Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors

PURPOSE: To evaluate the therapeutic effect of iodine-131-labeled metaiodobenzylguanidine (131I-MIBG) and unlabeled MIBG in patients with carcinoid tumor. MATERIALS AND METHODS: A therapeutic dose of 7.4 GBq (200 mCi) 131I-MIBG infused over 4 hours was administered to 30 patients with either carcinoid syndrome (n = 20) or tumor symptoms such as pain and fever due to carcinoid tumor (n = 10). In general, two courses were given, 6 weeks apart. Due to radioactivity, patients had to be isolated for 5 to 7 days. Subsequently, we studied the effect of unlabeled MIBG based on the possible pharmaceutic activity of MIBG and to avoid the isolation procedure. A doseescalation study of 8.5, 17, and 34 mg/m2 MIBG infused over 4 hours at 4-week intervals was performed in 20 patients with carcinoid syndrome who were not suitable for treatment with the radioactive compound. RESULTS: Following 131I-MIBG treatment, symptomatic responses were observed in 60% of patients (median duration, 8 months; maximum, 2 years). Side effects were mild and rapidly reversible in 16 patients, and were related to the isolation procedure in seven of these patients. Unlabeled MIBG resulted in symptomatic improvement in 60% of patients (median duration, 4.5 months). Side effects, which included changes in blood pressure, were mild and transient. Symptomatic responses were not accompanied by biochemical responses. CONCLUSION: Both MIBG treatment regimens were equally effective in the palliation of symptoms, but duration of response tended to be much longer with the radioactive compound. However, the unlabeled compound provided a simpler treatment, eg, in elderly patients and those in poor condition, without the need for isolation.     

Iodine-131-MIBG therapy of a patient with carcinoid liver metastases

Iodine-13I-metaiodobenzylguanidine (MIBG) is highly concentrated by >60% of carcinoid metastases and thus provides a therapeutic opportunity. METHODS: A symptomatic patient with carcinoid liver metastases, unresponsive to chemotherapy combined with interferon-alpha, was subsequently treated with 131I-MIBG. RESULTS: Radionuclide therapy, which was without significant side effects, resulted in symptomatic improvement and reduced urinary 5-hydroxyindoleacetic acid levels. No new metastases were observed for 15 mo after 131I-MIBG therapy. Gross cystic change occurred in existing liver metastases, presumably as a result of ischemic necrosis. Surgical deroofing and aspiration of cysts led to regeneration of normal liver tissue. CONCLUSION: Iodine-131-MIBG therapy can provide prolonged symptomatic relief and improved quality of life in patients with metastatic carcinoid disease unresponsive to other therapies. The antitumor effect of 131I-MIBG was accompanied by few side effects, suggesting that this therapy should be considered in symptomatic patients with an early stage of disease.     

Assessment of self-injurious behavior maintained by access to self-restraint materials

Metastatic tumor is one of several etiologies of space-occupying masses in the orbit that accounts for 1%-13% of all orbital masses (1). In the adult patient population, breast cancer is the most common tumor to metastasize to the orbit followed by metastases from the lung, prostate and gastrointestinal tract (2). It is rare for carcinoid tumors to metastasize to the eye or to the orbit. Carcinoid tumors arise from Kulchitsky cells that originate in the neural crest. Histologically, these tumors resemble, but are not as aggressive as, adenocarcinomas. Most carcinoids arise in the gastrointestinal tract or the lung. The most common site for carcinoid metastases is the liver. On anatomical imaging studies, such as CT and magnetic resonance imaging, metastatic orbital carcinoid tumors appear as nonspecific tumor masses. Carcinoid tumors have an affinity for uptake of the radiopharmaceutical 131I-metaiodobenzylguanidine (MIBG) (3). We report a case of a patient with a known carcinoid tumor who developed a left orbital mass that demonstrated abnormal uptake of 131I-MIBG indicative of metastatic carcinoid tumor to the orbit.     

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions

Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [131I]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 123I-, 125I-, 131I- and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([123I]MIBG and [125I]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [131I]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.     

No-carrier-added synthesis of meta-[131I]iodobenzylguanidine

No-carrier-added meta-[131I]iodobenzylguanidine ([131I]MIBG) was prepared starting with two different metallated precursors. Attempted preparation of 3-(tri-n-butylstannyl)benzylguanidine was not successful. An alternate two-step strategy using 3-(tri-n-butylstannyl)benzylamine could be used to prepare radio-iodinated [131I]MIBG in an overall radiochemical yield of 30-33%. Synthesis of [131I]MIBG via the radioiododesilylation of 3-trimethylsilylbenzylguanidine was also investigated. Yields were dependent on temperature, precursor concentration, solvent and nature of the oxidant. Radiochemical yields of 90% were obtained in 5 min at room temperature using either N-chlorosuccinimide or hydrogen peroxide in trifluoroacetic acid as oxidants. The percentage of specific binding in vitro of no-carrier-added MIBG to SK-N-SH neuroblastoma cells remained constant over a 2 log activity range, while the binding of MIBG prepared by isotopic exchange dropped by a factor of seven. In normal mice, heart and adrenal uptake of no-carrier-added [131I]MIBG was found to be higher than that of [131I]MIBG prepared by isotopic exchange.     

Radiochemical purity of iodine-131 labelled metaiodobenzylguanidine infusion fluids: a report from clinical practice

Iodine-131 labelled metaiodobenzylguanidine ([131I]MIBG) has a diagnostic and therapeutic role in the management of neural crest tumours, particularly neuroblastoma, malignant phaeochromocytoma and paraganglioma. With therapeutic amounts of [131I]MIBG it is essential that the amount of free [131I]iodide, the most important impurity, is known. In clinical practice the percentage of free [131I]iodide seen in a [131I]MIBG infusion concentrate increased from 2.2% +/- 0.67% to 3.6% +/- 0.39% (mean +/- SD; n = 23) 1 day after production. At the time of use the percentage of free [131I]iodide was always below our upper limit of acceptance of 5%. Since 5% of free [131I]iodide is within practical reach in our environment, a higher percentage at the time of preadministration quality control is not accepted in the Netherlands Cancer Institute.     

Occipital nerve neuralgia as postoperative complication. Views on etiology and treatment

INTRODUCTION: Meta-iodobenzylguanidine (MIBG) in its 131I-labeled form is clinically used as a tumor-targeted radiopharmaceutical in the diagnosis and treatment of adrenergic tumors. This well established drug may have additional clinical applications as a radiosensitizer or hyperthermic agent, ie., MIBG reportedly inhibits mitochondrial respiration in vitro. The mechanism for MIBG inhibition of cellular oxygen consumption is uncertain. Moreover, MIBG reportedly stimulates glycolysis both in vitro and in vivo. Our studies show the effect of MIBG on 9L glioma oxygen consumption and redox status with tumors cells in vitro and in vivo. MATERIALS AND METHODS: The effects on electron transfer were determined by following oxygen consumption with a Clark oxygen electrode. Fluorescence measurements were used to determine effects of MIBG on intracellular electron acceptors, NADPH and flavoproteins, in vitro and in vivo. 31P-NMR was used to determine alterations in tumor cell pH in vivo. RESULTS: Our results show the inhibition of oxygen utilization with MIBG for cell suspensions in vitro. The same results were demonstrated for tumor cell suspensions rapidly isolated from tumors grown in rats. Moreover, NAD(P)H and flavoprotein (Fp) fluorescence changes were observed to rapidly occur following MIBG addition in vitro. Changes in intracellular pH measured with 31P-NMR, in vivo, precede the changes in fluorescence of NAD(P)H and Fp obtained with frozen sections of tumor. CONCLUSIONS: We conclude that 31P-NMR measurements and fluorescence changes, following MIBG injection, can be used as criterion for selecting the proper time to treat tumors with ionizing radiation or hyperthermia.     

I-131 localization in acute megakaryocytic leukemia

A case of acute megakaryocytic leukemia in a 13-month-old infant was encountered in whom an abnormal bone scan was associated with abnormal I-131 MIBG uptake in the femoral bone marrow. The normal platelet will take up MIBG and thus, uptake of this radiopharmeceutical by the malignant megakaryocyte, a platelet precursor, may be caused by the same mechanism.     

Sympathetic tone assessed by washout of iodine 125-labeled metaiodobenzylguanidine from the murine left ventricle--influence of immobilization stress and inhibition of the renin-angiotensin system

BACKGROUND: Because it is not metabolized as is norepinephrine (NE), most of the metaiodobenzylguanidine (MIBG) taken up by the heart is considered to be lost subsequently by release concomitant with sympathetic stimulation. Therefore we examined whether the washout of MIBG is influenced by sympathetic tone, which we modulated by using immobilization stress or activation of the renin-angiotensin system (RAS). METHODS AND RESULTS: In 175 male ddY mice, left ventricular radioactivity was counted 30 minutes or 4 hours after injection of 74 kBq (2 microCi) of iodine 125- or iodine 131-labeled MIBG (125I- or 131I-MIBG). The washout rates of MIBG were determined under immobilization stress or under sodium loading or restriction in combination with losartan (10 mg/kg) or cilazapril (1 mg/kg) pretreatment. Immobilization enhanced the washout of 125I-MIBG (80.9% vs 57.9% in the control animals); this was determined to be related to washout from the neuronal compartment, because the nonneuronal component assessed through desipramine pretreatment was not affected. Pretreatment with losartan or cilazapril decreased the facilitation of 125I-MIBG washout in sodium-restricted mice (40.9% and 33.7%, respectively, vs 43.5% in the control animals), but not in sodium-loaded mice. CONCLUSIONS: Measurement of MIBG washout may be feasible for determining the changes in sympathetic tone caused by immobilization stress or activation of the RAS.     

Rate of insufficient samples for fine-needle aspiration for nonpalpable breast lesions in a multicenter clinical trial: The Radiologic Diagnostic Oncology Group 5 Study. The RDOG5 investigators

Metaiodobenzylguanidine (MIBG) was developed 18 yr ago for scintigraphic imaging of the adrenomedullary tumors pheochromocytoma and neuroblastoma. Many studies have shown the usefulness of this agent for the management of patients with neuroblastoma or pheochromocytoma, and the 131I-labeled form was recently approved by the Food and Drug Administration for use in the U.S. This article summarizes our current concepts on the diagnostic use of MIBG in children. The radioisotopes available for labeling of MIBG and related compounds, the dosimetry, metabolism and mechanisms of uptake and retention are discussed. Our protocols for imaging both 131I-MIBG and 123I-MIBG, along with the normal distribution of these compounds, are reviewed. The use of MIBG for the management of neuroblastoma, and comparisons with other radiotracers available for imaging neuroblastomas are also addressed.     

Iodine-131-metaiodobenzylguanidine dosimetry in cancer therapy: risk versus benefit

In the treatment of neural crest tumors, such as pheochromocytoma, with[131I]MIBG, bone marrow toxicity limits the amount of administered activity and, thus, a therapeutically useful tumor dose. METHODS: We calculated tumor doses in a series of diagnostic studies with [123I]MIBG using accurate quantification of SPECT and planar scintigraphy. By extrapolating diagnostic results to therapeutic activities of [131I]MIBG, we could compare the results with whole-body doses from a series of therapies. RESULTS: The tumor dose was DT = 2.2 mGy MBq(-1) (median value of 27 measurements, range 0.04 < or = DT < or = 20 mGy MBq(-1) and the whole-body dose in a series of 16 patients undergoing 50 therapies was DWB = 0.12 +/- 0.04 mGy MBq(-1) (mean +/- s.d.). The therapeutic ratio varied between 130 to below 10 in some patients. CONCLUSION: The results were compared with published data. We found clearly skewed distribution of tumor doses, with a majority of tumors receiving only a few mGy per MBq administered activity. In some patients, however, doses did reach 20 mGy MBq(-1).     

Clinical relevance of I-123/I-131-MIBG scintigraphy in intestinal carcinoid tumors

AIM: Of this retrospective study was to determine the value of MIBG-scintigraphy in patients with intestinal carcinoids dependent on histological, clinical, and biochemical parameters. METHODS: In 15 patients uptake in carcinoid tumors and metastasis was correlated with location of the primary tumor, intra- and extrahepatic tumor masses, histology, immunhistochemistry, neuroendocrinological markers, and clinical symptoms. RESULTS: High uptake was to be seen almost only in tumor masses of primary tumors located in the terminal ileum. There also was a positive correlation with clinical symptoms for carcinoids and urinary 5-HIAA level. No correlation between MIBG uptake and tumor masses, histology, and most of the immunhistochemical and neuroendocrinological markers could be found. CONCLUSION: There is a limited indication for MIBG-scintigraphy in follow up of intestinal carcinoids. In patient with proven uptake MIBG scintigraphy is suitable for long-term follow up and therapy monitoring.     

The elbow joint: osseous and ligamentous structures

PURPOSE: The analogue 131I-metaiodobenzylguanidine (MIBG), which is specifically targeted to neuroblastoma cells, may provide more effective and less toxic treatment for neuroblastoma than conventional external-beam radiotherapy. We report a dose escalation study of 131I-MIBG to define dose-limiting toxicity without and with autologous bone marrow support. PATIENTS AND METHODS: Thirty patients with relapsed neuroblastoma were treated in groups of six with escalating doses of 3 to 18 mCi/kg of 131I-MIBG. After rapid escalation in the first three patients treated at 3 to 6 mCi/kg, treatment was escalated in 3-mCi/kg increments from 9 to 18 mCi/kg. Autologous tumor-free bone marrow was cryopreserved in all patients receiving 12 mCi/kg and more. Toxicity and response were assessed. RESULTS: Eighty percent of patients who received 12 mC/kg or more experienced grade 4 thrombocytopenia and/or neutropenia. Dose-limiting hematologic toxicity was reached at 15 mCi/kg, at which level two of five assessable patients required bone marrow reinfusion for absolute neutrophil count (ANC) of less than 200/microL for more than 2 weeks, and four of nine at the 18-mCi/kg level. Prolonged thrombocytopenia was common, with failure to become platelet-transfusion independent in nine patients. One patient with extensive prior treatment developed secondary leukemia and three became hypothyroid. Responses were seen in 37% of patients, with one complete response (CR), 10 partial response (PR), three mixed response, 10 stable disease, and six progressive disease. The minimum dose of 131I-MIBG for 10 of the 11 responders was 12 mCi/kg. CONCLUSION: Treatment with 131I-MIBG has mainly hematologic toxicity, which can be abrogated with bone marrow rescue. The high response rate in refractory disease suggests that this agent may be useful in combination with myeloablative chemotherapy and autologous stem-cell rescue to improve outcome in advanced neuroblastoma.     

Iodine-131 metaiodobenzylguanidine scintigraphy for localization of lesions in children with neuroblastoma: comparison with computed tomography and ultrasonography

Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy, computed tomography (CT) and ultrasonography (US) were used to localize tumour lesions in 28 children with histologically proven neuroblastoma. Overall, a total of 73 lesions were detected on imaging studies. MIBG scintigraphy, CT and US localized 63 (86%), 49 (67%) and 36 (49%) of these lesions, respectively. The findings of the three imaging techniques were concordant in respect of only 31 (42%) of the lesions. The best agreement among MIBG scintigraphy, CT and US was observed for abdominal lesions (the techniques were concordant for 22 of 23 lesions, i.e. 96%). MIBG scintigraphy detected nine out of ten (90%) liver metastases, but agreement with CT and US was observed in only six instances (60%). The imaging findings were concordant in respect of only two (33%) out of six lymph node metastases; the MIBG scan was normal in the other four cases. Imaging agreement was observed for a lesion located in the pelvis. MIBG and CT findings were concordant in four lesions located in the chest, but US was not performed. MIBG scintigraphy depicted the majority (96%) of the skeletal lesions (23/24); CT showed five of these, but, again, US was not performed. The imaging findings were not concordant as regards the remaining five lesions located in different anatomical sites. The results indicated that MIBG imaging is more sensitive that CT and US in localizing the majority of neuroblastoma lesions. Since the metastatic spread of neuroblastoma is unpredictable, we recommend MIBG scintigraphy as the initial imaging modality for staging of these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patterns of oncogene activation in human neuroblastoma cells

The authors report 7 cases of intestinal carcinoids. They examine the clinical aspects and describe and discuss both surgical and medical treatment strategies. They also critically evaluate the value of monitoring some oncological markers and their prognostic significance. Each patient underwent an in-depth evaluation of tumour evolution (CAT, ultrasonography, NMR, angiography) and urinary 5HIAA and platelet 5HT were monitored. Surgery took the form of ileal or ileocolic resection, gastric resection, exeresis of the tumour using a transanal route, ligature of the right branch of the hepatic artery afferent to the metastasised lobe of the liver. Five patients were treated using chemotherapy and three, also suffering from carcinoid syndrome, with octreotide. On the basis of their personal experience the authors underline the limited value of the study of 5HT and 5HIAA tumour markers in the diagnosis of small carcinoid tumours. This is compensated by the outstanding role of these markers in the diagnosis of the hepatic and/or lymphoglandular diffusion of the tumour. These markers were not influenced by octreotide treatment in cases in which longastatin was successfully used to combat carcinoid syndrome. Their behaviour allowed useful information to be acquired regarding the tumour evolution following surgery.     

I-123 MIBG scintigraphy in adults. A report of clinical experience

Thirty-one adult patients with clinical findings suggestive of pheochromocytoma were studied with I-123 MIBG. All patients had images obtained at 24 and 48 hours. Five patients had abnormal uptake proved to be because of I-123 MIBG avid tumors. The remaining 26 patients had no proven tumors and showed physiologic uptake in various organs. The 24-hour images were of high quality. In all cases, the 48-hour images contributed no significant additional information. Only in 1 patient did the 48-hour image add some certainty. Physiologic uptake was seen in the salivary glands, liver, G.I. tract, and urinary bladder in all patients (100%). Uptake was also observed in the lung and heart (90%), normal adrenal glands (32%), thyroid (29%), spleen (23%) uterus (13%), and neck muscles (6%). The authors' experience indicates that I-123 MIBG gives superior images compared to the previously used I-131 MIBG, that the optimum imaging time for adults is 18-24 hours, and that normal distribution patterns including uterine and neck muscle uptake should be familiar to physicians interpreting the studies.     

Metaiodobenzylguanidine and heart rate variability in heart failure

It is assumed that the low-frequency power (LF) of heart rate variability (HRV) increases with progress of congestive heart failure (CHF), therefore positively correlating with cardiac 123I-metaiodobenzylguanidine (MIBG) washout. It is demonstrated here that HRV, including normalized LF, correlated inversely with MIBG washout and positively with the ratio of heart-to-mediastinum MIBG activity in controls and CHF patients, whereas these correlations were not observed within CHF patients. Thus MIBG washout may increase and HRV including normalized LF may decrease with CHF, although the HRV and MIBG measures may not similarly change in proportion to the severity of the cardiac autonomic dysfunction in CHF.     

Dual-tracer assessment of coupling between cardiac sympathetic neuronal function and downregulation of beta-receptors during development of hypertensive heart failure of rats

BACKGROUND: Heart failure is associated with activation of the sympathetic nervous system and downregulation of beta-receptors. However, the coupling between cardiac sympathetic neuronal function and the beta-receptor during the development of hypertensive heart failure is not clear. METHODS AND RESULTS: We determined cardiac neuronal function and beta-receptors with a dual-tracer method of [131I]metaiodobenzylguanidine (MIBG) and 125I-cyanopindolol (ICYP) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The rats were fed an 8% NaCl diet after the age of 6 weeks. Blood pressure was raised to >200 mm Hg at 12 weeks in DS rats and remained elevated until 18 weeks, but only slightly in DR rats. Left ventricular (LV) function of DS rats was preserved at 12 weeks but deteriorated at 18 weeks. Despite a 56% reduction of cardiac norepinephrine (NE) content at 12 weeks in DS rats, neither MIBG nor ICYP uptake in DS rats was different from that of DR rats. At 18 weeks, both MIBG and ICYP uptakes decreased, by 52% and 39%, respectively, in association with 71% reduction of cardiac NE, in DS rats. MIBG uptake of the LV was homogeneous at 6 weeks but was lower in the LV endocardial regions at 18 weeks in DS rats. CONCLUSIONS: The present results indicate that cardiac sympathetic neuronal function is relatively preserved at the compensated, hypertrophic stage of DS rats but deteriorates in association with beta-receptor downregulation at the failing stage. The cardiac neuronal dysfunction occurs heterogeneously. A combination of scintigraphic portrayal of beta-receptors with MIBG should provide valuable information regarding sympathetic nerve signaling in living hearts.     

Primary hepatic carcinoid tumor

A case of primary carcinoid tumor arising in the liver of a 69 year old woman with no endocrine symptoms is reported. Histopathologically, the tumor was diagnosed initially as a hepatocellular carcinoma in the biopsy specimen, and was shown subsequently to be a carcinoid tumor, demonstrating diffuse positive staining with Grimelius method. Mucin stained with periodic acid-Schiff (PAS), alcian-blue, and mucicarmine, and was shown partially in the glandular structures. Immunohistochemically, most of the tumor cells stained positively for chromogranin-A, epithelial membrane antigen (EMA) and neuron specific enolase (NSE). Ultrastructural examination revealed electron-dense core granules, measuring 40-120 nm in diameter in some of the tumor cells. Intensive and careful searches pre- and post-operatively revealed no other primary source of tumor other than the liver. The patient was reported well with no symptoms 3 1/2 years after the operation. This case is considered to be a primary hepatic carcinoid tumor. The recent literature is reviewed, and the possible histogenesis of hepatic carcinoid tumor is discussed.     

Validation of the full and short forms of the CAMDEX interview for diagnosing dementia: evidence from a one-year follow-up study

BACKGROUND: Metaiodobenzylguanidine (MIBG) labeled with 131I has been used for targeted radiotherapy of neural crest tumors, with bone marrow suppression being the primary dose-limiting toxicity. The purpose of this study was to examine the engraftment and toxicity of higher myeloablative doses of 131I-MIBG with autologous bone marrow support. PROCEDURE: Twelve patients with refractory neuroblastoma were given infusions of their autologous, cryopreserved bone marrow following 1-4 doses of 131I-MIBG. The median cumulative administered activity per kilogram of 131I-MIBG was 18.0 mCi/kg (range 14.1-50.2 mCi/kg), the median total activity was 594 mCi (range 195-1,353 mCi), and the median cumulative whole body irradiation from 131I-MIBG was 426 cGy (range 256-800 cGy). A median of 2.5 x 10(8) viable cells/kg (range 0.9-4.7 x 10(8) cells/kg) was given in the bone marrow infusion. RESULTS: All 12 patients achieved an absolute neutrophil count > 500/microliter with a median of 19 days, but only 5/11 evaluable patients achieved red cell transfusion independence, in a median of 44 days; and 4/11 evaluable patients achieved platelet count > 20,000/microliter without transfusion, in a median of 27 days. CONCLUSIONS: Autologous bone marrow transplantation may allow complete hematopoietic reconstitution following ablative 131I-MIBG radiotherapy in patients with neuroblastoma. Risk factors for lack of red cell or platelet recovery include extensive prior chemotherapy, progressive disease at the time of transplant, especially in the bone marrow, and a history of prior myeloablative therapy with stem cell support.