The currently available nucleoside analogs, such as fludarabine, have revolutionized the approach to the treatment of indolent lymphoid malignancies. Fludarabine is the most effective agent for the treatment of chronic lymphocytic leukemia (CLL) and also exhibits major activity in low-grade NHL. Despite the impressive rates of complete remissions, patients with these malignancies remain incurable, and new agents are needed.
The role of interferon-alfa (Intron A, Roferon) in the management of patients with low-grade NHL remains controversial. More than 10 randomized trials have been reported.
Overexpression of the bcl-2 gene can be detected in approximately 80% to 90% of patients with advanced-stage follicular NHL, as well as in 20% to 30% of those with diffuse large B-cell NHL. A number of studies have attempted to correlate outcome with residual disease using PCR in patients who have achieved a clinical complete response with chemotherapy, antibody treatment, or high-dose therapy with stem-cell support. However, the studies have been inconsistent, and, therefore, the clinical value of such measurements has been limited.
High-dose chemotherapy with autologous stem-cell support has clearly demonstrated efficacy in patients with relapsed or refractory Hodgkin’s disease (Horning et al: Blood 89:801-813, 1997) and is probably superior to salvage chemotherapy in this setting (Yuen et al: Blood 89:814-822, 1997). Disease burden and chemosensitivity have been shown to be predictive of long-term outcome following the transplant. However, a clear advantage may be difficult to demonstrate because of late complications, including secondary malignancies, particularly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) (Roberts et al, abstract #2984).
The relative clinical efficacy of autologous or allogeneic bone marrow transplantation (BMT) remains a controversial issue. In most series, outcomes with the two types of transplants have been comparable; relapse is more common with autologous BMT due to contamination of stem cells, whereas allogeneic BMT is associated with greater treatment-related mortality.
The use of all-trans-retinoic acid (ATRA [Vesanoid]) has revolutionized the treatment of patients with acute promyelocytic leukemia (APL)(Tallman et al: N Engl J Med 337:1021-1028, 1997). However, a significant proportion of patients still relapse and die from their disease. Studies from China have indicated that arsenic trioxide is effective even in patients who did not respond to ATRA, and subsequent research has suggested that it works by a different mechanism of action (Shen et al: Blood 89:3354-3360, 1997).
As more new therapeutic agents enter clinical trials, it becomes increasingly more important to have standardized response criteria. Uniform guidelines facilitate acquisition of comparable data, interpretation of data, comparisons of the results among various clinical trials, and identification of new agents with promising activity.
The role of combined-modality therapy for Hodgkin’s disease was the subject of several abstracts presented at the ASH meeting. Radiation therapy has traditionally been the standard approach for patients with early-stage disease. However, several recent studies have suggested an important role for chemotherapy, either alone or in combination with radiation.
Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody that has been studied most widely in patients with follicular non-Hodgkin’s lymphomas (NHLs). This antibody has induced responses in about half of these cases, including a 6% complete remission rate, with responses lasting a median of 11.6 months (McLaughlin et al: J Clin Oncol 16:2825-2833, 1998). Rituximab has only entered widespread clinical use over the past year. As a result, data are just beginning to emerge on the long-term results with this agent.
Gerhartz and coworkers (abstract #1293) and the German Hodgkin’s Group (Diehl et al, abstract #2002) presented their results with interoup (Diehl et al, abstract #2002) presented their results with intensified regimens. The former investigators used a time-intensified COPP (cyclophosphamide, Oncovin, procarbazine, and prednisone)/ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine, Prokine]) support. Complete remission rates were 62% with COPP/ABVD, as compared with 79% for the intensified regimen. This was taken as evidence of benefit from the higher-dose program. However, these findings are consistent with results that have been reportedfor ABVD and other anthracycline-containing regimens (Canellos et al:N Engl J Med 327:1478-84, 1992; Duggan et al: Proc Am Soc Clin Oncol 16:12a [abstract 43], 1997).
Although thousands of patients have been treated with rituximab to date, researchers are just beginning to understand the basis on which this agent works. Rituximab is believed to induce tumor regression by several mechanisms of action, including antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and induction of apoptosis. The mechanism by which apoptosis occurs also has not been clearly elucidated.
In general, rituximab has an acceptable toxicity profile. However, as the drug has been used more widely, new side effects have been identified that warranted a modification of the package insert. Approximately 70 serious infusion-related events have been reported, with 8 fatalities out of an estimated14,000 patients treated. Death was associated with bronchospasm, hypotension, and severe respiratory distress, with no clear predisposing factors.
Allogeneic BMT has generally been limited to patients younger than age 50 to 55 years, and to those with good performance status and renal function. Several approaches are being evaluated to allow these poorer-risk patients to safely undergo transplantation. The successful use of submyeloablative (“mini”) transplants has previously been reported by groups from Israel (Slavin et al: Blood 91:756-73, 1998) and M. D. Anderson (Khouri et al: J Clin Oncol 16:2817-2824, 1998). A moderately myelosuppressive agent, such as cyclophosphamide (Cytoxan, Neosar), and an immunosuppressive drug, such as fludarabine (Fludara), are used as the preparative regimen. Following BMT, allogeneic donor leukocytes may be used to eliminate residual disease or mixed chimerism. Further study of this interesting approach is ongoing.
Although rituximab was approved for the treatment of follicular, low-grade NHL, it is also being evaluated in other CD20+ tumors. Responses have previously been reported in large cell NHL and mantle cell NHL (Coiffier et al: Blood 92:1927-1932, 1998). These authors used 8 weekly infusions of rituximab at two different doses in 54 patients with intermediate- or high-grade NHL or mantle cell NHL. The complete remission rate was 9% with an overall response rate of 31%. Median time to progression as of publication was 246+ days.
The bcl-2 gene is overexpressed in 80% to 90% of patients with follicular NHL. The product of this gene, the bcl-2 protein, not only protects cells from apoptosis but also induces a form of acquired resistance to a wide array of chemotherapy agents (Kitada et al: Blood 91:3379-3389, 1998).
Early reports suggested that therapy with rituximab might be less effective in patients with bulky nodal disease. At the ASH meeting, Davis et al (abstract #1711) reported on 31 patients with indolent NHL and masses measuring ³ 10 cm who received rituximab in four weekly infusions. Of the 31 patients, 1 patient (4%) had a complete remission, and 11 patients responded partially, for an overall response rate of 43%. However, the duration of response was only 8.1 months.
The results published to date with Bexxar and IDEC-Y2B8 have been very promising. Bexxar is an iodine-131 anti-CD20 conjugate which, in a single-institution study including previously treated patients, achieved a response rate of 79%, including a 50% complete remission rate (Kaminski et al: J Clin Oncol 14:1974-1981, 1996), with complete remissions lasting a median of more than 16.5 months. Among previously treated patients, 71% achieved a complete remission and 39% attained a partial remission, for an overall response rate of 100%. The complete remissions lasted 3 to 17+ months (Kaminski et al : Proc Am Soc Clin Oncol 17:2a [abstract 6], 1998).
The low-grade NHLs remain incurable with conventional therapies. A variety of new, unique agents are being evaluated, which, hopefully, will improve these results. The purine analogs, particularly fludarabine (Fludara), have shown impressive activity in these patients and have become part of the standard treatment armamentarium. In patients who have not responded to an alkylating agent, fludarabine achieves a 12% to 15% complete remission rate with an overall response rate of about 50%. When used as initial therapy, fludarabine produces a complete remission in almost 40% of patients and an overall response rate of 60% to 70% (Solal-Céligny: J Clin Oncol 14:514-519, 1996).
Rituximab is highly effective in eradicating detectable lymphoma cells from the peripheral blood and bone marrow of patients with follicular NHL and can render most patientsPCR-negative. Several studies at ASH evaluated the ability of this antibody to provide effective in vivo purging, permitting the harvesting of large numbers of PCR-negative stem cells for autologous BMT (Gianni et al, abstract #481; Buckstein et al, abstract #2672). Engraftment has been successful in the few patients transplanted to date (Flinn et al, abstract #2673). Obviously, longer follow-up of larger numbers of patients is needed to better evaluate the long-term impact of this approach.
Pediatric soft-tissue sarcomas are managed with a multimodality treatment program that includes surgery, chemotherapy, and external-beam radiotherapy (teletherapy). The use of teletherapy in young children can
BACKGROUND: Extended-field radiotherapy is effective in patients with early-stage Hodgkin’s disease, and more than
PITTSBURGH-The addition of tamoxifen (Nolvadex) to lumpectomy plus radiation therapy in women with ductal carcinoma in situ (DCIS) significantly reduces the 5-year cumulative incidence of recurrent invasive ipsilateral breast tumors, Norman Wolmark, MD, chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), said at the San Antonio Symposium.
PARIS-Neoadjvant chemotherapy with the combination of paclitaxel (Taxol) and doxorubicin gave a pathologic complete response rate of 16% in a phase II randomized multicenter French clinical trial of women with previously untreated breast cancers.
ATHENS-Early results from a phase III multicenter study suggest that the major dose-limiting side effects of irinotecan (Camptosar) in colon cancer-neutropenia and delayed diarrhea developing 24 hours after administration-can be controlled by the use of G-CSF (Neupogen).
MADISON, Wisconsin-The addition of interferon-alfa to the COPA regimen (cyclophosphamide, 600 mg/m²; vincristine, 1.2 mg/m²; prednisone, 100 mg; and doxorubicin, 50 mg/m²) improves survival in patients with clinically aggressive low- and intermediate-grade non-Hodgkin’s lymphoma (NHL), Richard Smalley, MD, of Synertron, Inc., said at the American Society of Hematology meeting. He presented 10-year follow-up results of an ECOG trial begun in 1986.
ANN ARBOR, Michigan-A radiolabeled monoclonal antibody was more effective than previous chemotherapy had been in more than half of patients with indolent lymphomas, in a study reported at the American Society of Hematology meeting.
CLEVELAND, Ohio-Nearly half of the symptoms associated with cancer are gastrointestinal (GI), including anorexia, weight loss, dry mouth, constipation, early satiety, nausea and vomiting, taste change, and dysphagia. Yet these symptoms are among the most difficult to treat because their pathophysiology is not well understood, available drugs are not always effective, and multiple symptoms may occur together, Kristine A. Nelson, MD, said at a symposium on palliative medicine held at the Cleveland Clinic Foundation.
BALTIMORE-Fludarabine (Fludara) and cyclophosphamide are highly active agents for indolent lymphomas, but when given in combination, opportunistic infections such as Pneumocystis carinii pneumonia (PCP) and herpes zoster may be dose limiting.
NEW YORK-The addition of G-CSF (Neupogen) to standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) may improve disease outcome in elderly patients with large-cell lymphoma by allowing optimal drug dosing, Gerard Donnelly, MD, said at the Fortieth Annual Meeting of the American Society of Hematology (ASH).
WASHINGTON-One major problem in the adjuvant treatment of breast cancer is that tumors may become resistant to endocrine therapy, even if estrogen/progesterone (ER/PR) receptors remain. Furthermore, some tumor cells appear to be stimulated by the treatment itself. “An antagonist can act as an agonist,” Kathryn B. Horwitz, PhD, said at a basic science symposium sponsored by the National Foundation for Cancer Research.