Bruce D. Cheson, MD

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.

Campath-1H is an anti-CD52 monoclonal antibody that has demonstrated impressive activity in patients with relapsed chronic lymphocytic leukemia (CLL) and in those with T-cell prolymphocytic leukemia (T-PLL). Initial clinical trials with this agent were terminated early because of excessive toxicity, ie, myelosuppression and infections. Nevertheless, the investigators were impressed by the activity of the antibody in patients with advanced CLL.

Progress in the treatment of indolent non-Hodgkin’s lymphoma has been slow and the disease remains incurable despite the relatively long median survival of patients. Decades of clinical trials resulted in standard

Over the past few years, several promising new therapeutic agents have been approved by the FDA for the treatment of