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Originally published as JCO Early Release 10.1200/JCO.2006.09.4169 on August 6 2007 © 2007 American Society of Clinical Oncology. Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia
From the Department of Medicine, Division of Hematology and Oncology; Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center and Solove Research Institute; College of Pharmacy, and Department of Pathology, The Ohio State University, Columbus, OH; Cancer Therapy Evaluation Program, National Institutes of Health, Bethesda, MD; and the Department of Hematology, University of Freiburg Medical Center, Freiburg, Germany Address reprint requests to William Blum, MD, Division of Hematology and Oncology and the Comprehensive Cancer Center, The Ohio State University, B310 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: william.blum{at}osumc.edu
Purpose To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML). Patients and Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21).
Results The OBD of decitabine was 20 mg/m2/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P Conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m2/d for 10 days) alone or with an alternative deacetylating agent are warranted.
Epigenetic silencing of structurally normal genes by aberrant DNA methylation and/or histone deacetylation has been described in many different cytogenetic and molecular subsets of acute myeloid leukemia (AML).1-15 A promising drug in the treatment of AML and myelodysplastic syndrome (MDS) is the DNA methyltransferase (DNMT) inhibitor decitabine (5-aza-2'-deoxycytidine; Dacogen, Bloomington, MN).16 At doses  1 log below the maximum-tolerated dose (MTD), decitabine induces DNA demethylation, gene re-expression, and hematopoietic differentiation with clinical responses and low toxicity.17-20 Likewise, a variety of histone deacetylase (HDAC) inhibitors are currently in clinical development, such as valproic acid (VA), suberoylanilide hydroxamic acid (vorinostat), depsipeptide, phenylbutyrate, MGCD0103, and LBH589. Dual pharmacologic targeting of DNMT and HDAC enzymes may result in synergistic anticancer activity, as supported by several preclinical studies.23-25 Gore et al26 reported a clinical study of combination 5-azacitidine and phenylbutyrate in MDS/AML and showed a correlation between clinical response and demethylation of the p15 gene. More recently, Garcia-Manero et al27 reported a study of decitabine in combination with VA in MDS/AML, with an overall response rate of 22%. Despite these intriguing results, the optimal dosing schedule in AML of low-dose decitabine alone or in combination with an HDAC inhibitor has not been established. We report a phase I study performed to determine an OBD of single-agent decitabine based on re-expression of silenced genes and the MTD of a novel schedule of decitabine plus VA in adults with AML.
Eligibility Criteria and Study Design This study enrolled patients (age 18 years) with relapsed AML and those older than 60 years with previously untreated AML who were not candidates for intensive cytarabine/anthracycline-based induction therapy. Patients were required to have a stable WBC count (WBC < 40,000/µL for 1 week) before initiation of therapy, total bilirubin  1.5 mg/dL, creatinine 2.0 mg/dL, ALT/AST 2x upper limit of normal, and Eastern Cooperative Oncology Group performance status 2. Informed written consent approved by The Ohio State University Human Studies Committee was obtained from all patients before study entry.
Hydroxyurea was permitted before enrollment and for the first 4 days of treatment, if necessary to maintain WBC count less than 40,000/µL. No other therapies were allowed within 30 days. Decitabine was administered intravenously (IV) over 1 hour on days 1 through 10, every 28 days. Significant delay in administration of subsequent cycles (> 2 weeks) was permitted for inadequate recovery of counts in patients with no evidence of disease and hypocellular bone marrow (< 10% cellularity); blood and marrow recovery was then reassessed after an additional 2-week recovery period. Therapy was also withheld until resolution of serious infections, if present. Dose reduction of decitabine by 50% was permitted if clinically indicated for responders who subsequently experienced severe myelosuppression, defined as platelet count less than 20,000/µL, febrile neutropenic episode, or prolonged grade
There were two steps of the study. In step A, decitabine as a single agent was escalated in approximately 25% increments from 15 mg/m2/d intravenously during 1 hour to determine an optimal biologic dose (OBD; defined as the dose at which mRNA expression of ER and/or p15, genes frequently methylated in AML, increased Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Dose-limiting toxicities were established with the first cycle of therapy. Clinical responses were defined according to National Cancer Institute published criteria28 as complete response (CR), CR with incomplete count recovery (CRi), or partial response. Initial response assessment was performed after two cycles to rule out overt disease progression (defined as > 25% increase in marrow blasts or > 50% increase in blood blasts). Responders and patients without progression continued on study.
Pharmacokinetic Analysis
Correlative Studies
Statistical Analysis
Patient Characteristics and Treatment Groups Patient characteristics are listed in Table 1. In step A (decitabine alone), a total of eight patients were treated at 15 mg/m2/d; two were not assessable for the biologic end points and were replaced. Six patients were treated at 20 mg/m2/d. Given that five of these six patients achieved 100% increase in p15 and/or ER re-expression, decitabine at 20 mg/m2/d for 10 days was declared the OBD and taken forward into step B for combination with VA. In step B, patients received decitabine at the OBD plus escalating doses of VA (days 5 through 21) at 15 mg/kg (n = 3), 20 mg/kg (n = 6), or 25 mg/kg (n = 2).
Toxicities Grade 3 or higher nonhematologic toxicities at least possibly attributed to either investigational drug at any time during treatment are summarized in Table 2; toxicities were similar in patients with untreated or relapsed disease. Severe nonhematologic toxicities attributed to decitabine were minimal. Treatment delays of more than 4 weeks did not occur during the first three cycles of therapy; most patients received the first three cycles within 2 weeks after day 28 of the prior cycle. In cycles 4 and beyond, delays of 2 to 4 weeks were common and were usually related to infection. In these patients therapy was withheld, usually 2 to 4 weeks, until resolution of the infection. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. One patient (patient 1) treated with decitabine alone suffered a fatal myeloid differentiation syndrome similar to the retinoic acid syndrome seen in acute promyelocytic leukemia (detailed in Appendix, online only, see also correlative studies in Appendix Figs A1A, and A1B, online only). In patients who received postremission therapy, myelosuppression was seen clearly. There were nine cycles of postremission therapy administered; five cycles had grade 4 neutropenia and four cycles had grade 4 thrombocytopenia. However, grade 4 myelosuppression was relatively short—typically less than 2 weeks. Only one patient had dose reduction of decitabine (50%, with the eighth cycle of treatment).
The addition of VA to decitabine was associated with dose-limiting encephalopathy in three patients, age 68, 79, and 61 years, respectively. Grade 3 or 4 encephalopathy was observed in two of two patients treated with VA at 25 mg/kg/d and one of six patients at 20 mg/kg/d. Plasma levels of VA measured at the time of the observed toxicity were within or just above the upper limit of the therapeutic range (120 µg/mL). In each case, encephalopathy occurred within 5 days of starting VA with gradually increasing somnolence followed by confusion and gait disturbance. Symptoms were reversible within 48 hours of VA discontinuation. No patient was re-treated. After the only cycle given, one patient achieved CRi, one had disease progression, and the other died in hospice care within 3 weeks. On the basis of this toxicity, the MTD for the combination was decitabine 20 mg/m2/d (days 1 through 10) and VA 20 mg/kg/d (days 5 through 21).
Correlative Studies
In patients treated in step A, we evaluated levels of DNMT1 enzyme by Western blot at pretreatment and on day 4. Pretreatment DNMT1 protein levels were detectable for eight of 14 patients, although only seven patients were assessable for response (three CRi and four nonresponders [of whom two had a hematologic improvement]). A trend for decitabine-induced decrease in DNMT1 protein was observed by immunoblotting (P = .02, paired t test; Figs 2A and 2B), but only three patients had complete disappearance of DNMT protein on the gel by day 4 of cycle 1. No correlation was observed between DNMT1 protein depletion and clinical response, but the number of samples analyzed was relatively small.
Global DNA methylation was assessed on 13 patients treated in step A. Seven of 12 patients assessable for this end point had decreased global DNA methylation by day 11 after decitabine treatment. Each of these seven patients also had objective clinical response or hematologic improvement. The median percentage of global methylation at day 11 was 78% of baseline (range, 68% to 234%). Figure 2C shows changes in global DNA methylation during cycle 1 for responders (CR/CRi) and nonresponders. There was a mean increase in histone H3 acetylation above the untreated baseline of 55% on day 11 for patients treated with decitabine alone and 156% on day 15 in patients treated with decitabine plus VA. The difference between the two treatment groups was not statistically significant (P = .2; Fig 2D). There was no difference in histone hyperacetylation according to clinical response (CR/CRi v others) in patients treated with decitabine alone or with VA. Quantitative reverse transcriptase polymerase chain reaction studies for p15 and ER, both of which frequently are methylated in AML, were performed (Fig 2E and Appendix Table A1, online only). Increased expression of either one of these two genes (100% or more) occurred in five of six patients treated at the 20 mg/m2 dose level of single-agent decitabine; this was declared the OBD. Overall, achievement of CR/CRi was associated with drug-induced increased ER expression during the first cycle of therapy. There was a significant difference in ER expression for CR/CRi patients versus other patients. The results were significant at both the first time point (during decitabine treatment; day 4 for decitabine alone, day 8 for combined therapy; P = .03, t test) and second time point (after completion of decitabine treatment; day 11 for decitabine alone, day 15 for combined therapy; P = .05; Fig 2E). When analysis was limited to patients treated with decitabine alone, the results were similar; CR/CRi patients had a significant increase in ER expression at both day 4 (P = .003) and day 11 (P = .02, not shown). Changes in p15 expression did not correlate with clinical response. For patients who received single-agent decitabine, there was a trend to greater gene re-expression (either p15 or ER, all time points) with 20 mg/m2 decitabine compared with 15 mg/m2 (P = .08, not shown). Gene re-expression did not seem to be affected by the addition of VA; there was no difference in p15 or ER expression levels for patients who received combined therapy compared with those who received 20 mg/m2 decitabine alone. ER promoter methylation was assessed by COBRA in 12 patients (11 with at least 100% increase in ER expression; one patient [patient 9] with < 100% increase). Six of 12 patients had evidence of methylation in region 1 of the ER promoter (Fig 3A). For patients with available serial samples (n = 5), we showed a median decrease of 25% (range, –40% to +5%) and 30% (range, –53% to –10%) in methylation by BioCOBRA at the both of the time points (Fig 3B). The BioCOBRA results were validated by bisulfite sequencing in patient 1 (Fig 3C) and in patient 9 (data not shown).
Clinical Responses The overall response rate based on intent-to-treat was 44% (11 of 25). However, four patients were not assessable for response because of early complications (sepsis on day 5, n = 1; early toxicity, n = 3). In assessable patients, the response rate was 52% (11 of 21; Table 3). Four patients achieved both morphologic and cytogenetic CR. All four were previously treated, older than age 60, and had complex karyotype ( five cytogenetic abnormalities). Two of these received decitabine alone at 20 mg/m2/d and achieved CR after three or four courses, respectively; two received decitabine 20 mg/m2/d plus VA 20 mg/kg/d and achieved CR after only one course in both patients. Remission duration was relatively short for three of four patients, with progression after 8, 3, and 3 months, respectively. Notably, one CR patient refused any maintenance therapy after remission was achieved (this patient experienced relapse at 3 months). Another patient died 10 months after achieving CR due to complications from a stroke related to embolism from a mechanical aortic valve; he had been in continued CR at last follow-up.
Four patients achieved CRi (CR except for platelets, three patients; CR except for neutrophils, one patient). Three patients achieved partial response. Ten patients experienced treatment failure, although seven patients had clinical benefit.
Defined in this study by a gene re-expression end point, the OBD of decitabine as a single agent was 20 mg/m2/d during 1 hour for 10 consecutive days. The MTD of combination therapy was decitabine 20 mg/m2/d plus VA 20 mg/kg/d, with VA dose limited by neurologic adverse effects (encephalopathy). Exploratory correlative studies support the notion that low-dose decitabine induces gene re-expression via promoter demethylation of target genes, global DNA hypomethylation, and DNMT1 protein depletion. Interestingly, in this study there was an association between early re-expression of ER and subsequent achievement of CR/CRi, although this was not seen for p15. The addition of VA did not significantly alter gene expression compared with decitabine (20 mg/m2) alone. Response was not the primary end point in this phase I study but results were encouraging, particularly in previously untreated patients with complex karyotype. Of nine assessable patients with previously untreated AML, seven had a major response (four CR and three CRi). Morphologic CR was followed by cytogenetic CR in four of four patients. Remarkably, each CR patient had complex karyotype; all had five or more cytogenetic abnormalities which was associated with only 22% CR rate in another study of untreated AML in patients age 60 years.33 In this study, the MTD of VA in combination with decitabine was 50% lower than that reported recently in a similar phase I/II study.27 In that previous report, decitabine was administered at 15 mg/m2/d over 1 hour and VA dose was escalated at 20, 35, or 50 mg/kg/d on days 1 through 10. Grade 3 neurotoxicity (encephalopathy) occurred in two of nine patients treated at 35 mg/kg and in two of 10 patients treated at 50 mg/kg in the phase I portion; the rate of neurotoxicity from the phase II portion was not stated explicitly. Encephalopathy resolved 1 to 3 days after VA was stopped in all cases. It should be emphasized, however, that decitabine and VA were administered in a schedule different from the schedule used in our study. In the prior report, the drugs were administered together for 10 days, whereas in our study there was only partial overlap, with VA administered on days 5 to 21. Nevertheless, we observed encephalopathy within the first 5 days of VA administration. The erratic bioavailability of VA is well known, and therefore it is difficult to assess the reasons for the disparity in the reported toxicity between the two studies without taking into consideration clinical variables such as age, nutritional status, plasma protein levels, and other comorbidities. The impact on clinical response of adding VA was unclear in our study. CR was achieved after three and four cycles, respectively, for two patients receiving decitabine alone; in contrast, CR was achieved after only one cycle for both patients with CR in the combined-therapy group. However, VA impact on toxicity was more evident, given that VA markedly increased treatment-related toxicity at more than 20 mg/kg/d. Because we aimed to develop a dosing schema intended for elderly AML patients who may be infirm and not candidates for standard cytarabine-anthracycline (so-called 7 + 3) induction chemotherapy, we did not attempt to escalate further the VA dose above 25 mg/kg due to concern for neurologic adverse effects in this population. The observed association of ER re-expression and CR/CRi provides additional support to the hypothesis that epigenetic modulation of gene expression may lead to clinical response in AML. Importantly, in some patients (n = 4) ER re-expression occurred in conjunction with baseline promoter methylation and drug-induced demethylation in region of ER promoter. However, ER re-expression also occurred in patients who did not have detectable promoter methylation in this region (n = 6), suggesting demethylation in other promoter regions or gene re-expression due to alternative mechanisms yet to be elucidated. Whether induction of ER re-expression has a direct role in restoring normal hematopoiesis or is only a surrogate marker for decitabine epigenetic effects is uncertain. ER hypermethylation has been shown to be a favorable prognostic marker in younger AML patients and may also be a marker for minimal residual disease in AML.34,35 We were not able to demonstrate a significant effect on re-expression of either ER or p15 with the addition of VA, despite a trend for increased histone acetylation. However, VA plasma concentrations achieved in our study were relatively low (approximately 0.5 mmol/L); therefore, we cannot exclude the possibility of increased biologic activity of VA at higher doses, which were not achievable due to toxicity. Decitabine itself appeared to have a mild acetylating activity; a finding that has been reported previously.26 Although a role for VA as a therapeutic partner of decitabine may be explored further with different doses and schedules, we conclude that the narrow therapeutic index of this compound represents an important limitation to its use, at least in older AML patients. The lack of synergistic gene re-expression observed with VA and decitabine in this study further decreases enthusiasm for this combination; better understanding of alternative mechanisms of action for these classes of agents may be important in realizing their therapeutic potential. Given the biologic and preliminary clinical responses seen, larger studies with extended dosing schedules of decitabine alone or in combination with alternative HDAC inhibitors that may be more potent with reduced toxicity (such as suberoylanilide hydroxamic acid, MGCD0103, or LBH589) are warranted.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: William Blum, MGI Pharma Inc; John C. Byrd, Pharmion Inc; Guido Marcucci, MGI Pharma Inc Stock: N/A Honoraria: William Blum, Speaker's Bureau, MGI Pharma Inc Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: William Blum, Rebecca B. Klisovic, Anthony Murgo, Kenneth K. Chan, Michael R. Grever, John C. Byrd, Guido Marcucci Financial support: William Blum, Michael R. Grever, Guido Marcucci Administrative support: William Blum, Cheryl Kefauver, Michael R. Grever, Guido Marcucci Provision of study materials or patients: William Blum, Rebecca B. Klisovic, Bjoern Hackanson, Zhongfa Liu, Hollie Devine, Cheryl Kefauver, Steven M. Devine, Anthony Murgo, Kenneth K. Chan, Michael R. Grever, Guido Marcucci Collection and assembly of data: William Blum, Bjoern Hackanson, Zhongfa Liu, Shujun Liu, Tamara Vukosavljevic, Lenguyen Huynh, Gerard Lozanski, Cheryl Kefauver, Nyla A. Heerema, Kenneth K. Chan, Michael R. Grever, Guido Marcucci Data analysis and interpretation: William Blum, Rebecca B. Klisovic, Bjoern Hackanson, Zhongfa Liu, Shujun Liu, Gerard Lozanski, Christoph Plass, Steven M. Devine, Nyla A. Heerema, Kenneth K. Chan, Michael R. Grever, John C. Byrd, Guido Marcucci Manuscript writing: William Blum, Gerard Lozanski, Steven M. Devine, Nyla A. Heerema, Kenneth K. Chan, Michael R. Grever, John C. Byrd, Guido Marcucci Final approval of manuscript: William Blum, Rebecca B. Klisovic, Bjoern Hackanson, Zhongfa Liu, Shujun Liu, Hollie Devine, Tamara Vukosavljevic, Lenguyen Huynh, Gerard Lozanski, Cheryl Kefauver, Christoph Plass, Steven M. Devine, Nyla A. Heerema, Anthony Murgo, Kenneth K. Chan, Michael R. Grever, John C. Byrd, Guido Marcucci
Decitabine-induced myeloid differentiation syndrome. One patient experienced a clinical syndrome that appeared to be due to decitabine-induced differentiation of myeloid blasts. This 82-year-old male had acute myeloid leukemia (normal karyotype) arising from myelodysplastic syndrome and was treated with decitabine alone at 15 mg/m2/d for 10 days. At the time of initiation of therapy, peripheral blood showed WBC of 8,700/µL, absolute blast count (ABC) of 3,200/µL, and absolute neutrophil count (ANC) of 1,500/µL. On day 11, the patient had WBC of 10,600/µL, ABC of 1,590/µL, ANC of 4,700/µL, and was clinically well. On day 17, he presented with cough and dyspnea without fever. WBC count was 18,700/µL with decrease in ABC to 750/µL and increase in ANC to 11,000/µL. Chest radiograph demonstrated diffuse interstitial infiltrates (culture negative). Peripheral blood smears (Fig A1B) showed evidence of myeloid differentiation with an increasing WBC count that peaked on day 20 at 28,400/µL, with ABC of 1100/µL and ANC of 14,200/µL. By day 25, no circulating blasts were found (WBC 4,300/µL; ANC 3,000/µL). Because of concern for a differentiation syndrome similar to that occurring in acute promyelocytic leukemia with retinoic acid therapy, dexamethasone (10 mg intravenously every 12 hours) was instituted on day 18. The patient improved but subsequently died as a result of aspiration, pneumonia, and respiratory failure 5 weeks later. In addition to myeloid differentiation, this patient had promoter demethylation (Figs 3B and 3C) and more than seven-fold re-expression of the ER gene (Fig A1A). Promoter demethylation studies (BioCOBRA and bisulfite sequencing) for this patient (patient 1) are shown in Figure 3 of the printed manuscript; drug-induced demethylation of genes may have been associated with the clinical syndrome observed. Gene re-expression studies of ER and photomicrographs depicting maturation of neutrophils are shown in Figure A1.
published online ahead of print at www.jco.org on August 6, 2007. Supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) Grants No. K23CA120708 (principal investigator, W.B.); NIH/NCI R01 CA102031 (principal investigator, G.M.); NCI U01 CA 76576 (principal investigator, M.R.G.); Leukemia and Lymphoma Society (J.C.B. and C.P.), Dr Mildred Scheel Foundation for Cancer Research postdoctoral Fellowship Grant (B.H.), and D. Warren Brown Foundation (J.C.B.). Presented in part at American Society of Hematology, Orlando, FL, December 9-12, 2006; and the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 3-6, 2006. NCI Clinical Trials Network registration: NCT00079378. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
