Hematologic Oncology

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.

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.

Treatment with the thalidomide-like immune modulator lenalidomide (Revlimid) led to a 41% response rate in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL)

MK-0457, an investigational small molecule inhibitor of Aurora, JAK-2, and Bcr-Abl kinases, has demonstrated clinical activity in patients with Bcr-Abl T315i mutant chronic myelogenous leukemia (CML)

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)

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 US Food and Drug Administration (FDA) has approved, after a priority review, two additional uses for rituximab (Rituxan) for patients with CD20-positive, B-cell non-Hodgkin's lymphoma (NHL).

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.

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).

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.

Anemia is common in patients with hematologic malignancies, and it has negative effects on their quality of life. The current clinical practice guidelines recommend erythropoietic therapy in patients with cancer- or chemotherapy-related anemia, but anemia is often undertreated in patients with hematologic malignancies. Several randomized controlled trials have shown that treatment with erythropoiesis-stimulating proteins such as epoetin alfa (Procrit), epoetin beta, and darbepoetin alfa (Aranesp) increases hemoglobin levels, reduces the need for red blood cell transfusions, and improves quality of life in patients with hematologic malignancies and anemia receiving chemotherapy. Furthermore, preliminary data from a recent open-label study suggest that early treatment of mild anemia in patients with hematologic malignancies treated with chemotherapy produces marked improvements in quality of life and productivity. Increasing patients' hemoglobin levels may also improve their cognitive function. These findings support the use of erythropoietic therapy to manage anemia in patients with hematologic malignancies who are treated with chemotherapy.

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.

Concomitant administration of rituximab (Rituxan) and chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) appears effective in patients with stage III-IV follicular non-Hodgkin's lymphoma (NHL).

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.

Rituxan (rituximab) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or other anthracycline-based chemotherapy regimens has received approval from the FDA for use as first-line treatment of diffuse large B cell non-Hodgkin's lymphoma (DLBCL) in CD20-positive patients.

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.

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.

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.

Standard therapy for multiple myeloma, which accounts for 10% ofall hematologic malignancies, has been autologous stem cell transplantation(ASCT), alkylator-based chemotherapy, and corticosteroids. Severaladvances have been made in the treatment of multiple myelomaover the past decade, especially the arrival of new, active agents suchas thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide(Revlimid). These have shown significant clinical activity as singleagents. Trials are ongoing to incorporate these new agents into thevarious stages of treatment and to combine them with other effectivetreatment modalities, including ASCT.

Priming of leukemic cells with cytokines may enhance the efficacy of cell-cycle chemotherapy. In this study, we utilized these synergistic effects of granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]), hydroxyurea, and low-dose cytosine arabinoside to treat elderly patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). In a single-institution, retrospective study, we evaluated 94 treatments with concomitant hydroxyurea, cytosine arabinoside, and GM-CSF between the years of 1997 and 2003 in high-risk elderly patients with AML or MDS. A total of 80% of patients received all of the GM-CSF doses; 78% of patients received all of the cytosine arabinoside doses. Adverse events were minimal. No patient developed mucositis or alopecia. The most common adverse event was neutropenic fever, which was noted in 57% of patients. Twenty-one percent of patients remained neutropenic after treatment until death or relapse. Sixty-eight percent of patients reached an absolute neutrophil count of greater than 1,000 μL in a median of 33.5 days. Our data show an overall response rate of 52%, with a complete response rate of 39% and a partial response rate of 13%. Overall, our study showed that low-dose cytosine arabinoside given by continuous infusion together with continuous infusion GM-CSF and hydroxyurea was well-tolerated and effective in treating elderly AML and MDS patients who were not eligible for standard induction therapy.

Acute myelogenous leukemia (AML) is a disorder marked by infiltration of the bone marrow by abnormal hematopoietic progenitors. These cells are unable to differentiate in a normal fashion into myeloid, erythroid, and/or megakaryocytic cell lines and, unlike normal progenitors, are capable of infiltrating vital organs.

Drs. Thompson and Luger’spaper provides a comprehensivesurvey of issues surroundinghematopoietic stem celltransplantation (HSCT) in myelodysplasticsyndrome (MDS). Whilefinding much of value in the paper, Istrongly disagree with the authors’opinion that “it is clear that youngpatients with [human leukocyte antigen(HLA)]–identical siblings. . .should undergo allogeneic HSCT assoon as possible.” This view wouldseem to rest on two premises: first,that allogeneic HSCT is, as the authorscontend, the only therapy“shown to alter the natural history ofMDS,” and second, that results withallogeneic HSCT are sufficiently“good” that the procedure can be regardedas a fixed, standard elementof medical practice.

The curability of the aggressive, large-cell lymphomas was first convincinglyreported by Levitt et al in 1972.[1] Patients with “reticulum cellsarcoma” were treated with a regimen that came to be known as COMLA(cyclophosphamide, vincristine [Oncovin], methotrexate, leucovorin, cytarabine[Ara-C]). A more commonly quoted paper was published in 1975 by DeVita et aldescribing the cure of advanced “diffuse histiocytic lymphoma” with COPP (cyclophosphamide,vincristine [Oncovin], procarbazine, prednisone).[2] During the 1970sthe CHOP regimen (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin],prednisone) was described by McKelvey et al[3]; it quickly became the mostwidely used treatment for the aggressive large-cell lymphomas. Patients treatedwith two cycles of CHOP beyond documentation of a complete remission wereoften cured.[4]

Drs. Thompson and Luger have written a thoughtful and comprehensive review of the therapeutic options and issues facing physicians caring for patients with myelodysplastic syndrome (MDS). In our commentary, we would like to highlight and expand on several areas of their analysis.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hemopoietic stem cell [1-4]. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-cell lineages [4,5].