment of choice. It should not be overlooked that the higher frequency of unfavorable biologic and prognostic factors, rather than age per se, is the major determinant for the inferior prognosis for elderly patients. Hence, a major step forward in the treatment of AML in elderly patients can be expected from the development of more effective therapies for bad-prognosis subgroups and the further improvement of supportive measures. Deeper insights into the biology of AML subgroups and the development of novel drug combinations and molecular therapies justify the hope that this goal might soon be in reach.

	REFERENCES

TOP ABSTRACT INTRODUCTION BIOLOGY TREATMENT PROGNOSTIC DETERMINANTS AND... REFERENCES

 
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Submitted June 30, 1999; accepted July 7, 1999.

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