Lymphoma

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.

LUGANO, Switzerland-In previously untreated, advanced Hodgkin’s disease, the ChIVPP/EVA regimen, though associated with risk of sterility, is highly effective with a low incidence of secondary leukemias, according to a recent analysis of two randomized studies.

The past 30 years have seen tremendous advances in the treatment of pediatric leukemia. What was once an invariably fatal diagnosis is now quite curable in close to 80% of cases. Unfortunately for children with acute myelogenous leukemia (AML), most of these developments have been in the treatment of acute lymphoblastic leukemia (ALL); even today, nearly half of all children diagnosed with AML will die of the disease.

The use of intensive therapy over a brief period of time has produced dramatic improvements in outcome for pediatric patients with acute myelogenous leukemia (AML), as has been demonstrated in studies by the major cooperative groups in the United States and Europe. Still, despite high-intensity chemotherapy and bone marrow transplantation, only about half of the children diagnosed with AML are cured. Future improvements are unlikely to come from further increases in chemotherapy intensity. Alternative approaches, such as risk-directed therapy based on different prognostic criteria; differentiation therapy with all-trans-retinoic acid (ATRA, Vesanoid), arsenic trioxide (Trisenox), or azacytidine; and immunotherapy with monoclonal antibodies, tumor vaccines, or cytokines may lead to further advances. [ONCOLOGY 16:1057-1070, 2002]

Improvement in pediatric acute myelogenous leukemia (AML) over the past 30 years has been only modest. Although rates of complete remission induction have climbed steadily to 85% or 90%, cure rates remain in the 50% to 60% range. These figures may inspire envy from medical oncologists treating adults with AML, but they lag far behind the successes in treating pediatric acute lymphocytic leukemia (ALL).

PORTLAND, Oregon-Giving erythropoietic therapy to chronic myelogenous leukemia (CML) patients does not appear to interfere with their response to imatinib mesylate (STI571, Gleevec) therapy, according to a retrospective study of 37 patients treated in the Leukemia Center at Oregon Health and Science University in Portland (ASCO abstract 106).

In their review of the history of the management of stage I/II Hodgkin’s disease, Drs. Ng and Mauch describe the results of various treatment protocols and outline the questions posed by ongoing European, Canadian, and American trials. In a broad sense, the questions posed by these trials will help clinicians understand the benefits and complications of these treatments. However, as clinically oriented as they are, the current studies have yet to answer some common problems faced by private practitioners-the clinicians who, in North America, manage most patients with Hodgkin’s disease.

Drs. Ng and Mauch do an excellent job of summarizing the current conventional wisdom regarding the management of patients with clinical early-stage Hodgkin’s disease, although their citation of some studies is selective. Today nearly all patients with Hodgkin’s disease receive combined-modality therapy-usually an abbreviated course of a chemotherapy regimen (often one that has not been shown to cure the disease when used alone) followed by 20 to 40 Gy of involved-field radiation therapy. This approach certainly hides a multitude of sins. If you don’t give chemotherapy well, you can still achieve good disease control with the radiation therapy. If you can’t design a radiation port that encompasses known sites of disease, you can still get by because the systemic chemotherapy will leave relatively little for the radiation therapy to do.

Early-stage Hodgkin’s disease accounts for approximately 60% of all cases of the illness. Because of its excellent cure rate (80% to 90%) and high salvage rate, it is difficult to demonstrate survival advantages for

The optimal choice of treatment for early-stage Hodgkin’s disease depends on (1) knowledge of the prognostic factors that may influence treatment outcome and (2) the risk of acute and long-term complications incurred by treatment. For prognostic and therapeutic considerations, patients are divided into those with early-stage, favorable-prognosis disease (clinical stage I/II without risk factors) and those with early-stage, unfavorable-prognosis or intermediate-stage disease (clinical stage I/II with risk factors).

WASHINGTON-After further review, a committee of the Institute of Medicine (IOM) has rescinded its earlier finding of a suggestive link between the exposure of veterans to herbicides used during the Vietnam War and an increased risk of their offspring developing acute myelogenous leukemia (AML). The committee’s reanalysis followed the finding that one study that it had relied on was in error.

The Genitope Corporation is sponsoring a phase III double-blind, randomized trial of recombinant idiotype immunotherapy in previously untreated patients with follicular lymphoma.

Currently, patients with early-stage chronic lymphocytic leukemia (CLL) without active disease are observed. However, those patients with elevated beta-2-microglobulin levels appear to have a shorter median survival (6 years vs 10+ years).

ORLANDO-European researchers have found involved-field and extended-field radiotherapy following chemotherapy to be equally effective in treating patients with intermediate-stage Hodgkin’s disease. Andreas Engert, MD, University of Cologne, Germany, reported the results of the multicenter, international study at the 43rd Annual Meeting of the American Society of Hematology (abstract 3199).

Pure red cell aplasia is a rare occurrence in patients with chronic lymphocytic leukemia (CLL). This report is based on two cases-CLL patients with documented pure red cell aplasia who responded remarkably to anti-CD20 or rituximab (Rituxan

The humanized monoclonal antibody apolizumab (Remitogen, Hu1D10), directed against a polymorphic determinant of HLA-DR expressed on normal and malignant B cells, is capable of inducing antibody-dependent cellular cytotoxicity, complement-mediated lysis, and direct apoptosis of lymphoma cell lines (Int J Cancer 93:556-565, 2001).

The FM (fludarabine [Fludara], mitoxantrone [Novantrone]) combination is an effective strategy in follicular lymphoma. From October 1999, patients from 12 Italian centers were randomized for a comparative study of FM vs CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) chemotherapy with the addition of rituximab (Rituxan) in selected cases.

Alemtuzumab (Campath), a CDR-grafted monoclonal antibody, recognizes the CD52 antigen which is expressed on normal B and T cells as well as on leukemic B-cell chronic lymphocytic leukemia (B-CLL) cells.

The antiapoptotic protein bcl-2 is associated with chemotherapy failure in untreated large B-cell lymphomas, and with the recently described poor-prognosis large B-cell lymphoma subtype displaying an activated B-cell genotype (Nature 403:503, 2000).

Rituximab (Rituxan), a chimeric anti-CD20 antibody, is effective as a single agent in chronic lymphocytic leukemia (CLL), down-regulates antiapoptotic proteins in CLL cells in vivo, and is minimally immunosuppressive.

Front-line treatment of chronic lymphocytic leukemia (CLL) with single-agent fludarabine (Fludara) achieves complete remission in 35% of patients.

Advanced follicular lymphomas are incurable with conventional chemotherapy regimens. The Southwest Oncology Group (SWOG) investigated the safety and efficacy of a novel treatment approach by administering six cycles of standard CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar] at 750 mg/m², doxorubicin HCl at 50 mg/m², vincristine [Oncovin] at 1.4 mg/m², and oral prednisone at 100 mg for 5 days), given at 3-week intervals, followed by radioimmunotherapy. Four weeks after completion of the last cycle of CHOP, patients with a partial (PR) or complete remission (CR) to chemotherapy underwent dosimetry with 450 mg of unlabeled tositumomab (anti-CD20) antibody and 35 mg of trace-labeled iodine-131 tositumomab (Bexxar).

Wild-type bcl-2 protein is normally found within the bilaminar membrane of the mitochondrion, where it is believed to negatively regulate the release of cytochrome C into the cytoplasm after an apoptotic signal has triggered dimerization of bax protein.

Failure of treatment in chronic lymphocytic leukemia (CLL) is often characterized by increased expression of the antiapoptosis protein bcl-2. High levels of bcl-2 protein block the apoptotic death machinery at the mitochondrial level by maintaining the permeability transition pore (PTP) in the closed position.

ORLANDO-Treatments credited with improving 5-year survival rates for patients with childhood Hodgkin’s disease may lead to an increased risk of leukemia, breast cancer, and other neoplasms years later, according to a study by the Late Effects Study Group (LESG) presented at the American Society of Hematology annual meeting (abstract 3198).

Rituximab (Rituxan), a chimeric human-mouse anti-CD20 antibody, and alemtuzumab (Campath), a humanized rat anti-CD52 antibody, have each shown activity in chronic lymphocytic leukemia (CLL).

Although patients with small lymphocytic lymphoma and chronic lymphocytic leukemia (SLL/CLL) have CD20 expression on malignant lymphocytes, response rates with standard rituximab (Rituxan) courses in refractory patients have been low.

There have been significant advances in our understanding of the biology of acute myelogenous leukemia (AML), and to a lesser extent, in its treatment. Dr. Estey has provided an excellent overview of the current state of the clinical management of the disease. He has described both the standard therapeutic approaches, including allogeneic hematopoietic stem cell transplantation, as well as the role of investigational therapy. The present state of clinical research in AML is reviewed in some detail in the context of the broad clinical investigation of the disease at the M. D. Anderson Cancer Center. Dr. Estey makes a strong argument for the early consideration of investigational therapy, focusing on patients for whom "standard" therapy is demonstrably inadequate.

Therapeutic strategies are evolving for the treatment of patients with newly diagnosed acute myelogenous leukemia (AML), as well as for those with relapsed or refractory disease. Clinical and laboratory studies have demonstrated that AML is not a single disease, but a heterogeneous group of diseases with different clinical features and natural histories. There are variable responses to therapy depending on both the biologic characteristics of the disease and the clinical characteristics of the patient. Nevertheless, studies evaluating the outcomes of relatively large numbers of patients with newly diagnosed AML show that the majority still die of their disease.[1-3]

The treatment of patients with acute myelogenous leukemia (AML) ranges from palliative care only, to standard therapy, to investigational approaches. Acute myelogenous leukemia is, in fact, several different diseases, and the percentage of clinical responses varies with disease and prognostic subsets.