laromustine and Leukemia--Myeloid--Acute

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.

Topics: Adenine Nucleotides; Animals; Arabinonucleosides; Azacitidine; Benzamides; Clofarabine; Cytarabine; Cytosine; Daunorubicin; Decitabine; Dioxolanes; Farnesyltranstransferase; Histone Deacetylase Inhibitors; Humans; Hydrazines; Imatinib Mesylate; Leukemia, Myeloid, Acute; Liposomes; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases; Valproic Acid; Vascular Endothelial Growth Factor Receptor-1

In spite of the recent progress, the prognosis of acute myelogenous leukemia (AML) remains poor, particularly in patients with relapsed disease and in the elderly. In these situations, there is at present no standard of care, and new drugs are urgently needed.. Preclinical and clinical studies of Laromustine (formerly cloretazine, VNP-40101M), a new sulfonylhydrazine alkylator, in AML published between 2000 and September 2009 are presented and discussed.. Mechanisms of action of Laromustine and preclincal data that support the rationale for its use in patients with AML are summarized. Laromustine has limited extramedullary toxicity. In Phase II studies, it produced 32% complete responses in elderly patients with previously untreated AML. In a Phase III comparative study of its combination with cytarabine in relapsed AML, increased response rate was offset by excessive toxicity.. Laromustine has significant activity in AML. As a single agent, laromustine may represent an alternative to conventional treatments for elderly patients. Although significant activity was seen, safety and optimal dosing in combination regimen remain to be established and are now being investigated.

Topics: Aged; Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Hydrazines; Leukemia, Myeloid, Acute; Remission Induction; Sulfonamides; Treatment Outcome

Acute Myeloid Leukemia (AML) is a disorder affecting primarily elderly individuals and poses significant treatment challenges. Much has been learned about the underlying immunologic, cytogenetic and molecular features of AML in recent years, and many features have been identified that portend a poor prognosis for elderly patients with newly diagnosed AML. Despite this, treatment outcomes for elderly patients remain poor for both newly diagnosed and relapsed disease. While conventional treatment approaches may be appropriate for some elderly patients, the vast majority do not tolerate intensive chemotherapy well, thus alternative strategies have been investigated. Here we review both conventional and novel treatment approaches for elderly patients with AML, including agents in early clinical trials. Treatment options have been divided into several discussions, including conventional treatments, agents complementary to conventional treatments, alternatives to conventional induction therapies, post-induction treatment, and relapsed disease. Current and developing research focuses upon identifying subgroups of patients that benefit more from specific chemotherapeutic agents. Treating elderly patients with AML requires an organized, multidisciplinary approach, taking into account individual patient characteristics, preferences, and comorbidities when formulating treatment plans.

Topics: Adenine Nucleotides; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Arabinonucleosides; Arsenic Trioxide; Arsenicals; Azacitidine; Clofarabine; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Idarubicin; Leukemia, Myeloid, Acute; Middle Aged; Oxides; Recurrence; Sulfonamides

PURPOSE An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acute myeloid leukemia (AML). PATIENTS AND METHODS Laromustine 600 mg/m(2) was administered as a single 60-minute intravenous infusion. Patients were age 70 years or older or 60 years or older with at least one additional risk factor-unfavorable AML karyotype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or cardiac, pulmonary, or hepatic comorbidities. Results Eighty-five patients (median age, 72 years; range, 60 to 87 years) were treated. Poor-risk features included age 70 years or older, 78%; adverse karyotype, 47%; PS of 2, 41%; pulmonary disease, 77%; cardiac disease, 73%; and hepatic disease, 3%. Ninety-six percent of patients had at least two risk factors, and 39% had at least four risk factors. The overall response rate (ORR) was 32%, with 20 patients (23%) achieving complete response (CR) and seven (8%) achieving CR with incomplete platelet recovery (CRp). ORR was 20% in patients with adverse cytogenetics; 32% in those age 70 years or older; 32% in those with PS of 2; 32% in patients with baseline pulmonary dysfunction; 34% in patients with baseline cardiac dysfunction; and 27% in 33 patients with at least four risk factors. Twelve (14%) patients died within 30 days of receiving laromustine therapy. Median overall survival was 3.2 months, with a 1-year survival of 21%; the median duration of survival for those who achieved CR/CRp was 12.4 months, with a 1-year survival of 52%. CONCLUSION Laromustine has significant single-agent activity in elderly patients with poor-risk AML. Adverse events are predominantly myelosuppressive or respiratory. Response rates are consistent across a spectrum of poor-risk features.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Comorbidity; Europe; Female; Gene Expression Regulation, Leukemic; Heart Diseases; Humans; Hydrazines; Infusions, Intravenous; Kaplan-Meier Estimate; Karyotyping; Leukemia, Myeloid, Acute; Liver Diseases; Lung Diseases; Male; Middle Aged; Prospective Studies; Risk Assessment; Risk Factors; Sulfonamides; Treatment Outcome; United States

Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2) per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Double-Blind Method; Female; Humans; Hydrazines; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Remission Induction; Sulfonamides; Young Adult

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).. 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.. 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.. 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.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Female; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Middle Aged; Models, Chemical; Prognosis; Remission Induction; Risk; Sulfonamides; Time Factors; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Double-Blind Method; Female; Humans; Hydrazines; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Remission Induction; Sulfonamides

We have investigated the effect of cloretazine (VNP40101M or Laromustine), a novel sulfonylhydrazine alkylating agent with significant antileukaemic activity, alone, or combined with cytarabine or daunorubicin, on the proliferation, viability and apoptosis of cell lines and acute myeloid leukaemia blast cells in vitro. Cloretazine alone induced a concentration-dependent inhibition of proliferation, reduction in cell viability and an increase in apoptosis in all samples tested. Combinations of cloretazine with varying concentrations of cytarabine or daunorubicin further enhanced these inhibitory effects, suggesting VNP40101M may have a role in combined low dose chemotherapy regimes especially in the elderly.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hydrazines; Leukemia, Myeloid, Acute; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hydrazines; Leukemia, Myeloid, Acute; Sulfonamides

Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Azacitidine; Carbazoles; Clofarabine; Decitabine; Enzyme Inhibitors; Furans; Humans; Hydrazines; Immunotherapy; Lenalidomide; Leukemia, Myeloid, Acute; Quinolones; Staurosporine; Sulfonamides; Thalidomide