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Originally published as JCO Early Release 10.1200/JCO.2005.09.118 on April 11 2005 © 2005 American Society of Clinical Oncology. Phase I Study of Oblimersen Sodium, an Antisense to Bcl-2, in Untreated Older Patients With Acute Myeloid Leukemia: Pharmacokinetics, Pharmacodynamics, and Clinical ActivityFrom the Division of Hematology-Oncology, Department of Medicine, and Division of Pharmaceutics, College of Pharmacy, the Comprehensive Cancer Center and The Ohio State University, Columbus, OH; Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL; National Cancer Institute, Bethesda, MD; and Genta Inc, Berkeley Heights, NJ Address reprint requests to Guido Marcucci, MD, Division of Hematology-Oncology, The Comprehensive Cancer Center, The Ohio State University, 433A Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210; email: marcucci-1{at}medctr.osu.edu
PURPOSES: Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments.
PATIENTS AND METHODS: Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were RESULTS: Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05). CONCLUSION: G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.
Acute myeloid leukemia (AML) is characterized by maturation arrest and uncontrolled proliferation of malignant hematopoietic precursors.1 Among the factors predicting poor prognosis, age, cytogenetic aberrations, antecedent clonal hematologic disorders, and prior chemotherapy are the most important and probably interdependent factors.2,3 In fact, older patients are more likely to present with AML arising from a myelodysplastic syndrome (MDS) and/or unfavorable cytogenetic abnormalities.4-6 Therefore, it is not surprising that elderly AML carries a dismal prognosis, with a long-term survival rate of less than 10% when treated with conventional-dose chemotherapy.7,8 Furthermore, most of these patients are not eligible for potentially curative therapy with allogeneic stem-cell transplantation because of lack of suitable donors, treatment-related toxicity, and/or concurrent diseases. Therefore, novel approaches targeting leukemogenic mechanisms relevant to this subpopulation are needed.9,10 Most treatment failures in older AML patients are related to chemoresistance.11 Defects in apoptosis pathways contribute significantly to resistance to a variety of chemotherapeutic agents. Overexpression of Bcl-2, a member of a family of proteins operative in the mitochondrial pathway of apoptosis, results in resistance to a variety of apoptosis-inducing signals, including radiation, corticosteroids, and chemotherapeutics.12,13 Notably, Bcl-2 was found to be overexpressed in AML patients with a low complete remission (CR) rate and a significantly shorter survival12 and downregulated in patients with the favorable t(8;21) karyotype.14 Furthermore, a high ratio of Bcl-2 to Bax, a proapoptotic member of the Bcl-2 family of proteins, was shown to be predictive of worse outcome.15 From these observations, therefore, it is conceivable that targeting Bcl-2 downregulation might lower the apoptotic threshold of leukemic cells and, in turn, favor response to chemotherapy.16 Preclinical studies have demonstrated that oblimersen sodium (G3139), an 18-mer phosphorothioate oligodeoxynucleotide antisense designed to bind the first six codons of Bcl-2, downregulates expression of its target, lowers the threshold for apoptosis, and sensitizes malignant cells to chemotherapy.17 The feasibility of this approach in vivo was investigated in several phase I trials of G3139 alone or in combination with chemotherapy in both solid tumor and hematologic malignancies.18-25 Recently, our group reported the combination of G3139 with fludarabine, cytarabine, and granulocyte colony-stimulating factor in patients with refractory or relapsed acute leukemia and demonstrated in vivo downregulation of the Bcl-2 target.18 On the basis of these encouraging preliminary results, we investigated this antisense strategy in older patients with untreated AML by combining G3139 with a standard remission induction regimen of cytarabine and daunorubicin and, after achievement of CR, with high-dose cytarabine as a consolidation therapy. The goals of this trial were to demonstrate the feasibility of combining G3139 with a standard multicourse chemotherapeutic program that included anthracyclines and validate this antisense strategy in vivo by measuring intracellular levels of G3139 and quantifying changes in the Bcl-2 target.
Eligibility Criteria and Study Design This was an National Cancer Institute (NCI)/Cancer Therapy Evaluation Program–sponsored phase I dose-escalation study of patients 60 years or older with untreated AML according to WHO classification.26 Patients with de novo or primary AML were stratified to cohort 1, and patients with secondary AML evolving from a MDS or occurring after chemotherapy treatment for cancers other than MDS or AML were stratified to cohort 2. Left ventricular ejection fraction  50% and normal renal and hepatic functions were also required. Informed consent was obtained before entry onto the study. Induction chemotherapy consisted of G3139 7 mg/kg/d administered as a continuous intravenous infusion (CIVI) on days 1 through 10, cytarabine 100 mg/m2/d CIVI on days 4 to 10, and daunorubicin intravenously at two dose levels (dose level 1, 45 mg/m2/d; dose level 2, 60 mg/m2 over 0.5 hour) on days 4 through 6. Presence of more than 5% blasts in a bone marrow (BM) with at least 20% cellularity on day 14 indicated persistent disease, and a second abbreviated induction course was administered with G3139 on days 1 to 8, cytarabine on days 4 to 8, and daunorubicin on days 4 to 5. Patients who achieved CR underwent two consolidation treatments, with G3139 7 mg/kg/d CIVI on days 1 to 8 and cytarabine 2 g/m2 intravenously over 4 hours daily on days 4 to 8.
Granulocyte colony-stimulating factor was allowed according to the American Society of Clinical Oncology guidelines.27 Adverse events were graded according to the NCI Common Toxicity Criteria (version 3.0; http://ctep.info.nih.gov). Any grade 3 or 4 nonhematologic systemic toxicity was considered dose-limiting toxicity if probably or definitely related to G3139. Disease response was defined according to the published NCI criteria.28 Incomplete remission (IR) was defined as leukemia-free BM and blood without recovery of normal neutrophil counts (
Analysis of Plasma and Intracellular Levels of G3139 Quantification of G3139 plasma concentration was conducted by mixing the samples with a dilution buffer (10 mmol/L Tris-HCl, pH 8.0; 1 mmol/L EDTA, and 0.2% Triton X-100) before adding the 3'-biotinylated capture and the digoxigenin-labeled probes. For the quantification of G3139 intracellular concentrations (ICs), pellets of BM MNCs were treated with 0.1 µmol/L of phosphorothioate 28-mer polycytidine. After addition of 200 µL of lysis buffer (10 mmol/L Tris-HCl, pH 8.0; 0.5 mmol/L EDTA, and 1% Triton X-100) and incubation on ice for 10 minutes, the cells were mechanically lysed. The homogenate was centrifuged, and the supernatant was used in the drug and protein assays. The ICs of G3139 were measured in triplicate, and the results were normalized to the total protein amount.
Blood Sampling and Pharmacokinetic Analysis
Quantification of Bcl-2 Expression For protein analysis, lysates of MNCs were prepared in 200 µL per 10 x 106 cells, as previously reported.18 The cell lysates were diluted 1:10 to 1:20 in dilution buffer (phosphate-buffered saline) containing 1% bovine serum albumin and analyzed in triplicate using a Bc1-2 ELISA kit (Oncogene, Boston, MA), as per manufacturer's directions. Total proteins for each sample were determined by BCA assay (Pierce, Rockford, IL) and used for normalization of Bcl-2 protein levels.
Statistical Considerations
Patient Characteristics A total of 29 untreated AML patients aged more than 60 years were enrolled onto this study. Demographic and clinical features at diagnosis are listed in Table 1. The median age was 67 years (range, 60 to 80 years), and 13 patients were female. Of the 29 patients, 13 patients had primary AML and were enrolled onto cohort 1, and 16 patients had secondary AML (13 after MDS and three after chemotherapy for unrelated cancer) and were enrolled onto cohort 2. Of the enrolled patients, 20 had intermediate-risk and nine had poor-risk cytogenetics according to the Cancer and Leukemia Group B (CALGB) classification for achievement of CR.29
Toxicity All 29 patients developed pancytopenia after both induction and consolidation treatments. Compiled grade 3 and 4 toxicities from both cohorts of patients observed during induction are listed in Table 2. No significant differences were observed between the two dose levels of daunorubicin tested. Furthermore, toxicities were reversible and not dose limiting because they were reported previously with cytarabine-daunorubicin treatment alone and/or were not directly attributable to G3139. Although renal toxicity has previously been observed with G3139 exposure, in the current study, this occurred only after completion of the antisense infusion during induction therapy and/or in patients receiving other nephrotoxic drugs as part of the supportive treatment. Notably, grade 3 or 4 hypoxia was caused by pneumonia and/or fluid overload and promptly resolved after initiation of broad-spectrum antibiotics and/or aggressive fluid management. One patient treated with imipenem-cilastin developed seizures that were controlled by discontinuation of the antibiotic and institution of phenytoin.
Of the two reported cardiac events, both occurred during induction therapy. Patients developed transient supraventricular arrhythmias within 2 weeks of completing induction treatment without any evidence of myocardial ischemia or significant changes in the baseline left ventricular ejection fraction. No evidence of anthracycline-induced cardiomyopathy after G3139, cytarabine, and daunorubicin induction therapy was observed after one or two induction courses. One patient developed refractory thrombocytopenia and died at day 17 with diffuse alveolar hemorrhages, and one patient had fatal multiorgan failure caused by cytomegalovirus infection and died at day 42. Postmortem examination of the latter patient revealed no AML in the BM or blood. In one patient, the antisense infusion was held because of bleeding from colonic polyps during the initial 72 hours of G3139 infusion and restarted after polypectomy.
From the start of induction chemotherapy (ie, day 4), the median time for neutrophil recovery was 23 days (range, 18 to 38 days), and the median time for platelet recovery ( Of the 14 patients who achieved CR, eight received both prescribed consolidation treatments without unusual toxicity. Of the remaining six patients, two did not receive a second consolidation course because of transient grade 4 ataxia or dysarthria during the first consolidation course, whereas the remaining four patients refused the second consolidation treatment because of the anticipated lengthy hospitalization.
Disease Response Of the three patients with IR, two had primary AML, and one had secondary AML. Of this group of patients, two relapsed with morphologic evidence of disease, and one died of diffuse cytomegalovirus infection. Of the 11 patients who failed to achieve CR or IR, seven received a second induction course but had no response.
PK Studies
Pharmacodynamic Studies To evaluate changes in the antisense target, Bcl-2 mRNA levels were measured in BM samples collected before treatment and 72 hours from the start of G3139 infusion, just before initiation of chemotherapy. This analysis was restricted to these two time points to avoid Bcl-2 variations caused by the subsequent chemotherapy administration. Among 22 patients assessable for both clinical response and Bcl-2 levels, baseline Bcl-2/ABL copies (median, 85,325 copies; range, 19,120 to 149,100 copies) in the CR patients (n = 12) were higher than those (median, 30,375 copies; range, 8 to 163,500 copies) in the NR patients (n = 10; P = .003). After 72-hour G3139 infusion, the median Bcl-2/ABL mRNA copies (median, 52,575 copies; range, 13,210 to 158,500 copies) were decreased compared with baseline (P = .03) in CR patients and increased (median, 64,440 copies; range, 30 to 199,400 copies) in NR patients (P = .05). There was a difference between the CR and NR patients in changes in the Bcl-2 expression after 72 hours of exposure to G3139 (P = .002; Fig 2). In contrast, no differences in mRNA levels of Bax, Bcl-XL, and Mcl-1 were observed between the CR and NR patients at diagnosis and after 72-hour G3139 infusion (data not shown). Furthermore, there was no difference in response to induction therapy based on baseline levels of Bax, Bcl-XL, and Mcl-1 (data not shown). Finally, the median Bax to Bcl-2 ratios increased from 0.1 to 0.16 and 0.09 to 0.13 after 72 hours of G3139 infusion compared with baseline in CR and NR patients, respectively. However, the difference between the two groups was not significant.
After 72 hours of G3139 infusion, among 13 patients assessable for both clinical response and Bcl-2 protein levels, the median level of Bcl-2 normalized to total proteins (median, 52.3 arbitrary units; range, 10.3 to 99.7 arbitrary units) were decreased compared with baseline levels (median, 63.5 arbitrary units; range, 10.9 to 366.5 arbitrary units; P = .02) in CR patients (n = 7). In contrast, at the same time point, the median Bcl-2 protein level (median, 50.2 arbitrary units; range, 1.7 to 189.7 arbitrary units) was unchanged compared with baseline levels (median, 50.9 arbitrary units; range, 1.7 to 182.8 arbitrary units) in NR patients (n = 6). There was a difference between the CR and NR patients (P = .004) in changes in the Bcl-2 expression after 72 hours of exposure to G3139 (Fig 3).
ICs of G3139 were measured in BM samples collected after 72 hours of G3139 treatment in 17 patients with available material. The median IC was 10 pmol/mg protein (range, 0.3 to 30 pmol/mg protein). A higher median IC of G3139 was observed in CR patients (median, 17.0 pmol/mg protein; range, 1.5 to 30.0 pmol/mg protein) compared with NR patients (median, 4.4 pmol/mg protein; range, 0.3 to 28.3 pmol/mg protein; P = .05; Fig 4). However, no linear correlation was found between the ICs and downregulation of the Bcl-2 (data not shown).
In the current study, we tested the feasibility of administering G3139 within a multicourse chemotherapy program for older, previously untreated AML patients. Our data indicate that this combination is safe, with a toxicity profile similar to that expected with chemotherapy alone at both the dose levels of daunorubicin tested and with an overall treatment-related mortality rate as low as 6%. Notably, because Bcl-2 downregulation was shown to significantly increase ischemic damage in rat myocardium,30 it was important to carefully monitor treated patients for any potential, unexpected cardiac toxicity. Despite the high prevalence of coronary artery disease in patients aged 60 years and older, no ischemic event or anthracycline-induced cardiomyopathy were observed after G3139, cytarabine, and daunorubicin, even in patients who underwent a second course of induction therapy. It should also be emphasized that cerebellar toxicity, a well-known side effect of high-dose cytarabine, was only observed during two of the 22 consolidation courses administered, supporting the feasibility of including G3139 in intensive postremission therapy. Of the 29 treated patients, approximately 50% achieved CR. However, disease response was only a secondary end point of this phase I trial, and therefore, the potential therapeutic benefit of combining G3139 with chemotherapy remains to be determined. Nevertheless, because a remission rate of approximately 40% was shown in former studies of older AML patients treated with similar induction regimens but without G3139, our results seem to be at least comparable with these previous reports.8 With a median follow-up of 12.6 months, 50% of the patients who achieved CR remain free of disease, suggesting that durable responses are achievable with this regimen. Interestingly, the response of patients with secondary AML seemed quite favorable, with three of these patients remaining free of disease at 11.5, 13.5, and 21.7 months. Our study also provides detailed pharmacologic data of G3139 administered by CIVI in this older AML patient population. Consistent with the clinical results, PK parameters did not seem to be affected by the concomitant administration of the chemotherapy, and G3139 area under the curve and Css failed to correlate with toxicity or disease response. Notably, plasma concentrations of G3139 remained detectable up to 8 hours from the termination of the infusion, resulting in a terminal half-life at least three times longer than that previously reported by our group.18 It is likely that this discrepancy relates to a higher sensitivity of the ELISA-based assay used in the current study.31 In fact, this methodology is at least 3 orders of magnitude more sensitive than the previously used high-performance liquid chromatography assay, thereby allowing us to follow the plasma decay of the antisense over a longer period of time.31 The rationale for using antisense therapy in cancer has been supported by the potential of these compounds to downregulate oncogenic proteins that drive and/or maintain malignant transformation.32 Clear demonstration of antisense activity by these oligonucleotide compounds, however, has been difficult because a correlation between drug plasma levels, target downregulation, and disease response has not been observed in clinical trials.33 Furthermore, the G3139 antisense activity has often been questioned based on inconsistent reports of Bcl-2 changes in relevant or surrogate tissues from treated patients.18-20,22 It is likely that these difficulties stem from several factors, including the variability of the biologic response to the antisense from patient to patient and, perhaps, from cell to cell and the lack of adequate methodologies to investigate the metabolism and disposition of G3139 and correlate them with the observed clinical activity. In the current study, for the first time, we used an exquisitely sensitive analytic assay developed by our group for quantification of G3139 levels in distinct biologic matrices other than plasma.31 The application of this methodology to lysates of BM MNCs resulted in a direct determination of drug ICs, which tended to be higher in patients achieving CR. However, no linear correlation was observed between G3139 ICs and levels of Bcl-2 changes. This underscores the complexity of fully characterizing the antisense activity of this oligonucleotide, which likely depends on several factors including intracellular drug trafficking, endogenous levels of endonucleases, and positive feedback response of the leukemic cells to target downregulation. Nevertheless, using our assay in future studies, we anticipate measuring G3139 levels in different subcellular compartments and organelles and identifying specific patterns of intracellular distribution of the parent drug and its metabolites predictive of both biologic and clinical responses.31 Finally, our data support stratification of AML patients to G3139 therapy based on levels of Bcl-2 expression at diagnosis. In fact, pretreatment mRNA Bcl-2 copy number seemed higher in CR patients than in the NR patients, suggesting a better antisense activity in leukemic cells overexpressing the target. Conversely, in patients with lower Bcl-2 levels, whose blasts are likely to depend on other antiapoptotic pathways for survival, exposure to G3139 resulted in upregulation of the target, as also predicted by in vitro models.34 Importantly, for the first time, we reported an apparent correlation between the antisense activity of G3139 and clinical outcome because Bcl-2 downregulation at both mRNA and protein levels occurred preferentially in CR patients. No significant differences were observed in posttreament levels of other antiapoptotic (ie, Bcl-XL and Mcl-1) or proapoptotic (ie, Bax) Bcl-2 family members in CR and NR patients, which supports the specificity of this compound for Bcl-2. However, a key question is raised by our observations. To what degree must the Bcl-2 target be downregulated to obtain a clinically significant G3139 effect? In patients achieving CR, we showed only a modest Bcl-2 downregulation after 72 hours of G3139 administration. Thus, it is possible that either the target decay continued over the remaining 7 days of the antisense infusion to reach a clinically relevant Bcl-2 down regulation or that, in cells dependent on Bcl-2 for survival, a small reduction of this protein is sufficient to lower the apoptosis threshold. Furthermore, it is possible that even a lower degree of Bcl-2 downregulation might result in recruitment of a higher number of blasts to the cell cycle, thereby promoting synergism with cycle-active chemotherapeutics such as cytarabine.35 Alternatively, Bcl-2 downregulation might not be the primary biologic effect of G3139, which instead could exert its antitumor activity through mechanisms that have yet to be identified.36 Because the numbers of patients and tissue samples tested in this trial were small, our clinical and pharmacodynamic results require confirmation. Thus, using the current study as a platform, we have recently initiated a phase III randomized trial (CALGB 10201) in untreated AML patients aged more than 60 years to assess definitively the contribution of the G3139 antisense strategy to the chemotherapy activity in AML. This trial is available on the NCI Clinical Trials Support Unit Web site.
The following authors or their immediate family members have 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. Employment: Steven Novick, Genta. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Supported by grant Nos. P30-CA16058, U01-CA76576, K08-CA90469, R01-CA102031, and R21-CA 094552 from the National Cancer Institute, Bethesda, MD; The Sidney Kimmel Cancer Research Foundation; The Leukemia and Lymphoma Society of America; The D. Warren Brown Foundation; and The Coleman Leukemia Research Foundation. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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19. Waters JS, Webb A, Cunningham D, et al: Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 18:1812-1823, 2000
20. Tolcher AW, Kuhn J, Schwartz G, et al: A phase I pharmacokinetic and biological correlative study of oblimersen sodium (Genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 10:5048-5057, 2004
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34. Konopleva M, Tari AM, Estrov Z, et al: Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood 95:3929-3938, 2000 35. Bonnefoy-Berard N, Aouacheria A, Verschelde C, et al: Control of proliferation by Bcl-2 family members. Biochim Biophys Acta 1644:159-168, 2004[Medline]
36. Lai JC, Benimetskaya L, Santella RM, et al: G3139 (oblimersen) may inhibit prostate cancer cell growth in a partially bis-CpG-dependent non-antisense manner. Mol Cancer Ther 2:1031-1043, 2003 Submitted December 10, 2004; accepted February 7, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
