Hematologic Oncology

Drs. Thompson and Luger’spaper provides a comprehensivesurvey of issues surroundinghematopoietic stem celltransplantation (HSCT) in myelodysplasticsyndrome (MDS). Whilefinding much of value in the paper, Istrongly disagree with the authors’opinion that “it is clear that youngpatients with [human leukocyte antigen(HLA)]–identical siblings. . .should undergo allogeneic HSCT assoon as possible.” This view wouldseem to rest on two premises: first,that allogeneic HSCT is, as the authorscontend, the only therapy“shown to alter the natural history ofMDS,” and second, that results withallogeneic HSCT are sufficiently“good” that the procedure can be regardedas a fixed, standard elementof medical practice.

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]

Drs. Thompson and Luger have written a thoughtful and comprehensive review of the therapeutic options and issues facing physicians caring for patients with myelodysplastic syndrome (MDS). In our commentary, we would like to highlight and expand on several areas of their analysis.

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].

Supportive care remains the mainstay of therapy for patients withmyelodysplastic syndrome (MDS). Although allogeneic bone marrowtransplantation is the only known curative therapy for MDS, its risksmake this treatment prohibitive in many patients, who tend to be olderand have other medical problems. With advances in hematopoietic stemcell transplantation (HSCT), we can offer transplant to an increasingnumber of patients. It is, however, necessary to assess each patient andhis or her disease individually and evaluate prognostic factors, treatmentoptions, appropriateness of HSCT, and, if appropriate, type andtiming of HSCT. We will review the data on HSCT in MDS in order toexamine each of these issues and clarify the decision-making process.

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 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 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.