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
Background About 65 percent of previously untreated adults withprimary acute myeloid leukemia (AML) enter complete remissionwhen treated with cytarabine and an anthracycline. However,such responses are rarely durable when conventional postremissiontherapy is administered. Uncontrolled trials have suggestedthat intensive postremission therapy may prolong these completeremissions.
Methods We treated 1088 adults with newly diagnosed AML withthree days of daunorubicin and seven days of cytarabine andrandomly assigned patients who had a complete remission to receivefour courses of cytarabine at one of three doses: 100 mg persquare meter of body-surface area per day for five days by continuousinfusion, 400 mg per square meter per day for five days by continuousinfusion, or 3 g per square meter in a 3-hour infusion every12 hours (twice daily) on days 1, 3, and 5. All patients thenreceived four courses of monthly maintenance treatment.
Results Of the 693 patients who had a complete remission, 596were randomly assigned to receive postremission cytarabine.After a median follow-up of 52 months, the disease-free survivalrates in the three treatment groups were significantly different(P = 0.003). Relative to the 100-mg group, the hazard ratioswere 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 confidenceinterval, 0.60 to 0.94). The probability of remaining in continuouscomplete remission after four years for patients 60 years ofage or younger was 24 percent in the 100-mg group, 29 percentin the 400-mg group, and 44 percent in the 3-g group (P = 0.002).In contrast, for patients older than 60, the probability ofremaining disease-free after four years was 16 percent or lessin each of the three postremission cytarabine groups.
Conclusions These data support the concept of a dose-responseeffect for cytarabine in patients with AML who are 60 yearsof age or younger. The results with the high-dose schedule inthis age group are comparable to those reported in similar patientswho have undergone allogeneic bone marrow transplantation duringa first remission.
Approximately 65 percent of previously untreated adults withprimary acute myeloid leukemia (AML) enter complete remissionwhen treated with cytarabine and an anthracycline, with or withoutthioguanine1,2,3,4,5,6,7,8. However, with conventional maintenanceor consolidation therapy less than 25 percent of such patientsremain in remission2,9,10,11,12,13,14,15,16. The instabilityof the remission induced by cytarabine and an anthracyclinehas 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 resultsof a small randomized trial,3 but it has not been evaluateddefinitively.
Cytarabine is the mainstay of induction therapy for AML. Thedrug's steep dose-response curve24,25 motivated its use in highdoses in postremission therapy,3,7,8,17,18,19 but there hasbeen no comparison of the clinical efficacy of various intensivedose schedules.
The Cancer and Leukemia Group B (CALGB) designed a study comparingthe duration of complete remission in patients treated witheither high-dose cytarabine or standard or intermediate dosesof cytarabine administered by continuous infusion. The initialphase of this investigation, conducted between 1982 and 1985,established the maximal tolerated doses of high-dose cytarabineand continuous infusions of cytarabine in patients with AMLin first remission. These patients received four courses ofcytarabine, either at a dose of 3 g per square meter of body-surfacearea administered in a 3-hour infusion every 12 hours for threeto eight doses per course (high-dose cytarabine) or as a continuousfive-day infusion in doses ranging from 250 to 400 mg per squaremeter per day. The highest tolerated dose schedules were sixdoses of high-dose cytarabine administered twice daily everyother day and a five-day continuous infusion of 400 mg of cytarabineper square meter per day5. Therefore, these two regimens wereselected as the experimental treatments for the comparativetrial reported here.
Methods
Eligibility
Patients 16 years of age or older with primary AML, as definedby the French-American-British (FAB) classification system,26,27,28who had never received antileukemia therapy were eligible forentry into the trial. To support the diagnosis, a bone marrowaspirate had to show at least a 50 percent replacement of nonerythroidelements by myeloblasts, promyelocytes, or both or at leasta 25 percent replacement of nonerythroid elements by myeloblasts,promyelocytes, or both if there was neutropenia (fewer than1000 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 antecedenthematologic cancers, preexisting liver disease or alcohol abuse(or both), or an uncontrolled infection were excluded, as werepatients who had previously received nonsteroidal cytotoxicchemotherapy (except hydroxyurea) or radiation therapy and thosewho 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 participatinginstitutions at least once every three years to verify compliancewith federal regulations and protocol requirements29. The medicalrecords of 213 of the 1088 patients (20 percent) treated inthis study, drawn from all 28 participating institutions andtheir affiliates, were randomly selected and reviewed. All studydata were reviewed with respect to patient eligibility, responseto treatment, and extent of toxicity on a quarterly basis, andwritten summaries of these analyses were distributed to theparticipating investigators.
Study Design
Patients were treated with an induction regimen consisting ofcontinuous intravenous infusion of cytarabine (200 mg per squaremeter per day) for seven days, with daunorubicin given as abolus dose on the first three days of cytarabine therapy (45mg per square meter per day for patients 60 years of age oryounger and 30 mg per square meter per day for patients olderthan 60). Bone marrow aspiration and biopsy were performed 14days after the start of treatment. If the bone marrow was hypoplasticand contained less than 5 percent blast cells, further chemotherapywas deferred and the marrow examination was repeated weekly.However, if more than 5 percent leukemia cells persisted orif the marrow cellularity in the biopsy specimen exceeded 15percent, a second course of five days of cytarabine and twodays of daunorubicin at doses identical to the initial treatmentswas initiated. Patients who did not have a complete remissionafter a second course of induction chemotherapy were removedfrom the study. Patients who were considered to be in remissionon the basis of bone marrow analysis underwent a lumbar puncture;the presence of leukemic cells in the spinal fluid, indicativeof meningeal involvement, also resulted in removal from thestudy.
Patients in complete remission were stratified according tothe number of courses of induction therapy (one or two) andtheir age (less than 40 years, 40 to 60 years, or more than60 years) and were randomly assigned by the CALGB central officeto receive four courses of cytarabine in one of three regimens:100 mg per square meter per day for five days as a continuousintravenous infusion, 400 mg per square meter per day for fivedays as a continuous intravenous infusion, or 3 g per squaremeter administered in a 3-hour infusion every 12 hours (twicedaily) on days 1, 3, and 5 for a total of six doses per course(high-dose cytarabine). Thus, each postremission treatment schedulelasted five days. Patients began postremission cytarabine therapywithin 24 hours of randomization. The cytarabine, administeredthrough a constant-infusion device, was not interrupted forthe delivery of blood products or antibiotics. Sequential coursesof postremission therapy were given no sooner than every 28days or 1 week after marrow recovery (more than 1500 granulocytesper cubic millimeter and more than 100,000 platelets per cubicmillimeter), with the expectation that the maximal intervalbetween treatment courses would be 35 days or less. Platelettransfusions were recommended to maintain a platelet count ofmore than 20,000 per cubic millimeter. Hematopoietic growthfactors such as granulocyte colony-stimulating factor, granulocyte-macrophagecolony-stimulating factor, or erythropoietin were not given.After the four courses of cytarabine therapy, all patients receivedfour monthly treatments with cytarabine (100 mg per square meterevery 12 hours [200 mg per square meter per day] for five daysby subcutaneous injection) and daunorubicin (45 mg per squaremeter by rapid infusion on the first treatment day), after whichall chemotherapy was discontinued.
The dose of the induction treatment was not modified. Myelosuppressionalone did not warrant reduction of the dose of postremissioncytarabine. However, one dose of high-dose cytarabine or 20percent of the dose of the 24-hour infusions of cytarabine wassubtracted in the event that marrow recovery required more than28 days; a confluent maculopapular eruption or drug-induceddesquamation; photophobia or conjunctivitis unrelieved within24 hours by ophthalmic steroid drops; more than four episodesof watery diarrhea per day; or a fourfold increase in a previouslynormal serum aminotransferase or alkaline phosphatase levelor a total bilirubin level exceeding 3.0 mg per deciliter (51.3µmol per liter). Treatment with high-dose cytarabine wasdiscontinued in patients with severe cerebellar ataxia, confusion,or other central nervous system signs thought to be unrelatedto antiemetic medication. A high rate of neurotoxic effectsin patients older than 60 who were assigned to high-dose cytarabinetherapy led to a decision in April 1989 to restrict this treatmentto patients 60 years of age or younger.
Evaluation
Patients underwent full physical examinations and assessmentsof liver and renal function before each of the four coursesof single-agent cytarabine and each of the four maintenancecourses. Bone marrow examinations were performed at the startof maintenance treatment, after all eight postremission courseswere completed, and then every three months for one year, everysix months for two years, and annually for at least two additionalyears.
Criteria for Response
A complete remission was defined as the presence of normal bonemarrow and at least 1500 granulocytes per cubic millimeter and100,000 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 marrowhypoplasia, and death less than seven days after completionof the first course of induction therapy (early death)32. Relapsewas defined as the occurrence of more than 25 percent leukemiccells in the marrow of patients who were previously in completeremission or the detection of leukemic cells in previously normalcerebrospinal fluid.
In patients who had a complete remission, disease-free survivalwas measured as the length of time from randomization to relapseor death from any cause. In the comparisons of postremissiontherapies, survival was measured from the time of randomizationto that of death from any cause. Overall survival was measuredfrom the time of entry into the study to the time of death.Data on 14 patients who underwent allogeneic or autologous bonemarrow transplantation were censored on the date of the procedurefor the calculation of disease-free survival, but data continuedto be collected on these patients for the analysis of survival.
Statistical Analysis
Comparisons of the rates of complete remission according tothe patients' characteristics were evaluated by chi-square testsfor contingency tables33. Distributions of survival and disease-freesurvival were estimated by the product-limit method34. Comparisonsof these outcomes were based on the log-rank test35. Hazardratios were based on estimates from the proportional-hazardsmodel36. The primary treatment comparisons and related hazardratios were stratified according to the patients' ages (under40 years, 40 to 60 years, or older than 60) as planned fromthe inception of the study. Patients older than 60 were furtherstratified according to the date of entry (before vs. afterthe amendment restricting randomization to the two continuous-infusionregimens for these patients). All P values reported are two-sided.
Results
Between October 31, 1985, and October 1, 1990, a total of 1104previously untreated patients were registered for the study.The enrollment of patients older than 60 was curtailed on February16, 1990, at which time a protocol focusing on the treatmentof AML in the elderly was initiated by the CALGB. Sixteen patientswere considered ineligible or unable to be evaluated. Table 1shows the characteristics of the 1088 patients who could beevaluated. The median age was 52 years (range, 16 to 86) --slightly older than many,2,6,7,14 but not all,16 large, multicenterseries of adults with AML; 31 percent were younger than 40,37 percent were 40 to 60 years of age, and 32 percent were olderthan 60. The distribution of morphologic types of AML, accordingto the FAB classification system, was similar to that in previousreports37,38.
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 inductiontherapy (Table 2). The responsiveness to induction therapy decreasedwith age: 75 percent of the 340 patients younger than 40 enteredremission, as compared with 68 percent of the 402 patients whowere 40 to 60 years of age and 47 percent of the 346 patientsolder than 60. Death during a period of treatment-induced marrowhypoplasia was more frequent in the elderly, whereas resistanceto two courses of induction chemotherapy was the most commoncause of treatment failure in younger patients. The rates ofcomplete response were similar when analyzed according to theFAB classification, ranging from 60 percent (M4) to 74 percent(M3).
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) didnot continue in this trial for a variety of reasons. The remaining596 patients were randomly assigned to receive four coursesof 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 withregard to leukocyte count at the time of diagnosis and FAB subtype.The median and mean times from the documentation of completeremission 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 yearsafter randomization.
Tolerance and Toxicity of Postremission Cytarabine
All four courses of cytarabine therapy were administered to76 percent of the group receiving 100 mg per square meter, 74percent of those receiving 400 mg per square meter, and 56 percentof those receiving 3 g per square meter (Table 3). However,only 29 percent of the patients older than 60 could toleratethe four courses of high-dose cytarabine; indeed, only 14 ofthese 31 older patients received more than one course.
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 postremissioncytarabine therapy. The hematologic toxicity of each coursewas measured by determining the proportion of patients requiringhospitalization for fever and neutropenia and the need for platelettransfusions; there was a clear-cut relation between hematologictoxicity and the cytarabine dose schedule. Serious central nervoussystem abnormalities were reported only in the group given high-dosecytarabine and were especially common in patients older than60 (32 percent of 31 patients). As a result, in 1989 randomizationto high-dose cytarabine was restricted to patients 60 yearsof age or younger. Neurotoxicity may well have contributed tothe inability of older patients to receive all four coursesof high-dose cytarabine (Table 3). Symptoms of neurologic toxicityresolved within several days in about 20 percent of patientsand gradually receded in about 40 percent; however, there waspermanent disability in the remaining 40 percent. No furtherhigh-dose cytarabine therapy was administered to a patient afterthat patient recovered from a neurotoxic episode. There wasa transient, clinically unimportant increase in hepatic aminotransferaselevels in all three treatment groups. Treatment-related deathsduring remission, primarily due to infection, occurred in 1percent of the patients assigned to the 100-mg group, 6 percentof those assigned to the 400-mg group, and 5 percent of thoseassigned to the 3-g group.
Table 4. Toxic Effects Reported after Four Courses of Postremission Cytarabine Therapy.
Toxicity of Postremission Maintenance Therapy
After four courses of postremission cytarabine therapy, 383patients began treatment with four monthly maintenance coursesof daunorubicin and subcutaneous cytarabine; 79 percent of thesepatients received all four treatments. A total of 1382 coursesof maintenance therapy were administered; hospitalization becauseof fever and neutropenia was required in 26 percent of courses,and platelet transfusions were needed in 52 percent. The degreeof hematologic toxicity of the maintenance treatment was unrelatedto the dose of the previously administered postremission cytarabine.No treatment-related deaths or episodes of neurotoxicity wereassociated with maintenance therapy.
Disease-free Survival
The probability of remaining alive and free of recurrent AMLamong the 693 patients who had a complete remission was relatedto age. The estimated probability of being alive and disease-freeafter four years was 32 percent for patients younger than 40(95 percent confidence interval, 26 to 38 percent) and 29 percentfor patients 40 to 60 years of age (95 percent confidence interval,24 to 35 percent). This probability fell to 14 percent for patientsolder than 60 (95 percent confidence interval, 9 to 20 percent;P<0.001) (Figure 1).
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 postremissioncytarabine therapy. For all 596 patients who were randomly assignedto this therapy, the likelihood of remaining alive and disease-freeafter four years was 21 percent in the 100-mg group (95 percentconfidence interval, 15 to 26 percent), 25 percent in the 400-mggroup (95 percent confidence interval, 19 to 32 percent), and39 percent in the 3-g group (95 percent confidence interval,32 to 46 percent) (Figure 2A). The superiority of the high-dosecytarabine regimen in this analysis is somewhat exaggeratedby the smaller proportion of patients over the age of 60 whoreceived this treatment. Nonetheless, the stratified test correctingfor this imbalance demonstrated significant differences in disease-freesurvival among the three treatment groups (P = 0.003). The age-adjustedhazard ratios, relative to the 100-mg group, were 0.75 for thepatients treated with 400 mg of cytarabine per square meter(95 percent confidence interval, 0.60 to 0.94) and 0.67 forthose who received 3 g of cytarabine per square meter (95 percentconfidence interval, 0.53 to 0.86). Relapses continued to occurat a steady rate in the 100-mg and 400-mg groups during theinitial three years of follow-up but became less frequent aftertwo years in patients who received high-dose cytarabine.
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 thetype of postremission cytarabine treatment was not significantlydifferent in the 225 patients under the age of 40 and the 242patients who were 40 to 60 years of age, so these two groupswere combined for further analysis. Among these 467 patients,the likelihood of remaining disease-free after four years was24 percent in the 100-mg group (95 percent confidence interval,17 to 31 percent), 29 percent in the 400-mg group (95 percentconfidence interval, 21 to 36 percent), and 44 percent in the3-g group (95 percent confidence interval, 36 to 51 percent)(P = 0.002) (Figure 2B). In contrast, the corresponding figuresfor the 129 patients older than 60 were 16 percent or less foreach of the three groups (Figure 2C).
The 413 patients who entered remission after one course of inductiontherapy were more likely to remain disease-free than the 183patients 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 randomizationwas 31 percent for the 100-mg group (95 percent confidence interval,24 to 37 percent), 35 percent for the 400-mg group (95 percentconfidence interval, 27 to 42 percent), and 46 percent in the3-g group (95 percent confidence interval, 38 to 53 percent)(P = 0.04) (Figure 3A). The age-adjusted hazard ratios relativeto the 100-mg group were 0.78 for those who received 400 mgof cytarabine per square meter (95 percent confidence interval,0.61 to 1.00) and 0.74 for the patients treated with high-dosecytarabine (95 percent confidence interval, 0.57 to 0.96). Forpatients 60 years of age or younger, the likelihood of survivalafter four years was 35 percent in the 100-mg group (95 percentconfidence interval, 27 to 43 percent), 40 percent in the 400-mggroup (95 percent confidence interval, 32 to 49 percent), and52 percent in the high-dose group (95 percent confidence interval,44 to 60 percent) (P = 0.02) (Figure 3B).
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 studyand could be evaluated, the likelihood of remaining alive fouryears after the diagnosis of AML was 38 percent for patientsunder the age of 40 (95 percent confidence interval, 32 to 43percent), 27 percent for those 40 to 60 years of age (95 percentconfidence interval, 22 to 31 percent), and 9 percent for thoseolder than 60 (95 percent confidence interval, 6 to 12 percent)(P<0.001).
Discussion
This trial of postremission therapy for AML demonstrated a significantdose-response effect of cytarabine. Patients 60 years of ageor younger who received high-dose cytarabine were more likelyto remain in remission and to survive longer than similar patientswho received lower doses of cytarabine. Forty-four percent ofthe group treated with high-dose cytarabine remained in remissionafter 4 years of follow-up, with few relapses occurring after20 months of observation.
In conventional doses cytarabine acts primarily as an antimetabolite.When given in high doses such as those used in this study, cytarabinemay saturate the capacity of cytarabine-inactivating enzymes,enter cells in greater amounts, and increase levels of the activeintracellular metabolite ara-cytidine triphosphate. These effectshave been postulated to augment the inhibition of DNA synthesisfurther39 and to overcome cellular resistance to standard dosesof cytarabine. Reports of complete remission with high-dosecytarabine in 35 to 40 percent of patients whose AML was resistantto conventional doses of cytarabine support this possibility39.
The 64 percent rate of complete response found in this studyis similar to the rates of remission reported by others forcytarabine and daunorubicin, with or without thioguanine1,2,3,4,5,6,7,8,40.Surprisingly, two comparisons of high-dose cytarabine with standarddoses of cytarabine in induction programs have failed to showany difference in the remission rate in previously untreatedadults with AML41,42.
Myelosuppression, the main toxic effect of postremission cytarabinetherapy, was directly related to the cytarabine dose schedule.Hospitalization because of infection or fever and neutropeniawas required after 71 percent of high-dose cytarabine treatments.Only the superior outcome with high-dose cytarabine and thefew deaths due to toxic effects (5 percent) can justify suchdisruptive and expensive hospital admissions. The prophylacticuse of hematopoietic growth factors may reduce the frequencyof such hospitalizations in the future43.
Central nervous system toxicity is a well-described complicationof high-dose cytarabine therapy44. The neurotoxic effects includeseizures, cerebral dysfunction, and an acute cerebellar syndromeand are irreversible in 30 to 40 percent of cases. The mechanismby which cytarabine damages the central nervous system is unknown.Age over 40 years, serum creatinine levels exceeding 1.2 mgper deciliter (106 µmol per liter), and a threefold elevationin the serum alkaline phosphatase level were predictive factorsfor neurotoxic effects in the patients who received high-dosecytarabine in our trial45; the risk of neurotoxicity was lessthan 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 theuse of high-dose cytarabine in elderly patients who, ironically,have a higher likelihood of having drug-resistant leukemia andwould most likely benefit from more intensive treatment if itwere 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 everyother day) covered the same period as the 100-mg and 400-mgschedules, a feature we thought important in evaluating a drugwhose primary effect is on dividing cells. It is unclear whetherthis dose schedule increased the neurotoxicity of cytarabineor whether it is superior to other ways of administering high-dosecytarabine.
It is difficult to assess the impact of the four courses ofpostremission maintenance therapy that 383 of our patients received.When this study was designed, a previous CALGB trial had shownthat 32 months of postremission treatment was not superior to8 months of such therapy47. The subsequent demonstration ofthe ineffectiveness of low doses of maintenance therapy3 makesit unlikely that the last four months of treatment that ourpatients received contributed to the differences among the threetreatment groups. Postconsolidation maintenance therapy hasbeen eliminated from more recent CALGB studies.
Our results with high-dose cytarabine in patients 60 years ofage or younger deserve comparison with the results of two otherstrategies of postremission management -- allogeneic and autologousbone marrow transplantation. The merits of these approacheshave been the focus of debate48,49,50. Allogeneic marrow transplantationis generally restricted to patients 45 years of age or youngerwho have a histocompatible sibling, whereas patients as oldas 55 may qualify for autologous transplantation. The kindsof patients included in transplantation series may well be influencedby selection bias51. A comparison of our data with the resultsfrom some of the most recent experiences with allogeneic (singleinstitution52,53 and registry54) and autologous (registry55)transplantation reveals similar probabilities of disease-freesurvival after four years, particularly given the higher medianage in our patient population (Table 5). Prospective comparisonsof high-dose cytarabine chemotherapy and allogeneic transplantationin trials conducted by the Eastern Cooperative Oncology Group3and investigators at UCLA56 have reached similar conclusions.
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 ResearchFoundation.
We are indebted to Carol Connolly for assistance in the preparationof the manuscript, to Wendy Jo Rickard and Ersilia Sarno fordata-management assistance, and to Drs. Stephen L. George, RichardA. Larson, and Howard J. Weinstein for critically reviewingan 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 Cancerand Leukemia Group B institutions also participated in thisstudy: Long Island Jewish Medical Center, New York Hospital-CornellMedical Center, University of California at San Diego, Universityof Iowa Hospitals, Rhode Island Hospital, Walter Reed Army MedicalCenter, University of Missouri-Ellis Fischel Cancer Center,University of Tennessee (Memphis), SUNY Health Science Centerat 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 MedicalCenter, Mount Sinai Hospital (New York), Central MassachusettsOncology Group-University of Massachusetts Medical Center, WashingtonUniversity Medical Center (St. Louis), University of CincinnatiMedical Center, and University of Chicago Medical Center.
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(2005). Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood
105: 1810-1814
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Byrd, J. C., Marcucci, G., Parthun, M. R., Xiao, J. J., Klisovic, R. B., Moran, M., Lin, T. S., Liu, S., Sklenar, A. R., Davis, M. E., Lucas, D. M., Fischer, B., Shank, R., Tejaswi, S. L., Binkley, P., Wright, J., Chan, K. K., Grever, M. R.
(2005). A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood
105: 959-967
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Farag, S. S., Ruppert, A. S., Mrozek, K., Mayer, R. J., Stone, R. M., Carroll, A. J., Powell, B. L., Moore, J. O., Pettenati, M. J., Koduru, P. R.K., Stamberg, J., Baer, M. R., Block, A. W., Vardiman, J. W., Kolitz, J. E., Schiffer, C. A., Larson, R. A., Bloomfield, C. D.
(2005). Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study. JCO
23: 482-493
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Bradstock, K. F., Matthews, J. P., Lowenthal, R. M., Baxter, H., Catalano, J., Brighton, T., Gill, D., Eliadis, P., Joshua, D., Cannell, P., Schwarer, A. P., Durrant, S., Gillett, A., Koutts, J., Taylor, K., Bashford, J., Arthur, C., Enno, A., Dunlop, L., Szer, J., Leahy, M., Juneja, S., Young, G. A. R., for the Australasian Leukaemia and Lymphoma Group,
(2005). A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood
105: 481-488
[Abstract][Full Text]
Benke, S., Bow, E. J., Schacter, B., Loughery, J., Benjaminson, P., Seftel, M. D., Rubinger, M.
(2004). Infectious Morbidity and Hospitalization Requirements of Patients with Acute Myeloid Leukemia Receiving Intensive Outpatient Consolidation.. ASH ANNUAL MEETING ABSTRACTS
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[Abstract]
Kolitz, J. E., George, S. L., Dodge, R. K., Hurd, D. D., Powell, B. L., Allen, S. L., Velez-Garcia, E., Moore, J. O., Shea, T. C., Hoke, E., Caligiuri, M. A., Vardiman, J. W., Bloomfield, C. D., Larson, R. A.
(2004). Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621. JCO
22: 4290-4301
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Creutzig, U., Zimmermann, M., Reinhardt, D., Dworzak, M., Stary, J., Lehrnbecher, T.
(2004). Early Deaths and Treatment-Related Mortality in Children Undergoing Therapy for Acute Myeloid Leukemia: Analysis of the Multicenter Clinical Trials AML-BFM 93 and AML-BFM 98. JCO
22: 4384-4393
[Abstract][Full Text]
Castaigne, S., Chevret, S., Archimbaud, E., Fenaux, P., Bordessoule, D., Tilly, H., de Revel, T., Simon, M., Dupriez, B., Renoux, M., Janvier, M., Miclea, J.-M., Thomas, X., Bastard, C., Preudhomme, C., Bauters, F., Degos, L., Dombret, H.
(2004). Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood
104: 2467-2474
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Minami, H., Ohe, Y., Niho, S., Goto, K., Ohmatsu, H., Kubota, K., Kakinuma, R., Nishiwaki, Y., Nokihara, H., Sekine, I., Saijo, N., Hanada, K., Ogata, H.
(2004). Comparison of Pharmacokinetics and Pharmacodynamics of Docetaxel and Cisplatin in Elderly and Non-Elderly Patients: Why Is Toxicity Increased in Elderly Patients?. JCO
22: 2901-2908
[Abstract][Full Text]
Marcucci, G., Mrozek, K., Ruppert, A. S., Archer, K. J., Pettenati, M. J., Heerema, N. A., Carroll, A. J., Koduru, P. R.K., Kolitz, J. E., Sterling, L. J., Edwards, C. G., Anastasi, J., Larson, R. A., Bloomfield, C. D.
(2004). Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461. JCO
22: 2410-2418
[Abstract][Full Text]
Sekeres, M. A., Peterson, B., Dodge, R. K., Mayer, R. J., Moore, J. O., Lee, E. J., Kolitz, J., Baer, M. R., Schiffer, C. A., Carroll, A. J., Vardiman, J. W., Davey, F. R., Bloomfield, C. D., Larson, R. A., Stone, R. M.
(2004). Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia. Blood
103: 4036-4042
[Abstract][Full Text]
Ossenkoppele, G. J., Graveland, W. J., Sonneveld, P., Daenen, S. M. G. J., Biesma, D. H., Verdonck, L. F., Schaafsma, M. R., Westveer, P. H. M., Peters, G. J., Noordhuis, P., Muus, P., Selleslag, D., van der Holt, B., Delforge, M., Lowenberg, B., Verhoef, G. E. G.
(2004). The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. Blood
103: 2908-2913
[Abstract][Full Text]
Tallman, M. S., Kim, H. T., Paietta, E., Bennett, J. M., Dewald, G., Cassileth, P. A., Wiernik, P. H., Rowe, J. M.
(2004). Acute Monocytic Leukemia (French-American-British classification M5) Does Not Have a Worse Prognosis Than Other Subtypes of Acute Myeloid Leukemia: A Report From the Eastern Cooperative Oncology Group. JCO
22: 1276-1286
[Abstract][Full Text]
Byrd, J. C., Ruppert, A. S., Mrozek, K., Carroll, A. J., Edwards, C. G., Arthur, D. C., Pettenati, M. J., Stamberg, J., Koduru, P. R.K., Moore, J. O., Mayer, R. J., Davey, F. R., Larson, R. A., Bloomfield, C. D.
(2004). Repetitive Cycles of High-Dose Cytarabine Benefit Patients With Acute Myeloid Leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461. JCO
22: 1087-1094
[Abstract][Full Text]
Stone, R. M., O'Donnell, M. R., Sekeres, M. A.
(2004). Acute Myeloid Leukemia. ASH Education Book
2004: 98-117
[Abstract][Full Text]
Buchner, T., Hiddemann, W., Berdel, W. E., Wormann, B., Schoch, C., Fonatsch, C., Loffler, H., Haferlach, T., Ludwig, W.-D., Maschmeyer, G., Staib, P., Aul, C., Gruneisen, A., Lengfelder, E., Frickhofen, N., Kern, W., Serve, H. L., Mesters, R. M., Sauerland, M. C., Heinecke, A.
(2003). 6-Thioguanine, Cytarabine, and Daunorubicin (TAD) and High-Dose Cytarabine and Mitoxantrone (HAM) for Induction, TAD for Consolidation, and Either Prolonged Maintenance by Reduced Monthly TAD or TAD-HAM-TAD and One Course of Intensive Consolidation by Sequential HAM in Adult Patients at All Ages With De Novo Acute Myeloid Leukemia (AML): A Randomized Trial of the German AML Cooperative Group. JCO
21: 4496-4504
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Lancet, J. E., Karp, J. E.
(2003). Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy. Blood
102: 3880-3889
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Mengis, C., Aebi, S., Tobler, A., Dahler, W., Fey, M. F.
(2003). Assessment of Differences in Patient Populations Selected for or Excluded From Participation in Clinical Phase III Acute Myelogenous Leukemia Trials. JCO
21: 3933-3939
[Abstract][Full Text]
Kantarjian, H., Gandhi, V., Cortes, J., Verstovsek, S., Du, M., Garcia-Manero, G., Giles, F., Faderl, S., O'Brien, S., Jeha, S., Davis, J., Shaked, Z., Craig, A., Keating, M., Plunkett, W., Freireich, E. J
(2003). Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood
102: 2379-2386
[Abstract][Full Text]
Lowenberg, B., van Putten, W., Theobald, M., Gmur, J., Verdonck, L., Sonneveld, P., Fey, M., Schouten, H., de Greef, G., Ferrant, A., Kovacsovics, T., Gratwohl, A., Daenen, S., Huijgens, P., Boogaerts, M., the Dutch-Belgian Hemato-Oncology (HOVON) Cooperat,
(2003). Effect of Priming with Granulocyte Colony-Stimulating Factor on the Outcome of Chemotherapy for Acute Myeloid Leukemia. NEJM
349: 743-752
[Abstract][Full Text]
Suciu, S., Mandelli, F., de Witte, T., Zittoun, R., Gallo, E., Labar, B., De Rosa, G., Belhabri, A., Giustolisi, R., Delarue, R., Liso, V., Mirto, S., Leone, G., Bourhis, J.-H., Fioritoni, G., Jehn, U., Amadori, S., Fazi, P., Hagemeijer, A., Willemze, R.
(2003). Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood
102: 1232-1240
[Abstract][Full Text]
Delaunay, J., Vey, N., Leblanc, T., Fenaux, P., Rigal-Huguet, F., Witz, F., Lamy, T., Auvrignon, A., Blaise, D., Pigneux, A., Mugneret, F., Bastard, C., Dastugue, N., Van den Akker, J., Fiere, D., Reiffers, J., Castaigne, S., Leverger, G., Harousseau, J.-L., Dombret, H.
(2003). Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood
102: 462-469
[Abstract][Full Text]
Sievers, E. L., Lange, B. J., Alonzo, T. A., Gerbing, R. B., Bernstein, I. D., Smith, F. O., Arceci, R. J., Woods, W. G., Loken, M. R.
(2003). Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood
101: 3398-3406
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Stein, A. S., O'Donnell, M. R., Slovak, M. L., Snyder, D. S., Nademanee, A. P., Parker, P., Molina, A., Somlo, G., Fung, H. C., Krishnan, A., Rodriguez, R., Spielberger, R. T., Wang, S., Dagis, A., Vora, N., Arber, D. A., Niland, J. C., Forman, S. J.
(2003). Interleukin-2 After Autologous Stem-Cell Transplantation for Adult Patients With Acute Myeloid Leukemia in First Complete Remission. JCO
21: 615-623
[Abstract][Full Text]
Kern, W., Haferlach, T., Schoch, C., Loffler, H., Gassmann, W., Heinecke, A., Sauerland, M. C., Berdel, W., Buchner, T., Hiddemann, W.
(2003). Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood
101: 64-70
[Abstract][Full Text]
Byrd, J. C., Mrozek, K., Dodge, R. K., Carroll, A. J., Edwards, C. G., Arthur, D. C., Pettenati, M. J., Patil, S. R., Rao, K. W., Watson, M. S., Koduru, P. R. K., Moore, J. O., Stone, R. M., Mayer, R. J., Feldman, E. J., Davey, F. R., Schiffer, C. A., Larson, R. A., Bloomfield, C. D.
(2002). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood
100: 4325-4336
[Abstract][Full Text]
Frohling, S., Schlenk, R. F., Breitruck, J., Benner, A., Kreitmeier, S., Tobis, K., Dohner, H., Dohner, K.
(2002). Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood
100: 4372-4380
[Abstract][Full Text]
Anderson, J. E., Kopecky, K. J., Willman, C. L., Head, D., O'Donnell, M. R., Luthardt, F. W., Norwood, T. H., Chen, I-M., Balcerzak, S. P., Johnson, D. B., Appelbaum, F. R.
(2002). Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood
100: 3869-3876
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Stone, R. M.
(2002). The Difficult Problem of Acute Myeloid Leukemia in the Older Adult. CA Cancer J Clin
52: 363-371
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Seiter, K., Liu, D., Loughran, T., Siddiqui, A., Baskind, P., Ahmed, T.
(2002). Phase I Study of Temozolomide in Relapsed/Refractory Acute Leukemia. JCO
20: 3249-3253
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Baer, M. R., George, S. L., Dodge, R. K., O'Loughlin, K. L., Minderman, H., Caligiuri, M. A., Anastasi, J., Powell, B. L., Kolitz, J. E., Schiffer, C. A., Bloomfield, C. D., Larson, R. A.
(2002). Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood
100: 1224-1232
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Bass, A. J., Gockerman, J. P., Hammett, E., DeCastro, C. M., Adams, D. J., Rosner, G. L., Payne, N., Davis, P., Foster, T., Moore, J. O., Rizzieri, D. A.
(2002). Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma. JCO
20: 2995-3000
[Abstract][Full Text]
Perel, Y., Auvrignon, A., Leblanc, T., Vannier, J.-P., Michel, G., Nelken, B., Gandemer, V., Schmitt, C., Lamagnere, J.-P., De Lumley, L., Bader-Meunier, B., Couillaud, G., Schaison, G., Landman-Parker, J., Thuret, I., Dalle, J.-H., Baruchel, A., Leverger, G.
(2002). Impact of Addition of Maintenance Therapy to Intensive Induction and Consolidation Chemotherapy for Childhood Acute Myeloblastic Leukemia: Results of a Prospective Randomized Trial, LAME 89/91. JCO
20: 2774-2782
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Partridge, A. H., Avorn, J., Wang, P. S., Winer, E. P.
(2002). Adherence to Therapy With Oral Antineoplastic Agents. JNCI J Natl Cancer Inst
94: 652-661
[Abstract][Full Text]
Giles, F. J., Keating, A., Goldstone, A. H., Avivi, I., Willman, C. L., Kantarjian, H. M.
(2002). Acute Myeloid Leukemia. ASH Education Book
2002: 73-110
[Abstract][Full Text]
Goldstone, A. H., Burnett, A. K., Wheatley, K., Smith, A. G., Hutchinson, R. M., Clark, R. E.
(2001). Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood
98: 1302-1311
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Stone, R. M., Berg, D. T., George, S. L., Dodge, R. K., Paciucci, P. A., Schulman, P. P., Lee, E. J., Moore, J. O., Powell, B. L., Baer, M. R., Bloomfield, C. D., Schiffer, C. A.
(2001). Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood
98: 548-553
[Abstract][Full Text]
Bunjes, D., Buchmann, I., Duncker, C., Seitz, U., Kotzerke, J., Wiesneth, M., Dohr, D., Stefanic, M., Buck, A., Harsdorf, S. V., Glatting, G., Grimminger, W., Karakas, T., Munzert, G., Dohner, H., Bergmann, L., Reske, S. N.
(2001). Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study. Blood
98: 565-572
[Abstract][Full Text]
Bross, P. F., Beitz, J., Chen, G., Chen, X. H., Duffy, E., Kieffer, L., Roy, S., Sridhara, R., Rahman, A., Williams, G., Pazdur, R.
(2001). Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia. Clin. Cancer Res.
7: 1490-1496
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Stirewalt, D. L., Kopecky, K. J., Meshinchi, S., Appelbaum, F. R., Slovak, M. L., Willman, C. L., Radich, J. P.
(2001). FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood
97: 3589-3595
[Abstract][Full Text]
Creutzig, U., Ritter, J., Zimmermann, M., Reinhardt, D., Hermann, J., Berthold, F., Henze, G., Jurgens, H., Kabisch, H., Havers, W., Reiter, A., Kluba, U., Niggli, F., Gadner, H.
(2001). Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 93. JCO
19: 2705-2713
[Abstract][Full Text]
Davies, S. M., Robison, L. L., Buckley, J. D., Tjoa, T., Woods, W. G., Radloff, G. A., Ross, J. A., Perentesis, J. P.
(2001). Glutathione S-Transferase Polymorphisms and Outcome of Chemotherapy in Childhood Acute Myeloid Leukemia. JCO
19: 1279-1287
[Abstract][Full Text]
Woods, W. G., Neudorf, S., Gold, S., Sanders, J., Buckley, J. D., Barnard, D. R., Dusenbery, K., DeSwarte, J., Arthur, D. C., Lange, B. J., Kobrinsky, N. L.
(2001). A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children's Cancer Group. Blood
97: 56-62
[Abstract][Full Text]
Venditti, A., Buccisano, F., Del Poeta, G., Maurillo, L., Tamburini, A., Cox, C., Battaglia, A., Catalano, G., Del Moro, B., Cudillo, L., Postorino, M., Masi, M., Amadori, S.
(2000). Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood
96: 3948-3952
[Abstract][Full Text]
Estey, E. H.
(2000). How I treat older patients with AML. Blood
96: 1670-1673
[Full Text]
Tallman, M. S., Rowlings, P. A., Milone, G., Zhang, M.-J., Perez, W. S., Weisdorf, D., Keating, A., Gale, R. P., Geller, R. B., Laughlin, M. J., Lazarus, H. M., Luger, S. M., McCarthy, P. L., Rowe, J. M., Saez, R. A., Vowels, M. R., Horowitz, M. M.
(2000). Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood
96: 1254-1258
[Abstract][Full Text]
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