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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1237-1247
Phase I Study of 131I-Anti-CD45 Antibody Plus
Cyclophosphamide and Total Body Irradiation for Advanced Acute Leukemia
and Myelodysplastic Syndrome
By
Dana C. Matthews,
Frederick R. Appelbaum,
Janet F. Eary,
Darrell
R. Fisher,
Lawrence D. Durack,
T. Edmond Hui,
Paul J. Martin,
David Mitchell,
Oliver W. Press,
Rainer Storb, and
Irwin D. Bernstein
From the Division of Clinical Research, Fred Hutchinson Cancer
Research Center, and the Departments of Pediatrics, Medicine and
Radiology, University of Washington, Seattle, WA; and Pacific Northwest
National Laboratories, Richland, WA.
 |
ABSTRACT |
Delivery of targeted hematopoietic irradiation using radiolabeled
monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the
biodistribution of 131I-labeled anti-CD45 antibody and
determined the toxicity of escalating doses of targeted radiation
combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body
irradiation (TBI) followed by HLA-matched related allogeneic or
autologous transplant. Forty-four patients with advanced acute leukemia
or myelodysplasia received a biodistribution dose of 0.5 mg/kg
131I-BC8 (murine anti-CD45) antibody. The mean ± SEM
estimated radiation absorbed dose (centigray per
millicurie of 131I) delivered to bone marrow
and spleen was 6.5 ± 0.5 and 13.5 ± 1.3, respectively, with liver,
lung, kidney, and total body receiving lower amounts of 2.8 ± 0.2, 1.8 ± 0.1, 0.6 ± 0.04, and 0.4 ± 0.02, respectively. Thirty-seven
patients (84%) had favorable biodistribution of antibody,
with a higher estimated radiation absorbed dose to marrow and spleen
than to normal organs. Thirty-four patients received a therapeutic dose
of 131I-antibody labeled with 76 to 612 mCi
131I to deliver estimated radiation absorbed doses to liver
(normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was
level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute
myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia
(ALL), 3 survive disease-free 19, 54, and 66 months
posttransplant. We conclude that 131I-anti-CD45 antibody
can safely deliver substantial supplemental doses of radiation to bone
marrow (~24 Gy) and spleen (~50 Gy) when combined with conventional
CY/TBI.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
BONE MARROW transplantation offers the
best chance of cure for patients with advanced acute leukemia and
myelodysplastic syndrome (MDS), but the high doses of
total body irradiation (TBI) and/or chemotherapy used to kill leukemic
cells cause systemic toxicities in the majority of patients. Despite
this high-dose therapy, many patients relapse after transplantation,
especially those in relapse at the time of the procedure. Efforts to
decrease the incidence of relapse have included intensification of
cytoreductive therapy, either by increasing the TBI dose or adding
chemotherapy, but most attempts have resulted in higher
transplant-related mortality.
Two studies in particular have demonstrated the marked dose effect of
radiation for myeloid leukemias. In studies of patients with acute
myeloid leukemia (AML) in first remission1 or
chronic myeloid leukemia (CML) in chronic
phase2 with randomization between 12 or 15.75 Gy TBI
combined with 120 mg/kg cyclophosphamide (CY), the higher radiation
dose resulted in a lower relapse rate. For AML, the relapse rate was
12% after 15.75 Gy, compared with 35% after 12 Gy. For CML, the
relapse rate was 0% after 15.75 Gy, compared with 25% after 12 Gy.
However, in both studies, the higher radiation dose was associated with
greater regimen-related toxicities and mortality, with no difference in
long-term disease-free survival between the 2 radiation doses. These
studies led to the hypothesis that, if radiation could be targeted
directly to sites of leukemic involvement in hematopoietic tissues,
with relative sparing of normal organs, the radiation sensitivity of
leukemia could be exploited and survival might be improved without
increased toxicity.
Monoclonal antibodies labeled with radioisotopes have been used to
deliver targeted radiation in both preclinical3-12 and clinical13-31 studies, with varying success. Hematologic
malignancies may provide an optimum setting in which to use this
approach, given their relative radiosensitivity and the comparative
ease with which circulating antibody can gain access to cells in marrow and spleen. To maximize potential antibody binding sites in these tissues for patients in remission or relapse, we sought a target antigen expressed by as many cells as possible, including those of both
myeloid and lymphoid origin whether normal or malignant. When a
monoclonal antibody is labeled with 131I, the 0.8-mm path
length of the beta energy of this isotope will result in radiation
delivery to all cells in a tissue provided most cells distributed
throughout the tissue bind the antibody. We therefore chose to target
CD45, the most broadly expressed of the known hematopoietic antigens.
CD45 is a tyrosine phosphatase expressed in various isoforms between
180 and 220 kD. It is expressed on virtually all leukocytes, including
myeloid and lymphoid precursors in bone marrow and mature lymphocytes
in lymph nodes.32 More than 90% of AML samples and most
acute lymphoblastic leukemia (ALL) samples express this
antigen.33,34 Surface expression averages 200,000 copies
per cell, and the antigen does not internalize after antibody
binding.9
Preclinical experiments in both mice35 and nonhuman
primates36 demonstrated that 131I-anti-CD45
antibody could deliver relatively specific radiation to hematopoietic
tissues, with 2 to 3 times more radiation delivered to marrow, up to 12 times more to spleen, and 2 to 8 times more to lymph nodes as compared
with liver, lung, or kidney. We thus initiated a phase I dose
escalation study combining 131I-anti-CD45 antibody with CY
and 12 Gy TBI in patients with advanced AML, ALL, and MDS receiving
matched related or autologous stem cell rescue. The goals of this study
were to determine the biodistribution of 131I-anti-CD45
antibody in patients with leukemia in remission and relapse, to define
factors influencing antibody biodistribution, and to determine the
toxicity of targeted hematopoietic irradiation when combined with a
conventional preparative regimen. Our initial report of the first 23 patients entered on study demonstrated that the majority had successful
targeting of radiation to hematopoietic tissues and that up to 7 Gy of
radiation delivered by antibody to the normal organ receiving the
highest dose (liver) was well tolerated when combined with
CY/TBI.29 We now report the completion of the study,
demonstrating that 84% of 44 patients undergoing biodistribution
studies had good localization of antibody and that a maximum dose of
10.5 Gy delivered by radiolabeled antibody to the liver could be
tolerated in addition to CY and 12 Gy TBI.
| |
MATERIALS AND METHODS |
Patient selection.
Patients referred to the Fred Hutchinson Cancer Research Center
(Seattle, WA) for treatment of AML or ALL beyond first remission or for
advanced MDS (refractory anemia with excess blasts, refractory anemia
with excess blasts in transformation, or chronic myelomonocytic leukemia) were eligible for this study. Patients in relapse with peripheral blast counts in excess of 5,000/µL were eligible only if
their blast count could be brought below that level by treatment with
hydroxyurea. Patients were excluded if they had major organ dysfunction, were seropositive for human immunodeficiency virus (HIV),
were allergic to mouse protein or to iodine, or had pre-existing human
antimouse antibody (HAMA). Stem cell sources were either bone marrow
harvested from HLA-identical family members, cryopreserved autologous
marrow, or cryopreserved autologous peripheral blood stem cells.
Purging of autologous marrow with 4-HC37 or monoclonal antibodies and complement38 was allowed. Patients were
informed of the potential risks and benefits of participating in this
phase I study and signed a consent form approved by the Human Subjects Committee of the University of Washington and the Institutional Review
Board of the Fred Hutchinson Cancer Research Center.
Antibody production, purification, and radiolabeling.
The BC8 hybridoma (developed and provided by Dr Claudio Anasetti of the
Fred Hutchinson Cancer Research Center) secretes a murine IgG1 antibody
reactive with all CD45 isoforms. The initial lot of antibody was
derived from hybridoma culture supernatant produced in hollow fiber
bioreactors by Brunswick (San Diego, CA) and was purified by saturated
ammonium sulfate precipitation and ion exchange chromatography.
Subsequent lots were produced at the Fred Hutchinson Cancer Research
Center Biologics Production Facility. Hybridoma supernatant was
harvested from an Applikon bioreactor (Applikon Instruments, Shiedam,
The Netherlands), filtered, concentrated, pooled, and purified using
anion exchange and protein A affinity chromatography. This was followed
by virus inactivation using low pH treatment, SP-Sepharose cation
exchange chromatography, and diethylaminoethyl (DEAE) anion batch
processing. Processed antibody was 0.2-µm sterile filtered and stored
at 4°C. Twenty-nine of the first 32 patients also received
nonspecific (negative control) antibodies DT or LS (produced and kindly
provided by IDEC Pharmaceuticals, San Diego, CA). These antibodies are
murine IgG1 antibodies reactive with idiotypes expressed by B-cell lymphomas.
The BC8 antibody was labeled with 131I (specific activity,
8.0 Ci/mg; New England Nuclear, Boston, MA), and DT or LS antibodies were labeled with 125I (specific activity, 17.2 Ci/mg; New
England Nuclear) using the chloramine-T method and were purified and
tested as previously described.39,40 The immunoreactivity
of all 131I-labeled BC8 antibody doses was required to be
at least 80% of that of an 125I-trace-labeled
control aliquot of BC8 antibody.
Determination of antibody biodistribution and radiation absorbed
dose.
Patient serum was first tested for HAMA using an enzyme-linked
immunosorbent assay (ELISA) as previously described.39 For patients in relapse, the expression of CD45 on leukemic blasts was
determined by BC8 antibody with indirect immunofluorescence assays
using a fluorescein isothiocyanate (FITC)-labeled goat-antimouse-IgG+M F(ab')2 second-stage reagent (Tago, Inc, Burlingame,
CA) or by HLe-1 anti-CD45 antibody directly labeled with Peridinin
chlorophyll protein (Becton Dickinson, San Jose, CA). Relapse patients
were eligible if the CD45 expression on the blast cell population was clearly above that of negative control antibody. Patients in remission did not require leukemic cell phenotyping.
Organ volumes (liver, lungs, spleen, and kidney) were calculated from
chest and abdominal computed tomography (CT) or magnetic resonance
image (MRI) scans.40 Organ localization scans
(technetium-99m liver-spleen, lung, and kidney) were used in the first
16 patients but were subsequently omitted because organs were easily
localized (lungs), readily visualized after 131I-BC8
administration (liver and spleen), or demonstrated little uptake of
radionuclide (kidney). Thyroid uptake of free 131I was
blocked by oral Lugol's solution (strong iodine solution).
Biodistribution infusions consisted of 0.5 mg/kg BC8 antibody labeled
with 5 to 10 mCi 131I. For 29 patients, this was combined
with 0.2 mg/kg DT or LS antibody labeled with 2 to 5 mCi
125I. Patients were premedicated with diphenhydramine at 25 to 50 mg intravenously (IV), hydrocortisone at 50 to 100 mg IV, and acetaminophen at 650 mg orally. The infusion rate for BC8 antibody varied from 5 to 10 mg/h, as tolerated, with most patients receiving a
steady rate of 7.5 mg/h. Diphenhydramine doses were repeated as needed
up to every 2 hours, and other medications (meperidine for chills and
lorazepam for nausea) were administered as needed for symptoms. If
patients developed more severe symptoms, such as throat tightness or
shortness of breath, the infusion was slowed or stopped until the
symptoms improved.
Blood samples, which were obtained hourly during antibody infusion and
0, 30, 60, 90, and 120 minutes afterwards and then daily for 3 to 5 days, were analyzed for BC8 and nonspecific (where administered)
concentrations. Blood clearance curves were fit to determine the
long-term clearance half-time and where obvious, the early phase,
rapid-clearance half-time. A bone marrow biopsy was obtained the day
after infusion (ie, 16 to 24 hours, where hour 0 was the end of
infusion). The sample was weighed and counted against a weighed
reference aliquot of the expected dose to calculate the percentage of
injected dose per gram (% ID/g). For some patients, the biopsy
occurred 42 to 48 hours after infusion. The marrow radioactivity
clearance curves obtained by gamma camera imaging were scaled for
quantitation using the bone marrow biopsy 131I uptake
values. For patients receiving 125I-labeled anti-idiotype
control antibody, the marrow localization index (LI) was calculated
with reference to a concomitant serum sample: LI = (Specific % ID/g
[marrow]/Specific % ID/g [serum])/(Nonspecific % ID/g
[marrow]/Nonspecific % ID/g [serum]).
Quantitative gamma images were collected with a dedicated GE 400 AT
large-field-of-view camera (General Electric Medical
Systems, Milwaukee, WI) with a high energy collimator at hour 0 (end of infusion) and then daily for 2 to 3 days
(Fig 1). Regions of interest (spleen,
liver, lungs, kidneys if visible, and at least 2 marrow sites) were
imaged using a 180° opposing view quantitative planar technique.40 Results were compared with an 131I
imaging standard for quantitation and were corrected for whole-body thickness attenuation and radioactive decay. The time-activity curves
for each source organ were integrated to obtain residence times.
Because organ dose is roughly inversely proportional to mass,
corrections were made for patient weight and organ mass when actual
weights were known from CT or MRI. This correction was
made by multiplying the observed source-organ residence time by the
ratio of the defined reference man or woman organ mass to the known
organ mass. Radiation absorbed doses were then estimated using methods
consistent with those recommended by the Society of Nuclear Medicine's
special committee on Medical Internal Radiation Dose,41,42
as previously described.43 The marrow clearance curve was
scaled by correcting the biopsy-determined % ID/g of 131I-BC8 by a multiplication factor of 2, because antibody
cannot bind to the trabecular bone and fat that make up approximately half of the total biopsy weight.44,45 For dosimetry
purposes, patient marrow volumes were normalized to the MIRD model
values of 1,120 grams for an adult male and 1,050 grams for an adult female. For consistency, the same S values42 were used for
all marrow dose calculations throughout the study. Statistical
comparisons between disease type or stage and between anti-CD45 and
control anti-iodiotype antibody used the Student's t-test
(SPSS for Windows 8.0; SPSS Inc, Chicago, IL).
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| Fig 1.
131I-anti-CD45 antibody localization.
Posterior 131I-BC8 images of patient with AML in relapse
(UPN 9013) immediately after trace-labeled antibody infusion (A and C)
and 40 hours after infusion (B and D). Accumulation of labeled antibody
is shown in the ribs, vertebral column, ilium, pelvis, and sacrum, all
marrow-rich regions of the axial skeleton.
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Therapy.
Patients in whom the biodistribution study of 131I-BC8
showed that the target organs of marrow and spleen would receive a
greater estimated radiation absorbed dose than liver, lung, or kidney were said to have favorable biodistribution and were eligible for a
therapy dose of antibody. Patients were retested for HAMA the day
before administration of the therapy dose and were treated only if the
test was negative. The therapy dose was labeled with the amount of
131I calculated to deliver a specified dose to the normal
organ receiving the highest radiation absorbed dose. The starting dose
level delivered to this normal organ by 131I-BC8 antibody
was 3.5 Gy, and the dose was escalated in groups of not less than 3 patients. The dose was escalated by 1.75 Gy if 0 of 3 or not more than
1 of 6 evaluable patients developed grade III (life-threatening) or IV
(fatal) regimen-related toxicity46 at the previous dose level.
The therapy dose, administered at the same rate as the biodistribution
dose, was administered on day  14 of the transplant regimen. This
dose, generally 9 days after the trace-labeled biodistribution dose,
was administered in lead-lined radiation isolation rooms, where
patients remained until the total body 131I activity was
less than 30 mCi (usually 3 to 6 days). Patients were then admitted to
a marrow transplant ward, where they received CY 60 mg/kg IV on days
8 and 7, followed by TBI administered in daily 2 Gy
fractions from days 6 to 1. TBI was delivered at a dose
rate of 7.36 cGy/min from 2 opposing 60Co sources. Stem
cells were infused on day 0. Cyclosporine and methotrexate were used
for graft-versus-host disease (GVHD) prophylaxis in allogeneic
recipients.47 All patients received routine posttransplant supportive care. Results are current as of September 15, 1998.
| |
RESULTS |
Biodistribution studies.
Forty-four patients were entered on study and received a
biodistribution dose of trace 131I-labeled BC8 antibody.
The median age was 38 years (range, 16 to 55 years). Thirty-one had AML
(9 remission and 22 relapse), 10 had ALL (5 remission and 5 relapse),
and 3 had MDS (Table 1).
Grade I-III side effects were experienced by 75% of patients receiving
the biodistribution dose of 131I-BC8 antibody. Most common
were shaking chills and nausea or vomiting. Fever greater than
38.5°C occurred in 4 patients. Grade I-II hypotension developed in
11 patients and generally responded to IV crystalloid administration.
Side effects usually developed after the first hour of infusion and
responded to slowing of the infusion and treatment with meperidine,
diphenhydramine, and lorazepam. Twenty-five percent of patients
experienced respiratory symptoms including wheezing or sensations of
tightness in the chest or throat. These symptoms usually improved after
the antibody infusion was temporarily slowed or halted and
diphenhydramine ± hydrocortisone was administered, but in 3 patients, the antibody infusion was stopped after a total dose of 0.2 mg/kg because of these symptoms. In 2 of these patients, antibody
infusion rates were greater than 7.5 mg/h when they developed symptoms.
After the initial 21 patients, antibody infusion rates were limited to
7.5 mg/h. Biodistribution data from the 3 patients receiving 0.2 mg/kg
did not differ from the patients receiving 0.5 mg/kg and are included
in the data analysis reported below.
We wished to determine whether a preclearing dose of cold
antibody administered before the labeled antibody could decrease hepatic uptake of radiolabeled circulating white blood cells by causing
sequestration of cells by unlabeled antibody, as observed in previous
preclinical studies.48 We therefore administered the first
7.5 mg of antibody unlabeled or cold antibody in 10 patients after
initial experience in the first 9 patients demonstrated that
circulating white blood cells were saturated, and the white blood cell
count had fallen to near-minimum levels after this antibody dose.
However, there was no difference in the hour 0 liver uptake of
131I or the biological half-time (t1/2 of
131I in the liver) or in estimated radiation absorbed doses
to liver or marrow between the nonprecleared and the precleared group
(data not shown). Therefore, these 2 groups were combined for analysis.
The average peak (ie, end of infusion) concentration of BC8 antibody in
plasma was 0.0061% ± 0.003% ID/g. In 26 patients in whom
comparison between BC8 and nonspecific antibody was possible, the peak
concentration of BC8 antibody in plasma was 0.0057% ± 0.003%
ID/g, which is significantly lower than the peak concentration of
control antibody, 0.021% ± 0.006% ID/g (P < .001). This
presumably reflects the rapid antigen-specific binding of the anti-CD45
antibody. Twenty of these patients demonstrated a discernible rapid
initial disappearance phase of BC8 antibody (t1/2 = 1.4 ± 0.8 hours). This was followed by a slower disappearance phase
(t1/2 = 26.7 ± 12.5 hours) that was similar to that of the
nonspecific antibody (t1/2 = 27.3 ± 13.3 hours). There were no
differences in peak BC8 antibody concentration or clearance between
groups of patients with AML or ALL in remission or relapse.
Pharmacokinetic and biodistribution results for marrow, spleen, and
liver are summarized in Table 2. The
average peak concentration of 131I-BC8 antibody was 0.028% ± 0.012% ID/g for marrow, 0.060% ± 0.032% ID/g for spleen,
and 0.013% ± 0.004% ID/g for liver. For patients receiving
125I-anti-idiotype control antibody, the average marrow
antibody LI was 42.2 ± 29.0. The average marrow retention half-time
of 131I-BC8 antibody was 44.2 ± 14.7 hours. Patients
with AML in relapse, including the 3 patients with MDS, had somewhat
higher initial antibody uptake in marrow (0.030% ID/g) as compared
with those with AML in remission (0.025% ID/g, P = .21) and
longer retention of radioiodine in marrow (51.4 v 35.5 hours,
P < .001). There was also a trend towards a higher
LI for patients with AML in relapse (47.0 ± 41.0) as compared with
those with AML in remission (33.1 ± 18.6, P = .34). There
were no differences seen in initial uptake, LI (data not shown), or
half-life among patients with ALL in remission or relapse or AML in
remission. Cells from patients with AML and ALL in relapse did not have
appreciable differences in CD45 expression as determined by flow
microfluorimetry (data not shown).
Estimated radiation absorbed doses.
The mean estimated radiation absorbed doses calculated from the
biodistribution dose of trace-labeled antibody are shown in Fig 2. The mean radiation absorbed doses
(centigray per millicurie of 131I
administered ± SEM) were 6.5 ± 0.5 for marrow, 13.5 ± 1.3 for spleen, 2.8 ± 0.2 for liver, 1.8 ± 0.1 for lung, 0.6 ± 0.04 for kidney, and 0.4 ± 0.02 for the total body. Thus, the mean
ratio of estimated radiation dose was 2.3 for the marrow as compared with the liver, 3.6 for the marrow as compared with the lung, and 11 for the marrow as compared with the kidney. The liver was the normal
organ receiving the highest estimated radiation absorbed dose, except
in 1 patient with an unusually long retention of radioiodine in the
lungs. Overall, favorable biodistribution was seen in 37 of 44 patients
studied (84%).
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| Fig 2.
Estimated radiation absorbed doses per millicurie of
131I administered for (A) all patients, (B) patients with
AML or MDS, and (C) patients with ALL. Values are the means ± SD.
Estimated radiation absorbed doses to marrow were calculated using
published methods.41,42 Recently proposed marrow S values
incorporated in MIRDOSE3 software60 would result in lower
marrow doses than noted here. AML-Remission group includes a patient
in marrow remission with leukemia cutis. *P = .04 for
difference between marrow remission and relapse in patients with
AML/MDS; **P = .001 for difference between marrow remission
and relapse in patients with AML/MDS.
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Patients with AML in relapse (including MDS) had higher estimated
radiation absorbed doses to marrow (7.8 v 4.9 cGy/mCi,
P = .04) and to spleen (16.5 v 8.3 cGy/mCi, P = .001) as compared with patients with AML in remission. There was no
significant difference in the estimated radiation absorbed dose to the
liver between patients with active disease and those in remission, and therefore the ratio of radiation delivered to target as compared with
normal organs was higher for both marrow (2.7 v 2.0, P = .053) and spleen (5.4 v 3.3, P = .012) for patients
with AML in relapse. However, even for patients in relapse, there was
appreciable variability in estimated radiation dose to marrow and
spleen resulting from variation in initial uptake, half-time, or both.
For patients with ALL, there were no differences between estimated
radiation dose to marrow, spleen, or nontarget organs between patients
in remission or relapse (data not shown).
Although the liver was the normal organ receiving the highest radiation
dose per millicurie of 131I in all but 1 patient, there was
great variability between patients in the estimated radiation absorbed
dose to liver, ranging from 1.7 to 7.1 cGy/mCi 131I. No
correlations between clinical features such as disease state, type of
leukemia, or number of circulating blasts and the estimated liver dose
were apparent in this study.
Seven patients did not have favorable biodistribution of
131I-BC8 antibody, with a lower estimated radiation dose to
marrow or spleen than to liver or lung. Two were in remission and 5 were in relapse at the time of study. Whereas 3 had relatively low marrow cellularity (50% of normal), the other 4 had cellularity ranging from 100% to 200% of normal. The average weight of the 7 patients with unfavorable biodistribution was greater than that of the
patients with favorable biodistribution (105.4 v 76.0 kg, P < .001), and the patients with unfavorable biodistribution
were overweight (actual body weight divided by ideal body weight) by a
higher percentage than those with favorable biodistribution (141%
v 107%, P < .02). Of 15 patients weighing 89 kg or
more, 7 had unfavorable biodistribution. In contrast, all 29 patients weighing less than 89 kg had favorable biodistribution. Because the
antibody dose administered was calculated on actual as opposed to ideal
body weight, obese patients received a higher average dose of antibody
in relationship to circulating blood volume and to total CD45 antigen.
We found a negative correlation (Pearson correlation = .372,
P = .018) between weight and the percentage of injected dose
per gram of marrow at biopsy.
An eighth patient had favorable biodistribution of antibody to marrow
and spleen but had a low concentration of 131l-BC8 antibody
in a skin biopsy from a site of leukemia cutis and thus was not treated
on study. The remaining 2 patients that were not treated with
radiolabeled antibody included 1 that was positive for HAMA on the day
before the planned therapy (8 days after receiving the biodistribution
dose) and 1 that received only 0.2 mg/kg BC8 antibody and had an
estimated radiation absorbed dose of 1.3 cGy/mCi for liver. This
patient, whose antibody dose had been limited by side effects, was not
treated because the amount of 131I required to deliver dose
level 5 (830 mCi) would have resulted in a specific activity of more
than 50 mCi/mg, a level previously shown to damage the immunoreactivity
of BC8 antibody. Patients not receiving a therapy dose of
131I-BC8 antibody were treated with alternative marrow
transplant preparative regimens.
Therapy, toxicities, and engraftment.
Thirty-four patients proceeded to the transplant phase of the study and
were treated with the same dose of BC8 antibody received during the
biodistribution study labeled with the amount of 131I
activity calculated to deliver an estimated radiation dose to the
normal organ receiving the highest dose (ie, the liver) of 3.5 (dose
level 1) to 12.25 Gy (dose level 6). The 131I activity
administered and estimated radiation absorbed doses delivered to marrow
and spleen at each dose level are summarized in
Table 3 together with regimen-related
toxicities at each dose level. Side effects during the therapeutic
infusion of antibody were similar to those experienced with the
biodistribution dose. Some patients, particularly those treated at
higher dose levels, experienced mild to moderate nausea and vomiting
during the first few days after administration of the therapeutic dose
of antibody. Patients remained in radiation isolation for 3 to 7 days
after treatment.
Most regimen-related toxicities were typical for conventional marrow
transplant regimens. All patients developed at least grade II mucositis
(ie, requiring narcotic therapy). Grade III mucositis occurred in both
patients receiving dose level 6 (12.25 Gy to liver) and thus was the
dose-limiting toxicity in this study (see below).
A patient treated at dose level 1 (3.5 Gy to liver) developed ileus and
hemorrhagic enterocolitis 16 to 18 days posttransplant and thus was
considered to have grade III gastrointestinal toxicity. This patient
went on to develop gut GVHD that may have been the etiology of his symptoms.
A patient treated at dose level 3 (7 Gy to liver) did not engraft by
the time of her death from candida pneumonia 29 days posttransplant,
despite the administration of granulocyte colony-stimulating factor
(G-CSF). Minimal myeloid and erythroid engraftment was present in a
postmortem marrow biopsy, and the presence of macrophages and
eosiniphilic debris suggested marrow stromal damage. This patient
received an estimated radiation absorbed dose to the bone marrow of 31 Gy from 131I-BC8 antibody, in addition to 12 Gy external
beam TBI. It is possible that this high total radiation dose delivered
to marrow damaged the marrow microenvironment, and this patient was
considered to have grade IV marrow toxicity. In subsequent patients,
the estimated marrow dose from 131I-BC8 antibody was
limited to 28 Gy. Three subsequent patients with high ratios of
radiation delivered to marrow as compared with liver thus received
estimated liver radiation doses that were less than those specified by
the dose escalation schema to limit the marrow dose to 28 Gy.
One of 6 patients treated at dose level 5 (10.5 Gy to liver) developed
grade III hepatic toxicity, with a maximum serum bilirubin concentration of 11.7 mg/dL and severe ascites requiring paracentesis. Two of 2 patients treated at dose level 6 (12.25 Gy to liver) developed
grade III mucositis as defined by the need for endotracheal intubation
to protect the airway or by the development of aspiration pneumonia.
The first of these patients developed significant mucositis by the
fifth dose of TBI; thus, the sixth dose was omitted. This patient was
intubated because of severe mucositis and oropharyngeal bleeding on day
0 and remained intubated for 3 days. He also developed portal vein
thrombosis with ascites and a peak serum bilirubin concentration of 8.0 mg/dL, which was complicated by renal failure secondary to hepatorenal
syndrome, but recovered. The second patient developed fever and cough 9 days before transplant and a naso-pharyngeal culture grew respiratory
syncytial virus (RSV). He developed both severe mucositis and
progressive pulmonary impairment and was intubated on day 6 after
transplant. Squamous cells were demonstrated in pulmonary fluid
obtained by broncho-alveolar lavage, documenting aspiration. The
patient died 8 days posttransplant from progressive RSV pneumonia
despite treatment with Ribavirin.
Thus, the maximum tolerated dose estimated by this study was dose level
5 (10.5 Gy delivered to the normal organ estimated to receive the
highest dose from radiolabeled antibody in addition to CY and 12 Gy TBI).
Engraftment was analyzed for the patients receiving allogeneic marrow
who survived more than 30 days after transplant and did not relapse in
the first month. Of 19 such patients, an absolute neutrophil count of
500/µL (first day of 3 sustained days >500/µL) was achieved a
median of 21 days (range, 9 to 30 days) posttransplant. A platelet
count of 20,000/µL (first day of 7 sustained days >20,000/µL without transfusion) was achieved a median of 23 days (range, 16 to 36 days) posttransplant, with the exception of 1 patient (treated at dose
level 1) who developed chronic GHVD and remained platelet
transfusion-dependent at the time of discharge from the center at day
113 and a second patient who died from complications of influenza A at
day 40.
Methotrexate doses and GVHD.
Among 23 recipients of allogeneic marrow, 18 received all 4 scheduled
doses of methotrexate for GVHD prophylaxis. Two patients received 3 doses, and 1 patient each received 2, 1, or no scheduled doses.
Twenty-one allogeneic marrow recipients lived at least 30 days and were
evaluable for the development of acute GVHD. Twelve patients had no (n = 8) or grade I GVHD (n = 4). Nine patients developed grade II-IV GVHD
(grade II, 3; grade III, 5; and grade IV, 1). Sixteen patients were
evaluable for the development of chronic GVHD. Eight patients developed
clinical extensive chronic GVHD, 6 developed subclinical chronic GVHD,
and 2 did not develop chronic GVHD.
Outcome.
Of 25 patients with advanced AML and MDS, 3 died of infection in the
early posttransplant period and a fourth died of infection 4 months
posttransplant. One patient who had had poor engraftment after
receiving a 4-HC-purged autologous marrow required chronic transfusions and G-CSF support and died with infection 54 months posttransplant. This patient was treated at dose level 2 with an
estimated marrow dose of 12 Gy delivered by antibody (24 Gy total). Her
course was felt to be consistent with the poor engraftment seen in a
minority of AML patients whose autologous marrows have been incubated
with 4-HC. Thirteen patients relapsed 2 to 77 months posttransplant,
and 7 patients survive disease-free 15 to 89 months (median, 65 months)
posttransplant (Fig 3A). One of the 5 patients transplanted for AML in second or third remission and
surviving the first 100 days relapsed after transplant, as compared
with 11 of 15 patients transplanted in relapse and 1 of 3 patients with
MDS. Of the 9 patients with ALL, 2 died of infection and 4 relapsed 0.5 to 11 months posttransplant. Three survive disease-free 23, 58, and 70 months posttransplant (Fig 3B). Two of the survivors were transplanted
in second remission and a third had primary refractory disease.
View larger version (16K):
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| Fig 3.
Kaplan-Meier analysis of disease-free survival for
patients receiving therapeutic dose of 131I-BC8 antibody
followed by CY/TBI. (A) Patients with AML or MDS. (B) Patients with
ALL.
|
|
Fifteen of 18 evaluable patients became hypothyroid, as indicated by an
elevated thyroid stimulating hormone, at a median of 13 months (range,
1 to 40 months) posttransplant and were treated with thyroxine.
| |
DISCUSSION |
We have demonstrated that 131I-labeled anti-CD45 antibody
BC8 can deliver more radiation to marrow and spleen than to any normal organ in most patients with acute leukemia whether in remission or
relapse. On average, 131I-BC8 antibody delivered estimated
radiation doses to marrow that were 2.3-fold greater than liver and
doses to spleen that were 4.8-fold greater than liver. The ratios of
radiation delivered to marrow and spleen as compared with lung, kidney,
and total body were even greater. The maximum tolerated dose suggested
by this phase I study was 10.5 Gy delivered by 131I-BC8
antibody to the normal organ receiving the highest dose. Although the
liver was the normal organ receiving the highest dose in all treated
patients, the dose-limiting toxicity was mucositis. Based on the
average estimates of radiation absorbed dose, this dose level would
deliver an average of 24 Gy to marrow and 50 Gy to spleen, combined
with CY and 12 Gy TBI.
The ability to deliver such supplemental doses of radiation to sites of
leukemic involvement in marrow and spleen may improve the cure rate by
decreasing the risk of relapse. As noted, a 3.75 Gy increase of TBI
dose (from 12 to 15.75 Gy) decreased the relapse rate after matched
related marrow transplant for both AML in first remission and CML in
chronic phase. The estimates of radiation dose to marrow were based on
marrow biopsy and the measured retention half-times of radioiodine in
marrow from serial gamma scans. Because radiolabeled antibody
distribution may be heterogeneous in marrow, these may represent
overestimates or underestimates of radiation doses delivered at various
skeletal marrow sites. Also, the relative biological effectiveness
(RBE) of radiation delivered by antibody at low dose rate may be lower
than that of external beam TBI, such that we would not anticipate the
leukemic cell killing of 24 Gy delivered by antibody to be comparable
to the killing provided by the same dose of TBI. Although it is an area
of controversy, several studies suggest that hematopoietic progenitor
or stem cells possess some capacity for repair of sublethal DNA
damage49-52 and that there is apparent heterogeneity in
both radiation sensitivity and self-repair capacity in their malignant
counterparts.53-55 Although other factors, including
accumulation of cells in the radiosensitive G2 stage of the cell
cycle,56 can impact radiation sensitivity and dose-rate
effects, leukemic cells with such repair ability will generally sustain
less cell kill when a given radiation dose is delivered at a low dose
rate, as compared with TBI. However, we would predict that in some
patients these substantial supplemental doses of hematopoietic
irradiation delivered by antibody added to CY/TBI would decrease the
risk of relapse as compared with CY/TBI alone.
This phase I study was not designed to determine the efficacy of the
preparative regimen of 131I-anti-CD45 antibody combined
with CY/TBI. Given the small number of patients treated at each dose
level and the variability in disease stage and hematopoietic stem cell
source (allogeneic v autologous), it was not possible to
correlate the risk of relapse with the amount of radiation delivered by
antibody to the normal organ receiving the highest dose or with the
estimated radiation dose delivered to marrow.
There was significant variation in the estimated radiation absorbed
dose to liver per millicurie of 131I delivered by BC8
antibody. This variation could not be explained by disease stage,
disease type, or number of circulating blasts. This observed
variability supports the need to determine antibody biodistribution in
each patient to avoid delivery of excessive or inadequate radiation
dose. Biodistribution studies also identified the minority of patients
with unexpectedly low estimated radiation doses to the bone marrow,
which generally resulted from unexplained initial low uptake of
131I-BC8 antibody in marrow.
Other attempts to deliver targeted radiation to marrow have included
131I-labeled anti-CD33 antibody20,21,23,26 and,
recently, anti-CD33 antibody labeled with
213Bismuth,57 which emits a high-energy  particle of short path length. In our experience with conventionally
iodinated p67 (anti-CD33) antibody, only modest ratios of radiation
were delivered to marrow as compared with the highest normal organ
(average ratio, 1.2:1).21 The use of 131I-p67
antibody was limited by the short retention of 131I in the
marrow (t1/2, 21.4 hours), presumably because of the rapid internalization of the 131I-p67-CD33 complex into the cell
with subsequent dehalogenation and excretion of 131I from
the cell. Furthermore, because of restricted CD33 antigen expression,
CD33 antigen was saturated at relatively low antibody doses (0.05 mg/kg), not allowing attachment of sufficient 131I for
treatment of patients at the higher doses used. However, using a
different anti-CD33 antibody, 131I-M195, Scheinberg et
al20 found longer retention of 131I in the
marrow of some patients and thus improved biodistribution. It is
uncertain if greater retention was due to different binding properties
of the antibodies with subsequent decreased internalization by the
cell. The studies by Scheinberg et al20 also demonstrated that relatively low doses of antibody (3 mg/m2) resulted in
saturation of CD33 antigen.
Whether the delivery of supplemental hematopoietic irradiation using
131I-anti-CD45 antibody will benefit patients with advanced
leukemia remains unknown, but the experience reported here demonstrated that the approach is feasible; accordingly, phase II studies are underway. Based on the safety of this approach as detailed in this
report, we are also conducting a clinical trial in which 131I-BC8 antibody is combined with busulfan and CY for
patients with AML in first remission receiving HLA-matched
transplants.58 Ninety percent of patients have had
favorable biodistribution of 131I-BC8 antibody, and 24 patients in first remission have received 131I-BC8 antibody
labeled with the amount of 131I estimated to deliver 3.5 Gy
(first 4 patients) to 5.25 Gy to the liver and 6 to 16 Gy to marrow.
Eighteen of these 24 patients are surviving disease-free 10 to 63 months (median, 42 months) after transplant, with 4 nonrelapse deaths
and 2 relapses (manuscript in preparation). Accrual continues on this
study to better define the efficacy and toxicity of this preparative regimen.
In addition to its use for delivery of supplemental antileukemic doses
of radiation, radiolabeled anti-CD45 antibody may also provide
immunosuppressive effects, because CD45 is expressed by virtually all
lymphoid cells. Preclinical studies are underway to determine the
marrow ablative and immunosuppressive effects of
131I-anti-CD45 antibody. In murine transplant models, we
have determined that 131I-anti-CD45 antibody can replace
TBI when the donor and recipient differ only with respect to CD45
allotype and can partially replace TBI when transplanting
T-cell-depleted H2-mismatched marrow.59 These preclinical
studies suggest that it may be possible to increase the proportion of
radiation delivered by antibody and decrease the dose of TBI and/or
high-dose chemotherapy when transplanting allogeneic marrow without
increasing the probability of rejection. Such an approach should allow
the delivery of a higher total radiation dose to sites of leukemic
involvement with less toxicity.
In summary, substantial supplemental doses of radiation can be
delivered to bone marrow and spleen by 131I-anti-CD45
antibody when combined with CY and 12 GY TBI, with acceptable toxicity.
Phase II studies of this approach are underway for patients with
advanced AML/MDS and with ALL. These studies will include both
recipients of matched related as well as matched unrelated marrow and
should better define the toxicity and efficacy of this approach. The
ability to increase the radiation doses delivered to leukemic cells may
decrease the rate of relapse and thus improve the outcome of marrow
transplantation for acute leukemia.
| |
ACKNOWLEDGMENT |
The authors are indebted to Eileen Sickle and Sharon Bush for their
expert nursing assistance and to Minna Zheng and Jennifer Smith for
their expert technical assistance. We also acknowledge the excellent
care provided to these patients by the physicians and nurses of the
marrow transplant teams, as well as the work of the staff in the Long
Term Followup office.
| |
FOOTNOTES |
Submitted October 1, 1998; accepted April 20, 1999.
Supported by National Institute of Health Grants No. CA44991, CA18029,
CA18221, and HL36444.
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.
Address reprint requests to Dana C. Matthews, MD, Fred Hutchinson
Cancer Research Center D1-100, 1100 Fairview Ave N, PO Box 19024, Seattle, WA 98109; e-mail: dmatthew{at}fhcrc.org.
| |
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E. R. Nemecek, D. K. Hamlin, D. R. Fisher, K. A. Krohn, J. M. Pagel, F. R. Appelbaum, O. W. Press, and D. C. Matthews
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R. M. Sharkey and D. M. Goldenberg
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S. Modak and N.-K. V. Cheung
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W. A. Bethge, D. S. Wilbur, R. Storb, D. K. Hamlin, E. B. Santos, M. W. Brechbiel, D. R. Fisher, and B. M. Sandmaier
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Blood,
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[Abstract]
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J. M. Pagel, N. Hedin, K. Subbiah, D. Meyer, R. Mallet, D. Axworthy, L. J. Theodore, D. S. Wilbur, D. C. Matthews, and O. W. Press
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Blood,
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[Abstract]
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G. G. Wulf, K.-L. Luo, M. A. Goodell, and M. K. Brenner
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J. G. Jurcic, S. M. Larson, G. Sgouros, M. R. McDevitt, R. D. Finn, C. R. Divgi, A. M. Ballangrud, K. A. Hamacher, D. Ma, J. L. Humm, et al.
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B. M. Sandmaier, W. A. Bethge, D. S. Wilbur, D. K. Hamlin, E. B. Santos, M. W. Brechbiel, D. R. Fisher, and R. Storb
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Hematology,
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D. Bunjes, I. Buchmann, C. Duncker, U. Seitz, J. Kotzerke, M. Wiesneth, D. Dohr, M. Stefanic, A. Buck, S. V. Harsdorf, et al.
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K. L. Ruffner, P. J. Martin, S. Hussell, C. Nourigat, D. R. Fisher, I. D. Bernstein, and D. C. Matthews
Immunosuppressive Effects of 131I-Anti-CD45 Antibody in Unsensitized and Donor Antigen-presensitized H2-matched, Minor Antigen-mismatched Murine Transplant Models
Cancer Res.,
July 1, 2001;
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R. P. Witherspoon, H. J. Deeg, B. Storer, C. Anasetti, R. Storb, and F. R. Appelbaum
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A. Goel, S. Augustine, J. Baranowska-Kortylewicz, D. Colcher, B. J. M. Booth, G. Pavlinkova, M. Tempero, and S. K. Batra
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F. R. Appelbaum, J. M. Rowe, J. Radich, and J. E. Dick
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TOP
ABSTRACT
INTRODUCTION