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Originally published as JCO Early Release 10.1200/JCO.2006.07.0961 on December 4 2006 © 2007 American Society of Clinical Oncology. Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, in Patients Age 60 Years or Older With Previously Untreated Acute Myeloid Leukemia
From The University of Texas M.D. Anderson Cancer Center, Houston, TX; Duke University, Durham, NC; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Institut Paoli-Calmettes, Marseille, France; Indiana Oncology and Hematology Consultants, Indianapolis, IN; University Hospital Gasthuisbert, Leuven; Cliniques Universitaires Saint-Luc, Brussels, Belgium; Leyenburg Hospital, The Hague; University Hospital of Groningen, Groningen, the Netherlands; The Cleveland Clinic Lerner College of Medicine, Cleveland, OH; Weill Medical College of Cornell University, New York, NY; St Francis Hospital, Hartford; Vion Pharmaceuticals Inc, New Haven, CT; Quest Diagnostics Nichols Institute, San Juan Capistrano, CA; and Kings College, London, United Kingdom Address reprint requests to Francis J. Giles, MD, The University of Texas M.D. Anderson Cancer Center, Department of Leukemia, 1400 Holcombe Blvd, Box 428, Houston, TX 77030; e-mail: frankgiles{at}aol.com
Purpose Cloretazine (VNP40101M) is a sulfonylhydrazine alkylating agent with significant antileukemia activity. A multicenter phase II study of cloretazine was conducted in patients 60 years of age or older with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Patients and Methods Cloretazine 600 mg/m2 was administered as a single intravenous infusion. Patients were stratified by age, performance score, cytogenetic risk category, type of AML, and comorbidity. Results One hundred four patients, median age 72 years (range, 60 to 84 years), were treated on study. Performance status was 2 in 31 patients (30%) and no patient had a favorable karyotype. Forty-seven patients (45%) had cardiac disease, 25 patients (24%) had hepatic disease, and 19 patients (18%) had pulmonary disease, defined as per the Hematopoietic Cell Transplantation–Specific Comorbidity Index, at study entry. The overall response rate was 32%, with 29 patients (28%) achieving complete response (CR) and four patients (4%) achieving CR with incomplete platelet recovery. Response rates in 44 de novo AML patients, 45 secondary AML patients, and 15 high-risk MDS patients were 50%, 11%, and 40%, respectively. Response by cytogenetic risk category was 39% in 56 patients with intermediate cytogenetic risk and 24% in 46 patients with unfavorable cytogenetic risk. Nineteen (18%) patients died within 30 days of receiving cloretazine therapy. Median overall survival was 94 days, with a 1-year survival of 14%; the median duration of survival was 147 days, with a 1-year survival of 28% for those who achieved CR. Conclusion Cloretazine has significant activity and modest extramedullary toxicity in elderly patients with AML or high-risk MDS. Response rates remain consistent despite increasing age and comorbidity.
Acute myeloid leukemia (AML) is primarily a disease of the elderly, with a current median age at diagnosis of 68 years and an incidence that increases from approximately one per 100,000 at age 40 to more than 15 per 100,000 at age 75 and older.1 Elderly patients with AML or high-risk myelodysplastic syndromes (MDS) have a very poor prognosis, which is attributed to having disease that is inherently more resistant to current standard cytotoxic agents and/or relatively poor tolerance of these agents because of comorbidity and reduced tolerance of adverse effects.1-4 Treatment for elderly patients with AML has not improved for decades. Recently reported results from the Medical Research Council trials in elderly patients with AML and high-risk MDS including more than 1,200 patients who received intensive standard induction chemotherapy showed an overall survival at 5 years of only 13%.1,5 Thus, there is a need for novel, active, more tolerable agents for these patients. Alkylating agents are an important group of antileukemia agents that act by damaging DNA and/or impairing its replication.6 Alkylating drugs have a wide spectrum of antitumor activity and toxicity, and vary in their type of DNA damage, their relative specificity of attacking DNA or other cellular components, the specific DNA-repair mechanisms used by the malignant or normal cell after exposure, the drug's uptake and distribution in malignant and normal cells, and the drug's relative susceptibility to the tumor's resistance mechanisms.7-10 This diversity of properties allows room for the development of more efficient and/or less toxic alkylating agents. Cloretazine (VNP40101M; Vion Pharmaceuticals Inc, New Haven, CT [101M, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine]; Fig 1) belongs to a new class of alkylating agents, the 1,2-bis(sulfonyl)hydrazines and was selected for clinical development based on its broad antitumor activity in preclinical models.11-15 Cloretazine initially undergoes activation to yield 90CE [1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine] and methylisocyanate. The 90CE rapidly produces an alkylating, chloroethylating species, similar to the chloroethylating species generated by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU [carmustine]).13 However several features distinguish cloretazine from carmustine and possibly account for their different biologic behavior in vitro and in vivo. These agents produce different decomposition products, given that cloretazine does not yield hydroxyethylating, vinylating, or aminoethylating species; the chlorethylating species responsible for cloretazine's alkylation is relatively specific to the O6 position of guanine, whereas carmustine also attacks the N7 position of guanine.13 This chloroethyl adduct is recognized as one of the most cytotoxic lesions known, as it is a precursor to an interstrand cross-link. Cloretazine yields more than twice the molar yield of DNA cross-links than the nitrosoureas. No significant N7 alkylations are seen with cloretazine. Agents that cause primarily N7 alkylations are mutagenic and possess one thirtieth of the anticancer activity and the same mutagenic potential as their counterparts that form both N7 alkylations and cross-links.16 Cloretazine does not generate hydroxyethyl alkylations of the O6 position of guanine, which are considered therapeutically unimportant, yet carcinogenic, lesions.11-18
Cloretazine has significant activity against hematologic malignancy–derived cell lines (including against leukemia cell lines that are resistant to other alkylating agents) and has broad-spectrum antitumor activity in animal leukemia models.15,19 Cloretazine doses  20 mg/kg (60 mg/m2) administered intraperitoneally produces 100% long-term survival in 1-day-old intraperitoneally implanted L1210 leukemia and P388 leukemia mouse models.15 Cloretazine is associated with long-term survival in mice implanted with carmustine-, melphalan-, or cyclophosphamide-resistant L1210 cell lines. Cloretazine doses that were effective in both sensitive and resistant L1210-bearing mice caused moderate myelosuppression when administered to non–tumor-bearing mice.
In patients with solid tumors receiving cloretazine every 4 to 6 weeks, thrombocytopenia was the dose-limiting toxicity, with a maximum-tolerated dose of 305 mg/m2 with no significant nonhematologic toxicity, suggesting that substantial dose escalation of cloretazine might be possible in patients with hematologic diseases.20 In a phase I study of cloretazine in patients with refractory leukemia, mild reversible infusion-related toxicities were the most frequent adverse events, occurring in 24 patients (63%) on the first course.21 Dose escalation was terminated at 708 mg/m2 because of prolonged myelosuppression; 600 mg/m2 was selected as the recommended phase II study dose, with no significant extramedullary toxicity at this dose level. In a subsequent phase I study, the combination of cloretazine and cytarabine (ara-C) was studied in patients with refractory leukemia.22 Complete responses (CRs) were seen at cloretazine dose levels
The study was reviewed and approved by the institutional review board at all participating institutions. All patients provided signed informed consent indicating that they were aware of the investigational nature of this study.
Patient Eligibility
Treatment and Study Design
Response and Prognostic Criteria
Statistical Analysis Overall survival was measured from the day of cloretazine treatment to death as a result of any cause, with observations censored for patients known to be alive without report of relapse. Distributions of overall survival were estimated by the method of Kaplan and Meier. Quantitative factors were treated as continuous variables in regression analyses, but grouped when necessary for descriptive tables and figures. All P[r] values are two tailed.
Patient Characteristics One hundred four eligible patients were enrolled onto the study between April 2004 and April 2005. Patient baseline characteristics are summarized in Table 1. Sixty-nine patients (66%) were male. The median patient age was 72 years (range, 60 to 84 years), with 12% of patients older than 80 years; performance status was 2 in 31 patients (30%). Forty-four patients had de novo AML, 45 had secondary AML, and 15 had high-risk MDS. No patient had a favorable karyotype, with 56 in the intermediate category; 46 patients had the unfavorable karyotype. Using the HCT-CI criteria of Sorror et al,25 47 patients (45%) had cardiac disease, 25 patients (24%) had hepatic disease, and 19 patients (18%) had pulmonary disease at study entry. Within the patients with cardiac disease, 31 patients (66%) had one cardiac risk factor and 16 patients (34%) had multiple cardiac risk factors. Regardless of the number of cardiac risk factors present, a score of one was assigned to each patient with cardiac disease. Within the patients with hepatic disease, 18 patients (72%) had mild disease, seven patients (28%) had moderate to severe disease. Within the patients with pulmonary disease, eight patients (42%) had severe disease, whereas 11 patients (58%) had severe disease with dyspnea at rest and/or requiring oxygen.
Toxicity Nineteen (18%) patients, all with AML, died within 30 days of receiving cloretazine therapy. Sixteen (84%) deaths occurred in pancytopenic patients; the other three patients had persistent AML. Sepsis with or without persistent disease was the cause of death in 16 patients, one patient had severe tumor lysis syndrome, and one had a myocardial infarction. An early death considered possibly related to cloretazine occurred in a patient receiving multiple medications, including antivirals and antifungals, who died with liver failure on day 18. There was no difference in frequency of early deaths between patients with de novo AML or secondary leukemia. Grade 3/4 myelosuppression occurred in all patients. The median time to hematologic recovery for patients in CR was 31 days (range, 27 to 44 days) for granulocyte counts more than 109/L and 31 days (range, 23 to 55 days) for platelet count more than 100 x 109/L. Grade 3/4 adverse events potentially related to cloretazine are summarized in Table 2.
Response Twenty-nine patients achieved CR (25 with one course of therapy, four after two courses) and four patients achieved CRp, for an overall response rate of 32% (Table 3). Nine patients received a second cycle of cloretazine therapy in an attempt to induce CR, all three patients with AML achieved CR, and one of six patients with MDS achieved CR.
Response rates in 44 de novo AML patients, 45 secondary AML patients, and 15 high-risk MDS patients were 50%, 11%, and 40%, respectively. Response by cytogenetic prognostic category was 39% in 56 intermediate category patients and 24% in 46 unfavorable category patients. The CR rates remained consistent with increasing age as summarized in Table 3, with 14 patients age 60 to 69 years achieving CR (39%) and 19 responders (28%) 70 years or older. Response is tabulated in terms of established disease-related (secondary AML, unfavorable karyotype) and patient-related risk factors (Eastern Cooperative Oncology Group performance status 2; cardiac, pulmonary, or hepatic comorbidity as per the HCT-CI scale25), and categorized by the number of factors present (Table 4). Twelve patients (11%) had no risk factor in addition to age; 22 (21%), 41 (39%), and 29 patients (28%) had one, two, and three additional risk factors, respectively. The response rate remained consistent without an increase in the early death rate as risk increased within the study population. Survival is summarized graphically in Figure 2. The median overall survival was 3 months in all patients (2 months in nonresponders and 5 months in responders). The percentage of patients alive 12 months after receiving therapy was 14% for all patients (6% in nonresponders and 28% in the responder group). In the responder group, four patients (12%) are in ongoing CR.
The results of this international phase II study indicate that cloretazine has activity in older patients with previously untreated AML or high-risk MDS, even for patients with poor-prognosis disease and significant comorbidity. These data confirm the relative lack of extramedullary toxicity of cloretazine at doses that are both myelosuppressive and capable of significant leukemia tumor burden reduction.21,22,26,27 The clinical profile of cloretazine may be attributable to the role of O6-alkylguanine-DNA alkyltransferase (AGT) in repairing the DNA damage cloretazine causes.16,28 Alkylating agent mutagenesis frequently is mediated through formation and persistence of the DNA base adduct, O6-alkylguanine, which preferentially mispairs with thymine rather than cytosine. O6-alkylguanine is repaired by AGT, which removes the adduct, leaving an intact guanine base in DNA. Human myeloid precursors have low levels of AGT compared with other tissues and are thus particularly susceptible to some alkylating agents, particularly cloretazine.16,29,30 The preferential toxicity against AGT-negative tumor cells and decreased toxicity to AGT-positive cells in normal tissues constitutes the therapeutic basis for cloretazine, and ATG manipulation (eg, with temozolomide) is being investigated as an approach to increase cloretazine activity.16,31-35 Both the resistant nature of AML and the relatively greater comorbidity in older rather than younger patients dictate the specific investigation of novel agents in the elderly with AML.1,3,36 Although the majority of patients with AML are older than 60 years at the time of diagnosis, less than 50% of these patients are offered any specific care for AML.1,3,4,37,38 Results in these treated patients are poor, with low response rates, high complication rates, and short survival.1,3,4,38 With current standard AML cytotoxic induction regimens, the attendant morbidity is high and the cost/benefit perception is such that most patients are not offered such therapy, although recent investigators have advised against such a policy.37-39 Juliusson et al39 have recently reported, based on Swedish Leukemia Registry data, that the survival of patients age 70 to 79 years with non-APL AML was better in regions where more patients were deemed fit for remission induction, that the difference could not be explained by demographics, and that the difference was found with both de novo and secondary leukemias. These data would support the development of less toxic cytotoxic agents for this population—the currently reported data would support additional investigation of cloretazine in this context. A limitation of this and all other reports on induction therapy in AML is that study entry may define a relatively select population.40 This is a particularly important issue when one is attempting to enroll elderly patients onto studies of novel agents that are potentially more tolerable that standard induction regimens. If the majority of the elderly and/or those with extensive comorbidity have not been given standard induction regimens, comparative data are difficult for researchers to obtain. Randomized studies would be best but are neither ethical nor feasible if it is predictable that the control group would suffer excessively; the use of Bayesian designs would at least minimize the numbers of patients in the inferior arm(s).41,42 Random assignment of the elderly deemed fit to receive myelosuppressive therapy against hydroxyurea or supportive care is difficult to justify because the latter have no potential to confer CR. Our study deals with those patients who are considered fit for myelosuppressive therapy but who do poorly with current induction regimens (ie, those in whom it is currently not possible to generate a control group). The use of validated prognostic scales that focus on the impact of comorbidity on outcomes in patients with leukemia is a major help in this transition period—the broad application of these scales will help refine our expectation of current approaches and help us define reasonable benchmarks for novel agents in single-arm studies. In this regard, the HCT-CI recently proposed by Sorror et al25 is a major advance. Validation and refinement of the HCT-CI in elderly patients with AML can be anticipated and should allow standard scoring of comorbidity in study populations. Given that the safety and efficacy of a cloretazine and ara-C combination has been established, a study of this regimen in elderly patients with AML is warranted.22 As with all cytotoxic therapies, myelosuppression is the major toxicity of cloretazine. However, the relatively constant early death rate, even in the elderly, indicates that this is not prohibitive and may be amenable to improvement by novel supportive care measures.43 An important future area will be the introduction of consolidation and/or maintenance protocols for elderly AML patients in CR after a cloretazine-based regimen. These approaches are necessary to prolong CR significantly, and potentially include low-dose ara-C, hypomethylating agents, vascular endothelial growth factor, Ras/Raf inhibitors, or vaccines.1 On the basis of data from this study, an international pivotal phase II study of cloretazine in high-risk elderly patients with AML has been initiated.
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: Verena Karsten, Vion; Ann Cahill, Vion Leadership: N/A Consultant: N/A Stock: Verena Karsten, Vion; Ann Cahill, Vion Honoraria: N/A Research Funds: Francis Giles, Vion; David Rizzieri, Vion; Judith Karp, Vion; Norbert Vey, Vion; Khuda Dad Khan, Vion; Gregor Verhoef, Vion; Pierre Wijermans, Vion; Anjali Advani, Vion; Gail Roboz, Vion; Augustin Ferrant, Vion; Simon M.G.J. Daenen, Vion; Maher Albitar, Vion; Ghulam Mufti, Vion; Susan O'Brien, Vion Testimony: N/A Other: N/A
Conception and design: Francis Giles, Simon Daenen, Ann Cahill, Susan O'Brien Administrative support: Francis Giles Provision of study materials or patients: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Farhad Ravandi, Stefan Faderl, Khuda Dad Khan, Gregor Verhoef, Pierre Wijermans, Anjali Advani, Gail Roboz, Hagop Kantarjian, Syed Fazl Ali Bilgrami, Augustin Ferrant, Simon Daenen, Ann Cahill, Ghulam Mufti, Susan O'Brien Collection and assembly of data: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Farhad Ravandi, Stefan Faderl, Khuda Dad Khan, Gregor Verhoef, Pierre Wijermans, Anjali Advani, Gail Roboz, Hagop Kantarjian, Syed Fazl Ali Bilgrami, Augustin Ferrant, Simon Daenen, Verena Karsten, Ann Cahill, Maher Albitar, Ghulam Mufti, Susan O'Brien Data analysis and interpretation: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Farhad Ravandi, Stefan Faderl, Khuda Dad Khan, Gregor Verhoef, Pierre Wijermans, Anjali Advani, Gail Roboz, Hagop Kantarjian, Syed Fazl Ali Bilgrami, Augustin Ferrant, Simon Daenen, Ann Cahill, Maher Albitar, Ghulam Mufti, Susan O'Brien Manuscript writing: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Farhad Ravandi, Stefan Faderl, Khuda Dad Khan, Gregor Verhoef, Pierre Wijermans, Anjali Advani, Gail Roboz, Hagop Kantarjian, Syed Fazl Ali Bilgrami, Augustin Ferrant, Simon Daenen, Verena Karsten, Ann Cahill, Maher Albitar, Ghulam Mufti, Susan O'Brien Final approval of manuscript: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Farhad Ravandi, Stefan Faderl, Khuda Dad Khan, Gregor Verhoef, Pierre Wijermans, Anjali Advani, Gail Roboz, Hagop Kantarjian, Syed Fazl Ali Bilgrami, Augustin Ferrant, Simon Daenen, Ann Cahill, Maher Albitar, Ghulam Mufti, Susan O'Brien
published online ahead of print at www.jco.org on December 4, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Giles FJ, Keating A, Goldstone AH, et al: Acute myeloid leukemia. Hematology (Am Soc Hematol Educ Program) 2002:73-110, 2002 2. Hiddemann W, Kern W, Schoch C, et al: Management of acute myeloid leukemia in elderly patients. J Clin Oncol 17:3569-3576, 1999 3. Rowe JM, Li X, Cassileth PA, et al: Very poor survival of patients with AML who relapse after achieving a first complete remission: The Eastern Cooperative Oncology Group Experience. Presented at the American Society of Hematology, New Orleans, LA, December 2-6, 2005. ASH Annual Meeting Abstracts 106:546, 2005[Abstract] 4. Kantarjian H, O'Brien S, Cortes J, et al: Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: Predictive prognostic models for outcome. Cancer 106:1090-1098, 2006[CrossRef][Medline] 5. 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D'Atri S, Piccioni D, Castellano A, et al: Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: Studies with blasts of leukaemic patients. Ann Oncol 6:389-393, 1995 36. Giles FJ: New drugs in acute myeloid leukemia. Curr Oncol Rep 4:369-374, 2002[Medline] 37. Menzin J, Lang K, Earle CC, et al: The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 162:1597-1603, 2002 38. Lang K, Earle CC, Foster T, et al: Trends in the treatment of acute myeloid leukaemia in the elderly. Drugs Aging 22:943-955, 2005[CrossRef][Medline] 39. Juliusson G, Billstrom R, Gruber A, et al: Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival. Leukemia 20:42-47, 2006[CrossRef][Medline] 40. Mengis C, Aebi S, Tobler A, et al: Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials. J Clin Oncol 21:3933-3939, 2003 41. Giles FJ, Kantarjian HM, Cortes JE, et al: Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia. J Clin Oncol 21:1722-1727, 2003 42. Giles FJ, Kantarjian HM, Cortes JE, et al: Adaptive randomized study of idarubicin and cytarabine alone or with interleukin-11 as induction therapy in patients aged 50 or above with acute myeloid leukemia or high-risk myelodysplastic syndromes. Leuk Res 29:649-652, 2005[CrossRef][Medline] 43. Solberg LA Jr: Biologic aspects of thrombopoietins and the development of therapeutic agents. Curr Hematol Rep 4:423-428, 2005[Medline] Submitted April 24, 2006; accepted August 14, 2006.
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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
2; serum bilirubin of 
of 10% (95% CI) with a required 96 patients (nQuery Advisor Release 4.0; Statistical Solutions, Cork, Ireland). Based on the results of interim analyses by the study's independent data safety monitoring board (DSMB), the study would be modified only if the observed CR rates were lower than the preset rates. The first analysis was conducted after one third of patients were recruited; the second after two thirds of the patients were recruited. At both analyses, the DSMB recommended study continuation. 
