News

Rituximab (Rituxan) is active in low-grade non-Hodgkin’s lymphoma (NHL), but its efficacy in poor-prognosis intermediate-grade NHL is unknown. To address this issue, we administered rituximab to seven patients with CD20-positive diffuse large cell NHL who had progressive disease despite high-dose therapy and peripheral stem-cell transplantation (PSCT). The median age was 59 years (range, 45-62 years) with ECOG performance status 0-1. Prior to rituximab therapy, all patients had undergone PSCT, with responses of two complete responses (CRs), two partial responses (PRs), one patient with stable disease (SD), and two patients with progressive disease (PD). The CRs lasted 9 and 11 months. Upon relapse or progression of disease, the patients received 4 weekly infusions of rituximab (375 mg/m²).

About 20%-50% of patients with stage IV Hodgkin’s disease may suffer a relapse after initial chemotherapy-induced remission. Consolidative radiotherapy has been used in combination with chemotherapy to reduce relapse at areas of initial bulky disease; however, no survival benefit has been shown in the few randomized studies.

Our studies have shown that unconjugated antibody therapy targeted to the B-cell marker CD20 by the anti-CD20 antibody, C2B8, inhibits the growth of B-cell lymphomas in vitro. We have also demonstrated that B-lymphoma tumor cells can be sensitized to subtoxic doses of therapeutic drugs by the same antibody.

Contamination of the peripheral blood stem-cell (PBSC) graft with lymphoma and residual disease remaining in the patient after high-dose therapy are two potential causes of relapse after autologous transplantation. Using a tumor-specific monoclonal antibody may be one way to purge the stem-cell graft in vivo and increase the efficacy of the preparative regimen. Rituximab (Rituxan) is an IgG1 kappa chimeric mouse/human antibody containing murine light- and heavy-chain variable regions and human gamma 1 heavy-chain and light-chain constant regions. The antibody reacts specifically with the CD20 antigen found on the surface of malignant and normal B-cells.

NAPLES-Nearly one-third of the estimated 144,000 new non-small-cell lung cancer (NSCLC) patients diagnosed in the United States each year are over the age of 65, and these patients often do not have access to the range of treatment options available to younger patients. Platinum-based therapy is often avoided due to concerns about tolerability.

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.

AVENTURA, Florida-Herceptin (trastuzumab) has produced major objective responses in 20% to 25% of patients with previously untreated metastatic breast cancers that overexpressed the HER-2 breast cancer gene. The monoclonal antibody is approved for use as first-line therapy in combination with paclitaxel (Taxol) and as a single agent in second- and third-line therapy.

TORONTO-CD34+ selection of peripheral blood stem cells (PBSCs) significantly reduces tumor cell contamination while providing safe and rapid hematologic recovery for multiple myeloma patients receiving myeloablative therapy, Dr. A.K. Stewart, of Toronto Hospital, reported at ASH.

SAN ANTONIO-In a trial of first-line, single-agent therapy for metastatic breast cancers that overexpress the HER-2 breast cancer gene, Herceptin (trastuzu-mab) resulted in major objective responses in 20% to 25% of patients. The monoclonal antibody is approved for use as first-line therapy in combination with paclitaxel (Taxol) and as a single agent in second- and third-line therapy.

WASHINGTON-Walden-ström’s macroglobulinemia is a rare low-grade B-cell lymphoproliferative disorder. Patients with Waldenström’s also often have small lymphocytic lymphoma (SLL). Hyperviscosity in Waldenström’s responds temporarily to plasmapheresis. Alkylator therapy, fludarabine (Fludara), and cladribine (Leustatin) are effective in many cases, but there are no good options for patients refractory to purine analogs.

Rituximab (IDEC-C2B8 [Rituxan]) is a chimeric anti-CD20 monoclonal antibody (MoAb) that was recently approved by the FDA for the treatment of patients with low-grade or follicular B-cell non-Hodgkin’s lymphoma. Its potential efficacy in other B-cell malignancies is currently being explored. This article reviews the mechanisms of action of rituximab, as well as preclinical data and results of the clinical trials that led to its approval. Also discussed are the mechanics of administering rituximab on the recommended weekly ´ 4 outpatient schedule. Finally, the article describes ongoing and planned trials of rituximab in other dosage schedules, in other B-cell neoplasms, and in conjunction with chemotherapy. As the first MoAb to gain FDA approval for the treatment of a malignancy, rituximab signals the beginning of a promising new era in cancer therapy. [ONCOLOGY 12(12):1763-1770, 1998]

SAN DIEGO--The longest follow-up studies to date on dose-intensive therapy with peripheral blood stem cell or bone marrow support in patients with Hodgkin’s disease or non-Hodgkin’s lymphoma (NHL) show some promising results with specific drug regimens.

INDIANAPOLIS--Eli Lilly and Company’s Gemzar (gemcitabine) has received FDA approval for use as first-line treatment of inoperable, locally advanced, or metastatic non-small-cell lung cancer (NSCLC) in combination with cisplatin (Platinol). The agent was previously approved as first-line, single-agent therapy of locally advanced or metastatic pancreatic cancer

It was not until 1995 that a phase III randomized trial demonstrated that autologous stem cell transplants (ASCT) improve the progression-free and overall survival of patients with relapsed refractory diffuse aggressive non-Hodgkin’s lymphoma. Investigators are now focusing on improving the clinical benefit of transplants. The relative contributions made by more intensive preparative regimens, purging, concomitant immunotherapy, and the timing of transplants are under study. Also, as transplant trials shift from relapsed disease to initial therapy, anticipated benefits must be balanced against both short-term and long-term toxicities.[ONCOLOGY 12(Suppl 8):56-62, 1998]

Doctors at the University of Pittsburgh Cancer Institute are exploring a new experimental therapy in which they transfer the tumor-suppressing gene TP53 (alias p53) into patients to reverse tumor progression. University of Pittsburgh clinical

BETHESDA, Md--A Food and Drug Administration panel has urged expanding the use of Photofrin (porfimer sodium, QLT PhotoTherapeutics) in lung cancer. In a unanimous vote, the Oncologic Drugs Advisory Committee (ODAC) recommended that the FDA approve the photodynamic therapy (PDT) for reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC).

GENEVA--Highly active antiretroviral therapy (HAART), usually including a protease inhibitor, can suppress human immunodeficiency virus (HIV) so much that the immune system actually begins to heal, according to work presented at the 12th World Conference on AIDS. In patients who respond well to HAART, CD4+ and CD8+ cell counts move toward normal, and the risk of opportunistic infections decreases (see Oncology News International, August, 1998, pp 1 and 20).

WASHINGTON--Despite questions about dose levels and number of treatment courses, the FDA’s Oncology Drugs Advisory Committee (ODAC) gave a vote of confidence to Seragen’s Ontak (denileukin diftitox or DAB389IL-2) for its approval for use in cutaneous T-cell lymphoma (CTCL) that persists or recurs despite prior therapy. Ontak is an interleukin-2 (IL-2) fusion protein that delivers a diphtheria toxin fragment to lesions via IL-2 receptor binding. The panel was not asked to formally recommend the agent to the FDA.

It has been hypothesized that intratumoral thymidylate synthase (TS) gene expression might be used to select therapy for patients with disseminated colorectal cancer. We recently

LOS ANGELES--Preliminary results with a gene-therapy approach to recurrent prostate cancer suggest antitumor activity in at least some patients. Three of 18 patients have had decreases in PSA levels of more than 50%. The effects have persisted for 45 to 290 days, including one patient who became biopsy negative for a brief period of time.

CHICAGO--A role is emerging for multimodality therapy in the treatment of both resectable and unresectable stage III non-small-cell lung cancer (NSCLC). When given as an adjunct to radiotherapy or surgery, chemotherapy can downstage local disease and control systemic disease spread by eliminating micro-metastases or delaying the development of metastases, Ann Mauer, MD, a senior fellow in oncology at the University of Chicago, said at the International Conference of the American Thoracic Society and American Lung Association.

In order for the immune system to protect against cancer, it must recognize tumors as "non-self." Markers present on the surface of tumors, known as antigens, allow the immune system to recognize tumors as non-self. However, in order for the

Scientists at Ohio University Edison Biotechnology Institute have used a nonviral gene expression system, invented and patented by Ohio University several years ago, to eliminate human cancer cells in animals. The investigators reported achieving

HOUSTON--Adenoviral-p53 gene therapy with Introgen Therapeutics’ INGN 201 was well tolerated and showed evidence of clinical activity both alone and with cisplatin (Platinol) in patients with advanced non-small-cell lung cancer (NSCLC) who had failed conventional therapy. Stephen Swisher, MD, of the M. D. Anderson Cancer Center, presented the completed phase I/II trial results at an ASCO poster session.

CHICAGO--Molecular biologic markers may be able to identify patients with early-stage non-small-cell lung cancer (NSCLC) who are at the highest risk for metastasis and therefore may benefit from aggressive therapy.

NEW ORLEANS--After delivery with a cationic liposome complex, the tumor-suppressor gene E1A was expressed by cells in many places in the body, Naoto Ueno, MD, of the M.D. Anderson Cancer Center, reported at the 89th annual meeting of the American Association for Cancer Research (AACR).

BETHESDA, Md--Bristol-Myers Squibb went 2-for-2 before the FDA’s Oncologic Drugs Advisory Committee (ODAC). The panel recommended that the FDA approve injectable Taxol (pacli-taxel), in combination with cisplatin (Platinol), for both the first-line treatment of ovarian cancer and for the treatment of non-small-cell lung cancer (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Prophylactic cranial irradiation (PCI) is being reintroduced into multimodality treatment protocols of patients with small-cell lung cancer (SCLC). The history of its use brings interesting insights into clinical evaluations of treatment strategies and design of relevant and informative trials. The critical issues of effectiveness and overall health gains of prophylactic cranial irradiation have been addressed in a series of recently completed clinical trials. These trials tested prophylactic cranial irradiation in small-cell lung cancer patients achieving good response to induction therapy and confirmed the ability of standard prophylactic cranial irradiation schedules to significantly reduce the lifetime risk of brain metastases. A subset of these trials evaluated neurotoxicity in a formal and prospective manner. No sustained or significant detriment in neuropsychometric function could be linked to the use of prophylactic cranial irradiation. In addition, all the large trials have shown a consistent survival advantage in favor of the prophylactic cranial irradiation arm. None of the individual sample sizes were large enough to statistically confirm this survival benefit, but a meta-analysis is in progress and will report on this aspect of evidence shortly. Issues that remain to be answered are the optimal dose and schedule of prophylactic cranial irradiation as well as the timing of this administration. These questions form the nucleus of the next generation of collaborative trials that are being designed.[ONCOLOGY 12(Suppl 2):19-24, 1998]