Bruce D. Cheson, MD

Lung cancer is the number one cause of cancer death for both men and women in the United States. In the year 2001, it is

The 4th National Institutes of Health (NIH) Consensus Conference on Adjuvant Therapy of Breast Cancer, held November 1-3, 2000, concluded that decreasing breast cancer mortality rates in the United States were due, at least in part, to advances made in adjuvant treatment. This fact lends credence to the importance of incremental improvements that have resulted from randomized, controlled clinical trials of adjuvant therapy, and underscores the value of this approach. With 185,000 new diagnoses of breast cancer expected in the United States in 2000, over 100,000 women may be candidates for some form of adjuvant therapy each year.[1]

Despite impressive response rates, none of the current array of monoclonal antibodies has produced cures. The median duration of response following rituximab is about 1 year, and all patients eventually relapse and require additional treatment

Other active unconjugated antibodies are in various stages of their clinical development. CAMPATH-1H has recently been approved for the treatment of refractory chronic lymphocytic leukemia (Keating et al: Blood 94:705a[abstract 3118],

Once the radioimmunoconjugates (RICs) become more widely available, the practicing physician will be faced with important questions regarding their role relative to the unconjugated antibodies, and with a decision as to which is the

Rituximab is also being explored in other lymphoid malignancies. Some of the most interesting data are in patients with CD20-positive Hodgkin’s disease (abstract #3153). The Stanford group (abstract #3592) reported on 13 patients. Of the 9

The availability of a continually increasing menu of effective monoclonal antibodies has revolutionized the management of patients with indolent B-cell malignancies. The dilemma we now face is how to best incorporate these agents into our

In general, results with autologous stem-cell transplantation for patients with follicular NHL have been disappointing, without the evidence for cure observed in patients with large B-cell NHL (Rohatiner et al: J Clin Oncol 12:1177-1184, 1994;

Hairy cell leukemia is one of the success stories of hematologic oncology. The purine analogs cladribine (Leustatin) and pentostatin (Nipent) are similarly active, with responses in more than 90% of patients, including 65% to 85% CRs

Rituximab is generally well tolerated, with toxicities that tend not to overlap with those resulting from chemotherapy. Moreover, in vitro data suggest that monoclonal antibodies may sensitize lymphoma cells to the effects of chemotherapeutic

Campath-1H is an unconjugated, humanized monoclonal antibody directed against the CD52 antigen present on B cells, as well as T cells and other mononuclear cells. In phase II trials, this antibody has shown impressive activity in chronic lymphocytic leukemia (CLL) and T-cell prolymphocytic leukemia (T-PLL) but limited activity in NHL (Österborg et al: J Clin Oncol 15:1567-1574, 1997; Pawson et al: J Clin Oncol 15:2667-2672, 1997; Lundin et al: J Clin Oncol 16:3257-3263, 1998). In CLL, responses to Campath-1H have been reported in 30% to 70% of patients who had not responded to prior treatment, including fludarabine (Fludara), with complete response (CR) rates ranging from 4% to 50%. More than two-thirds of T-PLL patients have achieved CRs, but these do not seem to be durable. Only 14% of patients with low-grade NHL achieved partial responses (PRs), although responses were noted in about half of a small number of patients with mycosis fungoides.

Ibritumomab tiuxetan (Zevalin) is a murine IgG directed against CD20 and conjugated to yttrium-90. The basic antibody is the murine rituximab. The yttrium-90 isotope was selected because it has a number of properties that are considered to be more favorable than those of iodine-131. These include the fact that ibritumomab tiuxetan is a pure beta-emitter, with higher energy and a longer path length. Ibritumomab tiuxetan has been reported to induce responses in 67% of patients with intermediate- and high-grade NHLs and 82% of those with low-grade NHL who had not been treated previously with rituximab (Witzig et al: J Clin Oncol 17:3793-3803, 1999).

Few advances in the treatment of multiple myeloma have been made in recent years, and this disease remains incurable. The observation that about 20% of plasma cells from myeloma patients express CD20 has led to some interest in studying monoclonal antibodies in this disorder. Treon et al (abstract #1398) reported the preliminary results of their phase II trial with rituximab in previously treated multiple myeloma patients. Among nine patients evaluable for response at the time of the report, there was one PR in a patient with mostly CD20-positive bone marrow plasma cells.

Although responses to rituximab occur in approximately 50% of patients with follicular NHL, several studies in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have shown response rates in the range of only 10% to 15%

One logical next step in research on rituximab was to study its activity in previously untreated patients. At the 1999 ASH meeting, Solal-Céligny et al (abstract #2802) presented the French experience with 50 patients who had low-risk follicular NHL, as defined by the following characteristics: absence of B symptoms, no tumor mass > 7 cm, and a normal LDH and serum beta-2-microglobulin. The overall response rate to rituximab was 69%, including 31% complete remissions (CRs) and 10% unconfirmed complete remissions (CRu), as defined by the international response criteria (Cheson et al: J Clin Oncol 17:1244-1253, 1999). Of considerable interest was the fact that over 50% of patients who were positive for the bcl-2 rearrangement (as determined by polymerase chain reaction [PCR] assay) prior to therapy were PCR negative after treatment. A quarter of the patients had recurred at a median of 13 months. Therefore, longer follow-up will be required to determine whether a molecular response will be associated with more durable responses and the potential for prolongation of survival.

One of the unfortunate consequences of solid organ or bone marrow transplantation is the occurrence of a post-transplant lymphoproliferative disorder (PTLD). These tumors run a variable course; some regress with a reduction in the doses of immunosuppressive agents, whereas others progress to an aggressive NHL and require systemic therapy. Chemotherapy has been relatively unsuccessful against such tumors, and the outcome is generally fatal.

Mantle cell lymphoma is one of the most challenging of the NHLs. It exhibits the worst features of both the indolent and aggressive lymphomas. With its short survival of 2 ½ to 3 years, mantle cell lymphoma resembles an aggressive NHL, but,

Leonard et al (abstract #404) described their experience with a new humanized anti-CD22 monoclonal antibody, epratuzumab. This antibody has previously been studied conjugated to both iodine-131 and yttrium-90 in the treatment of

A number of mechanisms of action for rituximab have been proposed,includingantibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, induction of apoptosis, recruitment of effector cells, and elaboration of cytokines

Unfortunately, even with the high response rates achieved by rituximab relapse is inevitable. With traditional chemotherapeutic regimens, retreatment using the same or similar agents results in lower response rates, and the duration of

Monoclonal antibody therapy has proven to be expensive, and, therefore, it is important to compare the cost-efficacy of a drug such as rituximab with other standard therapies for low-grade lymphoma. Two abstracts presented at the 1998 ASH

One important future direction for rituximab (Rituxan) is to expand its therapeutic role into other CD-positive disorders. Rituximab induces responses in up to one-third of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma

At the 1999 ASH meeting, Vose et al (abstract #387) analyzed the overall multicenter experience with iodine-131 tositumomab in 179 patients as a function of histologic subtype. The overall response rate was 81%, with 39% CRs . The median time to progression for responders was 13 months, with a median duration of response of 11 months, although the median duration of CRs was 57 months. The response rates for the follicular small cleaved cell NHL and follicular mixed (follicular grades I and II) were similar (83% and 78%, respectively), as were the CR rates (38% and 39%, respectively). These histologies have shown similar responses to various chemotherapy regimens in most studies.

Mucosa-associated lymphoid tissue (MALT) lymphomas account for only 5% of NHLs, and yet they represent the most common low-grade lymphoma involving the stomach. Gastric MALT lymphomas tend to occur in association with

We are entering an extraordinary era in the treatment of patients with indolent non-Hodgkin’s lymphomas (NHL). Several decades were devoted to expending resources on comparing combinations and permutations of conventional agents, but with no beneficial impact on survival.

The CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) regimen has been the standard approach to patients with advanced-stage intermediate-grade non-Hodgkin’s lymphoma (NHL) for more than 20 years.A randomized comparison between CHOP, m-BACOD (methotrexate, bleomycin, Adriamycin, cyclophosphamide, Oncovin, and dexamethasone).

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).