Leukemia

ROCKVILLE, Maryland-The US Food and Drug Administration (FDA) has approved Gleevec (imatinib mesylate, Novartis) for the first-line treatment of patients with chronic myeloid leukemia (CML) (see January 2003 ONI, page 1). The agency initially approved the drug in May 2001 for treating the advanced stages of CML. Gleevec first received accelerated approval, which required the company to conduct phase IV postmar-keting research to show that the drug provided clinical benefit in advanced CML and to assess its effect in patients with early-stage disease. With its latest action, FDA has now approved Gleevec as therapy for all three stages of CML-blast crisis, accelerated, and chronic-either before or after other therapies.

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.

PHILADELPHIA-Updated data from the largest randomized, controlled (and only phase III) trial of imatinib mesylate (Gleevec) confirm the drug’s superiority to interferon-alfa and cytara-bine as first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML) but raise interesting questions about what happens within the marrow after CML-causing Philadelphia-chromosome-positive (Ph+) cells are beaten down to undetectable levels.

In the last 20 yearsof the past millennium,most clinical researchin leukemiawas directed towardimproving prognosisof acute leukemia andstudying the role ofstem cell transplantation(SCT), both autologousand allogeneic,in these diseases.The emergence of new treatments and therapeuticapproaches has dramatically changed the emphasisof clinical research in leukemia. The power ofeffective new agents to transform clinical research hasbeen illustrated by the emergence of the tyrosine kinaseinhibitor imatinib mesylate (Gleevec, STI-571) inchronic myeloid leukemia and monoclonal antibodiesin chronic lymphocytic leukemia (CLL).

EAST HANOVER, New Jersey-Novartis Oncology’s Gleevec (ima-tinib mesylate) has been granted priority review by the FDA for use as first-line treatment for newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. The previous indication allowed for the treatment only in the later stages of the disease or in chronic phase after interferon-alfa failure. The FDA also granted priority review to an application by Novartis to provide dosing information for Gleevec in pediatric patients with Ph+ CML. Both applications will be decided by December 28, 2002, the company said in a news release.

Novartis has submitted marketing applications with health authorities in the United States and Europe, seeking marketing authorization for Gleevec (imatinib mesylate) for the first-line treatment of patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

EAST HANOVER, New Jersey-Novartis has simultaneously submitted marketing applications with health authorities in the United States and the European Union seeking marketing authorization for Gleevec (imatinib mesylate) for the first-line treatment of newly diagnosed Philadelphia-chromosome-positive chronic myeloid leukemia (CML), the company said in a news release.

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).

ASCO-In a phase III study, imatinib mesylate (Gleevec), formerly known as STI571, produced a 96% complete hematologic response rate and a 68% complete cytogenetic response rate in newly diagnosed chronic myeloid leukemia (CML) patients, Brian Druker, MD, said on behalf of the IRIS (International Randomized Interferon vs STI-571) Study Group at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1).

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.

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).

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

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.

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.

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.

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]