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

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.     

Phase II trial of clofarabine and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age

We designed a phase II study evaluating the upfront combination of clofarabine and daunorubicin in acute myeloid leukemia (AML) patients ≥ 60 years old. The median age of the 21 patients was 69 (range 60–85) years. Fourteen patients (67%) had unfavorable risk features. The principal toxicities were grade ≥3 infections and prolonged myelosuppression. Three (14%) deaths occurred from infectious complications. Six (28.6%) patients achieved complete remission including three (21.4%) of 14 patients with unfavorable AML. The median disease-free survival was 6.8 months and the median overall survival was 11.2 months.     

Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia

Purpose: Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients >55 to 70 years of age during an Eastern Cooperative Oncology Group Study.Patients and methods: Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in- hospital care with or without an active infection. Sensitivity analyses were also reported.Results: When compared to AML patients who received placebo, GM-CSF patients had fewer grade 4–5 infections (9.6% versus 36.2%, P = 0.002) and grade 3–5 infections (52% versus 70%, P = 0.07) and $2,310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions.Conclusions: This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers.     

Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome

BACKGROUND: Elderly patients (age > or = 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 > or = 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 > or = 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.     

Analysis of treatment failure in acute nonlymphocytic leukemia patients over fifty years of age. A Southwest Oncology Group study.

Fourteen participating centers registered 33 patients on a Southwest Oncology Group Study of adults with acute non-lymphocytic leukemia (ANLL). Induction consisted of cytosine arabinoside 70 mg/m2 days 1-7 by continuous intravenous (i.v.) infusion, VP-16 50 mg/m2 i.v. over 1 hour days 1-3, and daunomycin 30 mg/m2 i.v. bolus days 1-3. Twenty-five patients (median age 69 years) were evaluable for response. Eleven (44%) achieved a remission marrow but only 8 fulfilled both blood and marrow criteria for complete remission. Of the 11 patients with a remission marrow, there were no patients over 70 years of age. Major coexisting disease data were evaluated. Only 5 patients had no major coexisting disease and 4 of those 5 achieved a remission marrow. The study illustrates and underscores the following problems of remission induction in the elderly: (a) increased susceptibility to the stress of the induction period, with 6 patients (24%) dying before treatment day sixteen; (b) disease resistance to antileukemic therapy with persistent ANLL in 6 patients (24%), despite two induction courses; and (c) hematopoietic stem cell sensitivity in the elderly with marrow regeneration failure documented in 2 patients (8%) following induction. Acute nonlymphocytic leukemia in the elderly has a poor prognosis, and novel therapeutic approaches are warranted.     

Long-term outcome of adult acute leukemia patients who are alive and well two years after allogeneic bone marrow transplantation from an HLA-identical sibling.

We studied the long-term outcome of 136 adults with acute leukemia (age 15-48 years at transplant, median 28; 112 myeloid, 22 lymphoblastic, 2 undifferentiated) who were alive in continuous remission two years after allografting from HLA-identical sibling donors. Six relapsed 25-46 months (median 30) after BMT. Fourteen (10%) died of non-relapse causes (12 transplant-related and 2 unrelated) 24-140 months (median 73) after BMT; mainly due to complications of chronic GVHD (8 infections, 3 secondary malignancies). One hundred and seventeen (86%) patients are alive in remission 25-226 months (median 103) after BMT; 116 (85%) in continuous remission. Eight survivors have symptomatic chronic GVHD requiring therapy (Karnofsky scores 60-90%, median 80%). The majority of those without chronic GVHD have Karnofsky scores of 100%. The 10-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 81%, 13%, and 5%. Twenty-two (19%) survivors had creatinine levels of > 110 mumol/L (one more than double), and 11 (9%) had bilirubin levels of > 17 mmol/L (one more than double) at the last follow-up. The absence of chronic GVHD at the 2-year mark (RR 3.5, P = .004), and female sex (RR 2.9, P = .04) influenced overall survival favorably, and the absence of chronic GVHD at the 2-year mark (RR 8.1, P = .001) influenced toxic death favorably. We conclude that patients with acute leukemia who are alive and well without chronic GVHD two years following an allograft have a high probability of being cured, whereas patients with active chronic GVHD requiring immunosuppression continue to be at risk of non-relapse death. The incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.     

Disease biology rather than age is the most important determinant of survival of patients > or = 60 years with acute myeloid leukemia treated with uniform intensive therapy

BACKGROUND: The objectives of the current study were to evaluate the outcome of patients > or = 60 years with acute myeloid leukemia (AML) treated uniformly with high-dose daunorubicin containing induction and modified high-dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival. METHODS: Between 1998 and 2002, the authors treated 117 newly diagnosed patients (acute promyelocytic leukemia excluded) with AML > or = 60 years (median, 67 years; range, 60-82 years). Karyotype (Medical Research Council classification) at diagnosis was categorized as good risk (n = 3), intermediate risk (n = 69), adverse risk (n = 26), and suboptimal/not done (n = 19). A normal karyotype was seen in 41 patients and 40 (34%) had secondary AML. RESULTS: The outcome of induction included the following: CR, 62 (53%); early death, 5 (4%); death during hypoplasia, 14 (12%); and resistant disease, 36 (31%). The 3-year event-free (EFS) and overall survival (OS) rates were 9% (95% confidence interval [95% CI], 3-16%) and 17% (95% CI, 9-29%), respectively. In a univariate analysis, cytogenetics, lactate dehydrogenase level, leukocyte count, and performance status were the significant factors for EFS and OS. Age was not a significant prognostic factor for either CR or survival. In a multivariate model, adverse-risk cytogenetics, previous history of myelodysplastic syndrome or antecedent hematologic disorder, and high leukocyte count (> 30 x 10(9)/L) were independent adverse prognostic factors for survival. The impact of adverse karyotype on EFS and OS was time dependent and was observed after 50 and 150 days, respectively. CONCLUSIONS: The authors concluded that candidacy for intensive therapy in older patients should be based on biologic features of disease and fitness, rather than on age.     

A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia.

PURPOSE: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML. EXPERIMENTAL DESIGN: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which > or =50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days). RESULTS: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients. CONCLUSIONS: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.     

Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A

BACKGROUND: Data on the impact of age in acute myeloid leukemia (AML) patients <30 years treated in pediatric and adult trials are scarce. METHODS: In all, 891 patients <18 years were treated in the pediatric trials AML-BFM 93/98 and 290 adolescents and young adults (>16 to <30 years) in the AMLCG 92/99 and AMLSG HD93/98A trials. Treatment schedules and dose intensities were comparable. RESULTS: Initial features and risk factors differed considerably between infants (<2 years) and older age groups and only slightly between children (2 to <13), adolescents (13 to <21) and young adults (21 to <30). Treatment results were most favorable in children (5-year event free survival [EFS]: 54% +/- 3%), slightly inferior in adolescents (46% +/- 4%, P = .03), and unfavorable in young adults (28% +/- 5%, P = .0001). Excluding patients with favorable karyotypes, the results were similar in infants and children (EFS: 44% +/- 4% and 46% +/- 3%, respectively) and inferior in adolescents (35% +/- 4%) and young adults (23% +/- 4%). There was an increased, age-related percentage and inferior outcome in patients with >5% bone marrow blasts after induction. EFS was especially poor in young adults, with blasts >5%. The blast count after induction was of no prognostic value in patients with favorable karyotypes, but a significant risk factor in patients with other cytogenetics. CONCLUSIONS: Biologic data differed mainly between infants and older age groups. When comparing the same age groups, outcome was similar between the trial groups, which differed from reports concerning acute lymphoblastic leukemia. However, the prognosis decreased after childhood independent of other risk factors. This indicates that even in the younger cohorts increasing age may be an additional unfavorable factor.     

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.

PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein-mediated multidrug resistance. PATIENTS AND METHODS: One hundred ten newly diagnosed patients > or = 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m(2)/d. The starting dose of daunorubicin was 30 mg/m(2)/d for 3 days. Etoposide was administered at a dose of 100 mg/m(2)/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m(2). PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide. RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m(2)/d for 3 days with etoposide 60 mg/m(2) for 3 days in the ADEP group and daunorubicin 60 mg/m(2)/d for 3 days and etoposide 100 mg/m(2)/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP. CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.     

Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups.

The therapeutic activity and toxicity profile of gemtuzumab ozogamicin were assessed in 40 patients >60 years of age with acute myeloid leukemia (AML) who were not considered eligible for conventional chemotherapy because of advanced age or poor performance status. The drug was administered at the dose of 9 mg/m2 as a single 2-h i.v. infusion on days 1 and 15. Patients who achieved a complete remission (CR/CRp) were to receive a consolidation with two additional injections of the immunotoxin at the same dose. The overall CR/CRp rate was 17% (95% CI, 8-32%). The CR/CRp rate in patients 61-75 years old was 33% (6/18), and 5% (1/22) in patients older than 75 years. Induction death occurred in seven patients (17%), all aged above 75 years. Overall survival was significantly longer in patients aged 61-75 years than in older individuals (P=0.05), and in CD33+ cases than in CD33- cases (P=0.05). We conclude that the dose/schedule of gemtuzumab ozogamicin used in this trial is too toxic in the age group over 75 years. For these patients, additional studies with reduced doses of the immunotoxin are warranted.