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High-Dose Therapy and Autologous Hematopoietic Stem-Cell Transplantation for Recurrent or Refractory Pediatric Hodgkin's Disease: Results and Prognostic Indices

From the Departments of Radiation Oncology and Pediatrics, Stanford University Medical Center; and Department of Health Research and Policy, Stanford Medical School, Stanford, CA

Address reprint requests to Sarah S. Donaldson, MD, Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847; e-mail: sarah{at}reyes.stanford.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To evaluate the outcome of pediatric patients with refractory or relapsed Hodgkin's disease (HD) who undergo high-dose therapy and autologous hematopoietic stem-cell transplantation (AHSCT).

PATIENTS AND METHODS: From 1989 to 2001, 41 pediatric patients with relapsed or primary refractory HD underwent high-dose therapy followed by AHSCT according to one of four autologous transplantation protocols at Stanford University Medical Center (Stanford, CA). Pretreatment factors were analyzed by univariate and multivariate analysis for prognostic significance for 5-year overall survival (OS), event-free survival (EFS), and progression-free survival (PFS).

RESULTS: At a median follow-up of 4.2 years (range, 0.7 to 11.9 years), the 5-year OS, EFS, and PFS rates were 68%, 53%, and 63%, respectively. Multivariate analysis determined the following three factors to be significant predictors of poor OS and EFS: extranodal disease at first relapse, presence of mediastinal mass at time of AHSCT, and primary induction failure. Two of these factors also predicted for poor PFS (extranodal disease at time of first relapse and presence of mediastinal mass at time of transplantation).

CONCLUSION: More than half of children with relapsed or refractory HD can be successfully treated with the combination of high-dose therapy and AHSCT, confirming the efficacy of this approach. Further investigation is now required to determine the optimal timing of AHSCT, as well as to develop alternative regimens for those patients with factors prognostic for poor outcome after AHSCT.

	INTRODUCTION

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Although children with Hodgkin's disease (HD) achieve a 5-year overall survival (OS) rate of close to 90% after combined-modality therapy, approximately 10% to 15% fail to attain a complete remission or subsequently relapse.^1,2 The cure rate after retrieval therapy (any combination of chemotherapy or radiation therapy, excluding high-dose therapy and autologous hematopoietic stem-cell transplantation [AHSCT]) is poor, as reported in adults treated with various regimens, and ranges from 20% to 25% at 5 to 10 years.^3-17 Remission rates for children who relapse after radiation alone and who are subsequently treated with chemotherapy or combined-modality therapy may be as high as 50% to 80%.¹⁸ However, children who relapse after combined-modality therapy, who develop refractory disease during or within 1 year of completing therapy, or who have multiple relapses respond poorly to conventional retrieval therapy.¹⁸ The use of high-dose chemotherapy with AHSCT is becoming standard management for adults with relapsed HD after combined-modality therapy, with 5-year OS rates reaching 30% to 50%.^19-28 A case-matched comparison of AHSCT in pediatric and adult patients with HD suggests that pediatric patients have similar event-free survival (EFS) and OS compared with their adult counterparts.²⁹ However, there are few data reporting the use of AHSCT for children with HD. A review of the literature reveals projected 5-year OS and EFS rates of 43% to 95% and 31% to 62%, respectively.^30,31

To augment the published experience of AHSCT for pediatric HD, we investigated the outcomes of children and adolescents with HD who underwent high-dose chemotherapy and AHSCT at Stanford University Hospital and Lucile Salter Packard Children's Hospital at Stanford (Stanford, CA). We present an analysis of treatment-related toxicity and prognostic implications of various disease characteristics.

	PATIENTS AND METHODS

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Study Design
We conducted a retrospective review of 41 consecutive pediatric HD patients who underwent AHSCT for either primary refractory or relapsed disease. Patients were entered onto one of four consecutive autologous transplantation protocols at Stanford University Hospital and/or Lucile Salter Packard Children's Hospital at Stanford between September 5, 1989, and December 31, 2001. All patients had a histologically confirmed diagnosis of HD at initial presentation. Before AHSCT, patients were required to demonstrate adequate hematologic parameters (WBC > 3,500/µL and platelets > 100,000/µL, unless there was biopsy-proven bone marrow involvement), pulmonary function (diffusion capacity > 60%), cardiac function (radionuclide ejection fraction > 50% or an appropriate increase with exercise), hepatic function (serum bilirubin < 2 mg/100 mL and AST/ALT < 3x normal, unless there was radiographic or biopsy evidence of involvement with HD), and renal function (serum creatinine < 1.5 mg/100 mL). Patients and/or their parents provided informed consent for high-dose chemotherapy and AHSCT. The institutional review board approved all clinical research protocols.

Definitions
Relapsed disease was defined as histologically proven disease recurrence 60 days after successful primary treatment. Primary refractory disease was defined as disease progression occurring during the initial planned treatment or a partial or transient response (lasting < 60 days) to planned therapy.³² Complete response was defined as no evidence of tumor by clinical, biochemical, or radiographic evaluation by day 30 after completion of primary treatment.³³ In addition, complete response after AHSCT was further defined as 80% tumor reduction in two tumor dimensions in patients who had persistent radiographic abnormalities that remained unchanged for more than 1 year.³⁴ Bulky disease was defined as mediastinal disease of one third or greater of the maximal intrathoracic diameter as measured on an upright posteroanterior chest radiograph. Stable disease was defined as no change in tumor dimensions over the stated time course. Early treatment-related mortality was defined as death without recurrent HD within 100 days after transplantation. Late treatment-related mortality was defined as death without recurrent HD greater than 100 days after transplantation.

Patient Characteristics
Patient characteristics are listed in Table 1. Initial HD staging was determined according to the Ann Arbor classification. At the time of AHSCT, all patients had previously received conventional multiagent chemotherapy. Twenty-six patients had received mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine² (MOPP/ABVD) or lomustine (CCNU), vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD).¹ The remainder of patients had received vincristine, cyclophosphamide, prednisone, and doxorubicin (VEPA)³⁵; vincristine, doxorubicin, methotrexate, and prednisone (VAMP)³⁶; vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide, prednisone (Stanford V)³⁷; or other similar drug regimens. Radiation therapy was administered to 31 patients as part of their initial or retrieval HD treatment.

High-Dose Therapy Regimen
Twenty-three patients received carmustine (BCNU), VP16, and cyclophosphamide on regimen 1; 10 patients received CCNU, VP16, and cyclophosphamide on regimen 2; and six patients received fractionated total-body irradiation (fTBI), VP16, and cyclophosphamide on regimen 3 (Table 2). High-dose VP16 (2,000 mg/m²) was administered to mobilize peripheral-blood progenitor cells, which were collected and cryopreserved.

Stem cells were thawed and infused on day 0. Patients were hospitalized in HEPA-filtered rooms, and standard supportive care measures were followed.

Two patients received sequential high-dose therapy followed by stem-cell rescue. Four alternating courses of mitoxantrone, thiotepa, and cyclophosphamide and CCNU, VP16, and cyclophosphamide were followed 48 hours later by infusion of one quarter of the previously collected peripheral-blood progenitor cells. Each cycle of high-dose chemotherapy was started 21 days after the preceding cycle if the absolute neutrophil count (ANC) was more than 1,500/µL and platelets were more than 80,000/µL and there was no dose-limiting toxicity.

Tumor Response Evaluation
Restaging studies (CBC, complete metabolic panel, chest x-ray, and computed tomography scans) were obtained between day +30 and day +60 after transplantation. Routine follow-up studies were repeated every 3 to 6 months for 2 years and then yearly thereafter, unless disease-related symptoms recurred.

Statistical Methods
End points analyzed were OS, EFS, and progression-free survival (PFS) calculated from time of AHSCT (day 0). OS, EFS, and PFS rates were estimated using the Kaplan-Meier method.⁴⁰ For calculation of EFS, we defined an adverse event as either relapse of HD, development of a second malignancy, or death. For calculation of PFS, we defined an event as relapse of HD (with non-HD–related deaths censored). Univariate analyses of seven patient characteristics (B symptoms at diagnosis, primary refractory disease, duration of first remission, B symptoms at first relapse, extranodal disease at first relapse, mediastinal mass at AHSCT, and bulky disease at AHSCT) were performed to select covariates for multivariate analyses. Characteristics with a P < .10 were determined for the three end points of interest. The influence of these factors on the three end points was estimated by Cox proportional hazards regression.⁴¹ The relative risk ratio was calculated for each variable with CIs. All factors with a P < .10 in univariate analysis were subject to stepwise Cox regression analysis.

	RESULTS

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Survival Data
OS at 5 years was 68% (95% CI, 52% to 84%; Fig 1). Actuarial 5-year EFS was 53% (95% CI, 37% to 69%; Fig 2). PFS at 5 years was 63% (95% CI, 46% to 80%; Fig 3). The median follow-up was 4.2 years (range, 0.7 to 11.9 years).

View larger version (9K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of overall survival (OS) probability.

View larger version (9K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimate of event-free survival (EFS) probability.

View larger version (9K): [in this window] [in a new window]   Fig 3. Kaplan-Meier estimate of progression-free survival (PFS) probability.

Patterns of Failure
Of the 13 patients who developed recurrent HD after transplantation, four had received prior irradiation at the site of failure (mean dose, 26 Gy; range, 15 to 36 Gy), six had not been irradiated at the site of failure, and three did not have available data. Of the four patients who relapsed in a previously irradiated site, only one recurred exclusively within a prior treatment field (dose, 36 Gy). The remaining three patients developed recurrent disease simultaneously in previously irradiated and unirradiated sites. All four of the patients had received irradiation as a part of their primary combined-modality treatment. Only one of the four patients relapsed in a site that had been involved at the time of transplantation.

Of the six patients who had not received prior radiation at the site of failure, five had undergone prior radiation (involved field in three patients as part of previous combined-modality treatment with a mean dose 40 Gy, and 12 Gy of fTBI in two patients as part of the high-dose therapy regimen), and one had not received any prior radiation.

Of the 10 patients who had not received any radiation before transplantation, four received fTBI as part of their high-dose therapy regimen, five underwent post-transplantation consolidative radiation therapy (mean dose, 33 Gy), and one did not receive any radiation.

Hematologic Engraftment
The median time to achieve an ANC of more than 0.5 x 1,000/µL was 12 days (range, 1 to 31 days) in 39 assessable patients (the remaining two patients underwent sequential stem-cell rescue, and thus, engraftment data were evaluated differently). The median time to achieve a platelet count of more than 20 x 1,000/µL was 17 days (range, 9 to 38 days) in 37 assessable patients (two patients had missing data). Three patients died after neutrophil engraftment but before platelet recovery more than 20 x 1,000/µL. The median time to achieve a platelet count of more than 100 x 1,000/µL was 26 days (range, 12 to 70 days) in 32 assessable patients (seven patients had missing data). One patient achieved an ANC of more than 0.5 x 1,000/µL by day 30 and a platelet count of more than 20 x 1,000/µL by day 38, but the patient died before achieving a platelet count of more than 100 x 1,000/µL. Another patient achieved an ANC of more than 0.5 x 1,000/µL by day 14 and a platelet count of more than 20 x 1,000/µL by day 13, but he experienced a subsequent drop in his blood counts, with ANC decreasing to 0 on day 35 and platelets decreasing to 6 x 1,000/µL on day 23. This patient recovered without supplemental hematopoietic cell reinfusion, achieved an ANC of more than 1 x 1,000/µL on day 64, and no longer required platelet support 7 months after AHSCT.

Toxicity
Early treatment-related mortality occurred in four (10%) of 41 patients. Three of the four patients had received mediastinal radiation as part of their primary combined-modality therapy or retrieval therapy. Two patients died of acute respiratory distress syndrome; one patient had received 25.5 Gy of mediastinal irradiation as part of primary combined-modality treatment as well as BCNU as part of the high-dose therapy regimen, and the second patient had received 9 Gy of mediastinal irradiation as part of primary combined-modality treatment that was stopped early because of progressive disease, followed by 12 Gy of fTBI as part of the high-dose therapy regimen. The third patient died of interstitial pneumonitis/Legionella pneumonia after having received mediastinal radiation as part of secondary combined-modality therapy as well as CCNU as part of the high-dose therapy regimen. The fourth patient died of cardiopulmonary arrest after a massive abdominal bleed caused by chest tube trauma. An additional patient died of late treatment-related mortality at day +206 after transplantation as a result of sepsis.

Sixteen patients (39%) developed post-AHSCT idiopathic diffuse lung injury syndrome (acute alveolitis, n = 2; diffuse alveolar hemorrhage, n = 2; acute respiratory distress syndrome, n = 2; delayed interstitial pneumonitis, n = 9; and bronchiolitis obliterans, n = 1). Of these 16 patients, 11 had received prior bleomycin, and seven had received mediastinal radiation as a component of their primary combined-modality treatment (mean mediastinal dose, 39 Gy). As a component of their high-dose therapy regimen, nine of 16 patients received BCNU, three of 16 patients received CCNU, and three of 16 patients received fTBI. The remaining patient received sequential high-dose therapy followed by stem-cell rescue. One patient developed acute lymphoblastic leukemia 10 months after transplantation and is alive 94 months later without evidence of HD recurrence.

Prognostic Implications
Cox regression analysis consistently identified two of the seven factors as predictors of poor outcomes for each of the three end points of OS, EFS, and PFS (P .10). These were extranodal disease at time of first relapse and presence of a mediastinal mass at time of transplantation (Table 3). These candidate variables were subsequently included in multivariate analysis for the three end points, respectively.

	DISCUSSION

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Our experience reveals projected 5-year OS, EFS, and PFS rates of 68%, 53%, and 63%, respectively. These results are similar to those reported by Baker et al,³¹ who reviewed the results of high-dose chemotherapy and AHSCT in 53 consecutive children and adolescents with relapsed or refractory HD. At a median follow-up of 64.6 months, they reported a 5-year actuarial OS rate of 43% and failure-free survival rate of 31%. Our results are also similar to those reported by Williams et al²⁹ of 81 pediatric HD patients who underwent AHSCT. With a median follow-up of 36 months, they reported an OS rate of 64% and a PFS rate of 39%. Verdeguer et al³⁰ reported projected 5-year OS and EFS rates of 95% and 62%, respectively, among 20 pediatric HD patients with a median follow-up of 40 months. These superb results have not been matched by other investigations.

These studies, as well as our data, suggest that a small but significant number of patients who relapse after AHSCT are effectively treated with additional retrieval therapy. However, the majority of these patients will ultimately succumb to their disease. With longer follow-up, it is likely that the OS for our study will approach the values for EFS.

There are no data in the pediatric HD literature comparing conventional retrieval therapy with AHSCT. In the adult literature, there are two prospective randomized trials comparing AHSCT with conventional chemotherapy for relapsed HD. The British National Lymphoma Investigation performed a randomized comparison of high-dose BCNU, VP16, cytarabine, and melphalan (BEAM) chemotherapy plus AHSCT versus mini-BEAM (the same drugs at lower doses, not requiring bone marrow rescue).⁵⁴ With 20 patients treated in each study arm and a median follow-up of 34 months, there were significantly better EFS and PFS rates in the BEAM-AHSCT arm. These authors recommended AHSCT for patients with first relapse of HD.

Similarly, the German Hodgkin's Disease Study Group and the European Group for Blood and Marrow Transplantation performed a randomized trial comparing BEAM plus AHSCT with BEAM plus dexamethasone (Dexa-BEAM) chemotherapy in adults with relapsed chemosensitive HD.⁵⁵ Sixty-one patients were treated with BEAM-AHSCT, and 56 patients began to receive cycles 3 and 4 of Dexa-BEAM. At a median follow-up of 39 months (range, 3 to 78 months), the 3-year survival rate of chemosensitive patients was 68%, with no significant difference between the treatment groups. The authors suggested that the similarity in survival reflected the fact that close to 50% of the patients who relapsed after Dexa-BEAM ultimately received AHSCT. The patients treated with BEAM-AHSCT had significantly better freedom from treatment failure (approximately 50% for BEAM-AHSCT v 35% for Dexa-BEAM at a follow-up of 60 months). In addition, adults in their first relapse of HD had significantly better freedom from treatment failure when treated with BEAM-AHSCT. The authors recommended high-dose chemotherapy and AHSCT for all patients with HD in first relapse with chemosensitive disease. There are multiple retrospective studies confirming the superiority of AHSCT compared with conventional therapy for adults with relapsed or refractory HD.^56-58

Long-term follow-up is important because our data reveal that 38% of deaths occurred between 4 and 12 years after transplantation, with 15% of our patients relapsing beyond 2 years. In fact, with a median follow-up of 4.2 years in our patient population, we may see additional relapses with longer follow-up. Late relapses after AHSCT have also been reported by others.^{15,24,34,43,45} These findings emphasize the importance of close long-term follow-up after AHSCT.

The adult literature has repeatedly identified several factors prognostic for poor outcome (bulk of disease at transplantation,^20,49,59-61 number of prior treatment regimens,^{20,28,49,59,61} duration of initial remission,⁶¹ systemic symptoms at relapse,^20,59,61 performance status,^28,50 extranodal disease at relapse,^20,61 and relapse within a prior radiation field⁶⁰). Data from the pediatric literature reveal several additional prognostic factors for poor outcome after AHSCT (lactate dehydrogenase ratio of more than 1,³¹ interval from diagnosis to AHSCT of 15 months,³¹ and female sex^29,62).

Among all these factors, we found extranodal disease at time of first relapse and large mediastinal mass at time of transplantation to be significant factors predictive for poor OS, EFS, and PFS after AHSCT. Thus, patients with these characteristics seem to need additional or alternative therapy. Novel treatments should be considered in this patient population, such as sequential high-dose therapy with stem-cell rescue,⁶³ supplemental involved-field radiotherapy, or immunologic agents.^64-66 We must continue to search for more effective systemic therapy in attempts to eliminate occult sites of disease because 46% of our patients developed recurrent disease in previously uninvolved sites.

A significant concern in this patient population is post-AHSCT idiopathic diffuse lung injury syndrome, of which there was an incidence of 39% in our study. The following factors were not predictive for the development of post-AHSCT diffuse lung injury syndrome by univariate analysis: prior treatment with bleomycin, pre-AHSCT pulmonary function tests, or prior thoracic irradiation.⁶⁷ Multivariate analysis revealed that a history of atopy was highly predictive of idiopathic pulmonary complications.⁶⁷ Given these findings, patients with known atopy should be closely observed after AHSCT for pulmonary complications and treated aggressively.

Long-term toxicity is an extremely important consideration in the management of children with HD. The risk of serious toxicity, including second malignancy, is related to the intensity and number of the prior therapies.⁶⁸ Thus, proceeding immediately to AHSCT at the time of first relapse may reduce the number and intensity of chemotherapeutic agents to which a patient is exposed and, thus, the overall toxicity.

The optimal timing of AHSCT is unclear. The adult experience recommends AHSCT at the first sign of progression after initial treatment with seven- or eight-drug regimens,^34,69-71 rather than after second and third retrieval regimens. This recommendation is based on poor cure rates with additional conventional chemotherapy regimens and a lower cumulative toxicity of immediate AHSCT. One potential exception may be in patients who have received primary treatment consisting only of minimal chemotherapy; these patients may be effectively treated with additional chemotherapy and involved-field radiation.

Our review of AHSCT for pediatric patients with relapsed or refractory HD demonstrates 5-year OS, EFS, and PFS rates comparable to those achieved at other centers and superior to results obtained by retrieval chemotherapy alone. Longer follow-up is important to fully evaluate efficacy and toxicity. However, mature data from several institutions show that high-dose therapy and AHSCT is superior to conventional retrieval therapy, particularly in adults who progress during or within 12 months of induction chemotherapy.^24,61,72,73 For the 10% to 15% of patients who have primary refractory HD or who relapse after initial planned therapy, reinduction therapy followed by planned AHSCT achieves an EFS rate of 53%, and we believe this is optimal retrieval management.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented abstract at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Salt Lake City, UT, October 21, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted February 18, 2004; accepted August 30, 2004.

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