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Keywords:

  • intensive chemotherapy;
  • AML;
  • MDS;
  • older patients

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Elderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I–II studies, low-intensity regimens, or ‘targeted’ therapies. However, baseline expectations for outcomes of elderly AML with ‘standard’ AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated.

METHODS

A total of 998 patients age ≥ 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods.

RESULTS

The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age ≥ 75 years, unfavorable karyotypes (often complex), poor performance (3–4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50–55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25–30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%.

CONCLUSIONS

Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups. Cancer 2006. © 2006 American Cancer Society.

Intensive combination chemotherapy with cytarabine and anthracyclines produces complete remissions (CR) in 40–80% of patients and cures in 5–50%.1–4 Prognosis depends on several factors including patient age and performance status, leukemic cell karyotype, functions of vital organs (pulmonary, hepatic, cardiac, renal), and comorbid conditions.5, 6 Patients with higher-risk myelodysplastic syndrome (MDS), particularly those with 20% or more blasts, are often treated like AML. The new World Health Organization (WHO) classification expanded the definition of AML to include the presence of 20% or more blasts.7

Many single-institution and cooperative group studies exclude elderly patients (age 65 years or older) with AML or high-risk MDS, or treat them on separate (usually less intensive) programs.2, 3, 5, 6, 8 As the median age of patients with AML or high-risk MDS is 65 years, the results of regimens studied in younger patients may not be applicable to elderly AML-MDS, particularly as many patients are also excluded from these trials because of poor performance status, organ dysfunction, and comorbid conditions. In a review by Hutchins et al.,8 the percentage of patients with AML ≥ 65 years on Southwest Oncology Group leukemia studies was 27%, whereas similarly aged patients represent 50–60% of those seen in community practice.

Several studies have addressed the outcome of elderly AML and high-risk MDS.9, 10 Some advised that it might be acceptable to offer such patients supportive care only, low-intensity therapy, or investigational (including Phase I–II) strategies, particularly if these patients were older than 75–80 years, rather than over 55–60 years.11–16 Others found a beneficial effect for intensive chemotherapy in candidate patients.17 Elderly patients are often judged to be ‘poor-risk for intensive chemotherapy’ without objective specifications of the criteria. Many oncologists feel uncomfortable offering intensive chemotherapy to such patients because of the high risks of induction mortality and morbidities. Many elderly patients with AML/high-risk MDS refuse such intensive regimens and seek alternative approaches. Several groups have summarized their experience in elderly AML and analyzed the significance of pretreatment host and leukemia-related characteristics on prognosis.18–23

In this study, our aim was to provide a large baseline experience of the outcome of patients with AML or high-risk MDS who had received intensive induction chemotherapy regimens, and to define their prognosis based on simple, readily available, pretreatment factors. This may define select prognostic categories in elderly AML and MDS, help patients and physicians in their choice of therapy, and define baseline expectations against which lower-intensity or investigational strategies might be compared.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Group

Adults with a diagnosis of AML or high-risk MDS who were 65 years or older, treated on frontline intensive chemotherapy regimens from 1980 until the present, were evaluated. For this analysis, high-risk MDS was defined by the presence of more than 10% myeloblasts. Patients with acute promyelocytic leukemia were excluded from this analysis.

Therapy

Induction therapy varied by treatment period (Table 1). Only patients treated with regimens containing conventional or high-dose (1 g/m2 daily or more) cytarabine, or noncytarabine intensive regimens, were included. Variations in these regimens included different anthracyclines (daunorubicin, idarubicin, liposomal daunorubicin), topoisomerase I inhibitors (topotecan), other nucleoside analogs (fludarabine, clofarabine, troxacitabine), with or without cytokines and differentiation agents.24–27

Table 1. Intensive Chemotherapy Induction Regimens in Patients Age 65 Years or Older with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Since 1980 at Our Institution
RegimenNo. patients (%)
  1. HD: high dose; ara-C: cytarabine.

Idarubicin + HD ara-C240 (24)
Idarubicin + HD ara-C + fludarabine164 (16)
Fludarabine + HD ara-C95 (10)
Topotecan + HD ara-C45 (5)
Topotecan + HD ara-C + cyclophosphamide84 (8)
Clofarabine + HD ara-C27 (3)
Miscellaneous + standard or HD ara-C215 (22)
Miscellaneous (no ara-C)128 (13)

Response Criteria and Statistical Methods

A complete response (CR) required normalization of bone marrow morphology with 5% or less blasts, and of peripheral counts with granulocytes 109/L or above and platelets 100 × 109/L or above.

Induction mortality was defined by the 8-week mortality, because this was the time when the weekly mortality rate was reduced from the high initial rates to the lower rates noted during maintenance. It is thus a measure of the combined effects of treatment-associated mortality and of mortality due to ineffective therapy that allows for persistence of disease and cytopenias. This definition eliminates the subjective investigator bias in attributing mortality to therapy versus leukemia.

Differences among variables were compared by chi-square tests. Survival and remission duration curves were plotted by the Kaplan–Meier method, and compared by the log rank test.28 Multivariate analyses of prognostic factors used the logistic regression methods for CR and induction mortality, and the Cox proportional hazard method for survival.29–31 A P-value of less than 0.05 was considered significant.

Pretreatment karyotype was categorized as follows: 1) favorable: t(8;21) or inversion 16 (alone or with other changes); 2) intermediate: normal or with loss of chromosome Y; and 3) unfavorable: these included noncomplex (one or two cytogenetic abnormalities), and complex (three or more abnormalities) chromosomal abnormalities. The reason for this subcategorization of unfavorable karyotypes is based on studies suggesting that only complex karyotypes may be poor prognostic. Patients with insufficient metaphases were grouped in the intermediate category based on similar prognosis from past experiences.

Because the analysis spanned a long period of 25 years, and because patients were selected to various regimens by different criteria, there were multiple strong interactions between different treatments and patient or other characteristics, other than age. We evaluated these interactions between treatments and patient/disease characteristics in all the multivariate analyses. The final prognostic models were validated after considering these effects when present. Still, when we interpret the treatment effects in the multivariate analyses, we are cognizant of the limitations in overinterpreting the results related to therapy effects.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 998 patients were analyzed. Their median age was 71 years (range, 65–89 years); 8% were 80 years or older. Twenty percent had high-risk MDS. Five hundred thirty-four (54%) patients had unfavorable karyotypes: noncomplex in 251 (25%); complex in 283 (28%). The incidences of prior malignancy (excluding skin carcinomas) and prior chemotherapy (32%; 33%) were higher than previously reported, perhaps because of the focus of this study on elderly AML or MDS (age 65 yrs or older), where the incidence of other malignancies may be higher, or possibly because of the more frequent referral of these worse-prognosis patients to tertiary cancer centers. The detailed characteristics are shown in Table 2. Response to chemotherapy is shown in Table 3. Overall, 454 patients achieved CR (45%), and 285 (29%) died during remission induction. The median survival of the study group was 5.4 months (95% confidence interval [CI]: 4.4–6.3). The 1- and 2-year survival rates were 30% and 16%, respectively (Fig. 1).

Table 2. Characteristics of the Study Group (n = 998)
CharacteristicCategoryPercentage
  1. ECOG: Eastern Cooperative Oncology Group; IPSS: International Prognostic Scoring System; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; NA: not available; IM: insufficient metaphases.

Age in years65–6937
 70–7435
 75–7920
 ≥ 808
DiagnosisAML80
 MDS ≥ 20% blasts9
 MDS 11–19% blasts11
Performance, ECOG0–163
 225
 3–412
SplenomegalyYes10
LymphadenopathyYes7
IPSS risk, MDS onlyIntermediate 13
 Intermediate 222
 High49
 NA26
Karyotypet(8;21); inversion 162
 Diploid40
 Noncomplex25
 Complex28
 IM4
Prior malignancyYes32
Prior induction chemotherapy for other malignanciesYes33
Prior therapy for MDSYes5
Hemoglobin, g/dL≤ 846
 8.1–9.938
 ≥ 1016
WBC, x109/L≥ 2527
Platelet count, x109/L< 10080
 > 4001
% marrow blasts> 5043
Lactic dehydrogenase, IU/L> 60031
Creatinine, mg/dL> 1.323
Bilirubin, mg/dL> 1.017
Treatment in the laminar airflow roomYes71
Antecedent hematologic disease, mos044
 1–524
 6–1111
 ≥ 1221
Table 3. Response Data
ResponseNo. (%)
Complete response454 (45)
Partial response4 (0.5)
Marrow complete response – low platelets20 (2)
Early death (≤ 2 wks)135 (14)
Induction death150 (15)
Resistant disease235 (24)
thumbnail image

Figure 1. Survival and duration of complete response is shown.

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Prognostic Factors Associated with Response, 8-Week Mortality, and Survival

Table 4 details response, 8-week mortality, and survival by pretreatment characteristics.

Table 4. Factors Associated with Complete Response, 8-Week Mortality, and Survival
ParameterCategoryNo.No. CR (%)PNo. (%) 8-wk mortalityPSurvival
Median (wks)1-yr %P
  1. CR: complete response; HD: high dose; ara-C: cytarabine; ECOG: Eastern Cooperative Oncology Group; IPSS: International Prognostic Scoring System; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; NA: not available; IM: insufficient metaphases; WBC: white blood cells; AHD: antecedent hematologic disorders.

Total age (years)65–69372183 (49)0.04101 (27)< 0.0012931< 0.001
 70–74347164 (47) 111 (32) 3429 
 75–7919777 (39) 76 (39) 1821 
 ≥ 808230 (37) 44 (54) 616 
DiagnosisAML798356 (45)0.50281 (35)0.0320270.10
 MDS ≥ 20% blasts9146 (51) 24 (26) 3435 
 MDS < 20% blasts10952 (48) 27 (25) 3538 
Performance, ECOG0 – 1633322 (51)< 0.001148 (23)< 0.0013435< 0.001
 2246104 (42) 98 (40) 1725 
 3–411928 (24) 86 (72) 37 
SplenomegalyYes9937 (37)0.0931 (31)0.6118130.005
 No899417 (46) 301 (34) 2331 
LymphadenopathyYes7430 (41)0.3726 (35)0.7522200.30
 No924424(46) 306 (33) 2230 
IPSS risk, MDSIntermediate 163 (50)0.971 (17)0.88112830.20
 Intermediate 24423 (52) 11 (25) 4043 
 High9853 (54) 22 (22) 3436 
 N/A5219 (37) 17 (33) 1830 
Karyotypet(8;21)119 (82)< 0.0011 (9)< 0.00115164< 0.001
 Inversion 16139 (69) 4 (31) 7869 
 Diploid396216 (55) 108 (27) 3537 
 Non-complex251108 (43) 73 (29) 2732 
 Complex28384 (30) 135 (48) 1011 
 IM4428 (64) 11 (25) 3634 
Prior malignancyYes315129 (41)0.05114 (36)0.1818300.53
 No683325 (48) 218 (32) 2429 
Prior induction chemotherapy for other malignanciesYes12039 (33)0.00248 (40)0.0915220.05
No878415 (47) 284 (32) 2430 
Prior therapy for MDS conditionTherapy5117 (33)0.0720(39)0.3611190.02
None947437 (46) 312 (33) 2330 
AHD (months)0440222 (51)< 0.001147 (33)0.0521290.002
 1–5241132 (55) 68 (28) 2834 
 6–1110647 (44) 32 (30) 3536 
 ≥ 1221153 (25) 85 (40) 1621 
Hemoglobin, g/dL≤ 8460189 (41)0.03165 (36)0.2618280.35
 8.1–9.9381185 (49) 120 (31) 2730 
 ≥ 1015780 (51) 47 (30) 3133 
WBC, x109/L≥ 2527393 (34)< 0.001119 (44)< 0.0011320< 0.001
 < 25725361 (50) 213 (29) 2631 
Platelet count, x109/L< 100797343 (43)0.003280 (35)0.0120280.001
 100–400194109 (56) 48 (25) 3635 
 > 40072 (29) 4 (57) 714 
% Marrow blasts≥ 50430194 (45)0.84154 (36)0.1419270.18
 < 50564258 (46) 177 (31) 2531 
Lactic dehydrogenase, IU/L> 600305109 (35)< 0.001142 (46)< 0.0011117< 0.001
 ≤ 600685341 (50) 216 (28) 3135 
Creatinine, mg/dL> 1.322771 (31)< 0.001116 (51)< 0.001817< 0.001
 ≤ 1.3770382 (50) 216 (28) 2933 
Bilirubin, mg/dL> 1.016665 (39)0.0773 (44)0.00115230.03
 ≤ 1.0826387 (47) 257 (31) 2431 
Treatment in the laminar airflow roomYes710369 (52)< 0.001173 (24)< 0.0013235< 0.001
No28885 (30) 159 (55) 615 
TherapyIdarubicin + HD ara-C + fludarabine404200 (50)< 0.001118 (29)< 0.0012733< 0.001
 Fludarabine + HD ara-C9546 (48) 35 (37) 2734 
 Topotecan + HD ara-C4523 (51) 8 (18) 3638 
 Topotecan + HD ara-C + cyclophosphamide8444 (52) 26 (31) 2933 
 Clofarabine + HD ara-C2717 (63) 2 (7) 5650 
 Miscellaneous + ara-C21592 (43) 95 (45) 1118 
 Miscellaneous (no ara-C)12832 (25) 47 (37) 1522 

A multivariate analysis of prognostic factors associated with CR identified the following to have independent adverse significance: older age, poor performance status, unfavorable karyotype, treatment outside the laminar airflow room (LAFR), anemia, leukocytosis, creatinine > 1.3 mg/dL, antecedent hematologic disorder (AHD) ≥ 6 months, or prior therapy for other cancer. On the basis of the number of adverse factors, patients could be predicted to have a high CR rate (estimated CR ≥ 70%, 22% of patients; 0–1 adverse factors), intermediate CR rate (estimated CR 47%; 53% of patients; 2–3 adverse factors), or low CR rate (estimated CR ≤ 20%; 25% of patients; ≥ 4 adverse factors) (Table 5). Adding the type of therapy (using idarubicin + high-dose cytarabine ± fludarabine as the benchmark) to the multivariate analysis identified miscellaneous noncytarabine regimens as being independently associated with significantly worse CR rates (P < 0.0001)

Table 5. Multivariate Analysis of Prognostic Factors Associated with Complete Response
Adverse factors for CRPHazard riskNo. adverse factorsNo. patientsNo. CR (%)No. (%) 8-wk mortalitySurvival
Median (mos)1-yr %
  1. LAFR: laminar airflow room; CR: complete response; ECOG: Eastern Cooperative Oncology Group.

Age ≥ 75 yrs0.0020.780–1218160 (73)29 (13)1249
Prior therapy for other cancer0.0010.462–3527247 (47)150 (28)631
AHD ≥ 6 mos< 0.0010.59≥ 425246 (18)153 (61)19
Treatment outside LAFR< 0.0010.42      
Unfavorable karyotype< 0.0010.40      
WBC ≥ 25 x 109/L0.0010.74      
Hemoglobin ≤ 8 g/dL0.0060.82      
Creatinine > 1.3 mg/dL0.0030.77      
Performance status > 2 (ECOG)0.0460.60      

A multivariate analysis of prognostic factors associated with 8-week mortality identified the following to have independent adverse significance: older age, poor performance status, complex karyotype, treatment outside the LAFR, creatinine > 1.3 mg/dL, and AHD ≥ 12 months (Table 6). Patients could be again predicted to have 8-week low mortality rate (estimated 8-week mortality ≤ 10%; 20% of patients; no adverse factors), intermediate mortality rate (estimated 8-week mortality 27%; 56% of patients; 1–2 adverse factors), and high mortality rate (estimated 8-week mortality ≥ 60%; 24% of patients; ≥ 3 adverse factors). Adding the type of therapy to the multivariate analysis, and interaction terms of treatment and other nontreatment covariates, identified the topotecan plus cytarabine (P = 0.017) and clofarabine plus cytarabine (P < 0.001) regimens to be associated with significantly lower 8-week mortality rates, whereas the miscellaneous cytarabine regimens (P < 0.001) were associated with significantly higher 8-week mortality rates.

Table 6. Multivariate Analysis of Prognostic Factors Associated with 8-Week Induction Mortality
Adverse factors for 8-week mortalityPHazard riskRisk groupNo. adverse factorsNo. patientsNo. (%) 8-wk mortalityNo. (%) CRSurvival
Median (mos)1-yr %
  1. LAFR: laminar airflow room; CR: complete response; ECOG: Eastern Cooperative Oncology Group.

Age ≥ 75 years0.0011.3Low019520 (10)134 (69)1658
Performance status ≥ 2, ECOG< 0.0011.5Intermediate129256 (19)166 (57)935
Complex karyotype< 0.0011.4 226998 (36)108 (40)422
Treatment outside LAFR< 0.0013.1High≥ 3242158 (65)46 (19)18
AHD duration ≥ 12 mos< 0.0011.4       
Creatinine > 1.3 mg/dL< 0.0011.4       

Application of the model for CR to mortality, and the model for mortality to CR, produced similar results, suggesting that they can be used interchangeably (Table 6).

Factors influencing overall survival are shown in Table 4. A multivariate analysis of prognostic factors for survival identified the following to have independent adverse significance: older age, poor performance status, unfavorable karyotype, treatment outside the LAFR, elevated LDH, creatinine > 1.3 mg/dL, and AHD ≥ 12 months. On the basis of the number of adverse factors, patients could be categorized into low risk (estimated 1-year survival rate above 60%; 12% of patients; no adverse factors), intermediate risk (estimated 1-year survival rate 33%; 57% of patients, 1–2 adverse factors), or high risk (estimated 1-year survival less than 10%; 30% of patients; ≥ 3 adverse factors) (Table 7, Fig. 2). Adding the type of therapy to the multivariate analysis did not demonstrate any significant independent prognostic associations with survival after including all the interactions between treatment and nontreatment covariates.

Table 7. Results of Multivariate Analysis of Prognostic Factors for Survival
Adverse factorsPHazard riskNo. adverse factorsNo. patientsSurvivalNo. (%) CRNo. (%) 8-wk mortality
Median (mos)1-yr %2-yr %
  1. LAFR: laminar airflow room; CR: complete response; ECOG: Eastern Cooperative Oncology Group.

Age ≥ 75 yrs< 0.0011.2012118633587 (72)12 (10)
Unfavorable karyotype< 0.0011.71–256873319292 (51)146 (26)
Treatment outside LAFR< 0.0011.6≥ 330119371 (24)171 (57)
AHD ≥ 12 months< 0.0011.3       
Performance status > 2, ECO)< 0.0012.1       
Lactic dehydrogenase > 600 u/L< 0.0011.4       
Creatinine > 1.3 mg/dl0.0011.2       
thumbnail image

Figure 2. Survival of patients from multivariate analysis by number of independent adverse prognostic factors is shown.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This study, in a large number of elderly patients with AML or high-risk MDS treated with intensive chemotherapy, provides insight into the pretreatment characteristics predictive for CR rates, induction mortality, and survival. Multivariate analyses identified consistent adverse prognostic factors across all three endpoints. These included: age ≥ 75 years, unfavorable karyotype (mostly complex), host status (defined by poor performance status or organ dysfunction), and longer duration of AHD. Treatment outside the LAFR was also a consistent independent poor prognostic factor for all three endpoints. In general, patients with three or more of these factors have expected CR rates of less than 20%, 8-week mortality rates above 50%, and 1-year survival rates of less than 10%. It is reasonable that such patients, who constitute about 25–30% of elderly patients with AML or high-risk MDS, would be considered for alternative, low-intensity, investigational therapies. Conversely, about 20% of elderly patients, who have none or at most one of these adverse factors, have a reasonable outcome with expected CR rates above 60%, 8-week mortality rates of 10%, and 1-year survival rates of 50% or more. Such patients should be encouraged to undergo intensive chemotherapy in leukemia centers with expertise in intensive supportive care. In such patients, supportive care only or investigational strategies that do not include cytarabine-based programs may not be justified.

These prognostic models could be criticized for including karyotype and treatment in the LAFR, two factors that may not be readily available. However, cytogenetic studies have acquired major prognostic importance in the therapy of AML and should be made readily available for treatment decisions. An LAFR-like environment, particularly in elderly patients with AML who have high mortality and morbidity rates with intensive chemotherapy, may be provided with reverse isolation, restriction of visits, and proper hygienic conditions (contact isolation, gowns, gloves, face masks, no plants or flowers) within a hospital setting during remission induction.

Recently, investigators have attempted to develop several investigational agents to fill an area of medical necessity, namely, the treatment of elderly AML ‘not fit for intensive chemotherapy.’ These have included clofarabine, decitabine, cloretazine, and tipifarnib. However, inability to receive intensive chemotherapy has been subjective, based on the physician's opinion or the patient's refusal of intensive chemotherapy. This was not based on poor performance or organ dysfunctions that are required to be favorable in such research protocols. Entry on these studies was often based on ‘comorbid’ conditions that are difficult to quantify, because they had not been the subject of prognostic factors analyses. These may include the presence of diabetes mellitus, hypertension, existing but stable heart conditions, chronic lung disease, and other subtle morbid conditions (whether controlled or uncontrolled) not quantifiable or not excluded in present investigational programs. Our analysis offers a partial solution. By defining ‘intolerance to standard chemotherapy’ as a condition that results in an 8-week mortality in excess of a certain percentage, e.g., ≥ 50%, such patients would then be objectively defined as poor-risk for intensive chemotherapy and offered new approaches. By inference, the benefit of these new approaches can now be compared with standard therapies by calculating observed to expected values for the prognostic endpoints. The 8-week mortality, rather than ‘induction death’ or ‘treatment-associated death’ reported in most studies, also removes the bias associated with these measures because the 8-week mortality is a combined measure of the toxicity as well as lack of efficacy of a particular approach. Because this mortality endpoint was not used previously, our mortality results may not be comparable to previous studies.

A limitation of this analysis is the difficulty in analyzing the effect of a particular therapy on outcome. This is because of the retrospective nature of the analysis, the long time interval in which different therapies were offered, and the different entry criteria on different regimens. This naturally resulted in strong interactions between various therapies and other characteristics. However, within these limitations we identified noncytarabine regimens to be associated with worse CR rates, and the 8-week induction mortality to be lower with topotecan plus cytarabine, and with clofarabine plus cytarabine regimens, and higher with miscellaneous cytarabine regimens. These issues were not the primary intent of this analysis, and should be interpreted cautiously and revisited in future prospective trials.

Table 8 summarizes some of the literature experience in elderly AML. The CR rates, mortality rates, and survivals varied in different studies. This is understandable in light of the differences in prognostic factors, as detailed in our analysis. None of the previous studies had proposed a simplified model, based on easily identifiable characteristics, to determine the important prognostic endpoints, i.e., CR, 8-week mortality, and survival. This is now available through this analysis.

Table 8. Results of Chemotherapy in Elderly Acute Myeloid Leukemia
StudyAge (yrs)No. patients% CR% MortalitySurvival
Median (Mos)% (x yrs)
  1. IC: intensive chemotherapy; LD ara-C: low-dose cytarabine; NA: not available; CR: complete response; ECOG: Eastern Cooperative Oncology Group; SWOG: Southwest Oncology Group.

Rowe–ECOG9> 55944NANA68 (5)
Leith–SWOG23> 552114518NSNS
Wahlin et al.22> 6021143NA3.5< 10 (5)
Grimwade et al.19≥ 4510655618NA13.5
Baudard et al.18≥ 60372292056 (5)
Goldstone et al.14≥ 55–6013145519∼916 (5)
Tilly et al.12> 65IC–4652311515 (2)
  LD ara C–413210925 (2)
Menzin et al. SEER32≥ 652657 (30% intensive IC)NANA26 (2)
Present study≥ 6599845295.416 (2)

Another possible criticism of this study is that the outcome of patients referred to tertiary cancer centers may be different from those in community practice because of a referral bias favoring more patients being able to receive intensive chemotherapy. Menzin et al.32 reviewed the Surveillance, Epidemiology, and End Results (SEER) data in elderly AML. Among 2657 patients age ≥ 65 years reviewed (1991–1996), the median survival was only 2 months and the 2-year survival rate 6%. Importantly, only 30% of patients underwent intensive chemotherapy during their course, whereas 70% never did (17% received hospice care only). While the cost of therapy was three times higher with intensive chemotherapy, the median survival of such patients was 6 months longer than the others. Again, it was very difficult, in the SEER analysis, to judge the basis for not receiving intensive chemotherapy. Thus, despite our study limitation concerning a referral bias, it offers for the first time objective criteria, based on short (CR, 8-week mortality) and longer-term endpoints (survival), for different treatment decisions.

In summary, this study defines different prognostic groups among elderly patients with AML and high-risk MDS. This will allow oncologists and patients to consider treatment options in a more informed manner. In addition, this analysis provides baseline data in prognostic subcategories with intensive chemotherapy, against which the efficacy of investigational approaches, particularly low-intensity or ‘targeted’ strategies, should be evaluated. Because of the retrospective nature of the study, the long period of accrual, and the heterogeneity of patient characteristics and therapies, these prognostic models will require prospective validation or application to other independent large study groups.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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