CLORETAZINE™ (VNP40101M) Is Active in Elderly Untreated Poor Risk Patients with Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS).
Authors: Giles Francis , O’Brien Susan , Rizzieri David , Karp Judith , Cooper Maureen , Mufti Ghulam , Johnson Bonny , Karsten Verena , Vey Norbert 
Published: April 2020

Abstract
Background: The majority of patients (pts) with AML and high risk MDS are ≥ 60 years of age at diagnosis (median age 70), and have a poor prognosis due to age-related risk factors and disease biology. Commonly accepted risk factors in this population include age ≥ 60 yrs, ECOG PS ≥2, secondary AML, unfavorable cytogenetics, and organ dysfunction. The response rate with induction treatment for these pts is lower than that of their younger counterparts, and additional risk factors worsen prognosis. Hepatic, pulmonary, and/or cardiac compromise is likely to determine both selection and tolerance of the induction regimen, and these pts are often not considered for aggressive chemotherapy such as “3+7”. In the US, up to 70% of elderly AML/MDS pts do not receive induction treatment (Menzin, et al; Arch Int Med; 2002;162:1597). CLORETAZINE, a novel sulfonylhydrazine alkylating agent, has significant activity in AML/MDS with a favorable safety profile. In an ongoing Phase II trial, pts with AML or high risk MDS, age ≥60 years, and no prior cytotoxic treatment, receive CLORETAZINE 600mg/m2 for remission induction, re-induction, and consolidation.
Methods: This elderly pt population was analyzed for the presence of risk factors and underlying organ dysfunction. Pts were assessed according to the commonly accepted risk factors described above and categorized by number of factors present. Organ dysfunction was defined as hepatic abnormalities (elevated liver function tests), moderate/severe pulmonary compromise (grade 2–4 dyspnea by NCI-CTC Version 3.0 or dependence on oxygen), and/or a history of significant cardiac disease. Data was obtained from case report forms of baseline demographics, medical history, physical exam, and concomitant medications.
Results: 105 pts with age ≥60 were enrolled as of April 21, 2005. Specific risk factors were as follows: 31 pts (30%) were PS 2; 36 pts (34%) had unfavorable cytogenetics; 43 pts (41%) had secondary AML. Forty-eight pts (46%) had cardiac dysfunction; 26 pts (25%) had hepatic disease; and 19 pts (18%) had pulmonary dysfunction. The response rate (CR+CRp) for the group as a whole was 31% (N=33). Non-hematologic toxicity was minimal, and the early death rate of 18% is within the range expected for cytotoxic induction regimens in the elderly AML population. The table below describes the risk categories for all patients, early deaths, and responders:
# Risk Factors N [%] # CR/CRp (%) # Early Deaths (%) Age + 0 12 (11) 7 (58) 2 Age + 1 24 (23) 9 (38) 4 Age + 2 39 (37) 8 (21) 7 Age ≥3+ 30 (29) 9 (30) 6 Total 105 33 (31) 19 (18)
Conclusions: According to risk assessment on the basis of age-related risk factors, the majority of the study pt population had multiple risk factors and represents a group for whom standard AML induction therapy may not be an option. In this elderly patient population with limited therapeutic options, CLORETAZINE is tolerable and results in a response rate of 31%.