Leukemia

First results of four phase II studies of the investigational oral, multitargeted kinase inhibitor dasatinib (BMS-354825) showed significant efficacy in imatinib (Gleevec) resistant and intolerant patients with chronic, accelerated, and blast phase (myeloid and lymphoid) chronic myeloid leukemia (CML).

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.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western hemisphere, accounting for 30% of the leukemias in this population. The disease results from a clonal expansion of small B-lymphocytes. CLL always involves the bone marrow and peripheral blood. The disease also can be demonstrated in lymph nodes, liver, and spleen.

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].

SAN DIEGO, California-An investigational drug, BMS-354825, overcame resistance to imatinib (Gleevec) in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients in two small but dramatic phase I trials presented at the 46th Annual Meeting of the American Society of Hematology (ASH). After up to 9 months of treatment with BMS-354825, 31 of 36 chronic-phase patients (86%) had a complete hematological response, Charles L. Sawyers, MD, a Howard Hughes Medical Institute researcher at UCLA, reported (abstract 1). Among 29 patients who reached 3 months on treatment and could be evaluated for cytogenetic response, 13 responses were observed overall, including 8 major cytogenetic responses (28%), of which 5 were complete.

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.

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.

SAN DIEGO- Doubling the standard dose of imatinib mesylate (Gleevec) to 800 mg provided more complete cytogenetic responses (CCRs) more quickly with higher rates of PCR (polymerase chain reaction) negativity than the standard dose (400 mg) in patients with previously untreated early-stage chronic myeloid leukemia (CML).

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.

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-Imatinib mesylate (Gleevec) is significantly more effective than interferon/cytarabine at reducing BCR-ABL protein blood levels in patients with chronic myeloid leukemia (CML); levels of BCR-ABL continue to drop with increasing duration of therapy; and patients in complete cytogenetic response (CCR) who have a 3-log or greater reduction in BCR-ABL rarely develop progressive disease, according to Timothy Hughes, MD.

PHILADELPHIA-Chronic myeloid leukemia (CML) patients treated with imatinib mesylate (Gleevec) reported better quality of life (QOL) than those on interferon/cytarabine, and those who switched from interferon/cytarabine to imatinib reported improved QOL, compared with those who remained on interferon, Elizabeth A. Hahn reported. This is clinically important because about 20% of CML patients drop out of interferon treatment within 6 months due to intolerable adverse effects.

PHILADELPHIA-Remissions induced by gemtuzumab ozogamicin (Mylotarg) monotherapy in patients with first-relapse acute myeloid leukemia (AML) can be prolonged with subsequent therapy. Allogeneic hematopoietic stem cell transplant was particularly effective and even produced some long-term remissions in patients who did not respond to gemtuzumab, Eric Sievers, MD, reported at the 44th Annual Meeting of the American Society of Hematology (ASH abstract 327).

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.

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.