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Autologous Hematopoietic Stem-Cell Transplantation for Relapsed or Refractory Hodgkin's Disease in Children and Adolescents

From the Department of Pediatrics, Section of Pediatric Bone Marrow Transplantation; Department of Internal Medicine, Section of Oncology/Hematology; and Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE.

Address reprint requests to K. Scott Baker, MD, Pediatric Blood and Marrow Transplant Program, University of Minnesota, 420 Delaware St SE, Box 484 Mayo, Minneapolis, MN 55455; email baker084@ tc.umn.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the treatment outcome and clinical factors that are of prognostic significance for children and adolescents with relapsed or refractory Hodgkin's disease (HD) who received treatment with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT).

PATIENTS AND METHODS: Fifty-three consecutive children and adolescents 21 years of age or younger with relapsed or refractory HD underwent HSCT.

RESULTS: At day 100 after transplantation, 29 patients (55%) were in a complete remission or maintained a continuous complete response, six (11%) had a partial response, and 11 (21%) failed to respond or had progressive disease. The failure-free survival (FFS) at 5 years was 31%, and overall survival was 43%. Twenty-one patients died of progressive HD, and nine died secondary to transplantation-related complications, including two secondary leukemias. Prognostic factors important for FFS were normal pretransplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P < .001), and disease sensitivity at the time of HSCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06). There was no statistically significant difference in FFS or overall survival between age subgroups that were analyzed (< 13, 13 to 18, 19 to 21) or in comparison with an adult cohort.

CONCLUSION: HSCT is an effective treatment modality that can result in long-term cures and should be considered for children and adolescents with relapsed HD.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CHILDREN WITH Hodgkin's disease (HD) currently enjoy an overall survival (OS) at 5 years approaching 90%. The majority of these children are cured with combination chemotherapy either alone or with the addition of low-dose radiotherapy.^1-4 Despite this, relapse and, less frequently, nonresponse to initial therapy do occur. Response to salvage therapy in pediatric HD is generally good, although durable remissions are few. In adults with relapsed HD, high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HSCT) is becoming the standard approach to management, resulting in OS in the range of 30% to 50%.^5-14 These outcomes have generally been superior to those seen with conventional salvage therapy.¹⁵ This approach to the treatment of relapse also is frequently undertaken in children and adolescents, although its efficacy lacks documentation in the current literature.

We report 53 children and adolescents with relapsed or refractory HD who underwent high-dose chemotherapy with HSCT at the University of Nebraska Medical Center. Analysis of survival as well as the prognostic implications of various disease characteristics of this group are presented.

	PATIENTS AND METHODS

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Patient Characteristics
Between October 1984 and October 1996, 53 consecutive children and adolescents ( 21 years of age) with HD underwent HSCT with either autologous bone marrow or peripheral-blood stem cells at the University of Nebraska Medical Center. A reference group of 282 adults underwent HSCT for HD over the same period. All patients either had relapsed after attaining an initial remission or were refractory to primary therapy, having failed at least one chemotherapy trial. Entry criteria required a histologically confirmed diagnosis of HD, as well as adequate cardiac, pulmonary, hepatic, and renal function. All transplantation protocols were approved by the institutional review board, and informed consent and assent were obtained before treatment.

Patient characteristics of the 21-and-under age group were categorized by ages (children < 13 years, early adolescents 13 to 18 years, and late adolescents 19 to 21 years) and are listed in Table 1. There were a total of 24 males and 29 females. Nodular sclerosis HD was the most frequent histologic subtype. Disease staging was determined with the Ann Arbor staging classification.¹⁶ "B" symptoms were present at the time of the initial diagnosis in 40% of the patients. Lactate dehydrogenase (LDH) levels of all patients were obtained within 1 month before transplantation conditioning and were standardized by converting absolute values into a ratio of the absolute value divided by the upper limit of the laboratory normal value. Therefore, any LDH level above the upper limits of normal for the laboratory in which it was obtained would have a value of greater than 1, and any measurement within the normal range would have a value of 1.

The number of prior chemotherapy regimens refers to the number of chemotherapy regimens a patient received before the transplantation conditioning regimen. Disease sensitivity at the time of transplantation was determined for all patients. A patient was considered to have sensitive disease if relapse had occurred after an initial complete response (CR, disappearance of all evidence of malignant disease as determined by physical examination and imaging studies) and then either a CR or a partial response (PR, reduction of 50% or more in tumor volume) was attained with additional chemotherapy. Resistant disease was defined as either never having achieved a CR after at least one chemotherapy regimen (primary induction failure), or, for patients who had achieved a CR but then relapsed, when a subsequent CR or PR was never achieved before transplantation conditioning. Untreated patients were those who were taken directly to transplantation at the time of relapse, without first receiving reinduction chemotherapy. Radiation therapy was delivered to 77% of patients sometime before conditioning therapy for transplantation.

The majority of patients (n = 44) were conditioned with the CBV regimen,¹⁴ consisting of cyclophosphamide (CY) 1,500 mg/m² x 4, carmustine 300 mg/m² x 1, and etoposide (VP) 125 mg/m² x 6. Three patients received a pilot protocol of CBV with ⁹⁰Y-labeled antiferritin antibody. Three patients received VP/thiotepa/CY (VP 1,500 mg/m² x 1, thiotepa 300 mg/m² x 3, and CY 50 mg/kg x 4). Two patients were conditioned with CEM (CY 1,500 mg/m² x 4, VP 125 mg/m² x 6, and mitoxantrone 30 mg/m² x 2), and one patient received BEAC (carmustine 300 mg/m² x 1, VP 100 mg/m² x 8, cytarabine 100 mg/m² x 8, and CY 35 mg/kg x 4). Bone marrow was the stem-cell source in 34 patients (64%), and peripheral-blood stem cells were the source in 19 patients (36%).

High-Dose Therapy and Stem-Cell Transplantation
Autologous bone marrow or peripheral-blood progenitor cells were collected and frozen as previously described.^12,13 Patients were admitted to the bone marrow transplantation unit and were kept in HEPA-filtered rooms. Empiric antibiotic therapy and blood product support was given according to institution protocols. Conditioning regimen chemotherapy was administered per protocol as described above. On day 0, the cryopreserved stem cells were thawed in a 37°C water bath and immediately infused through a central venous catheter without filtration.

Tumor Response Evaluation
Tumor response was evaluated at day 100 posttransplantation. A clinical CR was defined as the disappearance of all evidence of malignant disease as determined by physical examination and imaging studies. Patients with small residual radiographic abnormalities that had not progressed after transplantation were classified as having attained a CR. Patients who were in a CR at the time of transplantation were not assessable for response to the preparative regimen and were considered to be in a continuous complete remission after transplantation. A PR was defined as greater than 50% reduction of the surface area of all measurable disease. A reduction of less than 50% in tumor volume was considered to represent no response.

Statistical Methods
Fisher's exact test¹⁷ was used to detect differences in the distribution of categorical variables between patient subgroups. Transplantation outcome was analyzed with respect to OS and failure-free survival (FFS). Survival time was defined as the time from transplantation until death from any cause or until last follow-up. FFS time was defined as the number of months from transplantation until disease progression, relapse, or death from any cause for patients who achieved a CR or PR after transplantation. Survival times and failure-free distributions were calculated using the product-limit method of Kaplan and Meier.¹⁸ Comparisons of these time to event distributions were made using the log-rank test.¹⁹

A multivariate analysis using the Cox proportional hazards model²⁰ for survival was used to determine independent predictors of survival influencing FFS and OS. This same method was used to explore the impact of age on FFS and OS by using age as a continuous variable and stratifying by decade. For all tests, values of P .05 were considered significant, and all P values were two-sided.

	RESULTS

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The patient characteristics (Table 1) were evenly distributed among the age groupings with the exception of the number of prior chemotherapy treatments. A larger percentage of patients under 13 years had had more than two prior chemotherapy treatments in comparison to the other age groups (P = .025).

Tumor Response and Patient Follow-Up
At day 100 after transplantation, 29 patients (55%) either had achieved a CR or maintained a continuous complete remission, and six (11%) had achieved a PR. Eleven patients (21%) failed to respond or had progressive disease, and there were five early deaths (10%) before day 100. Two patients were lost to further follow-up.

At the time of data analysis, 35 relapses had occurred; three of these deaths occurred more than 2 years posttransplantation (26, 30, and 61 months). Overall, the median time to relapse was 6 months (range, 0.6 to 61 months).

As of October 1998, 23 patients were alive, with a median follow-up of 64.6 months (range, 3 to 143 months); 17 of these patients had no evidence of disease after stem-cell transplantation. The actuarial FFS of all 53 patients at 5 years posttransplantation was 31%, and the actuarial OS was 43% (Fig 1). At the time of data analysis, 21 patients had died of progressive HD, and seven had died from transplantation-related complications, including infection (three patients), multiorgan dysfunction syndrome (one patient), hemorrhage (one patient), and interstitial pneumonia (two patients). Two patients (described below) who were in remission from their HD developed secondary leukemias (one acute myelogenous leukemia, and one myelodysplastic syndrome) after transplantation and subsequently succumbed to complications related to those diseases.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier product-limit estimate of the cumulative probability of OS and FFS for 53 pediatric and adolescent patients with refractory or relapsed HD treated with HSCT.

Prognostic Factors for Survival
Transplantation outcome was evaluated with respect to the variables noted in Table 1. A comparison of each of the age subdivisions (< 13, 13 to 18, 19 to 21 years) failed to detect any statistically significant difference in FFS or OS among these groups (P = .71), and therefore, all groups were analyzed together.

Prognostic factors influencing FFS were a pretransplantation LDH ratio of 1 or less (5-year FFS = 42%), compared with patients with an LDH ratio of more than 1 (5-year FFS = 0%; P < .001) (Fig 2), and disease sensitivity at the time of HSCT, with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06) (Fig 3). LDH ratio was also found to influence OS significantly in the same manner (P = .021).

View larger version (8K): [in this window] [in a new window]   Fig 2. FFS curves comparing patients with LDH > 1 and those with LDH 1 (log-rank test, P < .001).

View larger version (10K): [in this window] [in a new window]   Fig 3. Probability of FFS by sensitivity of HD pretransplantation (log-rank test, P = .06).

A stepwise Cox proportional hazards model for survival analysis was used to determine which combination of prognostic factors (as listed in Table 1) influenced FFS and OS. An LDH ratio of more than 1 (P < .0001; risk ratio, 4.63) was associated with a shorter FFS. For OS, LDH ratio of more than 1 (P < .01; risk ratio, 3.2) and interval from diagnosis to HSCT of 15 months or less (P < .01; risk ratio, 3.1) were statistically significant independent predictors.

To explore the potential impact of age on survival, this patient cohort was compared with a historical group of adult patients age 21 years or older (n = 282, 128 of which have been previously reported^13,14) who had received autologous hematopoietic stem-cell transplants at the University of Nebraska over the same time period. In the adult group, the 5-year FFS and OS were 29% and 42%, respectively. Subsequently, a comparison between the pediatric and adult cohorts of patients failed to detect any significant difference in FFS or OS between these groups.

Hematologic Recovery
One patient died before neutrophil recovery. For the remaining patients, the median time to recover an absolute neutrophil count of 0.5 x 10⁹/L was 22 days (range, 8 to 93 days). This was not significantly different for bone marrow (median, 22 days; range, 10 to 93 days), compared with peripheral-blood stem cells (median, 21 days; range, 8 to 63 days). The use of growth factors among these patients was not uniform and varied depending upon the supportive care protocols in effect at the time of transplantation.

Late Effects
In this group of patients, there were 24 children who underwent transplantation before their 18th birthday during a phase of continued growth and development. Of these, six are long-term, disease-free survivors. All six have Karnofsky performance scores of 100%, and all are either in school full-time or employed. These patients have been followed annually with physical examinations (including growth curve monitoring and Tanner staging) and basic laboratory studies, such as complete blood cell counts and serum chemistry profiles. Screening for endocrine or cardiopulmonary abnormalities was not routinely undertaken in otherwise asymptomatic patients unless indicated owing to abnormalities present pretransplantation. Thus far, significant late effects have not been observed. Normal growth has been achieved without growth hormone supplementation. Two females did have delayed onset of puberty and/or menses but have progressed developmentally without hormone supplementation.

Second Malignancies
Two patients developed second malignancies. The first developed myelodysplastic syndrome 9 months after the autologous HSCT while still in remission from HD. She subsequently underwent an allogeneic HSCT only to succumb to an infection related to chronic graft-versus-host disease. OS was 41 months after the first transplantation. The second patient developed acute myelogenous leukemia while in remission from HD after HSCT and died 10 months after the first transplantation. Both patients had received alkylating agents and etoposide for transplantation conditioning; however, no cytogenetic analysis of the leukemia was available for either patient.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Relapse of HD in childhood is rare. Current therapeutic protocols for newly diagnosed patients can achieve cure rates of 85% or greater, even in advanced-stage disease.^21-23 However, salvage chemotherapy protocols for the rare relapse that occurs have been only minimally successful in inducing long-term remissions. Therefore, autologous HSCT is generally accepted to be a standard therapy for treatment of relapsed HD in both pediatric and adult patients, although the precise indications for which it should be performed remain unclear. This article reports a large series of children and adolescents with HD who have undergone HSCT at a single center.

A primary goal of this analysis was to determine the potential impact of age upon outcome for patients undergoing HSCT for refractory or relapsed HD. No difference in either FFS or OS could be detected between the age subgroups or when an additional comparison was made between this pediatric cohort of patients and a group of adult HD patients who received HSCT at the same institution over the same time period. A similar finding has been reported from the European Bone Marrow Transplant Group Lymphoma Registry²⁴; in that study, an adult-pediatric case-control retrospective analysis found no significant difference in progression-free survival rates post-HSCT for pediatric HD compared with adult HD (39% and 48%, respectively; P = .6395). These data would imply that refractory or relapsed HD responds similarly to transplantation regardless of age.

We also analyzed various patient characteristics to determine what prognostic significance they may carry and whether there seem to be any prognostic factors unique to the pediatric population. Several characteristics have previously been reported in association with an improved outcome (longer time to relapse, no debulking chemotherapy before transplantation, stage I or II disease, normal performance status, chemosensitive disease) or with a worse outcome (failing > two chemotherapy regimens, abnormal performance status, progressive or unresponsive disease, nodular sclerosing histology, > one extranodal site of disease, shorter time to relapse).^13,14,24,25 We found that disease sensitivity was a significant prognostic factor for improved FFS, with untreated relapse or sensitive disease faring best. In the multivariate analysis, a pretransplantation LDH ratio of more than 1 had a negative impact on FFS and OS, and an interval between diagnosis and HSCT of less than 15 months had a negative impact on OS. No other factors were found to be significant. Elevation of LDH is likely to be correlated with disease burden at the time of transplantation, and a shorter time between diagnosis and HSCT may indicate early relapsing aggressive disease, both of which may adversely affect outcome. The reason why patients with untreated relapse did best, however, is unclear, although this finding has been reported in several previous studies.^11,14,26 Increased chemoresistance after exposure to multiple chemotherapy agents and cycles may play a role.

Of concern is that three patients in this study experienced late relapses at 26, 30, and 61 months posttransplantation. All of these were of the nodular sclerosis histology, which has been reported to have a higher incidence of late relapses.^27,28 Therefore, on the basis of our experience, as well as that of other investigators who have also documented late relapses,^13,26,29,30 we think that patients with HD warrant close long-term follow-up posttransplantation.

Another area of significant concern is late effects posttransplantation, including second malignancies. These are important factors when considering aggressive treatment options such as HSCT in children. The two second malignancies that occurred in this patient cohort were both hematologic. There have not been any solid tumors thus far, although further long-term follow-up will be required. One recent report found the risk of second malignancies in children and adolescents treated for HD in childhood (without transplantation) to be 1.9% at 10 years, 6.9% at 20 years, and 18% at 30 years. Numerous reports of secondary malignancies (primarily acute myelogenous leukemia) have also been reported in other series of autologous HSCT recipients,^7,11,31 and therefore, long-term survivors must continue to be closely followed for the development of second malignancies as well.

Based on the results of this analysis, indications for HSCT in children with relapsed or refractory HD do not seem to be different from those in their adult counterparts. The clearest indications would be for children with relapsed HD who have chemotherapy-sensitive disease. Additionally, this report included a small number of children (n = 9) who underwent transplantation in untreated first relapse, and their FFS at 5 years was approximately 44%, suggesting that such an alternative approach may warrant further investigation. For those children with resistant relapses (< a PR), the outcome with transplantation is dismal (< 10%), and it is difficult to determine whether transplantation is justified for them. It may be more beneficial to attempt novel therapeutic approaches in these patients.

Although the outcome data reported here are within the range reported in other studies,^7,13,32 a 5-year FFS of 31% leaves significant room for improvement. We are unable to comment on the relative efficacy of different preparative regimens, owing to small numbers.

Overall, the results of HSCT for refractory and/or relapsed HD in children seem to justify its use as a primary therapeutic option. Further investigations, likely in a cooperative group setting, will be required to resolve issues such as significant prognostic factors, timing of high-dose therapy, optimal preparative regimens, the role of allogeneic transplantation, and whether other innovative pre- or posttransplantation therapies could ultimately decrease posttransplantation relapse rates.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 6, 1998; accepted November 17, 1998.

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