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Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?†
Results from a prospective randomized trial
Article first published online: 20 DEC 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 6, pages 1186–1194, 15 March 2013
How to Cite
Lamanna, N., Heffner, L. T., Kalaycio, M., Schiller, G., Coutre, S., Moore, J., Seiter, K., Maslak, P., Panageas, K., Golde, D. and Weiss, M. A. (2013), Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?. Cancer, 119: 1186–1194. doi: 10.1002/cncr.27901
- Issue published online: 4 MAR 2013
- Article first published online: 20 DEC 2012
- Manuscript Accepted: 20 SEP 2012
- Manuscript Revised: 4 SEP 2012
- Manuscript Received: 22 JUN 2012
- acute lymphocytic leukemia;
- T cell
Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m2 daily for 5 days with mitoxantrone 80 mg/m2 (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL.
The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.
The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20.
Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.
Therapy for adult patients with acute lymphoblastic leukemia (ALL) can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Despite marked improvement in the outcomes for pediatric patients with ALL, the same success has not been realized for adult patients.
Current regimens induce a complete response/complete remission (CR) in approximately 60% to 90% of patients. However, there is a substantial relapse rate, and only 20% to 40% of patients ultimately will be cured of their disease.1-8 Multiple studies have confirmed the importance of several prognostic features, including age, immunophenotype, white blood cell (WBC) count, cytogenetic abnormalities, and the time to achieve a CR.9, 10 On the basis of these observations, several groups have tested more aggressive acute myeloid leukemia “(AML)-style” induction therapies to induce more rapid CRs and, in this manner, attempt to increase the likelihood of a cure.11-13 Previously, we conducted a phase 2 study of “AML-style” therapy, the ALL-2 regimen, which combined high-dose cytarabine with a very high single dose of mitoxantrone (80 mg/m2). In that study, patients did not receive vincristine or steroids during induction therapy. The initial choice of high-dose mitoxantrone came from preclinical trials that demonstrated a steep dose-response curve for mitoxantrone when tested in vitro against leukemic blasts.14 This was then bolstered by a phase 1 clinical and pharmacologic evaluation.15 On the basis of the preclinical and phase 1 trial data, we tested this ALL-2 regimen in adult patients with ALL.
When the results of this regimen were compared with a historic control group (patients who were treated on the last Memorial Hospital vincristine/prednisone-based regimen [“L-20”]), we observed several differences. The incidence of CR (84% vs 67% for the ALL-2 regimen vs the L-20 regimen, respectively; P = .056) and the time to CR (34 days vs 61 days, respectively; P = .005) were superior on the ALL-2 regimen. ALL-2 also appeared to be superior in patients who had Philadelphia chromosome (Ph)-positive ALL, with improved incidence of complete hematologic response (100% vs 61%; P = .14) and complete cytogenetic response (100% vs 45%; P = .056). The survival curves for patients with Ph-positive disease also suggested a benefit for the patients who received ALL-2 (median not reached: >12 months vs 8.8 months; P = .052). These results suggested that the ALL-2 regimen may be a superior form of induction therapy for adult patients with ALL; and, given the limitations inherent in comparisons with historic controls, we conducted a prospective randomized trial of the ALL-2 regimen versus the L-20 program.
MATERIALS AND METHODS
The patients who participated had previously untreated ALL or lymphoblastic lymphoma. Patients were required to have adequate hepatic, renal, and cardiac function. All patients gave their written informed consent. The participating centers were Memorial Sloan-Kettering Cancer Center, Emory University, The Cleveland Clinic Foundation, University of California-Los Angeles, Duke University Medical Center, New York Medical College, and Stanford University Medical Center. This study was reviewed and approved by the institutional review boards at all participating institutions.
Patients were randomized to treatment on either the ALL-2 or L-20 treatment regimen. The ALL-2 regimen was comprised of induction with cytarabine and high-dose mitoxantrone followed by 4 cycles of consolidation as follows: Consolidation A with vincristine and prednisone, Consolidation B with high-dose cyclophosphamide, Consolidation C with etoposide and cytarabine, and Consolidation D with pegaspargase (if unavailable, then substitution with L-asparaginase was permitted). Maintenance therapy was administered for 2 years as previously described (Tables 1 through 7).
The L-20 regimen was comprised of induction with vincristine, prednisone, cyclophosphamide, and doxorubicin followed by 4 cycles of consolidation as follows: Consolidation A with cytarabine and daunorubicin, Consolidation B with cytarabine and methotrexate, Consolidation C with pegaspargase (if unavailable, then substitution with L-asparaginase was permitted), and Consolidation D with cyclophosphamide (Tables 8 through 12). Maintenance therapy was the same as the ALL-2 schedule (Tables 6 and 7).
Allogeneic stem cell transplantation in first remission was only permitted for patients with Ph-positive disease and a t(4;11) translocation. Such patients typically underwent transplantation after Consolidation A.
Responses were graded as complete if there was disappearance of all clinical evidence of leukemia for a minimum of 4 weeks. The patient had to have a neutrophil count >1000 × 106/L, a platelet count >100,000 × 106/L, no circulating blasts, and ≤5% blasts on bone marrow differential in a normal or hypercellular bone marrow. In contrast to many studies, we required 2 remission bone marrows performed at least 28 days apart. Studies of minimal residual disease using flow cytometric or molecular tests were not required.
Treatment failure included increasing bone marrow infiltrate or the development of organ failure or extramedullary infiltrates because of leukemia. Patients had to achieve a complete bone marrow response by the end of Consolidation A. Partial responses at the end of Consolidation A were considered treatment failures, and those patients were removed from study.
Toxicities were evaluated according to National Cancer Institute Common Toxicity Criteria.
Statistical Design and Methods: Sample Size
The primary endpoint for this trial was a comparison of the frequency of response between the 2 arms. The secondary endpoints comparisons of the time to CR, the length of hospital stay, efficacy in Ph-positive ALL, and the fraction of patients achieving durable (>5-year) responses. The study was designed to detect a 20% improvement in the probability of CR from 67% to 87% using a sequential design. The target accrual was 77 evaluable patients per arm to detect this difference with a power of at least 80%, and the O'Brien and Fleming stopping rule was used to maintain an overall significance level of 5%. The sequence of nominal significance levels used was P = .0005, P = .0124, and P = .0455 for the interim and final analyses, respectively. Randomization was accomplished by the method of random permuted block with treating institution as a stratification factor.
The frequency of the primary outcome (CR) was reported for each treatment arm. The proportion of CR for the 2 arms was compared using the Fisher exact test. Kaplan-Meier estimates also were computed for overall survival and duration of CR. Overall survival was defined as the time from randomization to death from any cause. Duration of CR was measured from the initial CR until progression of disease. Subgroup comparisons of overall and disease-free survival were performed using the log-rank test. Analyses were performed using both the intent-to-treat principle, which included all registered patients (eligible and ineligible), and all evaluable patients. Frequency of toxicities was reported based on National Cancer Institute Common Toxicity Criteria. The secondary endpoints comparing the 2 regimens were the time to CR, hospital days, and efficacy in Ph-positive ALL. All analyses were carried out using SAS version 9.2 (SAS Institute, Cary, NC).
Data Safety Monitoring Board
The data were reviewed at designated intervals by an independent Data and Safety Monitoring Committee. Members of the data safety monitoring board were provided tables of accrual and the frequencies of toxicity and adverse events for review. Interim analyses were performed at intervals of 1 year.
One hundred seventy-one patients were registered between August 1996 and October 2004, 164 patients were evaluable for response, and 7 patients were inevaluable for response, including 3 patients who had major protocol violations, 3 patients who were registered but withdrew consent or transferred their care before initiating chemotherapy, and 1 patient who was removed before initiating therapy for misdiagnosis. The median follow-up among survivors was 7 years. Seventy-eight patients received induction with the ALL-regimen, and 86 patients received the L-20 regimen. The median age of evaluable patients was 43 years (range, 18-78 years), 62% were men, 72% had B-lineage disease, and 17% had Ph-positive disease. The treatment arms were balanced in terms of pretreatment characteristics (see Tables 8-12).
Sixty-five patients (83%) achieved CR in the ALL-2 arm compared with 61 patients (71%) in the L-20 arm (P = .06) (see Table 14). There was no significant difference in deaths between the 2 arms (9% on ALL-2 vs 7% on L-20). Fewer patients failed with resistant disease on the ALL-2 arm (8% vs 21%; P = .02). The median time to CR was significantly shorter on the ALL-2 regimen compared with the L-20 regimen (32 days vs 55 days; P = .001) (Tables 8-12). Despite the superior outcome of induction therapy with the ALL-2 arm (higher CR frequency, less resistant disease, and shorter time to CR), there was no significant difference in overall survival (Fig. 1, Table 15). Survival curves for patients with B-lineage, T-lineage and Ph+ disease are illustrated in Figures 2-4.13
|Variable||ALL-2 Arm, N = 78||L-20 Arm, N = 86|
|Age: Median [range], y||43 [19-77]||43 [22-78]|
|WBC: Mean, ×109/L||28||28|
|Ph+ ALL: No. of patients (%)||14 (18)||15 (17)|
|T-lineage disease, %||28||27|
|Enrollment by site: No. of patients|
|Result||ALL-2, N = 78||L-20, N = 86||P|
|Incidence of CR||83||71||.06|
|Deaths during induction||9||7||NS|
|Time to CR, d||32||55||.001|
|5-Year survival rate||34||21||NS|
|CR in Ph+ ALL||85||47||.04|
|Survival Rate, %|
|Group||1 Year||2 Years||5 Years||Median Survival (range), y||P|
|ALL-20||74||57||52||5.9 (0.5 to NR)||.78|
|L-20||78||60||41||2.5 (1.4 to NR)|
Eighteen patients underwent allogeneic stem cell transplantation in first CR, and an additional 29 patients underwent transplantation in the salvage setting after they failed protocol therapy. Of these 47 patients (29%) who underwent allogeneic transplantation, there were 25 patients in the ALL-2 arm, and 9 of those patients remain alive; and there were 22 patients in the L-20 arm, and 5 of those patients remain alive.
Twenty-nine patients (18%) had Ph-positive disease. This study was designed and largely conducted in the preimatinib era, and patients did not receive tyrosine kinase inhibitors. The frequency of CR was greater for patients with Ph-positive disease in the ALL-2 arm compared with their counterparts in the L-20 arm (85% vs 47%; P = .04). Survival for patients with Ph-positive disease at 6 years was 36% in the ALL-2 arm compared with 7% in the L-20 arm (Fig. 4).
The incidence of severe adverse events was similar in both arms (77 events [44 patients] in the ALL-2 arm vs 70 events [39 patients] in the L-20 arm; P value nonsignificant). Although patients in ALL-2 arm spent more time in the hospital during induction (median, 32 days vs 28 days), they spent fewer days in the hospital overall (70 days vs 81 days for those on the L-20 arm). An unusual toxicity noted in the ALL-2 arm was a second wave of myelosuppression that typically occurred between days 60 and 120, which probably was caused by the high-dose mitoxantrone as previously reported.11-13, 16
In 1971, Clarkson and Fried reported the results of a 4-drug induction regimen in adults with ALL.17 Since that early report, numerous regimens have been developed to treat these patients, but it is not clear that any of these regimens offer a substantial improvement over this early experience nearly 40 years ago. It is widely accepted that attaining a CR is absolutely essential for long-term survival and that regimens that can induce very high proportions of CRs are likely to cure more patients than regimens that achieve lower frequencies of CRs. In addition, essentially every published study on treating adults with ALL has indicated that patients who achieve their CR rapidly are more likely to be cured than patients who take longer than 4 or 5 weeks to achieve a CR. On the basis of these findings, many programs over the last 3 decades have focused on developing more intensive regimens to achieve a high frequency of CRs and to do so in a shorter time frame.
Some groups have focused on developing regimens with a more intensive induction,1, 2, 18, 19 whereas others have studied intensifying consolidation or maintenance.3, 20-26 To our knowledge, none of these other intensified regimens have been compared in a prospective randomized fashion; therefore, it is not possible to know with certainty whether any of these approaches increase the likelihood of cure.
Against this background, Weiss et al reported a phase 2 trial of a novel regimen that demonstrated a high CR frequency and substantially reduced the time to CR compared with historic controls.11 Those results led to the current national, multicenter, prospective randomized trial of an induction based on high-dose mitoxantrone and cytarabine compared with a more traditional 4-drug induction regimen.
The results from this trial may suggest some far-reaching conclusions. In this study, several findings stand out. The more aggressive ALL-2 arm was superior in terms of time to CR (P = .001) and failure with resistant disease (P = .02). The frequency of CR appeared to be superior in the ALL-2 arm, though the P value had borderline significance (P = .06). Despite the apparent superiority of the ALL-2 regimen in terms of early surrogate markers, the 2 treatment arms had nearly identical survival curves.
This result calls into question the long-held belief that developing a regimen that induces more patients into remission faster would improve long-term outcomes. Rather, the results from this trial suggest that only a fraction of adults has a “curable” form of ALL and that, as long as certain treatment parameters are included, the specifics of the treatment regimen do not matter. Taking this argument 1 step further, regimens that tout high frequencies of CR or the ability to achieve a CR quickly are likely ultimately to be no better than less aggressive regimens that achieve a lower proportion of CRs. In this view, such CRs are more “cosmetic” than of true clinical importance.
Although, in the most technical sense, the results of this trial are applicable only to the 2 regimens that are compared, there are supporting arguments that need to be considered. In his landmark analysis, Ohno described a tight correlation between the median age of patients treated on a specific regimen and long-term (4-year, 5-year, or 6-year) survival.27 The analysis by Ohno used age as the only predictive feature; presumably an analysis that incorporated other prognostic features may have even more accurately predicted long-term survival. The ability to accurately predict treatment results based solely on patient characteristics, independent of treatment regimen, strongly supports the concept that selected individuals have curable disease regardless of the regimen used. A second finding that can be derived from the analysis of Ohno is that the predictive model is not influenced by the time to CR or the fraction of patients achieving CR. Indeed, the time to CR and the frequency of CR appear to be predictive only within individual trials and do not correlate with long-term survival across trials. This reinforces the well recognized problem of comparing different phase 2 trials and, ultimately, the vital importance of conducting phase 3 randomized trials.
Recently, several trials have reported high frequencies of CR. A closer look at 2 of those trials—the Eastern Cooperative Oncology Group-Medical Research Council (ECOG-MRC) 2993 trial3 and the University of Texas M. D. Anderson Cancer Center hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) regimens2—can be informative. The large ECOG-MRC United Kingdom ALL trial reported a CR frequency of 91% and a 5-year overall survival rate for all 1913 patients of 39%. Those results suggest that, in that study, the high CR frequency led to improved long-term survival compared with the regimens reported by others, including the regimens described in the current report. Such a simple comparison, however, ignores a fundamental issue: namely, differences in pretreatment patient characteristics. The ECOG-MRC trial was performed in patients predominantly aged ≤60 years, and the median age was 31 years.28 The younger age of patients treated on the ECOG-MRC trial compared with the current study likely accounts for the differences in outcome. Age at diagnosis powerfully affects outcomes in this disease, as can be seen in the ECOG-MRC trial, in which <15% of patients were long-term survivors if they were aged >50 years at the time of treatment.
Our colleagues at The University of Texas M. D. Anderson Cancer Center have reported the efficacy of Hyper-CVAD in 288 patients2 who had a CR frequency of 92%, but the estimated 5-year survival rate was 38%. That study included older patients (median age, 40 years), with 20% aged >60 years; and, as is typical, the older patient cohort in that study had a lower CR frequency and high frequency of treatment-related mortality.
All of these studies have succeeded in achieving a high frequency of CRs. But improvement in long-term survival has remained elusive. When the results of the current trial are viewed in the context of treatment results of other regimens it becomes more evident that the specifics of the treatment program may affect the fraction of patients achieving a CR and the time to CR but does not affect the likelihood of cure. Given this analysis it seems likely that improvements in curing more adults with ALL will require new drugs. Unfortunately the current structure of clinical research in adult ALL makes it difficult to evaluate new strategies and incorporate new drugs in a timely fashion. To study this uncommon disease cooperative groups are often needed and still these studies frequently require more than 10 years for meaningful accrual (this study was 1996-2004 at 7 sites; the MRC UKALL/ECOG was 1993-2006 at more than 100 sites).
Therefore, it is not surprising that progress in adult ALL has been so limited. Molecular markers in ALL have only recently been described, including the transcription factor Erg; expression of the orphan homeobox gene HOX11L2; cytoplasmic (BAALC) gene expression; Notch/F-box and WD repeat domain-containing 7 (FBXW7) mutations; and others. However, the best way to alter therapy based on this information remains uncertain. It seems likely that true progress in this disease depends on the development of new agents with novel mechanisms of action that target either common features of the disease, such as blinatumomab,29 or specific molecular subtypes, such as tyrosine kinase inhibitors for Ph-positive ALL and possibly gamma-secretase inhibitors for Notch-1–activating mutations in T-cell ALL. In conclusion, it remains clear that a concerted effort is needed to enroll these patients onto clinical trials that are evaluating novel therapies with the ultimate goal of increasing the fraction of patients who are cured of their disease.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 2Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004; 101: 2788-2801., , , et al.
- 3In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008; 111: 1827-1833., , , et al.
- 29Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011; 29: 2493-2498., , , et al.