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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3678-3684
Selective Ablation of Acute Myeloid Leukemia Using Antibody-Targeted
Chemotherapy: A Phase I Study of an Anti-CD33 Calicheamicin
Immunoconjugate
By
E.L. Sievers,
F.R. Appelbaum,
R.T. Spielberger,
S.J. Forman,
D. Flowers,
F.O. Smith,
K. Shannon-Dorcy,
M.S. Berger, and
I.D. Bernstein
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle; the Departments of Pediatrics and Medicine, University
of Washington, Seattle, WA; the Department of Hematology and Bone
Marrow Transplantation, City of Hope National Medical Center, Duarte,
CA; and Wyeth Ayerst Research, Radnor, PA.
 |
ABSTRACT |
Leukemic blast cells express the CD33 antigen in most patients with
acute myeloid leukemia (AML), but this antigen is not expressed by
hematopoietic stem cells. We conducted a study to determine whether
normal hematopoiesis could be restored in patients with AML by
selective ablation of cells expressing the CD33 antigen. In a dose
escalation study, 40 patients with relapsed or refractory CD33+ AML were treated with an immunoconjugate (CMA-676)
consisting of humanized anti-CD33 antibody linked to the potent
antitumor antibiotic calicheamicin. The capacity of leukemic cells to
efflux 3,3'-diethyloxacarbocyanine iodide (DiOC2) was used
to estimate pretreatment functional drug resistance. Leukemia was
eliminated from the blood and marrow of 8 (20%) of the 40 patients;
blood counts returned to normal in three (8%) patients. A high
rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most
common toxic effect. Two patients who were treated at the highest dose
level (9 mg/m2) were neutropenic >5 weeks after the last
dose of CMA-676. These results show that an immunoconjugate targeted to
CD33 can selectively ablate malignant hematopoiesis in some patients
with AML.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
PATIENTS WITH refractory or recurrent
acute myeloid leukemia (AML) have a dismal prognosis. Toxic effects
associated with additional conventional chemotherapy are often
life-threatening, and few patients achieve a complete remission (CR). A
therapy that more specifically targets leukemia is likely to be safer, and possibly more effective than current nonspecific chemotherapeutic agents.
During hematopoietic development, stem cells capable of establishing
long-term multilineage hematopoiesis give rise to progenitors with
diminished self-renewal capacity and a greater degree of differentiation. During this process, hematopoietic cells express distinct cell surface antigens that are also expressed by their malignant counterparts. Some of these antigens (eg, CD33) are present
on maturing normal hematopoietic cells and on AML cells, but not on
normal hematopoietic stem cells.1-4 These findings raise
the possibility that an antibody can be used to deliver cytotoxic agents to selectively ablate malignant myeloid and immature normal cells while sparing normal stem cells.
The myeloid cell surface antigen CD33 is an attractive target for this
approach, as it is expressed on AML blast cells from about 90% of
patients.2,3 CD33 also may be expressed by most, if not
all, of the malignant precursors in at least some cases of AML, as
precursor cells that lack CD33 from some patients give rise to normal
granulocyte/monocyte precursors in a marrow long-term culture
system.5,6 The possibility that anti-CD33 antibody could be
used to deliver a cytotoxic agent to malignant cells was suggested by
studies showing rapid saturation of leukemic blast cells in peripheral
blood and marrow after intravenous administration of approximately 5 mg/m2 radioiodinated anti-CD33 antibodies.7,8
Further, in vitro studies showed rapid internalization of the antibody
by the target cell.9 To test the concept of selective
ablation of malignant hematopoiesis and to evaluate the safety of this
approach, we treated patients with relapsed or refractory AML with
escalating doses of CMA-676, antibody-targeted chemotherapy consisting
of an engineered human anti-CD33 antibody linked with the potent antitumor antibiotic calicheamicin.10
| |
MATERIALS AND METHODS |
Patients.
Patients were required to have AML that was either refractory to
standard therapy or that had recurred after remission. Patients whose
leukemia relapsed after a marrow or peripheral blood stem cell
transplant were required to have had successful engraftment (platelets
 20 × 103/µL without transfusion and
an absolute neutrophil count [ANC] 500/µL) before relapse. Each
prospective patient underwent a bone marrow aspirate to confirm that
morphologic evidence of leukemia was present and to document leukemic
blast cell surface expression of the CD33 antigen. Patients were
required to have a Karnofsky performance status 60%, a white blood
cell count  30 × 103/µL, serum creatinine 2.0
mg/dL, and serum bilirubin 1.5 mg/dL, to have recovered from toxic
effects of previous antineoplastic therapy, and to be able to give
informed consent. Patients were ineligible if they had previously
received anti-CD33 antibody treatment, were pregnant or nursing, had a
prior malignancy, or had active symptomatic central nervous system
leukemia or an uncontrolled life-threatening infection.
Recombinant humanized anti-CD33-calicheamicin drug conjugate.
CMA-676 was produced and provided for clinical study by Wyeth-Ayerst
Research (Radnor, PA) under an Investigational New Drug Application.
Celltech Therapeutics, Ltd (Slough, UK) transformed the
murine-derived IgG1 monoclonal antibody (p67.6)8 into an engineered human IgG4 antibody (hP67.6), which was then conjugated to
the enediyne calicheamicin10 using a Nac-gamma linker
molecule (Hamann et al, manuscript in preparation).
Calicheamicin binds in a sequence-specific manner to the minor groove
of DNA and induces double-strand DNA breaks that ultimately induce cell
death.10 Specific cytotoxicity of CMA-676 against
CD33+ leukemia cells was documented in colony-forming
assays in vitro, against leukemic cell lines in vitro, and in vivo in
nude mice (data not shown).
Protocol design.
In this open, single-arm, phase I dose escalation study, CMA-676 was
administered to patients with relapsed or refractory CD33+
AML at two study sites. Informed consent was obtained from all patients
in accordance with the institutional review boards of the participating
institutions. In a single-dose tolerance study with CMA-676 in
chimpanzees, an intravenous dose of 0.5 mg/m2 (twice the
initial clinical dose of 0.25 mg/m2) was well tolerated,
with no compound-related clinical signs of clinical pathology changes
evident throughout a 15-day postinfusion period (data not shown). In
previous clinical studies in patients using radiolabeled mP67.6
antibody,8 dose-limiting toxicity was not observed at doses
up to and including 17 mg/m2 antibody trace-labeled with
131I. However, saturation of CD33 binding sites was
achieved at a dose level of approximately 5 mg/m2. Hence,
at least three patients were treated at each dose level of CMA-676 with
up to three infusions of 0.25, 0.5, 1, 2, 4, 5, 6, and 9 mg protein per
square meter of body surface area. If one or two of the first three of
these patients experienced a grade III toxic effect (see below), three
additional patients were to be treated at the same dose. The maximum
tolerated dose was defined as one dose level below the dose that was
associated with unacceptable CMA-676-related toxicity. Dose-limiting
toxicity was defined as severe marrow hypoplasia of more than 6 weeks
duration after a single dose of CMA-676, one grade IV study
drug-related toxic effect or two grade IV toxic conditions of ambiguous
relationship to CMA-676.
CMA-676 was administered as a single 2-hour intravenous infusion. All
cytokines or chemotherapeutic agents were withdrawn before treatment.
Patients without leukemic progression and drug-related, nonhematologic
toxic effects judged to be grade III or less could receive one or two
subsequent cycles of CMA-676 with at least 14 days between cycles.
Patients were treated with acetaminophen 650 mg orally and
diphenhydramine 25 to 50 mg intravenously 15 to 30 minutes before
infusion of CMA-676. Patients who achieved a CR and subsequently had a
relapse of their leukemia could receive retreatment at the dosage level
being evaluated at the time of retreatment.
Patient evaluation.
Patients were examined for acute toxic effects in accordance with the
World Health Organization toxic effect grades. Peripheral blood
specimens were obtained to study the pharmacokinetics of CMA-676, to
evaluate for evidence of CMA-676 binding to CD33-positive cells, and to
measure the effects of CMA-676 on hematologic variables and serum
chemistry parameters. A complete blood count was obtained before the
initial dose and each day for 2 weeks thereafter, or until recovery of
granulocyte and platelet levels to the prestudy levels. Hepatic and
renal function were measured before initial dose administration, three
times per week thereafter, and on day 28 after the last dose of
CMA-676.
Bone marrow aspirates were obtained before initial dose administration
with CMA-676 on days 1, 7, and 14 of each treatment cycle and on days
1, 7, 14, and 28 of the last treatment cycle. All marrow specimens were
examined by light microscopy to estimate cellularity and to detect any
residual leukemic blast cells. Patients with progressive disease were
removed from the study. Disappearance of leukemia was defined as the
absence of peripheral blasts and the presence of 5% blast cells in
the bone marrow by light microscopic evaluation. CR was defined as
disappearance of leukemia in addition to an ANC >1,500/µL and a
platelet count >100 × 103/µL, without transfusions.
Laboratory investigations.
Total hP67.6 antibody concentrations in plasma samples were determined
using an enzyme-linked immunosorbent assay (ELISA). Formation of
antigen-antibody CMA-676 bound to peripheral blood mononuclear cells
was detected by flow microfluorimetry. Cells were incubated with
biotinylated goat monoclonal anti-human IgG4, followed by
avidin-fluorescein isothiocyanate. Cells incubated with
avidin-fluorescein isothiocyanate alone comprised the negative control.
The saturation percentage was defined as 100 times the ratio of the
fluorescence intensity of patient mononuclear cells (minus the negative
control) over the maximum fluorescence intensity (minus the negative
control). Maximum achievable saturation was determined by incubating
patient mononuclear cells from the same time point with saturating
amounts of CMA-676 in vitro before the addition of the anti-human
IgG4 antibody. The efflux of
3,3'-diethyloxacarbocyanine iodide (DiOC2) from
CD33-positive blast cells was measured as an indication of functional
drug efflux.11 Serum samples obtained from each patient
before CMA-676 administration, on day 7 after initial doses,
and on days 7, 14, 21, and 28 after administration of the final
dose of CMA-676 were analyzed for anti-hP67.6 (humanized mouse
antibody) or anti-calicheamicin/linker immune response by ELISA.
| |
RESULTS |
Patient characteristics.
A total of 40 patients with relapsed or refractory AML were enrolled.
Patient characteristics are shown in Table
1. Three to eight patients were treated at each of eight dose levels of CMA-676: 0.25, 0.5, 1, 2, 4, 5, 6, and 9 mg protein per square meter of
body surface area.
Nonhematologic toxicity.
The most frequently reported drug-related adverse events are summarized
in Table 2. The most commonly observed
nonhematologic side effect, a syndrome of fever and chills, occurred in
32 of 40 (80%) patients beginning 2 to 4 hours after the start of the 2-hour intravenous infusion. The syndrome was limited to grade I to II
except in three instances. Grade III fever and chills occurred in two
patients after receiving CMA-676 at 6 and 9 mg/m2,
respectively. The third patient (COH-008) who had asymptomatic hypotension and was receiving low-dose dopamine before CMA-676 administration, had a temperature >40°C and reversible
symptomatic hypotension 5 hours after the initiation of the CMA-676
infusion at 6 mg/m2. Another patient (FH-007) developed
transient shortness of breath in association with retreatment with
CMA-676 after his leukemia relapsed, presumably caused by an immune
reaction to CMA-676 (see below). Nausea and fatigue were among other
less frequent toxic effects thought possibly related to CMA-676.
Reversible, possibly drug-related hepatic transaminase elevations from
5 to 10 times the normal range were observed in eight patients (Table
2). One additional patient with documented concurrent cholelithiasis
had a pretreatment alanine serum transaminase (AST) of 13 U/L that increased to 304 U/L 4 days after receiving the first dose of
CMA-676, and rapidly declined to the normal range within a week.
Immediately before receipt of the second dose of CMA-676, her AST
increased to 1,804 U/L and again rapidly returned to the normal range.
In this patient, elevated enzymes were thought to be primarily due to
the patient's cholelithiasis. No patient had a drug-related bilirubin
elevation of greater than five times the normal range. No significant
study drug-related central nervous system, cardiac, or renal toxic
effects were observed. With regard to nonhematologic toxic
effects, a maximum tolerated dose was not reached, and
dose-limiting toxicity was not observed.
Hematologic toxicity.
Because most patients had concurrent neutropenia and thrombocytopenia
caused by active AML at the time of enrollment, whether hematologic
toxic effects were directly attributable to CMA-676 was often
impossible to ascertain. However, among nine patients with neutrophil
counts >1,500 cells/µL before treatment, eight had severe
neutropenia (<200 cells/µL) within 14 days of CMA-676 infusion
regardless of dose level. Figure 1 shows
the decline and recovery of the neutrophil count from a representative
patient during the 2 weeks after each infusion. Although dose-limiting toxicity was not formally observed, two of seven evaluable patients had
prolonged drug-related neutropenia after treatment at a dose level of 9 mg/m2. The first patient (FH-023) required 38 days to
recover to an ANC >500 cells/µL after the third dose of CMA-676,
and the second patient (COH-015) did not achieve neutrophil recovery
and died of sepsis 50 days after receiving the second dose
(Table 3).
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| Fig 1.
Relationship between hematologic parameters and time for
a representative patient (FH-012) who received CMA-676 at 4 mg/m2 per dose. Arrows denote infusions of CMA-676. All
counts refer to peripheral blood counts.
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Elimination of blast cells from the peripheral blood and bone marrow.
Blast cells were identified on a peripheral blood smear in 31 (78%)
patients before infusion of CMA-676. One week after treatment, 22 (71%) of these patients had fewer blast cells and in six (19%) of
these patients, blast cells had completely disappeared from the
peripheral blood smears. The proportion of patients who experienced reductions in peripheral blast cell counts was highest among those who
received higher doses of CMA-676. Reduced numbers of peripheral blast
cells were observed in 10 of 11 patients treated with either 6 or 9 mg/m2 of CMA-676 compared with 12 of 20 patients treated at
dose levels from 0.25 to 5 mg/m2.
Morphologic evidence of leukemia within the bone marrow (>5% blast
cells) was seen in all patients before treatment. After treatment with
one to three doses of the drug conjugate, 8 (20%) of 40 patients had
<5% leukemic blast cells on morphologic examination of bone marrow
aspirate and biopsy specimens (Table 3). In one of these patients
(FH-007), blast cells were also eliminated from the bone marrow on a
second occasion after retreatment with CMA-676 (see below).
Recovery of normal blood counts.
Recovery of blood neutrophil counts to greater than 1,500 cells/µL
was observed in five of eight patients who had <5% leukemic blasts
by morphologic examination of bone marrow aspirate and biopsy specimens
(Table 3). In addition, three of these five patients achieved normal
platelet counts. The first patient, FH-007, achieved a complete
hematologic and cytogenetic remission 7 days after receiving the third
dose of CMA-676 at 1 mg/m2. After 140 days, local leukemia
recurrences in his femurs and iliac wing were identified by magnetic
resonance imaging and confirmed by surgical biopsy. He was treated with
conventional chemotherapy and local radiation and achieved another CR.
He experienced relapse again 293 days after completing the first course
of CMA-676, was treated with two additional doses of CMA-676 at 6 mg/m2, and his leukemia disappeared again for 56 days. His
leukemic cells expressed CD33 at the time of each of his relapses.
The second patient, FH-012, achieved a complete hematologic and
cytogenetic remission 35 days after the third dose of 4 mg/m2. In an attempt to consolidate his remission, he was
given an infusion of lymphocytes from his bone marrow donor 40 days
after infusion of the third dose of CMA-676. He remained in CR for 214 days after treatment until testicular and central nervous system relapses occurred.
The third patient, FH-023, received three doses of CMA-676 at 9 mg/m2, and his ANC recovered to >1,500/µL 42 days after
he received the third dose of CMA-676. His platelet count reached a
peak of 36 × 103/µL 23 days after he received the
third dose of CMA-676, but the patient subsequently became platelet
transfusion-dependent for approximately 3 weeks. Evidence of antibody
on the patient's platelet surfaces was documented. Megakaryocytes were
present and platelet maturation appeared normal on examination of the
marrow aspirate. In an attempt to consolidate his remission, he was
given an infusion of lymphocytes from his bone marrow donor 54 days
after receiving the third dose, and his platelet count eventually rose
to >100 × 103/µL 106 days later. At the time of
this report, he remained in continuous cytogenetic and hematologic
remission >623 days after receiving the third dose of CMA-676.
Pharmacokinetics and saturation of peripheral CD33 sites.
Detectable plasma levels of CMA-676 were identified in all patients
immediately after intravenous administration and the half-life of
CMA-676 was estimated to be 38 ± 21 hours for patients receiving the 9 mg/m2 dose. Figure 2
shows the relationship between the total number of cell surface CD33
sites and CD33 sites bound with CMA-676 in peripheral blood cells for a
characteristic patient over time. Thirty minutes after infusion, CD33
sites were almost completely saturated with CMA-676. Twenty-four hours
after administration, fewer CD33 sites and bound drug conjugate were
evident, suggesting internalization of the CD33-immunoconjugate
complex. In the patients who received the maximum dose (9 mg/m2), a median of 92.2% (range, 79.2% to 100%) of CD33
binding sites on peripheral blood blast-sized cells were bound by the
drug conjugate 30 minutes after infusion of a dose. Peak CD33
saturation levels in relation to treatment response are shown in
Fig 3. These results show that saturation
of sites is not, by itself, sufficient to insure treatment response.
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| Fig 2.
Relationship between total number and CMA-676-bound CD33
sites on peripheral blood cells in a characteristic patient over time.
The solid line represents the number of CD33 sites available for
binding to CMA-676 as estimated by the maximal fluorescence intensity
obtained by incubating an aliquot of cells in vitro with excess
CMA-676. The dashed line represents the fluorescence intensity of bound
CMA-676 to cell surfaces. Near-complete saturation is seen 30 minutes
after the start of the infusion.
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| Fig 3.
Relation of leukemic blast cell dye efflux and maximum
CMA-676 saturation of CD33 sites on peripheral blood blast-sized cells
with treatment response (N = 36). ( ) Denotes patients who had
<5% leukemic blasts by morphologic examination of bone marrow
aspirate and biopsy specimens after treatment. ( ) Denotes patients
whose leukemia did not disappear. Peripheral blood samples from four
patients were unavailable for analysis. The efflux from the dominant
population is represented in the five instances in which efflux
profiles were bimodal. *Leukemic cell specimens from patients FH-023
and FH-024 were 2 and 3 days old, respectively, at the time of efflux
measurement. Because blast-sized cells from each showed
uncharacteristically low DiOC2 loading, obtained efflux
values may underestimate true efflux.
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Response correlation with drug efflux.
We evaluated the efflux of DiOC2 from pretreatment leukemic
blast cells as a measure of functional drug resistance. Figure 3 shows
the relationship between measured leukemic blast cell drug efflux
levels and saturation of CD33 sites with response. Elimination of
leukemia appeared to be correlated with a low capacity by leukemic
blast cells to extrude DiOC2. For example, of the 30 patients evaluated with the assay in whom doses of CMA-676 saturated
>75% of available CD33 sites on peripheral blood blast cells, 8 of
17 patients with leukemic blast cells that showed 40 channel numbers
of DiOC2 efflux had <5% blasts in the bone marrow after
treatment. In contrast, none of the 13 patients with leukemic blast
cells expressing >40 channel numbers of DiOC2 efflux entered remission.
Immune responses.
No humoral responses to anti-hP67.6 antibody were detected. A humoral
response to the calicheamicin-linker complex was documented in one
patient after receiving a third dose of CMA-676 and in a second patient
during retreatment with CMA-676.
| |
DISCUSSION |
This study describes the use of an antibody-drug conjugate capable of
targeting and safely eliminating target leukemic cells in vivo.
Disappearance of AML cells from the bone marrow and peripheral blood of
eight patients with complete restoration of normal hematopoiesis in
three patients was observed after treatment with antibody-targeted chemotherapy. These results show that eradication of CD33+
AML cells can allow restoration of normal hematopoiesis by remaining CD33 precursors. For some patients, we hypothesize
that the CD33 precursors are predominantly or
completely nonmalignant. This is based on findings that, in some cases
of AML, the clonal abnormality originated in either a committed
progenitor or an early multipotent cell whose proliferative expression
is mainly restricted to the granulocyte/monocyte lineage.12
Because selection of CD33 precursors from some of
these leukemias allowed normal hematopoietic growth in culture, the
malignant clone may involve few, if any, CD33
precursors.5,6
In other cases of AML, particularly in older patients, the clonal
abnormality has been found in both the erythroid and myeloid lineages,
showing malignant involvement of multipotent precursors.12 In addition, clonal karyotypic abnormalities have been found in primitive precursor cells from some AML patients.13,14 It
is conceivable that normal hematopoiesis could also be restored in these patients even if a substantial portion of CD33
precursors were malignant because normal precursors express at least a
short-term proliferative advantage. While this explanation appears
inconsistent with the observed leukemic growth in a immunodeficient mouse model after infusion of isolated primitive (CD34+
CD38) precursors from human leukemia
specimens,15 it is consistent with the report that a
patient undergoing allogeneic transplantation who was inadvertently
given an infusion of donor AML cells initially recovered with normal
donor hematopoiesis.16
Each patient whose blood counts returned completely to normal had
experienced relapse after an allogeneic bone marrow transplant (data
not shown). Therefore, it is possible that a graft-versus-leukemia effect eliminated the remaining CD33 leukemic cells
after elimination of the bulk of AML cells. However, in a recently
initiated phase II study of CMA-676, normal hematopoiesis was restored
in some patients who had not received a transplant.17 Molecular remissions have been observed in a portion of patients with
acute promyelocytic leukemia who received unconjugated anti-CD33 antibody (HuM195).18 Although an AML patient with 8%
blasts in his bone marrow achieved a CR with HuM195 given at a
supersaturating dose, complete clinical responses have not been
reported in patients with large tumor burdens.19 Hence, the
observed elimination of leukemia after treatment with CMA-676 was not
likely due to antibody-mediated effects alone.
Myelosuppression was the most clinically significant adverse event. The
severe marrow hypoplasia observed in two patients who received 9 mg/m2 is consistent with depletion of CD33+
hematopoietic progenitor cells and with the time required for CD33 cells to restore hematopoietic
function.20 To prevent prolonged neutropenia, two (instead
of three) scheduled doses of CMA-676 at 9 mg/m2 are
generally administered in the phase II study. In that study, a third
dose can only be administered if bone marrow cellularity is >15%
after two doses of CMA-676. The 9-mg/m2 dose level was
selected for the phase II study because consistently >75% of CD33
sites were saturated at this dose and nonhematologic toxicity was not
considered to be dose-limiting in the phase I study.
Modest and reversible hepatic transaminase elevations and
hyperbilirubinemia were observed in some patients who received CMA-676 at high dose levels. Only two patients developed a positive immune response to the calicheamicin-linker complex after receipt of several
doses of CMA-676, in contrast with findings in other studies in which
frequent immune responses occurred after administration of
immunoconjugates containing either murine-derived monoclonal antibodies
or naturally occurring toxins.7
Only patients with relapsed or refractory disease were eligible for
this clinical trial. In this setting, the leukemia cells in many
patients expressed functional drug resistance that may have prevented
killing by the drug conjugate (a known substrate of p-glycoprotein,
data not shown). This was suggested by the correlation between clinical
response and low levels of dye efflux by leukemic blast cells. This
observation raises the possibility that the complete response rate
might be improved by using agents that specifically block
p-glycoprotein activity (eg, cyclosporine) in combination with CMA-676.
In summary, we found that CMA-676 selectively ablated malignant
hematopoiesis in some patients with refractory or relapsed AML and that
therapy was associated with few toxic effects. Studies are currently
underway to evaluate this agent in pediatric and elderly populations.
It is anticipated that CMA-676 will be evaluated in the setting of
newly diagnosed and minimal residual disease. Because CMA-676 was
associated with few nonhematologic toxic effects, it potentially could
be studied as a replacement for anthracycline in combination
chemotherapy regimens and combined with existing conditioning regimens
for hematopoietic stem cell transplant.
| |
ACKNOWLEDGMENT |
We are indebted to Drs Dan Schochat, Dennis Parenti, Geoff Yarrangton,
Phillip Hamann, and Lois Hinman for efforts in initiating and
supporting this work; Dr Irene Georgieff, Melissa Auen, and Rosalane
Dacanay for excellent technical assistance; and Penny Hoeltzel for
providing superb editorial comments.
| |
FOOTNOTES |
Submitted August 19, 1998; accepted January 29, 1999.
Supported by Wyeth-Ayerst Research. E.L.S. is supported by an
American Cancer Society Clinical Oncology Career
Development Award. I.D.B. is an American Cancer Society Clinical
Research Professor.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Presented in part at the 1997 Annual Meeting of the American Society of
Clinical Oncology, Denver, CO; the 1997 European Cancer Conference,
Hamburg, Germany; and the 1997 Annual Meeting of the American Society
of Hematology, San Diego, CA.
Address reprint requests to E.L. Sievers, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D5-280, PO Box 19024, Seattle, WA
98109-1024; e-mail: esievers{at}fhcrc.org.
| |
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TOP
ABSTRACT
INTRODUCTION