Lymphoma

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).

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.

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.

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.

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.

The US Food and Drug Administration (FDA) has approved rituximab (Rituxan) for use in the first-line treatment of patients with diffuse large B-cell, CD20-positive non-Hodgkin’s lymphoma, in combination with CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) or other anthracycline-based chemotherapy regimens. Rituximab has previously been approved as a single agent for use in relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma.

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.

DENVER-Among patients with early-stage Hodgkin’s disease (HD) without adverse features, outcomes with combined modality regimens are still very good when chemotherapy is reduced by half or radiation therapy is reduced by a third, according to interim results of a randomized trial. Rolf P. Müller, MD, head of the Department of Radiation Oncology at the University of Cologne, Germany, presented the study findings at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 2).

ORLANDO -Adding rituximab (Rituxan) to standard first-line chemotherapy (CVP) improved outcomes for patients with advanced follicular lymphoma, according to clinical trial results presented by Kevin Imrie, MD, at the American Society of Clinical Oncology 41st Annual Meeting (abstract 6525). "The benefit in terms of time to progression is observed in all prognostic groups,"said Dr. Imrie, director of postgraduate programs in medicine, Toronto Sunnybrook Regional Cancer Centre, Ontario, Canada.

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.

Although there have been many advances in the treatment of Hodgkin's disease, diagnosis of the disease still rests on the identification of the Reed-Sternberg cell. This distinctive, though nonspecific, cell was first described by Sternberg in 1898 and further elucidated by Reed in 1902. In most biopsies, the Reed-Sternberg cell accounts for only 1% of the cells present, with the remainder consisting of lymphocytes, granulocytes, histiocytes, plasma cells, and fibroblasts

While some improvement was achieved by adding etoposide and shortening the treatment intervals from 3 to 2 weeks (CHOEP-14), best results in young good-prognosis patients (age-adjusted International Prognostic Index [IPI] = 0,1) have been achieved with six cycles of CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone)-like chemotherapy in combination with the anti-CD20 antibody rituximab (Rituxan). The role of additional radiotherapy in this setting remains to be determined. With this approach, 2-year eventfree survival rates of > 90% and overall survival of > 95% can be achieved in a very favorable subgroup (patients without IPI risk factor and no bulky disease), while further improvement is warranted for the less favorable subgroup (event-free survival only 77%). For young poorprognosis patients (age-adjusted IPI ≥ 2), the 5-year survival is around 50%, and progress has not been convincingly and specifically demonstrated in these patients. Ongoing studies will show whether dose-dense conventional or high-dose chemotherapy regimens requiring stem cell support in combination with rituximab will result in similar improvements of outcome as has been reported recently for young patients with good-prognosis aggressive lymphoma. In elderly patients, CHOP interval reduction from 3 to 2 weeks (CHOP-14) and the addition of rituximab to CHOP-21 achieved similar improvements in outcome. The ongoing RICOVER-60 (rituximab with CHOP over 60) trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) evaluates whether the combination of both approaches (R-CHOP-14) can further improve the prognosis of elderly patients.

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]

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].

The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin’s lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.

Dr. Ganti and colleagues from the University of Nebraska provide a thorough review of the management of patients with follicular lymphoma, including many recent additions to the therapeutic armamentarium. The field is rapidly changing, and this article will be an enduring resource both for clinicians currently managing these patients and for anyone in the future who wants to understand what the state of the art was in 2004. Follicular lymphoma accounts for about one-third of non- Hodgkin’s lymphomas in the United States, making it likely that an individual oncologist will see one to three patients with follicular lymphoma each year. As the authors point out, numerous active agents have been developed for use in patients with follicular lymphoma over the past 5 years and additional promising new therapeutic agents and novel approaches (eg, vaccination) are in the development pipeline.

In their manuscript, Ganti et al tackle a very intricate and controversial subject: follicular non-Hodgkin’s lymphoma (NHL). The manuscript attempts to exhaustively cover multiple aspects of the disease, including pathology, prognostic factors, natural history, treatment of early-stage as well as advanced disease, relapsed disease, newer agents, monoclonal antibodies, interferon, radioimmunotherapy, stem cell transplantation, and future directions. To review all these topics thoroughly would almost require a textbook. To meticulously cover all of these aspects in a review article is a nearly impossible task. From my standpoint as a reviewer, to critique this article is an equally complicated task. I will therefore focus on only a few major issues.