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Original Article
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Volume 331:896-903 October 6, 1994 Number 14
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Intensive Postremission Chemotherapy in Adults with Acute Myeloid Leukemia
Robert J. Mayer, Roger B. Davis, Charles A. Schiffer, Deborah T. Berg, Bayard L. Powell, Philip Schulman, George A. Omura, Joseph O. Moore, O. Ross McIntyre, Emil Frei, for The Cancer and Leukemia Group B

 

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ABSTRACT

Background About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions.

Methods We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment.

Results Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups.

Conclusions These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

Approximately 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline, with or without thioguanine1,2,3,4,5,6,7,8. However, with conventional maintenance or consolidation therapy less than 25 percent of such patients remain in remission2,9,10,11,12,13,14,15,16. The instability of the remission induced by cytarabine and an anthracycline has prompted postremission treatment with high doses of chemotherapy4,7,8,17,18,19. This approach to AML20,21,22,23 has been encouraged by the results of a small randomized trial,3 but it has not been evaluated definitively.

Cytarabine is the mainstay of induction therapy for AML. The drug's steep dose-response curve24,25 motivated its use in high doses in postremission therapy,3,7,8,17,18,19 but there has been no comparison of the clinical efficacy of various intensive dose schedules.

The Cancer and Leukemia Group B (CALGB) designed a study comparing the duration of complete remission in patients treated with either high-dose cytarabine or standard or intermediate doses of cytarabine administered by continuous infusion. The initial phase of this investigation, conducted between 1982 and 1985, established the maximal tolerated doses of high-dose cytarabine and continuous infusions of cytarabine in patients with AML in first remission. These patients received four courses of cytarabine, either at a dose of 3 g per square meter of body-surface area administered in a 3-hour infusion every 12 hours for three to eight doses per course (high-dose cytarabine) or as a continuous five-day infusion in doses ranging from 250 to 400 mg per square meter per day. The highest tolerated dose schedules were six doses of high-dose cytarabine administered twice daily every other day and a five-day continuous infusion of 400 mg of cytarabine per square meter per day5. Therefore, these two regimens were selected as the experimental treatments for the comparative trial reported here.

Methods

Eligibility

Patients 16 years of age or older with primary AML, as defined by the French-American-British (FAB) classification system,26,27,28 who had never received antileukemia therapy were eligible for entry into the trial. To support the diagnosis, a bone marrow aspirate had to show at least a 50 percent replacement of nonerythroid elements by myeloblasts, promyelocytes, or both or at least a 25 percent replacement of nonerythroid elements by myeloblasts, promyelocytes, or both if there was neutropenia (fewer than 1000 segmented neutrophils and bands per cubic millimeter), thrombocytopenia (fewer than 50,000 platelets per cubic millimeter), or both. Patients with a history of myelodysplasia, other antecedent hematologic cancers, preexisting liver disease or alcohol abuse (or both), or an uncontrolled infection were excluded, as were patients who had previously received nonsteroidal cytotoxic chemotherapy (except hydroxyurea) or radiation therapy and those who had had a myocardial infarction within the previous year. Appropriate measures were taken to control any systemic infection, hydration and allopurinol treatment were initiated, and written, informed consent was obtained when a patient entered the study.

Members of the Data Audit Committee of the CALGB visit all participating institutions at least once every three years to verify compliance with federal regulations and protocol requirements29. The medical records of 213 of the 1088 patients (20 percent) treated in this study, drawn from all 28 participating institutions and their affiliates, were randomly selected and reviewed. All study data were reviewed with respect to patient eligibility, response to treatment, and extent of toxicity on a quarterly basis, and written summaries of these analyses were distributed to the participating investigators.

Study Design

Patients were treated with an induction regimen consisting of continuous intravenous infusion of cytarabine (200 mg per square meter per day) for seven days, with daunorubicin given as a bolus dose on the first three days of cytarabine therapy (45 mg per square meter per day for patients 60 years of age or younger and 30 mg per square meter per day for patients older than 60). Bone marrow aspiration and biopsy were performed 14 days after the start of treatment. If the bone marrow was hypoplastic and contained less than 5 percent blast cells, further chemotherapy was deferred and the marrow examination was repeated weekly. However, if more than 5 percent leukemia cells persisted or if the marrow cellularity in the biopsy specimen exceeded 15 percent, a second course of five days of cytarabine and two days of daunorubicin at doses identical to the initial treatments was initiated. Patients who did not have a complete remission after a second course of induction chemotherapy were removed from the study. Patients who were considered to be in remission on the basis of bone marrow analysis underwent a lumbar puncture; the presence of leukemic cells in the spinal fluid, indicative of meningeal involvement, also resulted in removal from the study.

Patients in complete remission were stratified according to the number of courses of induction therapy (one or two) and their age (less than 40 years, 40 to 60 years, or more than 60 years) and were randomly assigned by the CALGB central office to receive four courses of cytarabine in one of three regimens: 100 mg per square meter per day for five days as a continuous intravenous infusion, 400 mg per square meter per day for five days as a continuous intravenous infusion, or 3 g per square meter administered in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5 for a total of six doses per course (high-dose cytarabine). Thus, each postremission treatment schedule lasted five days. Patients began postremission cytarabine therapy within 24 hours of randomization. The cytarabine, administered through a constant-infusion device, was not interrupted for the delivery of blood products or antibiotics. Sequential courses of postremission therapy were given no sooner than every 28 days or 1 week after marrow recovery (more than 1500 granulocytes per cubic millimeter and more than 100,000 platelets per cubic millimeter), with the expectation that the maximal interval between treatment courses would be 35 days or less. Platelet transfusions were recommended to maintain a platelet count of more than 20,000 per cubic millimeter. Hematopoietic growth factors such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or erythropoietin were not given. After the four courses of cytarabine therapy, all patients received four monthly treatments with cytarabine (100 mg per square meter every 12 hours [200 mg per square meter per day] for five days by subcutaneous injection) and daunorubicin (45 mg per square meter by rapid infusion on the first treatment day), after which all chemotherapy was discontinued.

The dose of the induction treatment was not modified. Myelosuppression alone did not warrant reduction of the dose of postremission cytarabine. However, one dose of high-dose cytarabine or 20 percent of the dose of the 24-hour infusions of cytarabine was subtracted in the event that marrow recovery required more than 28 days; a confluent maculopapular eruption or drug-induced desquamation; photophobia or conjunctivitis unrelieved within 24 hours by ophthalmic steroid drops; more than four episodes of watery diarrhea per day; or a fourfold increase in a previously normal serum aminotransferase or alkaline phosphatase level or a total bilirubin level exceeding 3.0 mg per deciliter (51.3 µmol per liter). Treatment with high-dose cytarabine was discontinued in patients with severe cerebellar ataxia, confusion, or other central nervous system signs thought to be unrelated to antiemetic medication. A high rate of neurotoxic effects in patients older than 60 who were assigned to high-dose cytarabine therapy led to a decision in April 1989 to restrict this treatment to patients 60 years of age or younger.

Evaluation

Patients underwent full physical examinations and assessments of liver and renal function before each of the four courses of single-agent cytarabine and each of the four maintenance courses. Bone marrow examinations were performed at the start of maintenance treatment, after all eight postremission courses were completed, and then every three months for one year, every six months for two years, and annually for at least two additional years.

Criteria for Response

A complete remission was defined as the presence of normal bone marrow and at least 1500 granulocytes per cubic millimeter and 100,000 platelets per cubic millimeter in the peripheral blood30,31. Causes of therapeutic failure were subdivided into three categories: resistant leukemia, death during treatment-induced bone marrow hypoplasia, and death less than seven days after completion of the first course of induction therapy (early death)32. Relapse was defined as the occurrence of more than 25 percent leukemic cells in the marrow of patients who were previously in complete remission or the detection of leukemic cells in previously normal cerebrospinal fluid.

In patients who had a complete remission, disease-free survival was measured as the length of time from randomization to relapse or death from any cause. In the comparisons of postremission therapies, survival was measured from the time of randomization to that of death from any cause. Overall survival was measured from the time of entry into the study to the time of death. Data on 14 patients who underwent allogeneic or autologous bone marrow transplantation were censored on the date of the procedure for the calculation of disease-free survival, but data continued to be collected on these patients for the analysis of survival.

Statistical Analysis

Comparisons of the rates of complete remission according to the patients' characteristics were evaluated by chi-square tests for contingency tables33. Distributions of survival and disease-free survival were estimated by the product-limit method34. Comparisons of these outcomes were based on the log-rank test35. Hazard ratios were based on estimates from the proportional-hazards model36. The primary treatment comparisons and related hazard ratios were stratified according to the patients' ages (under 40 years, 40 to 60 years, or older than 60) as planned from the inception of the study. Patients older than 60 were further stratified according to the date of entry (before vs. after the amendment restricting randomization to the two continuous-infusion regimens for these patients). All P values reported are two-sided.

Results

Between October 31, 1985, and October 1, 1990, a total of 1104 previously untreated patients were registered for the study. The enrollment of patients older than 60 was curtailed on February 16, 1990, at which time a protocol focusing on the treatment of AML in the elderly was initiated by the CALGB. Sixteen patients were considered ineligible or unable to be evaluated. Table 1 shows the characteristics of the 1088 patients who could be evaluated. The median age was 52 years (range, 16 to 86) -- slightly older than many,2,6,7,14 but not all,16 large, multicenter series of adults with AML; 31 percent were younger than 40, 37 percent were 40 to 60 years of age, and 32 percent were older than 60. The distribution of morphologic types of AML, according to the FAB classification system, was similar to that in previous reports37,38.

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  		Table 1. Characteristics of 1088 Patients with AML Who Could Be Evaluated.

 
Response to Induction Therapy

Of the 1088 patients, 693 (64 percent) had a complete remission, with the majority of these requiring only one course of induction therapy (Table 2). The responsiveness to induction therapy decreased with age: 75 percent of the 340 patients younger than 40 entered remission, as compared with 68 percent of the 402 patients who were 40 to 60 years of age and 47 percent of the 346 patients older than 60. Death during a period of treatment-induced marrow hypoplasia was more frequent in the elderly, whereas resistance to two courses of induction chemotherapy was the most common cause of treatment failure in younger patients. The rates of complete response were similar when analyzed according to the FAB classification, ranging from 60 percent (M4) to 74 percent (M3).

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  		Table 2. Results of Induction Therapy for Patients with AML, According to Age.

 
Postremission Randomization

Of the 693 patients in complete remission, 97 (14 percent) did not continue in this trial for a variety of reasons. The remaining 596 patients were randomly assigned to receive four courses of cytarabine at a dose of 100 mg per square meter (203 patients; median age, 48 years), 400 mg per square meter (206 patients; median age, 49 years), or 3 g per square meter (187 patients; median age, 43 years). The three groups were well balanced with regard to leukocyte count at the time of diagnosis and FAB subtype. The median and mean times from the documentation of complete remission to randomization were 7 days and 10.5 days, respectively. The median length of follow-up from randomization was 52 months. Six patients were lost to follow-up within the first two years after randomization.

Tolerance and Toxicity of Postremission Cytarabine

All four courses of cytarabine therapy were administered to 76 percent of the group receiving 100 mg per square meter, 74 percent of those receiving 400 mg per square meter, and 56 percent of those receiving 3 g per square meter (Table 3). However, only 29 percent of the patients older than 60 could tolerate the four courses of high-dose cytarabine; indeed, only 14 of these 31 older patients received more than one course.

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  		Table 3. Tolerance of Postremission Cytarabine Therapy among Patients with AML Who Underwent Randomization.

 
Table 4 shows the toxic effects of the four courses of postremission cytarabine therapy. The hematologic toxicity of each course was measured by determining the proportion of patients requiring hospitalization for fever and neutropenia and the need for platelet transfusions; there was a clear-cut relation between hematologic toxicity and the cytarabine dose schedule. Serious central nervous system abnormalities were reported only in the group given high-dose cytarabine and were especially common in patients older than 60 (32 percent of 31 patients). As a result, in 1989 randomization to high-dose cytarabine was restricted to patients 60 years of age or younger. Neurotoxicity may well have contributed to the inability of older patients to receive all four courses of high-dose cytarabine (Table 3). Symptoms of neurologic toxicity resolved within several days in about 20 percent of patients and gradually receded in about 40 percent; however, there was permanent disability in the remaining 40 percent. No further high-dose cytarabine therapy was administered to a patient after that patient recovered from a neurotoxic episode. There was a transient, clinically unimportant increase in hepatic aminotransferase levels in all three treatment groups. Treatment-related deaths during remission, primarily due to infection, occurred in 1 percent of the patients assigned to the 100-mg group, 6 percent of those assigned to the 400-mg group, and 5 percent of those assigned to the 3-g group.

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  		Table 4. Toxic Effects Reported after Four Courses of Postremission Cytarabine Therapy.

 
Toxicity of Postremission Maintenance Therapy

After four courses of postremission cytarabine therapy, 383 patients began treatment with four monthly maintenance courses of daunorubicin and subcutaneous cytarabine; 79 percent of these patients received all four treatments. A total of 1382 courses of maintenance therapy were administered; hospitalization because of fever and neutropenia was required in 26 percent of courses, and platelet transfusions were needed in 52 percent. The degree of hematologic toxicity of the maintenance treatment was unrelated to the dose of the previously administered postremission cytarabine. No treatment-related deaths or episodes of neurotoxicity were associated with maintenance therapy.

Disease-free Survival

The probability of remaining alive and free of recurrent AML among the 693 patients who had a complete remission was related to age. The estimated probability of being alive and disease-free after four years was 32 percent for patients younger than 40 (95 percent confidence interval, 26 to 38 percent) and 29 percent for patients 40 to 60 years of age (95 percent confidence interval, 24 to 35 percent). This probability fell to 14 percent for patients older than 60 (95 percent confidence interval, 9 to 20 percent; P<0.001) (Figure 1).


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  		Figure 1. Probability of Disease-free Survival for All Patients with a Complete Response, According to Age.

The P value is for the differences among the three groups. The median follow-up was 52 months. Tick marks indicate surviving patients in continuous complete remission.

 
Disease-free survival was also related to the type of postremission cytarabine therapy. For all 596 patients who were randomly assigned to this therapy, the likelihood of remaining alive and disease-free after four years was 21 percent in the 100-mg group (95 percent confidence interval, 15 to 26 percent), 25 percent in the 400-mg group (95 percent confidence interval, 19 to 32 percent), and 39 percent in the 3-g group (95 percent confidence interval, 32 to 46 percent) (Figure 2A). The superiority of the high-dose cytarabine regimen in this analysis is somewhat exaggerated by the smaller proportion of patients over the age of 60 who received this treatment. Nonetheless, the stratified test correcting for this imbalance demonstrated significant differences in disease-free survival among the three treatment groups (P = 0.003). The age-adjusted hazard ratios, relative to the 100-mg group, were 0.75 for the patients treated with 400 mg of cytarabine per square meter (95 percent confidence interval, 0.60 to 0.94) and 0.67 for those who received 3 g of cytarabine per square meter (95 percent confidence interval, 0.53 to 0.86). Relapses continued to occur at a steady rate in the 100-mg and 400-mg groups during the initial three years of follow-up but became less frequent after two years in patients who received high-dose cytarabine.


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  		Figure 2. Probability of Disease-free Survival for All Patients (Panel A), Patients 60 Years of Age or Younger (Panel B), and Patients Older Than 60 (Panel C), According to the Dose of Cytarabine.

Only patients who underwent randomization are included. The P values are for the differences among the three treatment groups. The median follow-up was 52 months. Tick marks indicate surviving patients in continuous complete remission.

 
The probability of remaining disease-free in relation to the type of postremission cytarabine treatment was not significantly different in the 225 patients under the age of 40 and the 242 patients who were 40 to 60 years of age, so these two groups were combined for further analysis. Among these 467 patients, the likelihood of remaining disease-free after four years was 24 percent in the 100-mg group (95 percent confidence interval, 17 to 31 percent), 29 percent in the 400-mg group (95 percent confidence interval, 21 to 36 percent), and 44 percent in the 3-g group (95 percent confidence interval, 36 to 51 percent) (P = 0.002) (Figure 2B). In contrast, the corresponding figures for the 129 patients older than 60 were 16 percent or less for each of the three groups (Figure 2C).

The 413 patients who entered remission after one course of induction therapy were more likely to remain disease-free than the 183 patients who required two courses of induction therapy (P = 0.06); this pattern was most pronounced in the 100-mg group (data not shown).

Survival

The probability of remaining alive four years after randomization was 31 percent for the 100-mg group (95 percent confidence interval, 24 to 37 percent), 35 percent for the 400-mg group (95 percent confidence interval, 27 to 42 percent), and 46 percent in the 3-g group (95 percent confidence interval, 38 to 53 percent) (P = 0.04) (Figure 3A). The age-adjusted hazard ratios relative to the 100-mg group were 0.78 for those who received 400 mg of cytarabine per square meter (95 percent confidence interval, 0.61 to 1.00) and 0.74 for the patients treated with high-dose cytarabine (95 percent confidence interval, 0.57 to 0.96). For patients 60 years of age or younger, the likelihood of survival after four years was 35 percent in the 100-mg group (95 percent confidence interval, 27 to 43 percent), 40 percent in the 400-mg group (95 percent confidence interval, 32 to 49 percent), and 52 percent in the high-dose group (95 percent confidence interval, 44 to 60 percent) (P = 0.02) (Figure 3B).


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  		Figure 3. Probability of Survival for All Patients (Panel A) and Patients 60 Years of Age or Younger (Panel B), According to the Dose of Cytarabine.

Only patients who underwent randomization are included. The P values are for the differences among the three treatment groups. The median follow-up was 52 months. Tick marks indicate surviving patients.

 
For the entire population of 1088 patients who entered the study and could be evaluated, the likelihood of remaining alive four years after the diagnosis of AML was 38 percent for patients under the age of 40 (95 percent confidence interval, 32 to 43 percent), 27 percent for those 40 to 60 years of age (95 percent confidence interval, 22 to 31 percent), and 9 percent for those older than 60 (95 percent confidence interval, 6 to 12 percent) (P<0.001).

Discussion

This trial of postremission therapy for AML demonstrated a significant dose-response effect of cytarabine. Patients 60 years of age or younger who received high-dose cytarabine were more likely to remain in remission and to survive longer than similar patients who received lower doses of cytarabine. Forty-four percent of the group treated with high-dose cytarabine remained in remission after 4 years of follow-up, with few relapses occurring after 20 months of observation.

In conventional doses cytarabine acts primarily as an antimetabolite. When given in high doses such as those used in this study, cytarabine may saturate the capacity of cytarabine-inactivating enzymes, enter cells in greater amounts, and increase levels of the active intracellular metabolite ara-cytidine triphosphate. These effects have been postulated to augment the inhibition of DNA synthesis further39 and to overcome cellular resistance to standard doses of cytarabine. Reports of complete remission with high-dose cytarabine in 35 to 40 percent of patients whose AML was resistant to conventional doses of cytarabine support this possibility39.

The 64 percent rate of complete response found in this study is similar to the rates of remission reported by others for cytarabine and daunorubicin, with or without thioguanine1,2,3,4,5,6,7,8,40. Surprisingly, two comparisons of high-dose cytarabine with standard doses of cytarabine in induction programs have failed to show any difference in the remission rate in previously untreated adults with AML41,42.

Myelosuppression, the main toxic effect of postremission cytarabine therapy, was directly related to the cytarabine dose schedule. Hospitalization because of infection or fever and neutropenia was required after 71 percent of high-dose cytarabine treatments. Only the superior outcome with high-dose cytarabine and the few deaths due to toxic effects (5 percent) can justify such disruptive and expensive hospital admissions. The prophylactic use of hematopoietic growth factors may reduce the frequency of such hospitalizations in the future43.

Central nervous system toxicity is a well-described complication of high-dose cytarabine therapy44. The neurotoxic effects include seizures, cerebral dysfunction, and an acute cerebellar syndrome and are irreversible in 30 to 40 percent of cases. The mechanism by which cytarabine damages the central nervous system is unknown. Age over 40 years, serum creatinine levels exceeding 1.2 mg per deciliter (106 µmol per liter), and a threefold elevation in the serum alkaline phosphatase level were predictive factors for neurotoxic effects in the patients who received high-dose cytarabine in our trial45; the risk of neurotoxicity was less than 1 percent if none or one of these factors was present, but it increased to 37 percent if two or more were present. The potential for neurotoxicity has aroused concern about the use of high-dose cytarabine in elderly patients who, ironically, have a higher likelihood of having drug-resistant leukemia and would most likely benefit from more intensive treatment if it were tolerable46.

The five-day regimen of high-dose cytarabine used in this study (3 g per square meter in a three-hour infusion twice a day every other day) covered the same period as the 100-mg and 400-mg schedules, a feature we thought important in evaluating a drug whose primary effect is on dividing cells. It is unclear whether this dose schedule increased the neurotoxicity of cytarabine or whether it is superior to other ways of administering high-dose cytarabine.

It is difficult to assess the impact of the four courses of postremission maintenance therapy that 383 of our patients received. When this study was designed, a previous CALGB trial had shown that 32 months of postremission treatment was not superior to 8 months of such therapy47. The subsequent demonstration of the ineffectiveness of low doses of maintenance therapy3 makes it unlikely that the last four months of treatment that our patients received contributed to the differences among the three treatment groups. Postconsolidation maintenance therapy has been eliminated from more recent CALGB studies.

Our results with high-dose cytarabine in patients 60 years of age or younger deserve comparison with the results of two other strategies of postremission management -- allogeneic and autologous bone marrow transplantation. The merits of these approaches have been the focus of debate48,49,50. Allogeneic marrow transplantation is generally restricted to patients 45 years of age or younger who have a histocompatible sibling, whereas patients as old as 55 may qualify for autologous transplantation. The kinds of patients included in transplantation series may well be influenced by selection bias51. A comparison of our data with the results from some of the most recent experiences with allogeneic (single institution52,53 and registry54) and autologous (registry55) transplantation reveals similar probabilities of disease-free survival after four years, particularly given the higher median age in our patient population (Table 5). Prospective comparisons of high-dose cytarabine chemotherapy and allogeneic transplantation in trials conducted by the Eastern Cooperative Oncology Group3 and investigators at UCLA56 have reached similar conclusions.

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  		Table 5. Comparison of High-Dose Cytarabine Chemotherapy with Allogeneic and Autologous Bone Marrow Transplantation as Postremission Therapy for Patients with AML in First Remission.

 

Supported by grants from the National Cancer Institute (CA32291, CA33601, CA31983, CA03927, CA35279, CA47545, CA47577, CA31946), the T.J. Martell Foundation, and the York Cross of Honour Research Foundation.

We are indebted to Carol Connolly for assistance in the preparation of the manuscript, to Wendy Jo Rickard and Ersilia Sarno for data-management assistance, and to Drs. Stephen L. George, Richard A. Larson, and Howard J. Weinstein for critically reviewing an earlier draft of the manuscript.


Source Information

From the Division of Medical Oncology, Dana-Farber Cancer Institute, and the Department of Medicine, Harvard Medical School, Boston (R.J.M., D.T.B., E.F.); the Division of General Medicine and Primary Care, Beth Israel Hospital, Harvard Medical School, Boston (R.B.D.); University of Maryland Cancer Center, Baltimore (C.A.S.); Bowman Gray School of Medicine, Winston-Salem, N.C. (B.L.P.); North Shore University Hospital, Manhasset, N.Y. (P.S.); University of Alabama, Birmingham (G.A.O.); Duke University Medical Center, Durham, N.C. (J.O.M.); and Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, N.H. (O.R.M.). The Cancer and Leukemia Group B institutions that participated in this study are listed in the Appendix.

Address reprint requests to Dr. Mayer at Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115.

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Appendix

In addition to the authors' institutions, the following Cancer and Leukemia Group B institutions also participated in this study: Long Island Jewish Medical Center, New York Hospital-Cornell Medical Center, University of California at San Diego, University of Iowa Hospitals, Rhode Island Hospital, Walter Reed Army Medical Center, University of Missouri-Ellis Fischel Cancer Center, University of Tennessee (Memphis), SUNY Health Science Center at Syracuse, McGill Department of Oncology, University of Minnesota, Roswell Park Cancer Institute, Massachusetts General Hospital, University of North Carolina at Chapel Hill, Maimonides Hospital (Brooklyn), Finsen Institute, Columbia-Presbyterian Medical Center, Mount Sinai Hospital (New York), Central Massachusetts Oncology Group-University of Massachusetts Medical Center, Washington University Medical Center (St. Louis), University of Cincinnati Medical Center, and University of Chicago Medical Center.


 

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Post-Remission Chemotherapy for Acute Myeloid Leukemia
Estey E. H., Keating M. J., Atkins C. D., Mayer R. J., Davis R. B., Berg D. T.
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