Leukemia

With improved prognosis for patients with Hodgkin's lymphoma (HL), interest has increasingly focused on high-risk groups such as elderly patients. Advanced age at presentation is still one of the strongest negative risk factors. Many different factors influence the prognosis in elderly patients. These include biologic differences such as more aggressive histology, different distribution of disease, more frequent diagnosis of advanced stage, and shorter history of disease. In addition, however, aging itself and associated factors such as comorbidity, reduced tolerability of conventional therapy, more severe toxicity and treatment-related deaths, failure to maintain dose intensity, shorter survival after relapse, and death due to other causes contribute to the poorer outcome in elderly patients. Besides the evaluation of specific causes and risk factors, this review highlights recent and ongoing studies for elderly patients with HL as well as international approaches and recommendations for this age group.

With improved prognosis for patients with Hodgkin's lymphoma (HL), interest has increasingly focused on high-risk groups such as elderly patients. Advanced age at presentation is still one of the strongest negative risk factors. Many different factors influence the prognosis in elderly patients. These include biologic differences such as more aggressive histology, different distribution of disease, more frequent diagnosis of advanced stage, and shorter history of disease. In addition, however, aging itself and associated factors such as comorbidity, reduced tolerability of conventional therapy, more severe toxicity and treatment-related deaths, failure to maintain dose intensity, shorter survival after relapse, and death due to other causes contribute to the poorer outcome in elderly patients. Besides the evaluation of specific causes and risk factors, this review highlights recent and ongoing studies for elderly patients with HL as well as international approaches and recommendations for this age group.

The management of peripheral T-cell lymphoma may become more uniform with the release of the first set of clinical practice guidelines for the disease

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

The spectrum of CD30+ lymphoproliferative diseases of the skin includes CD30+ cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, as well as borderline cases. These entities constitute the second most common group of cutaneous lymphomas according to the newly revised World Health Organization and European Organisation for Research and Treatment of Cancer consensus classification. Recent progress in immune and molecular biology, and identification of therapeutic targets have increased our understanding of these diseases and have led to novel treatment approaches. This review will provide an update on recent findings of immunologic, molecular, cytogenetic features and treatment strategies for patients with CD30+ lympho-proliferative diseases.

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

The spectrum of CD30+ lymphoproliferative diseases of the skin includes CD30+ cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, as well as borderline cases. These entities constitute the second most common group of cutaneous lymphomas according to the newly revised World Health Organization and European Organisation for Research and Treatment of Cancer consensus classification. Recent progress in immune and molecular biology, and identification of therapeutic targets have increased our understanding of these diseases and have led to novel treatment approaches. This review will provide an update on recent findings of immunologic, molecular, cytogenetic features and treatment strategies for patients with CD30+ lympho-proliferative diseases.

In chronic myelogenous leukemia (CML) patients who have failed two tyrosine kinase inhibitor therapies—imatinib (Gleevec) and dasatinib (Sprycel)—the investigational agent nilotinib (Tasigna) has significant clinical activity

Despite significant improvements in the treatment of Hodgkin's lymphoma over the past 2 decades, physicians continue to face dilemmas in therapy for the disease, and many cured patients live with complications of treatment. Newer therapeutic options are still needed for the disease, to minimize complications and to improve the treatment of patients in relapse. This review considers the treatment of Hodgkin's lymphoma in younger patients, addressing such issues as which patients with early-stage disease may require radiotherapy, what prognostic factors provide information that can affect treatment choices in patients with advanced disease, and what we have learned about treatment complications in this setting.

Despite significant improvements in the treatment of Hodgkin's lymphoma over the past 2 decades, physicians continue to face dilemmas in therapy for the disease, and many cured patients live with complications of treatment. Newer therapeutic options are still needed for the disease, to minimize complications and to improve the treatment of patients in relapse. This review considers the treatment of Hodgkin's lymphoma in younger patients, addressing such issues as which patients with early-stage disease may require radiotherapy, what prognostic factors provide information that can affect treatment choices in patients with advanced disease, and what we have learned about treatment complications in this setting.

Despite significant improvements in the treatment of Hodgkin's lymphoma over the past 2 decades, physicians continue to face dilemmas in therapy for the disease, and many cured patients live with complications of treatment. Newer therapeutic options are still needed for the disease, to minimize complications and to improve the treatment of patients in relapse. This review considers the treatment of Hodgkin's lymphoma in younger patients, addressing such issues as which patients with early-stage disease may require radiotherapy, what prognostic factors provide information that can affect treatment choices in patients with advanced disease, and what we have learned about treatment complications in this setting.

While it may take more time than expected for newly diagnosed chronic myeloid leukemia (CML) patients to get a good response to imatinib (Gleevec), responses continue to improve with prolonged therapy

Two clinical studies with a total of 1,202 patients have found posaconazole (Noxafil) significantly more effective than two other antifungal agents in preventing fatal invasive fungal infections in acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) patients who develop neutropenia as a result of chemotherapy

Once-daily dosing with dasatinib (Sprycel) 100 mg gives similar cytogenetic responses with considerably fewer hematologic adverse events than three other dasatinib dosing schedules in patients with chronic mye-logenous leukemia (CML) who are resistant to or intolerant of imatinib (Gleevec)

Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.

Hana Biosciences, a biopharmaceutical company focused on advancing cancer care, recently announced that the US Food and Drug Administration (FDA) has granted orphan drug designation for vincristine sulfate liposomes injection (Marqibo) in the treatment of adult patients with acute lymphoblastic leukemia (ALL).

This challenging supplement to ONCOLOGY is based on the proceedings of a closed expert symposium, and provides an overview of our current knowledge on primary cutaneous T-cell lymphomas (CTCL). The complete spectrum from genetics to clinical practice is covered.

Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.

Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.

Chromosomal changes have been identified early in the disease process in cutaneous T-cell lymphoma (CTCL): both losses and gains of chromatin have been found on several chromosomes. The extent of chromosomal aberrations increases with disease stage and in more aggressive subtypes of the disorder. Changes in specific genes, such as NAV3, have been characterized in patients with CTCL, and may produce a proliferation advantage for affected cells. In addition, the expression of some genes can discriminate between controls and patients with CTCL. Therefore, the over- or under-expression of certain genes may be of diagnostic and pathogenic relevance in this disease, and may allow the development of selective treatments.

The diagnosis of cutaneous T-cell lymphoma (CTCL) requires accurate histopathology, including immunocytochemistry, as well as careful clinical appraisal and analysis for T-cell clonality. This paper reviews the key histologic features of mycosis fungoides (MF) and its variants, and of lymphomatoid papulosis (LyP). Mycosis fungoides is an epidermotropic CTCL that evolves through distinct disease stages of patch, plaque, and tumor, often leading to transformation in the final stages. Disease staging is made clinically, and diagnosis may be difficult during the early stages because several common dermatologic conditions share features with MF. Therefore, clinical appraisal plus the presence of characteristic histopathologic features are needed to ensure accurate diagnosis. Clinical information is particularly important in the diagnosis of LyP, as the disease appears malignant histologically, but has a benign clinical course. Several other T-cell lymphomas were defined in a recent classification of these cutaneous lymphomas, and some key features of these disorders are also briefly reviewed.

The role of autologous and allogeneic stem-cell transplantation (SCT) in the treatment of cutaneous T-cell lymphoma (CTCL) is reviewed. Patients most likely to benefit are those with advanced-stage disease, multiple relapses, and short remissions; chemosensitive disease is also a prerequisite for these treatments. Autologous SCT produces high response rates in patients with peripheral T-cell lymphoma, but these are generally of short duration. This therapy is relatively safe to administer, with little transplant-related mortality. In contrast, allogeneic SCT may be highly toxic and result in transplant-related mortality, but it has the potential to produce long-lasting responses. Prospective studies of these treatments in patients with CTCL are required. Nevertheless, selected patients could be considered for allogeneic SCT, preferably early in their disease when their performance status is still good.

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.