Hematologic malignancies: New developments and future treatments

Hematologic Malignancies: New Developments and Future Treatments Bruce D. Cheson An increasing number of unique active new chemotherapeutic and biologic agents are currently available for clinical research studies. Nucleoside analogs in development for non-Hodgkin’s lymphoma (NHL) include clofarabine, troxacitabine, and bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with demonstrated activity in NHL. Drugs directed at the cell cycle include flavopiridol and UCN-01. The proteasome plays a pivotal role in cellular protein regulation and activation of NF␬B, which maintains cell viability through the transcription of inhibitors of apoptosis. PS-341 is a specific, selective inhibitor of the 26S proteasome which induces apoptosis and has activity in cell types characterized by overexpression of Bcl-2. Response rates of 50%, including complete remissions, have been reported using this agent in patients with refractory multiple myeloma. Studies are ongoing in NHL and chronic lymphocytic leukemia. G3139, an antisense oligonucleotide, has shown promise in early studies. Rituximab has revolutionized the treatment of NHL. However, other active antibodies are now available, including alemtuzumab, epratuzumab, and Hu1D10. The radioimmunoconjugates 90Y-ibritumomab tiuxetan and 131Itositumomab may also play an important role in the management of NHL. Future therapeutic strategies should involve rational combinations of new chemotherapy drugs, biologic agents, and antisense compounds to increase the cure rate in patients with lymphoma. Semin Oncol 29 (suppl 13):33-45. Copyright 2002, Elsevier Science (USA). All rights reserved.

D

URING THE PAST few decades, results of clinical trials in the non-Hodgkin’s lymphomas (NHLs) have failed to show a major impact on patient survival. Research strategies in indolent NHL have largely focused on comparisons of combinations and permutations of regimens including alkylating agents, with or without an anthracycline or related compound, and nucleoside analogs, with or without interferon. After comparing various combination regimens in aggressive NHL, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) remained the standard.1 Therefore, there is considerable room for improvement in our current therapy. The recognition of distinct molecular targets provides an opportunity to evaluate new drugs with unique mechanisms of action rather than relying on empiric combinations of nonspecific chemotherapy agents. Seminars in Oncology, Vol 29, No 4, Suppl 13 (August), 2002: pp 33-45

NUCLEOSIDE ANALOGS

One of the most popular and active classes of agents are the nucleoside analogs, including fludarabine, cladribine, pentostatin, and the related agent bendamustine. These drugs have shown activity against a wide range of indolent B-cell malignancies, including chronic lymphocytic leukemia (CLL) and indolent NHL. Randomized trials have shown fludarabine to be more effective than other regimens in the treatment of CLL.2 In initial trials with fludarabine in patients with relapsed or refractory indolent NHL, responses were induced in 50% of patients, with 10% to 15% complete remissions (CR).3-5 When fludarabine was used as initial treatment, response rates in patients with follicular lymphoma were 65% with 37% CR.6 However, the median duration of response was only 18 months, with no evidence of cure. Fludarabine induces higher complete and overall response rates than alkylating agent-based regimens with more durable responses, but without a demonstrable prolongation of survival. Fludarabine is also associated with more myelosuppression than alkylating agents, but with similar rates of infection.7,8 Gemcitabine has shown impressive activity in Hodgkin’s disease,9 and somewhat less activity in indolent and aggressive NHL.9-11 Bendamustine is a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with activity seen in CLL, NHL, and multiple myeloma (MM).12 Other nucleoside analogs in development include nelarabine (Compound 506U),13 clofarabine (2-chloro,-2’-fluoro-arabinosyladenine), which has shown activity in patients with CLL and prolymphocytic leukemia,14 and troxacitabine.15 Giles et

From the National Cancer Institute, Clinical Investigations Branch, Bethesda, MD. Dr Cheson is a member of the speakers’ bureau for Berlex Laboratories and IDEC Pharmaceuticals. Address reprint requests to Bruce D. Cheson, MD, Lombardi Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2904-1308$35.00/0 doi:10.1053/sonc.2002.34878 33

34

BRUCE D. CHESON

al recently published the results of the first phase I trial of troxacitabine in 42 patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoid leukemia, or chronic myeloid leukemia.15 The dose-limiting toxicities were mucositis and hand–foot syndrome. There were four CRs in patients with AML (13%), one hematologic improvement in a patient with MDS, and a CR in a patient with chronic myeloid leukemia in blast crisis. Bone marrow hypoplasia occurred in 71% of the patients with AML. Trials are planned with troxacitabine in combination with cytarabine, idarubicin, topotecan, and gemtuzumab ozogamicin (Mylotarg, Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA). ARSENIC TRIOXIDE

In vitro, arsenic trioxide inhibits the growth of a variety of tumor types including myeloid leukemias, myeloma, lymphoid leukemia and lymphoma, and various solid tumors. Arsenicals also induce apoptosis with downregulation of Bcl-2 in CLL and NHL cells at clinically achievable doses.16-18 In the clinic, arsenic trioxide has shown impressive efficacy in acute promyelocytic leukemia.19 However, treatment may be associated with significant toxicities including skin changes with dryness, hyperkeratosis, pruritus, rash, erythema, and hyperpigmentation. Gastrointestinal toxicity includes nausea, vomiting, abdominal pain, anorexia, and stomatitis. Renal and hepatic toxicity and hyperglycemia are also observed. Patients can experience a variety of constitutional symptoms and musculoskeletal complaints including lassitude, fatigue, weight gain, arthralgia, bone pain, myalgia, toothache, and headache. Cardiovascular and neurologic complications may be a particular concern in patients who receive more than a few courses of therapy. Clinical trials in CLL and NHL are ongoing. DNA HYPOMETHYLATION AND HISTONE DEACETYLATION

The process of neoplastic progression is linked to imbalances in DNA methylation. Hypermethylation of gene promoter regions is associated with repression of genes that regulate tumor growth and differentiation. Two currently available hypomethylating agents are 5-azacytidine and 2⬘-deoxy-5-azacytidine (decitabine). These compounds are metabolized intracellularly to triphosphates

and subsequently incorporated into newly synthesized DNA where they directly inhibit DNA synthesis and inhibit the activity of DNA methyltransferase, the enzyme required for 5’-cytosine methylation of CpG dinucleotides. As a result, cytosine methylation is blocked in newly replicated DNA, but not in the DNA of resting or nondividing cells. Inhibition of methylation by 5-azacytidine and decitabine is associated with transcription of genes previously silenced by methylation of promoter region CpG-rich islands, and with cellular phenotypic changes; these effects can occur at concentrations that are too low to directly inhibit DNA synthesis or cause substantial cytotoxicity. Histone acetylation modulates higher-order chromatin structure. Acetylation of lysine tails leads to loosening of DNA– histone contacts, which results in increased accessibility of transcription factors and increased gene expression. Coactivator– histone acetylase complexes promote gene expression, whereas corepressor– histone deacetylase complexes inhibit gene expression. There is potential synergy between DNA methylation inhibition and histone deacetylase inhibition in restoring gene expression silenced by hypermethylation. Histone deacetylase inhibitors induce terminal differentiation in vitro as well as cell-cycle arrest and reversion of the malignant phenotype of a variety of malignancies. Depsipeptide (NSC 630176), a bicyclic peptide originally isolated from Chromobacterium violaceum, strain 968, by Fujisawa Pharmaceutical Co. Ltd. (Ibaraki, Japan), has been shown to be a histone deacetylase inhibitor.20 Incubation of CLL cells with depsipeptide resulted in an increase in BAX with no change in Bcl-2, and a decrease in p27 expression.21 Impressive activity has been noted in patients with T-cell lymphomas, particularly cutaneous T-cell NHL.22 The combined administration of a demethylating agent and a histone deacetylase inhibitor has been shown to be synergistic in reactivating genes that were silenced in cancer cells.23 Such combinations represent a unique strategy that is currently being studied in patients with AML and MDS. CELL CYCLE ACTIVE AGENTS

Progression through the cell cycle is a tightly regulated process controlled by the phosphoryla-

NEW DEVELOPMENTS AND FUTURE TREATMENTS

tion and proteolysis of regulatory proteins including cyclins, cyclin-dependent kinases (CDK), and their inhibitors. Positive regulatory function of the cell cycle is afforded by the p53 gene, pRb, and the p16 (INK4A) family of CDK inhibitors. Protein kinases play a central role in the function, proliferation, growth, transformation, and death of cells. Malignant transformation is associated with a progressive loss of CDK inhibitors and overexpression of cyclins, leading to a growth and proliferation advantage for the malignant cell. An important regulatory checkpoint occurs late in the G1 phase of the cell cycle where CDKs are activated by cyclins to drive cells to the S phase. The D-type cyclins that associate with CDK 4 and 6 to traverse G1, the Rb protein and the p53 protein that regulate G1/S progression, are often mutated in malignancy. Thus, blocking cell cycle progression with CDK inhibitors may lead to growth arrest and apoptosis. Flavopiridol Flavopiridol is a semisynthetic flavone derived from the plant alkaloid rohitukine, isolated from the leaves and stems of Dysoxylum binectarifererum, which is used in India in herbal medicines. Flavopiridol has in vitro activity against cycling as well as noncycling cells. Its antitumor activity may reflect the specific inhibition of cyclins and CDKs, including cyclin D1, which has been implicated in the pathogenesis of mantle cell lymphoma. Flavopiridol induces growth arrest, cytotoxic cell death, and apoptotic changes in a variety of tumor types, including CLL and lymphomas. It also exhibits sequence-specific synergy with fludarabine and cytarabine and other cell cycle active agents. Two trials with flavopiridol in mantle cell lymphoma have been conducted. The first of these was undertaken at The Dana Farber Cancer Institute (Boston, MA) using a 72-hour infusion (M. Shipp, unpublished observations) and activity was minimal. In the National Cancer Institute of Canada trial,24 flavopiridol was administered at a dose of 50 mg/m2 over 1 hour daily for 3 days every 3 weeks. Severe toxicities included diarrhea (N ⫽ 5, including three patients who did not receive appropriate prophylaxis) and fatigue (78% overall, ⬍ 5% grade 4). Hematologic toxicity has primarily been mild to moderate with a few cases of severe neutropenia. A number of patients also experienced thrombosis that was thought to be drug-

35

related. There were three partial responses and 11 patients with stable disease. Thus, in phase II trials using a 1-hour schedule, activity has been observed both in mantle cell lymphoma and CLL where no activity was noted using the longer infusion schedules. Other trials are exploring 1- and 3-hour infusion schedules in CLL and other hematologic diseases and solid tumors. Although this agent has limited potential as monotherapy in the lymphoid malignancies studied thus far, it may have potential in combination with other chemotherapy agents. UCN-01 UCN-01 is an analog of staurosporine isolated from a Streptomyces species. It has been found to inhibit a number of serine/threonine kinases with arrest of cells in G1 and abrogation of the G2/M checkpoint. UCN-01 showed cytotoxic effects in vitro and in vivo against a variety of murine and human malignant cell lines. UCN-01 can induce apoptosis in leukemia cells lacking functional p53 and resistant to apoptosis induced by DNAdamaging agents. Dose-limiting effects include hypoxia, self-limiting hyperglycemia, lactic acidosis with hyperglycemia, nausea and vomiting, and transient elevation of liver transaminases. UCN-01 appears to potentiate the activity of fludarabine25 and a combination of the two drugs in CLL is being studied at the National Cancer Institute. FARNESYL TRANSFERASE INHIBITORS

The family of Ras genes encode proteins which function as molecular switches that regulate diverse signaling pathways involved in cell growth, differentiation, and apoptosis. The first step in the processing involves the enzyme farnesyl transferase. Therefore, farnesyl transferase inhibitors are of interest for clinical trials. In phase I trials activity was seen in AML and MDS using R115777 (Janssen Pharmaceuticals, Titusville, NJ).26 ANGIOGENESIS INHIBITORS

Angiogenesis may play a role in hematologic malignancies such as MM, lymphoma, CLL, MDS, and AML.27,28 New antiangiogenesis agents available for clinical trials include thalidomide and bevacizumab.29,30 Thalidomide has shown interesting activity in refractory MM; however, its role

36

BRUCE D. CHESON

in this disease has not been established in randomized trials.29 Bevacizumab (Genentech, San Francisco, CA) is a monoclonal antibody against vascular endothelial growth factor that has shown activity against a number of solid tumors and is currently being tested in a phase II trial by the Southwest Oncology Group in relapsed/refractory aggressive NHL. PROTEASOME INHIBITORS

The proteasome is a large, multicentric protease complex that degrades proteins that have been conjugated to ubiquitin.31-34 The ubiquitin–proteasome pathway plays a critical role in the degradation of intracellular proteins involved in cell cycle control, transcription factor activation, apoptosis, cell trafficking, and tumor growth through an ATP-dependent process. Some of the proteins that undergo the degradation include the cyclins and CDK inhibitors, as well as I␬B. Proteasome inhibitors induce apoptosis despite cellular accumulation of p21 and p27, and irrespective of p53 status. The proteasome is also required for activation of NF␬B which plays a role in maintaining cell viability through the transcription of inhibitors of apoptosis in response to environmental stress or cytotoxic agents, leading to a form of multidrug resistance.35 In vitro studies have shown marked synergy between the proteasome inhibitor PS-341 and a number of chemotherapy drugs. PS-341 may block activation of NF␬B, thus potentiating the activity of chemotherapy drugs. Because NF␬B can induce drug resistance, this agent may make cells more chemosensitive.36 PS-341 is the first proteasome inhibitor to enter the clinic. This dipeptidyl boronic acid is a specific and selective inhibitor of the 26S proteasome, a multicatalytic protease central to the degradative pathway.34 PS-341 may also lead to induction of apoptosis and has been found to be active against several tumor lines in in vitro screening models. Enhanced antitumor efficacy was also noted with this compound in combination with other chemotherapy agents and radiation. PS-341 has activity against many tumor types in vitro, and is a poor substrate for the multidrug resistance transporter. It is even active against cell types characterized by overexpression of Bcl-2. PS341 has also been shown to inhibit growth, induce apoptosis, and overcome drug resistance in human

myeloma cells.37 These effects have been shown to be additive with dexamethasone, which is highly active agent against MM. In a recent study, PS-341 induced responses in more than 50% of heavily pretreated patients with MM, including some CRs.38 Increasing evidence suggests that proteasome inhibitors may have a role in the therapy of CLL. First, the ubiquitin–proteasome-dependent protein processing may be altered in CLL cells.38 In addition, proteasome inhibition has been shown to induce apoptosis in CLL lymphocytes at concentrations that do not have such an effect on normal cells. Masdehors et al39 studied cells from 50 patients with previously untreated CLL. When induction of apoptosis of CLL lymphocytes by the proteasome inhibitor lactacystin was compared with that induced in normal lymphocytes, CLL cells were found to be significantly more sensitive. Furthermore, lactacystin sensitized chemoresistant and radioresistant CLL cells to apoptosis induced by TNF-␣.40 CLL cells appear to be more sensitive to inhibition of proteasome function than normal lymphocytes.41 Proteasome inhibition also induces DNA fragmentation and apoptosis of CLL lymphocytes resistant to glucocorticoids.42 In a phase I trial in patients with hematologic malignancies, PS-341 was administered as a twiceweekly bolus injection for 4 consecutive weeks followed by a 2-week rest period.43 At the time of the preliminary publication, three patients had been treated at each of the first three dose levels; most of these patients were heavily pretreated. This study included patients with refractory anemia with excess blasts, Hodgkin’s disease (N ⫽ 2), NHL (N ⫽ 3), and MM (N ⫽ 3). Although the maximum tolerated dose had not yet been reached, two of the patients with MM experienced a major response with more than 50% decreases in IgG levels and normal numbers of bone marrow plasma cells. Toxicities have included neuropathy, fatigue, gastrointestinal symptoms, and thrombocytopenia. BIOLOGICAL AGENTS

The introduction of new and active biological agents has revolutionized our approach to the treatment of NHL. The first to be widely tested was alpha-interferon (IFN), which has modest activity in the treatment of patients with low-grade NHL.44-46 In a phase III study from the Groupe

NEW DEVELOPMENTS AND FUTURE TREATMENTS

d’Etude Lymphomes Folliculaire,47 242 evaluable patients with follicular NHL and a high tumor burden were randomized to treatment with doxorubicin, cyclophosphamide, teniposide, and prednisone for 1 year, either alone or with concurrent IFN, continued to 18 months. The group that received IFN experienced a superior response rate (85% v 69%), event-free survival (34 months v 19 months) and overall survival at 3 years (86% v 69%).48 However, at least nine other randomized trials evaluating IFN during induction,49 maintenance,50-52 or in both settings,53-56 have been reported, with inconsistent results. To resolve the controversy, Rohatiner et al57 conducted a metaanalysis based on 1,671 newly diagnosed patients from the randomized IFN trials. In five studies, the chemotherapy was considered to be less intensive, defined as not including an anthracycline or anthracene agent.52-56 In these studies, there was no evidence of any benefit from IFN. In contrast, the results of the analysis of the four trials of more intensive treatment did show an advantage for IFN.48-51 Whereas there was no improvement in the response rate when IFN was added to chemotherapy, time to disease progression was prolonged, with a significant survival advantage in favor of the IFN arms; 14% at 5 years and 22% at 8 years, although this benefit was seen only when the analysis was limited to responding patients. However, following publication of that metaanalysis, Fisher et al58 reported their study of 571 previously untreated patients with stage III or IV low-grade NHL who received a minimum of six courses of ProMACE-MOPP chemotherapy (prednisone/methotrexate/doxorubicin/cyclophosphamide/etoposide/mustargen/vincristine/prednisone/ procarbarzine), with involved-field radiation to convert a partial response with a negative bone marrow to a CR. Responding patients were randomized to IFN for 2 years or observation. There were no differences in progression-free or overall survivals. The problems encountered in comparing the various trials include that they differ in eligible histologies, patient risk factors, interferon type and dose, schedule, whether the agent was administered to all patients or only to the responders, and the percentage of patients actually able to complete the full course of IFN therapy. Unfortunately, these studies were all initiated before pub-

37

lication of the International NHL Prognostic Index,59 which permits comparison of prognostic groups among studies. The role of IFN in the treatment of NHL remains controversial and its future will depend on whether it interacts favorably with the new chemotherapeutic, antiangiogenic, and biological agents currently in development. MONOCLONAL ANTIBODIES

A growing number of monoclonal antibodies, immunotoxins, and radioimmunoconjugates are being evaluated for the treatment of B-cell malignancies (Table 1). Rituximab Rituximab is a chimeric IgG1 anti-CD20 monoclonal antibody that was genetically engineered in 1990 at IDEC Pharmaceuticals (San Diego, CA). This antibody showed excellent B-cell– depleting properties with no toxicity in preclinical animal models. In 1997, rituximab became the first monoclonal antibody approved by the US Food and Drug Administration for the treatment of a human malignancy, relapsed/refractory follicular/ low-grade NHL. The efficacy of rituximab against follicular/low-grade NHL is well established (Table 2).60-67 Rituximab binds with high affinity to CD20 present on the surface of most normal and malignant B cells. Proposed mechanisms of action include antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, induction of apoptosis, recruitment of effector cells, and elaboration of cytokines.68 Rituximab downregulates

Table 1. Monoclonal Antibodies and Radioimmunoconjugates for Non-Hodgkin’s Lymphoma Antibody Rituximab (Rituxan, MabThera) Alemtuzumab (Campath, MabCampath) Epratuzumab Hu-1D10 (apoltuzimab) Bevacizumab Tositumomab Ibritumomab Lym 1

Antigen

Conjugate

CD20

None

CD52 CD22 HLA-DR VEGF CD20 CD20 HLA-DR

None None, None None 131 I 90 Y 131 I

131

I,

90

Y

38

BRUCE D. CHESON

Table 2. Response of Follicular/Low-Grade Non-Hodgkin’s Lymphoma Study

No. of Patients

Prior Therapy

CR (%)

RR (%)

Median TTP (mos)

Maloney et al60* Maloney et al61 McLaughlin et al62 Piro et al63† Foran et al64 Davis et al65‡ Colombat et al66 Hainsworth et al67

15 37 166 37 70 31 50 41

yes yes yes yes yes yes no no

0 6 6 14 3 3 20 5

33 46 48 43 46 39 73 54

6.4 10.2 13.0 7.7⫹ 11.0 8.1 12 NR

Abbreviations: RR, response rate; CR, complete response; NR, not reached; TTP, time to progression. * Phase I. † 8 weekly infusions. ‡ Bulky disease.

Bcl-2 expression in some NHL cell lines through an IL-10 – dependent autocrine loop, which may reflect a decrease in STAT3 (signal transducer and activator of transcription-3) activation.69 In phase I trials, rituximab was administered at doses ranging from 10 to 500 mg/m2 as a single dose, then at 125 to 375 mg/m2 weekly for 4 weeks. No maximum tolerated dose was identified.60-70 Treatment-related adverse events included fever, chills, nausea, vomiting, urticaria, orthostatic hypotension, and bronchospasm, which occurred mostly during the infusion. Peripheral blood B cells were rapidly depleted but recovered within 6 months. Responses were noted in 40% of patients with a low-grade histology. The schedule of 375 mg/m2 weekly for 4 weeks was selected for subsequent testing, based on drug availability and because that schedule could be delivered on an outpatient basis. The first phase II multicenter trial included 37 patients who had relapsed after a median of two prior regimens.61 They were treated with 375 mg/m2 for 4 consecutive weeks. The response rate was 46%, including 6% CRs. Median time to progression for responders was 10.2 months, with a median duration of response of 8.2 months. The subsequent pivotal phase II multicenter trial was conducted in 166 patients with relapsed or refractory follicular/low-grade NHL, with a median of three prior regimens (range, 1 to 10). Forty-five patients were resistant to their most recent chemotherapy, and 22 were resistant to all prior treatments. Histologies were mostly follicular grades I and II, but 10 patients had follicular grade III

NHL, and 33 had small lymphocytic lymphoma.62 The overall response rate was 48%, including 6% CRs lasting a median of about 1 year. Adverse events occurred primarily during the initial infusion and included transient nausea, fever, bronchospasm, rash, hypotension, and pruritus.62 The use of rituximab for the retreatment of patients who had failed prior therapy with this agent was successful in 38% of patients treated. It was interesting that the duration of response and time to progression were extended following retreatment with rituximab (15⫹ months duration of response, 16.7⫹ months time to progression after retreatment; 9.8 months duration of response, 12.4 months time to progression after prior treatment).71 The role of rituximab in previously untreated patients is unclear. Colombat et al66 published the French experience involving 50 patients who had low-risk follicular NHL. The overall response rate was 73%, including 20% CRs and 6% unconfirmed CRs.72 Of those patients whose tumors were PCRpositive for the Bcl-2 rearrangement before therapy, 57% became negative in the peripheral blood after treatment and 31% became negative in the bone marrow. Unfortunately, the duration of response was disappointing at about 1 year. Hainsworth et al67 studied 41 previously untreated patients (39% small lymphocytic lymphoma, 39% grade I, 27% grade II, 21% stage II, 32% stage III, 44% stage IV NHL). Patients who responded to the initial course of therapy received repeated 4-week courses at 6-month intervals. After 6 weeks, the response rate was 54% with 5% CRs;

NEW DEVELOPMENTS AND FUTURE TREATMENTS

but this increased to 64% and 15% at 6 months before maintenance therapy. Response rates were similar in the SLL and follicular histologies. With a median follow-up of only 8 months, the actuarial 1-year progression-free survival was 77%. Increasing dose intensity. Increasing the dose or dose intensity of rituximab has been explored, including 8 instead of 4 weekly infusions, thriceweekly administration, or intensified dosing.63,73,74 No clear improvement in patient outcome has been reported. Whether consolidation courses are beneficial is an important clinical question.67 Rituximab and chemotherapy combinations. Czuczman et al75 first published a study of 40 patients with indolent NHL, 31 of whom were previously untreated, who received CHOP plus rituximab. The response rate was 100% with 58% CRs. Median duration of response and time to progression have still not been reached at 45.8⫹ and 47.2⫹ months, respectively. Almost 50% of the patients were still in remission from 36⫹ to 54.5⫹ months. Of interest was that seven of the eight patients tested became PCR-negative both in blood and bone marrow; six of these patients remained in CR. To confirm these promising results, the Southwest Oncology Group and Cancer and Leukemia Group B are comparing CHOP with CHOP plus rituximab, with CHOP followed by 131I tositumomab (Bexxar, Coulter Pharmaceutical, Inc, San Francisco, CA) in patients with previously untreated follicular and low-grade NHL. Fludarabine has also been combined with rituximab in indolent NHL with an overall response rate of 93% which included 80% CRs.76 The combination of bendamustine, mitoxantrone, and rituximab has shown promising activity with a response rate of 95% (including 35% CRs) in heavily pretreated patients.77 Further studies with the combination of bendamustine/ rituximab are needed to define the role of this “new” drug in the treatment of indolent lymphomas. Rituximab also has single-agent activity in aggressive NHL.78 In the first phase III trial, Coiffier et al of the Groupe d’e´tude des lymphomes de l⬘adulte79 randomized 399 patients between the ages of 60 and 80 years with diffuse large B-cell NHL to either CHOP or CHOP plus rituximab. Rituximab was administered on day 1 of each of the eight cycles. In the final analysis, the CR/ unconfirmed CR rate, the 24-month projected

39

progression-free survival, and the overall survival were superior with the combined modality approach. However, at 3 years, the difference between the two curves is only about 10% and decreasing.79 Therefore, longer follow-up is clearly required to determine if the differences will persist. The addition of rituximab did not add to the immediate toxicity of CHOP with the exception of grade 3/4 antibody-related infusion reactions in 9% of patients. A US Intergroup trial recently completed randomization of more than 630 patients onto a similar comparison of CHOP versus CHOP plus rituximab in patients over the age of 60 years, with a secondary randomization, following response, to observation or further antibody therapy. Hopefully, the results of this study will confirm the French observations, leading to a change in our approach to these patients. Combinations with other biological agents. Rituximab has also been combined with a number of biologicals. Davis et al80 combined IFN with rituximab in 38 patients with relapsed/refractory follicular/low-grade NHL. The overall response rate was comparable to single-agent rituximab, but the median time to progression was 25.2 months. Kimby et al81 presented preliminary results from a randomized phase II trial in 125 patients, almost two thirds of whom had not received prior therapy. They were first treated with 4-weekly infusions of rituximab; patients with a partial or minor response were randomized to receive either a second cycle of the antibody or IFN for 6 weeks in combination with a second cycle of the antibody. The response rate to the initial course of rituximab was 57% with 12% CRs. The response rate after the second cycle of antibody was 76% (11% CR), compared with 100% (54% CR) in patients who received IFN and rituximab. Brief partial remissions have been reported in about 13% of patients treated with rituximab in CLL, with no CRs (Table 3).61-63,84-87 This low response rate may be related to the dim expression of the CD20 antigen on CLL cells. Attempts to improve on the response rate with increased dose or frequency of administration have not been impressive.74,88 In vitro data suggest that the antibody may sensitize malignant lymphocytes to the effects of subsequent chemotherapy. Byrd et al89 reported their experience in a trial from the Cancer and

40

BRUCE D. CHESON

Table 3. Rituximab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study

No. of Patients

Prior Therapy

CR (%)

RR (%)

Maloney et al61 McLaughlin et al62 Nguyen et al84 Piro et al63* Winkler et al85 Foran et al86 Byrd et al73† O’Brien et al74‡ Hainsworth et al67

3 33 15 7 9 29 33 40 15

yes yes yes yes yes yes yes yes no

0 0 0 0 0 0 3 0 NA

0 13 7 14 11 14 45 36 57

Abbreviation: CR, complete response; PR, partial response; NA, not available. * Eight infusions. † Three times weekly. ‡ Phase I dose escalation.

Leukemia Group B, which was a randomized phase II study in which fludarabine and rituximab were administered either concurrently or sequentially. The concurrent regimen induced higher complete (47% v 28%) and overall (90% v 77%) response rates with promising progression-free and overall survival data, although with short follow-up. Greater neutropenia was observed with concurrent therapy, for reasons that are not understood. The concurrent regimen is being considered as one arm of a phase III comparison against fludarabine, with a third arm to be determined. A similar trial using bendamustine instead of fludarabine is being considered in Europe. Other Monoclonal Antibodies Other monoclonal antibodies in development for indolent NHL include alemtuzumab (Campath, ILEX Oncology, Cambridge, MA), a human IgG1 monoclonal antibody directed against the CD52 antigen present on most normal and malignant B and T cells. This antibody is effective in the treatment of cutaneous T-cell lymphoma,90 T-prolymphocytic leukemia,91 and CLL.92 Unfortunately, its activity in indolent NHL has been limited, with 14% partial responses,90 which may reflect its diminished activity in the setting of bulky lymphadenopathy. Combinations with fludarabine are being developed.93 Epratuzumab (Amgen Inc, Thousand Oaks,

CA), a humanized monoclonal antibody directed against CD22 on B-cells, has activity in indolent and aggressive NHL.94,95 Hu1D10 is a humanized antibody directed against an epitope of HLA-DR and has shown activity and excellent tolerability in early studies.96 An ongoing phase I trial at the National Cancer Institute is combining Hu1D10 with rituximab. Radioimmunoconjugates 131

I-Tositumomab. 131I-tositumomab consists of an anti-CD20 monoclonal antibody (B1) bound to 131 I. The isotope primarily emits gamma particles, and dosimetry is required to provide the correct infused dose (mCi) to deliver the desired absorbed therapeutic total body dose (cGy). The pilot study included 53 patients who had received a median of three prior regimens, with an overall response rate of 71% including 38% CRs, and a median progression-free survival of 12 months; 20.3 months for the complete responders.97,98 In a follow-up phase II trial, 47 patients with relapsed or refractory low-grade or transformed lymphomas were treated with tositumomab with an overall response rate of 57% and CR rate of 32%.99 The multicenter pivotal trial included 60 patients with a median of four prior regimens.100 Responses were induced in 65% (81% in those with a low-grade, [primarily follicular] histology) of patients, including 20% CRs. Response was found to correlate with histology, tumor burden, prior radiotherapy, and the number of prior therapies. Importantly, in 53% of patients, the response duration was longer than that observed with the last chemotherapy, which is an unusual observation in therapy for follicular NHL.101 The median duration of response of 6.5 months was also significantly longer than to the last therapy (3.4 months), and the median duration of response for the complete responders was not reached at a median follow-up of 47⫹ months, compared with 6.1 months for the patients’ last therapy. Kaminski et al102 reported on 76 previously untreated patients with follicular lymphoma of whom 97% achieved a response, with a CR in 76%. Further follow-up is needed to better assess the duration of response. These patients had less hematologic toxicity but a higher incidence of flulike symptoms and human anti-mouse antibodies

NEW DEVELOPMENTS AND FUTURE TREATMENTS

(65%) than had been observed in studies involving previously treated patients. A number of approaches are under investigation to improve the activity of 131I-tositumomab including repeated courses,98 dose escalation requiring stem cell support,103 and sequencing with chemotherapy. 90 Y-Ibritumomab tiuxetan. 90Y-ibritumomab tiuxetan (Zevalin, IDEC Pharmaceuticals, San Diego, CA) consists of the murine source antibody for rituximab covalently bound to tiuxetan, which stably chelates 90Y. 90Y differs from 131I; it is a beta emitter and this has a longer path length than 131I. Unlike 131I, 90Y cannot be used for imaging; 111In is therefore used instead. In phase I/II studies, patients with a low-grade histology had an overall response of 82% with 26% CRs.104 To better clarify the role of the radioisotope, a subsequent phase III trial was conducted with 143 patients with relapsed CD20-positive NHL (small lymphocytic, follicular, and transformed) who were randomized to receive either rituximab or 90Y-ibritumomab tiuxetan.105 The two treatment groups were similar with respect to known prognostic factors. 90Yibritumomab tiuxetan was associated with 32% grade 4 neutropenia, although only 7% required hospitalization for infection. Grade 4 thrombocytopenia occurred in 5% of patients. 90Y-ibritumomab tiuxetan was more active than rituximab, with an overall response rate of 80% compared with 56% for rituximab (P ⫽ .002). The CR/unconfirmed CR rate with the radioimmunoconjugate was 34%, and 20% with the unconjugated antibody. Surprisingly, no difference was seen in the median response durations (13.8⫹ and 15.5⫹ months). Based on these data, 90Y- ibritumomab tiuxetan was approved by the US Food and Drug Administration for the treatment of rituximab-refractory, follicular low-grade NHL and transformed NHL. Radioimmunoconjugates in rituximab-refractory patients. Both 90Y-ibritumomab tiuxetan and 131Itositumomab appear to be highly effective in patients who have failed rituximab therapy. Witzig et al106 reported on 54 patients refractory to rituximab treated with 131I-tositumomab. The overall response rate was 54% with 15% CRs, and the median duration of response (7.7⫹ months) compared favorably with that following the prior chemotherapy (6.5 months). Median time to progression had not been reached at the time of reporting. Toxicities included a median absolute neutrophil

41

count nadir of 700/mm3 and a platelets nadir of 50,000/mm3. Horning et al107 treated 21 patients with 131I-tositumomab, most of whom had follicular grade I or II NHL. The overall response rate was 57% with 14% CRs, with a median response duration of 16 months. Median times to progression for all patients and for responding patients were 6 months and 19 months, respectively. Median nadir for neutrophils was 1,200/mm3, and for platelets, 90,000/mm3. Further studies are needed to better define the role of 131I-tositumomab and 90Y-ibritumomab tiuxetan. Whether one or the other would better serve a particular subpopulation has yet to be determined. Furthermore, longer follow-up is needed to assess the impact on overall survival and the long-term adverse effects, including secondary malignancies and MDS. It appears that chemotherapy can be delivered safely and effectively following radioimmunoconjugate therapy.108,109 Antisense Oligonucleotides The Bcl-2 protein results from the t(14;18) translocation commonly found in NHL and is associated with inhibition of apoptosis. Attempts to downregulate Bcl-2 have led to the development of antisense Bcl-2 oligonucleotides. Waters et al110 published results of a phase I trial of a Bcl-2 antisense compound (G3139) in 17 patients with relapsed or refractory indolent NHL. The reduction in Bcl-2 protein that was achieved correlated with response, with one CR and two minor responses. The drug was relatively well tolerated; dose-limiting toxicities included thrombocytopenia, hypotension, fever, and asthenia. This agent will probably have its greatest effect by sensitizing tumor cells to other therapies. A randomized, phase III trial is ongoing in purine analog relapsed or refractory CLL in which patients are treated with fludarabine and cyclophosphamide with or without G3139. CONCLUSIONS

We are clearly in a transition period in the management of patients with CLL and indolent NHL. New technologies such as DNA microarray analysis, initially used for diffuse large B-cell lymphomas,111 are currently being evaluated for lowgrade lymphomas and CLL.112 This technology will allow us to classify patients more accurately

42

BRUCE D. CHESON

into prognostic subgroups and to direct more targeted therapies. New, unique chemotherapy agents, antisense compounds and, importantly, active monoclonal antibodies and radioimmunoconjugates have ushered in a new era of therapeutics. A number of interesting clinical trials are in development with newer chemotherapy agents. For example, bendamustine is currently being compared with fludarabine and will be compared with chlorambucil in CLL. In indolent NHL, CHOP plus rituximab will be compared with bendamustine plus rituximab. Bendamustine plus prednisone, with or without thalidomide, is a study of interest in MM. The encouraging data with bendamustine in hematologic malignancies need to be confirmed in large randomized trials to define the role and the optimal use of this promising “new” agent. It will be important to develop combinations of novel agents with other chemotherapy drugs, antiangiogenesis agents, antisense compounds and biological therapies, such as rituximab, alemtuzumab, epratuzumab, Hu1D10, and others. Increasing patient accrual onto clinical trials addressing important questions will be critical to continued progress towards increasing the likelihood of cure in patients with lymphoid malignancies. REFERENCES 1. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993 2. Rai KR, Peterson BL, Kolitz J, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000 3. Redman JR, Cabanillas F, Velasquez WS, et al: Phase II trial of fludarabine phosphate in lymphoma: An effective new agent in low-grade lymphoma. J Clin Oncol 10:790-794, 1992 4. Hochster HS, Kim K, Green MD, et al: Activity of fludarabine in previously treated non-Hodgkin’s low-grade lymphoma: Results of an Eastern Cooperative Oncology Group Study. J Clin Oncol 10:28-32, 1992 5. Pigaditou A, Rohatiner AZS, Whelan JS, et al: Fludarabine in low-grade lymphoma. Semin Oncol 20:24-27, 1993 6. Solal-Ce´ligny P, Brice P, Brousse N, et al: Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 14:514-519, 1996 7. Hagenbeek A, Eghbali H, Monfardini S, et al: Fludarabine versus conventional CVP chemotherapy in newly diagnosed patients with stages III and IV low grade malignant

non-Hodgkin’s lymphoma. Preliminary results from a prospective randomized phase III clinical trial in 381 patients. Blood 92:315a, 1998 (suppl 1) (abstr) 8. Klasa R, Meyer R, Shustik C, et al: Fludarabine versus CVP in previously treated patients with progressive low grade non-Hodgkin’s lymphomas (lg-NHL). Proc Am Soc Clin Oncol 18:9a, 1999 (abstr) 9. Santoro A, Bredenfeld H, Devizzi L, et al: Gemcitabine in the treatment of refractory Hodgkin’s disease: Results of a multicenter phase II study. J Clin Oncol 18:2615-2619, 2000 10. Fossa A, Santoro A, Hiddemann W, et al: Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 17:37863792, 1999 11. Dumontet C, Morschhauser F, Solal-Celigny P, et al: Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma. Br J Haematol 113:772-778, 2001 12. Kath R, Blumenstengel K, Fricke HJ, et al: Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol 127:48-54, 2001 13. Gandhi V, Keating M, O’Brien S, et al: Compound GW506U78 in refractory hematologic malignancies: Relationship between cellular pharmacokinetics and clinical response. J Clin Oncol 16:3607-3615, 1998 14. Kozuch P, Ibrahim N, Khuri F, et al: Phase I clinical and pharmacological study of clofarabine. Blood 94:127a, 1999 (suppl 1) (abstr) 15. Giles FJ, Cortes JE, Baker SD, et al: Troxacitabine, a novel dioxalone nucleoside analog, has activity in patients with advanced leukemia. J Clin Oncol 19:762-771, 2001 16. Akao Y, Mizoguchi H, Kojima S, et al: Arsenic induces apoptosis in B-cell leukaemic cell lines in vitro: Activation of caspases and down-regulation of Bcl-2 protein. Br J Haematol 102:1055-1060, 1998 17. Zhu XH, Shen YL, Jing YK, et al: Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91:772-778, 1999 18. Dai J, Weinberg RS, Waxman S, et al: Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 93:268-277, 1999 19. Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in replapsed acute promyelocytic leukemia. J Clin Oncol 19:3852-3860, 2001 20. Nakajima H, Kim YB, Terano H, et al: FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241:126-133, 1998 21. Byrd JC, Shinn C, Ravi R, et al: Depsipeptide (FR901228): A novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 94:1401-1408, 1999 22. Piekarz RL, Robey R, Sandor V, et al: Inhibitor of histone deacetylation, depsipeptide (FR 901228) in the treatment of peripheral and cutaneous T-cell lymphoma: A case report. Blood 98:2865-2868, 2001 23. Cameron EE, Bachman KE, Myohanen S, et al: Synergy of demethylation and histone deacetylase inhibition in the reexpression of genes silenced in cancer. Nat Genet 21:103-107, 1999

NEW DEVELOPMENTS AND FUTURE TREATMENTS

24. Connors JM, Kouroukis C, Belch A, et al: Flavopiridol for mantle cell lymphoma: Moderate activity and frequent disease stabilization. Blood 98:807a, 2001 (abstr) 25. Harvey S, Decker R, Dai Y, et al: Interactions between 2-fluoroadenine 9-␤-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells. Clin Cancer Res 7:320-330, 2001 26. Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase I clinical-laboratory correlative trial. Blood 97:3361-3369, 2001 27. Salven P, Teerenhovi L, Joensuu H: A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma. Blood 90:3167-3172, 1997 28. Molica S, Vitelli G, Levato D, et al: Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br J Haematol 107:605-610, 1999 29. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 30. Smolich BD, Yuen HA, West KA, et al: The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in human myeloid leukemia blasts. Blood 97:14131421, 2001 31. Maki C, Huibregtse J, Howley P: In vivo ubiquination and proteasome-mediated degradation of p53. Cancer Res 56: 2649-2654, 1996 32. Yoshida H, Kitamura K, Tanaka K, et al: Accelerated degradation of PML-retinoic acid receptor ␣ (PML-RAR␣) by all-transretinoic acid in acute promyelocytic leukemia: Possible role of the proteasome pathway. Cancer Res 56:2945-2948, 1996 33. Adams J, Stein R: Novel inhibitors of the proteasome and their therapeutic use in inflammation. Ann Rep Med Chem 31:279-288, 1996 34. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res 59:2615-2622, 1999 35. Beg AA, Baltimore D: An essential role for NF-␬B in preventing TNF-␣-induced cell death. Science 274:782-784, 1996 36. Lin ZP, Boller YC, Amer SM, et al: Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: Involvement of NF-␬B activation in drug resistance. Cancer Res 58:3059-3065, 1998 37. Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071-3076, 2001 38. Richardson PG, Berenson J, Irwin D, et al: Phase II study of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy. Blood 98:774a, 2001 (abstr) 39. Masdehors P, Omura S, Merle-Beral H, et al: Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haemtaol 105:752-757, 1999

43

40. Delic J, Masdehors P, Omura S, et al: The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemoand radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 77: 1103-1107, 1998 41. Masdehors P, Merle-Beral H, Magdelenat H, et al: Ubiquitin-proteasome system and increased susceptibility of B-CLL lymphocytes to apoptotic death activation. Leuk Lymphoma 38:499-504, 2000 42. Chandra J, Niemer I, Gilbreath J, et al: Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemia lymphocytes. Blood 92:4220-4229, 1998 43. Stinchcombe TE, Mitchell BS, Depcik-Smith N, et al: PS-341 is active in multiple myeloma: Preliminary report of a phase I trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies. Blood 96:516a, 2000 (abstr) 44. Merigan TC, Sikora K, Breeden JH, et al: Preliminary observations on the effect of human leukocyte interferon in non-Hodgkin’s lymphoma. N Engl J Med 299:1449-1553, 1978 45. Foon KA, Sherwin SA, Abrams PG, et al: Treatment of advanced non-Hodgkin’s lymphoma with recombinant leukocyte A interferon. N Engl J Med 311:1148-1152, 1984 46. O’Connell MJ, Colgan JP, Oken MM, et al: Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin’s lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study. J Clin Oncol 4:128-136, 1986 47. Solal-Ce´ligny P, Lepage E, Brousse N, et al: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 329:1608-1614, 1993 48. Solal-Ce´ligny P, Lepage E, Brousse N, et al: A doxorubicin-containing regimen with or without interferon alpha-2b for advanced follicular lymphomas: Final analysis of survival and toxicity in the GELF 86 trial. J Clin Oncol 16:2332-2338, 1998 49. Smalley RV, Andersen JW, Hawkins MJ, et al: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med 327:1336-1341, 1992 50. Avile´s A, Duque G, Talavera A, et al: Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymph 20: 495-499, 1996 51. Unterhalt M, Hermann R, Koch P, et al: Long term interferon alpha maintenance prolongs remission duration in advanced low grade lymphomas and is related to the efficacy of initial cytoreductive therapy. Blood 88:453a, 1996 (abstr 1801) 52. Hagenbeek A, Carde P, Meerwaldt JH, et al: Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant nonHodgkin’s lymphoma. J Clin Oncol 16:41-47, 1998 53. Chisesi T, Congiu M, Contu A, et al: Randomized study of chlorambucil (CB) compared to interferon (alfa-2b) in lowgrade non-Hodgkin’s lymphoma: An interim report of a randomized study. Eur J Cancer 27:S31-S33, 1991 54. Price CGA, Rohatiner AZS, Steward W, et al: Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: Preliminary results of a randomized trial in progress. Eur J Cancer 27:S34-S36, 1991 55. Peterson BA, Petroni G, Oken MM, et al: Cyclophos-

44

phamide versus cyclophosphamide plus interferon alfa-2b in follicular low grade lymphomas: A preliminary report of an intergroup trial (CALGB 8691 and EST 7486). Proc Am Soc Clin Oncol 12:366, 1993 (abstr) 56. Arranz R, Garcı´a-Alfonso P, Sobrino P, et al: Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin’s lymphoma: Results from a prospective, multicenter trial with double randomization. J Clin Oncol 16:1538-1546, 1998 57. Rohatiner AZS, Gregory W, Peterson B, et al: A metaanalysis (MA) of randomised trials evaluating the role of interferon (IFN) as treatment for follicular lymphoma (FL). Proc Am Soc Clin Oncol 17:4a, 1998 (abstr) 58. Fisher RI, Dana BW, LeBlanc M, et al: Alpha-interferon consolidation following intensive chemotherapy does not prolong the failure-free survival of patients with low grade nonHodgkin’s lymphoma: results of SWOG-8809, a randomized phase III study. J Clin Oncol 18:2010-2016, 2000 59. Shipp MA, Harrington DP, Anderson JR, et al: Development of a predictive model for aggressive lymphoma: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993 60. Maloney DG, Grillo-Lo´pez AJ, Bodkin DJ, et al: IDECC2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 15:32663274, 1997 61. Maloney DG, Grillo-Lo´pez AJ, White CA, et al: IDECC2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188-2195, 1997 62. McLaughlin P, Grillo-Lo´pez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy of relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998 63. Piro LD, White CA, Grillo-Lo´pez AJ, et al: Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 10:655-661, 1999 64. Foran JM, Gupta RK, Cunningham D, et al: A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 109:81-88, 2000 65. Davis TA, White CA, Grillo-Lo´pez AJ, et al: Singleagent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: Results of a phase II trial of rituximab. J Clin Oncol 17:1851-1857, 1999 66. Colombat P, Salles G, Brousse N, et al: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patents with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 97:101-106, 2001 67. Hainsworth JD, Burris HA III, Morrissey LH, et al: Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin’s lymphoma. Blood 95: 3052-3056, 2000 68. Ansell SM, Tschumper RC, Witzig TE, et al: Chemokine upregulation in response to rituximab in B-cell nonHodgkin’s lymphoma. Blood 94:86a, 1999 (abstr 377) 69. Alas S, Bonavida B: Rituximab inactivates signal transducer and activator of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the inter-

BRUCE D. CHESON

leukin 10 autocrine/paracrine loop and results in down-regulation of bcl-2 and sensitization to cytotoxic drugs. Cancer Res 61:5137-5144, 2001 70. Maloney DG, Liles TM, Czerwinski DK, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994 71. Davis TA, Grillo-Lo´pez AJ, White CA, et al: Final report on the safety and efficacy of retreatment with rituximab for patients with non-Hodgkin’s lymphoma. Blood 94:88a, 1999 (suppl 1) (abstr) 72. Cheson BD, Horning SJ, Coiffier B, et al: Report of an International Workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244-1253, 1999 73. Byrd JC, Murphy T, Howard RS, et al: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19:21532164, 2001 74. O’Brien SM, Kantarjian H, Thomas DA, et al: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165-2170, 2001 75. Czuczman MS, Grillo-Lo´pez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999 76. Czuczman MS, Jonas C, Stephan M, et al: Pilot study of Rituxan in combination with fludarabine chemotherapy in patients with low-grade or follicular non-Hodgkin’s lymphoma. Proc Am Soc Clin Oncol 18:17a, 1999 (abstr) 77. Weide R, Heymanns J, Gores A, et al: Bendamustine, mitoxantrone and rituximab (BMR): A new effective treatment for refractory or relapsed indolent lymphomas. Leuk Lymph 43:327-331, 2002 78. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 79. Coiffier B, Lepage E, Brie`re J, et al: CHOP plus rituximab compared with CHOP chemotherapy in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 346:235-242, 2002 80. Davis TA, Maloney DG, Grillo-Lo´pez AJ, et al: Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res 6:2644-2652, 2000 81. Kimby E, Geisler C, Hagberg H, et al: Rituximab as a single agent and in combination with interferon alfa-2a as treatment of untreated and first-relapse follicular or other lowgrade lymphomas: A randomized phase II study. Blood 96:577a, 2000 (abstr) 82. van der Kolk LE, Grillo-Lo´pez AJ, Baars JW, et al: Treatment of relapsed B-cell non Hodgkin’s lymphoma with a combination of chimeric anti-CD20 monoclonal antibodies (rituximab) and G-CSF: Final report on safety and efficacy. Blood 96:732a, 2000 (abstr) 83. Ansell SM, Witzig TE, Kurtin PJ, et al: Phase I study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin’s lymphoma (NHL). Blood 96:577a, 2000 (abstr) 84. Nguyen DT, Amess JA, Doughty H, et al: IDEC-C2B8

NEW DEVELOPMENTS AND FUTURE TREATMENTS

anti-CD20 (rituximab) immunotherapy in patients with lowgrade non-Hodgkin’s lymphoma and lymphoproliferative disorders: Evaluation of response on 48 patients. Eur J Haematol 62:76-82, 1999 85. Winkler U, Schulz HR, Jensen M, et al: Toxicity and efficacy of the anti-CD20 antibody rituximab (Rituxan) in patients with B-cell chronic lymphocytic leukemia: A phase I/II study. Blood 94:312a, 1999 (suppl 1) (abstr) 86. Foran JM, Rohatiner AZ, Cunningham D, et al: European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 18:317-324, 2000 87. Iadetto M, Bergui L, Ricca I, et al: Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukemia patients. Med Oncol 17:203-210, 2000 88. Byrd JC, Murphy T, Howard RS, et al: Rituximab using a thrice-weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19:21532164, 2001 89. Byrd JC, Peterson BA, Park K, et al: Concurrent rituximab and fludarabine has a higher complete response rate than sequential treatment in untreated chronic lymphocytic leukemia (CLL) patients: Results from CALGB 9712. Blood 98: 772a, 2001 (abstr) ¨ sterborg A, Brittinger G, et al: CAM90. Lundin J, O PATH-1H monoclonal antibody therapy for previously treated low-grade non-Hodgkin’s lymphomas: A phase II multicenter study. J Clin Oncol 16:3257-3263, 1998 91. Pawson R, Dyer MJS, Barge R, et al: Treatment of T-cell prolymphocytic leukemia with human CD52 antibody. J Clin Oncol 15:2667-2672, 1997 92. Keating MJ, Byrd J, Rai K, et al: Multicenter study of CAMPATH-1H in patients with chronic lymphocytic leukemia refractory to fludarabine. Blood 94:705a, 1999 (suppl 1) (abstr) 93. Faderl S, Thomas DA, O’Brien S, et al: An exploratory study of the combination of monoclonal antibodies CAMPATH-1H and rituximab in the treatment of CD52- and CD20-positive chronic lymphoid disorders. Blood 98:365a, 2001 (abstr) 94. Leonard JP, Coleman M, Schuster MW, et al: Epratuzumab, a new anti-CD22, humanized, monoclonal antibody for the therapy of non-Hodgkin’s lymphoma: Phase I/II trial results. Blood 94:92a, 1999 (suppl 1) (abstr) 95. Leonard JP, Coleman M, Chadburn A, et al: Epratuzumab (anti-CD22 humanized monoclonal antibody) is an active and well-tolerated therapy for refractory/relapsed diffuse large B-cell non-Hodgkin’s lymphoma. Blood 96:578a, 2000 (abstr) 96. Link BK, Wang H, Byrd JC, et al: Phase I trial of humanized 1D10 (Hu1D10) monoclonal antibody targeting class II molecules in patients with relapsed lymphoma. Proc Am Soc Clin Oncol 19:24a, 2000 (abstr) 97. Kaminski MS, Zasadny KR, Francis IR, et al: 131I -

45

anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14:1974-1981, 1996 98. Kaminski MS, Estes J, Zasadry KR, et al: Radioimmunotherapy with 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000 99. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/ refractory low-grade and transformed low-grade B-cell nonHodgkin’s lymphomas. J Clin Oncol 18:1316-1323, 2000 100. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of Bexxar (Iodine 131I tositumomab) for chemotherapyrefractory low-grade or transformed low-grade B-cell nonHodgkin’s lymphomas. J Clin Oncol 19:3918-3928, 2001 101. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986 102. Kaminski MS, Estes J, Tuck M, et al: Iodine 131I tositumomab for previously untreated follicular lymphoma (FL). Proc Am Soc Clin Oncol 19:5a, 2000 (abstr) 103. Press OW, Eary JF, Gooley T, et al: A phase I/II trial of 131 I-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 96:2934-2942, 200 104. Witzig TE, White CA, Wiseman GA, et al: Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(⫹) B-cell non-Hodgkin’s lymphoma. J Clin Oncol 17:3793-3803, 1999 105. Witzig TE, White CA, Gordon LI, et al: Response to Zevalin is superior to response to rituximab regardless of age and extent of disease. Proc Am Soc Clin Oncol 20:279a, 2001 (abstr) 106. Witzig TE, White CA, Flinn IW, et al: Zevalin radioimmunotherapy of rituximab-refractory follicular nonHodgkin’s lymphoma. Blood 96:507a, 2000 (abstr 2183) 107. Horning SJ, Lucas JB, Younes A, et al: 131I tositumomab for non-Hodgkin’s lymphoma (NHL) patients who progressed after treatment with rituximab: Results of a multicenter phase II study. Blood 96:508a, 2000 (abstr) 108. Kaminski M, Bahm V, Estes J, et al: Tolerance of treatment subsequent to frontline Bexxar (tositumomab and iodine 131I tositumomab) in patients with follicular lymphoma. Blood 98:603a, 2001 (abstr) 109. Ansell SM, Ristow KM, Habermann TM, et al: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with Zevalin for non-Hodgkin’s lymphoma. Blood 98:604a, 2001 (abstr) 110. Waters JS, Webb A, Cunningham D, et al: Phase I and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 18:1809-1811, 2000 111. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503-511, 2000 112. Rosenwald A, Alizadeh AA, Widhopf G, et al: Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194:1639-1647, 2001