Hematologic Oncology

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 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

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.

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.

With the increasing successof both autologous and allogeneicmarrow transplantationin achieving cure of inheritedand acquired disorders, the numberof people who have become longtermsurvivors has steadily increasedworldwide. Concomitant with thisincrease has been greater attention tothe long-term health needs of theserecipients. Many studies have outlinedthe problems experienced bylong-term survivors and have betterinformed physicians about the medicalproblems that may require interventionand consultation.[1]

As increasing numbers of stemcell transplant recipients becomelong-term survivors, interestin understanding their longtermimmune status also assumesgreater urgency. One important strategyfor protecting patients againstcertain infections is the use of vaccinations.Just a few years ago, therewere no published recommendationsregarding this issue. Since then, boththe European Group for Blood andMarrow Transplantation (EBMT)and the Centers for Disease Controland Prevention (CDC) have publishedrecommendations. Drs. Goldberg,Cicogna, Rowley, and Pecoracritically review the CDC recommendationsin a nicely written articleand provide important backgroundinformation.

Blood and marrow transplantation, a curative treatment for avariety of serious diseases, induces a period of sustained immunosuppressionpredisposing recipients to opportunistic infections. Both forthe protection of the individual transplant recipient and as a matter ofpublic health policy, the US Centers for Disease Control and Prevention(CDC) has developed guidelines for the use of vaccination in theprevention of infectious disease following transplantation. This reviewexamines the primary clinical research supporting vaccinationpolicies in this target population. Widely accepted recommendationsfor transplant recipients based on scientific data are sparse, as fewlarge studies have been conducted in this population. Anecdotalreports, expert advice, summaries, and limited series involving lessthan 50 patients using surrogate end points form the basis of thescientific literature, with the result being a wide variation in practice.Although based largely on inadequate scientific data, the CDC recommendationsoffer a pragmatic approach to the prevention of opportunisticdisease in hematopoietic transplant recipients and serve as auseful starting point for standardization of practice while defining thedirection of future studies in transplant recipients and other immunocompromisedhosts.

High-dose myeloablative therapy with allogeneic hematopoietictransplantation is an effective treatment for hematologic malignancies,but this approach is associated with a high risk of complications.The use of relatively nontoxic, nonmyeloablative, or reduced-intensitypreparative regimens still allows engraftment and the generation ofgraft-vs-malignancy effects, is potentially curative for susceptiblemalignancies, and reduces the risk of treatment-related morbidity.Two general strategies along these lines have emerged, based on theuse of (1) immunosuppressive chemotherapeutic drugs, usually apurine analog in combination with an alkylating agent, and (2) lowdosetotal body irradiation, alone or in combination with fludarabine(Fludara).

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).

ORLANDO-A gene-profiling chip might help identify children with acute lymphoblastic leukemia (ALL) who are at low risk of relapse and could be spared intensive therapy, or who are at high risk for treatment-induced acute myeloid leukemia (AML) and should not be treated with topoisomerase II inhibitors.

ORLANDO-Low-dose cytarabine can be safely administered in combination with imatinib mesylate (Gleevec, also known as STI-571) to chronic myelogenous leukemia (CML) patients in blast crisis, but is unlikely to provide substantial benefit or salvage relapses.

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.

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.

HOUSTON-The farnesyl transferase inhibitor R115777 (tipifarnib, also known as Zarnestra) produced an overall response rate of 33% in patients with chronic myelogenous leukemia (CML) and decreased splenomegaly in most patients with myelofibrosis, but was not effective in multiple myeloma, reported Deborah Thomas, MD, at the 43rd Annual Meeting of the American Society of Hematology. Dr. Thomas is assistant professor in the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center in Houston.

ORLANDO-Patients with chronic myelogenous leukemia (CML) who have a complete cytogenetic response (CCgR) to interferon-alfa have a long survival, and low-risk patients have a projected 10-year survival of more than 80%, Francesca

ORLANDO, Florida-Updated data from two phase II trials show that imatinib mesylate (Gleevec, STI571) continues to improve response rates for patients with chronic myelogenous leukemia (CML) who did not respond to interferon therapy or are in blast crisis. With follow-up of 12 months or more, overall and complete response rates are proving to be durable and toxicities tolerable

ORLANDO-Imatinib mesylate (STI-571, Gleevec) is showing excellent results in newly diagnosed patients with chronic myelogenous leukemia (CML) in the early chronic phase, scientists reported at the 43rd Annual Meeting of the American

ORLANDO, Florida-Two phase I/II studies indicate that combination treatment with imatinib mesylate (Gleevec, also known as STI571) produces a high rate of hematologic response in patients in the chronic phase of chronic myelogenous leukemia (CML). Dose-limiting toxicities were mainly hematologic, and researchers advocate further studies were recommended to establish efficacy and recommended dosing.

MANNHEIM, Germany-Despite encouraging initial responses, patients with chronic myelogenous leukemia (CML) frequently become resistant in the advanced, or blast crisis, phase of the disease after initially responding to selective inhibition of the Bcr-Abl tyrosine kinase by imatinib (Gleevec, also known as STI571).

ROME-Best outcomes from donor lymphocyte infusion in chronic myelogenous leukemia (CML) occur when the first dose does not exceed 0.2 × 108 mononuclear cells/kg, Cesare Guglielmi, MD, reported in a presentation at the 43rd Annual Meeting of the American Society of Clinical Oncology.

MIAMI BEACH -The Bcr-Abl tyrosine kinase inhibitor PD173955 (PD17) binds to the target ATP binding pocket even more efficiently than STI-571 (imatinib mesylate, Gleevec). It shows 15 to 20 times greater efficacy in chronic myelogenous leukemia (CML) cell lines because it can bind to either open or closed activation loops.

Myeloproliferative disorders originate in the clonal expansion of a transformed pluripotential hematopoietic progenitor cell. This results in a group of syndromes that include polycythemia vera, essential thrombocythemia,

Myeloproliferative disorders originate in the clonal expansion of a transformed pluripotential hematopoietic progenitor cell. This results in a group of syndromes that include polycythemia vera, essential thrombocythemia,

SOUTH SAN FRANCISCO-The FDA has approved a supplemental biological license application (sBLA) for Rituxan (rituximab), the monoclonal antibody developed by Genentech, Inc. and IDEC Pharmaceuticals (San Diego) for treatment of patient with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL). The new product labeling includes re-treatment with rituximab after a prior course, initial treatment with eight weekly infusions instead of four, and treatment of bulky disease.