Leukemia

Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.

There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon α, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.

When patients with chronic phase chronic myeloid leukemia (CP-CML) receiving imatinib (Gleevec) progress to accelerated phase (AP) or blast phase (BP), their prognosis is poor.

The investigational agent nilotinib (Tasigna) has shown significant clinical activity and an acceptable safety and tolerability profile in the treatment of imatinib (Gleevec) resistant or intolerant, chronic phase chronic myelogenous leukemia (CP-CML)

The FDA has granted approval to Velcade (bortezomib for injection, Millennium) for the treatment of mantle cell lymphoma (MCL) in patients who have received at least one prior treatment.

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.

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.

The Food and Drug Administration has approvedZolinza (vorinostat, Merck) as a once-a-day oral treatment of the skinmanifestations of cutaneous T-cell lymphoma(CTCL) in patients whose diseasehas persisted, progressed, or recurredduring or following two systemic therapies.

Merck & Co, Inc, recently announced that the Food and Drug Administration (FDA) has approved oral vorinostat (Zolinza), 400 mg once daily, for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin's lymphoma, who have progressive, persistent, or recurrent disease on or following two systemic therapies. CTCL is a cancer of the T cells that affects the skin.

Patients with advanced follicular non-Hodgkin's lymphoma who received a new combination of chemotherapy and targeted radiation (radioimmunotherapy) lived significantly longer than patients treated with standard chemotherapy alone on previous trials. Five-year follow-up data from the phase II trial was published in the September 1 issue of the Journal of Clinical Oncology.

Interim results from a pivotal trial of depsipeptide in cutaneous T-cell lymphoma (CTCL)

Improved compliance with imatinib (Gleevec) therapy for patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) is associated with decreased total and disease-related health care costs

Hana Biosciences recently announced the initiation of a multicenter phase II clinical trial of vincristine sulfate liposomal injection (Marqibo) in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

A 5-year follow-up of the largest study to evaluate imatinib (Gleevec) in the treatment of patients with chronic myeloid leukemia (CML) continues to show prolonged response to treatment and a steady decline in rate of disease progression with each additional year of treatment.

The FDA has granted accelerated approval to Bristol-Myers Squibb's Sprycel (dasatinib) Tablets for the treatment of adults in all phases of chronic myeloid leukemia (CML) (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy, including imatinib (Gleevec). Sprycel also received regular FDA approval for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

ChemGenex Launches Trial of Ceflatonin in TKI-Resistant CML

At a median of 4.9 months of therapy with the investigational agent nilotinib (Tasigna, formerly AMN107), 92% of patients with treatment-resistant chronic phase Ph+ chronic myeloid leukemia (CML) achieved a complete hematologic response with normalization of white blood cell counts, and 35% had a complete cytogenetic response. All patient had shown resistance or intolerance to optimized imatinib (Gleevec) therapy

In a randomized open-label phase II clinical trial (START-R) presented at the 42nd Annual Meeting of the American Society of Clinical Oncology (abstract 6507), the oral multitargeted kinase inhibitor dasatinib achieved major cytogenetic responses in 35% of patients with chronic myeloid leukemia (CML) in chronic phase who had resistance or intolerance to imatinib (Gleevec) (aee also report on page 1 on FDA approval of dasatinib).

Molecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.

A phase I study of AMN107 (Novartis) in Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) shows the new agent induces responses in patients with imatinib (Gleevec)-resistant Bcr-Abl mutations, according to a presentation at the 47th Annual Meeting of the American Society of Hematology (abstract 37).

The FDA has granted priority review to dasatinib (BMS-354825), developed by Bristol-Myers Squibb, for treatment of imatinib (Gleevec)-resistant or refractory chronic myelogenous leukemia (CML) in adults.

Analysis of an early trial of a peptide vaccine, CMLVAX100, provides evidence of disease responses, including some complete molecular responses in patients with previously treated chronic myelogenous leukemia (CML), according to Monica Bocchia, MD, Department of Hematology, University of Siena, Italy. "Despite high rates of clinical and cytogenetic remission achieved by imatinib [Gleevec], most patients still have some degree of molecular residual disease," Dr. Bocchia said at the 47th Annual Meeting of the American College of Hematology (abstract 167). Furthermore, she noted that discontinuation of imatinib (Gleevec) usually results in recurrence of leukemia.

According to a study of late transplant outcomes for more than 6,500 chronic myeloid leukemia (CML) patients, those patients alive in remission 5 years after allogeneic hematopoietic cell transplantation (HCT) enjoy relatively low rates of subsequent disease relapse and death.

An updated analysis of IRIS (International Randomized trial of Interferon/Ara-C versus ST1571), a trial of imatinib (Gleevec) vs interferon, shows that patients with chronic myelogenous leukemia (CML) who respond well to treatment after 12 months may go on to even further eradication of disease after 4 years.

The past 20 years have brought significant advances in our ability to manage patients with non-Hodgkin's lymphoma. More precise classification systems, improvements in diagnosis and staging, and effective new treatments have improved outcomes and made cure a reasonable goal for many patients with these disorders.