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Idarubicin including regimens in acute myelogenous leukemia in elderly patients

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Idarubicin including regimens in acute myelogenous leukemia in elderly patients
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  Critical Reviews in Oncology / Hematology 32 (1999) 59–68 Idarubicin including regimens in acute myelogenous leukemia inelderly patients Giuseppe Leone*, Simona Sica, Livio Pagano Cattedra di Ematologia ,  Uni   ersita` Cattolica del Sacro Cuore ,  Largo Francesco Vito  1 ,  I  - 00168   Roma ,  Italy Accepted 21 May 1999 Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592. Idarubicin including regimens in elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . 602.1. Intravenous idarubicin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602.1.1. Pilot studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602.1.2. Randomized studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623. Oral idarubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633.1. Induction treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633.2. Consolidation / maintenance treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643.3. Palliative therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654. Addition of growth factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Reviewers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67www.elsevier.com / locate / critrevonc 1. Introduction Acute myeloid leukemia (AML) is predominantly adisease of elderly persons. Incidence increases with ageand the median age is probably more than 65 years [1].However the management of acute myeloid leukemia inelderly patients remains controversial and mostly disap-pointing [2]. Outcome information is derived fromthose patients considered suitable for treatment in clini-cal trials, and therefore may convey an overoptimisticimpression. In fact many of these patients are notoffered intensive treatment in the belief that it willshorten their survival [3].Randomized clinical trials investigating elderly AMLtherapies are rare compared with trials dealing withyoung adults [4]. Furthermore metanalyses are ham-pered by extreme variability of inclusion criteria of patients, median age, chemotherapy schedules. In anycase the percentage of remission is more than 50% onlyin selected series and rarely long survivors are morethan 10% [5]. The unfavorable outcome of leukemia inthe elderly has been attributed both to the poor toler-ance to chemotherapy and to biological features deter-mining an increased resistance to chemotherapy. Thepoor tolerance to chemotherapy is in relation to areduced proliferative capacity of normal hemopoietic * Corresponding author. Tel.:  + 390-6-30154180; fax:  + 390-6-35503777. E  - mail address :   gleone@mware.it (G. Leone)1040-8428 / 99 / $ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.PII: S1040-8428(99)00028-1  G  .  Leone et al  .  /   Critical Re  iews in Oncology / Hematology  32 (1999) 59–68  60 stem cell in elderly people [6] and to preexisting internaldiseases, mainly cardiovascular. Resistance tochemotherapy is in relation to a major frequency of antecedent hematological disorders and myelodysplasia[7], unfavorable karyotype [8], and MDR phenotype of leukemic blasts [9,10].From a therapeutical point of view, it is well-estab-lished that the incidence of early death and deathoccurring during aplasia induced by standard inductionchemotherapy increases with age, contributing to lowCR rate [11]. Thus high resistance of leukemic cells tochemotherapic agents and low treatment tolerance areboth responsible for the poor outcome in the elderly.The double exigency to limit treatment-related mortal-ity and to overcome resistance to chemotherapy justifiesthe conflicting results obtained with attenuated doses of anthracyclines [12,13].Addition of growth factors has only marginally im-proved the outcome of leukemia, reducing the durationof the therapy-induced neutropenia but not the inci-dence of severe infections [14–18].Idarubicin (IDA), an analog of daunorubicin (DNR)with a higher therapeutic index, has been advocated asthe choice anthracycline in the elderly because of itsreduced cardiotoxicity, its capacity to circumventMDR, and finally the possibility of oral administration.Experiments in rats showed that IDA was less car-diotoxic than DNR [19], IDA-related cardiomyopathyis uncommon in leukemic patients treated with cumula-tive IDA dose of up 290 mg / m 2 [20], a dosage verymuch higher of that attained in standard protocols(about 150 mg / m 2 ). At this cumulative dose the proba-bility of IDA-related cardiomyopathy was less than 5%[20].Idarubicin seems significantly more toxic to leukemicblast cells as well as normal progenitor cells thandaunorubicin [21]. In vitro studies indicate that IDA ismore effective than the parent compounds in leukemiacell lines with the multidrug resistant phenotype [22];furthermore its main metabolite derivative, the C-13alcohol analog, idarubicinol, has a striking growth in-hibitory activity in MDR cell lines [23]. IDA is alsobioavailable in an oral dosage form. After oral adminis-tration of IDA to the patients, the concentration of idarubicinol quickly exceeds that of IDA and is re-tained in the plasma for a longer period [24]. There areseveral advantages to an oral dosage form. Currentlyanthracyclines must be administered by the intravenous(i.v.) route, and then requiring a direct intervention of the physician. An oral dosage form would improve theease of administration, avoid the costs associated withi.v. therapy, eliminate the potential for tissue damagefrom drug extravation, and possibly improve patientcompliance. Furthermore, the oral administration couldavoid the potential toxic peaks of concentration whilemaintaining the overall drug exposure, simulating aprolonged i.v. exposure and allowing tumor cells to becontinuously exposed to the drug [25], however phar-macokinetic studies have shown that the meanbioavailability of the unchanged compound is about30% of administered dose [24]. This observation in-duced to increase the doses of oral idarubicin in respectto intravenous administrations.Since the early 1980s, idarubicin has been extensivelyused in pilot studies in refractory or relapsed acuteleukemia [26–30]. At present, it is considered a validoption in first line chemotherapy in patients with adultmyeloid leukemia [18,31], being equivalent or superiorto conventionally used parent compound, daunorubicin[32–35]. 2. Idarubicin including regimens in elderly patients 2  . 1 .  Intra  enous idarubicin 2  . 1 . 1 .  Pilot studies In elderly patients IDA has been used, as first linetherapy, associated with cytarabine (Ara-C) at standard[36], or intermediate dose [37], Ara-C and etoposide[38,39], Ara-C and fludarabine plus G-CSF (FLAG-IDA) [40,41]; in patients with acute promyelocyticleukemia it has been used with success in induction as asingle agent; in the past [42], and at present, too,associated with all trans retinoic acid (ATRA) [43,44].In these pilot studies (Table 1) IDA including regi-mens induced always a CR rate higher than 50%. In 23elderly patients, median age 66 years (range 60–75)treated with conventional-dose Ara-C (200 mg / m 2 days1–5) and idarubicin (12 mg / m 2 days 1–3), the CR rateafter one induction course was 65% [36]. Toxicity wasacceptable, with four patients dying in induction. Al-though 80% of the patients in CR received two addi-tional cycles of Ara-C and IDA, only two patients werein CR 1 year after diagnosis. Median survival of pa-tients achieving CR was 11.5 months. Thus conven-tional-dose of Ara-C / IDA is an effective protocol forinduction CR, yet consolidation therapy with twocourses of the same regimen is not able to produce arelevant rate of long-term disease-free survival. Attenu-ated doses (8 mg / m 2 , days 1, 3, 5), when associated toetoposide (60 mg / m 2 , days 1–5) and Ara-C (200 mg / m 2 ,days 1–7), were able to induce an high complete remis-sion rate (69%) in patients aged more 60 years [38].Despite the reduced dose of IDA, the serum concentra-tion in this group of elderly patients was similar to thatof a group of younger patients treated with a conven-tional-dose of IDA, suggesting a reduced catabolism of this drug in elderly people [38].Anthracyclines show a particular efficacy as singleagent in the treatment of acute promyelocytic leukemia[42). Idarubicin, when associated to ATRA, induce a   G  . L  e  o n e  e  t   a l     .    /      Cr  i    t   i    c  a l   R e      i    e  w s  i    n O n c  o l    o  g  y     /        H e  m a t   o l    o  g  y  3  2    (    1   9   9   9    )     5   9  – 6   8    6   1    Table 1Pilot studies including idarubicin in the treatment of elderly patientsResistant (%)Authors (references) DFS (months)Treatment Median overall survival (months)No. of patients Age (range) CR (%) Deaths in induction (%) 17 11.5 1065 1766 (60–75)23IDA / Ara-CHeyll [36]20 – Invernizzi [37] 5IDA / Ara-C 10   65 20* 1019 14.5 13126965 (61–75)Leoni [38] IDA / Ara-C / Vp16 2620IDA / Ara-C / Vp16 5 10.5 10.520 75 (63–89) 75Hernandez-Boluda [39]87.5 12.5 0 19 – Latagliata [44] 20**IDA / ATRA 65.5 (60–81)* 50% PR.** All acute promyelocytic leukemia patients, nine of them received only ATRA; Vp16 = etoposide; ATRA = all trans retinoic acid.  G  .  Leone et al  .  /   Critical Re  iews in Oncology / Hematology  32 (1999) 59–68  62 CR rate higher than 80% in younger as well as olderpatients with promyelocytic leukemia [43,44]. In theGIMEMA study [43], IDA was administered intra-venously at the dosage of 12 mg / m 2 on days 2,4,6,8, andATRA (45 mg / m 2 ) from day 1 until CR was obtained.Resistant patients are less than 5% and no majorextrahematological toxicity was observed. In the el-derly, the same protocol [44] induced a CR rate superiorto 80%. Thrombotic complications (phlebo-thrombosis,myocardial infarction, pulmonary embolism) were ob-served in five out of 20 treated patients. 2  . 1 . 2  .  Randomized studies  (  Table  2)  The first randomized study [32], published in 1991,comparing two groups of leukemic young patients (agedless 60 years) treated with IDA or DNR and Ara-C(IDA 12 mg / m 2 , or DNR 60 mg / m 2 both for 3 days,associated with Ara-C 200 mg / m 2 continuous infusionfor 5 days) showed a superior response for IDA group.The advantage of IDA was evident in terms of completeremission rate (80 vs. 58%) and median overall survival(19.5 vs. 13.5 months).In the same year a GIMEMA study was published[33], comparing idarubicin with daunorubicin (12 mg / m 2 IDA or 45 mg / m 2 DNR for 3 days, both associatedto 100 mg / m 2 Ara-C for 7 days) in elderly patients (agedmore than 55 years) with acute myeloid leukemia. Thisrandomized multicentric trial failed to demonstrate sig-nificant difference in terms of complete response rate(CR), overall survival, relapse free survival between thetwo arms. In this study idarubicin showed a more rapideffect in eradicating leukemia; chemoresistance was lessfrequently observed in idarubicin treated patients butthis beneficial effect was counterbalanced by a highertoxicity, as manifested by increased number of patientswho died in induction. This fundamental experiencesuggested a major efficacy of IDA but also a majorhematological toxicity.Two important American trials, including peopleaged more 60 years and comparing idarubicin withdaunorubicin in association with Ara-C, were publishedin 1992 by Vogler et al. [34] and by Wiernik et al. [35].In the study conducted by Vogler [34], 230 patients withnewly diagnosed AML were given a daily infusion of Ara-C (100 mg / m 2 for 7 days) and were assigned ran-domly to receive DNR (45 mg / m 2 ) or IDA (12 mg / m 2 )daily for the first 3 days. Those patients who achieveda complete remission were given three consolidationcourses that consisted of Ara-C (100 mg / m 2 intra-venously) and thioguanine (100 mg / m 2 orally) every 12h for 5 days and either DNR (50 mg / m 2 ) or IDA (15mg / m 2 ) on the first day of each cycle. The CR rateswere 71% on the IDA arm and 58% on the DNR arm.On the IDA arm, the median survival and medianremission were 297 and 433 days, respectively; on theDNR arm, the median survival and median remissionwere 277 and 328 days, respectively. People aged more60 years represented 50% of all enrolled patients; of these 63% of IDA arm and 53% of DNR arm achievedCR; median survival was 235 days in IDA arm and 209days in DNR arm without significant difference.In the study conducted by Wiernik et al. [35], medianage of all enrolled patients was 55 years and 40% wereolder 60 years. Idarubicin (13 mg / m 2 / day) or daunoru-bicin (45 mg / m 2 / day) were used on the first 3 days andAra-C (100 mg / m 2 / day) was continuously infused for 7days. The CR rate of patients was significantly higher inthe group treated with IDA (67%) than in the grouptreated with daunorubicin (58%). In patients aged morethan 60 years the CR rate was 50% in the group treatedwith IDA and 44% in the group treated with daunoru-bicin. More importantly when the response durationcurves were subjected to logrank analysis, a significantdifference in favor of the IDA treatment emerged. Inthis trial, patient age had no significant effect on remis-sion duration.Recently, three randomized French trials [45–47]have tested the efficacy of intravenous idarubicin vs.different anthracyclines in elderly AML patients.In the BGMT study [45], 220 patients aged 55–75were randomized to receive as induction chemotherapyAra–C (100 mg / m 2 / day, continuous infusion for 7 days) Table 2Randomized trials comparing idarubicin with other anthracyclines in elderly patientsAnthracyclines No. of patients Age CR (%) Deaths in in- Median overallResistant (%)Authors (refer- DFSduction (%)ences) survivalIDA / DNR 24 / 22Vogler [34] 50–60 71 / 45 – – – 364 / 179 days52 / 59 235 / 209 days – IDA / DNR – Vogler [34] – 63 / 53  60IDA / DNR 127 / 128   55 40 / 39Mandelli [33] 37.9 / 21.6 21.7 / 39.2 299 / 284 days 87 / 169 daysIDA / DNR 17 / 20 50–60 71 / 65Wiernik [35] – – – – IDA / DNR 38 / 45   60 50 / 44Wiernik [35] – – – 102 / 9620.5 / 14.8 11.6 / 24 647 / 283 328 / 273Reiffers [45] IDA / DNR 112 / 108 55–75 68 / 6173 / 60IDA / RBD 8.6 / 16.2 15.5 / 22.2 12 / 24 months Not reported116 / 117 50–65Pignon [46]IDA / MIT 60–83 59 / 63 Not reported 6 months noArchimbaud Not reported79 / 79difference[47]  G  .  Leone et al  .  /   Critical Re  iews in Oncology / Hematology  32 (1999) 59–68   63Table 3Idarubicin vs. daunorubicin: Induction failure and complete remission by age a Age (years) Late induction failure (%)Early induction failure (%) Complete remision (%)DNR IDA DNRIDA IDA DNR  40 2 / 93 (2.2) 6 / 78 (7.6) 11 / 93 (11.8) 24 / 78 (30.7) 80 / 93 (86) 48 / 78 (61.5)20 / 143 (14.0)40–59 22 / 170 (12.9) 22 / 143 (15.4) 44 / 170 (25.9) 101 / 143 (70.6) 104 / 170 (61.1)68 / 284 (23.9) 58 / 285 (20.3) 85 / 284 (29.9)83 / 285 (29.1) 144 / 285 (50.5)60 +  131 / 284 (46.1)105 / 521 (20.2)All patients 96 / 532 (18.0) 91 / 521 (17.5) 53 / 532 (28.8) 325 / 521 (62.4) 283 / 532 (53.2)Effect:  P = 0.4 Effect:  P  0.0001 Effect:  P = 0.002Trend:  P = 0.2 Trend:  P = 0.006Trend:  P = 0.06 a Metanalysis from the studies: GIMEMA, Italy; MSKCC, US; SECSG, US; A. Einstein, US; BGMT, France. Reported from Brit J Haemat1998;103:100. Effect = difference between IDA vs. DNR; trend = standard test of heterogeneity among different groups of age. combined with either daunorubicin (50 mg / m 2 / day, i.v.bolus for 3 days) or idarubicin (8 mg / m 2 / day, i.v. bolusfor 5 days). The CR rate was similar after IDA (68%)and DNR (61%). For patients aged 55–65, the CR ratewas significantly higher after IDA (83%) than afterDNR (58%). Persistent leukemia was more frequentafter DNR (26 / 108) than after IDA (13 / 112). The sur-vival and DFS were similar in both groups. However,there was a trend for a longer event free survival in theIDA group.In the GOELAM study [46], 251 patients, aged 50–65years with de novo AML were recruited to a multiinsti-tutional randomized clinical trial. Induction therapyconsisted of Ara-C (200 mg / m 2 , continuous infusion,days 1–7) with either Zorubicin (200 mg / m 2 , i.v., days1–4) or IDA (8 mg / m 2 , days 1–5). Consolidation ther-apy consisted of a single course of intensive chemother-apy with high dose Ara-C (3 g / m 2 , 3-h infusion, q 12 h,days 1–4) and  m -amsacrine ( m -AMSA) (100 mg / m 2 / day, i.v., days 5–7). The CR rate was significantlyhigher in IDA arm (73 vs. 60%) Overall survival was notsignificantly different in the two arms.In the study of Archimbaud et al. [47], idarubicin hasbeen compared in elderly patients to Mitoxantrone; 158patients of median age 69 years (range 60–83) withAML at diagnosis, were randomized to receive IDA (8mg / m 2 / day for 5 days) or Mitoxantrone (7 mg / m 2 onday 1, 3, 5) both associated to etoposide (100 mg / m 2 , i.v.on days 1–3) and Ara-C (100 mg / m 2 / day on continuousinfusion on day 1-7). G-CSF, 5   g / kg / day was adminis-tered after chemotherapy in patients aged more than 70years. Patients achieving CR received one course of consolidation using the same schedule with Ara-C over5 days. There was no significant difference in CR ratebetween IDA (59%) and Mitoxantrone (63%). Mediantime to recovery of polymorphonucleates (PMN) andplatelets (PLTs), and severe toxicity of induction did notdiffer between the two arms; 10% of patients died ininduction and 9% died from toxicity in consolidationphase. Survival and disease-free survival, respectively 8and 6 months, did not differ in the two arms.A metanalysis of different trials comparing IDA withDNR was recently published [48]. Difference in remis-sion rate in favor of IDA was greater in younger thanin older patients (Table 3). The mortality during the first40 days was much greater in those aged  60 years thanin those aged   40 years. At older ages such deathsappeared to be slightly more numerous with idarubicinthan with daunorubicin, but at younger ages the oppo-site appeared to be the case, though this trend was notquite significant ( P = 0.06). After 40 days there werefewer deaths with idarubicin at all ages, though thedifference appeared slightly smaller in the older patientsthan in the younger (trend:  P = 0.2). The cumulativeeffect of these two trends was a highly significant trend( P = 0.0006) for the difference in a complete remissionrates between idarubicin to be greater in younger thanin older patients (Table 3). 3. Oral idarubicin Oral idarubicin has been employed as first line ther-apy aiming at CR in untreated, late relapsing elderlypatients considered unsuitable for standard intensivetherapy, or as consolidation / maintenance therapy aim-ing at increasing the treatment compliance, or as pallia-tive therapy. Oral idarubicin has been used as singleagent [49] or in association with Ara-C [50,51],etoposide with [52] or without [53] thioguanine. 3  . 1 .  Induction treatment Oral idarubicin, given as a single agent [49] at thedose of 30 mg / m 2 / day for 3 days in 20 patients aged65–79 years with previously untreated AML, inducedCR in eight patients; induction and / or early deaths infive and failures in seven. All patients experiencedprofound neutropenia requiring in-patient assistance.Oral idarubicin (25 mg / m 2 for 3 days) has been givenassociated to Ara-C at standard [50], or low dose Ara-C[51] as initial induction treatment of AML in elderlypatients.
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