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Outcomes of Treatment of Children and Adolescents With Recurrent Non-Hodgkin’s Lymphoma and Hodgkin’s Disease With Dexamethasone, Etoposide, Cisplatin, Cytarabine, and L-Asparaginase, Maintenance Chemotherapy, and Transplantation: Children’s Cancer Group Study CCG-5912

From the Roger Maris Cancer Center, Fargo, ND; University of Southern California School of Medicine, Los Angeles, and Children’s Cancer Group, Arcadia, CA; Geisinger Medical Center, Danville, and Children’s Hospital, Philadelphia, PA; University of Nebraska Medical Center, Omaha, NE; Children’s Hospital Medical Center, Cincinnati, and University Hospitals, Cleveland, OH; Children’s Hospital, Denver, CO; Mayo Clinic, Rochester, MN; and Riley Hospital for Children, Indianapolis, IN.

Address reprint requests to Nathan L. Kobrinsky, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and L-asparaginase (DECAL) for recurrent non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD).

PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy.

RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% ± 9% and 23% ± 5% in patients with HD and NHL, respectively. Five-year survival was 31% ± 14% and 30% ± 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P = .002; survival, P = .011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach.

CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.

	INTRODUCTION

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THE PROGNOSIS FOR children with non-Hodgkin’s lymphoma (NHL) has markedly improved during the past 20 years. In the early 1970s, the survival rate was less than 30%.^1,2 Today, survival rates of 65% to 75% for advanced lymphoblastic lymphoma^3-9 and 75% to 90% for advanced Burkitt’s and other B-lineage lymphomas^10-13 are reported.

Despite these improvements, the outcome for children with recurrent NHL remains bleak. For 159 children whose disease recurred after treatment on Children’s Cancer Group’s 551 study, survival at 5 years was 12%. Survival after relapse as described by histologic subtype was 9% for patients with undifferentiated lymphoma, 17% for patients with large-cell lymphoma, and 10% for patients with lymphoblastic lymphoma.¹⁴ For children who developed recurrent B-cell lymphoma after treatment in the Societe d’Oncologie Pediatrique LMB 84 study, two (13%) of 15 survived with intensive chemotherapy, then autologous marrow transplantation, and no patients (zero of 12) treated with intensive chemotherapy alone survived.¹⁵

Patients with advanced Hodgkin’s disease (HD) whose disease recurs after combination chemotherapy also have a relatively unfavorable prognosis. Complete response rates after second-line chemotherapy range from 20% to 60%. Survival at 5 years has generally been less than 35%.^16-20 Results with third-line regimens for treatment after a second relapse have been disappointing.²¹

The best results for adults with recurrent NHL^22-25 and HD^26-28 have been achieved with autologous bone marrow transplantation (BMT) performed after a partial or complete response to various retrieval chemotherapy regimens, but disease recurrence is still a major obstacle to cure. To facilitate cure, a more effective salvage regimen is clearly required.

This report describes the efficacy and toxicity of DECAL, a regimen containing dexamethasone, etoposide, cisplatin, high-dose cytarabine (ara-C), and L-asparaginase, for the treatment of recurrent NHL and HD in children. This regimen contains agents known to be effective in HD and in NHL that have not been incorporated into first-line regimens. The regimen is built on a backbone of high-dose ara-C, then L-asparaginase to arrest cell cycling and limit ara-C–induced toxicity. The combination of high-dose ara-C and L-asparaginase (known as Capizzi II) has been extensively used in the treatment of acute myelogenous leukemia. Synergy between high-dose ara-C and L-asparaginase has been demonstrated.²⁹ L-Asparaginase has not been reported to be effective in the treatment of HD; however, L-asparaginase has L-glutaminase activity and azaserine, an analog of L-glutamine, has demonstrated activity against HD.³⁰

	PATIENTS AND METHODS

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Study Population
Patients with NHL experiencing their first or a subsequent relapse, patients with HD previously treated with a chemotherapy-containing regimen who were experiencing their first relapse, and patients with HD who were experiencing a second or subsequent relapse regardless of previous therapy were eligible for this study. Tissue confirmation of tumor recurrence was required. Other eligibility criteria included age less than 21 years, a minimum 3-week interval between previous therapy and study registration, a life expectancy of at least 12 weeks, and a creatinine clearance of more than 60 mL/min/1.73 m². Study approval by the review board of the treating institution and written informed consent obtained from the patient or legal guardian were required before registration.

DECAL Induction Chemotherapy
Patients received two cycles of the following chemotherapy regimen at 3-week intervals: intrathecal methotrexate at hour 0 (only patients with NHL); dose, 6 mg in children younger than 1 year, 8 mg in children aged 1 to 2 years, 10 mg in children aged 2 to 3 years, and 12 mg in children older than 3 years; dexamethasone 10 mg/m² intravenous (IV) bolus at hours 0, 12, 24, and 36; etoposide 100 mg/m² and ara-C 3,000 mg/m² in 375 mL/m² dextrose 5% in water (D₅W)-1/2 normal saline (NS) intravenously (IV) over the course of 3 hours at hours 0, 12, 24, and 36; L-asparaginase 25,000 U/m² intramuscularly at hour 39; cisplatin 90 mg/m² in 750 mL/m² NS with mannitol 15 g/L and potassium chloride 15 mEq/L IV over the course of 6 hours at hour 42; and granulocyte-colony stimulating factor (G-CSF, or filgrastim) 5 µg/kg subcutaneously daily after completion of chemotherapy until the peripheral-blood count recovered.

After induction, patients received either four courses of maintenance chemotherapy or autologous or allogeneic BMT, at the discretion of the treating investigator. Investigators were permitted to discontinue chemotherapy and proceed with BMT consolidation at any time during maintenance. Maintenance chemotherapy was discontinued if unacceptable toxicity occurred or if disease progressed.

Maintenance Therapy
Each course of maintenance therapy included a cycle of ifosfamide with mesna uroprotection and etoposide alternating with a cycle of DECAL at 3-week intervals. Each cycle of ifosfamide with mesna uroprotection and etoposide was administered daily for 5 days as follows: etoposide 100 mg/m² in 250 mL/m² NS IV over the course of 1 hour at hour 0; ifosfamide 1,800 mg/m² and mesna 360 mg/m² in 250 mL/m² D₅W-1/4NS IV over the course of 1 hour at hour 1; mesna 360 mg/m² in 600 mL/m² D₅W-1/4NS IV at hours 2 to 5, then mesna 360 mg/m² IV bolus at hours 5, 8, and 11; and G-CSF 5 µg/kg subcutaneously daily after completion of chemotherapy until the peripheral-blood count recovered.

Amendments
The protocol (CCG-5912) was amended on March 3, 1992, to replace intrathecal ara-C with intrathecal methotrexate to prevent neurotoxicity from the simultaneous administration of high-dose systemic ara-C and intrathecal ara-C. The study was further amended on May 24, 1994, to mandate the use of G-CSF during induction and maintenance because of severe and prolonged neutropenia. The study was also amended at this time to permit patients with HD to receive radiation therapy to all sites of disease remaining after induction therapy to a total dose of 30 Gy in 15 fractions during 3 weeks, if tissue tolerance and previous treatment permitted.

Statistical Methods
The primary end point for statistical survival analysis was event-free survival (EFS), defined as the minimum time to disease progression, disease relapse, the occurrence of a second malignant neoplasm, or death from any cause. Nonparametric estimates of EFS probabilities were obtained by means of the product limit estimate, with SEs computed with the Greenwood formula.³¹ Because the assumption of proportional hazard on which the log-rank test relies does not hold in these data, the differences between patients with HD and NHL in EFS and survival were based on a parametric cure model of the form

equation

Here, i denotes either HD or NHL, S₁ is the survival function, _i is the long-term EFS or survival rate, and F(t;µ_i) is a log-normal distribution function with median µ_i and scale .³² Estimates and SEs of parameters in the model were obtained by means of maximum-likelihood methods.³³ The overall difference between distributions was based on a two-degree-of-freedom likelihood ratio ² test of the hypothesis

equation

Differences in median time to treatment failure and long-term outcome were based on a one-degree-of-freedom likelihood ratio test of either of the subhypotheses above. Cox regression analysis with time-dependent covariates was used to test the efficacy of BMT.³²

	RESULTS

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The CCG-5912 study was opened on November 18, 1991. The accrual goal of 99 patients was met and the study closed to patient entry on August 29, 1994. Two patients were considered ineligible because they were enrolled onto the study before full institutional review board review had been completed. These subjects are not included in the following analyses. This report is based on data available through July 1997.

Patient Demographics and Disease Characteristics
Patients with NHL were somewhat younger than those with HD, with a median age of 11 years and 15 years, respectively. A male predominance was observed for patients with NHL (74%) but not for patients with HD (55%) (P = .08). In this study, a predominance was observed for both NHL (72%) and for HD (75%) to occur in white patients. Patient disease characteristics are summarized in Table 1.

View larger version (15K): [in this window] [in a new window]   Fig 1. EFS from study entry for patients with HD (n = 29) and patients with NHL (n = 68). Solid lines are product-limit estimates. Broken lines are the predictions from the parametric cure model.

Long-Term (> 36 Months) Survivors
Patients with HD. Of the 29 patients with HD, 11 were alive more than 3 years from study entry. Five patients were free of disease after DECAL induction and maintenance chemotherapy. Three patients were free of disease after DECAL induction and BMT consolidation. One patient developed recurrent disease 3 months after study entry but was later rendered free of disease after BMT. Two patients developed recurrent disease after BMT at 9 months and at 4 years, respectively, from study entry.

Patients with NHL. Of the 68 patients with NHL, 16 were alive more than 3 years from study entry. Four of these patients relapsed during the study. Two patients experienced relapses after postinduction BMT at 9 months and 2 years from study entry. A third progressed during induction and underwent immediate BMT. A fourth progressed after induction and was treated with alternative chemotherapy. Of the remaining 12 patients, eight underwent BMT. The 16 patients included eight patients with lymphoblastic lymphoma, five patients with large-cell lymphoma, two patients with small noncleaved cell lymphoma, and one patient with unclassified NHL. This distribution of histologies is representative of the patients with NHL initially enrolled onto the study.

BMT
BMT was not a formal part of the CCG-5912 study design, although patients were allowed to proceed to allogeneic or autologous BMT after induction therapy at the discretion of the treating physician. Of the 97 eligible patients entered onto the study, 50 patients underwent BMT. Forty-two of these were performed in patients responsive (ie, complete response or partial response) to CCG-5912 retrieval therapy. BMT was performed after induction in 27 patients, during or after maintenance course 1 in 13 patients, and during or after maintenance course 2 in two patients. BMT was performed a median of 13 weeks (range, 3 to 29 weeks) from study entry. Twenty of these patients relapsed or died of progressive disease, and five died of BMT-related complications. A Cox regression analysis of patients with responsive disease did not show a significant benefit for patients who underwent BMT (²_ldf = 0.23, P = .63). In fact, a nominally higher treatment failure rate was observed among responding patients who received BMT (relative treatment failure rate 1.17; 95% confidence interval, 0.6 to 2.3).

The remaining eight patients underwent BMT after later disease relapse or progression. In these patients, BMT was performed between 5 and 84 weeks (median, 14 weeks) from study entry.

Effect of G-CSF
CCG-5912 was amended on May 24, 1994, to mandate G-CSF administration during induction and maintenance. During induction, 56 patients (58%) received and 41 patients (42%) did not receive G-CSF. A difference in EFS was not observed between these two groups (P = .84). Similarly, a difference in EFS by growth factor use was not observed for the 32 patients who began maintenance therapy (P = .11).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present study demonstrates that DECAL is an effective regimen for the treatment of recurrent NHL and HD. After two cycles of DECAL induction therapy, 33 (40.2%) of 82 complete and 15 (18.3%) of 82 partial responses were observed in 82 assessable patients for a total response rate of 58.5% (48 of 82). For patients with HD, the response rate in assessable patients was 79.2% (19 of 24). For patients with NHL, the response rate in assessable patients was 50.0% (29 of 58). Similar response rates have been reported in adults treated with salvage regimens containing cisplatin, etoposide, and high-dose ara-C^34-36 and dexamethasone, high-dose ara-C, and cisplatin.^37,38

DECAL induction was associated with marked hematologic toxicity and a high rate of systemic infection. A survival benefit from the use of G-CSF was not observed. Nonhematologic toxicities, including nephrotoxicity after administration of cisplatin and ifosfamide, were not significant problems.

For patients with recurrent HD, the EFS was 40% ± 9% at 2 years and 26% ± 9% at 5 years. Overall survival was 57% ± 9% at 2 years and 31% ± 14% at 5 years. These results are particularly encouraging, considering that all patients had been previously treated with a chemotherapy-containing regimen or had experienced a second or subsequent relapse before study entry. In a recent series of children with recurrent HD, EFS and overall survival were 31% and 43%, respectively, at 5 years from the time of autologous BMT.²⁸ These results, although similar, cannot be compared directly with the results of the present study, for which EFS and overall survival were calculated from the time of disease recurrence rather than from the time of BMT.

For patients with recurrent NHL, the EFS was 24% ± 5% at 2 years and 23% ± 5% at 5 years. Overall survival was 33% ± 6% at 2 years and 30% ± 6% at 5 years. In comparison, the survival of patients with recurrent NHL initially treated on the Children’s Cancer Group Study CCG-551 (1976 to 1983) was 12% at 5 years. Similarly, the overall survival of patients with recurrent B-cell lymphoma initially treated on the Societe d’Oncologie Pediatrique LMB 84 study was 13% (two of 15 patients) with intensive chemotherapy then autologous BMT and 0% (none of 12 patients) with intensive chemotherapy alone.

In the present study, a difference in induction success rate was not observed for patients with HD or NHL. EFS and overall survival at 2 years were better for patients with HD than for patients with NHL; however, this survival advantage was not sustained. At 5 years, EFS and overall survival were comparable for patients with HD and NHL.

Patients were assigned to maintenance chemotherapy or BMT consolidation at the discretion of the treating physician. Overall, 50 (51.5%) of 97 patients underwent BMT consolidation. A comparison of outcome of patients treated by these two therapies is difficult because selection of therapy was not random and therefore could have been determined by factors that confound such a comparison. Furthermore, BMT was not performed in a standardized fashion. Uncontrolled variables included the source of stem cells (peripheral blood or bone marrow; autologous or allogeneic; related or unrelated), the stem-cell dose, and the conditioning regimen. Accepting the limitations of such a comparison, a difference in survival for DECAL-responsive patients who underwent BMT consolidation versus maintenance chemotherapy was not observed.

In conclusion, the efficacy of DECAL in the setting of recurrent disease justifies the incorporation of this regimen into protocols for children with newly diagnosed advanced NHL and HD.

APPENDIX

	ACKNOWLEDGMENTS

 
Supported in part by grants from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

We thank Diane E. Sjolander, BUS, for her help with preparation of the article.

	NOTES

 
Contributing Children’s Cancer Group investigators, institutions, and grant numbers are given in the Appendix.

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Submitted April 4, 2000; accepted February 6, 2001.

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