THERAPY IN PRACTICE

Drugs Aging 2002; 19 (8): 571-581 1170-229X/02/0008-0571/$25.00/0 © Adis International Limited. All rights reserved.

Acute Myeloid Leukaemia Optimising Treatment in Elderly Patients Graham H. Jackson and Penelope R. A. Taylor Department of Haematology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . 1. Biology of the Patient . . . . . . . . . . . . . . . 2. Indicators of Prognosis . . . . . . . . . . . . . . . 2.1 Myelodysplasia . . . . . . . . . . . . . . . . 2.2 Cytogenetics . . . . . . . . . . . . . . . . . 2.3 Multidrug Resistance Protein (MDR1) . . . . 2.4 Other Biological Markers . . . . . . . . . . . 3. Treatment Considerations . . . . . . . . . . . . . 4. Treatment Options . . . . . . . . . . . . . . . . . 4.1 Intensive Intravenous Chemotherapy . . . 4.2 The Role of Maintenance Chemotherapy 4.3 Allogeneic Stem Cell Transplantation . . . 4.4 Growth Factors . . . . . . . . . . . . . . . . 4.5 Alternatives to Intensive Treatment . . . . . 4.5.1 Oral Regimens . . . . . . . . . . . . . 4.5.2 Subcutaneous Cytarabine . . . . . . 4.6 Novel Therapies . . . . . . . . . . . . . . . . 4.6.1 Anti CD33 Antibody . . . . . . . . . . 4.6.2 Tretinoin . . . . . . . . . . . . . . . . . 4.6.3 MDR1 Modulators . . . . . . . . . . . . 4.7 Palliative Regimens . . . . . . . . . . . . . . 4.8 ’Watch and Wait’ . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . .

Abstract

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

571 572 572 572 573 574 574 574 575 575 576 576 577 577 577 577 578 578 578 578 578 578 579

Acute myeloid leukaemia (AML) is a disease of the elderly (median age at presentation 64 years). The outcome in older patients with AML is much worse than that for similarly treated younger patients. Older patients have a high incidence of recognised poor prognostic features (poor performance status, unfavourable cytogenetics, CD34 positive phenotype, raised serum lactate dehydrogenase levels and increased incidence of multidrug resistance protein expression). In addition, treatment is less well tolerated as there is an increased incidence of comorbidity in the elderly. The outlook for most patients is poor (4% survival at 5 years). However, it is possible to select a group of patients who are fit, with no pre-existing problems and good performance status who will respond well to intensive chemotherapy, and these patients should be treated aggressively. Less intensive treatment is probably more suitable for patients not fitting these criteria. Patients and their

572

Jackson & Taylor

relatives should be counselled appropriately as to the prognosis of AML, the choices of treatment available and that intensive regimens are not an appropriate choice for many patients.

Acute myeloid leukaemia (AML) is primarily a disease of the elderly with over 50% of cases presenting in patients aged over 60 years and with a median age of onset of 64 years (figure 1).[1] With improving healthcare and thus increases in the elderly population there will be a marked rise in the number of cases of AML in this age group even if there is no increase in the overall incidence of the disease.[2] In every study of patients with AML, age has been shown to be one of the most important adverse prognostic factors. Both clinical trials and population-based studies show a steady decline in remission rates and reduction in overall survival with age (figure 2).[1] In 1975, Burge et al.[3] wrote: ‘the aim of treatment is too often to induce a haemalogical remission (an irrelevance to the patient) rather than improve quality of life. Treatment that involves the patient and his family in much suffering can only be justified if the chances of cure are high’. This is still true today but an understanding of the biology of the leukaemia can lead to more logical decision making.

1. Biology of the Patient Elderly patients are more likely to have a poorer performance status and serious pre-existing medical conditions that can affect the patient’s response to therapy. A poor performance status at presentation is associated with a higher frequency of early death and shorter overall survival. Older patients are also more prone to serious morbidity and mortality relating to infections and bleeding associated with the severe pancytopenias that inevitably follow aggressive chemotherapy. It is postulated that this is because of a combination of causes including their physiological response to infection, a reduced ability to regenerate haematopoiesis (in part because of an increased incidence of pre-existing myelodysplasia, observed in over 30% of older patients), and changes in renal and hepatic function that alter drug metabolism. In addition age-related reduction in cardiac function may increase the risk of anthracyline- or mitozantrone-induced cardiac failure. 2. Indicators of Prognosis Table I contains a summary of factors that are known to predict prognosis in AML.

No. of patients

300

2.1 Myelodysplasia

250 200 150 100 50 0 10 9 -1 20 9 -2 30 9 -3 40 9 -4 50 9 -5 60 9 -6 70 9 -7 80 9 -8 9 90 +

0

Age (years)

Fig. 1. Incidence of acute myeloid leukaemia (AML) according to

age from a population-based study, Northern Health Region, UK, 1988-2000 (population 3.08 million). AML is a disease of the elderly (61% of cases occur in patients aged >60 years and 26% in those aged >75 years).[1]

© Adis International Limited. All rights reserved.

A significant proportion of elderly patients have a clinically documented myelodysplastic syndrome before developing AML. In addition, around one-third of elderly patients presenting with apparently ‘de novo’ AML have evidence of pre-existing tri-lineage myelodysplasia (TLMD) at the time of diagnosis compared with 15% of younger patients presenting with ‘de novo’ AML.[4] Pre-existing TLMD is associated with a poor response to chemotherapy, longer periods of cytopenia, lower complete remission (CR) rates and shorter duration of CR. Drugs Aging 2002; 19 (8)

AML in the Elderly

573

% surviving

100

Age (years) <15 (n = 45) 15-29 (n = 91) 30-44 (n = 138) 45-59 (n = 233) 60-74 (n = 406) 75+ (n = 301)

50

0 0

50

100

150

200

250

Months Fig. 2. Overall survival rate according to age. Age alone is an important predictor for survival in acute myeloid leukaemia (AML) – outcome in patients >60 years is poor with a few patients surviving beyond 4 years.[1]

2.2 Cytogenetics

Cytogenetics is one of the most important prognostic determinants in AML. The term ‘favourable’ was first given by Keating et al.[5] in 1988 who reported that patients with AML with certain acquired chromosomal abnormalities [t(15; 17), inv(16) and t(8; 21)] had a better survival than patients without these abnormalities. Others have confirmed this, including a study of 1612 patients (aged <55 years) entered into the UK Medical Research Council (MRC) AML 10 trial.[6] They defined three prognostic groups on the basis of response to treatment, relapse risk and overall survival as follows: • favourable prognosis: t(8;21); t(15;17); inv(16) • unfavourable prognosis: –5; del (5q); –7; abnormal (3q); complex >4 abnormalities • intermediate prognosis: all other groups.[6] © Adis International Limited. All rights reserved.

Other groups have developed their own cytogenetic prognostic groupings, but they are very similar to the MRC classification.[7,8] A recent population-based study[9] confirms that the incidence of favourable cytogenetics is higher in younger patients (accounting for 1 in 4 cases in those aged <30 years) but this decreases with each decade and is found in less than 10% of elderly patients. The reverse is true of unfavourable karyotypes which were seldom found in younger patients but were detected in 1 in 4 of the elderly cohort. Patients with unfavourable karyotypes also have a much increased mortality rate during induction therapy – as high as 67% in one study for a group of patients with a stem cell phenotype (CD34 positive) and complex karyotype.[10] The term ’favourable’ is perhaps misleading in older patients as even patients in this prognostic Drugs Aging 2002; 19 (8)

574

Jackson & Taylor

category have a survival of <30%.[11] The impact of additional cytogenetic abnormalities on outcome in this group is controversial. The MRC[6] reported that these abnormalities had no impact in younger patients, but others[12] have found they predict a less favourable outcome. 2.3 Multidrug Resistance Protein (MDR1)

Older patients also have a higher rate of multidrug resistance protein (MDR1) expression compared with younger, de novo, patients. A recent study [13] demonstrated that 71% of patients over 55 years of age who were enrolled in a randomised trial had overexpression of the MDR1 and, in this study, resistant disease was associated with MDR1 expression and unfavourable cytogenetics. They found that the CR rate in patients with no overexpression of MDR1 and favourable/intermediate karyotype was 81 versus 12% in those with MDR1 overexpression and who possessed unfavourable cytogenetics. However, this difference in CR rate did not translate to a difference in overall survival. 2.4 Other Biological Markers

Other ‘markers’ of poor prognosis have also been described. Raised serum lactate dehydrogenase (LDH) is an independent prognostic factor for overall survival in patients aged >55 years with AML.[14,15] Table I. Risk factors for outcome in elderly patients with acute myeloid leukaemia Favourable

Unfavourable

Good performance status

Poor performance status

No pre-existing TLMD

Pre-existing TLMD

‘Favourable’ cytogenetics

‘Unfavourable’ cytogenetics

Hypocellular leukaemia

Secondary and treatment-related leukaemia

MDR1 negative

MDR1 positive

CD34 negative

CD34 positive

Normal serum LDH levels

Raised serum LDH levels

LDH = lactate dehydrogenase; MDR1 = multidrug resistance protein; TLMD = tri-lineage myelodysplasia.

© Adis International Limited. All rights reserved.

3. Treatment Considerations Since the first studies of combination chemotherapy for the treatment of AML were published in the early 1970s, results in younger patients have improved dramatically. Unfortunately, this has not been the case in older patients where the outlook for the majority remains dismal. A population-based study demonstrated that only around 62% of elderly patients with AML were considered fit enough for any form of chemotherapy by their physician and in only 42% of these was treatment given with a curative intent. The 4-year survival for the entire cohort of elderly patients was 4%.[16] Most studies of intensive remission induction therapy in the elderly have shown reasonable CR rates varying from 38 to 58% (table II).[17-22] Unfortunately these CRs are of short duration and the long-term outlook even for patients achieving CR is poor, with an overall survival at 5 years for these selected patients of <10% in most of these studies.[17-22] The overall outcome in older patients is poorer than in younger patients, even in those who have been given the same treatment in the same trial.[15,17] Optimal treatment for the younger patient might not be the case in older patients.[21,23] Achieving a balance between giving too much and too little is difficult as reducing treatment may result in more relapses.[24] Published studies of intensive chemotherapy regimens have a heavy selection bias. In one centre involved in trials of intensive chemotherapy in elderly patients with AML, only 46% of their elderly patients were entered into studies.[25] Excluded patients were older, had a poorer performance status and a higher incidence of pre-existing TLMD, thus confirming what has long been recognised which is that patients entered into AML trials for the elderly are highly selected and account for only a minority of patients. Extrapolating results of trials with a selection bias can be misleading for patients and their relatives as they are usually over-optimistic and may not reflect outcomes in the ‘real world’. Physicians Drugs Aging 2002; 19 (8)

AML in the Elderly

575

Table II. Clinical outcome in trials of acute myeloid leukaemia (AML) in patients aged ≥60y receiving combination chemotherapy Authors

Age range (y)

No. of patients

CR rate (% of patients)

Early death rate (% of patients)

4/5 year survival (% of patients)

Rees et al. (1986)[17]

60-83

305

41

52

9

Preisler et al. (1987)[18]

60+

104

41

N/A

10

Dillman et al. (1991)[19]

60-83

100

41

27

3

Liu Yin et al. (1991)[20]

60-81

108

58

11

10

Mayer et al. (1994)[21]

60-86

346

47

31

9

Lowenberg et al. (1988)[22]

60-88

489

38a

18

6a

47b a

Daunorubicin (daunomycin) plus cytarabine arm.

b

Mitoxantrone plus cytarabine arm.

9b

CR = complete remission; N/A = not available; y = years.

are now becoming more aware of this problem and data on patients not entered into trials are now being collected, evaluated and compared. A recent report from Italy on 1005 patients aged >60 years treated in the 1990s compared outcome in the 62% of patients who were treated aggressively on the trial with those treated conservatively and found no difference in survival between aggressive and non-aggressive treatment.[26] Importantly the authors note that the patients treated aggressively had a longer duration of hospital stay (37 vs 16 days) which would suggest a reduced quality of life. It should be remembered that for patients and relatives the quality of life is as important as the quantity. 4. Treatment Options There are several options available to the physician treating elderly patients with AML, which include intensive treatment, moderately intensive therapy, palliation and supportive care only. 4.1 Intensive Intravenous Chemotherapy

Patients who are fit with no pre-existing problems and good performance status are suitable for intensive intravenous chemotherapeutic regimens. We have reviewed six studies including 1452 such patients aged ≥60 years treated with combination chemotherapy (table II). CR rates range from 38 to 58% with an early death rate of 11 to 52%, but © Adis International Limited. All rights reserved.

5-year survival of only 3 to 10% even in these selected patients. In younger patients with AML, there has been considerable interest in the use of higher doses of cytarabine (cytosine arabinoside; ara-c) which is associated with higher response rates, but this approach is not possible in elderly patients because of the increasing neurotoxicity of cytarabine in this population.[21] Fludarabine potentiates the intracellular accumulation of the active metabolite of cytarabine, ara-CTP, in leukaemia cells.[27] This observation has led to interest in the combination of fludarabine, cytarabine and granulocyte colony-stimulating factor (G-CSF) [FLAG] in the treatment of AML.[28,29] It has been used mainly in studies including patients who have relapsed or who have myelodysplasia.[28] These studies have been across a wide age range of patients but have included many elderly patients. This combination regimen is associated with increased haematological toxicity in older patients but non-haematological toxicity is similar to that seen in younger patients. Efficacy results specific for older patients receiving a combination of fludarabine and cytarabine have not been presented. Jackson et al.[29] studied 18 patients (median age 60 years) with refractory anaemia with excess blasts in transformation receiving this combination chemotherapy and reported a CR rate of 56%. In 112 patients with relapsed AML or myelodysplasia (median age 63 years), Drugs Aging 2002; 19 (8)

576

Estey et al.[28] reported a CR rate of 63% and a median survival of 38 weeks with FLAG. There is little doubt that FLAG represents an alternative to more traditional chemotherapy regimens in patients >60 years of age and fit enough to receive intensive chemotherapy. There are not many published randomised trials in patients >60 years of age and even in those trials that are published, results can be conflicting e.g. the trials comparing daunorubicin plus cytarabine with mitoxantrone plus cytarabine.[20,30] Acute promyelocytic leukaemia (APML) is a well recognised, specific subtype of AML, which has long been recognised morphologically[31]and clinically. APML is associated with the t(15;17) translocation, which fuses the PML gene on chromosome 15 to the retinoic acid receptor gene on chromosome 17. It is rarely detected in older patients, but confers a favourable prognosis. In 1988 tretinoin (all-trans-retinoic acid) was found to differentiate the abnormal promyelocytes into mature granulocytes.[32] Some patients achieve CR using this agent alone. Over the last decade a way to optimally utilise this agent in association with chemotherapy has been investigated. The best results are seen when tretinoin is combined with chemotherapy (daunorubicin and cytarabine). After consolidation chemotherapy, patients should be given maintenance treatment with intermittent tretinoin, methotrexate and mercaptopurine.[33] A study of this approach in patients with APML included patients up to the age of 75 years; in 42 patients aged >65 years who were treated with a combination of tretinoin chemotherapy followed by maintenance treatment, the CR rate was 90% and 2-year survival rate was 69%.[33] Elderly patients with the APML subtype are rare but should be given optimal treatment. Unless patients have APML, standard remission induction regimens for older adults should include cytarabine for 7 to 10 days plus an anthracycline for 3 days. If there is not a CR after the first course of treatment, further conventional treatment is probably futile. If the patient does achieve remission then the best consolidation therapy would be © Adis International Limited. All rights reserved.

Jackson & Taylor

two shorter courses of treatment with similar drugs. Whilst high-dose consolidation treatment is beneficial in younger patients, it has been demonstrated that this results in a higher remission death rate in the elderly.[21] Additionally, the older patients had a higher incidence of cerebellar ataxia which was irreversible in some patients. 4.2 The Role of Maintenance Chemotherapy

The role of maintenance treatment following induction and consolidation therapy remains controversial. A recent randomised study[22] demonstrated a significant difference in disease-free survival at 3 years: 20% in patients taking maintenance low dose cytarabine (10 mg/m2 subcutaneously every 12 hours on days 1 to 12 at 42 day intervals for a year) versus 7% for the control group. However, overall survival at 6 years was no different between the two groups. A study in 1981,[34] in which all patients were on maintenance treatment, showed a significant advantage in patients >60 years for a monthly regimen which included subcutaneous cytarabine versus regimens where cytarabine was given intravenously (both agents given in association with other drugs). The median duration of CR was 31 months for the subcutaneous route versus 9 months with the intravenous route. In addition, the recent French study of the use of maintenance in APML also showed a significant difference in favour of the maintenance arm in comparison with no maintenance.[33] Some previously conducted studies have shown no advantage of maintenance chemotherapy but these were mainly in younger patients. 4.3 Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation has until recently largely been restricted to patients aged <50 years. Traditional conditioning regimens in association with allogeneic stem cell transplantation are generally too toxic for older patients, resulting in a high treatment-related mortality. The development of less intensive conditioning regimens, so-called ‘mini-transplants’, has made allogeneic Drugs Aging 2002; 19 (8)

AML in the Elderly

transplantation less toxic with reduced morbidity and mortality rates. This has allowed stem cell transplantation to become a treatment option for older patients. Workers at the Fred Hutchinson Cancer Center (Seattle, Washington State, USA) have developed a transplant protocol involving intensive immunosuppression but a light total body irradiation regimen (total dose 200cGy) without chemotherapy.[35] This regimen has allowed them to safely perform allogeneic transplants in older patients; they have performed transplantations in 11 patients aged >50 years with AML. There were no treatment-related deaths and there was little acute graft versus host disease (GVHD), although six patients had chronic GVHD (three patients had extensive chronic GVHD and three had mild). This approach remains experimental, but the rapid development of safer allogeneic transplantation regimens may make transplantation an option for older patients with AML. 4.4 Growth Factors

There have been a number of studies that have looked at the use of growth factors [G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)] to reduce the morbidity and mortality associated with intensive chemotherapy in elderly patients with AML.[36,37] The rationale behind the use of growth factors was that since the elderly were particularly liable to die from infection, shortening the period of severe neutropenia might improve the chance of CR by reducing the rate of early deaths, which varies between 11 and 52% in published studies (table II). However, trials evaluating the use of growth factors have been disappointing. A randomised study assessing the impact of GM-CSF which included a quality of life assessment,[36] showed no difference in CR rate or survival and, in fact, found that the administration of GM-CSF resulted in more problems with regard to depressed mood, diarrhoea and rash/eczema. A randomised study of G-CSF was similarly disappointing; although there was a trend for fewer infection-related deaths © Adis International Limited. All rights reserved.

577

in older patients, the main benefits were a reduction in the duration of hospitalisation and administration of amphotericin B.[37] 4.5 Alternatives to Intensive Treatment 4.5.1 Oral Regimens

There is clearly a requirement in some older patients for alternative, moderately intensive therapy where quality-of-life issues, such as reduced hospitalisation, are as important as CR rates. The advent of the orally active agent idarubicin has led to considerable interest in oral regimens for the treatment of elderly patients with AML. A number of idarubicin-based regimens, often combined with etoposide, have shown considerable efficacy. Ruutu et al.[38] compared an oral induction/ consolidation idarubicin-based regimen with standard treatment in patients with AML aged >65 years and showed a CR rate of 60%. Another study investigated an all-oral regimen of idarubicin and etoposide in patients considered unsuitable for standard intensive aggressive treatments.[39] Of the 25 patients, nine achieved a CR. In addition, some of the patients received all their care as outpatients during the consolidation courses. 4.5.2 Subcutaneous Cytarabine

Low-dose subcutaneous cytarabine was initially introduced as a differentiating agent, although most investigators now believe that it mainly produces its effects via cytotoxic mechanisms. A randomised study[40] in 87 patients aged >65 years in which patients received either intensive chemotherapy or low dose cytarabine showed no difference in overall survival between the two groups. The number of CRs was higher in the intensively treated group but so were the infectious complications. Patients treated with low-dose subcutaneous cytarabine required fewer transfusions and had a shorter duration of hospital stay, and some had sustained survival of more than 2 years. Cytarabine can be a valuable therapeutic option in selected patients. Drugs Aging 2002; 19 (8)

578

4.6 Novel Therapies 4.6.1 Anti CD33 Antibody

Humanised monoclonal antibodies have been developed to bind the CD33 antigen, which is strongly expressed on the myeloblasts of over 90% of patients with AML. Gemtuzumab ozogamicin (CMA-676) is a conjugate of calicheomycin (a cytotoxic agent) linked to a humanised anti CD33 antibody. Two doses of this agent are given, 2 weeks apart, at a dosage of 9 mg/m2, as a 2-hour intravenous infusion. There are considerable adverse effects associated with the infusion including fever, chills, hypertension and shortness of breath. This agent is also associated with considerable haematological toxicity as well as abnormalities of liver function.[41] When given to 104 patients with untreated first relapse of AML, 28% of patients aged >60 years achieved a second CR. The median overall survival was 7.5 months.[41] The role of this agent and other monoclonal antibodies as single agents or as part of a multidrug regimen in the treatment of elderly patients with AML is uncertain but needs to be assessed in randomised trials i.e. the future MRC trials. The agent is very powerful and will be a significant addition to the treatment of elderly patients with AML. 4.6.2 Tretinoin

All patients with APML should be treated with tretinoin and chemotherapy. Tretinoin may also increase the sensitivity of other leukaemias to chemotherapy, and there is some suggestion that tretinoin may improve CR rate when combined with conventional chemotherapy, although this remains to be proven. There are a number of ongoing studies using tretinoin in elderly patients with AML. 4.6.3 MDR1 Modulators

One feature of AML in older patients is an increased expression of MDR1 in the myeloblasts (see section 2.3). Overexpression of MDR1 in older patients is associated with a lower CR rate and resistant disease but does not predict overall or © Adis International Limited. All rights reserved.

Jackson & Taylor

relapse-free survival.[13] Nevertheless, there has been much interest in modulators of the MDRprotein, such as cyclosporin and valspodar (PSC833). There has been one study in elderly patients aged >60 years which showed that whilst valspodar increased drug toxicity there was no benefit on remission rates.[42] P-glycoprotein (Pgp) is the product of the MDR gene and older patients have a higher incidence of Pgp expression in their blast cells. Quinine is an agent capable of reverting the MDR1 phenotype and its use as a biological modulator in conjunction with conventional chemotherapy has been studied in a total of 131 patients of whom 52 had myelodysplasia-related AML.[43] Patients were randomised to receive mitoxantrone and cytarabine with or without quinine as induction therapy. Analysis of Pgp expression was successful in 91 of the patients. In Pgp-positive patients, 13 out of 25 achieved a CR when quinine was added to the therapy versus 3 out of 17 in Pgp-positive patients who did not receive quinine. The addition of quinine to the regimens of patients who were Pgp-negative made no difference to CR rates. 4.7 Palliative Regimens

Palliative treatment is another option for the management of some elderly patients with AML. Intensive supportive therapy and palliative oral chemotherapy with agents such as thioguanine, hydroxyurea and etoposide to control the white cell count can be useful in patients with pre-existing medical conditions and a poor performance status at presentation.[16] 4.8 ’Watch and Wait’

A small minority of patients with acute leukaemia present with a more ‘smouldering’ course. These patients have clinical problems secondary to pancytopenia (low platelets, anaemia) rather than hyperleukocytosis. Delaying treatment with chemotherapy in these patients whilst giving transfusion support can be of benefit. Chemotherapy can then commence when the white cell count rises. Drugs Aging 2002; 19 (8)

AML in the Elderly

579

Diagnosis

Unfavourable cytogenetics Yes

No "Fitness" status

Novel therapies or palliative treatment

Poor

Good

Intensive treatment

Assess after one course

CR

No CR

Continue

Palliative

Fig. 3. A suggested algorithm for an approach to making decisions regarding treatment in older patients (≥60 years) with acute myeloid leukaemia. CR = complete remission.

5. Conclusion Elderly patients and their relatives should be made aware of the prognosis of the AML and treatment should be individualised. Decisions with regard to treatment should take into account the known prognostic factors shown in table I, but also the patient’s wishes. They and their relatives should be fully involved in discussions with regard to treatment and be made aware that intensive chemotherapy is not the appropriate choice for many patients. Younger and fitter patients with good prognostic features should be offered intensive treatment with standard regimens (figure 3). In patients with indolent AML, severe comorbidity or poor risk factors (table I), the role of supportive care with transfusions and control of leucocytosis should be considered. Since so many questions remain unan© Adis International Limited. All rights reserved.

swered in the management of this disease, entry into an appropriate trial should be considered where one is available. Where active treatment is not appropriate, more modest regimens, which induce a short remission with minimal hospitalisation, is the treatment of choice. Acknowledgements Dr Taylor is funded by a grant from the R & D Department of the Northern and Yorkshire Health Region, UK. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. The authors would like to thank Jane Lord for secretarial support.

References 1. Northern Region Haematology Group. Annual Report. England: Northern Region Haematology Group, 2000 2. Johnson PRE, Hunt LP, Liu Yin JA. Prognostic factors in elderly patients with acute myeloid leukaemia: development of a model to predict survival. Br J Haematol 1993; 85: 300-6

Drugs Aging 2002; 19 (8)

580

3. Burge PS, Richards JDM, Thompson DS, et al. Quality and quantity of survival in acute myeloid leukaemia. Lancet 1975; 2: 621-4 4. Letendre L, Noel P, Litzow MR, et al. Treatment of acute myelogenous leukemia in the older patient with attenuated highdose Ara-C. Am J Clin Oncol 1998; 21: 142-4 5. Keating MJ, Smith TL, Kantarjian H, et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988; 2 (7): 403-12 6. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood 1998; 92 (7): 2322-33 7. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 2001; 58 (18): 4173-9 8. Buchner T, Hiddemann W, Wormann B, et al. Late events in AML. Data from long-term observation of patients in two trials starting in 1981 and 1985 [abstract]. Blood 1997; 90 (10): 504a 9. Taylor P, Bown N, Cuthbert G, et al. A population based study of de-novo AML to assess karyotype incidence pattern and its impact on survival by age cohorts [abstract]. Ann Haematol 2001; 80: S19 10. Bow EJ, Sutherland JA, Kilpatrick MG, et al. Therapy of untreated acute myeloid leukemia in the elderly: remission induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide. J Clin Oncol 1996; 14 (4): 1345-52 11. Proctor SJ, Taylor PRA. Age cohort subgroups in adult acute myeloid leukaemia studies: the population perspective. Leukemia 2001; 15 (1): 188-9 12. Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8; 21)(q22; q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia 1996; 10 (8): 1288-95 13. Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89 (9): 3323-9 14. Ferrara F, Mirto S. Serum LDH value as a predictor of clinical outcome in actue myelogenous leukaemia of the elderly. Br J Haematol 2001; 92 (3): 627-31 15. Behringer B, Kunzmann R, Schmoor C, et al. Serum lactate dehydrogenase (LDH) as an independent prognostic factor for overall survival in patients with acute myeloid leukemia (AML) aged > 55 years [abstract]. Blood 2000; 96 (11): 123a 16. Taylor PRA, Reid MM, Stark AN, et al. De-novo acute myeloid leukaemia in patients over 55 years old: a population based study of incidence, treatment and outcome. Leukemia 1995; 9 (2): 231-7 17. Rees JKH, Gray RG, Swirsky D, et al. Principal results of the Medical Research Council’s 8th acute myeloid leukaemia trial. Lancet 1986; II: 1236-41 18. Preisler H, Davis RB, Kirshner J, et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukaemia: a Cancer and Leukemia Group B study. Blood 1987; 69 (5): 1441-9 19. Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991; 78 (10): 2520-6

© Adis International Limited. All rights reserved.

Jackson & Taylor

20. Liu Yin JA, Johnson PRE, Davies JM, et al. Mitozantrone and cytosine arabinoside as first-line therapy in elderly patients with acute myeloid leukaemia. Br J Haematol 1991; 79: 415-20 21. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 331 (14): 896-903 22. Lowenberg B, Suciu S, Archimbaud E, et al. Mitroxantrone vs daunorubicin in induction-consolidation chemotherapy: the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly. J Clin Oncol 1998; 16 (3): 872-81 23. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 1982; 60 (2): 454-62 24. Kahn SB, Begg CB, Mazza JJ, et al. Full dose vs attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1984; 2 (8): 865-70 25. Baudard M, Marie JP, Cadiou M, et al. Acute myelogenous leukaemia in the elderly: retrospective study of 235 consecutive patients. Br J Haematol 1994; 86: 82-91 26. Pulsoni A, Pagano L, Tosti ME, et al. Retrospective survival analysis of elderly patients with acute myeloid leukemia (aml) treated with aggressive or non aggressive therapy [abstract]. Blood 2000; 96 (11): 2166a 27. Gandhi V, Plunkett W. Modulation of arabinosyl nucleoside metabolism by arabinosyl nucleotides in human leukaemia cells. Cancer Res 1988; 48: 329-34 28. Estey E, Thall P, Andreeff M, et al. Use of granulocyte colonystimulating factor before, during, and after fludarabine plus cytarbine induction therapy of newly diagnosed acute myelogenous leukaemia or myelodysplastic syndromes: comparison with fludarabine plus cytarbine without granulocyte colony-stimulating factor. J Clin Oncol 1994; 12 (4): 671-8 29. Jackson G, Taylor P, Smith GM, et al. A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 2001; 112: 127-37 30. Arlin Z, Case Jr DC, Moore J, et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphoctytic leukemia (ANLL). Leukemia 1990; 4 (3): 177-83 31. Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukaemia: a report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103 (4): 620-5 32. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72 (2): 567-72 33. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999; 94 (4): 1192-200 34. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood 1981; 58: 1203-11 35. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumour effects. Blood 2001; 97 (11): 3390-400

Drugs Aging 2002; 19 (8)

AML in the Elderly

36. Groot C-D, Lowenberg B, Vellenga E, et al. Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukaemia. Br J Haematol 1998; 100 (4): 629-36 37. Heil G, Hoelzer D, Sanz MA, et al. A randomized, doubleblind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 1997; 90 (12): 4710-8 38. Ruutu T, Almqvist A, Hallman H, et al. Oral induction and consolidation of acute myeloid leukemia with etoposide, 6thioguanine, and idarubicin (ETI) in elderly patients: a randomized comparison with 5-day TAD. Leukemia 1994; 8 (1): 11-5 39. Jackson GH, Taylor PRA, Iqbal A, et al. The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy. Leukemia 1997; 11: 1193-6 40. Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990; 8 (2): 272-9

© Adis International Limited. All rights reserved.

581

41. Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtruzumab ozogamicin in patients with CD-33positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19 (13): 3244-54 42. Lee EJ, George SL, Caligiuri M, et al. Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of Cancer and Leukemia Group B study 9420. J Clin Oncol 1999; 17 (9): 2831-9 43. Wattel E, Solary E, Hecquet B, et al. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing p glycoprotein: results of a randomized study. Br J Haematol 1998; 102: 1015-24

Correspondence and offprints: Dr Graham H. Jackson, Department of Haematology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle Upon Tyne, NE1 4LP, UK. E-mail: [email protected]

Drugs Aging 2002; 19 (8)