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Hematologic Toxicity of High-Dose Iodine-131–Metaiodobenzylguanidine Therapy for Advanced Neuroblastoma

From the Departments of Pediatrics, Nuclear Medicine, and Epidemiology and Biostatistics, University of California San Francisco, CA; and Department of Pediatrics and Nuclear Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA

Address reprint requests to Katherine K. Matthay, MD, Department of Pediatrics, Box 0106, University of California, San Francisco, San Francisco, CA 94143; e-mail: matthayk{at}peds.ucsf.edu

	ABSTRACT

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

 
PURPOSE: Iodine-131–metaiodobenzylguanidine (¹³¹I-MIBG) has been shown to be active against refractory neuroblastoma. The primary toxicity of ¹³¹I-MIBG is myelosuppression, which might necessitate autologous hematopoietic stem-cell transplantation (AHSCT). The goal of this study was to determine risk factors for myelosuppression and the need for AHSCT after ¹³¹I-MIBG treatment.

PATIENTS AND METHODS: Fifty-three patients with refractory or relapsed neuroblastoma were treated with 18 mCi/kg ¹³¹I-MIBG on a phase I/II protocol. The median whole-body radiation dose was 2.92 Gy.

RESULTS: Almost all patients required at least one platelet (96%) or red cell (91%) transfusion and most patients (79%) developed neutropenia (< 0.5 x 10³/µL). Patients reached platelet nadir earlier than neutrophil nadir (P < .0001). Earlier platelet nadir correlated with bone marrow tumor, more extensive bone involvement, higher whole-body radiation dose, and longer time from diagnosis to ¹³¹I-MIBG therapy (P .04). In patients who did not require AHSCT, bone marrow disease predicted longer periods of neutropenia and platelet transfusion dependence (P .03). Nineteen patients (36%) received AHSCT for prolonged myelosuppression. Of patients who received AHSCT, 100% recovered neutrophils, 73% recovered red cells, and 60% recovered platelets. Failure to recover red cells or platelets correlated with higher whole-body radiation dose (P .04).

CONCLUSION: These results demonstrate the substantial hematotoxicity associated with high-dose ¹³¹I-MIBG therapy, with severe thrombocytopenia an early and nearly universal finding. Bone marrow tumor at time of treatment was the most useful predictor of hematotoxicity, whereas whole-body radiation dose was the most useful predictor of failure to recover platelets after AHSCT.

	INTRODUCTION

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Neuroblastoma is the most common extracranial solid cancer in children. The majority of patients present with metastatic disease at diagnosis. Despite recent improvements in outcome with intensification of therapy for metastatic neuroblastoma, the majority of patients will ultimately experience relapse and die as a result of disease.¹

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative with specific affinity for neural crest tissues.² MIBG labeled with iodine-131 (¹³¹I-MIBG) has been shown to be active against neuroblastoma, with one third to one half of patients with refractory or relapsed disease having some response.^3-5 Although ¹³¹I-MIBG typically has been used as a single agent for patients with refractory or relapsed disease, several groups have used ¹³¹I-MIBG combined with chemotherapy earlier in the course of disease.^4,6,7 With this expanding role, an understanding of the toxicity of ¹³¹I-MIBG has become increasingly important.

In a phase I trial of ¹³¹I-MIBG for advanced neuroblastoma, the primary toxicity of ¹³¹I-MIBG was myelosuppression, particularly thrombocytopenia.³ At doses of 15 mCi/kg or higher, almost half of patients required autologous bone marrow or stem-cell infusion (autologous hematopoietic stem-cell transplantation [AHSCT]) for prolonged myelosuppression. Despite AHSCT, not all patients had complete bone marrow recovery. Previous reports have suggested potential risk factors for increased myelosuppression after ¹³¹I-MIBG therapy, including bone marrow metastases, prior transplantation, multiple courses of ¹³¹I-MIBG, increased prescribed activity of ¹³¹I-MIBG, and increased radiation dose.^3,8-13 Another study suggested that possible risk factors for failure to engraft stem cells after ¹³¹I-MIBG include prior transplantation, increased prescribed activity, and progressive disease after therapy.¹⁴ The conclusions from these studies are limited by small sample sizes and differing doses used within individual studies.

The purpose of this study was to analyze the hematologic toxicity of ¹³¹I-MIBG in a group of 53 patients with advanced neuroblastoma treated with a uniformly high dose of ¹³¹I-MIBG. Specific risk factors for requiring AHSCT and for failure to engraft were evaluated.

	PATIENTS AND METHODS

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Patients
Patients older than 1 year and younger than 30 years of age were enrolled in a phase I/II trial of ¹³¹I-MIBG therapy for neuroblastoma refractory to conventional therapy. Eligible patients had MIBG-avid tumors, had a minimum life expectancy of 6 weeks, and had recovered from any preceding therapy. A baseline platelet count of more than 75 x 10³/µL and an absolute neutrophil count (ANC) of more than 1.0 x 10³/µL were required, with exceptions made for patients with low counts because of metastatic bone marrow disease (n = 3). Because of constraints on the timing of treatment, two patients with counts still recovering from chemotherapy were treated before recovery to protocol levels. Both patients recovered counts to protocol levels before nadir counts from ¹³¹I-MIBG occurred. Patients on the phase I/II trial who received a prescribed activity within 10% of the intended 18 mCi/kg (666 MBq/kg) ¹³¹I-MIBG before April 1, 2002, were included in this analysis. Eight patients were treated during the phase I trial and were included in a previous report.³ Some of the dosimetry data on 20 of the patients was reported previously.⁸ Patient characteristics and sites of disease were recorded at study entry. Bone marrow involvement was defined by either positive bone marrow biopsy or positive bone marrow immunocytology (> one tumor cell per 100,000 cells). Extent of bone involvement typically was determined from the last diagnostic MIBG scan before treatment. All patients were required to have either autologous peripheral-blood stem cells (minimum 1.5 x 10⁶ CD34⁺ cells/kg) or purged bone marrow (minimum 1 x 10⁸ mononuclear cells/kg) available.

Treatment
The ¹³¹I-MIBG was prepared and administered during 90 to 120 minutes with thyroid protection achieved using potassium iodide and potassium perchlorate as previously described.³ Patients were treated at the University of California, San Francisco or the Children's Hospital of Philadelphia. The study protocol was approved by the Committee on Human Research of each institution and informed consent was obtained for all patients.

Evaluation of Hematologic Toxicity
Patients were required to have CBCs obtained twice weekly for at least 6 weeks after their treatment date. Thereafter, CBCs were obtained in accordance with standard practice until counts were normal. Use of granulocyte colony-stimulating factor was recommended for neutropenia (ANC < 0.5 x 10³/µL). Platelet or red cell transfusions were given at the discretion of the primary oncologists, but were recommended for platelets less than 10 to 20 x 10³/µL and hemoglobin less than 7 g/dL. Hematologic toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The ANC nadir was defined as the lowest ANC after treatment, regardless of granulocyte colony-stimulating factor administration. The platelet nadir was defined as the lowest platelet count after treatment before any platelet transfusions. Neutrophil recovery was defined as an ANC more than 0.5 x 10³/µL after nadir ANC. The date of transfusion independence, for platelets and red cells, was defined as the date of last transfusion required to maintain counts at minimum levels, typically more than 20 x 10³/µL for platelets. The time spent dependent on platelet transfusion was defined as the time from the first platelet transfusion to the date of platelet transfusion independence. Criteria for AHSCT were ANC less than 0.2 x 10³/µL for more than 2 weeks despite use of hematopoietic growth factors, or requirement for platelet transfusions more frequently than once weekly for 3 to 4 weeks. In eight patients, AHSCT was not given even though criteria were met. Two patients had progressive disease and imminent death and six patients had signs of imminent marrow recovery, all six of whom had full recovery of platelets, neutrophils, and red cells.

Whole-Body Dosimetry and Red-Marrow Index Calculations
Dosimetry calculations were performed as previously described, with the exception that weight-specific interpolated rather than age-specific S values (mean absorbed dose to a target organ per unit cumulated activity in the source organ) were used.⁸ Whole-body cumulative activity calculations for patients with insufficient exposure measurements after infusion were based on the prescribed activity and published biokinetics of ¹³¹I-MIBG.¹⁵ Weight-specific S values were also used for these patients.

Statistical Analysis
Clinical variables were analyzed for correlation with outcome variables related to hematologic toxicity for all patients and to engraftment for patients who required AHSCT. Clinical variables included age, bone marrow tumor at treatment, extent of bone involvement at treatment by MIBG scan, tumor not involving bone or bone marrow, prior transplantation, time from prior transplantation, time from diagnosis to ¹³¹I-MIBG, prior total-body irradiation, prescribed total activity of ¹³¹I-MIBG, whole-body and red-marrow radiation dose received, use of stem cells or bone marrow for AHSCT, time from ¹³¹I-MIBG to AHSCT, number of cells infused for AHSCT, use of purged cells for AHSCT, use of cells harvested after a prior transplantation, time from diagnosis to cell harvest, and disease status at time of AHSCT. Outcome variables included timing of platelet and neutrophil nadir counts, platelet and neutrophil counts at nadir, duration of thrombocytopenia and neutropenia, need for red cell transfusions, need for AHSCT, and failure to engraft after AHSCT. Statistical analyses were performed with STATA 6.0 (StataCorp, College Station, TX). Associations between groups were tested using the Wilcoxon rank sum test for continuous outcomes and the Fisher's exact test for categoric outcomes. Paired comparisons used the signed rank test for continuous outcomes and the McNemar test for paired proportions. Associations between two continuous variables were assessed with the Spearman rank correlation. Right-censored variables were compared between groups using the log-rank test for unpaired comparisons. Paired comparisons used the stratified log-rank test, with each patient defining a stratum.

	RESULTS

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Patient Characteristics
A total of 53 patients received ¹³¹I-MIBG at 18 mCi/kg and were eligible for analysis (Table 1). Patients had advanced disease and were heavily pretreated, including 43 patients (81%) who had experienced relapse after prior myeloablative therapy. Twenty-eight percent of patients had detectable bone marrow tumor by morphology and/or immunocytology at the time of ¹³¹I-MIBG therapy. The median whole-body and red-marrow radiation doses received were 2.92 Gy (range, 1.73 to 4.18 Gy) and 3.47 Gy (range, 2.06 to 5.02 Gy), respectively.

The time course of hematologic recovery for the patients who did not require AHSCT is shown in Fig 1. Patients were platelet transfusion dependent more than seven times longer than they were neutropenic (median of 5 days neutropenic v 5.4 weeks platelet transfusion dependent; P < .0001). This difference remained significant even after excluding patients who never required platelets or became neutropenic (median, 1.4 weeks neutropenic v 5.4 weeks platelet transfusion dependent; P < .0001). After excluding the eight patients described above who met criteria for AHSCT but did not receive AHSCT, the median time spent platelet transfusion dependent was 3.8 weeks (range, 0 to 8.7 weeks). Patients with bone marrow tumor were neutropenic longer than patients without bone marrow disease (median, 2.1 v 0.43 weeks; P = .009). Patients with bone marrow tumor required platelet transfusions for longer than patients without bone marrow disease (median, 6.4 v 5.4 weeks; P = .03). History of prior transplantation or total activity administered did not predict any aspect of platelet or neutrophil toxicity. Two patients with rapidly progressive disease did not receive AHSCT and remained dependent on platelet and red cell transfusion until the time of death; 2.7 and 3.8 months, respectively, from ¹³¹I-MIBG treatment.

View larger version (9K): [in this window] [in a new window]   Fig 1. Neutrophil recovery to more than 0.5 x 103/µL and platelet recovery to transfusion independence in 34 patients without autologous hematopoietic stem-cell transplantation. Tic marks indicate time to last follow-up for patients not assessable for recovery. (A) Recovery from iodine-131–metaiodobenzylguanidine (131I-MIBG) treatment. (B) Recovery from nadir count.

Engraftment After AHSCT
Nineteen patients (36%) received AHSCT. Of these, 15 patients (79%) received AHSCT for either isolated thrombocytopenia or thrombocytopenia with neutropenia, and four patients received AHSCT for isolated neutropenia. None of the clinical variables examined, including bone marrow tumor, were able to predict which patients received AHSCT. In an attempt to determine if certain patients were at low risk for requiring AHSCT, a logistic regression analysis was performed to evaluate bone marrow tumor, history of prior transplantation, time from prior transplantation, and extent of bone disease. No combination of these variables provided a profile of patients at low risk for requiring AHSCT.

Of the 19 patients who received AHSCT, three patients received chemotherapy before AHSCT infusion and one patient died as a result of progressive disease 5.6 weeks after ¹³¹I-MIBG treatment. The characteristics of the remaining 15 patients who received AHSCT and were assessable for engraftment are listed in Table 4. The clinical features of this group did not differ significantly from the group of patients who did not receive AHSCT, except that patients who required AHSCT were more likely to be female (data not shown; P = .03).

View larger version (8K): [in this window] [in a new window]   Fig 2. Neutrophil recovery to more than 0.5 x 103/µL and platelet recovery to transfusion independence in 16 patients who received autologous hematopoietic stem-cell transplantation (AHSCT). Tic marks indicate time to last follow-up for patients not assessable for recovery. (A) Recovery from iodine-131–metaiodobenzylguanidine (131I-MIBG) treatment. (B) Recovery from AHSCT.

Six assessable patients failed to engraft platelets by the time of death after AHSCT (Table 5). The median time from ¹³¹I-MIBG to death or additional myelosuppressive therapy for these patients was 24.9 weeks (range, 12.7 to 51.6 weeks). Three of these patients had bone marrow tumor at the time of ¹³¹I-MIBG treatment. An additional two patients developed new bone marrow tumor at the time of disease progression, such that five of the six patients with failure to engraft platelets had bone marrow tumor involvement around the time of treatment. Nevertheless, bone marrow tumor at treatment was not significantly correlated with failure to engraft platelets.

Late Effects and Nonhematologic Toxicity
Two patients developed myelodysplastic syndrome with leukemia more than 6 months after treatment with ¹³¹I-MIBG and are described in a separate report.¹⁶ Nonhematologic toxicity after ¹³¹I-MIBG treatment was rare. Four patients developed hypothyroidism requiring therapy. One patient with a history of intracranial metastasis and who later developed progressive leptomeningeal disease had a self-limited seizure the day after ¹³¹I-MIBG treatment. Prolonged dry mouth (n = 1), prolonged diarrhea (n = 1), hypertension during ¹³¹I-MIBG infusion (n = 1), and posttreatment hypertension (n = 1) were the only other significant toxicities reported.

	DISCUSSION

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¹³¹I-MIBG administered at 18 mCi/kg to heavily pretreated patients has substantial hematologic toxicity, with 36% of patients receiving AHSCT for prolonged myelosuppression. Consistent with previous findings that higher administered activities per kilogram of ¹³¹I-MIBG correlate with greater hematotoxicity,^3,8,10,11 the degree of hematotoxicity in this group of patients treated at a uniformly high dose was greater than that described previously. Thrombocytopenia requiring transfusion and neutropenia were more frequent, platelet nadir count occurred earlier, and the duration of thrombocytopenia and neutropenia was greater than in previous reports of ¹³¹I-MIBG at lower doses.^{3,5,9,11-13,17}

As in previous studies, ¹³¹I-MIBG therapy resulted in more prominent thrombocytopenia than neutropenia.^3,5,11,18 This differential toxicity might, in part, be related to selective uptake of ¹³¹I-MIBG by platelets and possibly by mature megakaryocytes as well.^19-21 In vitro work has suggested that specific blockade with selective serotonin reuptake inhibitors may provide one method of reducing thrombocytopenia after ¹³¹I-MIBG treatment.¹⁹

Although previous studies have suggested that bone marrow tumor involvement might result in more pronounced myelosuppression after treatment with ¹³¹I-MIBG,^3,9,22 our study is the first to demonstrate significant differences between patients with and without bone marrow tumor involvement in terms of timing and duration of thrombocytopenia and neutropenia. The differences observed, despite being statistically significant, were not major. These findings suggest that patients with bone marrow tumor should be monitored more closely for hematotoxicity, but the impact is not so great as to preclude the use of ¹³¹I-MIBG in these patients. Bone marrow tumor might result in more severe myelosuppression through two possible mechanisms. First, bone marrow tumor that is not completely responsive to ¹³¹I-MIBG therapy will result in bone marrow progression and myelosuppression. Second, because of the long path length of radiation from ¹³¹I, ¹³¹I-MIBG taken up by neuroblastoma cells in the bone marrow might damage adjacent hematopoietic and stromal cells.²³ The use of a radiolabel, such as iodine-125, with a shorter range might diminish this effect.⁴

Previous studies also have suggested greater hematotoxicity in patients who had previously received myeloablative therapy with transplantation.^3,9,13,24 Although the rationale that patients posttransplantation have less marrow reserve is appealing, a history of prior transplantation did not predict any measure of hematotoxicity in the current study. Given that only 10 patients in the current study were not posttransplantation, it is possible that a study with a more heterogeneous population might demonstrate differences in hematotoxicity on the basis of transplantation status.

Prior reports of patients treated with varying doses of ¹³¹I-MIBG have demonstrated a significant relationship between higher whole-body radiation dose and lower nadir platelet and neutrophil counts.^8,10 Our study was unable to confirm these findings, despite the fact that a wide range of whole-body radiation doses was obtained. Although these associations likely exist, they might have been obscured by the uniformly high dose of ¹³¹I-MIBG, resulting in severe hematotoxicity in all patients. The importance of whole-body radiation dose in predicting hematotoxicity was instead demonstrated in this study by evaluating other variables, including timing of nadir and duration of myelosup-pression. These variables were correlated significantly or nearly significantly with whole-body radiation dose. Whole-body radiation dose also was shown to correlate with failure to engraft platelets or red cells in those patients requiring AHSCT. It is possible that high whole-body radiation doses of ¹³¹I-MIBG might damage marrow stromal cells, resulting in an unfavorable environment for engraftment.

Of particular concern are the six patients with prolonged thrombocytopenia despite AHSCT. Other than having received higher whole-body and red-marrow radiation doses, no other clinical variables predicted failure to engraft. Although whole-body radiation dose plays a part in predicting failure to recover platelets, previous researchers using more moderate doses of ¹³¹I-MIBG also have described patients with prolonged thrombocytopenia after treatment.^3,12,13,25 In contrast, three separate groups have reported a total of 40 patients treated with ¹³¹I-MIBG combined with myeloablative chemotherapy and stem-cell rescue.^7,26,27 All 40 patients recovered platelets. It is possible that chemotherapy before ¹³¹I-MIBG therapy facilitates marrow recovery by clearing micrometastases resistant to ¹³¹I-MIBG. Alternatively, the patients in the reported series might have had less prior damage to their marrow stroma because of a much lower frequency of prior myeloablative therapy. It also is likely that the whole-body radiation dose received was lower in these other studies in which the activity infused generally was less than 15 mCi/kg. Earlier reinfusion of stem cells after ¹³¹I-MIBG therapy might also favor recovery, although the results of our study failed to demonstrate a significant relationship between timing of infusion and failure to engraft platelets over the range of intervals observed in this study.

In fact, earlier AHSCT correlated with a longer time to neutrophil engraftment. It is possible that patients with a longer time from ¹³¹I-MIBG to AHSCT were beginning to recover neutrophils on their own, resulting in a shorter observed time to recovery. Given the late neutrophil nadir with ¹³¹I-MIBG, patients who received earlier AHSCT might still not have reached their neutrophil nadir, resulting in a longer observed time to recovery. Another possibility is that earlier AHSCT might expose cells to residual ¹³¹I-MIBG activity and therefore slow engraftment. Reports from other studies using lower doses of ¹³¹I-MIBG with routine early infusion of stem cells, which have shown excellent engraftment, argue against this possibility.^7,26 Finally, patients who received AHSCT earlier might have had less bone marrow reserve, resulting in a longer time to engraftment.

The substantial hematotoxicity of high-dose ¹³¹I-MIBG was manageable with transfusion and cytokine support. Despite a long period of platelet dependence, the frequency of platelet transfusions often diminished to less than once per week during recovery. No toxic deaths were observed and hospitalization for infection was rare. However, the duration of myelosuppression after treatment with ¹³¹I-MIBG could delay additional treatment of an aggressive tumor. Additional studies should prospectively evaluate strategies for diminishing the hematotoxicity of ¹³¹I-MIBG without compromising its efficacy in treating neuroblastoma. Some potential strategies currently being evaluated by the New Approaches to Neuroblastoma Therapy consortium include incorporating early empiric stem-cell support with consecutive treatments of ¹³¹I-MIBG given in rapid sequence or ¹³¹I-MIBG combined with myeloablative chemotherapy.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
The authors acknowledge the invaluable assistance provided by the University of California, San Francisco Pediatric Clinical Research Center staff, and Amanda Doherty and Pat Brophy, of the Children's Hospital of Philadelphia.

	NOTES

 
Supported by funds from the National Institutes of Health (P01 CA81403, 2MO1 RR01271 to UCSF Pediatric Clinical Research Center, and M01-RR00240 to the Children's Hospital of Philadelphia General Clinical Research Center), the Kasle and Tkalcevik Neuroblastoma Research Fund, the Conner Research Fund, and the Campini Foundation.

Presented in part at the American Society of Clinical Oncology 39th Annual Meeting, Chicago, IL, June 2, 2003.

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

	REFERENCES

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

 
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Submitted August 8, 2003; accepted March 31, 2004.

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