Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes

Authors


Abstract

BACKGROUND.

It is unclear whether intensive chemotherapy is beneficial to patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) if they are aged ≥60 years.

METHODS.

The authors studied 160 patients with a median age of 67 years who received intensive chemotherapy for MDS or AML with cytosine arabinoside and an anthracycline.

RESULTS.

At diagnosis, cytogenetic analysis was available in 146 patients. Karyotype was normal in 78 patients and abnormal in 68 patients. Of the abnormal karyotypes, 32 belonged to the high-risk category, ie, they involved either ≥3 chromosomes or chromosome 7. Complete remission (CR) was achieved by 94 patients (56%). CR rates were 70% among the patients who had a normal karyotype, 69% among the patients who had an abnormal (noncomplex) karyotype, but only 46% among the patients ho had a high-risk karyotype. The median survival was 9.5 months in the entire group, 18 months in patients with normal karyotype, 6 months in patients with abnormal, and 4 months in patients with a high-risk karyotype. A poor prognosis was attributable to low rates of CR and a high risk of early recurrence.

CONCLUSIONS.

According to the current data, elderly patients with AML or advanced MDS do not benefit from intensive chemotherapy if they show karyotype anomalies, especially those in the high-risk category. Cancer 2007. © 2007 American Cancer Society.

In elderly patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), the role of intensive chemotherapy has not been defined clearly, because many trials exclude patients aged > 60 years.1 However, the incidence of AML strongly increases with age. At diagnosis, the median age of patients with AML is approximately 70 years. In individuals aged > 65 years, the incidence is almost 10 times higher than in the younger population (12.2 per 100,000 vs 1.3 per 100.000).2

A few studies have demonstrated an unfavorable outcome of chemotherapy in elderly patients with AML.3–7 Chemotherapy presents several problems for these patients, including increased treatment toxicity, a high rate of infectious and hemorrhagic complications, and an increased proportion of incomplete remissions. In addition, AML in the elderly often is associated with cytogenetic findings that portend a poor prognosis.8–10 With these prospects, prolonged hospitalization and seriously impaired quality of life associated with intensive chemotherapy may not be acceptable.

To evaluate the role of intensive chemotherapy further in elderly patients with AML and high-risk MDS, we performed a unicenter trial for patients aged ≥60 years. In patients with MDS, chemotherapy was started because of severe cytopenia, increasing medullary blast count, or transformation to AML. Some patients fulfilled more than 1 criterion.

MATERIALS AND METHODS

Patients

Between 1991 and 2004, 160 patients aged ≥60 years were entered into the trial. The median age was 66 years (range, 60–77 years). The trial included 94 men and 66 women. A diagnosis of MDS according to the French-American-British (FAB) classification was made if patients met the following criteria: 1) peripheral cytopenia despite normal or increased bone marrow cellularity, 2) morphologic evidence of dysplasia in blood and bone marrow, and 3) absence of exclusion criteria (vitamin B12 and folic acid deficiency; antibody-mediated cytopenia; paroxysmal nocturnal hemoglobinuria; hypersplenism; solid tumors; chronic inflammatory diseases; metabolic disorders; and bone marrow toxicity through drugs, alcoholism, or occupational toxins). At the time of entry into the study, 32 patients had MDS (3 patients had refractory anemia [RA], 7 patients had RA with excess blasts [RAEB], and 22 patients had RAEB in transformation [RAEB-T]). AML was diagnosed in 128 patients. The median blast count among the patients with AML was 75%. In 46 patients, AML had developed from MDS, including 2 patients who had RA, 3 patients who had RA with ringed sideroblasts (RARS), 8 who had RAEB, 32 patients who had RAEB-T, and 1 patient who had chronic myelomonocytic leukemia. Patients who had AML-M3 were not included in the study.

Patient characteristics with regard to median blood counts, medullary blasts, lactate dehydrogenase (LDH), organomegaly, and clinical symptoms are summarized in Table 1.

Table 1. Outcome of Intensive Chemotherapy in 160 Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia According to Various Pretreatment Characteristics
VariableNo. of patientsNo of CRs (%)PMedian Survival, moPMedian DFS, moP
  1. CRs indicates complete remissions; DFS, disease-free survival; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; LDH, lactate dehydrogenase; BM, bone marrow.

Disease duration, mo
 ≤311983 (70).00912.0711.31
 >32511 (44) 8 9 
Age, y
 <706043 (72).17410.758.47
 ≥708451 (61) 10 11 
Sex
 Men8352 (63).4411.211.94
 Women6142 (69) 10 9 
Disease type
 MDS3018 (60) 19 15 
 AML de novo7250 (69).569.137.46
 AML from MDS4226 (62) 12 13 
Fever
 Present2016 (80).188.5311.6
 Absent8857 (65) 10 8 
LDH, U/L
 < 4009559 (62).3714.0113.01
 ≥4003726 (70) 8 6 
BM blasts
 ≤50%6542 (65).9213.6511.56
 > 50%7851 (65) 9 8 
Auer rods
 Present2219 (86).0110.58.12
 Absent10060 (60) 10 11 
Karyotype
 Normal7452 (70) 17 14 
 Abnormal3222 (69).075.00016.01
 High risk2612 (46) 4 6 
Karyotype      .08
 Normal/abnormal10674 (70) 14.000111 
 High risk26 .0234 6 

The median time from diagnosis of MDS or AML to initiation of chemotherapy was 7 days (range, from 1 day to 41 months). In the MDS group, the median time from diagnosis to initiation of chemotherapy was 1 month (range, from 8 days to 21 months); in the de novo AML group, the median time from diagnosis to initiation of chemotherapy was 6 days (range, from 1 day to 25 months); and, in the group of patients who had AML that derived from MDS, the median time from diagnosis to initiation of chemotherapy was 8 days (range, from 1 day to 41 months). The differences were not statistically significant.

Some patients had received previous treatment with low-dose chemotherapy, hydroxyurea, or investigational drugs. The decision to proceed with intensive chemotherapy was made by the attending physician, whose judgment was influenced by a good performance score of the patient, lack of concomitant nonhematologic disorders, and the patient's wish to be treated. The study was approved by the ethics committee, and written informed consent was obtained from all patients.

Cytomorphology

Cytomorphologic assessment was based on May-Grunwald-Giemsa, peroxidase, and α-naphthyl-esterase stains. Subtypes of MDS and AML were diagnosed according to FAB criteria.11, 12

Cytogenetic Studies

The karyotype was classified as abnormal if aberrations were identified in <3 chromosomes and as high-risk either if ≥3 chromosomes were involved or if chromosome 7 was involved. Chromosome studies were performed on bone marrow aspirates. Trypsin-Giemsa-banded metaphases that were obtained from direct preparations and from 24- or 72-hour cultures without added mitogens were examined. In each patient, ≥20 metaphases were karyotyped and classified according to the International System for Human Cytogenetic Nomenclature.13 Karyotype at diagnosis was available in 146 patients and was normal in 78 patients. Noncomplex aberrations were identified in 36 patients, with 5q−, inv16, and trisomy 8 the most frequently identified anomalies. Aberrations of the high-risk category were identified in 32 patients. The frequency of chromosomal abnormalities, including high-risk karyotypes, did not differ between MDS, de novo AML, and AML deriving from MDS. Involvement of chromosome 7 was observed in 17 patients.

Chemotherapy Regimens

Induction chemotherapy with cytosine arabinoside (Ara-C) (200 mg/m2 intravenously [IV] on Days 1–5) and idarubicin (12 mg/m2 IV on Days 1–3) was given to 129 patients. Thioguanine (100 mg/m2 orally on Days 3–9) was included in 25 patients, and etoposide (100 mg/m2 on Days 1, 3, and 5) was included in 6 patients.

A second course of idarubicin plus an increased dose of Ara-C (1000 mg/m2 on Days 1–5) were administered as consolidation chemotherapy. In patients in ongoing complete remission (CR), maintenance therapy with low-dose, subcutaneous Ara-C (100 mg/m2 monthly on Days 1–5) plus oral idarubicin (10 mg/m2 monthly on Days 1–3) was planned for up to 3 years.

Supportive Care

Prophylactic treatment against infections included oral antibiotics (ciprofloxacin 1000 mg daily or trimethoprim/sulfamethoxazol 320 mg daily plus colistine 384 mg daily) and antifungal prophylaxis with oral amphotericin B (2000 mg daily). Red cell transfusions were given to keep the hemoglobin level above 8 g/dL. The objective of platelet transfusions was to maintain a platelet count >10,000 μL to 20,000 μL. Febrile patients were treated empirically with broad-spectrum antibiotics and IV amphotericin B if they had a suspected fungal infection. Hematopoietic growth factors were not given.

Criteria for Response and Definition of Recurrence

A CR, as defined according to International Working Group criteria,14, 15 required the presence of a morphologically normal bone marrow as well as neutrophils >1.0 × 109/L and platelets >100.000/μL in the peripheral blood. Relapse was defined as >4% blasts in the bone marrow aspirate or extramedullary leukemic infiltrates in patients who previously achieved CR after induction or consolidation therapy. Early death was attributable to treatment complications within 30 days from the start of induction chemotherapy. A nonresponse was defined as the failure to achieve CR or partial remission in patients who survived ≥30 days of treatment.

Statistical Analysis

The product-limit method was used to estimate the probability of survival, disease-free survival (DFS), and risk of leukemic transformation. Survival was measured from the start of induction therapy to the time of death or last follow-up (March 31, 2005). DFS was calculated from the date of documented CR to the time of relapse (MDS or AML) or death without relapse. Survival curves for different cytogenetic subgroups (normal, abnormal, and high-risk) were compared by using the log-rank test.16 Clinical and hematologic data from patients at the time of diagnosis were compared using the chi-square test with Yates correction17 and the Wilcoxon rank-sum test. Parameters that were predictive of achieving CR were analyzed using logistic regression analysis. Prognostic factors that were related to DFS were determined using the stepwise multivariate regression method of Cox.18

RESULTS

Induction Therapy

During induction therapy, patients stayed in hospital for a median of 31 days (range 15–83 days), they were febrile for a median of 10 days (range, 1–47 days), and they received antibiotic treatment for a median of 19 days (range, 1–66 days). CR was obtained in 94 patients (59%), which was somewhat less than would be expected in a younger patient population. Eight patients achieved a partial remission (5%), and 42 patients showed no response (26%). The rate of fatal complications was not excessive: Early death occurred in 16 patients (10%).

Consolidation Therapy

Only 56 of 160 patients received consolidation chemotherapy; because, among 96 patients who achieved CR, 40 patients had clinical problems, mainly relating to infectious complications, which precluded further chemotherapy. Karyotypes were available for 53 of 56 patients who received consolidation therapy. The initial karyotype had been normal in 33 patients, had been abnormal (noncomplex) in 13 patients, and had shown high-risk features in 7 patients. After consolidation chemotherapy, only 25 patients went on to receive at least 1 cycle of maintenance chemotherapy (18 patients with an initially normal karyotype, 6 with abnormal karyotype, and 1 patient with high-risk karyotype anomalies).

Survival

For the entire group of 160 patients, the median survival from the start of induction chemotherapy was 9.5 months (range, from 10 days to 157 months) (Fig. 1). The median survival from diagnosis was 14 months (range, from 1 day to 157 months). Treatment outcome did not differ between the 3 variants of induction chemotherapy (Table 2). Patients who achieved CR after induction chemotherapy, as expected, survived significantly longer than patients who did not (17 months vs 6 months; P < .00005) (Fig. 2).

Figure 1.

Cumulative survival in the entire group.

Figure 2.

Survival of patients after induction chemotherapy: complete remission (CR) versus non-CR.

Table 2. Response to Polychemotherapy According to Induction Regimen
Induction protocol*No. of patientsAge, yNo. of patients (%)
MedianRangeCRPREDNR
  • CR indicates complete remission; PR, partial remission; ED, early death; NR, no response; ara-C, cytosine arabinoside.

  • *

    For details of the chemotherapy protocols, see text.

Idarubicin/ara-C1296660–7777 (50)5 (4)13 (10)34 (26)
Idarubicin/ara-C/ thioguanin256561–7312 (48)3 (12)2 (8)8 (32)
Idarubicin/ara-C/ etoposide66361–715 (83)0 (0)1 (17)0 (0)
Total1606660–7794 (59)8 (5)16 (10)42 (26)

There was no significant difference in treatment outcomes between patients who had MDS, AML derived from MDS, or de novo AML. Survival from the day of diagnosis and survival from the start of induction chemotherapy were similar in patients with de novo AML and patients with MDS/AML (see Table 1). Both measures of survival indicated that the prognosis was worse for patients with de novo AML than for patients with primary MDS, but the differences did not reach statistical significance (P = .08 and P = .09, respectively). DFS also did not differ significantly between patients with MDS, MDS/AML, and de novo AML.

Influence of Karyotype on Treatment Outcome

The pretreatment karyotype influenced the response to induction chemotherapy. CR was achieved by 70% of patients who had a normal karyotype, by 69% of patients who had an abnormal (noncomplex) karyotype, and 46% of patients who had high-risk karyotype anomalies. A partial remission was considered no response. The difference in CR rate was statistically significant between the high-risk and normal karyotype groups (P = .02) but failed to reach statistical significance between the high-risk and abnormal (noncomplex) karyotype groups (P = .08).

The initial karyotype influenced not only CR rates but also long-term survival (Fig. 3). This part of the analysis excluded cases of early death. The median survival was 18 months for patients with a normal karyotype, 6 months for patients with an abnormal karyotype, and only 4 months for patients with a high-risk karyotype. Differences were statistically significant between patients with normal and abnormal (noncomplex) karyotypes (P = .0019), between patients with normal and high-risk karyotypes (P < .00005), and between patients with normal and all pathologic karyotypes (abnormal plus high-risk; P = .001). The difference between abnormal (noncomplex) and high-risk karyotype was not statistically significant (P = .15). Regarding high-risk karyotype anomalies, there was no difference in survival between patients with or without involvement of chromosome 7 (P = .95).

Figure 3.

Survival of patients with normal versus abnormal versus high-risk karyotypes.

For those patients who achieved CR after induction chemotherapy, the initial karyotype maintained its importance as a prognostic parameter. Patients who had a normal karyotype had a relapse rate of 66% and a median survival of 19 months. Patients who had an abnormal (noncomplex) karyotype had a recurrence rate of 59% and a median survival of 13 months. There were relapses in 11 of 12 patients who had high-risk karyotype anomalies, and their median survival was 11 months. In the latter group, the only patient who did not develop a relapse died of infectious complications 4 months after diagnosis. Among the patients who entered CR, the difference in survival was statistically significant only between those with a normal karyotype and those with a high-risk karyotype (P = .03).

The DFS of patients who entered CR was 13 months (range, 1–157 months) for patients with a normal karyotype, 5 months (range, 1–30 months) for patients with an abnormal karyotype, and 6 months (range, 1–27 months) for patients with a high-risk karyotype. The difference was statistically significant between patients with normal and abnormal (noncomplex) karyotypes (P = .01), between patients with normal and high-risk karyotypes (P = .03), and between patients with normal and all pathologic karyotypes (P = .003).

Auer Rods

In the entire group, we identified 31 patients with Auer rods. Of these, 25 patients entered CR (86%). Of 129 patients without Auer rods, 69 patients entered CR (60%; P = .008). The different CR rates were not important for long-term prognosis, because differences in survival and DFS were not statistically significant (DFS: 7 months vs 11 months; P = .09; survival: 9 months vs 11 months; P = .41).

Auer rods were detected in 25.6% of patients with normal karyotype, in 16.7% of patients with abnormal (noncomplex) karyotypes, and in only 3% of patients with high-risk karyotype. Because Auer rods indicate at least some degree of myeloid differentiation, their absence in leukemic cells with extensive chromosomal damage suggests an immature phenotype.

Multivariate Analysis of Outcome After Chemotherapy

The influence of pretreatment variables on outcome is shown in Table 1. With respect to achieving CR, no variables had adequate statistical significance to be included in a multivariate analysis. Regarding survival, independent prognostic variables were karyotype, LDH (with a cut-off level at 400 U/L), and a prolonged time from diagnosis to the start of induction therapy (>3 months). For DFS, karyotype, Auer rods, and time from diagnosis to induction therapy were identified as independent prognostic factors (Table 3).

Table 3. Multivariate Regression Analysis of Prognostic Factors*
Endpoint variableEntry stepP
  • LDH indicates lactate dehydrogenase.

  • *

    Parameters that were considered in the multivariate regression analysis were age, sex, high-risk karyotype, LDH (cut-off level, 400 U/L), bone marrow blast count, Auer rods, and time between diagnosis an induction therapy (cut-off level, 3 months).

  • †Including 95% confidence intervals.

Survival
 Karyotype1.0005
 LDH2.004
 Time between diagnosis and induction therapy3.027
Disease-free survival
 Karyotype1.002
 Auer rods2.005
 Time between diagnosis and induction therapy3.006

DISCUSSION

The current data suggest that intensive chemotherapy in elderly patients is not necessarily associated with an excessive risk of early death. In our group of 160 patients with high-risk MDS or AML aged ≥60 years, the rate of early deaths was similar to that reported for intensive chemotherapy of de novo AML in younger patients.19

The important question is whether the survivors of induction chemotherapy benefit in terms of long-term survival. The answer depends, to a considerable extent, on cytogenetics. Those patients in our trial who presented with a high-risk karyotype at the time of diagnosis derived no survival benefit from chemotherapy compared with best supportive care. Because there are no outcome data available for best supportive care in AML, we suggest drawing upon patients with RAEB-T instead. In the Dusseldorf MDS Registry, patients with RAEB-T have a median overall survival of 4 months with best supportive care. The same overall survival was observed in our AML patients with karyotype anomalies who received intensive chemotherapy. This unfavorable result was attributable to a low rate of CR and a high risk of early recurrence. Our finding that karyotype is an important predictor of response facilitates the appropriate selection of elderly patients for intensive chemotherapy.

Along with karyotype, other pretreatment variables may contribute to predicting outcome. Our data confirm that the time from diagnosis to the start of induction chemotherapy is an important prognostic factor. This was demonstrated previously in a large trial by the European Organization for the Research and Treatment of Cancer in which patients aged ≥65 years had a shorter median survival with a wait-and-see strategy than with induction therapy shortly after diagnosis (11 weeks vs 21 weeks).20 Several groups have reported a trend toward higher CR rates among patients who were treated during the MDS phase compared with patients who were treated after the evolution to AML.21, 22 The CR rates were 62.5% and 35%, respectively, according to a meta-analysis of 370 patients.23

Even if it is started early, cytotoxic treatment benefits only those patients who enter CR after induction chemotherapy. This has been observed in AML patient populations that were not restricted to the elderly, as in the German AML Cooperative Group 1992 trial, for example, which included patients who ranged in age from 16 years to 76 years.24 Our data show that this conclusion also applies to patients aged >60 years. We were able to induce CR in 59% of our patients, and 25% of those who achieved a complete response maintained remission for at least 2 years.

Irrespective of whether patients entered CR after induction chemotherapy, our data show that the survival of patients with MDS, AML from MDS, and de novo AML strongly depends on the initial karyotype. In our study, there was a small group of 14 elderly patients with MDS or AML who had a normal karyotype and achieved long-term remission, which lasted from 3 years to 10 years. Conversely, among 34 patients who survived for ≥2 years, only 2 patients had a high-risk karyotype. Those patients died after 25 months and 26 months, respectively, from recurrent disease.

Although several studies have demonstrated the influence of karyotype on response to induction therapy, chance of survival, and risk of relapse in patients with AML,25–35 few studies specifically have examined the influence of karyotype anomalies in elderly patients.36 It appears that only 20% to 30% of older patients achieve CR when they have a low performance status and/or an abnormal or even high-risk karyotype.7, 37–39

Because elderly patients with high-risk karyotype anomalies do not benefit from intensive chemotherapy, other approaches must be tried. Oral etoposide plus idarubicin has been studied in elderly patients (median age, 69 years) in patients with high-risk AML, but none of the patients achieved CR, and the median overall survival was only 100 days.40 Recently, demethylating agents such as decitabine41–43 or 5-azacytidine44, 45 and inhibitors of histone deacetylases such as valproic acid46–49 have produced promising results. Patients can be treated in an outpatient setting and experience fewer side effects. It is noteworthy that these agents did not produce CR rates or overall survival that were inferior compared with intensive chemotherapy in patients who had high-risk karyotype anomalies.

Ancillary