Lymphoma

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.

Ganti et al present quite an extensive overview of follicular lymphoma, with most of their emphasis on clinical practice. Many of the issues they touch upon demonstrate that we cannot draw firm conclusions about the superiority of various treatments over others, due to a variety of study limitations. These challenges to interpretation include the indolent course of the disease in most patients (and thus the long follow-up needed to draw firm conclusions), the often small number of patients in this category, the retrospective nature of most studies, differences in risk factors, and the relative lack of randomized studies. As is also the case with efficacy, the most beneficial treatment strategy in follicular lymphoma remains to be established.

Chronic lymphocytic leukemia (CLL) is a clonal malignancy that results fromexpansion of the mature lymphocyte compartment. This expansion is aconsequence of prolonged cell survival, despite a low proliferative index. Theaffected lymphocytes are of B-cell lineage in 95% of cases, and the remainingcases involve T lymphocytes, likely representing a distinct disorder.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorderresulting from the neoplastic transformation of the primitive hematopoietic stemcell. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid,megakaryocytic, B-cell, and, sometimes, T-cell lineages. Bone marrowstromal cells are not involved.

Bcl-2 functions as a key survival factor for lymphocytes and is highlyexpressed in a majority of non-Hodgkin's lymphomas. The ability ofoblimersen sodium (Genasense, previously known as G3139) to targetbcl-2 messenger RNA and decrease Bcl-2 protein levels has the potentialto enhance the activity of cytotoxic chemotherapy. Pretreatmentwith oblimersen followed by cyclophosphamide (Cytoxan, Neosar)markedly improved survival relative to single-agent cyclophosphamidein a murine xenograft model. Oblimersen has also enhanced the cytotoxicityof a variety of other agents against non-Hodgkin's lymphoma,including etoposide, rituximab (Rituxan), and alemtuzumab (Campath).An initial phase I study of oblimersen in non-Hodgkin's lymphomademonstrated modest single-agent activity. Recent reports suggest thatoblimersen may add to the activity of R-CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone) in previously untreatedmantle cell lymphoma and to rituximab alone in a variety of subtypesof relapsed non-Hodgkin's lymphoma. Additional studies in both treatment-naive and relapsed patients will define the role of oblimersen inthe treatment of non-Hodgkin's lymphoma.

NEW ORLEANS-For 25 years, oncologists made no progress in treating diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL). Then, in 2000, the anti-CD20 antibody rituximab (Rituxan, MabThera in Europe) was shown to improve results in

The field of radioimmunotherapy for the treatment of non-Hodgkin'slymphoma (NHL) has advanced significantly over the past decade, andseveral radioimmunoconjugates are being tested in clinical trials. Twoof these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomabtiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeledtositumomab (Bexxar). Other agents target either CD22 (Y-90epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1),respectively. In February 2002, Y-90-labeled ibritumomab tiuxetanbecame the first radioimmunoconjugate to be approved by the US Foodand Drug Administration (FDA) for the treatment of cancer.Tositumomab/I-131 tositumomab was approved in June 2003. Thus,two radioimmunoconjugates have been approved for the treatment ofNHL. Both agents, when administered as a single dose, have producedimpressive tumor response rates with an acceptable toxicity profile. Themain side effect is reversible myelosuppression. Radioimmunotherapyproduces overall response rates of approximately 80% in patients withlow-grade lymphomas, and 25% to 30% of patients achieve a completeremission. Lower response rates (approximately 40%) have been reportedin patients with large-cell lymphomas. This review discusses theclinical trials of radioimmunotherapeutic agents for NHL that demonstratedtheir safety and efficacy and outlines the current status of theseagents.

SAN DIEGO-In the IRIS study, newly diagnosed chronic myelogenous leukemia (CML) patients who crossed over from interferon (IFN)-alfa plus cytarabine (ara-C) to imatinib mesylate (Gleevec) and achieved a complete cytogenetic response (CCR = elimination of Ph+ cells), had reductions in bcr-abl similar to those on first-line imatinib, according to a presentation at the 45th Annual Meeting of the American Society of Hematology (ASH abstract 635). Their probability of achieving a CCR, is somewhat diminished, however, compared with those treated with first-line imatinib, said Jerald P. Radich, MD, Fred Hutchinson Cancer Research Center, Seattle.

Together, parts 1 and 2 of thearticle by Drs. Wilson andSmith on the “Management ofMycosis Fungoides” serve as an excellentreference for the diagnosis andmanagement of this subtype of cutaneousT-cell lymphoma. Part 1, whichdeals with the diagnosis, staging, andprognosis of mycosis fungoides, appearedin the September 2003 issue ofthis journal. Part 2, which deals withtreatment, appears in the current issue.The article is a concise overviewof the numerous treatment strategiesand specific treatments available forvarious stages and presentations ofmycosis fungoides.

Mycosis fungoides is a low-grade lymphoproliferative disorder ofskin-homing CD4+ lymphocytes that may produce patches, plaques,tumors, erythroderma, and, ultimately, systemic dissemination. Treatmentselection is generally guided by institutional experience, patientpreference, and toxicity profile, as data from phase III clinical trials arelimited. Effective topical treatments currently include mechlorethamine(Mustargen), carmustine (BCNU, BiCNU), corticosteroids, bexarotene(Targretin, a novel rexinoid), psoralen plus ultraviolet A, ultraviolet B,and total-skin electron-beam radiotherapy. Effective systemic treatmentsinclude interferon, retinoids, bexarotene, denileukin diftitox(Ontak), extracorporeal photopheresis, chemotherapy, and high-dosechemotherapy with allogeneic bone marrow transplant. Each of thesetreatments is discussed in detail, followed by specific recommendationsfor each stage of mycosis fungoides.

Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin’s lymphomas. Patients usually present with advanced disease, with a tendency for extranodal involvement. MCL is an aggressive lymphoma with moderate chemosensitivity, but it remains one of the most difficult therapeutic challenges. Complete response rates to chemotherapy range from 20% to 40%, with median survivals of 2½ to 3 years. Anthracycline-containing regimens do not prolong survival compared with nonanthracycline regimens. Single-agent rituximab (Rituxan) has produced response rates of about 30%, and when combined with an anthracycline-containing regimen, response rates increase to above 90%; however, an impact on survival has not yet been demonstrated. More intensive regimens such as hyperCVAD (hyperfractionated cyclophosphamide [Cytoxan, Neosar], vincristine, doxorubicin [Adriamycin], dexamethasone, methotrexate, cytarabine) with either stem cell transplant or rituximab have been associated with promising results.

Drs. Baidas, Cheson, Kauh, and Ozdemirli present a thorough and balanced review of mantle cell lymphoma (MCL) and the various current treatment options. MCL has been recognized as a distinct pathologic entity for over a decade. It represents 6% to 9% of all non- Hodgkin’s lymphoma cases, and the diagnosis is based on a combination of morphologic, immunophenotypic, and cytogenetic criteria as discussed in the article. The hallmark of MCL is t(11;14)(q13;q32), a translocation that juxtaposes the Bcl-1 gene on chromosome 11 and immunoglobulin (Ig)H promoter on chromosome 14, leading to overexpression of cyclin D1. Although it had been considered an indolent lymphoma for many years, MCL has a poor prognosis with short remissions and a median survival of 3 to 4 years.[1,2]

This special supplement to Oncology News International includes updated results of studies with anti-CD20 therapy and other targeted therapies in the treatment of lymphomas, chronic lymphocytic leukemia, and immune thrombocytopenic purpura. The results were presented at the American Society of Hematology 44th Annual Meeting in Philadelphia, December 6 to 10, 2002.

This special supplement to Oncology News International includes updated results of studies with anti-CD20 therapy and other targeted therapies in the treatment of lymphomas, chronic lymphocytic leukemia, and immune thrombocytopenic purpura. The results were presented at the American Society of Hematology 44th Annual Meeting in Philadelphia, December 6 to 10, 2002.

This special supplement to Oncology NewsInternational includes updated results ofstudies with anti-CD20 therapy and othertargeted therapies in the treatment oflymphomas, chronic lymphocytic leukemia,and immune thrombocytopenic purpura. Theresults were presented at the American Societyof Hematology 44th Annual Meeting inPhiladelphia, December 6 to 10, 2002.

This special supplement to Oncology News International includes updated results of studies with anti-CD20 therapy and other targeted therapies in the treatment of lymphomas, chronic lymphocytic leukemia, and immune thrombocytopenic purpura. The results were presented at the American Society of Hematology 44th Annual Meeting in Philadelphia, December 6 to 10, 2002.

This special supplement to Oncology News International includes updated results of studies with anti-CD20 therapy and other targeted therapies in the treatment of lymphomas, chronic lymphocytic leukemia, and immune thrombocytopenic purpura. The results were presented at the American Society of Hematology 44th Annual Meeting in Philadelphia, December 6 to 10, 2002. City Hall in Philadelphia, Pennsylvania

This special supplement to Oncology News International includes updated results of studies with anti-CD20 therapy and other targeted therapies in the treatment of lymphomas, chronic lymphocytic leukemia, and immune thrombocytopenic purpura. The results were presented at the American Society of Hematology 44th Annual Meeting in Philadelphia, December 6 to 10, 2002.

It has been demonstrated that completemolecular remission in follicularlymphoma is associatedwith an improved outcome. Therefore,the object of modern therapyfor indolent lymphoma should be toachieve this goal.

PHILADELPHIA-A single four-dose cycle of rituximab (Rituxan) produced an overall response rate of 72% and median progression-free survival of 2.78 years in a phase II trial in patients with newly diagnosed, asymptomatic, advanced-stage follicular grade 1 non-Hodgkin’s lymphoma (NHL).

Dr. Nabhan and his coauthorshave written a comprehensivereview of the use of monoclonalantibodies in the treatment ofchronic lymphocytic leukemia (CLL).They have highlighted importantclinical trials with newer antibodies,including apolizumab (Hu1D10,Remitogen) and IDEC-152 (anti-CD23). The authors concisely describethe use of rituximab (Rituxan)and alemtuzumab (Campath) as singleagents and in combination therapy.Both antibodies have efficacy inthe treatment of CLL, but both havelimitations when used as singleagents.

Drs. Nabhan, Dyer, and Rosenprovide an excellent and comprehensivereview of the therapeuticrole of rituximab (Rituxan)and alemtuzumab (Campath) inchronic lymphocytic leukemia (CLL).We take this opportunity to offer ourcomments concerning these two monoclonalantibodies in CLL.

Despite many therapeutic options for chronic lymphocytic leukemia(CLL), the disease remains incurable. Since monoclonal antibodiesand recombinant toxins that bind surface antigens expressed on themalignant lymphocytes have been developed, targeted therapy hasbecome a vital option in treating CLL. Rituximab (Rituxan), a chimerichuman-mouse anti-CD20 antibody, and alemtuzumab (Campath), ahumanized anti-CD52 monoclonal antibody, have both shown activityin CLL-as single agents and in combination with conventionalchemotherapy. The possibility of combining antibodies has beenexplored as well, with some efficacy. In this review, we discuss theclinical data on the activity of commercially available antibodies inCLL, both as monotherapy and in combination with other agents.

HOLLYWOOD, Florida-There were several significant changesto the National Comprehensive CancerNetwork (NCCN) Hodgkin’s diseaseguidelines announced at the SeventhAnnual NCCN Conference (seeTable for NCCN member institutions).

ORLANDO, Florida-Addingrituximab (Rituxan) to standard chemotherapyfor follicular lymphomaregimens improves the rate and qualityof responses and increases clearanceof the bcl-2/IgH chimeric gene,according to studies from US andItalian cooperative groups reportedat the 43rd Annual Meeting of theAmerican Society of Hematology.

This special “Annual Highlights” supplement to Oncology NewsInternational is a compilation of the major advances in the managementof the lymphomas and leukemias during 2002, as reported in ONI.Commentaries by the editors, Drs. Gregory Bociek, James Armitage,and Michael Keating, provide perspective and prediction as to howthese developments may affect clinical practice.