Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

Cancer Treatment Reviews (2009) 35, 97– 120

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ANTI-TUMOUR TREATMENT

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly Andrea Kuendgen, Ulrich Germing

*

Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, ¨sseldorf 40225, Germany Moorenstr 5, Du Received 4 March 2008; received in revised form 1 September 2008; accepted 2 September 2008

KEYWORDS

Summary Acute myeloid leukemia (AML) is more prevalent in older adults, with an incidence in the United States of 17.6 per 100,000 for those P65 years of age, compared with an incidence of 1.8 per 100,000 for those <65 years of age. While there have been improvements in survival during the last decade for younger patients, prognosis in elderly patients is still poor; approximately 50% achieve complete responses, but many of them relapse. With increasing age, more patients are suboptimal candidates for standard induction chemotherapy due to poor performance status, pre-existing myelodysplasia, unfavorable cytogenetics, treatment-related AML, multidrug resistance protein expression, and CD34 positivity, which are often characteristic of this patient population. In addition, the presence of comorbid conditions make many treatment options less tolerable for elderly patients. Several investigators have described subgroups showing no benefit after intensive treatment approaches in recent years. However, several novel agents have been developed to treat elderly AML patients. These include new chemotherapeutic agents, such as nucleoside analogs, as well as targeted therapies like farnesyltransferase inhibitors, tyrosine kinase inhibitors, epigenetic drugs, and antibodies. On the other hand new insights into the biology of the disease lead to a better understanding of its heterogeneity. Thus, with a variety of novel substances at hand it is increasingly important to introduce a risk-adapted approach for the optimal management of patients. This review will identify subgroups not likely to benefit from intensive chemotherapy and highlight the efficacy and tolerability of new agents in the treatment of AML. c 2008 Elsevier Ltd. All rights reserved.

Acute myeloid leukemia; Elderly; New drugs; Targeted therapy



Introduction

* Corresponding author. Tel.: +49 2118117720. E-mail address: [email protected] (U. Germing).



Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. The majority of patients are >60 years and median age at diagnosis is 65–70 years. While there have been improvements in survival during the last

0305-7372/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.09.001

98 decade for younger patients with AML, the prognosis in elderly patients remained poor and although the majority of clinical trials include primarily or exclusively younger individuals, the elderly comprise the larger subgroup, presenting with distinct biological and clinical characteristics.1,2 Chemotherapy affects elderly patients different from younger patients. Patients >60 years have a lower complete response (CR) rate after intensive chemotherapy and a much higher relapse rate. AML in the elderly often arises from myelodysplastic syndromes and tends to show a less acute progression compared to de novo AML in younger adults. Good-risk karyotypes, like t(15;17) occur only rarely, while high-risk, especially complex karyotypes, are common as well as overexpression of multidrug resistance (MDR) phenotypes.3–9 Furthermore, comorbidities are common, leading to an increased early death rate. These differences are best described in a retrospective analysis by Appelbaum et al. on the effect of age in 968 adults with AML treated in five recent Southwest Oncology Group trials performed. The authors found that a poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts correlate with increased age. Multidrug resistance occurred in 33% of AML patients below the age of 56 as compared to 57% in patients older than 75 years. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than 56 to 4% in those older than 75 years, while the proportion of patients with unfavorable cytogenetics increased from 35% to 51%. The difference in treatment outcome could not only been explained by the higher percentage of poor-risk karyotypes in the elderly patients, but was seen in all cytogenetic risk groups, with the greatest influence of age seen in the intermediate and goodrisk subgroups.10 Thus, elderly patients with AML require different treatment approaches that account for disease biology, performance status, and comorbidities. It is of major importance to define which prognostic subgroups will benefit from intensive treatment regimens and which subgroups will benefit more from supportive care. These latter patients are candidates for novel targeted therapies. Several of these agents have recently entered clinical trials, and some have shown promising results that represent an opportunity for the treatment of this poor-risk subgroup in the future.

Chemotherapeutic approaches in AML and prognostic factors Intensive combination chemotherapy usually includes cytarabine and anthracyclines (e.g. 3 + 7 schedule), with a CR rate between 45% and 60%. The probability of remaining in remission 3 years after diagnosis is below 10%, the median overall survival (OS) 5–10 months, and the 5-year survival rate 6–12%.11–13 These already disappointing results are still likely to overestimate the efficacy of chemotherapy in elderly AML patients, as most studies included only patients considered to be medically fit. Attempts have been made to improve induction chemotherapy results by substituting other anthracyclines or structurally different chemotherapeutic drugs (including fludarabine, topotecan, cyclophosphamide, or etoposide) for daunorubicin. The results have mainly been disappointing with regard to OS, but topotecan-cytarabine regimens have demonstrated significantly

A. Kuendgen, U. Germing lower induction mortality rates, suggesting a possible benefit of this combination in elderly patients with AML.12–15 Additionally, the optimal postremission treatment regimen remains unclear.7,12,15 The inclusion of novel agents may improve the so far disappointing results seen with maintenance treatment in the future. Because of the short duration of remission, short survival and the high early mortality rate associated with intensive treatment in the elderly, it is important to assess predictive prognostic factors for outcome. A study by Leith and colleagues (n = 211) showed that 32% of patients >55 years of age with AML had unfavorable cytogenetics and 71% had overexpression of MDR1, which was associated with a CR rate of 12% in this subgroup.8 Recently, our group reported data on the unfavorable effect of abnormal cytogenetics on treatment outcome with intensive chemotherapy in 146 patients with AML and high-risk MDS (Table 1).16 Other investigators have found similar results.13,17 Although cytogenetic status is the most important prognostic factor for elderly patients with AML, several factors can contribute to the poor-prognosis: age P70–75 years, poor performance status, pre-existing myelodysplastic or myeloproliferative disorders, treatment-related leukemia, CD34 positivity, elevated serum lactate dehydrogenase (P2 · upper limit of normal), leukocytosis (P100 · 109/L), thrombocytopenia (620 · 109/L), and existence of comorbidities.9,13,17–21 Kantarjian and colleagues recently suggested a predictive model including age P75 years, unfavorable karyotype, poor performance status, longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ function as poor prognostic factors. CR rates, induction mortality and 1-year survival according to the proposed risk groups are shown in Table 2.13

Table 1 CR rate and OS in elderly patients treated with intensive chemotherapy according to cytogenetic abnormalities Karyotype

CR rate (%)

Overall survival (median)

Overall n = 146 Normal n = 78 Abnormal, noncomplex n = 36 Abnormal, complex n = 32

56 70 69

9.5 mo 18 mo 6 mo

46

4 mo

Table 2 CR rate, induction mortality, and 1-year survival according to a proposed score for elderly patients receiving intensive chemotherapy12 Risk group

CR rate (%)

Induction mortality (%)

1-year survival (%)

Favorable-risk Intermediate-risk Unfavorable-risk

60 50 <20

10 30 >50

>50 30 <10

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly Treatment alternatives until recently included low-dose chemotherapy or best supportive care. Several studies were published on the outcome of patients treated with these different strategies. Still, only a limited number compare the different approaches and almost all of these publications share the same bias due to different patient characteristics in the groups receiving either curative or palliative therapies. These studies were recently reviewed by Deschler et al.22 Randomized trials comparing the different strategies are even scarcer and were carried out approximately 20 years ago. In a study conducted by the European Organisation for Research and Treatment of Cancer (EORTC)23 60 patients (>65 years) were treated with immediate chemotherapy (Arm A) vs.‘‘wait and see’’ and supportive care in combination with cytoreduction if needed (Arm B). Overall survival duration was significantly longer in Arm A (21 vs. 11 weeks). Tilly et al found, treating 87 patients over 65 years of age with de novo acute nonlymphocytic leukemia, that a higher number of CRs may be obtained with intensive chemotherapy, but with low-dose ARA-C, the number of early deaths was lower, and long-lasting PRs were obtained, resulting in a similar overall survival.24

Novel chemotherapeutic agents Although several attempts have been made to improve the combination of ara-C plus anthracyclines, few have demonstrated promising results. In a phase 1 dose-escalation trial, the maximum tolerated dose (MTD) of clofarabine, a novel purine nucleoside, was 40 mg/m2 in adult patients, and the dose-limiting toxicity (DLT) was hepatic toxicity. Among 32 patients with acute leukemia (AML, n = 16; acute lymphocytic leukemia (ALL), n = 13; blast crisis chronic myeloid leukemia (CML), n = 3), two patients achieved CRs and three had complete marrow responses.25 Kantarjian and colleagues investigated clofarabine (40 mg/m2/day for 5 days every 3–6 weeks) in a phase 2 study including 62 patients with relapsed or refractory AML (n = 31, median age: 54 years), MDS (n = 8), blast crisis CML (n = 11), and ALL (n = 12).26 A total of 13 of 31 AML patients achieved CR (42%) and four had complete responses with incomplete platelet recovery (CRp) (13%), resulting in an overall response rate (ORR) of 55%. Grade 3–4 liver toxicity was common. In the subgroup of elderly AML patients (P65 years) not suitable for intensive chemotherapy, preliminary data have shown high response rates to clofarabine (30 mg/m2/ day for 5 days) when used as first-line treatment (n = 66).27 The ORR was 48%. Of note, the CR/CRp rate in patients >70 years (49%) compared well to that observed for younger patients (36%). Furthermore, eight of 19 patients (42%) with adverse cytogenetics and five of 16 patients (31%) with secondary AML achieved remissions. Given promising results as a single-agent, combination clofarabine regimens were studied. Of special interest is the combination of clofarabine with ara-C, since it is hypothesized that clofarabine leads to accumulation of ara-C triphosphate and increases its antileukemic activity. In a phase 1/2 study in 32 patients including 25 with relapsed AML, clofarabine was given at increasing doses followed 4 h later by ara-C 1 g/m2/day, both given on days 1–5.28 Median age was 59 (18–84) years. The clofarabine dose selected for the phase 2 portion of the study was 40 mg/m2/day. In AML

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patients seven (28%) achieved CR and three (12%) had CRp (ORR of 40%). The major toxicities were nausea, vomiting, diarrhea, skin rash, hand–foot syndrome, mucositis, and transient liver dysfunctions. One patient (3%) died during induction.28 In a very recent study conducted by the same group clofarabine 30 mg/m2 for 5 days was compared in a randomized fashion to clofarabine in combination with lowdose Ara-C (20 mg/m2 for 14 days).29 This study was restricted to patients above the age of 60. After an induction a consolidation was given consisting of 3 days clofarabine and 7 days ara-C. Seventy patients were enrolled and the CR rate in the combination arm was as high as 63% while it was only 31% in the clofarabine monotherapy arm (p = 0.025). The combination showed significantly better event free, but not overall survival, although survival was 11, 4 vs. 5, 8 months. Since the number of patients in the arm receiving monotherapy was only 16, the number of patients might just have been too small to demonstrate a survival benefit.29 In another phase 2 trial, 23 patients with de novo, secondary, or relapsed AML and a median age of 68 (39–79) years received a 5-day regimen consisting of clofarabine 40 mg/m2 followed by ara-C 1000 mg/m2. One early death occurred due to disease progression. In 20 patients evaluable for response, 10 CRs (50%) and 2 PRs (10%) were observed (ORR 60%). Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation.30 In two phase 1 dose-finding studies, various combinations of clofarabine were explored in patients with relapsed or refractory AML and high-risk MDS (median age: 56 (24–71) years). A total of 44 patients (clofarabine plus idarubicin, n = 23; clofarabine plus idarubicin and ara-C, n = 21) were evaluable for response. With the former combination, three DLTs (diarrhea, rash and hyperbilirubinemia) and three CRs (13%) were observed. With the latter 3-drug combination, two patients developed DLTs (diarrhea, hyperbilirubinemia, renal failure) and 10 responses (48%; nine CR, one CRp) were achieved.31 Troxacitabine is another nucleoside analog being investigated in the treatment of patients with refractory leukemia.32,33 In a phase 1 study, patients (n = 30) with refractory AML received doses of troxacitabine ranging from 0.72 to 10 mg/m2/day i.v. for 5 days. Median age was 61 years (23–79). Three patients achieved a CR (10%) and one a PR.32 In a subsequent phase 2 study, of 16 assessable patients with relapsed/refractory AML (median age 51 years (23–80)) treated with troxacitabine (8 mg/m2/day i.v. for 5 days every 3–4 weeks) 2 patients (13%) achieved a CR that lasted >18 months and >12 months, respectively, and 1 had a PR.33 In another phase 1/2 study in patients with refractory AML and a median age of 58 (21–81) years, patients received continuous infusion with increasing doses of troxacitabine.34 The DLTs were mucositis and hand-foot syndrome; the MTD was established at 12 mg/m2/day for 5 days. Seven out of 48 patients (15%) achieved CR or CRp. A larger phase 2/3 study is being conducted to determine the precise role of troxacitabine in AML. Troxacitabine has also demonstrated efficacy in combination with other agents. A 3-arm randomized trial comparing idarubicin plus ara-C with troxacitabine plus ara-C and troxacitabine plus idarabucin in untreated patients was studied in patients P50 years of age with AML and adverse cytogenetics.35 Response rates were 55%, 27%, and 0%, respectively.

100 Giles and colleagues conducted a study of the novel sulfonylhydrazine alkylating agent cloretazine in 104 elderly patients with untreated AML. Patients treated with a dosage of 600 mg/m2 achieved an ORR of 32% (28% CR, 4% CRp). Median OS was 94 days; in patients who achieved CR, median survival was 147 days.36 Novel chemotherapeutic drugs including nucleoside analogs as well as alkylating agents appear promising in elderly patients with AML and may become a less cardiotoxic alternative to anthracyclines, alone or in combination with other chemotherapeutic drugs, such as ara-C. Especially the data for clofarabine appears very promising since it achieves very high response rates in elderly patients and is active in patients with adverse cytogenetics, too. Further studies are warranted, especially phase III studies to evaluate if these new agents might truly be able to improve the outcomes of the standard 3 + 7.

A. Kuendgen, U. Germing OS (22% vs. 12%, P = 0.046).40 However, the CR rate was not significantly improved (39% vs. 33%, P = 0.14). Another, more selective P-gp inhibitor currently being investigated is zosuquidar trihydrochloride. Promising phase I/II data was presented at ASH 2007. Of 66 evaluable patients with Pgp + AML enrolled on the study, 32 (48%) achieved CR/CRp (CR = 25, CRp = 7). 48% of patients with secondary AML, 32% with poor-risk cytogenetics, and 57% of those aged P70 responded.41 First data from a randomized trial in AML patients above the age of 60 indicated no significant difference in OS between daunorubicin (45 mg/m2/day, 3 days) and cytarabine (100 mg/m2/day, 7 days) with or without zosuquidar, although there might have been a difference in the distribution of risk groups between the two arms.42 Thus, the role for the newer MDR inhibitors has to be further defined, but ciclosporin is currently the only drug that has shown a significant benefit when combined with chemotherapy.

Low-dose chemotherapy Farnesyltransferase (FTase) inhibitors In one of the few trials comparing low-dose and intensive chemotherapy Tilly et al. found no significant survival benefit for either 3 + 7 or low-dose Ara-C, but patients in the low-dose Ara-C arm spent less days in the hospital.24 More recently, a comparison between LDAC and hydroxyurea (with or without all-trans retinoic acid (ATRA)) in patients (median age 74 (51–90) years) with AML or high-risk MDS showed a better ORR (18% vs. 1%) and improved OS (P = 0.0009) with LDAC; however, patients with adverse cytogenetics did not benefit from this treatment.37

Targeted therapies Despite a growing understanding of the pathophysiology of leukemias, few advances have been made in the treatment of these disorders. However, the development of so-called targeted therapies has led to impressive results in some small subgroups, including Philadelphia-positive ALL, CML, and acute promyelocytic leukemia. Non-M3-AML targets include enzymes involved in signal transduction pathways like farnesyltransferase (FTase), vascular endothelial growth factor (VEGF), FLT3 and ras, cell surface antigens such as CD33, mediators of MDR such as p-glycoprotein (P-gp), aberrant epigenetic modifications like methylation and histone acetylation, and angiogenesis.

Multidrug resistance inhibitors As P-gp is a major cause of MDR, several MDR inhibitors have been tested in phase 3 trials to determine their efficacy in the treatment of patients with AML. Trials with PSC-833 (valspodar) have yielded disappointing results. PSC-833 even led to an increased early mortality rate, and the arm was closed early. However, further follow-up demonstrated no overall survival difference.38,39 In contrast, List and colleagues reported a randomized study (n = 226; sequential treatment with cytarabine and daunorubicin with or without ciclosporine A i.v., median age 53 and 54 years, respectively) where the addition of ciclosporine significantly reduced the frequency of resistance to induction chemotherapy (31% vs. 47%, P = 0.0077), improved relapse-free survival (34% vs. 9% at 2 years, P = 0.031) and

One target for AML therapy is FTase, which is a key enzyme that regulates cancer cell growth. Farnesylation of several proteins, including the ras oncogene, is involved in cellular functions including cell signaling, proliferation, and differentiation.43 Tipifarnib (ZARNESTRA, R115777; Johnson and Johnson PRD) is a potent and specific farnesyltransferase inhibitor (FTI).44 Based on in vitro findings45, a phase 1 study was conducted to determine the effect of tipifarnib on patients (n = 35, median age 65 (24–77) years) with relapsed or refractory AML.46 Cohorts of patients received doses of tipifarnib ranging from 100 to 1200 mg twice daily by mouth for 21 days. Clinical responses were seen in 10 of 34 evaluable patients (29%), including 2 CRs. There was a low incidence of serious (grade 3–4) nonhematologic toxicities. The most commonly reported toxicities were fatigue and nausea.46 Interestingly, genomic analyses did not detect N-ras gene mutations in any of the 34 evaluable leukemic samples, suggesting that tipifarnib may inhibit signaling pathways other than ras.46 A phase 2 trial subsequently evaluated tipifarnib in elderly adults with poor-risk, untreated AML.47 Patients (n = 158) received tipifarnib 600 mg by mouth (PO) twice a day (bid) for 21 days; the ORR was 23% and a CR was achieved in 14% of patients.47 Moreover, a survival benefit was demonstrated for responders. The median OS for all patients was 5.3 months. Patients who achieved CR had a median survival of 18.3 months, and patients who achieved PR or hematologic improvement (HI) had a median survival of 12.6 months.47 The majority of grade 3 nonhematologic toxicities included infectious and gastrointestinal AEs.47 Harousseau and colleagues conducted a similar phase 2 study of tipifarnib 600 mg PO bid (21 days every 28 days) in patients with relapsed or refractory AML (n = 252, median age 62 years), and reported an ORR of 15% (4% CR/CRp, 11% HI).48 In patients with CR or CRp, the median duration of survival was 369 days. In addition to AML, tipifarnib has also demonstrated activity in patients with MDS. Interestingly, the response to treatment appeared to be independent of ras mutations as well.49–51 A very recent phase II study explored tipifarnib as maintenance treatment after intensive chemotherapy. The trial included 48 adults with poor-risk

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly AML in first CR. Median disease-free survival was 13.5 months (range, 3.5–59 + months), with 30% having DFS >2 years. The investigators compared this data to historical controls and found a prolongation of disease-free survival in patients with secondary AML and poor-risk cytogenetics. This very interesting approach warrants further evaluation in a phase III setting.52 Other FTIs are currently being evaluated in the treatment of hematologic malignancies. One of these agents, lonafarnib (Sarasar, Sch-66336; Schering-Plough Research Institute), has been studied in patients with AML and MDS. In a phase 1 study of patients (n = 18) with advanced hematologic malignancies (CML in blast crisis; CMML; advanced MDS; relapsed, refractory, or poor-risk AML; ALL) who received lonafarnib 200–300 mg PO bid, clinical activity was observed in 37.5% of patients, and the 200 mg PO bid dose was well tolerated.53 In a phase 2 study, patients with advanced hematologic malignancies (n = 54) received lonafarnib 200 mg PO bid.54 Preliminary results indicated that 10 patients (19%) achieved HI and one achieved a marrow response.54 Like tipifarnib, lonarfarnib showed activity in patients (n = 67) with MDS and clinical responses were achieved in 29% of patients (5% CR, 24% HI).55 A third FTI, BMS-214662 (Bristol-Myers Squibb), is being investigated in phase 1 trials of patients with acute leukemias and MDS.56 Patients (n = 30) received BMS-214662 as a 1-h bolus once weekly at doses ranging from 42 to 157 mg/m2 and then a 300 mg/m2 24 h continuous infusion once weekly after the MTD was determined.56 Median age was 53 (22–96) years. DLTs occurred at 157 mg/m2, and the MTD was determined to be 118 mg/m2 for the 1 h infusion; however, the MTD was not determined for the 24 h infusion. Infusion resulted in approximately 60% inhibition of FTase activity and antileukemic activity occurred in five patients (two CRp, one HI, and two morphologic leukemiafree state).56 Clinical trials with FTIs are summarized in Table 3. The results from these phase 1 and 2 studies demonstrate that FTIs achieve promising responses only in a small subgroup of patients with AML and MDS, but offer an oral, less intensive treatment alternative for elderly patients with AML. For future trials, it will be important to further define those patients likely to respond to FTIs, as it has become clear that ras-mutations do not play a role for response prediction. Another goal is to find combination regimens that further improve response rates and duration. An attractive approach for further investigation is the use of FTIs as maintenance treatment, especially in poor-risk patients.

Tyrosine kinase inhibitors The majority of small molecule tyrosine kinase inhibitors (TKIs) target a variety of kinases including FLT3, VEGF receptors (VEGFRs), platelet derived growth factor receptor (PDGFR), and KIT. FLT3 is a receptor tyrosine kinase which is involved in the proliferation and differentiation of hematopoietic progenitor cells. Approximately 30% of patients with AML have an internal tandem duplication mutation or a point mutation in the activating loop of the FLT-3 gene.57 These are associated with a worse prognosis, a lower CR rate, and lower OS.57 Increased bone marrow angiogenesis and VEGF are adverse prognostic indicators in patients with

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AML. Patients with untreated AML often have elevated VEGF and VEGF-2 levels in their bone marrow,58 which are associated with reduced CR rates, disease-free survival, and OS.59 In patients with MDS, elevated VEGF levels correlate with reduced survival,60 suggesting that VEGF and VEGFR-2 are potential therapeutic targets in AML and MDS.61 More than 70% of patients with AML have blast cells that express the receptor tyrosine kinase c-KIT,62 which plays a role in survival and proliferation of AML cells. Several small molecule TKIs exist, varying in their potency for FLT3 inhibition, as well as their spectra of other kinases targeted. A number of FLT3 inhibitors have been tested in phase 1/ 2 trials. Lestaurtinib (CEP701) is an FLT3-selective indolocarbazole TKI studied in a phase 1/2 clinical trial involving 17 patients with relapsed, refractory, or poor-risk AML harboring FLT3 mutations. The doses ranged between 40 mg and 80 mg twice daily. Median age was 61 (18–74) years. Transient, limited responses were observed in five patients, including reductions in peripheral blast count and transfusion frequency.63 In a phase 2 trial involving previously untreated elderly patients with AML, the initial lestaurtinib dose of 60 mg twice daily, was increased to 80 mg twice daily PO, for 8 weeks. Clinical activity was observed in eight patients (30%), including 3 of 5 patients (60%) with mutant FLT3. Responses included transient declines of peripheral and marrow blast counts and HIs, but no CRs or PRs. Median time to progression was only 25 days.64 Tandutinib (MLN518) is a quinazoline-based TKI that inhibits FLT3, PDGFR, and KIT. MLN518 was tested in a phase 1 trial in patients with AML and high-risk MDS (n = 40) (50–700 mg bid PO) and a median age of 70.5 years. The DLTs were generalized muscular weakness and fatigue. No CR or PR was observed, but 2 of 8 patients with FLT3-ITD mutations exhibited an antileukemic effect, with reductions in peripheral and bone marrow blast counts, again occurring for only a short duration (61 month).65 SU11248 is an oral kinase inhibitor of FLT3, KIT, PDGF, and VEGF receptors.66 In a phase 1 study, patients with refractory or elderly untreated AML received 4-week cycles of SU11248 given once daily, followed by either a 1- or 2week rest period. No DLTs were observed at the starting dose level of 50 mg (n = 13). However, only two patients were treated at the 75 mg dose level, as one of these patients developed grade 4 fatigue, hypertension, and cardiac failure. All four patients with FLT3 mutations achieved morphologic remission or PR (defined as a reduction of peripheral and marrow blasts P50%), while two PRs occurred in patients without FLT3 mutations. Although responses were longer in patients with FLT3 mutations, they were still generally short-lived, lasting from 4 weeks to 16 weeks. SU5416, another small molecule TKI of VEGF-2, c-KIT, and FLT-3, has been evaluated in patients with AML and MDS.67 In a phase 2 study, patients (n = 55, median age 64 (23–76) years) with refractory AML or MDS received SU5416 145 mg/m2 i.v. twice weekly. Three patients achieved a PR and one patient had HI.68 The median OS was 12 weeks in patients with AML. The most commonly reported nonhematologic grade 3–4 adverse events were headache, dyspnea, and fatigue.63 In another phase 2 study conducted in patients (n = 43) with refractory AML or elderly patients with untreated AML (145 mg/m2 i.v. twice weekly)69 median age was 65 years. One patient achieved

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Table 3

Clinical trials with farnesyltransferase inhibitors (FTI) in acute myeloid leukemia (AML)

Author

Karp et al. (Blood, 2001)42

Lancet et al. (Blood, 2007)47

Harousseau et al. (Blood, 2007)48

List et al. (ASH, 2002)53

Cortes et al. (ASH, 2002)54

Cortes et al. (JCO, 2005)56

Drug

R115777 Zarnestra

R115777 Zarnestra

R115777 Zarnestra

I 100–1200 mg ·2 po for 21 days AML (n = 25)

II 600 mg ·2 po

II 600 mg ·2 po

Sch-66336 Lonafarnib II 200 mg ·2 po

BMS-214662

Phase Schedule

Sch-66336 Lonafarnib I 200–300 mg ·2 po

AML (n = 158) MDS (n = 13)

AML (n = 252)

Median 65 Relapsed, refractory, not eligible for chemotherapy 2 (8%) CR, 6 (24%) PR

Median 74 Untreated poorrisk AML or MDS

Median 62 Relapsed, refractory

AML (n = 6), MDS (n = 2) (CML, CMML, ALL) Not given Relapsed, refractory, poorrisk

AML (n = 19), MDS (n = 15) (CML, CMML, ALL) Not given Relapsed, refractory, poorrisk

22 (14%) CR, 3 (2%) PR, 12 (8%) HI

9 (4%) CR, 2 (1%) CRp

1 AML patient reduction in blast count 3 HI in MDS patients

CNS toxicity, polydipsia, transient renal dysfunction, parethesias

Infectious, gastrointestinal, rash, CNS

Myelosuppression, fever, nausea, and hypokalemia

0% in AML and MDS Hematologic improvements and blast reduction in 37.5% of patients but only with CML, CMML and ALL) Diarrhea, hypokaliaemia, nausea, vomiting

Patient Number and Diagnosis Age/ years Disease stage

Responses

Toxicity

Not given

I 42–300 mg AML (n = 19) MDS (n = 8) Median 53 Relapsed, refractory, not eligible for chemotherapy 2 (7%) CRp, 1 (4%) HI

Gastrointestinal, fatigue, hypokaliaemia, cardiac

A. Kuendgen, U. Germing

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly complete morphologic remission that lasted 2 months, and seven additional patients achieved PRs lasting 1–5 months. PKC412 (N-benzoylstaurosporine) was developed as a protein kinase C inhibitor, but has shown potent inhibitory activity against FLT3, VEGFR-2, c-KIT, and PDGFR.70 In a phase 2 trial, 20 patients with mutant FLT3 relapsed/refractory AML or high-risk MDS (median age 62 years (29–78)) were treated at an oral dose of 75 mg thrice daily. Although the drug was generally well tolerated, 2 patients experienced fatal pulmonary events of unclear etiology. Fourteen of 20 patients (70%) achieved a P50% reduction of peripheral blast counts. In six patients, bone marrow blast counts were reduced by >50%. The median response duration was 13 weeks. PTK787/ZK 222584 (PTK/ZK; vatalanib) is an oral angiogenesis inhibitor targeting the VEGF receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/ Flt-4, PDGFR, and c-KIT. In a phase 1 study, PTK/ZK was administered in 63 patients (500–1000 mg bid) with refractory, relapsed, or poor-prognosis AML or advanced MDS (mean age 70 years).71 AML patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. DLTs were lethargy, hypertension, nausea, emesis, and anorexia. The MTD of PTK/ZK was 750 mg. CR was observed in five of 17 patients treated with PTK/ZK plus chemotherapy. AG-013736 is another oral angiogenesis inhibitor targeting VEGFR-1, -2, -3, c-KIT and PDGFR-b, and was studied in a phase 2 trial that included six patients with AML and six with MDS. Toxicities included hypertension, mucositis, and deep venous thrombosis. No objective responses were seen, and only two patients with MDS had stable disease (for 8.3 and 6.2 months, respectively).72 More than 70% of patients with AML have blast cells that express c-KIT. Because imatinib mesylate (STI571, Gleevec, Novartis) is a selective TKI of c-abl, bcr/abl, c-KIT, and PDGFR, with strong activity in bcr-abl-positive CML, it has also been explored for use in AML. After the first report of a complete hematologic remission through treatment with imatinib mesylate in a patient with refractory c-KITpositive AML, further trials were conducted to evaluate the efficiacy of this TKI in AML.73 Kindler and colleagues treated 21 patients with a median age of 66 (21–82) years and c-KIT-positive AML. The dosage was 600 mg/d orally. Two patients (10%) achieved CR, one patient showed no evidence of leukemia, and two patients achieved minor responses. In both patients with CR, imatinib was started shortly after intensive chemotherapy and bone marrow blast counts were low (5–10% and 2%, respectively).74 In another study, 18 patients with AML or MDS (median age 70 (23–83) years) were treated with imatinib at a dosage of 400 mg daily, and none responded.75 In a trial of imatinib in combination with LDAC, the objective response rate was low (11%), including one CR, one PR and two HIs.76 While the efficacy of imatinib in patients with AML appears to be minimal, there are several case reports describing successful treatment of patients with the rare entities of bcrabl-positive and FIP1L1-PDGFRA-positive AML with imatinib alone or in combination with conventional chemotherapy.77–81 Taken together, patients with mutant FLT3 appear to be more sensitive to treatment with TKIs when compared

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with wild-type FLT3. However, responses to small molecule TKIs targeting FLT3, c-KIT, VEGF, PDGF, and other tyrosine kinase receptors are usually short-lived and often restricted to reductions in peripheral or bone marrow blast counts (see Table 4). True PRs or CRs occur rarely. Current trials are combining FLT3 inhibitors with conventional chemotherapeutic drugs in an attempt to achieve synergistic cytotoxicity and improve the poor response rates seen in patients with AML with FLT3/ITD mutations.

Antiangiogenic therapies In addition to small molecule TKIs targeting VEGF-R, other strategies targeting angiogenesis in AML have also been developed. The rationale for this is based on the finding that several angiogenic factors, such as HGF, FGF, VEGF, and angiogenin, are elevated in patients with AML and MDS. Adding further support, increased vascularity hase been described in the bone marrow of patients with AML and MDS.82 Thus, the immunomodulatory drugs thalidomide and lenalidomide have been investigated for the treatment of leukemia. Thalidomide, in addition to its teratogenic effects, possesses antiangiogenic and immunomodulatory capacities. Treatment of patients with MDS with thalidomide resulted in HI in 31–56% of patients, but was associated with a high drop-out rate due to fatigue and polyneuropathy.83,84 In patients with AML, thalidomide was tested at a dose of 200–400 mg daily for at least 1 month.85 Thirteen patients with a median age of 69 (58–85) years were assessable for both toxicity and response. In four patients, a PR was observed, with a median duration of response of 3 months. In another study, the addition of thalidomide to chemotherapy did not result in a clinical benefit in patients with AML or high-risk MDS.86 In this study, 84 patients with AML or high-risk MDS (median age 65 (27–84) years) were randomized to receive liposomal daunorubicin and ara-C or daunorubicin and topotecan. Within each arm, patients were randomized to receive chemotherapy alone or with thalidomide.86 The second generation immunodulatory drug lenalidomide (Revlimid, Celgene Corporation) is better tolerated and has demonstrated very high response rates, including complete cytogenetic responses, in patients with MDS with 5q-deletions.87 Interestingly, there was no association between karyotype complexity and the frequency of cytogenetic response (P = 0.27). Survival was similar among patients with isolated 5q-deletion and patients with additional cytogenetic abnormalities, suggesting possible efficacy of lenalidomide in higher-risk patients with MDS and AML with 5q deletions and even within complex karyotypes. Bevacizumab is a monoclonal antibody directed against the VEGF receptor that has shown antiangiogenic activity in AML. Although no evidence of antileukemic activity was seen in a very small study involving only 9 patients (median age 63 years), the safety profile of bevacizumab was favorable and investigation in a larger cohort as part of a combined antiangiogenic and cytotoxic chemotherapy regimen might further evaluate the possible role of this drug for AML treatment.88

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Table 4

Clinical trials with small molecule tyrosine kinase inhibitors in acute myeloid leukemia (AML)

Author

Smith et al. (Blood, 2004)63

Knapper et al. (Blood, 2006)64

DeAngelo et al. (Blood 2006)65

Fiedler et al. (Blood, 2005)66

Giles et al. (Cancer, 2003)68

Fiedler et al. (Blood, 2003)69

Stone et al. Blood 200570

Roboz et al. Leukemia 200671

Giles et al. Leuk Re 200672

Kindler et al. Blood 200474

Cortes et al. Cancer 200375

Drug

CEP-701 lestaurtinib FLT3, VEGFR, TrkA

CEP-701 lestaurtinib FLT3, VEGFR, TrkA

MLN518 tandutinib FLT3, PDGFR, KIT

SU11248, sunitinib

SU5416 semaxanib

SU5416 semaxanib

Imatinib

Imatinib

VEGFR, FLT3, KIT

VEGFR, FLT3, KIT

PTK787/ZK 222584, vatalanib VEGFR, KIT, c-fms, PDGFR

AG-013736

FLT3, PDGFR, KIT, VEGFR

VEGFR, KIT, PDGFR-b

ABL, PDGFR, KIT

ABL, PDGFR, KIT

Phase Schedule

I/II 40 mg ( 60) ·2 po

II 60 mg ( 80) ·2 po

I 50 ( 700) mg ·2 po

I 50 ( 75) mg po 4 weeks (1 or 2 weeks rest period)

II 145 mg/m2 twice weekly iv

II 145 mg/m2 twice weekly iv

PKC412 midostaurin FLT3, VEGFR-2, KIT, PDGFR, PKC II 75 mg ·3 po

II 10 mg po

II 600 mg po

II 400 mg po

Patient Number and Diagnosis Age/ years Disease stage Inclusion criteria

AML (n = 17)

AML (n = 29)

AML (n = 16)

Median 73 First line

AML (n = 33), MDS (n = 22) Median 64 Relapsed, refractory, not eligible for chemotherapy

AML (n = 43) Evaluable n = 25 Median 65 Relapsed, refractory, not eligible for chemotherapy, c-kit positiv

AML (n = 6) MDS (n = 6) Median 80 Poor-prognosis

AML (n = 21)

Median 61 Relapsed, refractory, FLT3 mutations

AML (n = 39), MDS (n = 1) Median 70,5 Relapsed, refractory, not eligible for chemotherapy

I 500–1000 mg ·2 po (in a subset combination with Ara-C and daunorubicin n = 17) AML (n = 43) MDS (n = 20) Median 68 and 72 Relapsed, refractory, not eligible for chemotherapy

Responses

0 (0%) CR, 5 (29%) improvements (mainly peripheral blasts and blood counts)

0 (0%) CR, 8 (30%) improvements (HI and marrow response)

1 (6%) CRp, 5 (31%) PR

3 (6%) PR, 1 HI (2%)

1 (4%) CRp, 7 (28%) PR

AML (n = 10), MDS (n = 8) Median 66 Relapsed, refractory, not eligible for chemotherapy, c-kit positive 0 (0%) CR, 0 (0%) PR

Toxicity

mild nausea, mild emesis, mild generalized weakness, fatigue

mild nausea, emesis, constipation, diarrhea, and elevations in alkaline phosphatase

Nausea, vomiting, diarrhea,fatigue, hypertension

Flushing, pruritus, hypotension, injection side reactions,headache, dyspnea, fatigue, thromboembolic events

Pneumonia, sepsis, nausea, bone pain, headache,insomnia, vomiting, vertigo, fatigue, abdominal pain, sweating

Targets

0 (0%) CR, 2 of 8 patients with FLT3 -ITD mutations, treated at 525 mg and 700 mg exhibited evidence of an antileukemic effect Muscular weakness, nausea, vomiting, diarrhea, edema

>70 Relapsed, refractory, not eligible for chemotherapy

AML (n = 19) MDS (n = 1) Median 62 Relapsed, refractory, not eligible for chemotherapy, FLT3 mutations 0 (0%) CR, 1 (5%) PR, 14 (70) >50% reduction in peripheral blast count

0 (0%) CR, 0 (0%) PR

Lethargy, hypertension, nausea, emesis, anorexia

Hypertension, mucositis, deep venous thrombosis

Edema, gastrointestinal symptoms, headache

Fatigue, edema, bone pain

A. Kuendgen, U. Germing

Nausea, vomiting, diarrhea, edema, elevated liver enzymes, hypoxia, pleural effusion, cardiac and pulmonary

5 (29%) CR, 2 (12%) CRp, 1 (6%) PR (responses occurred only in combination with chemotherapy)

Median 66 Relapsed, refractory, not eligible for chemotherapy, c-kit positive 2 (10%) CR

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

BCL-2 antisense molecule Overexpression of inhibitors of apoptosis, such as bcl-2, can lead to apoptosis resistance in tumor cells.89 In patients with AML, a poor prognosis and resistance to chemotherapy is associated with an elevated level of bcl-2.89 In vitro, the downregulation of bcl-2 by antisense molecules results in increased sensitivity to chemotherapy in AML cell lines.90 Oblimersen sodium (Genasense, Aventis), an antisense oligonucleotide that downregulates bcl-2 expression, has been studied in combination with chemotherapy.91–93 In a phase 1 study of oblimersen sodium combined with fludarabine, ara-C, and G-CSF (FLAG) as salvage chemotherapy in elderly patients (n = 17) with relapsed/refractory AML, five patients (29%) achieved CR and two had no evidence of disease but failed to achieve normal neutrophil or platelet counts.93 In another phase 1 study of untreated AML patients (n = 29), P60 years of age, patients were treated with oblimersen sodium, ara-C, and daunorubicin. Fourteen patients (48%) achieved CR, and AEs reported were similar to those reported with chemotherapy alone.94 The role of oblimersen sodium in both induction and consolidation therapy is currently being evaluated in a randomized phase 3 study conducted by the Cancer and Leukemia Group B (CALGB).

Proteasome inhibition Proteasome inhibitors disrupt the regulatory proteins involved in tumorigenesis, thereby causing an imbalance of proteins within the cell, inhibiting cell growth and inducing apoptosis in cancer cells. Studies have demonstrated that proteasome expression is increased in malignant hematopoietic cell lines and blast cells from patients with leukemia,95 suggesting that proteasome inhibition may be a promising therapeutic option for patients with AML. Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals) is the first proteasome inhibitor evaluated in clinical trials. A phase 1 dose-escalation trial combining bortezomib with idarubicin and ara-C was conducted in patients >60 years of age or 18 years or older with relapsed disease.96 Patients received idarubicin 12 mg/m2 (d1–3), cytarabine 100 mg/ m2 (d1–7), and bortezomib IV (d1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m2). All investigated doses of bortezomib were tolerable. A total of 31 patients with a median age of 62 years were enrolled. 19 of these patients (61%) achieved complete remission (CR) and three further patients had CRp. As a result of this study the recommended dose of bortezomib for phase II studies with idarubicin and cytarabine was 1.5 mg/m2.96

Epigenetic drugs Epigenetic phenomena refer to changes in gene expression that are not coded in the DNA sequence itself. This includes post-translational modification of the main chromatin components, like histone proteins, and DNA methylation. These modifications can lead to the loss of function of tumor suppressor genes. Evidence is increasing that in addition to genetic alterations, aberrant epigenetic regulation plays an important role in carcinogenesis. Most importantly, in contrast to genetic alterations, epigenetic modifications are transient, and can, at least partially, be reversed. Thus,

105

treatment with epigenetic drugs can lead to de-repression of silenced tumor suppressor genes. The two most thoroughly studied epigenetic modifications are DNA methylation and histone acetylation, and inhibitors of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) have already been tested in several clinical trials. Methyltransferase inhibitors Methylation takes place at cytosine residues contained within the cytosine-phosphate diesterguanin-(CpG) dinucleotide. A number of genes are commonly hypermethylated in AML including ER, MYOD1, PTX2, GPR 37, MDR1, ID4, and SDC4.97 The prototype of genes methylated in leukemia is probably p15. Hypermethylation of the tumor suppressor gene has been observed in at least half of all patients with AML, ALL, and CML, and it correlates with transformation to AML in high-risk MDS.98–100 The DNMT-inhibitors 5-azacytidine (5-aza) and decitabine (DAC) are pyrimidine analogs of cytidine that can be incorporated into RNA and/or DNA. At higher doses, they are cytotoxic, due to direct interference with DNA synthesis. The majority of studies in the 1980s, focused on salvage therapy in relapsed or refractory disease, confirmed activity in AML, but treatment-related toxicity, especially prolonged bone marrow suppression, was considerable.101,102 More recently, both drugs were studied using low-dose treatment schedules. Several studies demonstrated their activity in the treatment of MDS and led to the approval of 5-aza in 2004 and DAC in 2006.103–106 These studies demonstrated promising responses in patients with RAEB-T that are now considered AML according to the WHO classification. The first data on low-dose azacytidine treatment of AML patients were published by Lee and colleagues in 1990.107 Eleven patients with AML were treated with 5-aza 75 mg/m2/day for 7 days for a maximum of three cycles. Median age was 55 (36–78) years. After a median of two cycles, no responses were observed. In contrast, Sudan and colleagues treated 20 elderly patients with AML with bone marrow blast counts between 21% and 38% and a median age of 68 years with 5-aza (75 mg/m2/day, subcutaneously on an outpatient basis) and reported an ORR of 60% (20% CR, 25% PR, and 15% HI).108 The median survival of responders was 15+ months compared with 2.5 months for nonresponders. Case reports suggest possible benefits in patients refractory to chemotherapy or patients with relapse after allogeneic transplantation.109,110 The first data on treatment with DAC at lower doses in AML patients were published by Pinto and colleagues in 1989.111 Twenty-one patients with a median age of 74 years (range, 65–83 years) were treated with DAC at doses of 15– 90 mg/m2 given intravenously over a 4 h period every 8 h for 3 days. The overall response rate was 45% (CR and PR combined). Later, Issa and colleagues treated patients with different hematological malignancies in a phase 1 study. A total of 48 patients received various doses of DAC, ranging from 5 to 20 mg/m2 i.v. daily for 10–20 days every 6 weeks. Median age was 60 (2–84) years. Of 37 patients with AML, 5 patients (14%) achieved a CR, and 3 (8%) had a PR. The dose of 15 mg/m2 for 10 days induced the most responses (11 of 17, 65%). Treatment with higher doses and over longer treatment cycles was associated with lower response rates.112 Preliminary data presented at ASH 2007 showed

106 that low-dose DAC is very well tolerated by older AML patients ineligible for more aggressive treatment, with myelosuppression being the major toxicity. In vivo reexpression of genes was noted in leukemic blasts. CRs and PRs occured in 25% of patients receiving DAC (135 mg/m2 i.v. over 72 h, every 6 weeks for up to 4 courses). Maintenance with 20 mg/m2 DAC i.v. over 1 h on 3 days every 6–8 weeks was offered to patients completing all 4 courses.113 Interestingly, demethylating drugs appear to be a treatment alternative with at least comparable efficacy in high-risk disease and in patients with chromosome 7 abnormalities.114–116 Therefore, these drugs, like clofarabine, might belong to the very few substances active as monotherapy in AML treatment, representing an alternative to standard chemotherapy which might improve our armamentarium against poor-risk AML. HDAC-inhibitors HDACs, together with histone acetyltransferases, are involved in chromatin modification, which plays a crucial role in the regulation of gene transcription. Addition of chargeneutralizing acetyl groups to lysine residues disrupts DNA– histone interaction, resulting in a more open DNA conformation and a transcriptionally active state. It is hypothesized that by this mechanism HDAC inhibitors achieve de-repression of silenced tumor suppressor genes.117 AML lends itself to treatment with HDAC inhibitors, as the aberrant recruitment of HDACs seems to be a common feature in AML. Oncogenic fusion proteins, like PML-RARa, PLZF-RARa, and AML1-ETO were shown to suppress target genes and block myeloid differentiation via recruitment of the HDAC corepressor complex. In leukemic cells, chromatin acetylation may not only be impaired by aberrant recruitment of HDACs, but also by defective acetyltransferases. The histone acetyltransferases CBP and p300, encoded on chromosomes 16p13, and 22q13, respectively, are considered tumor suppressors. Their function can be disrupted in leukemia as a result of chromosomal translocations. Possible fusion partners are MOZ (t(8;16) or (t(8;22), MORF (t(10;16)) and MLL (t(11;22); (t(11;16)).118,119 Diverse, structurally different HDAC inhibitors have entered clinical trials.120–125 (see Table 3) Preliminary, mainly phase I data of patients with AML showed diminishing blast counts in a subset of patients, but few responses according to conventional AML response criteria. With phenylbutyrate, a short-chain fatty acid, 4 of 16 patients with AML and MDS (median age 69 years) achieved HI. Other patients developed transient increases in neutrophils or platelets and decreases in circulating blasts.120 Gozzini and colleagues reported the in vitro selectivity of butyrate for blasts from core binding factor AML.121 Possibly, the best responses to treatment with HDAC inhibitors may be expected in patients with core binding factor leukemia.122 This view is supported by a study with depsipeptide, where responses occurred preferentially in patients with translocations known to recruit histone deacetylases.123 In a phase 1 study of depsipeptide, constitutional symptoms like fatigue and nausea prevented repeated dosing. While some patients experienced transient declines in blood and marrow blast counts and 1 patient developed tumor lysis syndrome, no CRs or PRs were observed.124 Similarly, a phase 1 study involving MS-275 produced no CRs or PRs in 38 patients with advanced

A. Kuendgen, U. Germing acute leukemias (median age 65 (25–86) years), but a decrease in transfusion requirements or an increase in ANC in seven patients and increased protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation was demonstrated.125 Vorinostat (suberoylanilide hydroxamic acid; SAHA) was investigated in a phase 1 trial using two oral dosing schedules: 100–300 mg twice or thrice a day for 14 days every 21 days. The study included patients with relapsed or refractory leukemias or MDS and untreated patients ineligible for chemotherapy with a median age of 68 (18–90) years. Toxicities were predominantly gastro-intestinal and the MTD was 200 mg administered twice or 250 mg administered thrice daily. Forty-one patients were enrolled and seven patients (17%) had an objective evidence of response (>50% decrease in blast count with incomplete blood count recovery), including 2 CR and 2 CRi. All responses occurred in patients with AML at or below the MTD. Median duration of response was 6 weeks.126 Studies with different HDAC inhibitors are summarized in Table 5. Several trials have been conducted with the antiepileptic drug valproic acid (VPA), which acts also as HDAC inhibitor, alone or in combination with all-trans retinoic acid (ATRA) (see Table 6). The response rate was highest in patients with low-risk MDS.127 In a study in AML (n = 58, median age 67 (21–84) years), the response rate was 5% when International Working Group [IWG] criteria for AML were applied, but 16% when the IWG criteria for MDS, which capture hematologic improvement, were used. One patient with early relapse after previous intensive chemotherapy achieved a CR, lasting for 16 months.128 The inferior response rates when compared to low-risk MDS were confirmed in a follow-up study.129 Several other groups have investigated the clinical effects of VPA in myeloid malignancies (see Table 4). All of these studies were small phase II trials investigating VPA in combination with ATRA. Bug et al. treated 26 patients with a diagnosis of poor-risk AML (median age 69 (59–84) years) with VPA plus ATRA (45 mg/m2, continuously).130 In 58% of patients an additional cytoreductive treatment with LDAC or hydroxyurea to control leukocytosis was required. While no CR was observed, one AML patient showed minor HI, and two patients with sAML arising from a myeloproliferative disorder achieved PR. Another study investigated VPA plus ATRA (45 mg/m2) in 20 elderly patients with recurrent or refractory AML or MDS achieving HI in six, leading to platelet transfusion independence in most. No reduction in blast count was observed. In four cases Grade 3 neurotoxicity occurred.131 Cimino and coworkers reported results of a pilot study in 8 refractory or high-risk AML patients (median age 61, 5 (31–69) years) with VPA, followed by the addition of ATRA on a sequential schedule.132 While no response according to AML criteria was observed, HI, according to established criteria for MDS, occurred in two patients. In this study hyperleukocytosis in the course of VPA treatment was observed in three patients, including the two responders with sAML/MDS. Increased WBC was linked to a decrease in the percentage of immature cells. Differentiation of the leukemic clone could be demonstrated by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q in differentiating cells. In another small study including 20 AML patients, four out of these responded, including one CR and two PR. Combined treatment with VPA and ATRA resulted in increased levels of histone

Clinical trials With HDAC-inhibitors in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)

Author

Gore et al. (Clin Cancer Res, 2001)120

Gore et al. (Clin Cancer Res, 2002)176

Zhou et al. (Blood, 2002)177

Odenike et al. (ASH, 2006)123

Byrd et al. (Blood, 2005)124

Giles et al. (Clin Cancer Res, 2006)178

Garcia-Manero et al. (Blood, 2008)126

Gojo et al. (Blood, 2007)125

HDI

Phenylbutyrate

Phenylbutyrate

Depsipeptide

Depsipeptide

LBH589

Vorinostat (SAHA)

MS-275

Phase Schedule

I i.v., 125-500 mg/ kg/d 7/28 days continuous infusion MDS (n = 11), AML (n = 16)

I i.v., 375 mg/kg/d 7/14 or 21/28 days cont. infusion

Phenylbutyrate plus ATRA I i.v., 200–400 mg/ kg/d 25 days

II i.v., 18 mg/m2/d d 1, 8 and 15 every 28 days

I Oral, 4-10 mg/m2, 1·/week for 2 or 4 weeks

AML M3 (n = 5)

AML (n = 21)

I i.v., 4.8– 14 mg/m2, d 1–7 every 21 days, AML (n = 13), MDS (n = 1)

I Oral, 100–300 mg 2–3·/d, 14/21 days

MDS (n = 9), AML (n = 14)

I i.v., 13 mg/ kg/m2 d 1, 8, 15 every 28 days AML (n = 10)

AML (n = 38)

Responses

4 HI, 4 decline of PB blasts

2 HI (21/28 schedule)

1 RT-PCR neg. CR

Transient declines in PB and BM blasts

8 patients transient decline in PB blasts

Toxicity

CNS toxicity, hypo-calcemia, nausea/ vomiting

CNS toxicity, skin reaction, hypocalcemia

Transient CNS depression

2 bone marrowblast clearance, 2 reduction in marrow blasts >50%, all responders had core binding factor leukemia Nausea, vomiting, fatigue

AML (n = 31), MDS (n = 3), CML (n = 1) ALL (n = 2) CLL (n = 4) 2 CR, 2 CRp, 3 HI

Fatigue, vomiting, nausea, tumor lysis syndrome, diarrhea

QT prolongation, nausea, vomiting, hypokalemia

Patient number and diagnosis

Nausea, vomiting, diarrhea, neutropenia, typhlitis, fatigue

7 HI, transient decline in peripheral and marrow blasts

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

Table 5

CNS toxicity, infections, fatigue, nausea, vomiting

107

108

Table 6

Clinical trials With valproic acid (VPA) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)

Author

Kuendgen et al. (Cancer, 2007)129

Bug et al. (Cancer, 2005)130

Pilatrino et al. (Cancer, 2005)131

Raffoux et al. (Haematologica, 2005)134

Cimino et al. (Cancer Res, 2006)132

Siitonen et al. (Haematologica, 2007)175

Craddock et al. (ASH, 2005)133

Schedule

VPA monotherapy (n = 90) (serum concentration 50– 100 lg/ml), VPA/ ATRA I (n = 10), VPA/ATRA II (n = 22) MDS (n = 60), AML (n = 62) 1 CR, 1 PR, 22 HI CNS toxicity, Thrombocytopenia

VPA orally, continuously max. 50 mg/kg; ATRA 45 mg/m2/d

VPA (serum concentration 45– 100 lg/ml), ATRA added later 45 mg/m2/d

VPA (serum concentration 50– 100 lg/ml), ATRA added later45 mg/ m2/d, +theophylline

VPA (serum concentration P50 lg/ml), ATRA added later, 45 mg/ m2/d

VPA (serum concentration 70– 100 lg/ml), 13-cis retinoic acid (20 mg/d), Vitamin D3 1 lg/d

VPA/ATRA, theophylline in non-responders

MDS (n = 2), AML (n = 24) 2 PR, 1 HI CNS toxicity, hyperleukocytosis, impairment of coagulation

MDS (n = 7), AML (n = 13) 6 HI CNS toxicity

AML (n = 11)

AML (n = 7), CML (n = 1) 2HI CNS toxicity, hyperleukocytosis, hyperbilirubinemia

MDS (n = 19)

AML (n = 20) 1CR, 2 PR, 4HI Not specified

6

4

4

3 HI Dry skin, fatigue, elevated transaminases, pneumonitis, CNS toxicity 8

Patient number and diagnosis Response Toxicity

Dis-continuation (Toxicity)

1 CR, 2 CRi, 2 HI CNS toxicity, bone pain

2

1

Not specified

ATRA I: all-trans retinoic acid 80 mg/m2, every other week. ATRA II: all-trans retinoic acid 15 mg/m2, daily. MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; CR, complete response; PR, partial response; HI, hematologic improvement; CRi, complete response with incomplete recovery; CNS, central nervous system.

A. Kuendgen, U. Germing

CNS toxicity Toxicity

CNS toxicity, fever, nausea, fatigue

2 (18%) CR, 2 (18%) CRi, 2 (18%) PR CNS toxicity, myelosuppression, infection, myeloid differentiation syndrome 12 (22%) CR, 3 (5%) CRp, 7 (13%) BM responses CNS toxicity 10 (19%) CR, 2 (3%) CRp

3 (30%) PR

AML (n = 11) AML (n = 49), MDS (n = 4) AML (n = 48), MDS (n = 6)

Patient number and diagnosis Response

AML (n = 8), MDS (n = 2)

DAC 20 mg/m2 d1– 10 + VPA escalating doses (d5–21) 15, 20 or 25 mg/ kg AZA 75 mg/m2 d1–7 + VPA orally 50, 62,5 and 75 mg/ kg (d1-7) + ATRA 45 mg/ m2/d (d3–7) DAC 15 mg/m2 d1– 10 + VPA orally 20, 35, 50 mg/kg (d1–10) Schedule

Maslak142 Soriano136 Garcia-Manero135 Author

Table 7

One attractive combination that is currently being investigated is directed towards reversing the combined epigenetic silencing that occurs through histone deacetylation and DNA methylation. Indeed, the complementary activity of demethylating agents and HDAC inhibitors has been shown in vitro by several research groups.137–139 Whitman et al. have shown that the combination of DNMT and HDAC inhibitors can reactivate the transcription of the wild-type allele in MLL + blasts.140 Recently, several phase I/II studies have reported encouraging results (Table 7).135,136,141,142 Garcia-Manero et al.135 treated 54 patients (AML or high-risk MDS) with a fixed dose of decitabine (15 mg/m2, i.v., daily for 10 days) administered concomitantly with escalating doses of VPA (orally, 10 days). Median age was 60 (5–84) years. A dosage of 50 mg/kg/day was chosen as safe for the phase 2 part of the study. The ORR was 22%, including a 19% CR rate. Survival was 15.3 months in responders. Similar results were observed in a study on 5-aza in combination with VPA and ATRA .136 This study had a phase I/II design as well, with 5-aza administered at a fixed dose of 75 mg/m2/d for 7 days and VPA was again concomitantly dose escalated (orally, 7 days). ATRA was given at 45 mg/m2/d (d3–7). On the 7day schedule as well, a dose of 50 mg/kg was the maximum tolerated dose for VPA. 53 patients with AML or high-risk MDS and a median age of 69 (5–84) years were included. ORR was 42%, including 22% CRs, 5% CRps and 13% bone marrow responses. DLT was neurotoxicity in both trials. Evidence for a beneficial effect of VPA in this combination can be derived from a higher response rate in patients with higher VPA levels in the second study. In the first study a trend for a higher response rate was observed in patients with higher VPA levels in the subgroup of previously untreated patients. There also was an association of responses with higher VPA doses, and responses were attained already after a median of only one cycle, which is earlier than expected with decitabine monotherapy. A smaller phase I study141 on decitabine plus VPA in 25 AML patients (median

Clinical trials With demethylating agents in combination with HDAC-inhibitors

Combination regimen

AZA 75 mg/m2 d1–7 + PB 200 mg/kg for 5d after AZA

Blum141

Gore143

acetylation and methylation and induced expression of p15, p16 and p21 in blasts from treated patients as well as consistent changes in HDAC expression patterns.133 In a small study on the treatment of elderly AML with VPA, ATRA and theophylline the authors found a high rate of marrow responses (3/11 patients), including one CR as well as two additional HI according to MDS criteria.134 Interestingly, 4 of 5 responders had a normal karyotype. All of these studies administered VPA orally on a continuous schedule in conventional doses and demonstrated clinical activity. Activity of VPA inducing histone acetylation132 as well as degradation of HDAC2130 could be shown. Despite the evidence for HDAC inhibitory and clinical activity at conventional doses, the optimal treatment schedule remains unclear. In combination studies with demethylating agents and cytotoxic drugs, much higher doses of VPA were demonstrated to be associated with an acceptable toxicity, when administered on a short time intermittent schedule.135,136 The clinical results obtained so far imply that HDAC inhibitors might not be sufficiently active as monotherapy in AML treatment. 135,136

109

AZA 50 mg/m2 d1–14, 1– 10 or 1–5; 75 mg/m2 d1– 5; 25 mg/m2 day 1– 14 + PB 375 mg/kg/d for 7d after AZA AML (n = 18), MDS (n = 13), CMML (n = 1) 4 (14%) CR, 1 (3%) PR, 6 (21%) HI CNS toxicity, mild nausea, injection side reactions, asthenia, myelosuppression

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

110 age 70 years) could not verify this beneficial effect of VPA, although responses appeared to occur earlier with the combination treatment vs. single-agent decitabine as well. In this trial 14 patients received decitabine alone to determine the optimal biologic dose, which was 20 mg/m2/d (d1–10). Only 11 patients received the combination with dose-escalating VPA (d5–21). Dose-limiting encephalopathy already occured in 2 patients at 25 mg/kg/d. Responses included 2 CRs, 2 CRis, and 2 PRs (ORR 54%), but the authors conclude that VPA might be associated with too much toxicity in this elderly patient population. Two further studies were conducted with PB plus 5-aza. In a pilot trial 10 patients (8 AML, 2 MDS) were treated with 5-aza (75 mg/m2, 7 days) followed by 5 days of sodium PB (200 mg/kg).142 Median age was 66.5 (38–78) years. Five patients achieved a beneficial clinical response (PR or SD) and one patient received subsequent allogeneic stem cell transplantation. Another study by Gore et al. investigated the optimal dosing schedule for 5-aza in this combination.143 In this study median age was 66 (41–85) years. The ORR was 38% (11/29 but it was 56% (5/9) and 50% (3/6) in the dose cohorts receiving prolonged 5-aza schedules (50 mg/m2/d for 10 days and 25 mg/m2 for 14 days, respectively). Major toxicity for PB was neurotoxicity in both studies. The benefit of adding VPA to demethylating agents can only be determined within a randomized trial. However, the CR rates of the existing studies compare well with trials of DAC or 5-aza as single agents. Furthermore, an association between higher VPA doses, serum concentrations, and treatment response has been shown. Responses were also attained earlier at higher dosages, and the median number of cycles given prior to the observation of response was lower compared with single-agent DAC or 5-aza treatment.135,136 HDAC inhibitors modulate cell cycle regulatory proteins. Therefore, combination with cell cycle-specific cytotoxic drugs may provide greater cytotoxicity than seen with either class of agents alone. As an example, some studies have shown synergy between HDAC inhibitors and araC.144,145 The combination caused G1 arrest and upregulation of cyclin-D1 expression. Because VPA also blocks ara-C-induced p27-Kip1 downregulation, the German Leukemia Study Group I (AMLSG) compared standard chemotherapy with the same regimen complemented by VPA and/or ATRA in patients above and below the age of 60.146 The results of these studies are not yet published, but in the study for elderly patients the VPA arm had to be closed early due to prolonged bone marrow suppression and infectious complications. The same group previously reported a beneficial effect of the addition of the vitamin A derivative and differentiation inducing agent ATRA to induction and consolidation therapy in elderly AML patients. In this study a total of 242 patients aged P61 years with AML were randomly assigned to ATRA beginning on day 3 (45 mg/m2 d3–5 and 15 mg/m2 d6–28) after the initiation of chemotherapy or no ATRA. The induction therapy consisted of ICE (idarubicin 12 mg/m2 i.v. d1 + 3, cytarabine 100 mg/m2 cont. i.v. d1–5, etoposide 100 mg i.v. d1 + 3). Patients achieving CR or PR received a second induction cycle. Patients with refractory disease were assigned to a second induction therapy with AHAE (cytarabine 0.5 g/m2/12 h i.v. d1–3, etoposide 250 mg/m2 i.v. d4 + 5, ATRA 45 mg/m2 d3–5 and 15 mg/ m2 d6–28). All patients in CR following two cycles of induc-

A. Kuendgen, U. Germing tion therapy received a first consolidation therapy with HAM (cytarabine 0.5 g/m2/12 h i.v. d1–3, mitoxantrone 10 mg/ m2 i.v. d2 + 3) or A-HAM (ATRA 15 mg/m2 d3–28). A total of 61 patients in CR were randomly assigned to a second intensive consolidation or 1-year oral maintenance therapy. After induction a significant difference in CR rates was observed between the ATRA- and standard-arm (52 vs. 39%; P = 0.05). EFS as well as OS (11.3 vs. 7 months) were significantly better in the ATRA arm (P = 0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P = 0.001).147 This is one of the few trials describing a survival benefit of a targeted agent added to conventional chemotherapy. Antibodies Approximately 90% of myeloid blast cells from patients with AML express CD33, making this antigen a target for antineoplastic therapy.148 Gemtuzumab ozogamicin (GO), a humanized CD33 antibody linked to N-acetyl-c-calicheamicin, a potent antitumor antibiotic, is approved in the United States for adults >60 years of age who are in first relapse and not eligible for intensive chemotherapy.93,149 In phase 1 studies, the major toxicity of this drug was myelosuppression. Some patients experienced acute infusion-related symptoms that were generally transient. The recommended phase 2 dose was 9 mg/m2 i.v. for two doses.150 GO induced a CR in 16% of patients and an additional 13% of patients achieved a CRp in a phase 2 study (n = 142, median age 61 years) in AML in first relapse.151 Larson and colleagues reported on 277 patients with a median age of 61 years treated with GO (9 mg/m2 d1 + 15).152 The ORR was 26% (13% CR and 13% CRp). Notably, the median OS was 4.9 months in all patients and 12.6 months in responders. Further trials in poor-risk AML reported remission rates of 14–25%.152–154 In a study by Amadori and colleagues, the CR/CRp rate was 33% in patients aged 61–75 years, but only 5% in those patients >75 years. Studies on gemtuzumab ozogamicin are summarized in Tables 8 and 9. The initial responses to GO monotherapy led to several trials that incorporated GO in combination chemotherapy regimens (see Table 9). One study in 59 patients with previously untreated AML and high-risk MDS combined GO (6 mg/ m2 on day 1) with fludarabine, cytarabine, and cyclosporine, a potential P-gp modifier.156 Median age was 57 (27–76) years. The ORR was 48%, with a median OS of only 8 months. Toxicities were considerable, with infections complicating 38% of the courses, and hepatotoxicity, with venoocclusive disease (VOD) in 7% of patients. The EORTC/Gruppo Italiano Malattie Ematologiche dell’Adulte (GIMEMA) group reported a regimen consisting of GO followed by mitoxantrone, cytarabine, and etoposide in previously untreated elderly patients with AML.157 This combination yielded a response rate of 35% (23% CR and 12% CRp). GO with different intensive chemotherapy regimens yielded 86–91% CR/CRp rate in newly diagnosed AML and 12–42% in relapsed-refractory AML.158–162 Interestingly, a small study involving 17 patients with relapsed or refractory AML (median age 54 (21–68) years) who received a chemotherapeutic regimen combining ara-C and mitoxantrone with GO given on day 4, in contrast with other regimens that typically administered GO on day 1, reported a CR rate of 76%.163 Currently, several phase 3

Clinical trials with gemtuzumab ozogamicin (go) in acute myeloid leukemia (AML)

Author

Larson et al. (Leukemia, 2002)148

Larson et al. (Cancer, 2005)152

Roboz et al. (Leuk Lymphoma, 2002)153

Amadori et al. (Leukemia, 2005)154

Nabhan et al. (Leuk Res, 2005)155

Phase Schedule

II 9 mg/m2 d1 and d14 ( 28)

II 9 mg/m(2) 1–3 infusions

II 9 mg/m(2) d1 and d15

II 9 mg/m(2) d1 and d15

Patient Number and Diagnosis Age Disease stage

AML (n = 101)

II 9 mg/m(2) d1 and d14( 28) AML (n = 277)

AML (n = 40)

AML (n = 11)

Median 69 years First relapse

Median 61 years First relapse

Median 76 years Ineligible for intensive chemotherapy

>65 years Ineligible for intensive chemotherapy

Responses

28 (28%) ORR 13 (13%) CR 15 (15%) CRp Myelosuppression, chills, hypotension, fever, elevated liver enzymes, mucositis, infection

71 (26%) ORR, 35 (13%) CR, 36 (13%) CRp Myelosuppression, sepsis, fever, chills, nausea or emesis, pneumonia, dyspnea, hypertension, hypotension

AML (n = 36), CML (n = 14), RAEB-T (n = 2) Mean 62 years Relapsed, refractory, ineligible for intensive chemotherapy 6 (14%) ORR, 4 (9%) CR, 2 (5%) CRp Myelosuppression, neutropenic fever

7 (17%) ORR, 4 (10%) CR, 3 (7%) CRp Infection, hemorrhage, liver toxicity, VOD, HUS, myelosuppression, febrile neutropenia

3 (27%) ORR, 3 (27%) CR

Toxicity

Cardiac toxicity, fever, fatigue, pulmonary, hypotension, nausea, edema, myelosuppression, elevated liver enzymes, neutropenic fever

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

Table 8

111

112

Table 9

Combination regimens including gemtuzumab ozogamicin (GO) in acute myeloid leukemia (AML)

Author

Tsimberidou et al. (Cancer, 2003)156

Amadori et al. (Haematologica, 2004)157

Kell et al. (Blood, 2003)158

Tsimberidou et al. (Leuk Res, 2003)159

Alvarado et al. (Cancer Chemother Pharmacol, 2003)160

Apostolidou et al. (Leuk Res, 2003)161

Cortes et al. (Cancer Chemother Pharmacol, 2002)162

Chevallier et al. (Leuk Res, 2005)163

Estey et al. (Blood, 2002)165

Moore et al. (Leuk Res, 2006)166

Nand et al. (ASH, 2006)167

Phase GO-Schedule

II 6 mg/m2 i.v. d1

II 6 mg/m2 i.v. d1 and 15 Idarubicin 12 mg/m2 d2–4, ara-C 1.5 mg/m2 d2–5

Pilot 6 mg/m2 i.v. d6 liposomal daunorubicin 75 mg/m2 d6– 8, cytarabine 1 g/m2 d1–5 and cyclosporine 6 mg/kg d6, 16 mg/kg continuous IV d6–8

ara-C 1 mg/m2 d1–5, topotecan 1.25 mg/m2 d1–5

ara-C, 1 g/m2 every 12 h d1– 5, mitoxantrone 12 mg/m2 d1– 3

II 9 mg/m2 iv d1 and 8 or 15 With or without IL11; 15 lg/kg d3–28

II 9 mg/m2 iv d4 and 18 Oblimersen sodium 7 mg/kg/day, d1–7 and 15–21

II 3 mg/m2 iv d8 Azacytidine 75 mg/m2 sc d1–7

Patient Number and Diagnosis Median Age/ years Disease stage

AML (n = 39), RAEB/ RAEBT (n = 20)

AML (n = 57)

AML (n = 72)

II 4,5 mg/m2 i.v. d1 Fludarabine, 15 mg/m2 i.v. every 12 h · 10, d2– 6; ara-C, 0.5 g/ m2 every 12 h · 10 d2–6, CSA loading dose of 6 mg/ kg,16 mg/kg continuous i.v. infusion d1 + 2 AML (n = 32)

II 9 mg/m2 iv d4

Fludarabine, 15 mg/ m2 i.v. every 12h · 10, d2–6; araC, 0.5 g/m2 every 12 h · 10 d2–6, CSA loading dose of 6 mg/kg,16 mg/kg continuous i.v. infusion d1 + 2

I/II 3 ( 6) mg/m2 i.v. d1 Induction: HDAT, S-DAT , SDA, or FLAGIda; consolidation: MACE, HiDAc, MiDaca

Pilot 9 mg/m2 iv d1

Combination

II 9 mg/m2 i.v. d1 and 15 (after response assessment) mitoxantrone 7 mg/ m2/d d 1, 3, 5, etoposide 100 mg/ m2/d d1–3, ara-C 100 mg/ m2/d d 1–7

AML (n = 14)

AML (n = 11)

AML (n = 17)

AML (n = 17)

AML n = 48

57

68

46,5

53

61

37

55

54

AML (n = 37), RAEB (n = 8), RAEB-T (n = 6) 71

67

AML (n = 11), MDS (n = 2) 77

First line

First line

First line CR (after course 1) 86%

Relapsed, refractory 2 (12%) ORR, 2 (12%) CR

Toxicity

VOD, infections, elevated liver enzymes

Relapsed, refractory 13 (76%) ORR, 12 (70%) CR, 1 (6%) CRp VOD, elevated liver enzymes, myelosuppression

First line

20 (35%) ORR, 13 (23%) CR, 7 (12%) CRp 6 (11%) PR Febrile neutropenia, infection, elevated creatinine, elevated liver enzymes, VOD, nausea

Relapsed, refractory 2 (18%) ORR, 1 (9%) CR, 1 (9%) CRp Sepsis, elevated liver enzymes, mucositis

First relapse

28 (48%) ORR, 27 (46%) CR, 1 (2%) CRp

Relapsed, rrefractory 6 (41%) ORR, 3 (21%) CR, 3 (21%) CRp

First line

Responses

Relapsed, refractory 11 (34%) ORR, 9 (28%) CR, 2 (6%) CRp Elevated liver enzymes, VOD

2 (8%) CR For GO; 9 (36%) CR for GO + IL-11 VOD

12 (25%) ORR, 5 (10%) CR, 7 (15%) CRp Myelosuppression, nausea, rigors, pyrexia, vomiting diarrhea, constipation, febrile neutropenia, hypokalemia

10 (76%) ORR, 10(76%) CR neutropenic fever and typhlitis

Myelosuppression, sepsis, elevated liver enzymes, VOD, diarrhea

Elevated liver enzymes, VOD

H-DAT: Daunorubicin 50 mg/m2, d1, 3, and 5, Ara-C 200 mg/m2 · 2, d1–10, Thioguanine 100 mg/m2 · 2, d1–10; S-DAT: Daunorubicin 50 mg/m2, d1, 3, and 5, Ara-C 100 mg/m2 · 2,d1–10, Thioguanine 100 mg/m2 · 2, d1–10, FLAG-Ida:

Fludarabine 30 mg/m2, d2–6, Ara-C 2 g/m2 d2–6, G-CSF 263 g SC, d1–7, Idarubicin 10 mg/m2, d4–6; MACE: Amsacrine 100 mg/m2, d1–5, Ara-C 200 mg/m2, d1–5, Etoposide 100 mg/m2 IV, d1-5; MiDac: Mitoxantrone 10 mg/m2 d1–5, Ara-C 1 g/m2 · 2, d1–3; HiDAc: Ara-C 3 g/m2 · 2, d1, 3, and 5.

A. Kuendgen, U. Germing

a

Prolonged myelosuppression, VOD, elevated liver enzymes

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly trials combining standard-dose chemotherapy and GO are underway. Very interesting preliminary data was published at ASH 2006 on the MRC AML15 trial. This trial included mainly patients below the age of 60, but the analysis of 1115 randomised patients indicates that the addition of GO to induction chemotherapy reduces the relapse risk without adding significant extra toxicity, thus leading to significantly improved disease-free survival in the GO arm. To evaluate the impact on survival a longer follow-up is required.164 Several combinations with other new agents are under investigation. In a randomized trial, evaluating GO alone or in combination with interleukin-11 in 51 patients aged 65 years or older with newly diagnosed AML, RAEBt, or RAEB, the CR rate was 8% for GO alone and 36% for GO plus interleukin-11, but no survival difference was observed.165 When results were compared with those achieved in a similar population treated with idarubicin plus ara-C, however, the idarubicin plus ara-C regimen was associated with a CR rate of 48% and superior survival (P = 0.03). A phase 2 study of oblimersen sodium plus GO in elderly AML patients in first relapse demonstrated a response rate of 25% (10% CR and 15% CRp).166 Preliminary but very promising data on the combination of GO with 5-aza in 13 patients with AML or MDS (and a median age of 77 years) showed a CR rate of 76%.167 Finally, a combination of GO, daunorubicin and clofarabine is currently being investigated and very early results confirm the feasibility of this regimen.168 In conclusion, monotherapy with GO leads to CR/CRp in approximately 25% of patients. Its value has yet to be determined in the current phase 3 trials combining GO with chemotherapy. When used in combination with other agents, GO can be associated with considerable hepatotoxicity, including VOD, and the specific risk factors for this treatment need to be identified. Still, the early results from the MRC AML15 trial which were mainly derived from younger adults raise the hope for a reduction of the high relapse rates in elderly patients as well. Especially patients with good or intermediate risk features might benefit from the addition of GO.

Conclusions As a disease entity, AML in the elderly differs substantially from AML in younger patients, and separate treatment recommendations are needed. According to recent reports from several investigators, standard remission induction therapy should be restricted to patients presenting with the following features: younger age (<70 years), ECOG performance status of <2, normal organ function, normal or good-risk karyotype, de novo AML, and white cell count <100 · 109/L. Still, even in this favorable subgroup median OS is only about 1 year. Even elderly patients with good risk karyotypes have a disappointing 5-year survival-rate below 15%169 According to our opinion, investigational therapies should be seen as the preferred option for AML patients above the age of 60 years, and patients without poor-risk features should receive intensive chemotherapy including novel agents during induction, consolidation, or as maintenance treatment, which is in accordance with recent NCCN guidelines.170 It is possible that the increasing knowledge on

113

molecular genetic abnormalities will help to better define subgroups that will have a benefit from intensive chemotherapy.171 For patients in good clinical condition, allogeneic stem cell transplantation without myeloablative conditioning remains a curative option. However, more clinical trials are needed to better define the role of stem cell transplantation in the treatment of elderly patients with AML. Regarding patients too old, patients with poor-risk disease features, or patients otherwise not medically fit for intensive treatment approaches, supportive care, low-dose chemotherapy, and investigational drugs represent the spectrum of current alternatives. While LDAC has demonstrated a survival benefit compared to supportive care, especially patients with reduced performance status and adverse cytogenetics appear not to benefit from this drug.24,35 Still this treatment can be used as standard arm in randomized trials for patients not fit for intensive treatments. Since the median survival of patients receiving supportive care only with or without cytoreduction (e.g. hydroxyurea) is only a few weeks (11 weeks in the study by Lowenberg et al.24), experimental treatment should be applied whenever possible. Recent studies with targeted therapies have shown some promising results, although only few, like the novel chemotherapeutic agent clofarabine and the demethylating agents have demonstrated sufficient activity to be considered as monotherapy. It is difficult to review and compare the existing data due to the lack of phase III trials and an abundance of different response criteria. This is due to the fact that the traditional AML response criteria, CR and PR, are suitable mainly for the evaluation of conventional treatment approaches. They are still useful to assess the value of a new drug, but unfortunately, unlike CML, in AML very few of the so-called targeted therapies are effective enough as monotherapy to achieve a considerable number of true remissions. Reductions in blast count or responses like leukemia-free state might not lead to a survival benefit, but demonstrate a certain antileukemic activity. Based on these phase I/II results, combinations with conventional regimens, other investigational drugs, or the use as maintenance treatment can be the next step of evaluation. Hematologic improvements, on the other hand, may at least improve quality of life. It is possible that, comparable to MDS patients, patients with a smoldering form of AML might benefit from such improvements and from disease stabilization in terms of survival.169 Future studies should not only investigate new drugs, but seek to define optimal treatment schedules for currently available agents, and to explore the efficacy and safety of new combination regimens. Some of the existing drugs will likely improve the standard of care in elderly patients with AML. Although most trials of low-dose 5-aza and DAC have been conducted in MDS,169 it is likely that both will add to the arsenal of clinically useful therapies for AML. Both drugs appear to be effective in patients with high-risk karyotypes, in particular in chromosome 7 abnormalities.114–116 For patients with complex karyotypic abnormalities including del5q, lenalidomide should be further evaluated. In the rare cases of AML with t(9;22) or AML with associated eosinophilia that are FIP1L1-PDGFRA positive, imatinib needs to be included in treatment schedules. In FLT3-positive AML, small molecule TKIs have shown limited efficacy when

114 administered alone. However, current and future clinical trials may reveal a role for FLT3 inhibitors within combination chemotherapy regimens, thereby improving outcome in this poor-risk group. Because aberrant recruitment of corepressor complexes by leukemogenic fusion genes appears to be a common feature in AML, HDAC inhibitors may be of benefit in core binding factor leukemia. Combination of epigenetic drugs has shown promise in several in vitro studies and early clinical trials. This approach might be especially attractive to be further evaluated in patients with MLLPTD.140 Combination treatment with GO is another treatment alternative for patients with relapsed AML and phase 3 trials are currently underway to determine its role in combination chemotherapy regimens for patients with previously untreated AML. The very promising preliminary analysis from the MRC AML-15 trial showing a significant improvement in disease-free survival needs to be confirmed in elderly patients. This treatment is likely to show the greatest benefit in patients with good or intermediate-risk cytogenetics. Moreover, several other drugs have shown in vitro synergism with chemotherapeutic agents, some of these combinations are already in phase 3 trials. One successful example of this approach is ATRA in the treatment of acute promyelocytic leukemia. Interestingly, ATRA has recently demonstrated a slight, but significant, effect on survival in combination with chemotherapy in non-M3 AML. There is now evidence that this effect might be restricted to patients with NPM1 mutations.172,173 Another interesting area of application for novel drugs is maintenance therapy. For example first promising data exists for the FLT3-inhibitor tipifarnib, awaiting confirmation in a phase III setting. Regarding the heterogeneity and the multistep pathogenesis of AML,174 the future of its treatment belongs to combination therapy and treatment approaches specifically tailored to the different patient subtypes.

Conflict of Interest Statement We would like to confirm that none of the authors has any financial or other relationship that might lead to a conflict of interest concerning the submitted review article ‘‘Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly’’.

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