A multicenter, phase II study of maintenance azacitidine in older patients with acute myeloid leukemia in complete remission after induction chemotherapy.

Older patients with acute myeloid leukemia (AML) have poor outcomes, with median durations of complete remission lasting less than 1 year. Increased toxicity in older patients limits the delivery of standard consolidation therapies, such as allogeneic stem cell transplant or high-dose cytarabine. Azacitidine, a nucleoside analog/DNA methyltransferase inhibitor, has demonstrated significant activity and favorable tolerability in patients unable to tolerate intensive induction chemotherapy; however, the role of azacitidine in the maintenance setting has not been fully evaluated. We undertook a pilot study of low-dose subcutaneous azacitidine [50 mg/(m(2) day)] for 5 days every 4 weeks) in AML patients ≥60 years of age in first remission following standard induction therapy. The primary objective was to determine the 1-year disease-free survival (DFS); secondary objectives were to determine safety and tolerability. We enrolled 24 patients (median age 68, range 62-81 years), the majority of whom received anthracycline-cytarabine induction regimens. From the time of first complete remission, the estimated 1-year DFS was 50% and the median overall survival was 20.4 months. Thrombocytopenia and neutropenia were the most common grade 3/4 toxicities (50 and 58%, respectively). In our study population, maintenance therapy with subcutaneous azacitidine was safe and well tolerated.

Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome.

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation.

Targeted therapies in myelodysplastic syndrome.

Therapeutic alternatives for patients with myelodysplastic syndrome (MDS) have expanded in recent years but remain limited. While agents approved by the US Food and Drug Administration (FDA), including azacitidine, decitabine, and lenalidomide, have yielded hematologic and cytogenetic responses in a substantial portion of patients, these therapies are not curative. Active investigation of novel targets with biological relevance in myelopoiesis has stimulated the pharmacologic development of a multitude of agents that show promise in the treatment of MDS. Many of these drugs have entered or completed early phase clinical testing in MDS and include immunomodulatory agents, immunosuppressive therapies, survival signal inhibitors, thrombopoiesis-stimulating agents, pharmacologic differentiators, and anti-angiogenic and apoptotic agents. As we continue to collect clinical experience with these agents, the repertoire of available therapeutics for the treatment of MDS will expand and provide a foundation for novel therapeutic combinations.

Management of RBC-transfusion dependence.

Strategies for the management of anemia in patients with myelodysplastic syndrome (MDS) have evolved following the U.S. Food and Drug Administration (FDA) approval of three new therapeutics from one of symptom amelioration with red blood cell (RBC) transfusions to one of active treatment. Most patients develop transfusion-dependent anemia over the course of their disease, however, and its adverse consequence on the natural history of disease has only recently been appreciated. Although severe anemia contributes to symptoms of fatigue and reduced quality of life, transfusion dependence increases the risk of organ complications from iron overload coupled with an increased risk of leukemia transformation. Among World Health Organization categories without elevation in bone marrow myeloblasts, an incremental rise in RBC transfusion burden is associated with a proportionate reduction in both overall survival and leukemia-free survival, implying that anemia severity is an important variable limiting the otherwise favorable natural history of patients with lower risk disease. Moreover, therapeutic strategies that successfully restore effective erythropoiesis, such as erythropoetic stimulating agents, immunomodulatory agents, immunosuppressive therapies, or hypomethylating agents, may favorably affect the natural history of this disease, creating perhaps a new urgency for the initiation of erythropoietic promoters that have durable clinical benefit. Selection of primary therapy for the management of anemia should consider four response determinants: age, RBC transfusion burden and duration, endogenous erythropoietin production, and karyotype.

The thalidomide saga.

Over the past 50 years, thalidomide has been a target of active investigation in both malignant and inflammatory conditions. Although initially developed for its sedative properties, decades of investigation have identified a multitude of biological effects that led to its classification as an immunomodulatory drug (IMiD). In addition to suppression of tumor necrosis factor-alpha (TNF-alpha), thalidomide effects the generation and elaboration of a cascade of pro-inflammatory cytokines that activate cytotoxic T-cells even in the absence of co-stimulatory signals. Furthermore, vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) secretion and cellular response are suppressed by thalidomide, thus antagonizing neoangiogenesis and altering the bone marrow stromal microenvironment in hematologic malignancies. The thalidomide analogs, lenalidomide (CC-5013; Revlimid) and CC-4047 (Actimid), have enhanced potency as inhibitors of TNF-alpha and other inflammatory cytokines, as well as greater capacity to promote T-cell activation and suppress angiogenesis. Both thalidomide and lenalidomide are effective in the treatment of multiple myeloma and myelodysplastic syndromes for which the Food and Drug Administration granted recent approval. Nonetheless, each of these IMiDs remains the subject of active investigation in solid tumors, hematologic malignancies, and other inflammatory conditions. This review will explore the pharmacokinetic and biologic effects of thalidomide and its progeny compounds.

The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes.

PURPOSE OF REVIEW: The aim of this article is to discuss the relevant pathobiologic effects of lenalidomide and the most recent clinical evidence to support its use in patients with myelodysplastic syndrome. RECENT FINDINGS: Lenalidomide is an immunomodulatory agent with biological activity in several hematologic malignancies, including myelodysplastic syndrome. The precise mechanism yielding benefit in patients with myelodysplastic syndrome and 5q- syndrome is not clear, but various molecular and pathogenic targets have been identified. Enhancement of cellular immunity through T-cell and NK-cell activation and suppression of inflammatory cytokines and pro-angiogenic peptides upon lenalidomide treatment has been demonstrated in in-vitro models of myelodysplastic syndrome. Furthermore, lenalidomide induces a direct cytotoxic effect against 5q- clones in leukemia cell lines and enhances ligand-induced erythropoietin receptor signaling in erythroid progenitors. Clinical trials with lenalidomide in myelodysplastic syndrome have supported the in-vitro evidence of karyotype-dependent activity by demonstration of a high frequency of cytogenetic and pathologic responses in patients with myelodysplastic syndrome and deletion of chromosome 5q. Lenalidomide was approved for the treatment of transfusion-dependent patients with low to intermediate risk myelodysplastic syndrome and chromosome 5q deletion. SUMMARY: Lenalidomide is an active immunomodulatory agent for the treatment of myelodysplastic syndrome with encouraging erythropoetic and cytogenetic remitting activity that is karyotype dependent.

Managing acute myeloid leukemia in the elderly.

Acute myeloid leukemia (AML) is a disease of the elderly, with the majority of patients diagnosed in their 6th and 7th decade of life. Older patients with AML are less likely to achieve complete remission after induction chemotherapy, and they suffer from higher rates of leukemia relapse compared to younger cohorts. Suboptimal outcomes are the result of adverse biologic characteristics of leukemia in the elderly, as well as the presence of medical comorbidities and patient or physician preferences as to initiating treatment. In addition, there is a distinct lack of randomized, prospective data to guide management decisions for the treatment of AML in the elderly. Patients who are over age 75, with poor performance status, multiple comorbidities, or poor prognostic features, should be considered for a clinical trial or palliative therapy. Elderly patients who are candidates for standard induction chemotherapy and achieve complete remission are unlikely to benefit from intensive postremission therapy and should be referred to a clinical trial when possible. Further prospective trials are needed to identify a tolerable, effective treatment regimen for older patients with AML.