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Annals of Oncology 12 549-555.

2001 2001 Khmer Academic Publishers Printed m the Netherlands

Original article
Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors
F. R. Dunphy, T. L. Dunleavy, B. R. Harrison, C. L. Cantrell, J. L. Visconti, S. M. Pincus, J. M. Richart & P. J. Petruska
Division of Hemutology and Oncology, Department of Internal Medicine, Saint Louis Umversit\ Health Science: Center, Si Loui.s. Missouri, USA

Summary Background Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximumtolerated dose of topotecan in combination with paclitaxel and carboplatin Patients and methods Patients with advanced cancer and performance status ECOG < 2 The starting dose was paclitaxel 175 mg/m 2 day 1, carboplatin AUC 6 0 day 1, and topotecan 0 5 mg/m 2 daily day 1-5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued Results Fifty-one patients were entered, men women ratio 30 . 21 Dose-limiting toxicity (DLT) for the early sequence was

neutropenia at doses paclitaxel mg/m~/carboplatin AUC5/ topotecan mg/m 2 (PCT) 175/5/0 75 for four to five days DLT for the late sequence was neutropenia at PCT doses of 175/5/ I 0 for four days G-CSF 5 ug/kg subcutaneously starting day 6 permitted further topotecan dose escalation After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1 25 for four days Forty-six patients were evaluable for response and of those, there were thirteen partial responses Conclusions The late sequence resulted in less toxicity and was better tolerated The early sequence maximum-tolerated dose (MTD) was 175/6/0 5 for five days The late sequence MTD was PCT 175/5/0.75 for five days The late sequence MTD with G-CSF was 175/5/1 0 for four days The recommended phase II PCT dose is the late sequence 175/5/1 0 for four days with G-CSF Key words' carboplatin, hycamtin, paclitaxel, phase I, Taxol, topotecan

Introduction Paclitaxel acts by promoting assembly of microtubules and stabilizing them against depolymerization. Clinical trials have shown it to be clinically active in breast, lung, and other solid tumors using both 24-hour and shorter (1-3 hour) intravenous infusions [1, 2]. Brief neutropenia is the principal toxicity [3] Carboplatin causes cell death by forming irreversible DNA-DNA intrastrand crosslinks. It has shown activity in the treatment of ovarian, testicular, head and neck, and lung cancer [4-7]. The combination of paclitaxel and carboplatin has been observed to be well tolerated and highly active in the treatment of a wide range of solid tumors including lung, ovarian, breast, head and neck, esophageal, and urothehal cancers [8-14] Major toxicities include cumulative anemia, thrombocytopenia, and neuropathy. Few three-drug combinations using these two agents have been developed recently. Topotecan is a semisynthetic analog of the alkaloid camptothecin which inhibits topoisomerase I It has been demonstrated to be active for ovarian and small-cell lung cancer when administered as second-line and front-line

therapy [15-19]. Other malignancies in which topotecan has significant antitumor activity include untreated nonsmall cell lung cancer, head and neck cancer, and leukemia [20-23]. In all studies, the dose-limiting toxicity was myelosupression Because of the different mechanism of action, topotecan seemed a promising third drug to add to the pachtaxel-carboplatin combination. There is laboratory evidence that in vitro synergy exists among paclitaxel, platinum, and topotecan, with late schedule having improved cytotoxicity. Chou et al [24] identified anti-tumor synergy between two- and three-drug combinations of topotecan, cisplatin, and paclitaxel against in vitro human teratocarcinoma cell lines In human solid tumor cell lines, the combination of cisplatin and topotecan revealed schedule dependent synergistic toxicity with cisplatin followed by topotecan as the most active sequence [25, 26]. Synergy was partly explained by the increased retention of platinumDNA intrastrand cross-links in the presence of topotecan [26] In March 1997, a phase I clinical trial was initiated using the combination of paclitaxel, carboplatin, and topotecan in patients with incurable solid tumors. The

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Table 1 Drug schedule Early sequence Day Pachtaxel Carboplatin Topotecan 1 2 / / / 3 4 5 Late sequence 1 2 3 4 5
Treatment plan

/ / / / /

toxicities and maximum-tolerated dose (MTD) were identified.

Patients and methods


Patient criteria Eligible patients had biopsy proven incurable malignancy They had either failed prior standard therapy or had tumors for which standard therapy was ineffective Other eligibility criteria included age greater than 16. Eastern Cooperative Oncology Group performance status 2 or less, estimated life expectancy at least 12 weeks, and measurable or cvaluable disease Adequate hematological, hepatic, and renal function were required and were defined respectively as neutrophil count greater than or equal to 1500/ul, platelets greater or equal to 100,000/ul, serum bihrubin less than or equal to 1 25 times upper limit normal (ULN). SGOT less than or equal to 2 5 times ULN, and serum creatinine less than or equal to 1 5 times ULN Patients were required to be greater than four weeks from prior radiotherapy or chemotherapy There were no limits on amount of prior chemotherapy lnehgibility criteria included peripheral neuropathy greater than or equal to grade 3 Patients were entered consecutively after giving informed consent in accordance with the Institutional Review Board at Saint Louis University Health Sciences Center

Three patients were treated with each sequence at each dose level, minimum six patients per level, using a phase 1 design If a patient experienced a DLT, then an additional three patients were treated with that sequence before dose escalating to the next level (Table 1) DLTs were defined as any of the following events occurring during the first course of treatment absolute neutrophil count nadir <500/(il more than five days or febrile neutropenia, platelet nadir < 25,000, any other grade 3-4 nonhematologic toxicity (excluding alopecia and untreated vomiting) Dose escalation decisions were based on to\icity observations of the first course The maximum-tolerated dose (MTD) was defined as the highest dose level producing DLTs in less than one-third of patients Once MTD and DLT were determined, the dose was escalated to identify MTD and DLT with the addition of granulocyte colony-stimulating factor (G-CSF) Patients were treated until complete response, disease progression, or unacceptable toxicity was observed Treatment continued for two courses after maximal response All patients received pachtaxel, followed by topotecan, then followed by carboplatin The pachtaxel dose was fixed and topotecan was dose escalated in sequential cohorts During conduct of the trial, two dose modifications were implemented to adjust for cytopenia At level 3, carboplatin was reduced to AUC 5, and at level 4, topotecan schedule was shortened to four days (Table 2) Treatment courses were repeated every 21 days The sequence of drug administration was reversed with each course in each patient The sequence was altered in each subsequent patient enrolled Early sequence administered pachtaxel day 1, carboplatin day I, and topotecan five consecutive days (days 1-5) Late sequence administered pachtaxel day 5, carboplatin day 5, and topotecan five consecutive days (days 1-5) (Table 1) Pachtaxel 175 mg/m 2 was administered intravenously over one hour The calculated dose was mixed in 250 cc normal saline, or in an adequate volume to ensure pachtaxel concentration not > 1 2 mg/cc Carboplatin dose was calculated using an AUC of 6 as described by Calvert et al [27] Glomerular filtration rate (GFR) was calculated by the Cockcroft-Gault mathematical formula GFR = [(140 - age) x weight in kilograms/(72) x (serum creatinine)] x 0 85 female or 1 0 male

Table 2 Dose, sequence. and hematological toxicity Level Number of courses Pachtaxel (mg/m 2 ) Carboplatin (AUC) Topotecan (mg/m 2 ) (days) 0 5 (5) 0 75(5) 0 75(5) 0 75(4) 0 75(4) 10 (4) 10 (4) 1 25(4) Early sequence U/DLTQ 4/anc 0 pit 1 6/anc 5 pit 4 3/anc2 pit 1 4/anc 2 pit 1 3/anc0 pit 1 NA NA NA Late sequence

G
_

/DLT
3/anc 1 pit 1 5/anc2 pit 2 4/anc 1 pit 1 6/anc0 pltO

26

175 175 175 175 175 175 175 175

36

32

10

42

14

+
NA

0/NA 3/anc 2 pltO 7/anc 1 pit 1 3/anc 2 pltO

14

20

NA

10

NA

Abbreviations AUC area under the curve. DLT - cycle one dose limiting toxicity, G - granulocyte colony-stimulating factor, anc - absolute neutrophil count, pit platelets. NA - not applicable " Number of patients

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Table 3 Patient characteristics Characteristics Patients entered Age (years) Mean Range Sex Male Female Cancer diagnosis Bile duct Breast Colon Head/Neck Hepatic Lung Melanoma Mesothelioma Osteosarcoma Pancreatic Rectal Renal Unknown primary Prior chemotherapy Chemotherapy-naive Early/late sequence (number of courses) Number of patients 51 54 28-78 30 21 2 3 10 6 1 9 6 2 1 4 2 3 2 31 20 76/1 18

It was mixed in 100 cc normal saline and administered over one hour intravenously Topotecan was mixed in 100-150 cc of dextrose in water and infused intravenously over 30 minutes The starting dose was 0 5 mg/m 2 , and was escalated as shown in Table 2 Prior to paclitaxel administration, patients were premedicated with dexamethasone 20 mg p o 12 hours and 4 hours prior and 20 mg intravenously 30 minutes prior, cimetidine 300 mg intravenously and diphenhydramine 50 mg intravenously 30 minutes prior Granisetron I mg intravenously was administered as premedication daily before each dose of topotecan After reaching MTD, G-CSF 5 ug/kg/day was prophylactically administered subculaneously starting day 6 (24 hours after last topotecan dose) through day 19 or until the neutrophil count was above 10,000/ul Pretreatment evaluation included a complete medical history and physical examination Interval history, physical, blood chemistries, and hematologic profile were evaluated before each course A complete blood count was obtained after completing each course, three times per week, until blood counts normalized Additionally, if absolute neutrophil count fell below 500/ul, complete blood count was obtained daily

Results Between March 31, 1997 and August 17, 1998, 51 patients were enrolled. Patient characteristics are listed in (Table 3) A total of 194 courses were administered through six dose escalations (Table 2). Through the first four dose levels the number of courses for early/late sequence were similar 76/74, respectively The late sequence was exclusively administered for forty-four additional courses at levels 5 and 6. There was a mean 3.8 courses administered per patient (range 1-14). Eight patients received one course, thirteen received two

courses, six received three courses, ten received four courses, and fourteen received more than four courses. Using the early sequence, a total of 76 courses were administered through 4 dose levels At the second level, dose-limiting neutropenia and thrombocytopenia were observed in five of six (83%) and four of six patients (66%), respectively The first dose modification, implemented at level 3, reduced carboplatin to AUC5, after which was observed unacceptable dose-limiting neutropenia and thrombocytopenia in two of three (66%) and one of three patients (33%), respectively The second dose modification, implemented at level 4, shortened topotecan duration to four days. However, there remained unacceptable dose-limiting neutropenia and thrombocytopenia observed in two of four (50%) and one of four patients (25%), respectively Dose-limiting neutropenia was eliminated after adding G-CSF. However doselimiting thrombocytopenia persisted in one of three patients (33%) The clinical relevance of schedule was neutropenic fever observed in 37% of courses using the early sequence versus 7% using the late sequence. Early sequence dose escalation with growth factor was not explored after the fourth level due to dose limiting thrombocytopenia The late sequence was deemed safer to explore at higher levels because at level 4- there was no need for hematopoietic growth factor and no observed neutropenic or thrombocytopenic DLT (Table 2). Using the late sequence, dose-limiting neutropenia was not observed at the fourth level. 108 courses were administered through five levels at which point neutropenic DLT was observed in two of three patients (66%). After adding G-CSF, neither neutropenia or thrombocytopenia was dose limiting until the sixth level where neutropenic DLT was observed in two of three patients (66%) (Table 2). Dose-limiting thrombocytopenia was observed at the second dose level using both early and late sequences After carboplatin was reduced to AUC5 at level 3, thrombocytopenia was eliminated from the late sequence, but persisted with the early sequence. Furthermore, at level 4, thrombocytopenia persisted after the early sequence in spite of reduced topotecan duration from five days to four days. However, after the late sequence, no dose limiting thrombocytopenia was observed at level 4. Furthermore, with the late sequence, thrombocytopenia was not dose-limiting throughout the remainder of the dose escalation (Table 2). The clinical relevance of schedule impacted on platelet transfusion requirements. Twice as many platelet units were transfused after the early sequence (58 units) compared to after the late sequence (27 units). Two patients with pancreatic cancer were observed to have prolonged grade 4 thrombocytopenia. Both had normal bone marrow cellulanty, hepatic metastases, and splenomegally Both underwent splenectomy. In one, thrombocytopenia resolved and she received eight additional courses. The second received no further therapy due to intrapentoneal carcinomatosis, disease progression, and death two weeks post spleenectomy due to disease progression.

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Table 4 Non-haematologic toxicity Level Number of Nausea/vomiting (% of courses) Grade 0-2 1 26 36 31" 56 34 8b 96 94 97 100 94 100 Grade 3-4 4 6 Neuropathy (% of courses) Grade 0-2 92 96 97 100 94 89 Grade 3-4
Breast

Table 5 Response Diagnosis Number of evaluable patients 3 10 6 I 7 6 2 1 4 2


3 2 47

Number of patients

PR
1

SD
2 4 3 1 2 2

PD 6 3
1 3

2
3 4 5 6
u

3
0 6 0

8 4 3 0 3 11

One course inevaluable due to neutropenic death Two courses inevaluable due to one cardiac death and one neutropenic death and paralytic ileus

Colon Head/neck Hepatic Lung Melanoma Mesothehoma Osteosarcoma Pancreatic Rectal Renal Unknown primary Total

4 3

2 1 1 1 13 19

1 1 15

The mean hemoglobin before starting this therapy was 12.0 (range 8.9-15 3) All patients experienced anemia It was severe (grade 34) in 56 of 194 (29%) of courses. A total of 168 units of packed red blood cells were administered over 194 courses. Schedule was also clinically relevant regarding packed red blood cell transfusions Eighty-six units were transfused during early sequence versus fifty-one units during late sequence. Nonhematologic toxicity was generally mild, mostly limited to nausea/vomiting and neurosensory Severe (grade 34) was not dose limiting at any level. In five patients neuropathy was grade 3 and reversible One patient at level 6 was scored as grade 4 neuropathy, paralytic ileus, died of sepsis and neutropenia (Table 4) Two patients experienced acute bleeding requiring red cell transfusions (one acute gastric ulcer while taking excessive aspirin, one suffered trauma with resultant soft tissue hemorrhage) Grade 3 hypersensitivity reactions to paclitaxel were observed in 2 of 194 (1%) of courses. Three patients experienced unexpected early death (Table 4) At level 3, one died of neutropenic sepsis nine days after receiving the second course of therapy He was also receiving steroids for brain metastases. Two deaths were observed at level 6. One patient with ischemic heart disease died of an acute myocardial infarction eleven days after the third course. One died of neutropenic sepsis nine days after the first course Treatment efficacy The treated cohort represented a heavily pretreated group of patients. Thirty-one of fifty-one (61%) had received and failed prior chemotherapy Twenty-two of fifty-one (43%) had been treated with prior radiotherapy Responses were observed in. rectal, lung, pancreatic, melanoma, renal, breast, and unknown primary cancers. Prolonged duration of stable disease was observed in mesothehoma Partial response was observed in three of six malignant melanomas The mean duration of response in these three melanoma patients was six months (range 4-11). All three were chemotherapy-naTve and one had received prior immunotherapy. In the forty-seven with evaluable tumors, thirteen

Abbreviations PR - partial response, SD - stable disease, PD progressive disease

(28%) had a partial response Analysis of prior chemotherapy in the 13 responders revealed that the majority were chemotherapy-naive: 10 (77%) were chemotherapynaive and 3 (23%) had received prior chemotherapy. Response could not be evaluated in relation to sequence, through level 4, because the sequence of drug administration was reversed with each course in each patient. However, at level 5 and level 6, exclusively the late sequence was administered. Two thirds of patients treated at levels 5 and 6 had received prior chemotherapy six often (60%) at level 5 and two of three (66%) at level 6. Tumor response showed no relationship to dose: Level 1, 2 of 7 (28%), level 2, 3 of 10 (30%), level 3, 2 of 6 (33%); level 4, 4 of 12 (33%), level 5, 1 of 10 (10%), level 6, Oof 2(0%) (Table 5).

Discussion Single-agent topotecan has been shown to be active in relapsed cancers. Two human trials have shown topotecan to have equivalent activity to paclitaxel, the best salvage chemotherapy, for platinum refractory ovarian cancer, and equivalency to cyclophosphamide, doxorubicin, and vincnstine in previously treated small cell lung cancer [15,28]. Combining topotecan with other cytotoxics has been problematic due to marrow suppression. Three trials of cisplatin plus topotecan observed delayed administration of cisplatin induced less marrow suppression. Miller et al. [29] conducted a phase I trial of topotecan administered intravenously daily for five days with cisplatin administered on day 1. Dose-limiting toxicity was neutropenia and the identified MTD was topotecan 1 mg/m 2 for five days and cisplatin 75 mg/m 2 day 1 with G-CSF support. The author reported 30% incidence of dose-limiting neutropenia. A subsequent phase II trial reported an unacceptable septic death rate of 25% and further

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Table 6 Reports of topotecan combinations Author [reference] Percentage prior Ch/RT/Ch + RT MTD T (mg/m2) Miller [29, 30] Rowinsky [31] O'Reilly [32] Jacobs [33] Miller [30] Lilenbaum [34] Lynch [35] Hochster [36] Herben [37] Hainsworth [38] Dunphy" 32/8/5 12/24/24 86/0/5 0/0/0 0/0/0 42/7/31 0/0/0 89/11/0 0/0/0 84/NA/NA 61/43/33 1 0 75 1 25 1 NA 1 1 03 03 0 75 1 75 5Cb b 5Cb
b

Limiting dose C (mg/m2) 75 50 135 135 NA 230 175 135 110 135 175 P (mg/m2) T (mg/m2 ) 1 0 75 1 5 1 25 1 NA NA 04 04 1 1 25 75 5Cb b 5Cb
h

GCSF ( + /-) P (mg/m2) + 135 135 230 NA NA 135 110 135 175 + + + + + + + +

Drug sequence

DLT

C (mg/m2) 100 75

C-.T

ANC

C^T T-C P-T T^P T-+P P-.T


P->T

ANC. Pit 0 ANC. Pit ANC. Pit


ANC ANC 0 0 ANC ANC Pit ANC

P-vr
P-T

P. C - T P. C b - T T - P . Cb

Abbreviations GCSF - granulocyte stimulating factor, DLT - dose limiting toxicity, + - administered. - - not administered, C - cisplatin. Cb - carboplutin, T - topotecan, P - paclitaxel, ANC - absolute neutrophil count. Pit - platelet. Ch - chemotherapy. RT - radiotherapy. Ch + RT - chemotherapy plus radiotherapy " Data from present study b Carboplatin AUC dose

accrual was stopped [30] Rowinsky et al. [31] was the first to report that sequence affected toxicity. The author conducted a trial of topotecan for five days plus alternating sequences of cisplatin administered either on day 1 or day 5. Results showed less hematologic toxicity when cisplatin was administered after the last day of topotecan (Table 6). Six human trials of paclitaxel plus topotecan have been conducted. Two trials investigated 24-hour schedules of paclitaxel 135 mg/m 2 combined with topotecan 0.751.25 mg/m 2 daily x 5 days The authors were unable to dose escalate topotecan above 1.0-1.25 mg/m 2 due to dose-limiting neutropenia, thrombocytopenia, and septic deaths. Marrow suppression was not dependant on drug sequence [32, 33]. Three trials investigated three-hour schedules of paclitaxel 175-230 mg/m 2 day 1 followed by topotecan 1 mg/m 2 for five days with G-CSF support At paclitaxel dose 230 mg/m 2 , one trial observed unacceptable dose-limiting neutropenic deaths which resulted in trial termination [30, 34]. At 175 mg/m 2 , one trial is ongoing and reported grade 4 neutropenia in 38% [35]. One trial reported dose-limiting neutropenia after paclitaxel 135 mg/m 2 day 1 and topotecan as a prolonged low-dose infusion 0.4 mg/m 2 daily x 14 days [36] (Table 6). Two trials of paclitaxel, a platinum, and topotecan have reported marrow suppression as dose limiting which prevented significant dose escalation of topotecan. Both trials administered paclitaxel and a platinum on the first day followed by topotecan for three to five days Herben et al. [37] investigated paclitaxel as 24-hour continuous

infusion and observed dose-limiting neutropenia at the initial dose level. The MTD of paclitaxel, cisplatin, and topotecan was identified at doses of 110/75/0.3 mg/m 2 , respectively, with G-CSF started on the sixth day. Hainsworth et al. [38] investigated paclitaxel as one-hour intravenous infusion. The author observed dose-limiting thrombocytopenia at the initial topotecan dose. The MTD of paclitaxel, carboplatin, topotecan without G-CSF was identified at doses of 135 mg/m 2 /5 AUC/ 0.75 mg/m 2 , respectively (Table 6). The present study demonstrated that drug sequence had a significant influence on marrow suppression The late sequence induced less neutropenia and thrombocytopenia The MTD of the late sequence without growth factor was observed at doses of paclitaxel 175 mg/m 2 , carboplatin AUC 5, and topotecan 0 75 mg/m 2 intravenously for five consecutive days The addition of G-CSF allowed dose escalation of topotecan to 1.0 mg/m 2 for four consecutive days. Topotecan duration was shortened to four days at level 4 in an attempt to eliminate neutropenia observed with the early sequence. It is unknown whether a less protracted 4 day topotecan duration with a higher, 1 mg/m 2 , daily dose (dose intensity 4 mg/m 2 / week) would be more advantageous than a more protracted five-day regimen with a lower, 0.75 mg, daily dose (dose intensity 3 75 mg/m 2 /week). Compared to other studies, dose intensity of topotecan was escalated more than three-fold higher than the schedule reported by Herben et al [37], and 25% higher than the schedule reported by Hainsworth et al [38]. Furthermore, the dose intensity of paclitaxel was 1.6 and 1.3 fold higher than that

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of Herben [37] and Hainsworth's [38] trials, respectively Both Herben [37] and Hainsworth's [38] designs administered paclitaxel and a platinum before topotecan (Table 6). Furthermore, the present study population had a higher proportion of heavily pretreated patients compared to Herben, and more combined chemotherapy plus radiotherapy compared to Hainsworth (Table 6). The present study corroborates Rowinsky's [31] observation that administration of a platinum compound after the last day of topotecan induced less myelotoxicity. It was hypothesized that cisplatin or carboplatin administration before topotecan lead to subclinical glomerular injury with resultant decreased clearance of topotecan and marrow suppression. It is possible paclitaxel sequence, early versus late, could affect the observed difference in toxicity However, disputing this hypothesis are published results, which observed no difference in topotecan pharmacokinetics or pharmacodynamics when administered concurrent with paclitaxel [32] Even though the proportion of responders appeared lower for the late sequence exclusively administered at levels 5 and 6, compared to the earlier dose levels with alternating sequences, two thirds of the patients treated at the higher levels had received prior chemotherapy and would potentially have chemotherapy resistance. Even though the late sequence theoretically may be mechanistically inferior according to in vitro cell line data [24-26], this laboratory observation may not translate into a human model. Furthermore, with the addition of hematopoietic growth factor, 25% more topotecan was successfully administered at MTD, level 5, compared to level 4 without growth factor In the present study, delayed administration of paclitaxel and carboplatin enabled successful addition of topotecan without severe myelosupression. Topotecan doses achieved were equivalent to therapeutic doses used in doublet or single-agent trials. The recommended phase II dose and schedule for further evaluation is the late sequence with GCSF support administering paclitaxel 175 mg/m" on day 4, carboplatin AUC5 on day 4, and topotecan 1.0 mg/m 2 for four consecutive days, day 1-4. Phase II trials of this combination are planned for lung cancer and warranted in ovarian plus other malignancies
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Acknowledgement Supported in part by protocol developmental grant from SmithKline Beecham Pharmaceuticals

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Received 25 July 2000, accepted 22 December 2000 Correspondence to F Dunphy, MD Saint Louis University Health Sciences Center Division of Hematology and Oncology Department of Internal Medicine 3635 Vista Avenue at Grand Blvd PO Box 15250 St Louis, MO 63110-0250 USA E-mail dunphyfr(H)aol com