downloaded from clincancerres.aacrjournals.org on february ... · fix human complement in vitro...

Published OnlineFirst September 21, 2010; DOI: 10.1158/1078-0432.CCR-10-0382

Downloa
Research. on July 28, 20clincancerres.aacrjournals.org ded from 21. © 2010 American Association for Cancer
http://clincancerres.aacrjournals.org/


antibofix hushowetientsresiduand pBism

tal thaclinicator. UadmiAMLrapidspleen1,000in a stientsCR. Tly preactivitone-creasecells a213Bi-ducteda nonmic b

Mate

213Bi-The

diethywas coby TS(16–1Inc., wor theconstreverySCN-C

(17,adjustservefinal5 min

PatienPat

thosedue toease,fractopatienCD333 weewas dther oteria i>60 mtase aPatienmab okemiaat MeapprosubjecDecla

TreatPat

dose5 dayto foueach)were lwe esber owere18.5,were37 M

Translational Relevance

This report offers proof of principle that targetedα-particle immunotherapy can produce remissionsin patients with advanced myeloid leukemia. Becauseof the short range and high energy of α-emissions,this approach may be beneficial in the setting ofsmall-volume or micrometastatic disease in a varietyof tumors. This study provides the rationale for thefurther development of α-particle immunotherapyusing 213Bi and alternative radioisotopes in leukemiaas well as other cancers, such as breast and prostatecarcinoma, where micrometastatic disease is present.

Rosenblat et al.

Clin C5304


dy-dependent cell-mediated cytotoxicity and canman complement in vitro (9). Previous studiesd that lintuzumab can target leukemia cells in pa-without immunogenicity (10), eliminate minimalal disease in acute promyelocytic leukemia (11),roduce occasional remissions in AML (12–14).uth-213 (213Bi; t1/2 = 45.6 minutes) is a radiome-t emits an α-particle of 8 MeV and is prepared forl use from an actinium-225 (225Ac)/213Bi genera-p to 37 MBq/kg of 213Bi-lintuzumab were safelynistered to patients with relapsed or refractoryin a phase I trial (15). γ-Camera imaging showeduptake of 213Bi in the bone marrow, liver, and, with tumor-to-whole body absorbed dose ratios-fold greater than β-emitting anti-CD33 constructsimilar patient population. Although 14 of 18 pa-had reductions in marrow blasts, none achievedhis was likely due to large tumor burdens in heavi-treated patients and to the relatively low specificies of 213Bi-lintuzumab. We hypothesized that ato two-log reduction in tumor burden could in-the number of 213Bi atoms delivered to leukemiand produce remissions. To determine the effects oflintuzumab against cytoreduced disease, we con-a phase I/II trial in which patients first received

remittive dose of cytarabine to decrease the leuke- minisand tothe lotionrequirlowedety oantibily. ToicityCancedid bistratiafterpatien

urden.

rials and Methods

lintuzumab preparationbifunctional chelate 2-(4-isothiocyanatobenzyl)lenetriamine pentaacetic acid (SCN-CHX-A-DTPA)njugated to lintuzumab (Protein Design Labs, Inc.)I Washington, with a ligand-to-protein ratio of 4.59). 225Ac, supplied by Actinium Pharmaceuticals,as obtained from Oak Ridge National LaboratoryInstitute for Transuranium Elements. Following

uction of 225Ac/213Bi generators, 213Bi was eluted
3 to 4 hours and conjugated to lintuzumab–HX-A-DTPA using previously described methods
singlephysic

ancer Res; 16(21) November 1, 2010

Research. on July 28, 20clincancerres.aacrjournals.org Downloaded from

20–23). Unconjugated antibody was added tothe specific activity to 555 to 740 MBq/mg to pre-the immunoreactivity of the radioconjugate. Theproduct was administered as an injection overutes.

t eligibilityients with previously untreated AML age >60 years orwho were unable to receive intensive chemotherapycomorbid conditions, such as cardiovascular dis-

were eligible. Patients with relapsed or primary re-ry AML were also included. More than 25% of thets' bone marrow blasts were required to express. No antileukemic therapy was administered forks before study entry except for hydroxyurea, whichiscontinued before treatment. Concurrent use of ei-ral or intravenous antibiotics was allowed. Entry cri-ncluded creatinine <2 mg/dL or creatinine clearanceL/min, bilirubin ≤2 mg/dL, and alkaline phospha-nd aspartate aminotransferase ≤2.5 times normal.ts could not have detectable antibodies to lintuzu-r active central nervous system involvement by leu-. Patients were treated from April 2001 to June 2006morial Sloan-Kettering Cancer Center on a protocolved by the Center's institutional review board. Allts gave written informed consent according to theration of Helsinki.

mentients were hospitalized and received cytarabine at aof 200 mg/m2 daily by i.v. continuous infusion fors. Within 8 days after completion of cytarabine, twor injections of 213Bi-lintuzumab (518-1,262 MBqwere given over 1 to 2 days. Because 213Bi yieldsimited by the activity of each 225Ac/213Bi generator,calated radioactivity doses by increasing the num-f injections. Four dose levels of 213Bi-lintuzumabadministered in the phase I portion of the trial:27.75, 37, and 46.25 MBq/kg. Additional patientstreated at the maximum tolerated dose (MTD) ofBq/kg in the phase II portion of the trial. Total ad-tered activities ranged from 1,195 to 4,755 MBq,tal antibody doses ranged from 2 to 6.3 mg. Givenw level of γ-emissions from 213Bi, radiation isola-for patients and precautions for staff were noted. Hematopoietic growth factor support was al-if clinically indicated according to American Soci-

f Clinical Oncology guidelines (24). Prophylacticotic and antifungal therapy was not given routine-xicity was assessed according to the Common Tox-Criteria version 2.0 established by the Nationalr Institute. To measure antileukemic effects, weone marrow aspirations at baseline, before admin-on of 213Bi-lintuzumab, and then 4 and 8 weeksthe start of treatment. Four of the six respondingts received consolidation therapy, generally with
-agent cytarabine, at the discretion of the treatingian.
Clinical Cancer Research

21. © 2010 American Association for Cancer



BiodiThe

tion sPatien60 miinjectiγ-camin thein thewas ewere gcentagthe spnominbrae acokinimage

pixel/previo

RespoCR

neutr>100,compexcepting owas dwith a

StatisThr

Tab

Cha

MedSex

MF

DiseU

C

P

R

CytoInP

Med(r

*Inc

Cytarabine and α-Particle Immunotherapy for AML

www.a


stribution and pharmacokinetics440-keV γ-emissions of 213Bi allowed biodistribu-tudies to be done as previously described (15, 25).ts underwent continuous γ-camera imaging fornutes beginning immediately after the first and lastons of 213Bi-lintuzumab using a dual-head Vertexera (ADAC Laboratories). We calculated activityliver as the geometric mean of the counts/minutesanterior and posterior images. Activity in the spinestimated from the posterior view. Kinetic curvesenerated, corrected for decay, and converted to per-e injected dose (%ID) for each region. The %ID forine was converted to marrow %ID by scaling aal estimate of the red marrow mass in the verte-ccording to body weight (25). Additional pharma-
etic data were obtained through parametric rates by fitting a linear expression to the counts in each
phasehigheicity (hemafunctilastinof >1,tion oend pvival.ties oThis dresultWe

varioufollow213Bi-t test.of prirow bpatiensalvagtory Atwo-sisurviv

Resu

PatienThi

were t(18.5-treateAML)(46%lishedinduclapsedand 3the Csystemyotypnorm

le tics

ra No. pa %

ia 67 (37

alem 1 32asnt 1 42DSM 74 (51ha0 4 311 3 232 3 233 0 04 2 155 1 8rim 3 10M 60 (37ela 1 48U 25P(n

7 (1- 23

M(rM 65 (49gete 2 71

ludes two patients who underwent allogeneic HSCT.

acrjournals.org


minute over the 60-minute imaging period asusly described (26).

nse definitionswas defined as <5% bone marrow blasts with aophil count of >1,000/μL, a platelet count of000/μL, and no extramedullary disease. CR with in-lete platelet recovery (CRp) was defined similarly,t that the platelet count was <100,000/μL in the set-f transfusion independence. Partial remission (PR)efined as a >50% decrease in bone marrow blastsll of the hematologic values for CR (27).

tical analysisee to six patients were treated at each dose level in theI portion of the study. The MTD was defined as thest dose for which the incidence of dose-limiting tox-DLT) is <33%. DLTs included (a) any grade 4 non-tologic toxicity, (b) grade 3 abnormalities of liveron or serum creatinine, and (c) grade 4 leukopeniag ≥35 days in patients with baseline leukocyte counts000/μL. The primary end point in the phase II por-f the trial was response (CR + CRp + PR). Secondaryoints included disease-free survival and overall sur-A two-stage design was used in which the probabili-f type I and II errors were 0.05 and 0.2, respectively.esign yielded at least 80% probability of a positiveif the true response rate was at least 20%.correlated toxicity and antileukemic effects withs clinical parameters. Reductions in marrow blastsing cytarabine alone and in combination withlintuzumab were compared using the two-sidedWe compared clinical parameters, such as numberor treatment regimens, baseline percentage of mar-lasts, and level of CD33 expression, between thosets with untreated AML/relapsed AML receiving firste treatment and those patients with primary refrac-ML/multiply treated relapsed disease using theded t test. We estimated the probability of overallal using the Kaplan-Meier method.

lts

t characteristicsrty-one patients (median age, 67 years; range, 37-80)reated with sequential cytarabine and 213Bi-lintuzumab46.25 MBq/kg; Table 1). Thirteen patients had un-d AML (5 with de novo AML; 8 with secondary. Among these previously untreated patients, six) had Charlson comorbidity scores of >1, an estab-adverse prognostic factor for response to standard

tion chemotherapy (28, 29). Fifteen patients had re-AML (7 of whom received prior salvage treatment),patients had primary refractory AML. According toancer and Leukemia Group B risk classification(30), 22 patients (71%) had intermediate-risk kar-

1. Patient characteris

cteristic
tients1) (N = 3
n age (range), y
-80)
e 21 68
ale 0 e status reated 3 e novo 5 16econdary 8 26 edian age (range), y -80) rlson comorbidity index
ary refractory
edian age (range), y -66) psedntreated
5

reviously treatedo. prior regimens)*

84)

edian CR1 duration
39) ange), mo
4 (3-

edian age (range), y
-75) netics rmediate-riskr-risk
2
oo 9 29ian CD33 expressionange), %
88 (36-100)

es, whereas 9 (29%) had poor-risk cytogenetic ab-alities. Fifteen patients were treated in the phase I

Clin Cancer Res; 16(21) November 1, 2010 5305




portio27.75withenroll

AdverAs e

toxiciabsolgrade15 pabefore4 (n =the stpeniarespo≥1,00time(rangerelatedof CDcytaralimitinlastingwith 4213Bi-Mye

in morial innegat(61%had cfeverinducoccurrand inLive

trameof 31

irubingrade(16%syndrabnorduratiatininopedliposotientsminisby fev3 brograde

AntilePat

line, aof 213

of theeach tseenhad inafter(77%reducreducCD33(P = 0leukemradiatA b

pletio213Bi-butionmen.of tre

Table

Toxicity el

BilirubGra 3Gra 1

Alkalin 1AST/A 1CreInfuGI b

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; GI, gastrointestinal.

Rosenblat et al.

Clin C5306


n of the trial: 3 patients each received 18.5 andMBq/kg, 5 received 37 MBq/kg, and 4 were treated46.25 MBq/kg. An additional 16 patients wereed in the phase II portion of the study.

se effectsxpected, myelosuppression was the most commonty. Among 10 patients who began therapy with anute neutrophil count of ≥1,000/μL, 9 (90%) had3 (n = 1) or grade 4 (n = 8) neutropenia. Amongtients who were platelet transfusion independenttreatment, all developed grade 3 (n = 4) or grade11) thrombocytopenia. The median time from

art of cytarabine until recovery from grade 4 leuko-was 29 days (range, 2-59). In the six patients whonded, the median time to neutrophil recovery0/μL was 30 days (range, 25-57), and the medianto platelet transfusion independence was 34 days, 23-87). The duration of myelosuppression was un-to the administered activity (P = 0.221) or the level

33 expression (P = 0.084) due in part to the effect ofbine. During the phase I portion of the trial, dose-g myelosuppression (defined as grade 4 leukopenia≥35 days) was seen in two of four patients treated6.25 MBq/kg. Therefore, we determined the MTD oflintuzumab following cytarabine to be 37 MBq/kg.losuppression-associated febrile episodes occurredst patients. Twenty (65%) had documented bacte-fections, predominantly catheter-related coagulase-ive Staphylococcal bacteremia. Nineteen patients) developed presumed fungal pneumonia, and 1andidemia. Eight patients (26%) had neutropenicwithout an identifiable source of infection. Peri-tion mortality related to infectious complicationsed in 2 of 21 patients (10%) receiving 37 MBq/kg1 of 4 patients (25%) treated with 46.25 MBq/kg.r function abnormalities were the most common ex-
dullary toxicity (Table 2). Across all dose levels, 21patients (68%) developed transient elevations of bil-
abinewhose



, alkaline phosphatase, or transaminases; however,3 or 4 abnormalities were seen in only 5 patients). No patients had evidence of sinusoidal obstructiveome. The median time to the onset of liver functionmalities was 7 days (range, 3-30), and the medianon was 6 days (range, 1-27). Increases in serum cre-e occurred in 11 patients (35%), but only 1 devel-a grade 3 elevation while receiving concomitantmal amphotericin and aminoglycosides. Nine pa-(29%) had infusion-related reactions following ad-tration of 213Bi-lintuzumab, typically characterizeder, chills, and rigors, including 1 patient with gradenchospasm. Additionally, 1 patient developed a4 gastrointestinal hemorrhage.

ukemic activity and responsesients underwent bone marrow aspirations at base-fter receiving cytarabine but before administrationBi-lintuzumab, and finally 4 or 8 weeks after the startrapy. Not all patients had evaluable specimens atime point. Reductions in bone marrow blasts wereat all dose levels (Fig. 1). Of the 31 patients, 26terpretable bone marrow aspirations 4 or 8 weeksthe start of therapy. Among these 26 patients, 20) had a >20% decrease in marrow blasts. The meantion ± SD was 47 ± 71% (range, −223 to 99). Thetion of marrow blasts was not related to level ofexpression (P = 0.083) or the administered activity.439), likely due to variability in disease burden andia subtypes, and in resistance to chemotherapy or

ion.one marrow aspiration done following the com-n of cytarabine but before administration oflintuzumab served to evaluate the relative contri-of each agent to the overall activity of the regi-

Typically, the marrow was assessed on day 6 or 7atment before the full antileukemic effects of cytar-

2. Extramedullary toxicity

Dose lev

may be apparent. Nebone marrow was ev

21. © 2010 American

vertheless, among 2aluable at this time

Clinical Cancer

Association for Can

18.5 MBq/kg(n = 3)

27.75 MBq/kg(n = 3)

37 MBq/kg(n = 21)

46.25 MBq/kg(n = 4)

in
de 3 0 0 1 de 4 0 0 0 e phosphatase (grade 3) 0 0 0 LT (grade 3) 0 0 0 ine (grade 3) 0 0 0 atin 1
sion-related reaction (grade 3) 0 0 1 0leeding (grade 4) 0 0 1 0

5 patientspoint, all

Research

cer



had d7% tomarro(rangeA to

luatiolintuzFollowtions(rangerecovepatien6 (29Five pparedcrease−90 tenhanpatien

Clin(24%dosespoor-AML;<37 MwithequalCRp (patienpriorof thmultithat eremisExcepno cl

Fig. 1.blasts aand 213

Table ct f n

Patien /s n g r t eq/

poat

7 /M M om 7 PR10 /M AM (7 AT

A,7 CR

11 /M L, 7 R141518

Abbnoic tic.


www.a


etectable disease with blast counts ranging from96%. Only 11 (40%) had a >20% reduction in

w blasts, and the mean decrease was 10 ± 55%, −116 to 88).tal of 21 patients had assessable bone marrow eva-ns before treatment, after cytarabine but before 213Bi-umab, and 4 or 8 weeks after the start of treatment.ing cytarabine alone, 13 patients (62%) had reduc-

in marrow blasts with a mean decrease of 10 ± 58%, −116 to 88). From the postcytarabine time point tory following treatment with 213Bi-lintuzumab, 16ts (76%) had reductions in marrow blasts, including%) who showed progression with cytarabine alone.atients (24%) had increases in marrow blasts com-with the postcytarabine evaluation. The mean de-in blasts during this interval was 41 ± 57% (range,o 98). These data suggest that 213Bi-lintuzumab

acid; IDR, idarubicin; Ara-C, cytarabine; APL, acute promyelocy

ced the antileukemic effect of cytarabine in mostts.

perce

Bi-lintuzumab in 26 evaluable patients.

acrjournals.org


ical responses were seen in 6 of the 25 patients; 95% confidence interval, 11-44) who receivedof ≥37 MBq/kg (Table 3). All responders had

risk features, including age ≥70 years or secondaryhowever, none of the 6 patients receivingBq had a clinical response. Among the 11 patients

untreated AML who received doses greater than orto the MTD, 2 achieved CR (18%), 1 achieved9%), and 2 achieved PR (18%). Among the sevents with AML in first relapse who had not receivedsalvage therapy, one (14%) attained a CRp. Nonee seven patients with primary refractory AML orply treated relapsed disease responded, indicatingffective cytoreduction was necessary to achievesion after administration of 213Bi-lintuzumab.t for the number of prior regimens (P < 0.005),inical differences, such as baseline marrow blast
ntage (P = 0.779) or level of CD33 expression
(P = 0.258), between the group with untreated AML

Percentage change in bone marrowfter treatment with sequential cytarabine

3. Chara
eristics o responding patie ts
Clin Cancer Res;

21. © 2010 American Assoc

16(21) Novemb

iation for Can

t no. Age
ex Diag osis Cyto enetics Prio herapy Dos(MB
levelkg)

Res(dur

nseion, mo)

5-Aza (MDS) 3
7479
2° A2°

L after MDS CL, h/o APL der

plex), t(1,7)
O, SAHA (AML); 3
(4)(9)

ATR
IDR/Ara-C × 3 (APL) 80 AM M2 de novo 8 None 3 C (12) 74 2° A L after MDS N rmal None 4 5 (7) /M M o 6.2 PR70/F AML, M2, relapsed Normal IDR/Ara-C × 3 46.25 CRp (5)75/M 2° AML after MDS del(9q) Decitabine (MDS) 37 CRp (2)
reviations: MDS, myelodysplastic syndrome; 5-Aza, azacitidine; ATO, arsenic trioxide; SAHA, vorinostat; ATRA, all-trans reti-

er 1, 2010 5307

cer



or recrefractent. Tindicaden bto ach

The21 pa(95%CR, oed 9AML;vage;AML.of agepriorThe

2-12)tientsspond5-30)AMLfor pamedia

BiodiFou

biodiγ-camareas

Fig. 2.with prdisease

Fig. 3.show uretentio

Rosenblat et al.

Clin C5308


eiving first salvage therapy and the group withory or multiply treated relapsed AML were appar-he lack of responses in heavily pretreated patientstes the need for effective reduction in disease bur-

eviously untreated AML and those with relapsed or refractory.

efore administration of α-particle immunotherapy of the

ptake of Bi by target organs over 1 h after the first injection (C) and clearancen of 213Bi in the marrow (E) and liver (F). (-○-), first injection; (-♦-), fourth injectio



overall response rate (CR + CRp + PR) among thetients receiving the MTD of 37 MBq/kg was 19%confidence interval, 7-41). Two patients achievedne had a CRp, and one had a PR. This group includ-patients with previously untreated AML (3 de novo6 secondary AML), 10 with relapsed AML (6 first sal-4 previously treated), and 2 with primary refractoryAlthough all four responding patients were >70 yearsand three had secondary AML, none had received

therapy for AML.median response duration was 6 months (range,

. The median overall survival duration for all pa-was 4.6 months (range, 1-30). Among the six re-ers, the median survival was 13.7 months (range,. The median survival for patients with untreated(n = 13) was 7.7 months (range 1-30), whereastients with previously treated AML (n = 18), then survival was 3.1 months (range, 1-13; Fig. 2).

stribution and pharmacokineticsr patients (one at each dose level) underwent detailedstribution and pharmacokinetic studies. Posteriorera imaging showed rapid localization of isotope toof leukemic involvement, including the bone marrow

Kaplan-Meier plot showing the probability of survival for patients

vertebrae and pelvis, the liver, and the spleen in all

ieve remission. patients (Fig. 3). Despite avidity for free bismuth, the

γ-Camera images show targeting of isotope to marrow, liver, and spleen after the first injection (A) and blood pooling after the last (B). Rate images213
after the last (D). Time-activity curves show localization and
n.

Clinical Cancer Research




kidne213Bi-the inwithowas swith 2sites wand Bby parof isodepicgreen.lintuzpatiensites aD). Thof targleukeinjectleukemUpt

70% t10 mithe 1-ter thconstaafter mcreasecatingtargetwithinantibo

Discu

In tof cytproduthougwas inthat tat redthat fα-emior adExc

with ltreatinbecauof noshort-selectyieldiity. Daloneties. Iferageavaila

are fethe rato twocausesmall-high lstudy,ther rto proAlth

dose lwith rsuggeremissuggemic aseen oabineobtaintime ptientThe ato indeffectof 18relapswhereAMLgroupcant rabinewith 2

produThe

from(31).singlethis stresponof 200theseof sign30 yealiteratlow-deral, mrandodroxymediaCR afThe

antibosinglebodyreach38%


www.a


ys were not visualized, confirming the stability oflintuzumab in vivo. In contrast to the results seen initial phase I trial, inwhich 213Bi-lintuzumabwas givenut prior cytoreduction (15), cardiac blood poolingeen after the last injection in one patient treated7.5 MBq/kg, indicating saturation of CD33 antigenithin the bone marrow, liver, and spleen (Fig. 3A). Additional pharmacokinetic data were obtainedametric rate imaging, in which an increase in the ratetope accumulation over the 1-hour imaging period isted by red-orange, and clearance is shown in blue-Reduced bone marrow uptake or clearance of 213Bi-umab was seen after multiple injections in all fourts who were studied, indicating saturation of antigenfter partial cytoreduction with cytarabine (Fig. 3C andis is consistent with a reduction in the total numberet antigens by cytarabine and not due to loss of targetmia cells because imaging was done at the time ofion and α-particle–mediated cytoreduction of theia would not be expected for several days.

ake of 213Bi by the marrow and liver, accounting foro 90% of the injected activity, occurred within 5 tonutes after injection and was maintained throughouthour period of image collection. Marrow activity af-e first and last injections of 213Bi-lintuzumab wasnt in three patients and decreased in one patientultiple injections (Fig. 3E). All four patients had de-s in liver uptake following multiple injections, indi-a “first-pass” binding effect with CD33 saturation ofcells (including leukemia cells and Kupffer cells)the imaged liver space after several milligrams ofdy, as previously observed (Fig. 3F; ref. 15).

ssion

his study, we show that sequential administrationarabine and 213Bi-lintuzumab is tolerable and cance remissions in some patients with AML. Al-h a relatively small group of heterogeneous patientscluded in this trial, it provides proof of principle

argeted α-particle immunotherapy may be effectiveucing low-volume disease. These results suggesturther investigation of radioimmunotherapy withtters after cytoreduction and in the postremissionjuvant setting is warranted.ept as conditioning for HSCT, radioimmunotherapyong-range, low-energy β-emitters is useful only ing bulky, radiosensitive cancers such as lymphomase DLT usually results from nonspecific irradiationrmal tissues. Conversely, therapy with high-energy,range α-particles can provide far more potent andive delivery of radiation to individual tumor cells,ng enhanced antitumor activity with decreased toxic-espite these advantages, CRs with 213Bi-lintuzumabwould require extraordinarily high injected activi-we assume tumor burdens of 1012 cells with an av-
CD33 density of 10,000/cell, ∼1016 binding sites areble to lintuzumab. With the specific activities that
decreaThis s

acrjournals.org


asible, only 1 in 2,700 lintuzumab molecules carriesdiolabel. Therefore, it remains difficult to deliver one213Bi atoms to every leukemia cell, particularly be-of its 46-minute physical half-life. In the setting ofvolume disease, however, the short path length andinear energy transfer of α-particles are ideal. In thiscytoreduction provided by cytarabine allowed fur-

eduction of residual leukemia by 213Bi-lintuzumabduce remissions.ough decreases in marrow blasts were seen at allevels, we observed a 213Bi dose-response relationshipemission occurring only at doses ≥37 MBq/kg. Thissts that cytarabine was not likely the sole cause ofsions. Moreover, serial bone marrow evaluationsst that 213Bi-lintuzumab augmented the antileuke-ctivity of cytarabine alone. Although blasts weren all marrow samples after administration of cytar-but before 213Bi-lintuzumab, these specimens wereed before day 14 of therapy. Because of this earlyoint, it is impossible to determine whether any pa-would have achieved a CR with cytarabine alone.bility of sequential cytarabine and 213Bi-lintuzumabuce remissions was seen only in patients where

ive cytoreduction with cytarabine was possible. Sixpatients (33%) with untreated AML or untreated firste who received doses of ≥37 MBq/kg responded,as none of the 7 patients with primary refractoryor multiply treated relapsed disease benefited. Thisof patients would not be expected to have a signifi-eduction in leukemic burden after single-agent cytar-, and, as noted in an initial phase I study, treatment13Bi-lintuzumab alone at similar activities did notce CRs in patients with large disease volumes.response rate in this trial was higher than expecteda single course of standard-dose cytarabine aloneBodey et al. (32) reported a 3% response rate after acourse of cytarabine at the dose and schedule used inudy. Similarly, in a report by Bickers et al. (33), noses were seen after one course of cytarabine at dosesmg/m2/d for 5 days. The response rate reported in

early trials may be lower than expected today becauseificant improvements in supportive care over the pastrs. There are numerous nonrandomized trials in theure that report a response rate of 10% to 20% withose cytarabine in older patients with AML, but, in gen-ultiple cycles of therapy are necessary. The largest

mized trial of low-dose cytarabine compared with hy-urea confirmed a response rate of 18%but only after an of three courses. One of 103 patients (1%) achievedter the first cycle of therapy (34).current study shows the effect of disease burden ondy biodistribution. In the initial phase I study of-agent 213Bi-lintuzumab, in which similar total anti-doses were used, the percentage of injected activitying the marrow after multiple doses increased inof patients, whereas activity in the liver and spleen
sed in 75% and 56% of patients, respectively (15).uggested that CD33 sites in the liver and spleen can




Refe1. Ca

comtionN E

2. StotraThtra

3. HotistAvNosite

4. Buiodtio20

5. JurwitSo

6. Mcα-e

7. Anfermo

8. Griclopro

9. CaBioCD

10. Camotar

11. JurremanRe

12. Cahuno

13. Ferefclo

14. Raacua p

15. Jurno

16. BrecymoJ C

17. NiScica19

18. Mirlabtobglo

19. Pipricmo

20. Nik


www.a


heanJ N

21. MctioJ N

22. Finprorad

23. Mc225

co24. Oz

daevi35

25. Sgdo(an

26. KoSg21

27. ChtiotiostaOn

28. Chclame

29. Etidedu13

30. Bynoofmy(CA

31. Boleuvin19

32. Bo(Nmo

33. BickeInt

34. Bucytacpa11

35. Feticzualokem

36. Lacawit

rencesssileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapypared with autologous or allogeneic bone marrow transplanta-in the management of acute myeloid leukemia in first remission.ngl J Med 1998;339:1649–56.ckerl-Goldstein KE, Blume KG. Allogeneic hematopoietic cellnsplantation for adult patients with acute myeloid leukemia. In:omas ED, Blume KG, Forman SJ, editors. Hematopoietic cellnsplantation. Oxford: Blackwell Science, Inc.; 1999, p. 823–34.rner MJ, Ries LAG, Krapcho M, et al., editors. SEER cancer sta-ics review, 1975-2006. Bethesda (MD): National Cancer Institute.ailable from: http://seer.cancer.gov/csr/1975_2006/, based onvember 2008 SEER data submission, posted to the SEER Web, 2009.rke JM, Caron PC, Papadopoulos EB, et al. Cytoreduction withine-131-anti-CD33 antibodies before bone marrow transplanta-n for advanced myeloid leukemias. Bone Marrow Transplant03;32:549–56.cic JG, Divgi CR, McDevitt MR, et al. Potential for myeloablationh yttrium-90-HuM195 (anti-CD33) in myeloid leukemia. Proc Amc Clin Oncol 2000;19:8a.Devitt MR, Sgouros G, Finn RD, et al. Radioimmunotherapy withmitting nuclides. Eur J Nucl Med 1998;25:1237–47.drews RG, Torok-Storb B, Bernstein ID. Myeloid-associated dif-entiation antigens on stem cells and their progeny identified bynoclonal antibodies. Blood 1983;62:124–32.ffin JD, Linch D, Sabbath K, Larcom P, Schlossman SF. A mono-nal antibody reactive with normal and leukemic human myeloidgenitor cells. Leuk Res 1984;8:521–34.ron PC, Co MS, Bull MK, Avdalovic NM, Queen C, Scheinberg DA.logical and immunological features of humanized M195 (anti-33) monoclonal antibodies. Cancer Res 1992;52:6761–7.ron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanizednoclonal antibody M195 (anti-CD33) in myeloid leukemia: specificgeting without immunogenicity. Blood 1994;83:1760–8.cic JG, DeBlasio T, Dumont L, Yao TJ, Scheinberg DA. Molecularission induction with retinoic acid and anti-CD33 monoclonal

tibody HuM195 in acute promyelocytic leukemia. Clin Cancers 2000;6:372–80.ron PC, Dumont L, Scheinberg DA. Supersaturating infusionalmanized anti-CD33 monoclonal antibody HuM195 in myeloge-us leukemia. Clin Cancer Res 1998;4:1421–8.ldman E, Kalaycio M, Weiner G, et al. Treatment of relapsed orractory acute myeloid leukemia with humanized anti-CD33 mono-nal antibody HuM195. Leukemia 2003;17:314–8.za A, Jurcic JG, Roboz GJ, et al. Complete remissions observed inte myeloid leukemia following prolonged exposure to lintuzumab:hase 1 trial. Leuk Lymphoma 2009;50:1336–44.cic JG, Larson SM, Sgouros G, et al. Targeted α particle immu-therapy for myeloid leukemia. Blood 2002;100:1233–9.chbiel MW, Gansow OA. Synthesis of C-functionalized trans-clohexyl-diethylenetriaminepentaacetic acids for labeling ofnoclonal antibodies with the bismuth-212 α-particle emitter.hem Soc Perkin Trans 1992;1:1173–8.kula TK, Curcio MJ, Brechbiel MW, Gansow OA, Finn RD,heinberg DA. A rapid, single vessel method for preparation of clin-l grade ligand conjugated monoclonal antibodies. Nucl Med Biol95;22:387–90.zadeh S, Brechbiel MW, Atcher RW, Gansow OA. Radiometaleling of immunoproteins: covalent linkage of 2-(4-isothiocyana-enzyl) diethylenetriaminepentaacetic acid ligand to immuno-bulin. Bioconjug Chem 1990;1:59–65.pin CG, Parker TA, McMurry TJ, Brechbiel MW. Spectrophotomet-
method for the determination of a bifunctional DTPA ligand in DTPAnoclonal antibody conjugates. Bioconjug Chem 1992;3:342–5.ula TK, McDevitt MR, Finn RD, et al. α-Emitting bismuth cyclo-
Ca37. Mc

na

acrjournals.org


xylbenzyl DTPA constructs of recombinant humanized anti-CD33tibodies: pharmacokinetics, bioactivity, toxicity and chemistry.ucl Med 1999;40:166–76.Devitt MR, Finn RD, Ma D, Larson SM, Scheinberg DA. Prepara-n of α-emitting 213Bi-labeled antibody constructs for clinical use.ucl Med 1999;40:1722–7.n RD, McDevitt MR, Scheinberg DA, et al. Refinements and im-vements for Bi-213 production and use as a targeted therapeuticiopharmaceutical. J Labelled Compds Radiopharm 1997;40:293.Devitt MR, Finn RD, Sgouros G, Ma D, Scheinberg DA. AnAc/213Bi generator system for therapeutic clinical applications:nstruction and operation. Appl Radiat Isot 1999;50:895–904.er H, Armitage JO, Bennett CL, et al. 2000 Update of recommen-tions for the use of hematopoietic colony-stimulating factors:dence-based, clinical practice guidelines. J Clin Oncol 2000;18:58–85.ouros G, Ballangrud ÅM, Jurcic JG, et al. Pharmacokinetics andsimetry of an α-particle emitter labeled antibody: 213Bi-HuM195ti-CD33) in patients with leukemia. J Nucl Med 1999;40:1935–46.lbert KS, Hamacher KA, Jurcic JG, Scheinberg DA, Larson SM,ouros G. Parametric images of antibody pharmacokinetics in Bi-3-HuM195 therapy of leukemia. J Nucl Med 2001;42:27–32.eson BD, Bennett JM, Kopecky KJ, et al. Revised recommenda-ns of the International Working Group for diagnosis, standardiza-n of response criteria, treatment outcomes, and reportingndards for therapeutic trials in acute myeloid leukemia. J Clincol 2003;21:4642–9.arlson ME, Pompie P III, Ales K, MacKenzie CR. A new method ofssifying prognostic comorbidity in longitudinal studies: develop-nt and validation. J Chron Dis 1987;40:373–83.enne A, Esterni B, Charonnier A, et al. Comorbidity is an indepen-nt predictor of complete remission in elderly patients receiving in-ction chemotherapy for acute myeloid leukemia. Cancer 2007;109:76–83.rd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic ab-rmalities are predictive of induction success, cumulative incidencerelapse, and overall survival in adult patients with de novo acuteeloid leukemia: results from Cancer and Leukemia Group BLGB 8461). Blood 2002;100:4325–36.dey GP, Coltman CA, Freireich EJ, et al. Chemotherapy of acutekemia: comparison of cytarabine alone and in combination withcristine, prednisone, and cyclophosphamide. Arch Intern Med74;133:260–6.dey GP, Freireich EJ, Monto RW, et al. Cytosine arabinosideSC-63878) therapy for acute leukemia in adults. Cancer Che-ther Rep 1969;53:59–66.kers JN, Gehan EA, Freireich EJ, et al. Cytarabine for acute leu-mia in adults: effect of schedule on therapeutic response. Archern Med 1974;133:251–9.rnett AK, Milligan D, Prentice AG, et al. A comparison of low-dosearabine and hydroxyurea with or without all-trans retinoic acid forute myeloid leukemia and high-risk myelodysplastic syndrome intients not considered fit for intensive treatment. Cancer 2007;109:14–24.ldman EJ, Brandwein J, Stone R, et al. Phase III randomized mul-enter study of a humanized anti-CD33 monoclonal antibody, lintu-mab, in combination with chemotherapy, versus chemotherapyne in patients with refractory or first-relapsed acute myeloid leu-ia. J Clin Oncol 2005;23:4110–6.

rson RA, Sievers EL, Stadtmauer EA, et al. Final report of the effi-cy and safety of gemtuzumab ozogamicin (Mylotarg) in patientsh CD33-positive acute myeloid leukemia in first recurrence.ncer 2005;104:1442–52.
Devitt MR, Ma D, Lai LT, et al. Tumor therapy with targeted atomicnogenerators. Science 2001;294:1537–40.




2010;16:5303-5311. Published OnlineFirst September 21, 2010.Clin Cancer Res Todd L. Rosenblat, Michael R. McDevitt, Deborah A. Mulford, et al. Leukemia

Lintuzumab (HuM195) for Acute Myeloid−Bismuth-213 -Particle Immunotherapy withαSequential Cytarabine and

Updated version

10.1158/1078-0432.CCR-10-0382doi:

Access the most recent version of this article at:

Cited articles

http://clincancerres.aacrjournals.org/content/16/21/5303.full#ref-list-1

This article cites 35 articles, 15 of which you can access for free at:

Citing articles

http://clincancerres.aacrjournals.org/content/16/21/5303.full#related-urls

This article has been cited by 17 HighWire-hosted articles. Access the articles at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://clincancerres.aacrjournals.org/content/16/21/5303To request permission to re-use all or part of this article, use this link

Research. on July 28, 2021. © 2010 American Association for Cancerclincancerres.aacrjournals.org Downloaded from


http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-10-0382

http://clincancerres.aacrjournals.org/content/16/21/5303.full#ref-list-1

http://clincancerres.aacrjournals.org/content/16/21/5303.full#related-urls

http://clincancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://clincancerres.aacrjournals.org/content/16/21/5303


downloaded from clincancerres.aacrjournals.org on february ... · fix human complement in vitro...

Documents