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Intensification of Therapy for Children With Lower-Risk Acute Lymphoblastic Leukemia: Long-Term Follow-Up of Patients Treated on Children’s Cancer Group Trial 1881

Raymond J. Hutchinson, Paul S. Gaynon, Harland Sather, Salvatore J. Bertolone, Herbert A. Cooper, Raymond Tannous, Linda M. Wells, Nyla A. Heerema, Scott Sailer, Michael E. Trigg for the Children’s Cancer Group/Children’s Oncology Group

From the University of Michigan Health System, Ann Arbor, MI; Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA; University of Louisville, Louisville, KY; University of North Carolina, Chapel Hill, NC; University of Iowa Hospital and Clinics, Iowa City, IA; Richland Memorial Hospital, Columbia, SC; Ohio State University, Columbus, OH; and Alfred I. DuPont Hospital for Children, Wilmington, DE.

Address reprint requests to Raymond J. Hutchinson, MD, C.S. Mott Children’s Hospital, Bone Marrow Transplant Unit, 1500 E Medical Ctr Dr, CCGC-B1-207, Ann Arbor, MI 48109-0914; email: rhutchin{at}umich.edu.

	ABSTRACT

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Purpose: From December 1988 through December 1992, the Children’s Cancer Group (CCG) conducted a randomized trial (CCG-1881) designed to evaluate the impact of adding a single delayed intensification phase of therapy to standard therapy for patients with newly diagnosed low-risk acute lymphoblastic leukemia (ALL).

Patients and Methods: Patients (n = 778) with newly diagnosed ALL, 2 to 9 years of age at diagnosis with an initial WBC count less than 10,000/µL, were eligible for this protocol. All patients received induction, consolidation, and interim maintenance phases of therapy over the first 16 weeks. At week 16, patients remaining in remission were randomly assigned to receive or not receive a single 7-week delayed intensification (DI) phase of therapy. Maintenance therapy was given in lieu of or after DI, with total duration of therapy approximately 3 years for boys and 2 years for girls.

Results: Patients randomized to receive DI experienced fewer relapse events in all categories. Kaplan-Meier life-table estimates for continuous complete remission (CCR) at 7 years for the randomized regimens were 77% (SE, 2.4%) for the standard regimen and 83% (SE, 2.7%) for the DI regimen (P = .072). The only prognostic factor of significance postrandomization in this selected low-risk population was the day 14 marrow response (P = .0001).

Conclusion: The addition of a single DI phase of therapy was well tolerated and augmented 7-year CCR by 6% (SE of the difference, 3.3%), resulting in 26% fewer adverse events. Overall survival for eligible patients at 7 years is 90% (SE, 1.2%).

	INTRODUCTION

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RISK-ADJUSTED THERAPY has long been a primary principal in the treatment of childhood acute lymphoblastic leukemia (ALL).¹ A variety of presenting clinical and laboratory features² and early marrow response³ have been used to define risk of relapse. Attempting to balance harms and benefits, more aggressive therapy is allowed for patients who are at higher risk of relapse, and less aggressive therapy is provided to patients who are at lower risk of relapse. Novel interventions with incompletely defined benefits and harms are introduced first for higher-risk patients and only later for lower-risk patients, after proof of benefit and definition of morbidity have been obtained.

Historically, the Goldie-Coldman hypothesis has been a second principal guiding the treatment of ALL.⁴ On the basis of the observations that mutation rates are constant and the risk of emergence of a resistant cell depends on the number of cancer cells present and the duration of time for which they are present, this strategy argues for rapid cytoreduction that will minimize the opportunity for resistance and treatment failure. In pursuit of this goal, clinicians have accepted substantial morbidity and even mortality.

For children with ALL, even those with favorable presenting features, postinduction intensification has seemed critical. Bleyer et al⁵ showed the benefit of monthly vincristine-prednisone pulses in maintenance therapy. For intermediate-risk patients, Tubergen et al⁶ showed that postinduction intensification at 4 months from diagnosis (ie, delayed intensification [DI] that is based on Protocol II of the Berlin-Frankfurt-Münster [BFM] 76/79 study⁷) improved event-free survival (EFS). Conversely, intensive induction-consolidation, including anthracycline, cyclophosphamide, and cytarabine, provided no additional benefit for National Cancer Institute standard-risk patients² who also received DI. More is not always better.

In 1986 and 1987, the question remained whether one might identify a favorable subset of the ALL population that achieved the same excellent outcome with or without postinduction intensification. Preliminary analyses of BFM 79/81 failed to show a benefit for postinduction intensification (ie, Protocol III v historical controls) for lower-risk patients.⁸ In 1983, the BFM group began a randomized trial, but patients did not receive maintenance vincristine-prednisone pulses or maintenance intrathecal methotrexate.⁹ Omission of these proven interventions might actually have augmented the benefits of postinduction intensification; a similar but reversed interaction between treatments was seen in the study of Tubergen et al,⁷ wherein postinduction intensification made intensive induction-consolidation redundant. The BFM 86 study began with no postinduction intensification for lower-risk patients because no benefit was yet apparent for Protocol III on BFM 83.¹⁰ Although some argued that a 75% EFS rate might be obtained with minimal therapy and that DI might be too toxic, the majority in the Children’s Cancer Group (CCG) chose to study the value of DI in a favorable population where all patients received vincristine-prednisone pulses and intrathecal methotrexate in maintenance therapy. This debate embodies the dilemma faced by oncologists who must balance the substantial harms of treatment against a clinical imperative to improve outcome, especially with a disease for which the outcome after relapse is often death.¹¹

The CCG-1881 trial for lower-risk ALL was initiated in late 1988. This report details the long-term results for 778 patients. Long follow-up is critical for a standard-risk, B-cell precursor ALL population that has an extended period of risk of relapse.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients with newly diagnosed ALL, 2 to 9 years of age at diagnosis, with an initial WBC count less than 10,000/µL, were eligible for this protocol. Blasts had to be negative for Sudan black and myeloperoxidase, and fewer than 25% blasts could be French-American-British L3. Patients with leukemia-lymphoma syndrome¹² were excluded and were eligible for the leukemia-lymphoma protocol (CCG-1901). Boys with presenting platelet counts less than 100,000/µL were excluded and were eligible for the intermediate-risk protocol (CCG-1891). No prior chemotherapy was allowed, such as corticosteroids. However, radiotherapy to an airway-impinging mediastinal mass or to enlarged, functionally compromised kidneys was acceptable. Central immunophenotyping was provided by the CCG ALL Reference Laboratories (Minneapolis, MN; Seattle, WA; Washington, DC). Positivity was defined as more than 20% of leukemic cells positive for the marker of interest. Local institutional karyotypes were submitted centrally for review by the CCG Cytogenetics Committee (N.A.H., chair). The protocol was approved by the Clinical Trials Evaluation Panel of the National Cancer Institute and local institutional review boards. Informed consent was obtained from families and patients as per federal guidelines.

Treatment
The treatment flow diagram is depicted in Fig 1, whereas the actual drugs and dosages are detailed in Table 1.

View larger version (11K): [in this window] [in a new window]   Fig 1. Children’s Cancer Group (CCG)-1881 study schema.

Consolidation therapy began at day 28 of induction. Patients with CNS leukemia at diagnosis received craniospinal radiation therapy during consolidation at a dose of 24 Gy to the cranial midplane and 12 Gy to the spine, with daily fractions of 2 Gy. Similarly, patients with overt testicular leukemia at diagnosis received 24 Gy in eight fractions to both testicles during consolidation.

Interim maintenance followed day 28 of consolidation (Table 1). Randomization to regimen A or B took place at the end of interim maintenance on day 56. A small number of patients were excluded from random assignment to treatment. Patients with prior relapse were removed from protocol therapy. Patients meeting one or more of the following criteria were not randomly assigned to treatment: M3 marrow response on day 14 of induction or adverse blast cell cytogenetics with t(9;22), t(4;11), t(8;14), t(2;8), or t(8;22). These patients were assigned to receive DI.

Regimen A was the standard arm. Subsequent therapy consisted of 84-day maintenance cycles which continued for either 22 months for females or 34 months for males; that is, 24 and 36 months from the initiation of interim maintenance (Table 1).

Regimen B was the experimental arm. Patients received a 49-day DI phase and then proceeded to maintenance as above (Table 1). The duration of therapy was sex-specific and again measured from the initiation of interim maintenance: 24 months for males and 36 months for females.

Treatment for patients who were not randomly assigned to treatment was identical to that of patients on regimen B. At the completion of therapy, patients had bone marrow aspirations and lumbar punctures to assess marrow and CSF status.

Statistical Considerations
In the initial planning of this study, sample size and power calculations were based on a proportional hazards (PH) assumption for the treatment regimens, with few treatment failures assumed to occur after 6 years of follow-up. The primary outcome index used to judge efficacy was continuous complete remission (CCR) from time of randomization, which occurred at the end of the interim maintenance phase for patients still in a first complete remission. CCR is defined in this study as the time to the first occurrence of any one of the following events: relapse at any site after initial remission, death in remission, or second malignant neoplasm. The study was sized so that a change in outcome from 80% to 89% CCR at 6 years from randomization would be detected; this would amount to approximately a 48% reduction in relative hazard for events of interest. The planned study accrual would allow detection of an effect of this magnitude with statistical power in excess of 80%. The power to detect an effect of lesser magnitude would necessarily be less.

CCR and survival life-table estimates use the Kaplan-Meier (KM) method.¹³ Point estimates are provided at 7 years of follow-up from randomization. Life-table outcome is also provided for the entire study population, but these estimates are calculated from the baseline time of study entry, as are analyses of patient prognostic factors; as a consequence, the outcome index used when the entire study population is analyzed is EFS. EFS is defined in this study as the time to the first occurrence of any one of the following events: induction death, no response to induction therapy, relapse at any site after initial remission, death in remission, or second malignant neoplasm. The SE of the KM estimate was calculated using Peto’s variance formula (provided in parentheses after the KM estimate in the text).¹⁴ Relative hazard rates are estimated by the log-rank observed/expected method.¹⁵

The log-rank test, which assumes PH, was the prospectively planned test for comparison of the regimens.¹⁵ The two regimens had similar CCR outcome for the first 2 years, but a difference emerged after that time, which is a moderate departure from the PH assumption. Hence, comparisons of outcome were also performed with the 7-year life-table point estimates. This test compared the standardized difference in CCR outcome (ie, the difference in life-table estimates for the two regimens divided by the SD of the difference, assuming the statistic is approximated by the standard normal distribution). This test does not require the PH assumption and is a useful statistic for examining long-term CCR values. ² tests for homogeneity of distributions were used in some comparisons (such as similarity of patient characteristics). Comparison of treatment regimen outcome used the intent-to-treat approach and attributes all CCR events to the regimen that was initially assigned, irrespective of the length of compliance with the treatment regimen.

The database for CCG-1881 was frozen for analysis on January 26, 2001. At that time, 67% of patients had follow-up current to within 1 year, 28% had a last date of contact between 1 and 2 years, and 5% had a last date of contact of more than 2 years.

	RESULTS

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Between December 1988 and December 1992, 782 patients were entered onto CCG-1881. Of these 782 patients, 778 met eligibility criteria, whereas four patients were ineligible. The rate of accrual of eligible patients to CCG-1881 was 16.3 patients per month, which was better than the projected accrual rate of 13.7 patients per month.

Presenting characteristics are listed in Table 2 for the whole study population and for the two groups of patients randomly assigned to treatment. A total of 20 patients (2.6%) were reported as having Down’s syndrome. CNS leukemia was present at diagnosis in 10 patients (1.3%).

A breakdown of CCR events by randomized regimen follows. Standard (regimen A): isolated marrow relapse, n = 41; isolated CNS relapse, n = 21; isolated testicular relapse, n = 4; isolated other relapse, n = 6; marrow plus CNS relapse, n = 4; marrow plus testicular relapse, n = 2; second malignant neoplasms, n = 3; and remission death, n = 1. DI (regimen B): isolated marrow relapse, n = 31; isolated CNS relapse, n = 16; isolated testicular relapse, n = 1; isolated other relapse, n = 2; marrow plus CNS relapse, n = 3; marrow plus testicular, n = 1; second malignant neoplasms, n = 5; and remission deaths, n = 3. The DI regimen had fewer relapses in every category and 24 relapses fewer overall, but had two more second malignant neoplasms and two more remission deaths. A total of 82 CCR events occurred in the standard regimen and 62 CCR events occurred in the DI regimen.

Remission Induction
Marrow response was assessed on days 14, 28, and, if necessary, day 42. Induction data are lacking for 18 of 778 eligible patients. Of 733 patients with day 14 marrow ratings, 91% (n = 668) were M1, 7% (n = 49) were M2, and 2% (n = 16) were M3; for 45 patients, the day 14 rating was not reported. Eight patients died in induction before day 28. Infection was the most common cause. By day 28, 740 (98%) of 752 of the patients achieved M1 status, whereas 1% (n = 11) were M2, and only one patient was M3. The latter patient was found to have translocation t(8;14). In total, 749 patients (99%) of 760 achieved M1 marrow status by either day 28 or 42. Three patients experienced treatment failure with induction therapy: one M3 at day 28 and two M2 at day 42; as mentioned above, eight patients died during induction before remission status could be fully assessed.

CCR by Randomized Regimen
Three hundred fifty-one patients were randomly assigned to regimen A (standard), and 349 were assigned to regimen B (DI). Compliance with randomization was good, with only 17 patients of the 700 randomly assigned patients not complying with their assignment; these 17 patients are included in the randomized analysis, on the regimen to which they were assigned. Four other patients with adverse features were randomly assigned inappropriately, two with M3 day 14 marrow results and two with t(8;14) in their blasts at diagnosis: two were randomly assigned to regimen A and two were randomly assigned to regimen B. These four patients are not included in the randomized analysis. CCR by allocated regimen in the critical intent-to-treat analysis demonstrated a 7-year CCR of 77% (SE, 2.4%) for regimen A and 83% (SE, 2.7%) for regimen B (P = .069 comparing the point estimates; SE of the difference, 3.3%; Fig 2a). DI provided a 26% reduction in risk of an event. The magnitude of advantage for regimen B is similar to that of other studies using DI. However, the log-rank statistic did not reach a conventional level of significance (P = .072).

View larger version (21K): [in this window] [in a new window]   Fig 2. (A) Continuous complete remission from the time of randomization by regimen. (B) Survival from the time of randomization by regimen.

View larger version (24K): [in this window] [in a new window]   Fig 3. Continuous complete remission (CCR; measured from the end of interim maintenance) for two patient groups (those M3 on the day 14 marrow [NR-M3] and those with adverse blast cytogenetics at diagnosis [NR-CYTO]) nonrandomly assigned to delayed intensification (DI) as contrasted with CCR for the randomized DI patients.

View larger version (28K): [in this window] [in a new window]   Fig 4. Continuous complete remission from the time of randomization by regimen and the day 14 marrow response. Abbreviation: DI, delayed intensification.

Toxicities and Complications
Nonhematopoietic toxicities consisted predominantly of elevated AST, ALT, and bilirubin levels, nausea and vomiting, peripheral nervous system toxicity, skin rash, hypofibrinogenemia, and infection (Table 3). Elevated serum bilirubin levels were reported more often on regimen A (standard therapy), whereas serum amylase and glucose elevations, stomatitis, and hypofibrinogenemia were observed more often on regimen B. In general, toxicities were tolerable. Other than rare mortality from infection, no deaths were attributed to toxicity.

Prognostic Factor Analysis
Within this already highly selected group of low-risk ALL patients, analysis of prognostic factors revealed that the early marrow response at day 14 was the most significant factor predicting freedom from adverse events (P < .0001; Table 2). Blast cell cytogenetics at diagnosis were predictive of a poor outcome for the two patients with Philadelphia chromosome–positive ALL [t(9;22)], but not for the group with t(1;19) (n = 6). No other factors demonstrated significant predictive value for CCR.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Reports from Germany,⁹ Great Britain,^16,17 and the United States⁷ have shown the value of postinduction intensification for National Cancer Institute/Rome standard-risk patients. The results for CCG-1881 are consistent with these reports and confirm the value of DI in the management of low-risk ALL. We were unable to identify a favorable population with a similarly excellent outcome with or without DI. Toxicities and complications were modest and entirely acceptable. No patient died from toxicity with DI.

DI resulted in a mean of 5 additional hospital days per patient. For every 100 lower-risk patients treated with DI, six relapses are prevented at a cost of 500 additional hospital days or 83 days per additional relapse prevented.¹⁸

Patients with an M3 day 14 marrow response were assigned to receive DI but had CCR and overall survival that was much inferior to that of the randomly assigned patients who had been either M1 or M2 on day 14. However, the 7-year CCR at 57% is superior to that achieved by similar patients in the past.¹⁹ More recently, CCG investigators have shown that daunorubicin and longer and stronger postinduction intensification (the augmented regimen²⁰) can rescue standard-risk patients who are still M3 on day 14.²¹

The benefit of DI was found among the 91% of patients who were already M1 on day 14 of induction. Among M2 patients, no benefit for DI is apparent, and outcome is similar to that of day 14 M3 patients. Recently, CCG-1891 found benefit for two courses of DI for standard-risk patients.²² When day 7 marrow response groupings were examined, the value of the second DI course was among day 7 M2 and M3 patients. Day 7 M1 patients showed no benefit.

Although DI added 6 percentage points to CCR, overall survivals were virtually identical. Similarly, vincristine-prednisone pulses increased the EFS of lower-risk patients from 61% to 79% on CCG-161, yet no statistically significant effect on survival has emerged. Statistical power is based on the number of events of interest, and survival after late or extramedullary relapses erodes power for analysis of survival in studies sized primarily for EFS/CCR comparisons. In addition, some speculate that retrieval may be more successful after less effective primary therapy (eg, for relapses after regimen A therapy).

Addition of DI—an intervention applied 4 months into therapy—for children with lower-risk ALL results in a 26% reduction in event rate and a 6% increase in CCR. The CCR curves separate late, and the value of DI seems more to be prevention of late relapse than prevention of early relapse. The greatest impact of DI is among the 91% of patients with an M1 day 14 response. The lack of benefit for overall survival likely reflects successful retrieval of more patients on regimen A after relapse. The prognostic value of the day 14 marrow response is preserved. The magnitude of benefit of DI for lower-risk ALL is consistent with other reports, even though we failed to achieve a conventional level of statistical significance with the log-rank test. The benefit is real.

The aim of risk-adjusted therapy is to provide each patient with the minimal therapy required to obtain maximum outcome. Postinduction intensification has been a useful strategy. A single DI course may suffice for the 50% of standard-risk patients with a day 7 M1 response,²² whereas the 10% of standard-risk patients with a day 14 M2 or M3 response may need daunorubicin rescue and augmented therapy.²¹ Standard-risk patients with a day 7 M2 or M3 response and a day 14 M1 response benefit from two courses of DI therapy.²² In a similar vein, low-risk patients with an M1 response on day 14 derive the greatest benefit from DI; alternative strategies are needed for patients M2 or M3 on day 14. Patients M2 on the day 14 marrow analysis have outcomes similar to patients with an M3 day 14 marrow response; persistent leukemia on the day 14 marrow analysis seems to indicate very adverse biology, the adversity of which cannot be overcome by the addition of a DI phase of therapy. The use of molecular markers and more precise assessment of response in the future may lead to more accurate treatment allocation for these difficult patients.

	ACKNOWLEDGMENTS

 
We thank Robert Neerhout, MD, the CCG-1881 Study Committee’s vice chair until his death, and Donna Hummell, MD, who provided valuable expertise in the immunophenotypic evaluation of leukemic cells.

	NOTES

 
Supported in part by the Children’s Cancer Group Chairman’s grant no. CA-13539 from the National Cancer Institute, National Institutes of Health.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 4, 2002; accepted February 14, 2003.

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