Abstract
Purpose
Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML).
Patients and Methods
AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis.
Results
A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival.
Conclusion
Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients.
INTRODUCTION
Intensive treatment regimens have improved outcomes in younger patients with acute myeloid leukemia (AML), but clinical trials in patients age 60 years and older have shown consistent and inferior results, with lower complete remission (CR) rates and only 10% to 15% of patients surviving 3 years.1-8 New approaches are needed not only for remission induction, but for postremission therapy, to prolong both disease-free survival (DFS) and overall survival (OS) for older patients who achieve remission.
Interleukin-2 (IL-2) augments the cytotoxic effect of natural killer (NK) cells,9 which are known to be able to mediate an antileukemic effect.10,11 IL-2–activated NK cells can lyse fresh leukemic blasts12,13 and IL-2 alone or in combination with IL-2–activated NK cells generated ex vivo has been effective in treating leukemia in animals13-15 and has induced CR in some patients with AML in relapse.16-18 Caligiuri et al19-21 demonstrated that low-dose infusion of IL-2 results in selective expansion in vivo of a CD56brightCD16dim subset of NK cells expressing the high-affinity IL-2 receptor. These cells demonstrate cytotoxic activity against NK cell–resistant AML blasts when incubated in IL-2 at higher concentrations that saturate the intermediate-affinity IL-2 receptors. A regimen of prolonged exposure to low-dose IL-2 with interval pulses of intermediate-dose IL-2 was designed to exploit these in vitro observations.22 This regimen was well tolerated when administered to AML patients 60 years and older after induction and consolidation chemotherapy in a pilot study, Cancer and Leukemia Group B (CALGB) study 9420.23
CALGB 9720 was initiated as a phase III trial in untreated AML patients 60 years and older evaluating multidrug resistance (MDR) modulation by valspodar (PSC-833) during induction and consolidation therapy with cytarabine, daunorubicin, and etoposide, and the subcutaneous IL-2 regimen previously piloted in older AML patients in CALGB 9420 as maintenance therapy. The valspodar (PSC-833)-containing induction and consolidation arm was closed after random assignment of 120 patients because of excessive early deaths.24 CALGB 9720 continued as a phase III study of IL-2 maintenance therapy, with all patients receiving cytarabine, daunorubicin, and etoposide chemotherapy, without PSC-833. We report here the results of this phase III trial of recombinant IL-2 (rIL-2) immunotherapy versus no further therapy in AML patients age 60 years and older in first CR after induction and consolidation therapy.
PATIENTS AND METHODS
Eligibility
Eligibility criteria for enrollment onto CALGB 9720, previously described,24 included a diagnosis of AML with French-American-British (FAB) types M0-M2 or M4-M7, no prior treatment for AML, and age 60 years or older, with no upper age limit. Patients with antecedent myelodysplastic syndromes (MDS) and with therapy-related AML (t-AML) after chemotherapy and/or radiation therapy for prior malignant or nonmalignant conditions were eligible. Prior MDS was defined by cytopenias and bone marrow morphology diagnostic of MDS at least 3 months before diagnosis of AML. Prior treatment for AML or MDS was not permitted, except for growth factor or cytokine support and leukapheresis, hydroxyurea, or cranial irradiation to manage hyperleukocytosis. The protocol was reviewed and approved by local institutional review boards, and written informed consent was obtained from all patients.
Induction and Consolidation Chemotherapy
Induction and consolidation chemotherapy was previously described.24 Patients were randomly assigned to receive cytarabine, daunorubicin, and etoposide induction and consolidation chemotherapy with (ADEP) or without (ADE) PSC-833. The ADEP arm was permanently closed to accrual after random assignment of 120 patients because of excessive early deaths on this arm, but the study continued with all patients after the initial 120 patients receiving ADE induction and consolidation chemotherapy.
All patients received cytarabine 100 mg/m2/d by continuous infusion for 7 days. ADE also included daunorubicin 60 mg/m2/d by intravenous bolus injection and etoposide 100 mg/m2/d by 2-hour infusion, both for 3 days, initiated concurrently with cytarabine. ADEP also included daunorubicin 40 mg/m2/d by bolus injection and etoposide 60 mg/m2/d by 2-hour infusion, both for 3 days, and PSC-833 as a 2-hour intravenous loading dose of 2.8 mg/kg before the first daunorubicin and etoposide doses, followed by a 72-hour 10 mg/kg/d infusion begun concurrently with the first daunorubicin and etoposide doses.
Patients with persistent marrow leukemia, defined by at least 20% cellularity with more than 5% blasts on day 14 of induction or later, received a second induction course identical to the first course (ADE or ADEP) but with cytarabine for 5 rather than 7 days, 2 rather than 3 doses of daunorubicin and etoposide, and PSC-833 as a 48-hour rather than a 72-hour infusion after the loading dose.
Patients who achieved CR received a single course of postremission chemotherapy identical to the initial induction regimen (ADE or ADEP) except, as in the reinduction regimen, with cytarabine for 5 rather than 7 days, 2 rather than 3 doses of daunorubicin and etoposide, and PSC-833 as a 48-hour rather than a 72-hour infusion after the loading dose. Postremission chemotherapy started as soon as possible after attainment of CR, but not before day 28 of induction. Full recovery from infection and stomatitis and attainment of a CALGB performance status of 0 or 1 were required. Marrow testing was repeated if postremission chemotherapy was delayed more than 4 weeks after attainment of CR.
rIL-2 Random Assignment
After recovery of the absolute neutrophil count (ANC) to at least 0.75 × 109/L and platelet count to at least 50 × 109/L after consolidation therapy, resolution of all nonhematologic toxicities to no worse than grade 1, and documentation of recovery of all three cell lineages and lack of recurrence of AML in the marrow, patients were randomly assigned with equal probability to rIL-2 maintenance or no further therapy. Random assignment occurred as soon as possible after recovery from consolidation, and no later than 5 months after the last day of consolidation therapy, and was stratified by institution and by presence or absence of prior MDS.
rIL-2 Therapy
rIL-2 (aldesleukin, Chiron Therapeutics, Emeryville, CA) was administered as 0.9 × 106 U/m2/d subcutaneously on days 1 through 14, 19 to 28, 33 to 42, 47 to 56, 61 to 70, and 75 to 90, followed by 12 × 106 U/m2/d subcutaneously on days 15 to 17, 29 to 31, 43 to 45, 57 to 59, and 71 to 73, with rests on days 18, 32, 46, 60, and 74 (Fig 1). The low doses were generally self-administered at home, whereas the higher doses were also administered in the outpatient setting, but under observation.
Fig 1.
Interleukin-2 (IL-2) administration schema. (→) Daily low-dose subcutaneous recombinant (r-)IL-2 (0.9 × 106 U/m2/d) on days 1 to 14, 19 to 28, 33 to 42, 47 to 56, 61 to 70, and 75 to 90. (X) High-dose 3-day subcutaneous bolus sequence of rIL-2 (12 × 106 U/m2/d) on days 15 to 17, 29 to 31, 43 to 45, 57 to 59, and 71 to 73. (*) Rest days in which patients received neither low-dose nor bolus IL-2 were on days 18, 32, 46, 60, and 74.
rIL-2 Dose Modifications
Hematologic toxicity.
Low-dose and bolus rIL-2 therapy was stopped when the ANC fell to less than 0.5 × 109/L, and was reinitiated with 20% dose reductions when it rose to at least 0.75 × 109/L. Low-dose and bolus rIL-2 therapy was stopped for platelet counts 10 × 109/L or less, and were resumed when it increased to more than 10 × 109/L, with or without transfusion. rIL-2 therapy otherwise continued at full dose despite thrombocytopenia, in the absence of bleeding. If transfusion requirements increased significantly and marrow examination did not show relapse, low-dose rIL-2 could be interrupted for 2 days, then resumed at 0.7 × 106 U/m2/d.
Nonhematologic toxicity.
If incapacitating fatigue or other grade 3 or worse nonhematologic toxicity occurred, low-dose rIL-2 was interrupted for 2 days, then resumed at 0.7 × 106 U/m2/d. If fatigue persisted beyond 2 weeks, or if other grade 3 or worse nonhematologic toxicity recurred, low-dose rIL-2 was interrupted for 3 days again, then resumed at 0.5 × 106 U/m2/d. Continued toxicity despite these two dose reductions mandated discontinuation of rIL-2 therapy. If patients experienced grade 3 or worse nonhematologic toxicity during rIL-2 bolus therapy, treatment was interrupted for 48 hours, then restarted at 6 × 106 U/m2/d for all subsequent bolus doses. Recurrent grade 3 or worse nonhematologic toxicity despite this dose reduction mandated discontinuation of bolus rIL-2 therapy. Low-dose rIL-2 therapy was then resumed after a 2-day rest period.
Response and Toxicity Definitions
CR was defined according to the criteria of the National Cancer Institute workshop published in 1990,25 and included ANC of at least 1.5 × 109/L, platelet count more than 100 × 109/L, absence of leukemia cells in the peripheral blood and of extramedullary disease, and marrow cellularity more than 20% with less than 5% blasts and normal myeloid maturation. Relapse was defined as marrow infiltration by more than 5% blasts not attributable to another cause or development of extramedullary disease in a patient previously in CR. In the analysis of outcome of rIL-2 maintenance therapy, DFS was measured from date of rIL-2 random assignment after induction and consolidation therapy until relapse or death from any cause, and OS was measured as the time from rIL-2 random assignment to death from any cause. Toxicity was graded according to Common Toxicity Criteria (CTC) version 2.0 (National Cancer Institute, Bethesda, MD).
Auditing
As part of the CALGB quality assurance program, Data Audit Committee members visit all participating institutions at least once every 3 years to review source documents. The auditors verify compliance with federal regulations and protocol requirements pertaining to eligibility, treatment, adverse events, tumor response and outcome in a sample of protocols at each institution. Such on-site review of medical records was performed for 226 (33.8%) of the 669 patients on this study.
Cytogenetic Analysis
Cytogenetic analyses were performed as part of CALGB 8461, “Cytogenetic Studies in Acute Leukemia,” a mandatory companion study for CALGB 9720, as previously described.24 The cytogenetic risk groups used in the analysis were those established by Farag et al26 for AML patients 60 years and older. Specifically, complex karyotypes with five or more abnormalities predicted inferior DFS, complex karyotypes with five or more abnormalities and rare aberrations predicted inferior OS, and core-binding factor (CBF) abnormalities predicted longer OS.
Statistical Analyses
As specified in the statistical analysis plan, the distributions of DFS and OS times were estimated using the Kaplan-Meier method,27 and differences were tested with the log-rank statistic stratified by treatment arm (rIL-2 v no further treatment). Follow-up data available as of December 2007 were used in the analyses.
RESULTS
A total of 669 AML patients were enrolled on CALGB 9720 between March 1998 and April 2002 (Fig 2). Three hundred twenty patients (48%) achieved CR, a CR rate comparable to those in other trials in older AML patients.1-8 Two hundred fifty-four (79%) of the 320 patients who achieved CR received consolidation therapy, and 163 (64%) of the 254 patients who received consolidation therapy were randomly assigned to rIL-2 immunotherapy (n = 81) or no further therapy (n = 82). The most common reasons for lack of random assignment of 91 patients after consolidation therapy included patient refusal (n = 43) and relapse before random assignment (n = 26).
Fig 2.
CONSORT patient flow diagram. CR, complete remission; rIL-2, recombinant IL-2.
Patients randomly assigned to IL-2 immunotherapy or no further therapy were balanced with regard to both patient- and disease-specific characteristics (Table 1). Median ages of patients randomly assigned to IL-2 or no further therapy were 68 years (range, 60 to 81 years) and 69 years (range, 60 to 83 years), respectively. Proportions of patients with prior MDS were similar: 13 (16%) of 81 patients randomly assigned to rIL-2 and 14 (17%) of 82 patients randomly assigned to no immunotherapy. Proportions of patients with t-AML were also similar: six (7%) of 81 patients randomly assigned to rIL-2 and seven (9%) of 82 patients randomly assigned to no immunotherapy. For patients for whom cytogenetic data were available, categories were similarly balanced between the arms, with three (5%) of 60 IL-2 patients and four (6%) of 65 non–IL-2 having either complex karyotypes with five or more abnormalities or rare cytogenetic aberrations, and three (5%) of 60 IL-2 patients and four (6%) of 65 non–IL-2 patients confirmed having CBF abnormalities.26 Finally, eight patients (10%) in each arm had received the PSC-833–containing induction regimen, ADEP.
Table 1.
Characteristics of Randomly Assigned Patients
| Characteristic | rIL-2 Immunotherapy (n = 81)
|
No Further Treatment (n = 82)
|
||
|---|---|---|---|---|
| No. | % | No. | % | |
| Age, years | ||||
| Median | 68 | 69 | ||
| Range | 60-81 | 60-83 | ||
| Male sex | 41 | 51 | 52 | 63 |
| White race | 70 | 86 | 75 | 91 |
| Type of AML | ||||
| De novo | 62 | 77 | 61 | 74 |
| Prior MDS | 13 | 16 | 14 | 17 |
| t-AML | 6 | 7 | 7 | 9 |
| Karyotype | ||||
| Complex or rare karyotypes* | 3† | 5 | 4† | 6 |
| CBF | 3† | 5 | 4† | 6 |
| Non-CBF, nonrare, noncomplex | 54† | 90 | 57† | 88 |
| Induction/consolidation regimen | ||||
| ADE | 73 | 90 | 74 | 90 |
| ADEP | 8 | 10 | 8 | 10 |
Abbreviations: rIL-2, recombinant interleukin-2; AML, acute myeloid leukemia; t-AML, therapy-related AML; MDS, myelodysplastic syndromes; CBF, t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), abnormalities characteristic of core-binding-factor AML; ADE, cytarabine, daunorubicin, and etoposide; ADEP, cytarabine, daunorubicin, etoposide, and valspodar (PSC-833).
Complex karyotypes defined as containing ≥ 5 chromosome abnormalities, rare abnormalities as defined by Farag et al.26
60 karyotyped.
‡65 karyotyped.
Fifteen of the 81 patients randomly assigned to rIL-2 did not initiate this therapy, because of refusal (n = 10), relapse (n = 3), or medical problems (n = 2). Twenty-four patients started rIL-2 but ended it early for reasons including toxicities (n = 9), relapse (n = 8), discontinuation of rIL-2 after futility analysis (n = 4), and refusal to continue (n = 3). Toxicities experienced during rIL-2 therapy are shown in Table 2. Grade 4 toxicities included thrombocytopenia (65%), neutropenia (64%), anemia (6%), dyspnea (3%), and malaise/fatigue (1%). Grade 3 toxicities included anemia (33%), infection (24%), and malaise/fatigue (14%). Additionally, grade 4 and grade 3 lymphopenia was seen in 43% and 24% of patients, respectively, as was also found in the pilot study, CALGB 9420.23 Forty-two (52%) of the 81 patients randomly assigned to IL-2 completed the full 90-day course. Among these 42 patients, 30 completed the full 90-day course without dose reductions, and 12 had dose reductions during therapy, including 50% reduction in bolus doses in eight patients, 25% reduction in bolus doses in one patient, discontinuation of bolus doses in one patient due to logistic difficulties, 20% dose reductions in low and bolus doses in one patient and reduction of low doses to 0.7 × 106 U/m2/d in one other.
Table 2.
Grade 3 and 4 Toxicities Occurring in >1% of Patients During Interleukin-2 Therapy
| Toxicity | Grade 3
|
Grade 4
|
||
|---|---|---|---|---|
| No. | % | No. | % | |
| Thrombocytopenia | 8 | 11 | 47 | 65 |
| Leukopenia | 8 | 11 | 45 | 63 |
| Neutropenia | 2 | 3 | 46 | 64 |
| Lymphopenia | 17 | 24 | 31 | 43 |
| Hemoglobin | 24 | 33 | 4 | 6 |
| Infection | 17 | 24 | ||
| Malaise/fatigue | 10 | 14 | 1 | 1 |
| Dyspnea | 5 | 7 | 2 | 3 |
Outcomes of all 81 patients randomly assigned to rIL-2 immunotherapy were analyzed in an intention-to-treat analysis. To date, 158 (97%) of the randomly assigned patients have had an event (relapse or death), and 154 patients (94%) have died. Patients randomly assigned to IL-2 or to no maintenance therapy had similar distributions of both DFS (combined median = 6.1 months; P = .47) and OS (combined median = 14.7 months; P = .61), measured from the time of random assignment (Fig 3A and 3B). In addition to the lack of benefit seen in the intention-to-treat analysis, neither DFS nor OS was longer in the 42 patients who completed the full planned 90-day rIL-2 course or in the 66 who received any rIL-2 therapy (data not shown). There was also no evidence of DFS or OS benefit of rIL-2 in any subgroup of patients, including those with noncomplex (n = 120) or noncomplex, nonrare, non-CBF (n = 111) karyotypes, and those who entered CR after a single induction course (n = 143; data not shown). Detailed analyses of the treatment effect by race and sex, not reported here, revealed no suggestion of a treatment effect in any of the four subgroups defined by race (white, nonwhite) and sex (male, female).
Fig 3.
(A) Disease-free and (B) overall survival of patients randomly assigned to receive interleukin-2 (IL-2) immunotherapy (n = 81) versus no maintenance therapy (n = 82).
DISCUSSION
The outcome of treatment of AML in older patients is poor. On the basis of in vitro data demonstrating cytotoxicity of IL-2–primed NK cells toward AML blasts, the short DFS and OS of older AML patients with established therapies, and pilot data demonstrating safety of the planned rIL-2 regimen in older AML patients, we tested low-dose rIL-2 with pulse higher-dose therapy as a maintenance regimen after consolidation chemotherapy as an approach to prolonging DFS and OS in this patient population. Unfortunately, this low-dose rIL-2 immunotherapy regimen with intermediate doses pulses did not prolong either DFS or OS in the older patient population studied here.
The IL-2 regimen tested consisted of repeated cycles of a low-dose regimen aimed at expanding NK cell populations, followed by a 3-day higher-dose regimen aimed at activating the cytotoxicity of this expanded effector population to produce lysis of residual AML cells. The total planned duration of therapy was 90 days. Only 163 (64%) of the 254 patients who received consolidation therapy were randomly assigned to IL-2 immunotherapy or no further therapy, and the most common reason for lack of random assignment was patient refusal. Additionally, despite a very low incidence of nonhematologic toxicities, only 42 (52%) of the 81 patients randomly assigned to IL-2 completed the full planned 90-day course of therapy. The low rates of both initiation and completion of rIL-2 therapy reflect poor acceptance by patients and likely also physicians. Nevertheless, in addition to the lack of benefit seen in the intention-to-treat analysis, neither the patients who completed the full planned course of therapy nor the combined group of those who received partial or full therapy showed prolongation of DFS or OS, indicating lack of beneficial effects, as well as lack of detrimental effects, of rIL-2. rIL-2 therapy in this schedule was associated with lymphopenia, rather than lymphocytosis, but in the absence of additional studies such as immunophenotyping and in vitro cytotoxicity assays, it cannot be determined whether biologic end points were achieved and, therefore, whether lack of clinical benefit was attributable to lack of the desired biologic effect or lack of clinical benefit of the desired biologic effect.
It is possible that immunotherapy might be more effective in younger AML patients because of greater chemosensitivity of AML cells and administration of more intensive induction and postremission therapy, both of which likely result in lower levels of residual disease at the time of initiation of maintenance therapy. In addition, therapies directed at enhancing the immune response might be more effective in younger patients than in older patients because of immunosuppression associated with aging. Another CALGB study, CALGB 19808, has tested IL-2 immunotherapy in younger AML patients. Patient enrollment on CALGB 19808 has been completed, and patients are being followed for DFS and OS. Preliminary analysis28 suggests possible benefit of rIL-2 in this younger adult population, in contrast to our findings in older patients. However, it should be noted that randomly assigned trials of rIL-2, in different doses and schedules, did not show benefit in acute leukemia after autologous bone marrow transplantation in first CR,29 nor, recently, in children with AML in first CR.30
Another recent phase III trial31 evaluated postconsolidation immunotherapy with both rIL-2 and histamine dihydrochloride in adult AML patients (median age, 57 years; range, 18 to 84 years) in first or subsequent CR, based on in vitro and in vivo results demonstrating that histamine dihydrochloride stimulates NK-cell activity and that cotreatment with IL-2 and histamine dihydrochloride stimulates NK-cell–mediated destruction of AML blasts and other malignant cells more effectively than treatment with either compound alone.32 Treatment consisted of 10 21-day cycles of rIL-2 (16,400 U/kg) and histamine dihydrochloride (0.5 mg), both administered by subcutaneous injection twice daily. For patients in first CR (n = 261), the 3-year DFS estimate was 40% on the treatment arm, compared with 26% on the control arm (P = .01). It is unclear whether the success of this trial, in contrast to the results of the trial reported here, derived from addition of histamine dihydrochloride to rIL-2, administration of a different rIL-2 regimen, or differences in the patient population studied, including younger age.
Outcome is poor even in AML patients who achieve CR, because DFS is short. On the basis of the results presented here, immunotherapy with rIL-2 is not a useful approach to prolonging DFS in older AML patients. Alternative approaches are being explored, including nonmyeloablative allogeneic hematopoietic stem-cell transplantation. The role of IL-2 maintenance immunotherapy in younger AML patients, and the additional effect of histamine remain to be determined.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Maria R. Baer, Michael A. Caligiuri, Richard A. Larson
Provision of study materials or patients: Maria R. Baer, Jonathan E. Kolitz, Bayard L. Powell, Joseph O. Moore, Richard M. Stone, Richard A. Larson
Collection and assembly of data: Maria R. Baer, Sandra M. Bothun
Data analysis and interpretation: Maria R. Baer, Stephen L. George, Ben L. Sanford, Krzysztof Mrózek, John Anastasi, Clara D. Bloomfield
Manuscript writing: Maria R. Baer
Final approval of manuscript: Maria R. Baer, Stephen L. George, Michael A. Caligiuri, Ben L. Sanford, Sandra M. Bothun, Krzysztof Mrózek, Jonathan E. Kolitz, Bayard L. Powell, Joseph O. Moore, Richard M. Stone, John Anastasi, Clara D. Bloomfield, Richard A. Larson
Acknowledgments
We thank the many patients, treating physicians, nurses and CALGB clinical research associates who participated in this study, and CALGB Protocol Coordinator Michael Kelly for his assistance.
Appendix
Participating institutions and principal investigators: CALGB Statistical Center, Duke University Medical Center, Durham, NC—Stephen George, PhD, supported by CA33601; Baptist Cancer Institute CCOP, Memphis, TN—Lee S. Schwartzberg, MD, supported by CA71323; Christiana Care Health Services Inc CCOP, Wilmington, DE—Stephen Grubbs, MD, supported by CA45418; Dana-Farber Cancer Institute, Boston, MA—Eric P. Winer, MD, supported by CA32291; Dartmouth Medical School—Norris Cotton Cancer Center, Lebanon, NH—Marc S. Ernstoff, MD, supported by CA04326; Duke University Medical Center, Durham, NC—Jeffrey Crawford, MD, supported by CA47577; Georgetown University Medical Center, Washington, DC—Minetta C. Liu, MD, supported by CA77597; Green Mountain Oncology Group CCOP, Bennington, VT—L. Herbert Maurer, MD, supported by CA35091; Illinois Oncology Research Association, Peoria, IL—John W. Kugler, MD, supported by CA35113; Massachusetts General Hospital, Boston, MA—Michael L. Grossbard, MD, supported by CA12449; Medical University of South Carolina, Charleston, SC—Mark Green, MD, supported by CA03927; Mount Sinai Medical Center, Miami, FL—Rogerio Lilenbaum, MD, supported by CA45564; Mount Sinai School of Medicine, New York, NY—Lewis R. Silverman, MD, supported by CA04457; North Shore—Long Island Jewish Medical Center, Manhasset, NY—Daniel R Budman, MD, supported by CA35279; Rhode Island Hospital, Providence, RI—William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY—Ellis Levine, MD, supported by CA02599; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC—James N. Atkins, MD, supported by CA45808; Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV—John Ellerton, MD, supported by CA35421; State University of New York Upstate Medical University, Syracuse, NY—Stephen L. Graziano, MD, supported by CA21060; Syracuse Hematology-Oncology Assoc. CCOP, Syracuse, NY- Jeffery Kirshner, MD, supported by CA45389; The Ohio State University Medical Center, Columbus, OH—Clara D Bloomfield, MD, supported by CA77658; University of California at San Diego, San Diego, CA—Joanne Mortimer, MD, supported by CA11789; University of Chicago, Chicago, IL—Gini Fleming, MD, supported by CA41287; University of Iowa, Iowa City, IA—Gerald Clamon, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD—Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical School, Worcester, MA—William V. Walsh, MD, supported by CA37135; University of Minnesota, Minneapolis, MN—Bruce A Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO—Michael C Perry, MD, supported by CA12046; University of Nebraska Medical Center, Omaha, NE—Anne Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC—Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN—Harvey B. Niell, MD, supported by CA47555; Vermont Cancer Center, Burlington, VT—Hyman B. Muss, MD, supported by CA77406; Virginia Commonwealth University Massey Cancer Center CCOP, Richmond, VA—John D. Roberts, MD, supported by CA52784; Wake Forest University School of Medicine, Winston-Salem, NC—David D Hurd, MD, supported by CA03927; Walter Reed Army Medical Center, Washington, DC—Thomas Reid, MD, supported by CA26806; Washington University School of Medicine, St. Louis, MO—Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY—Scott Wadler, MD, supported by CA07968; Western Pennsylvania Cancer Institute, Pittsburgh, PA—Richard K. Shadduck, MD.
published online ahead of print at www.jco.org on June 30, 2008.
Supported in part by grants from the National Cancer Institute (NCI) to the Cancer and Leukemia Group B (NCI CA31946) and to the CALGB Statistical Center (CA33601); and NCI Grants No. CA31983 (M.R.B.), CA02599 (M.R.B.), CA77658 (M.A.C., K.M., C.D.B.), CA35279 (J.E.K.), CA03927 (B.L.P.), CA47577 (J.O.M.), CA32291 (R.M.S.), and CA41287 (J.A., R.A.L.).
Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL, and the 12th International Symposium on Acute Leukemias, February 16-20, 2008, Munich, Germany.
The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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