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United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia

From the Leukemia and Developmental Chemotherapy Services, Department of Medicine, and Pediatric Department, Memorial Sloan-Kettering Cancer Center and Joan and Sanford Weill Medical College of Cornell University, New York, NY; Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; Norris Cancer Center and University of Southern California Keck School of Medicine, University of Southern California, Los Angeles; Stanford University Medical Center, Stanford, CA; Northwestern University of Medical School, Chicago, IL; M.D. Anderson Cancer Center, Houston, TX; Dana-Farber Cancer Center, Boston, MA; Cleveland Clinic Foundation, Cleveland, OH; and Fred Hutchinson Cancer Research Center and Cell Therapeutics Inc, Seattle, WA.

Address reprint requests to Steven L. Soignet, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: soignets{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL).

PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study.

RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/µL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes.

CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ACUTE PROMYELOCYTIC leukemia (APL) is characterized by a specific t(15;17) genotype, a distinct morphologic picture, and a clinical coagulopathy that contributes to the morbidity and mortality of this disease.^1,2 Current treatment of APL entails the use of all-trans-retinoic acid (ATRA), usually combined with chemotherapy for remission induction, followed by several cycles of anthracycline-based consolidation chemotherapy and ATRA maintenance. The incorporation of ATRA into the treatment regimen has significantly improved the remission rate and has more than doubled the survival rate of newly diagnosed patients over that achieved with chemotherapy alone.^2-5 However, despite these improvements, 25% to 30% of these patients relapse and are often resistant to further treatment with ATRA.² Salvage therapy often involves high doses of cytotoxic chemotherapy followed by either autologous or allogeneic transplantation. With this approach, these patients are exposed to and a certain proportion die from the toxic effects of chemotherapy, an important consideration in treating young or elderly patients. Clearly, there remains a critical need for new therapeutic options in treating relapsed APL.

The most common cytogenetic abnormality associated with APL is a balanced, reciprocal translocation bringing together and fusing the nuclear retinoic acid receptor-alpha (RAR-) gene on chromosome 17 to the promyelocytic leukemia (PML) gene on chromosome 15.^1,2,6,7 This fusion gene then encodes a chimeric protein (PML/RAR-) that blocks myeloid differentiation, which results in the accumulation of abnormal promyelocytes in the bone marrow.⁸

Two major isoforms of PML/RAR- can be encoded, depending on the location of the PML breakpoint. Breakpoints occurring within PML bcr 3 produce a short-type fusion mRNA, whereas breakpoints occurring in PML bcr 1 result in the formation of a long-type fusion mRNA. In a small number of patients, breakpoints in bcr 2 result in a variable-length transcript.^9,10 The vast majority of patients with APL (92% to 98%) have the PML gene rearranged in bcr 1 or bcr 3, yielding the long- or short-type fusion mRNA.^9,11 The long type has been reported more frequently (55%) than the short (37%) or the variable type (8%).¹¹

The presence of a positive reverse transcriptase polymerase chain reaction (RT-PCR) assay for PML/RAR- after therapy is a sensitive predictor of relapse in patients with APL.⁹ Some evidence suggests that the position of the PML breakpoint may also predict response to treatment. Results of a laboratory study suggest that the short isoform may partially protect against apoptosis, but the long form may accelerate cell death.¹² In clinical trials of ATRA, no differences have been found between isoform types in terms of rate of complete response (CR). However, in several studies, a larger number of early deaths and relapses within 2 years of CR were observed in patients having the short isoform when compared with those having the long isoform.^9-11,13 Interestingly, the short isoform is also associated with a higher incidence of secondary chromosomal abnormalities, a higher median WBC count, and a greater percentage of blasts and promyelocytes at presentation.^11,13 In two studies that adjusted for high WBC counts at presentation, a factor associated with a poor prognosis, the first found no difference in outcome between the long and short isoforms,¹¹ but the second study found the short form to be independently associated with shorter disease-free and overall survival times.¹⁰

Abandoned 30 years ago as an anticancer medicinal, arsenic has recently attracted renewed attention as a treatment for APL. On the basis of impressive results from China obtained in early studies of arsenic trioxide (ATO) in the treatment of this disease,^14-16 a pilot trial in 12 patients with relapsed APL was conducted at Memorial Sloan-Kettering Cancer Center that also demonstrated the effectiveness of ATO in inducing CR in this population.¹⁷ In the expanded multicenter study reported here, we evaluated the efficacy of ATO for remission induction and for consolidation in a larger population of patients with APL who had relapsed from prior retinoid and anthracycline-based chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Eligible patients were required to have a diagnosis of either relapsed and/or refractory APL by bone marrow morphology. Confirmation was obtained in blood or bone marrow mononuclear cells by conventional cytogenetics showing t(15;17), by positive RT-PCR assay for PML/RAR-, or by fluorescence in situ hybridization (FISH) analysis that showed evidence of RAR- or PML translocations. All PCR analyses were conducted in a central laboratory (LabCorp of America, Research Triangle Park, NC). In addition, patients were required to have relapsed from or not to have experienced response to induction chemotherapy using an anthracycline and at least one course of induction therapy with either ATRA or 9-cis retinoic acid. Patients were excluded from participation in the study if they were receiving concurrent treatment with cytotoxic chemotherapy, radiation or investigational agents, if they had a history of grand mal seizures, if they had active serious infections that were not controlled by antibiotics, or if serum creatinine or bilirubin was 2.5 mg/dL. Written informed consent was required, and the protocol was reviewed and approved by the institutional review boards at each of the nine participating institutions.

Induction Therapy
ATO was administered at a dose of 0.15 mg/kg given daily until bone marrow remission was observed (defined as the complete disappearance of all leukemic myeloblasts and promyelocytes and 5% overall myeloblasts by morphologic evaluation of the marrow), up to a cumulative maximum of 60 doses. Treatment could be given in either the in-patient or out-patient setting. PolaRx Pharmaceuticals, Inc, New York, NY (acquired by Cell Therapeutics, Inc, Seattle, WA) supplied ATO as an aqueous solution in 10-mL vials containing 1 mg of drug per milliliter. The prescribed daily dose was diluted in 5% dextrose and administered intravenously for 2 hours. Treatment was discontinued before 60 doses if the patient met the criteria for bone marrow remission or if substantial toxicity occurred. Dose escalation was not permitted.

Dose Attenuation or Interruption of Therapy
Treatment was discontinued if drug-related grade 3 toxicity (per National Cancer Institute common toxicity criteria) occurred or for any nonhematologic grade 4 adverse event. After resolution of the toxic event or recovery to baseline status, treatment resumed at 50% of the preceding daily dose. If the toxic event did not recur within 3 days of restarting treatment at the reduced dose, the daily dose was increased to the original dose. Patients who experienced a recurrence of such toxicity were removed from the study.

Consolidation Treatment
Patients who met all criteria for a clinical CR were eligible to receive an additional course of ATO as consolidation beginning 3 to 4 weeks after completion of their induction therapy. The dose for the consolidation course was the same as that administered during induction, and the treatment was given either daily, weekdays only, or on some combination thereof until a cumulative total of 25 doses were administered. All consolidation therapy had to be completed within 5 weeks (35 days).

Maintenance Therapy
Those patients who remained in CR after receiving their consolidation course of ATO were given the option to receive up to four additional cycles of ATO therapy on a dose schedule similar to consolidation on a separate protocol.

Monitoring
Physical examination, neurologic assessment, and review of systems were performed and complete blood count with differential and platelet count, hepatic and renal function tests, coagulation parameters, and concomitant treatments were assessed and recorded at least twice per week during induction, before beginning consolidation, and weekly during consolidation. A 12-lead ECG was obtained at least weekly during treatment.

Bone marrow aspirates were performed on or before day 28 of therapy, then weekly until bone marrow CR, before the initiation of consolidation therapy, 1 to 3 weeks after completing consolidation, and then once approximately every 3 months for the first year after achieving CR. Patients who elected to be treated on the maintenance protocol had a bone marrow aspirate performed before each maintenance cycle. Bone marrow morphology, differential count, and conventional cytogenetics were performed on bone marrow samples, along with RT-PCR for PML/RAR- protein or FISH analysis for evidence of RAR- or PML translocations. LabCorp of America performed RT-PCR assays.

Statistical Methods
All eligible patients were included in the analysis. The patient characteristics, response evaluation, and toxicity assessment were evaluated using descriptive statistics. Survival and RFS were described using the method of Kaplan and Meier.¹⁸ Differences in ordinal data between patient groups were assessed using a two-sided log-rank test.¹⁹ Survival duration was calculated from the time of first ATO administration until death from any cause or last contact. The median follow-up was calculated for all patients at the date they were last known alive. RFS duration was calculated from the time of CR until relapse or death, and patients alive without disease were censored at the time of last contact. Patients were not censored at the time of transplantation.

Efficacy Evaluation
Clinical CR was defined as a bone marrow aspirate with 5% blasts with no evidence of leukemic cells, peripheral-blood leukocyte count 3,000/µL or absolute neutrophil count 1,500/µL, and a platelet count 100,000/µL. Clinical CR was considered to have occurred on the date at which the last of these criteria was met.

	RESULTS

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Clinical Efficacy
Between April 22, 1998, and April 8, 1999, 40 patients at nine centers were enrolled onto the study (Table 1). Thirty-four (85%) of the 40 patients enrolled onto this study achieved a clinical CR and were eligible to receive a single consolidation course of ATO. However, six of these 34 patients who achieved clinical CR did not receive further ATO therapy for the following reasons: two received bone marrow transplants, two discontinued treatment as a result of adverse events (one due to peripheral neuropathy and one due to disease-related seizures and pulmonary hemorrhage), and two who refused further treatment for personal reasons not related to an adverse event. Two of the six patients who did not achieve clinical CR received a second course of ATO as a protocol exception. One patient achieved bone marrow and molecular remission but did not meet the platelet criterion for clinical CR. The other patient was believed to be responding to therapy but discontinued treatment after 28 doses. The latter individual was retreated with a second induction course beginning 4 weeks later that was discontinued after 41 doses because of lack of response.

A confirmatory remission bone marrow was obtained in 32 of the 34 patients at least 30 days after the initial documented bone marrow remission. Two patients did not have a confirmatory bone marrow. One patient refused further treatment, relapsed, and died 141 days after achieving CR, and the other patient died 114 days after achieving a bone marrow CR with disease progression.

Cytogenetic and Molecular Response
All patients who achieved a clinical CR had at least one cytogenetic or molecular test after treatment that was negative for the t(15;17) translocation. Of the six patients who did not achieve CR, three remained positive for the presence of t(15;17) by one or more assays, and two had negative findings but did not achieve CR (Table 2). One of these patients was found to have a residual, non-APL acute myeloid leukemia. The other patient (who had relapsed after bone marrow transplantation [BMT]) failed to achieve a clinical CR because of persistent thrombocytopenia (posttreatment platelet count of 59,000/µL), but met all other criteria for CR. One patient died before any on-treatment tests were scheduled and, therefore, was not evaluated by any cytogenetic measures.

Survival
With a median of 17.1 months of follow-up, the 18-month Kaplan-Meier estimates of overall survival and RFS were 66% and 56%, respectively (Fig 1A and B). Twenty-six patients were alive, and 21 of the 34 CR patients are alive without disease at last contact. Among these 21 patients, 11 received either an all orgeneic (eight patients) or autologous transplant (three patients), and nine received additional ATO as maintenance.

View larger version (13K): [in this window] [in a new window]   Fig 1. Overall survival (A) and RFS (B) rates.

Adverse Events
Adverse events were reported on all patients. At least one grade 3 or 4 adverse event occurred in 27 patients (68%). Severe or life-threatening adverse events were considered by the investigator to be related or possibly related to study treatment in 19 patients (48%). The most commonly reported of these events were hypokalemia (13%), hyperglycemia (10%), and neutropenia (8%).

The most common non–life-threatening adverse events were nausea (75%), cough (65%), fatigue (63%), fever (63%), headache (60%), vomiting (58%), tachycardia (55%), diarrhea (53%), hypokalemia (50%), and skin rash (43%) (Table 5). Nausea, headache, hypokalemia, and hyperglycemia were the events in which the majority of occurrences were considered to be probably or definitely related to ATO therapy. Eleven patients had treatment interrupted due to adverse events. Nine of these patients were able to resume treatment and subsequently obtained a CR. There were no treatment-related deaths.

ECG Abnormalities
Twelve patients had abnormal baseline ECG findings. One patient had QT prolongation (interval from the beginning of the Q wave complex to end of the T wave) at baseline ( 450 msec for males and 470 msec for females). Sixteen patients had at least one on-study ECG that showed prolonged QT corrected for heart rate (QTc) intervals of more than 500 msec. Two patients had an absolute QT interval of more than 500 msec. One patient who was on telemetry monitoring had an asymptomatic, 7-beat run of torsade de pointes that resolved spontaneously. At the time of the event, this patient was receiving multiple concomitant medications, including amphotericin B, and had a serum magnesium and potassium levels of 1.6 mEq/L and 3.4 mEq/L, respectively. ATO therapy was held and electrolytes (magnesium and potassium) were repleted. Subsequently, the QT interval returned to the pretreatment baseline, and no further cardiac arrhythmias were observed. This patient achieved a CR and received a consolidation course of ATO as an out-patient with no further episodes of QT prolongation. In the other patient, the prolongation occurred during induction therapy while hospitalized for febrile neutropenia. Other findings included 24 patients with sinus tachycardia, and 31 patients with nonspecific ST and T-wave abnormalities.

Leukocytosis
The median WBC count for all 40 patients at presentation was 2,050 cells/µL (range, 440 to 72,300 cells/µL). Twenty patients (50%) developed leukocytosis (range, 10,300 to 169,400 cells/µL). Six patients had baseline WBC counts of more than 5,000 cells/µL. In five of these patients, WBC counts increased to more than 15,000 cells/µL during induction. For the patients with leukocytosis, the peak WBC count occurred at a median of 19 days after receiving their first dose of ATO (range, 3 to 36 days). One patient whose baseline WBC count was 3,200 cells/µL had an increase to 169,400 cells/µL on day 20 of ATO, which resolved to less than 10,000 cells/µL by day 35. No patient who developed leukocytosis received additional treatment with cytotoxic agents or leukapheresis. With the continuation of ATO therapy alone, the leukocytosis resolved at a median of 10.5 days after the peak (range, 3 to 27 days). WBC counts during consolidation were never as high as during induction, and only two patients had a WBC count of more than 10,000 cells/µL during consolidation. As reported recently, there did not seem to be a correlation between baseline WBC count and peak WBC count.²¹

Retinoic Acid Syndrome
Treatment with ATO for remission induction is associated with the development of a complex of symptoms identical to retinoic acid syndrome.^21,22 Considering that this complex of symptoms is not specific to the use of retinoic acid, it now referred to as the APL syndrome (APLS). Ten patients (25%) in this study developed symptoms clinically suggestive of this syndrome, three of whom had a specific diagnosis of serious APLS. The other seven patients had simultaneous fever and dyspnea, in addition to one or more symptoms such as weight gain, generalized edema, respiratory failure, or lung infiltrates without evidence of infection. Of note, all 10 of these patients also had leukocytosis and were treated with dexamethasone (10 mg bid for at least 3 days). All of these patients achieved a CR. Therapy with ATO was briefly interrupted (1 to 5 days) in eight of these patients.

Neuropathy
Seventeen patients in this study had adverse events related to neuropathy. One patient who had extensive prior therapy, including allogeneic bone marrow transplantation, discontinued treatment after receiving 14 of 25 scheduled doses of ATO consolidation therapy after development of grade 3 peripheral neuropathy. This patient had baseline grade 1 peripheral neuropathy that progressed to grade 2 at the completion of the induction course, but had improved to baseline grade 1 before initiating consolidation therapy. Subsequently, this patient’s symptoms progressed and the daily dose of ATO was reduced by 25%. Despite this reduction in dose, this patient developed difficulty with fine motor skills and gait disturbance associated with numbness. ATO therapy was discontinued, and improvement of symptoms was noted 18 days later. His neuropathy improved 18 days after discontinuing ATO therapy. The majority of symptoms reported by other patients were mild and consisted of grade 1 peripheral neuropathy. Most of these events were considered possibly related to study treatment and resolved without sequelae.

Clinical Laboratory Evaluation
Transient elevations in serum transaminases (AST, ALT) and/or total bilirubin were observed in 10 patients. These events generally occurred during induction in the setting of multiple concomitant medicines. No significant hepatotoxicity was observed. Acute renal insufficiency occurred in three patients in the settings of acute respiratory distress, gastrointestinal bleeding, and sepsis. Hemodialysis was required for one patient. In general, laboratory values were either stable or, if abnormal during the study, had returned to normal by the end of the treatment period.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The CR rate of 85% achieved in this multicenter study compares favorably with the results reported initially by investigators from China¹⁶ and the United States.¹⁷ All patients who achieved a CR also showed evidence of elimination of the t(15;17), as measured either directly by traditional cytogenetics or by assays using FISH or RT-PCR for PML/RAR-. These responses were particularly encouraging given that more than one third of these patients had multiple relapses and were heavily pretreated (including five patients with prior BMT). The median times to achievement of bone marrow remission (35 days) and clinical CR (59 days) were similar to what has been reported when ATRA is given alone for remission induction in patients with newly diagnosed APL.^2,4,5 The delay between bone marrow remission and clinical CR was generally a result of persistent thrombocytopenia and leukopenia. However, these events were confined to induction and were not observed during consolidation or maintenance. Myelosuppression has also not been reported in other clinical studies of ATO in patients with advanced hematologic malignancies²³ or solid tumors.²⁴

In addition to the high clinical and molecular response rates, many of the remissions seemed to be quite durable. The estimated RFS rate at 18 months was 56%. However, these results are somewhat confounded because 11 patients underwent either an allogeneic or autologous transplant in remission after induction or consolidation with ATO. Of note, 10 of 21 patients who received only ATO are alive and without evidence of recurrence. If censored at the time of BMT, the 18-month estimate RFS is 58%. When data from the 12 patients in the United States pilot trial were added to those of the 40 patients in this study, the Kaplan-Meier estimates of 18-month RFS (50%) and overall survival (66%) rates were similar to estimates obtained with the smaller sample size. The data suggest that BMT may not have meaningfully contributed to RFS observed in these patients.

Most patients (86%) in this trial had PML breakpoints that yielded either the long or short isoform of PML/RAR-. The clinical significance associated with various breakpoints remains unclear. In this study, we observed no appreciable difference in these subgroups with respect to CR rate or overall survival. However, in contrast to other studies, the 12-month estimated RFS associated with the short form was slightly higher.

Several adverse events associated with the use of ATO in patients with APL warrant careful monitoring and management. In this study, 10 patients (25%) developed signs and/or symptoms clinically suspicious for APLS that prompted physicians to initiate therapy with dexamethasone. In the majority of cases, therapy with ATO was not interrupted, and the symptoms improved. Twenty patients (50%) experienced leukocytosis. However, in all of these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leukapheresis was not required. Prognostic indicators were analyzed that might identify patients at risk for developing APLS or hyperleukocytosis, that might suggest a different management strategy, but none have emerged to date.

An important adverse event related to ATO treatment is prolongation of the QT/QTc interval on ECG. Two patients in this study had at least one on-study ECG showing an absolute prolonged QT interval greater than 500 msec (16 patients had one QTc interval > 500 msec). One woman had a QT interval of 580 msec on her ECG on her last day of induction therapy temporally associated with a single brief episode of torsade de pointes, which was asymptomatic and resolved spontaneously. A number of other drugs commonly used in oncology are also known to directly prolong the QT interval or affect the metabolism of agents with this potential.

Recently, other investigators have reported episodes of nonsustained ventricular tachycardia in patients being treated with ATO for relapsed APL.²⁵ Ventricular arrhythmias, other than the episode of torsades discussed above, were not observed in patients on this study, and these events have not been reported by Chinese investigators with clinical experience in using ATO. Nonetheless, vigilant monitoring, particularly during induction, is warranted. Careful attention to electrolyte balance, particularly potassium and magnesium levels, and limiting the concomitant use of other agents known to prolong QT intervals or induce ventricular arrhythmias are strongly recommended. ECG monitoring for QT prolongation is recommended at regular intervals, and the drug should be withheld if the QT interval is greater than 500 msec.

Peripheral neuropathy has long been associated with the use of arsenic. Seventeen of the 40 patients treated experienced this reaction. Although several patients had baseline neuropathy related to prior treatment, the incidence of neuropathy was similar to that reported elsewhere.¹⁶ This event required the discontinuation of the drug in only one patient. The neuropathic symptoms were generally mild (grade 1) and resolved after the end of ATO treatment.

In summary, the results of this study establish ATO as a highly effective therapy for patients with APL despite prior therapy with retinoids and chemotherapy. Moreover, responses have proven to be durable for at least 18 months in over half the patients who achieved CR. ATO is a particularly important advance because few treatment options have been available for patients who experience relapsed disease. Considering the high molecular remission rate, ATO also provides an option for stem-cell collecting and future autologous transplant, which may also be curative in the event of later relapse.^26,27 ATO may be associated with potentially serious adverse effects. However, considering the curative potential, the minimal degree of myelosuppression, and the severity of the underlying illness, these risks, which seem readily manageable, seem to be far outweighed by patient benefit.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CA87441 from the National Cancer Institute, Bethesda, MD, and a grant from the Lymphoma Foundation, and by PolaRx Pharmaceuticals, Inc, New York, NY.

We are indebted to Dr Steven Hirshfeld of the Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, Rockville, MD, for his guidance and advice. We thank all the collaborating investigators, research and clinical nurses, and study assistants involved in this trial. In particular, we acknowledge the contributions and assistance of Suzanne Chanel, Carolyn Paradise, Amy Eisenfeld, Peter Maslak, Joseph Jurcic, Ellen Bermin, Mark Weiss, Katherine Cathcart, Mark Heaney, Dan DeAngelo, Ilene Galinsky, Steven Sallan, Susan McKenzie, Raymond Ho, Danielle Camastrata, Monica Kwari, Farah Daftary, Christine Chang, Kristy Watkins, Vicky Soto, Kathleen Dugan, Marge Bluso, Kathleen Shannon-Dorcy, and Lynn Rundhaugen.

	NOTES

 
S.L.S. is a Mortimer J. Lacher fellow.

Presented in part at the Annual Meeting of the American Society of Hematology, San Francisco, CA, December 1-5, 2000.

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Submitted February 28, 2001; accepted May 4, 2001.

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