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Comparison of Preparative Regimens in Transplants for Children With Acute Lymphoblastic Leukemia

From the International Bone Marrow Transplant Registry, Health Policy Institute, and Division of Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; University of California–Los Angeles, CA; University of Minnesota, Minneapolis, MN; Cleveland Clinic Foundation, and University Hospitals of Cleveland, Ireland Cancer Center, Cleveland, OH; Centre Hospitalier Universitaire Bescancon, Besancon, and Hôpital Saint-Louis, Paris, France; M.D. Anderson Cancer Center, University of Texas, Houston, TX; Righospitalet, Copenhagen University Hospital, Copenhagen, Denmark; University of South Carolina, Columbia, SC; Brown Cancer Center, Louisville, KY; University of Michigan Medical Center, Ann Arbor, MI; University of Toronto, Toronto, Ontario, Canada; Fundaleu, Buenos Aires, Argentina; University of Pittsburgh, Pittsburgh, PA; The Royal Marsden NHS Trust, Surrey, United Kingdom; Royal Free Hospital, London, United Kingdom; Sydney Children’s Hospital, Randwick, New South Wales, Australia; University of North Carolina–Chapel Hill, Chapel Hill, NC; and Emory University School of Medicine, Atlanta, GA.

Address reprint requests to Mary M. Horowitz, MD, MS, International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226; email marymh{at}mcw.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy.

PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months.

RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P = .003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P = .005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P = .1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P = .012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1.39; P = .017 for death; RR, 1.42; P = .006 for treatment failure).

CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

	INTRODUCTION

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THE TREATMENT OF children with acute lymphoblastic leukemia (ALL) presents unique challenges. In particular, influences on growth and development are important factors in the evaluation of treatment outcomes. Bone marrow transplantation is often used for children with ALL who fail to respond to conventional chemotherapy. Many high-dose preparative or conditioning regimens administered before bone marrow transplantation include total-body irradiation (TBI) together with cyclophosphamide (CY) or other chemotherapy.^1-3 The long-term effects of TBI are well-documented, with growth impairment, cataracts, gonadal failure, and hypothyroidism occurring in substantial numbers of patients.^4-7 The risks of secondary malignancy may also be increased by high doses of TBI.^8-10

An alternative to CY/TBI treatment in pretransplant conditioning is the use of busulfan and cyclophosphamide (Bu/CY). Two Bu/CY regimens are commonly used: Bu/CY4, busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each given over 4 days, and Bu/CY2, busulfan 16 mg/kg given over 4 days and cyclophosphamide 120 mg/kg given over 2 days.^11,12 These regimens have been extensively studied in acute myelogenous leukemia (AML), and data in this setting suggest that fewer late effects of growth delay, gonadal dysfunction, thyroid dysfunction, and cataracts occur with Bu/CY regimens than with TBI.^5,13-15 These regimens also offer logistic advantages for the treatment of small children who may require sedation or anesthesia for radiation. Despite these potential advantages, there is no convincing data regarding the relative antileukemic efficacy and early toxicity of Bu/CY, compared with CY/TBI, in children with ALL. In this study, we used data reported to the International Bone Marrow Transplant Registry (IBMTR) to compare the outcomes in children with ALL who receive transplants from HLA-identical sibling donors after being conditioned with CY/TBI versus Bu/CY.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
IBMTR
The IBMTR is a voluntary working group of over 300 transplant teams worldwide that contribute detailed data on their allogeneic and identical-twin bone marrow transplants to a statistical center at the Health Policy Institute of the Medical College of Wisconsin.¹⁶ Participants must register all consecutive transplants. The IBMTR database includes 40% to 45% of all allogeneic transplants performed since 1970. Patients are followed up longitudinally. Computerized error checks, physician reviews of submitted data, and on-site audits of participating institutions ensure data quality.

Patients
This study included all transplants from HLA-identical siblings in children (< 20 years of age) who received CY/TBI (n = 451) or Bu/CY (n = 176) treatment for conditioning before transplants performed between 1988 and 1995 and reported to the IBMTR by 144 institutions.

Statistical Analysis
The primary end points of this study were posttransplant relapse, treatment-related mortality (death while in continuous complete remission [CR]), survival, and leukemia-free survival. The probabilities for posttransplant relapse and treatment-related mortality were calculated using cumulative incidence estimates.¹⁷ Survival and leukemia-free survival rates were calculated using Kaplan-Meier estimates. Univariate comparisons were performed using the log-rank test.¹⁸ For analyses of leukemia-free survival, treatment was considered to have failed at the time of clinical or hematologic relapse at any site or at the time of death from any cause; data for patients who were alive and in CR were censored at the time of their last follow-up visit. For analyses of treatment-related mortality, failure was defined as death that occurred while the patient was in continuous CR; data were censored at time of relapse or, among patients with continuous remissions, at the time of their last follow-up visit. For analyses of relapse, failure was defined as clinical or hematologic recurrence of ALL at any site; data were censored at the time of death during remission or at the time of their last follow-up visit.

To adjust for the potentially confounding effects of factors other than conditioning regimen, multivariate Cox proportional hazards regression models were used.¹⁹ Table 1 lists the variables considered in the multivariate analyses. Preliminary analyses showed that several variables had nonproportional hazards; this was handled by stratification or the use of time-dependent covariates.

	RESULTS

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Outcomes: Univariate Analysis
The cumulative incidences (and 95% confidence intervals [CIs]) of relapse at 3 years were 35% (95% CI, 30% to 40%) in the CY/TBI cohort and 41% (95% CI, 32% to 49%) in the Bu/CY cohort (P = .07) (Fig 1). Sites of relapse (bone marrow v extramedullary) did not differ in the two cohorts (P = .3). Relapse rates were similar for those who received unfractionated, fractionated, and hyperfractionated TBI (28% [95% CI, 19% to 39%] v 37% [95% CI, 30% to 44%] v 35% [95% CI, 24% to 46%], respectively; P = .3). The three-year cumulative incidences of treatment-related mortality were 15% (95% CI, 12% to 18%) in the CY/TBI cohort and 23% (95% CI, 17% to 30%) in the BuCY cohort (P = .02) (Fig 2). The actuarial 3-year probabilities of survival were 55% (95% CI, 50% to 60%) and 40% (95% CI, 32% to 48%), respectively (P = .003). Figure 3 shows the actuarial probabilities of leukemia-free survival: 50% (95% CI, 45% to 55%) in the CY/TBI cohort and 35% (95% CI, 28% to 43%) in the Bu/CY cohort (P = .005).

View larger version (11K): [in this window] [in a new window]   Fig 1. Actuarial probability of relapse after HLA-identical sibling bone marrow transplant for childhood ALL, by pretransplant conditioning regimen.

View larger version (11K): [in this window] [in a new window]   Fig 2. Actuarial probability of treatment-related mortality after HLA-identical sibling bone marrow transplants for childhood ALL, by pretransplant conditioning regimen.

View larger version (12K): [in this window] [in a new window]   Fig 3. Actuarial probability of leukemia-free survival after HLA-identical sibling bone marrow transplants for childhood ALL, by pretransplant conditioning regimen.

View this table: [in this window] [in a new window]   Table 2. Relative Risks of Relapse, Treatment-Related Mortality, Overall Mortality,* and Treatment Failure With Bu/CY Versus TBI/CY in Multivariate Analysis

The risk of treatment-related mortality was significantly higher in children who received Bu/CY than in those who received CY/TBI. The only other factor significantly associated with higher treatment-related mortality in multivariate analysis was transplantation not in CR.

In multivariate analysis, the use of Bu/CY as a preparative regimen was associated with a significantly higher risk of mortality (lower probability of survival) than was the use of CY/TBI. Other factors associated with lower survival rates by multivariate analysis were transplantation not in CR, short duration of first CR (for transplants performed after a first relapse), t(4;11) translocation, and use of T-cell depletion or combined methotrexate and cyclosporine versus cyclosporine or methotrexate alone for GVHD prophylaxis. Use of Bu/CY as a preparative regimen was also associated with a significantly higher risk of treatment failure (lower probability of leukemia-free survival) than CY/TBI. Other factors associated with lower leukemia-free survival rates in multivariate analysis were transplantation not in CR, t(4;11) translocation, short duration of first CR, and use of combined methotrexate and cyclosporine for GVHD prophylaxis.

Because younger children were more likely to receive Bu/CY, the effect of age on outcome was examined carefully. In Cox models, there were no differences in posttransplant relapse, treatment-related mortality, survival, or leukemia-free survival among children 5 years of age or younger, 5 to 10 years of age, and more than 10 years of age. Additionally, there was no interaction between age and treatment effect.

The dose of CY used with Bu varies significantly among institutions, depending on whether Bu/CY2 or Bu/CY4 is used.²⁰ To determine whether the CY dose affected outcome, the CY dose was included in Cox models, both as a continuous and a categorical variable for the Bu/CY group. There was no evidence for an effect of CY dose on relapse, treatment-related mortality, survival, or leukemia-free survival. Additionally, the addition of other drugs to Cy/TB1 or BuCy was examined; no significant effects or interactions were seen.

In some, but not all, institutions, the dose of Bu is adjusted according to pharmacokinetic parameters. In this study, data regarding this approach were not available; although the prevalence of this practice may have increased, there was no trend toward a change in treatment-related mortality over time, suggesting that temporal changes in clinical practice were not affecting outcomes (P = .8).

Causes of Death
Table 3 summarizes the causes of death reported to the IBMTR. One hundred seventy-five CY/TBI recipients (39%) and 93 Bu/CY recipients (53%) died. Leukemia relapse accounted for most deaths in both groups, with more deaths from infection, interstitial pneumonitis, and veno-occlusive disease (VOD) in the Bu/CY group. Multisystem organ failure was more frequent in those receiving CY/TBI.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

This study is the first to specifically compare Bu/CY and CY/TBI in children with ALL. The Nordic Bone Marrow Transplantation Group reported a randomized study that compared CY 120 mg/kg plus either busulfan 16 mg/kg or TBI in pediatric and adult patients with acute or chronic leukemia.²³ Patients were stratified for diagnosis, disease status, and age greater and less than 17 years. Patients who were randomized to treatment with Bu/CY were significantly more likely to have VOD, symptomatic hemorrhagic cystitis, and grades III–IV acute GVHD than were those who were randomized to CY/TBI. Treatment-related mortality was also higher in patients with advanced leukemia (patients with acute leukemia beyond first remission) who received Bu/CY rather than CY/TBI. The 3-year relapse-free survival was 50% for patients with ALL who received CY/TBI versus 36% for patients who received BuCY, similar to results in the study presented here; this difference was not statistically significant in the smaller Nordic study. Ringdén et al²⁴ reported a matched-pair comparison of Bu/CY versus CY/TBI in adults and children with acute leukemia, using data from the European Group for Blood and Marrow Transplant. This study included 246 ALL and 536 AML patients who received allogeneic transplants, half having received Bu/CY and half, CY/TBI. The Bu/CY and CY/TBI cases were matched for remission status, age, and GVHD prophylaxis; 246 patients were less than 20 years of age. There were no differences in relapse, treatment-related mortality, or leukemia-free survival between the two regimens. Interestingly, this analysis found a difference in relapse between Bu/CY2 and Bu/CY4 treatments in patients with ALL in first remission, with relapse rates significantly higher in recipients of Bu/CY4. Analyses in our study show no difference in outcome between Bu/CY2 and Bu/CY4 treatments.

The study presented here indicates that leukemia-free survival rates are lower with Bu/CY because of increased treatment-related mortality. Some, though not all, prior studies of patients with AML who received Bu/CY show increased transplant-related toxicity, particularly VOD and hemorrhagic cystitis.^21-24,25 Morgan et al²⁵ compared toxicities in 67 recipients of Bu/CY2 with those of 166 recipients of CY/TBI and showed more fatal VOD and hemorrhagic cystitis in the former group. Blaise et al²¹ reported a randomized comparison of CY/TBI and Bu/CY2 in patients with AML in first CR; CY/TBI produced superior survival and leukemia-free survival, with lower treatment-related mortality and a trend toward lower relapse. Michél et al²⁶ compared the outcomes of 42 children with AML in first CR who received Bu/CY2 or Bu/CY4 with the outcomes in 32 similar children receiving CY/TBI before receiving HLA-identical sibling transplants. Relapse was significantly higher in the Bu/CY2 group but not with Bu/CY4; treatment-related mortality was not different. A previous analysis from the IBMTR that examined risk factors for hepatic VOD in 1,717 recipients of HLA-identical sibling transplants indicated that the use of Bu in conditioning is an important risk factor for VOD, with a relative risk of 2.8 compared with TBI.²⁷ In the study presented here, deaths from VOD, pulmonary toxicity, and infection were all more frequent in the Bu/CY cohort.

This study also examined the influence of additional factors on transplant outcomes. Relapse and treatment-related mortality rates were higher and leukemia-free survival rates lower in patients who received transplants while they were in relapse, confirming previous observations.^1,28 Similarly, relapse rates were higher and survival rates lower in children who had the t(4:11) translocation, although the number of children in this category was small (n = 10). Perhaps more surprisingly, relapse rates were higher and leukemia-free survival rates lower in children who received combined methotrexate and cyclosporine for GVHD prophylaxis. A previous analysis from the IBMTR reported higher risks of relapse after HLA-identical sibling transplants for ALL with cyclosporine alone versus methotrexate alone as GVHD prophylaxis.²⁹ A smaller study of patients with leukemia also reported more relapses with combined cycloporine and methotrexate treatment than with treatment with either drug alone, an association that was attributed to diminished graft-versus-leukemia effects.³⁰ This study also showed that survival after a transplant performed beyond the occurrence of a first CR is associated with the length of the first CR, with higher leukemia-free survival rates in children with a first CR duration of more than 18 months. This suggests that the characteristics of the leukemia which lead to early relapse also predispose patients to treatment failure after bone marrow transplantation.

In summary, the data in this study indicate that in children with ALL, Bu/CY preparative regimens for HLA-identical sibling bone marrow transplants are likely to result in lower leukemia-free survival rates than are CY/TBI regimens because of an increase in treatment-related mortality. Because considerations of growth and development make the use of non-TBI conditioning regimens in children attractive, further efforts to study alternative chemotherapy regimens for children with ALL are needed.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
This study was supported by Public Health Service grants no. P01-CA-40053 and U24-76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the U.S. Department of Health and Human Services, Washington, DC, and grants from Alpha Therapeutic Corporation, Los Angeles, CA; Amgen, Inc, Thousand Oaks, CA; Anonymous; Baxter Fenwal, Deerfield, IL; Berlex Laboratories, Richmond, CA; BioWhitakker, Inc, Walkersville, MD; Blue Cross and Blue Shield Association, Chicago, IL; Lynde and Harry Bradley Foundation, Milwaukee, WI; Bristol-Myers Squibb Company, Princeton, NJ; Cell Therapeutics, Inc, Seattle, WA; Centeon, King of Prussia, PA; Center for Advanced Studies in Leukemia, Santa Monica, CA; Chimeric Therapies, Costa Mesa, CA; Chiron Therapeutics, Emeryville, CA; Charles E. Culpeper Foundation, Stamford, CT; Eleanor Naylor Dana Charitable Trust, New York, NY; Eppley Foundation for Research, New York, NY; Genentech, Inc, South San Francisco, CA; Human Genome Sciences, Rockville, MD; Immunex Corporation, Seattle, WA; Kettering Family Foundation, Denver, CO; Kirin Brewery Company, Tokyo, Japan; Robert J. Kleberg, Jr, and Helen C. Kleberg Foundation, San Antonio, TX; Herbert H. Kohl Charities, Inc, Milwaukee, WI; Nada and Herbert P. Mahler Charities, Mequon, WI; Milstein Family Foundation, New York, NY; Milwaukee Foundation/Elsa Schoeneich Research Fund, Milwaukee, WI; NeXstar Pharmaceuticals, Inc, Boulder, CO; Samuel Roberts Noble Foundation, Ardmore, OK; Novartis Pharmaceuticals, East Hanover, NJ; Orphan Medical, Minnetonka, MN; Ortho Biotech, Inc, Raritan, NJ; John Oster Family Foundation, Milwaukee, WI; Jane and Lloyd Pettit Foundation, Milwaukee, WI; Alirio Pfiffer Bone Marrow Transplant Support Association, Curitiba, Brazil; Pfizer, Inc, New York, NY; RGK Foundation, Austin, TX; Roche Laboratories, Nutley, NJ; Rockwell Automation Allen Bradley Company, Milwaukee, WI; SangStat Medical Corporation, Fremont, CA; Schering AG, Berlin, Germany; Schering-Plough Oncology, Kenilworth, NJ; Searle, Skokie, IL; SEQUUS Pharmaceuticals, Menlo Park, CA; SmithKline Beecham Pharmaceuticals, Collegeville, PA; Stackner Family Foundation, Hartland, WI; Starr Foundation, New York, NY; Joan and Jack Stein Foundation, River Hills, WI; SyStemix, Palo Alto, CA; United Resourse Networks, Golden Valley, MN; Wyeth-Ayerst Laboratories, Philadelphia, PA.

	NOTES

 
All support information is given in the Appendix.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted June 1, 1998; accepted August 18, 1999.

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