Investigational New Drugs17: 81–87, 1999.© 1999Kluwer Academic Publishers. Printed in the Netherlands.

81

Phase I study of liposomal daunorubicin in patients with acute leukemia

Jorge Cortes, Susan O’Brien, Elihu Estey, Francis Giles, Michael Keating and Hagop KantarjianDepartment of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Key words:Liposomal daunorubicin, acute leukemia, phase I

Summary

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acuteleukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity andprobably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapyin acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxomer ; DNX) in patients withrefractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m2

on each cycle, to a total dose of 225, 300, 450, and 600 mg/m2, respectively. At least three patients were included ateach dose level before escalating to the next level, and patients could receive more than one course at the next doselevel. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven receivedtwo courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines.The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m2, 2of 9 treated at 150 mg/m2 and 1 of 6 at 100 mg/m2. Other non-hematologic toxicity was mild and infrequent.There was no change in post-LVEF among 9 patients with available data and no significant cardiac events weredocumented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blastphase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved athird complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m2

and has significant anti-leukemia activity.

Introduction

The prognosis of patients with acute leukemia has im-proved significantly over the past three decades. Still,most patients die due to disease progression. With cur-rent frontline regimens, 60% to 80% of adult patientswith acute myelogenous leukemia (AML) and 75% to85% of those with acute lymphocytic leukemia (ALL)achieve a complete remission (CR). However, mostpatients eventually relapse and long-term disease-freesurvival (DFS) rates are 20% to 30%, and 30% to 45%,respectively [1–4]. This emphasizes the need to dis-cover new agents for the treatment of acute leukemiato improve the long-term prognosis of patients.

Anthracyclines are effective anti-leukemia agentsused in most frontline regimens for AML and ALL

[1–4]. Several studies suggest that dose-intensive an-thracycline therapy is associated with improved pro-gnosis in acute promyelocytic leukemia [5], AML[6], and ALL [7]. However, anthracyclines are doselimited by mucositis and, in the long term, dose-dependent cardiac toxicity [8], thus limiting the pos-sibility of dose escalation. Liposomal encapsulationof anthracyclines changes the pharmacologic proper-ties of the active compound and has been advocatedto reduce toxicity, therefore, potentially allowing forhigh-dose anthracycline therapy [9, 10]. Althoughliposomal anthracyclines have been reported to inducesignificant hand-foot syndrome, in contrast to lipo-somal doxorubicin, lipsomal daunorubicin (DNX) hasbeen reported to induce this event very rarely [11].Also, in vitro studies using several acute leukemia

82

cell lines have shown an increased activity of DNXcompared to conventional daunorubicin at equivalentdoses (DaunoXome, Investigator’s Brochure, Nex-star Pharmaceutical), prompting our interest in thisformulation.

DNX is the citrate form of daunorubicin encapsu-lated in a unilamellar liposome (mean diameter about45 nm) composed of cholesterol and the phospholipiddistearoylphosphatidylcholine (DSPC), typical lipidcomponents of cell membranes [12]. Human pharma-cokinetic studies with liposomal daunorubicin showedthat the peak plasma level is increased 100-fold com-pared to equivalent doses of conventional daunoru-bicin, and that there is a 36-fold increase in meanarea under the plasma curve compared to conven-tional drug [13]. Initial phase I trials in solid tumorsshowed that the dose-limiting toxicity was myelosup-pression at doses of between 100 mg/m2 and 120mg/m2 repeated every three weeks, with no signific-ant extramedullary toxicity [14]. In subsequent trialsusing liposomal daunorubicin in patients with AIDS-related Kaposi’s sarcoma, no cardiac toxicity wasfound among patients receiving cumulative daunoru-bicin doses of >600 mg/m2 (range 600 to 3159 mg/m2)[15].

These properties of liposomal daunorubicin makeit an attractive drug to explore the concept of dose-intensive anthracycline therapy in acute leukemias.We therefore conducted a phase I study of liposomaldaunorubicin to investigate the toxicity and maximumtolerated dose of this drug among patients with acuteleukemias.

Patients and methods

Between May 1997 and October 1997, 24 patientswere included in this study. Eligibility criteria in-cluded: 1) refractory or relapsed acute myelogenousleukemia, refractory or relapsed acute lymphoblasticleukemia, or chronic myelogenous leukemia in myel-oid or lymphoid transformation, 2) age≥ 15 years,3) total bilirubin≤ 2.0 mg/dl, 4) serum creatinine≤2.0 mg/dl, 5) performance status (PS) (Zubrod) 0–2,and 6) no clinical evidence or past medical history ofheart disease. Patients were eligible regardless of theirprevious exposure to anthracyclines. The protocolwas approved by the IRB and all patients signed aninformed consent according to institutional guidelines.

Treatment schedule

Liposomal Daunorubicin (Daunoxomer; Nexstar,Boulder, CO) was administered via a central catheteras a two-hour infusion daily for three days. The doselevels investigated were 75, 100, 150 and 200 mg/m2

daily for three days (total dose 225, 300, 450, and 600mg/m2). The daily dose was mixed in 200 ml D5Wand infused using a pump to ensure proper duration ofthe infusion. This schedule was chosen to mimic theschedule used with conventional daunorubicin and thestarting dose selected to represent a minor (25%) in-crement in the dose from the commonly used dosing ofconventional daunorubicin of 60 mg/m2. The rationalewas that if a dose increase of at least this magnitudecould not be achieved, the concept of dose escalationusing DNX would not be considered safe. Treatmentwas repeated every 3 to 4 weeks provided full recov-ery from any prior toxicity and dose escalation wasallowed within patients if there was no evidence ofgrade 3 or 4 non-hematologic toxicity.

All patients received antibacterial (quinolone orsulfamethoxazole/trimethoprim) and antifungal (fluc-onazole± itraconazole) prophylaxis and mouth carewith salt and soda mouth washes as per conven-tional practice at MDACC. Growth factors were notroutinely used. Prior to the administration of DNX allpatients had a complete history and physical exam,CBC, SMA-12, andbone marrow aspiration. Everyeffort was made to measure left ventricular ejectionfraction by MUGA or echocardiogram. After admin-istration of DNX patients were evaluated for toxicityat least three times per week if outpatient or dailyas inpatient with a CBC on every visit, and SMA-12every two to four weeks. An effort was made to obtainMUGA or echocardiogram after 28 days of the firstdose, and in all patients prior to receiving a secondcycle of DNX.

Dose escalation and statistical considerations

This was a Phase I study with a “3+3” design. Atleast three patients were included at each dose level.If none of the patients experienced dose-limiting tox-icity (DLT), then the next three patients were enrolledat the next higher level. If one patient experiencedDLT at a given dose level, at least three more pa-tients were to be accrued at the same dose level. Ifno more than one of six patients experienced DLT,then the next cohort of patients was treated at the nexthigher dose level. If more than two patients at any dose

83

level experienced DLT, it was considered that the max-imally tolerated dose had been exceeded and at leastthree more patients were treated at the next lower doselevel. The MTD was defined as the dose level at whichno more than two of six patients experienced a DLT.DLT was defined as any first-course grade 3 or 4 non-hematologic toxicity as defined by the NCI CommonToxicity Criteria.

Results

Twenty-four patients were treated on this study, andtheir clinical characteristics are presented in Table 1.The median age was 52 years (range, 24 to 78 years).All patients except one had a PS of 0 to 2 (median1, range 0 to 4). The one patient with PS 4 at thestart of therapy was registered while PS was 1 butupon admission requested to delay therapy; when shereturned for therapy, her PS was 4 with very highWBC and extreme fatigue. Nineteen patients had re-fractory (n=6) or relapsed (n=13) acute myelogenousleukemia (AML), two refractory acute lymphoblasticleukemia (ALL), two chronic myelogenous leukemiain myeloid blast phase (CML-BP), and one relapseacute promyelocytic leukemia. Ten AML patients hadan initial diagnosis of myelodysplastic syndrome (re-fractory anemia with excess of blasts-RAEB, n=4, orrefractory anemia with excess of blasts in transform-ation -RAEB-T, n=6) which had transformed to AMLby the time they were included in this study.

Seven patients had not received prior anthracyc-lines: two patients with CML-BP had received andfailed combination chemotherapy with cyclophosph-amide, cytarabine, and topotecan (CAT) [16] and fivepatients had received topotecan alone or in combina-tion with ara-C as their initial therapy for RAEB orRAEB-T [17]. One additional patient had receivedanthracyclines as part of the initial therapy for mul-tiple myeloma (single agent idarubicin at unspecifiedcumulative doses prior to referral to MDACC), butno anthracyclines with the initial therapy of a sec-ondary RAEB. The cumulative dose of anthracyclinesreceived previously cannot be calculated in 7 patientswho received at least part of their initial therapy beforereferral to MDACC, including only one course of a“3+7”-like regimen in one patient, to multiple coursesand combinations of induction and salvage anthracyc-lines. Among the 9 for whom complete informationis available, six had received idarubicin as their onlyanthracycline, with a median cumulative dose of 76

Table 1. Clinical characteristics of 24 patients.

Characteristics Median (Range)

Age (years) 52 (24–78)

Performance status (Zubrod) 1 (0–4)**

WBC (×109/L) 8.3 (0.2–103.5)

Platelets (×109/L) 22 (5–215)

Creatinine (mg/dl) 0.9 (0.6–1.6)

Bilirubin (mg/dl) 0.6 (0.3–1.9)

LVEF (%)* 55 (50–80)

Prior salvage regimens 1 (0–6)

First CR duration (weeks)a 22 (8–150)

Diagnosis No.

AML 19

APL 1

CML-BP 2

ALL 2

* Available for 9 patientsa Ten patients had never achieved a CR* Distribution of patients by performance status: PS 0, n=4; PS 1,n=12; PS 2, n=7; PS 4, n=1.

mg/m2 (range, 36 to 96 mg/m2), one had receivedidarubicin 252 mg/m2 and mitoxantrone 30 mg/m2,one had received idarubicin 72 mg/m2 and doxorubi-cin 200 mg/m2, and one had received only doxorubicin200 mg/m2 (all cumulative doses). Three patients hadreceived an allogeneic bone marrow transplant beforeentering this trial. Two were conditioned with busulfanand cyclophosphamide, and one with etoposide andtotal body irradiation.

One patient was inevaluable for toxicity becauseshe received only one dose of DNX (100 mg/m2).This patient had relapsed AML and was registered onthis study but requested to delay therapy for personalreasons. By the time treatment was started four weekslater, she had a rapidly increasing WBC with DIC andfever. She died of progressive disease and sepsis be-fore receiving the second dose of DNX. The other 23patients received 32 courses of DNX.

Toxicity is presented in Table 2. The most commontoxic effect was mucositis which was dose limiting.Eleven of 23 evaluable patients (48%) developed mu-cositis after the first course of DNX, with 5 patientswith grade 1–2 and 6 with grade 3–4. Grade 3–4 mu-cositis occurred in 1 of 6 patients (17%) treated at 100mg/m2, 2 of 9 (22%) treated at 150 mg/m2, and 3of 5 (60%) treated at 200 mg/m2. Thus, 150 mg/m2

was defined as the MTD. Other common toxic effectsincluded rash (n=2, both at 200 mg/m2), nausea (n=1,

84

at 150 mg/m2), and diarrhea (n=1, at 100 mg/m2), inall cases grade 1–2. Myelosuppresion was universal.Fever and documented infections were common butnot dose-related. Nine patients had an episode of feverof unknown origin, and 4 patients had an episode ofsepsis or pneumonia after DNX. Nine patients hadtheir left ventricular ejection fraction (LVEF) meas-ured before and after (≥28 days) DNX. The medianpre-DNX was 55% (range, 50% to 80%) and the me-dian post-DNX LVEF was 55% (range 40% to 85%).An additional four patients had only post-DNX eval-uation with a median LVEF of 60% (range, 55% to67%). Six patients had only a pre-DNX assessment(median LVEF 63%, range 51% to 78%). One pa-tient developed significant tachycardia (rate 140–160x′) after two courses of DNX (first at 100 mg/m2 andsecond at 150 mg/m2), with a LVEF of 40% after thesecond course (baseline 55%). This patient had historyof Hodgkin’s disease treated with MOPP/ABVD andradiotherapy to a mantle field and later received an-thracyclines as part of the induction regimen for AML,but doses and schedules for these regimens were un-available. At the time of the cardiac event, the patientwas septic and receiving broad-spectrum antibioticsand antifungals as well as white blood cell transfusionsand the tachycardia was thought to be secondary tosepsis. No other events clinically suggestive of car-diac toxicity or declines in the LVEF below 50% wereseen. Only one patient developed an acute event thatwas attributed to the infusion of the liposomal formu-lation, consisting of transient, asymptomatic rash withthe first dose of the first cycle of DNX, but no morerashes were seen with the second and third doses.

Eight patients received more than one course ofDNX. One patient received a total of three courses,with the 2 consolidation courses given at 150 mg/m2

daily for 2 days (initial course at 150 mg/m2 daily for 3days). The other seven patients received a total of twocourses each, 4 at 150 mg/m2 and 3 at 200 mg/m2,all cases representing a one dose level escalation fromtheir first course. Toxicities for these 9 courses wereall grade 1-2 and included mucositis (3 at 150 mg/m2,1 at 200 mg/m2), nausea (n=1 at 150 mg/m2), anddiarrhea (n=1 at 200 mg/m2). One patient developedfever of unknown origin and four developed sepsis orpneumonia.

After a median follow-up of 10 weeks, 6 patientsare alive. Two patients achieved a complete remissionwith DNX. One patient is a 24-year-old female whowas initially diagnosed with CML in early chronicphase. She refused interferon-based therapy or al-

logeneic bone marrow transplant and received onlyhydroxyurea which she took erratically with moder-ate control of her disease. She developed a myel-oid blast phase 42 months after diagnosis and wastreated with one course of cyclophosphamide, cyta-rabine and topotecan (CAT [16]) with no response.She then received DNX 150 mg/m2 daily for 3 dayswhich was well tolerated except for grade 2 nauseaand vomiting. On day 14 after the start of therapythe bone marrow as hypoplastic and the patient wasseverely pancytopenic and requiring transfusions. Byday 21 the platelets recovered to 272×109/L andWBC 7.2×109/L, with 3% blasts, and the bone mar-row on day 28 showed 3% blasts, confirming thatthe patient was back in chronic phase, although still100% Philadelphia chromosome-positive. The patientrefused any more chemotherapy and has stayed on hy-droxyurea only. She is still in second chronic phase16 months after treatment with DNX. The secondpatient was diagnosed with acute promyelocytic leuk-emia and achieved a CR after treatment with oralall-trans retinoic acid (ATRA). He received consol-idation and maintenance with alternating cycles ofidarubicin and POMP (6-mercaptopurine, vincristine,methotrexate and prednisone) for 18 months. He re-lapsed after 42 months in first remission and receivedliposomal-ATRA with which he achieved a secondCR. He was consolidated with alternating coursesof idarubicin, liposomal ATRA, and mitoxantrone +etoposide. He relapsed after 15 months (cumulativedose of idarubicin 252 mg/m2 and mitoxantrone 30mg/m2) and received DNX 150 mg/m2 daily for 3days. He achieved a 3rd CR by day 35 after DNX withno adverse effects other than subclinical disseminatedintravascular coagulation. He received 2 consolidationcourses of DNX at 150 mg/m2 daily for 2 days alsowith no complications. He relapsed after 6 months andhas now achieved a fourth CR with arsenic trioxide.The LVEF before the start of DNX was 50% and itwas again 50% at the time of the third relapse.

Discussion

Liposomal encapsulation of anthracyclines has beenadvocated as a means of decreasing the toxicity andpossibly increasing the efficacy of these agents [9].Initial phase I studies in patients with solid tumorsusing DNX reported myelosuppression at doses ofbetween 100 mg/m2 and 120 mg/m2 repeated everythree weeks, with no significant extramedullary tox-

85

Table 2. Toxicity by dose of DNX (first course only).

No. with toxicity (grade)

Dose No. of Sepsis/

(mg/m2/day) patients Nausea Diarrhea Mucositis Skin FUO pneumonia

75 3 – – – – 1 1

100 7 – 1(2) 2(1,3) – 2 1

150 9 1(2) – 4(1,2,3,4) – 4 2

200 5 – – 5(1,1,3,4,4) 2(1,2) 2 0

icity [14], but no phase I study has been done inpatients with acute leukemias where myelosuppres-sion is not considered a dose-limiting toxicity. In thisstudy we escalated the dose of anthracyclines usingDNX and identified an MTD of 150 mg/m2 in a pop-ulation of heavily pretreated patients with refractoryor relapse. The dose-limiting toxicity was mucositis,which was present in all 5 patients treated at 200mg/m2, including three patients with grade 3–4. Thetreatment was myelosuppressive in all patients andfever and infectious complications were common, butdoses of≤ 150 mg/m2 were well tolerated.

There is only limited information on the MTD forconventional daunorubicin. Phase I studies are scarceand were conducted in patients with solid tumors withmyelosuppression, nausea and vomiting being thedose-limiting toxicities [18, 19]. We could not identifyany formal phase I study in patients with leukemia butsome investigators have used high-dose daunorubicinin patients with acute leukemia. Weil et al. [20] admin-istered single-agent daunorubicin 60 mg/m2/day for 3,5, or 7 days (total dose 180, 300, or 420 mg/m2) to124 patients with AML, 91 of which were previouslyuntreated. The overall CR rate was 22%, with no sig-nificant differences between the 3-(29%), 5-(16%) and7-day (22%) schedules. Clinically significant cardiactoxicity was noted in 10 patients (no measurementof LVEF was reported), elevation of BUN in 4, andabnormal liver function tests in 2. Gastrointestinaltoxicity was not mentioned in this report [20]. In asecond phase of this study, 211 patients were treatedand the schedules were modified to 60 mg/m2d for 5days, versus weekly or bi-weekly administrations. Thedaily administration was more effective (CR rate 34%)than the weekly (20%) and bi-weekly (16%) sched-ules. Clinically significant cardiotoxicity occurred in9 patients, most significant in the intermittent sched-ules, but no information on LVEF was available [20].In another study looking at high-dose daunorubicin,

23 patients with AML (16 previously untreated) re-ceived daunorubicin 180 mg/m2. A bone marrow wasdone on day 9–10 and patients with persistent blastsreceived a second dose of 120 mg/m2 if the bone mar-row was hypocellular, or 180 mg/m2 if it was normo-or hypocellular. If the bone marrow was “improvedor severly hypocellular”, therapy was deferred and abone marrow repeated 4–7 days later. A third dosecould be given following the same guidelines as for thesecond dose. The median dose administered was 360mg/m2 (range, 180 to 540 mg/m2). The CR rate was22%. Fifteen of the 50 doses of daunorubicin admin-istered were associated with nausea and/or vomitingand 11 patients (48%) developed moderate to severepharyngitis. One patient developed fatal cardiotox-icity after 360 mg/m2 of daunorubicin but no data wasavailable on changes in LVEF, and there were no renalor hepatic toxic events [21].

Comparisons between these studies and the presentstudy using DNX cannot be made considering thedifferent schedules used, but it is notable that mu-cositis was the only clinically significant toxic eventin our series. Although mucositis was also frequent(48% of the patients), it was grade 3–4 in only 6 pa-tients (26%) and was dose-related (17% at 100 mg/m2,22% at 150 mg/m2, 60% at 200 mg/m2), constitut-ing the dose-limiting toxicity. We did not see anyevents of hand-foot syndrome, supporting the obser-vation of Rarick et al. [11] of the rarity of this eventwith DNX. We observed only one event suggestiveof cardiac toxicity with a decrease in the LVEF andtachycardia, with the LVEF as measured by echocar-diogram or MUGA scan remaining unchanged in mostpatients. This lack of clinically significant cardiotox-icity is encouraging, specially considering that mostpatients had received prior anthracyclines. In studiesof patients with Kaposi’s sarcoma, cumulative dosesin excess of 600 mg/m2, and in some cases >2000mg/m2, have been used without evidence of cardi-

86

otoxicity [15]. However, the schedule used in thosepatients is a bi-weekly administration of one dose of40 to 60 mg/m2 [15, 22]. Also, it has to be recognizedthat the follow-up after DNX for most of the patientsreported in this series was short and although no signi-ficant clinical cardiac events were noticed, informationon LVEF changes is lacking in a number of patientspreventing full evaluation of subclinical changes. Still,it is possible that using DNX from the start of ther-apy might allow the use of higher cumulative dosesof anthracyclines and/or more dose-intensive regimensand further studies with more attention to cumulativecardiotoxicity are warranted.

It was encouraging to see significant antileukemiaactivity with DNX in this series, including two patientswith significant responses. One patient with CMLin blast phase had not received prior anthracyclines,but had already failed an effective chemotherapy regi-men (CAT) which in our experience induces a secondchronic phase in 60% of patients [16]. The secondpatient had APL and had received ATRA, both oraland liposomal, and significant doses of anthracyclinesprior to DNX. It has been proposed that liposomalencapsulation of anthracyclines favors localization ofthe drug in tumor tissues making it more effectivethan regular anthracyclines [12] although the relev-ance of this effect in hematologic malignancies isunclear. It has also been suggested that liposomal en-capsulation of doxorubicin can overcome multi-drugresistance [23–26]. Increased intracellular accumula-tion of the drug and redistribution with more drugshifted to the nucleus have been proposed as the mech-anisms of this effect [23], although an inhibition ofthe P-glycoprotein function by direct interaction hasbeen suggested [24]. Most of these studies howeverhave been done using liposomal doxorubicin, whereboth the anthracycline and the liposome are differentto DNX, and studies are underway to investigate theeffect of DNX on MDR.

We conclude that with the schedule used in thistrial, the MTD for DNX is 150 mg/m2 daily for 3 dayswith mucositis being the dose-limiting toxicity. Theavailability of this formulation of daunorubicin couldmake use of anthracyclines safer in acute leukemiasand will allow us to explore the value of high-doseanthracyclines in several hematologic malignancies.Studies using high-dose DNX in several combinationsfor acute leukemias are currently being conducted.

References

1. Cortes JE, Kantarjian HM: Acute lymphoblastic leukemia. Acomprehensive review with emphasis on biology and therapy.Cancer 76: 2393–2417, 1995

2. Copelan EA, McGuire EA: The biology and treatment of acutelymphoblastic leukemia in adults. Blood 85: 1151–1168, 1995

3. Estey EH: Treatment of acute myelogenous leukemia andmyelodysplastic syndromes. Seminars in Hematology 32:132–151, 1995

4. Rowe JM, Liesveld JL: Treatment and prognostic factors inacute myeloid leukemia. Baillieres Clinical Hematology 9:87–105, 1996

5. Head D, Kopecky KJ, Weick J et al.: Effect of aggressive daun-omycin therapy on survival in acute promyelocytic leukemia.Blood 86: 1717–1728, 1995

6. Usui N, Dobashi N, Kobayashi T et al.: Role of daunorubi-cin in the induction therapy for adult acute myeloid leukemia.Journal of Clinical Oncology 16: 2086–2092, 1998

7. Todeschini G, Meneghini V, Pizzolo G et al.: Relationshipbetween Daunorubicin dosage delivered during induction ther-apy and outcome in adult acute lymphoblastic leukemia.Leukemia 8: 376–381, 1994

8. Von Hoff DD, Rozencweig M, Layard M et al.: Daunomycin-induced cardiotoxicity in children and adults. A review of 110cases. American Journal of Medicine 62: 200–208, 1977

9. Kim S: Liposomes as carriers of cancer chemotherapy. Currentstatus and future prospects. Drugs 46: 618–638, 1993

10. Rahman A, Fumagalli A, Goodman A et al.: Potential ofliposomes to ameliorate anthracycline-induced cardiotoxicity.Seminars in Oncology 11: 45–55, 1984

11. Rarick MU, Gill PS, Wernz JC et al.: Dermatological toxicitiesassociated with chemotherapy using liposomal encapsulateddaunorubicin (DaunoXome). Proc Am Soc Clin Oncol 16:248a (Abstract #878), 1997

12. Forssen EA, Coulter DM, Proffitt RT: Selectivein vivo loc-alization of daunorubicin small unilamellar vesicles in solidtumors. Cancer Research 52: 3255–3261, 1992

13. Gill PS, Espina BM, Muggia F et al.: Phase I/II clinicaland pharmacokinetic evaluation of liposomal daunorubicin.Journal of Clinical Oncology 13: 996–1003, 1995

14. Guaglianone P, Chan K, DelaFlor-Weiss E et al.: Phase Iand pharmacologic study of liposomal daunorubicin (Daun-oXome). Investigational New Drugs 12: 103-110, 1994

15. Cohen P, Gill PS, Wernz J et al.: Absence of cardiac toxicity inpatients who received 600 mg/m2 of liposomal encapsulateddaunorubicin (DaunoXome). Proceedings ASCO 16: 217a(Abstract #761), 1997

16. Cortes J, Kantarjian H, Talpaz M et al.: Cyclophosphamide,ara-C, and Topotecan (CAT) for patients with chronic myelo-genous leukemia in transformation. Blood 92: 627a (Abstract#2586), 1998

17. Beran M, Kantarjian H, O’Brien S et al.: Topotecan, atopoisomerase I inhibitor, is active in the treatment of myel-odysplastic syndrome and chronic myelomonocytic leukemia.Blood 88: 2473–2479, 1996

18. Harvey J, Goodman A, McFadden M et al.: A phase I study ofdaunorubicin in advanced untreatable malignancies. Seminarsin Oncology 11: 33–35, 1984

19. Woodcock TM, Allegra JC, Richman SP et al.: Pharmacologyand phase I clinical studies of daunorubicin in patients withadvanced malignancies. Seminars in Oncology 11: 28–32,1984

87

20. Weil M, Glidewell OJ, Jacquillat C et al.: Daunorubicin in thetherapy of acute granulocytic leukemia. Cancer Res 33: 921–928, 1973

21. Greene W, Huffman D, Wiernik PH et al.: High-dose daunoru-bicin therapy for acute nonlymphocytic leukemia: correlationof response and toxicity with pharmacokinetics and intracel-lular daunorubicin reductase activity. Cancer 30: 1419–1427,1972

22. Gill PS, Wernz J, Scadden DT et al.: Randomized phase IIItrial of liposomal daunorubicin versus doxorubicin, bleomy-cin, and vincristine in AIDS-related Kaposi’s sarcoma. Journalof Clinical Oncology 14: 2353–2364, 1996

23. Thierry AR, Vige D, Coughlin SS et al.: Modulation of dox-orubicin resistance in multidrug-resistant cells by liposomes.FASEB Journal 7: 572–579, 1993

24. Thierry AR, Dritschilo A, Rahman A: Effect of liposomes on

P-glycoprotein function in multidrug resistant cells. Biochem-ical & Biophysical Research Communications 187: 1098–1105, 1992

25. Mickisch GH, Rahman A, Pastan I et al.: Increased effect-iveness of liposome-encapsulated doxorubicin in multidrug-resistant-transgenic mice compared with free doxorubicin.Journal of the National Cancer Institute 84: 804-805, 1992

26. Oudard S, Thierry A, Jorgensen TJ et al.: Sensitization ofmultidrug-resistant colon cancer cells to doxorubicin encap-sulated in liposomes. Cancer Chemotherapy & Pharmacology28: 259–265, 1991

Address for offprints:Jorge Cortes, Anderson Cancer Center, De-partment of Leukemia, 1515 Holcombe Blvd., Box 61, Houston,Texas 77030, Tel.: (713) 794-5783, Fax: (713) 794-4297