Review

Nature Clinical Practice Oncology (2005) 2, S24-S29
doi:10.1038/ncponc0355  
Received 17 August 2005 | Accepted 30 August 2005

Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection

Jean-Pierre Issa

Correspondence MD Anderson Cancer Center, University of Texas, 1515 Holcombe Boulevard, Unit 0428, Houston, TX 77030, USA

Email jpissa@mdanderson.org

Summary

Azacitidine (Vidaza®, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogen™, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA) are DNA methyltransferase (DNMT) inhibitors that have clinical activity in patients with myelodysplastic syndromes. Mechanism-based laboratory studies suggest that clinical optimization of therapy with DNMT inhibitors needs to include optimizing intracellular drug uptake and maximizing drug exposure over time while still using lower doses to avoid cytotoxicity. Clinical studies suggest that increased dose intensity and multiple cycles of administration substantially increase response rates. Other strategies for optimizing the efficacy of DNMT inhibitor therapy also include identification of patients that are best qualified for treatment, and defining in vivo mechanisms of patient responses. In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results.

Keywords:

azacitidine, decitabine, hypomethylation, myelodysplastic syndrome

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Introduction

Myelodysplastic syndromes (MDSs) are a collection of diseases of bone marrow stem cells, characterized by peripheral cytopenias and dysplasia of hematopoietic progenitor cells.1, 2 Treatment options range from BEST SUPPORTIVE CARE (BSC; transfusions, antibiotics, and erythropoietin) for low-risk patients, to stem-cell transplantation (SCT; the only curative option) for young patients.1 DNA methyltransferase (DNMT) inhibitors are a new class of EPIGENETIC DRUG THERAPIES, which exhibit promising response rates in MDS patients.

Methylation of a subset of DNA cytosine residues is integral in the control of gene expression.3, 4 DNMT inhibitors reduce DNA methylation and reactivate abnormally suppressed gene expression, which leads to clearing of the neoplasm clones by various mechanisms. This ameliorates anemia and other symptoms in MDS.5, 6, 7, 8, 9 Azacitidine (5-azacytidine; Vidaza®, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogen™, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA; received an approvable letter in September 2005, pending further FDA review) are DNMT inhibitors that, on the basis of clinical trials, are better than BSC in the management of patients with MDS.10, 11 Studies with these agents report total response rates ranging from 50% to 80%, with some experience reporting a significant impact upon progression of acute myelogenous leukemia (AML), patient quality of life, and, in some cases, survival.11, 12, 13

Selection of the best therapy option remains a challenge for the hematology/oncology practitioner. A therapy option (i.e. BSC, DNMT inhibitor, or SCT) prescribed for one patient may differ significantly from that for another, because of considerations relating to the patient, the stage of the disease, and treatment (e.g. administration, toxicity, efficacy). Furthermore, recent pilot data suggest that lower doses and longer applications of DNMT inhibitors may be better than previously studied dosing regimes.13 The purpose of this review is to examine strategies for optimizing therapeutic response by reviewing studies of DNMT inhibitors with an emphasis on dose, duration of therapy, and patient selection criteria.

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Clinical hypomethylation trials

A number of studies have examined the efficacy of azacitidine and decitabine in the treatment of MDS. Azacitidine was the first DNMT inhibitor to receive the approval of the FDA for MDS14 and is indicated for both high- and low-risk patients. At the time of this publication, the FDA is reviewing phase I–III decitabine trial data for consideration of approval in patients with high-risk MDS.15, 16

Azacitidine experience in MDS and AML

Early studies with azacitidine performed in the 1970s used dosing schedules much higher than current clinical levels. Saiki and co-workers17 examined 100 relapsing or refractory patients and treated them with three relatively high dose schedules. Patients received azacitidine 100 mg/m2 every 8 h intravenously for 5 days, 750 mg/m2 intravenously every 2–3 weeks, or 300 mg/m2 per day continuous infusion over 5 days.17 Twelve patients achieved complete remission (CR), and six achieved partial remission (PR) after a median time of 5 weeks. The median duration of CR was 21 weeks, and only 5 weeks for PR. Similar studies found CR rates as high as 25% after a median of 59 days of treatment.18 A review of approximately 200 azacitidine-treated patients found a 36% response rate, including 20% CR.19 Adverse effects included vomiting and leukopenia.19 Schiffer and co-workers examined the efficacy of azacitidine in 27 patients with high-risk MDS in blast crisis.20 They were given a combination of azacitidine (150 mg/m2 daily intravenously in three divided doses for 5 days) and VP-16-213 (75 mg/m2 daily for 5 days). No patient had lymphoid histology, and terminal transferase was not present in a subset of 12 patients that were tested. One CR and 15 PRs (58% response rate in all) were observed, with a median survival of 231 days for responders and 73 days for nonresponders (P = 0.008). More recent studies examined lower doses. In a small series of 11 patients with AML, researchers examined the efficacy of azacitidine administered as 7-day, continuous infusions at a dose of 75 mg/m2 daily. Five of the subjects were unavailable for follow-up, and there was no response in the remaining six. However, patients receiving the lower dose presented with limited extrahematological effects.21 Specifically, five patients developed bone marrow hypocellularity in six courses, though none became aplastic. Increased bone marrow cellularity percentage of blasts occurred in eight courses in six patients.

This lowered-dose approach was next applied to MDS. After promising phase II studies, a phase III study compared the effects of azacitidine (75 mg/m2 given subcutaneously daily for 7 days repeated every 4 weeks) with those of BSC and found an overall response rate of 60% (7% CR, 16% PR, 38% hematological improvement). There was a 60% response rate in lower-risk patients with refractory anemia or with refractory anemia with ringed sideroblasts, and a 61% average response rate in the higher-risk groups.10 The median response duration was 14 months.10 Remarkably, the mean time to response was six treatment cycles, underscoring the importance of clinician and patient education in order to avoid abandoning treatment after a few cycles.

An analysis of quality of life, the first of its kind in DNMT inhibitor therapy in MDS, was performed in the same study population.22 Using the EORTC (European Organisation for Research and Treatment of Cancer) dyspnea and fatigue scale and the Mental Health Inventory (MHI) psychological well-being subscale assessment subscore, Kornblith et al. found that fatigue and dyspnea levels between treatment groups worsened for patients receiving supportive care and improved for patients treated with azacitidine.22 Patients treated with azacitidine presented with greater improvement in fatigue (EORTC, P = 0001), dyspnea (EORTC, P = 0.0014), physical functioning (EORTC, P = 0.002), positive affect (MHI, P = 0.0077), and psychological distress (MHI, P = 0.015).22 In summary, azacitidine effectively produces partial or complete regression in MDS and improves the patients' quality of life.

Decitabine experience in MDS and AML

Decitabine has also been studied in comparable patient populations. Schwartsmann et al.23 reported an impressive 65% CR rate in newly diagnosed patients with MDS whose disease had already progressed to AML and who were treated with decitabine as a 4-h intravenous infusion at the dose of 90 mg/m2 daily on days 1–5. Petti et al.24 examined the efficacy of decitabine in high-risk MDS patients who had progressed to AML. In 10 patients, 90–120 mg/m2 was infused for 4 h three times daily for 3 consecutive days every 4–6 weeks, and it produced CR in 30% of patients and PR in 10%. Decitabine has also been used in combination therapy regimens. In one study,25 63 patients with a relapse of AML or lymphocytic leukemia received decitabine 125 mg/m2 as a 6-h infusion every 12 h for 6 days. Thirty patients received amsacrine, 120 mg/m2 as a 1-h infusion on days 6 and 7, as adjunctive therapy, and the remaining 33 patients received idarubicin 12 mg/m2 as a 15-min infusion on days 5, 6, and 7. CR was attained by 36.5% of all participants (8 receiving amsacrine and 15 receiving idarubicin). Patients with normal cytogenetic findings had a higher CR rate (61%) than patients with abnormal ones (15.8%).25

Decitabine was next studied as a single agent in MDS. Wijermans and co-workers tested a 72-h continuous infusion of low-dose decitabine, 45 mg/m2 daily for 3 days every 6 weeks, in a group of 29 elderly patients with high-risk MDS.26 Even among patients with cytogenetic findings associated with a poor prognosis, CR was achieved in 28% and PR in 26%. Myelosuppression, leading to a prolonged cytopenic period and toxic death, occurred in 5 (17%) of these high-risk patients.26 This was followed by a larger, phase II trial in which decitabine was given at 15 mg/m2 intravenously over 4 h three times a day for 3 days, and a response rate of 49% was seen in 66 patients.27 Combined analysis of all the phase II data found a total response rate of 49% associated with decitabine (Table 1).28

Table 1 Cumulative analysis of 187 patients with myelodysplastic syndrome treated with low-dose decitabinea
Table 1 - Cumulative analysis of 187 patients with myelodysplastic syndrome treated with low-dose decitabinea
Full tableFigures & Tables index

The first phase III data16 for decitabine was presented at the 2005 American Society of Clinical Oncology (ASCO) annual meeting. Eighty-nine patients with high-risk MDS received decitabine 15 mg/m2 intravenously every 8 h over 3 h for 3 consecutive days in 6-week cycles, and 81 patients received BSC. Patients were observed until they achieved CR or PR or until their disease transformed to AML or they died. Patients receiving decitabine had overall response rates better than those receiving BSC (P < 0.001). Responses were seen in 17% of patients (9% CR, 8% PR, hematological improvement not reported). Cytogenetic responses were observed in 37% of decitabine patients and 10% of BSC patients. Patients receiving decitabine therapy had increased time to AML transformation or death16 and had an improved quality of life.16 Survival was longer in patients who responded to decitabine than in nonresponders.

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Clinical issues: Optimizing the impact of DNMT inhibitor Therapy

Treatment of lower-risk patients

Improving hematologic deficits and quality of life are the primary therapeutic goals in the management of low-risk patients with MDS.29 Therefore, the first-line therapy in the low-risk patient consists of BSC, including platelet and red blood cell transfusions, erythropoietin, and antibiotics to control infection.1, 30, 31, 32 In the low-risk patient population, those most likely to respond to BSC have, at diagnosis, low blood transfusion requirements (<2 units/month), low endogenous levels of erythropoietin (<100 mU/ml), and morphologic subtypes of refractory anemia and of refractory anemia with ringed sideroblasts.

Low-risk patients who fail to respond to BSC may be considered candidates for DNMT inhibitor therapy. The aforementioned randomized, multicenter trials demonstrate that DNMT inhibitors are superior to BSC and produce multilineage hematopoietic effects. While SCT may also be considered, a comparative registry analysis finds that life expectancy for low-risk patients may be curtailed by early allografting.33 Allowing disease progression to occur before SCT may provide the greatest opportunity for life extension.33 DNMT inhibitors may represent a viable therapeutic alternative. However, in considering them, one must also weigh the risks associated with this therapy (e.g. myelosuppression) and keep in mind that multiple courses may be required before responses are observed. There are also new agents being investigated that offer hope to patients whose main problem is anemia.34

Treatment of higher-risk patients

The prognosis of higher-risk MDS is poor and the goal of treatment here is to achieve a remission and try to prolong survival or at least delay the emergence of acute leukemia. SCT is indicated as early as possible in eligible patients with high-risk MDS. Consequently, SCT is indicated in young patients. Unfortunately, most MDS patients are older and not SCT candidates, and histocompatible stem cells are available only for some of the younger MDS patients. Therefore, in the majority of high-risk MDS patients, DNMT inhibitors are now the preferred therapy. Indeed, high-risk patients benefit in terms of both leukemia-free survival and quality of life.22, 35, 36 Once again, important considerations in treating high-risk patients include the need for close attention to the (expected) risks of infections and for persistence in treating these patients.

Predicting responses

There are no clear clinical or molecular indicators that can predict which patients are most likely to respond to DNMT inhibitors. Responses have been seen across all FAB (French–American–British) and IPSS (International Prognostic Scoring System) subtypes, as well as in secondary MDS. Efforts are under way to identify patients likely to respond, using DNA methylation or gene expression profiles, but these studies have not yet matured. Preliminary data suggest that patients with high degrees of methylation of the p15 tumor-suppressor gene are less likely to respond to these agents,13, 37 but this may reflect the overall tendency to rapid disease progression in this group of patients.

While patients are receiving therapy, there are also no reliable early markers of response. A rise in platelet count has been reported to be the first sign of response to decitabine38 and (anecdotally) to azacitidine as well. Nevertheless, it is not unusual to see no hematologic improvements after 1 to 2 cycles in patients who subsequently proceed to achieve partial or complete responses with further treatment cycles.

Dosing

Critical questions in the field are those of dosing, administration, and duration of treatment.39 The degree of hypomethylation induced by a DNMT inhibitor is dose-dependent initially but rapidly reaches a plateau. Increasing the dose beyond the plateau actually inhibits the differentiation effect.40 A second issue relates to pharmacokinetics.41 These agents have a short serum half-life, but the half-life of the drugs once incorporated into DNA may be quite different. Finally, given that responses to DNMT inhibitors may be different than to chemotherapy, clinical strategies need to be carefully considered.

Early clinical trials17 studied higher doses of DNMT inhibitors than those used in current dosing regimens. However, more recent clinical trials used much lower doses, with substantial responses. This issue was formally tested in a modified phase I study of decitabine in relapsed/refractory myeloid leukemias, which concluded that lower doses (5–15 mg/m2 intravenously daily times 10) had higher response rates than higher doses (Table 2).13 Consistent with the in vitro data, it was demonstrated that maximal hypomethylation with decitabine in vivo occurs between total doses of 150 and 200 mg/m2 per cycle. At higher doses, hypomethylation plateaus and responses are lost.

Table 2 Responses to decitabine in a phase I, low-dose study
Table 2 - Responses to decitabine in a phase I, low-dose study
Full tableFigures & Tables index

The issue of pharmacokinetics versus response has also been tested in clinical trials. Continuous infusions of azacitidine and decitabine were consistently found to be less effective and/or more toxic than bolus infusions.26, 42 Taking this concept further, a recent study12 found that responses to decitabine could be doubled by doubling the dose intensity (20 mg/m2 intravenously over 1 h daily times 5 compared with 10 mg/m2 intravenously over 1 h daily times 10), or by giving the drug intravenously rather than subcutaneously.

Finally, the issue of treatment duration deserves considerable attention. Phase III studies of azacitidine and decitabine showed that median time to response was 3–6 months, underscoring the importance of patience with this therapy. A possible explanation for this is the hypothesized immune component to responses.43 In responders, the duration of therapy is not known and, given that relapses eventually occur in most patients, a strategy of maintaining patients on therapy for at least a year after achieving best response is recommended.

Overall, it is clear that careful attention to dosing schedules and duration of therapy will substantially improve clinical results with this class of agent.

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Conclusion

In MDS, therapy with DNMT inhibitors is indicated in stable, low-risk patients with high-level transfusion requirements who fail to respond to BSC and in high-risk patients who are ineligible for SCT. Response rates to decitabine and azacitidine improve with careful consideration of dosing schedules (low dose, high dose-intensity) and adequate treatment duration (minimum of 3–5 cycles). The optimal dosing levels have yet to be determined for azacitidine and decitabine and are the subject of current clinical trials. However, lower doses appear to be associated with hypomethylation activity, encouraging response rates, and a more manageable toxicity profile. When adequate treatment duration is allowed, azacitidine and decitabine appear to provide a real clinical alternative to BSC in MDS.

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Competing interests

Prof Jean-Pierre Issa has received consulting fees, lecture fees, and research support from SuperGen Corp., MGI Pharma Inc., and Pharmion Corp.

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