New technology has made it possible to rapidly develop agents that appear promising as therapy for patients with lymphomas, although clinical trials are still needed to fully characterize the potential for these drugs. The possibilities have expanded to include those with mechanisms of action that appear to be very different from those of classic chemotherapeutic agents, although the eventual downstream targets are still apoptosis and death of the lymphoma cell. For example, based on the excellent experience obtained with the monoclonal antibody, rituximab, scientists have developed newer antibodies that may play an important role in treatment of both B- and T-cell lymphomas. Because of the success of the tyrosine kinase inhibitor imatinib in treatment of chronic myelogenous leukemia, other agents that target critical molecules in oncogenesis and cellular proliferation are also under development, including mTOR, CDK, HDAC, and farnesyl transferase inhibitors. Other drugs include those developed to specifically treat T-Cell lymphomas, and multiple investigators have studied agents that are not so new, but are being used in innovative ways to expand their utility. This review focuses on some of these new agents, with an update from the most recent annual meetings of the American Society of Clinical Oncology and American Society of Clinical Oncology.
Background: What Problems Still Exist?
In the United States, about 70,000 persons a year develop lymphomas, including Hodgkin’s disease and non-Hodgkin’s lymphomas. More than 90% of patients with these malignancies will have a response to initial therapy, most of which are complete responses. However, about 30-40% of patients with aggressive B-cell lymphomas, 10-20% of those with Hodgkin’s lymphomas, and most patients with indolent B-cell and t-cell lymphomas will develop progressive disease, and, except for high-dose therapy followed by stem cell rescue for selected patients with lymphoma, most who receive standard treatments for relapse will eventually develop progressive disease and die. For this reason, newer agents are needed to increase the number of patients who will enter initial remission, with an intent to cure. In lymphoma therapy, as opposed to treatment of many solid tumors, new agents are always studied first in patients with relapsed disease, and, following demonstration that the agents induce responses, investigators attempt to combine these agents with standard treatments, not only to see if response and progression-free rates improve, but also to study potential additive toxicities. Investigators have made many attempts to find new drugs that can improve results obtained with standard chemotherapy regimens in management of all lymphomas, but only rituximab has made a significant impact on lymphoma management in the last 10 to 15 years. However, it appears that some of the new drugs being studied have a chance at improving results within the next few years, and only clinical trials can answer the question of how they should be best used in treatment of lymphomas.
Monoclonal antibodies: Can they improve results obtained with rituximab and chemotherapy?
Recently, a number of monoclonal antibodies have been developed that appear to meet the criteria for tolerable single agents in therapy of lymphomas. These include: galiximab, a humanized antibody that targets CD80, found on most B-cells 1; epratuzumab, an antibody against CD22, now being combined with R-CHOP in trials 2, 3; SGN40 and SGN30, directed against CD40 and CD30, respectively 4,5; CMC-544, directed against CD22, also containing an added immunotoxin that causes added cytotoxicity 6; mapatumumab, an antibody that is an agonist for Trail-R1, a member of the death receptor family that induces apoptosis when activated 7; and zanolimumab, a potentially important antibody for T-Cell lymphomas, approved in the United states for therapy of cutaneous T-cell lymphomas 8. Of these antibodies, galiximab and epratuzumab have been studied the most, and galiximab is being evaluated in a randomized study that tests rituximab versus rituximab with galiximab for patients with relapsed indolent lymphomas.
Galiximab is a fully humanized antibody, with the parent antibody produced in the macaque: in the original phase 1/11 trial involving 34 patients with relapsed indolent lymphomas, doses up to 50 mg/m2 given weekly for four weeks induced PR in 12% of patients, although about 50% had minor and partial responses 1. In addition, some patients had delayed responses, similar to the experience with rituximab. The drug was subsequently combined with rituximab given at standard doses for four weeks; investigators have reported an overall response rate (ORR) of 64% in 64 patients with relapsed or chemotherapy- refractory follicular lymphomas, with 31% achieving complete response (CR) or CR, unconfirmed (CRu). Forty-three percent of these patients were rituximab-naïve, and the median progression–free survival (PFS) rate was 12 months. This combination is now being compared to single agent rituximab in a large European trial. If response and PFS rates are better with the combination than with rituximab alone, this drug may eventually be combined with rituximab-containing chemotherapy for patients with indolent and aggressive lymphomas.
Epratuzumab has also been found to be an active antibody in therapy of relapsed lymphomas, particularly aggressive lymphomas 2. It was first studied as a single agent, and then combined with rituximab in therapy of lymphomas, and works by activating CD22, via phosphorylation and ADCC activity. In the original phase I/II studies, it induced an overall response rate of 15% in patients with relapsed aggressive lymphomas, and in combination with rituximab, induced an OR in 47% of patients with diffuse large B-cell lymphomas (DLBCL) and 67% in another study that included various histologies. Investigators have recently reported the activity and tolerability of the drug when combined with R-CHOP in treatment of 17 patients with DLBCL: 87% of the patients had a response, with 67% CR and 20% partial response (PR). The median age of the patients in this trial was 63 years, and grade 4 neutropenia occurred in 87%. A phase II trial is ongoing, and if results appear similar to those in the pilot study, the combination may be studied in a phase III randomized trial versus R-CHOP.
Targeted inhibitors: Small molecules with a big future?
The rapid development of targeted inhibitors for treatment of cancer is directly related to technologic events which have made it possible to better understand stoichiometric and molecular attachment of these agents within the proteins that they target, and have made it possible to rationally design drugs which can directly interfere with specific protein function without causing toxicity to cells that do not express or depend upon these proteins for their normal functions. One of the best studied of these is the mTOR (molecular target of rapamycin) inhibitor temsirolimus, also known as CCI-779. This dihydroester of rapamycin was developed by Wyeth laboratories in conjunction with the National Cancer Institute. It binds to the 12 kDa intracellular FK506-binding protein: this subsequent complex binds near the catalytic site of the mTOR kinase and inhibits phosphorylation of targets for mTOR, inhibiting their translation into proteins. Because this pathway has been found important in the proliferation of mantle cell lymphoma (MCL), temsirolimus has been first studied in therapy of this disease, at varying doses 9. In the initial phase I/II study, investigators administered 250 mg of temsirolimus to 34 patients with MCL and obtained 12 PR and 1 CR for an OR rate of 38%. Thrombocytopenia was a dose-limiting factor in this study. However, in a second trial, a dose of only 25 mg was administered, and 12 (44%) of 27 evaluable patients had a response, with 1 CR and 11 PR, with a median PFS of 5.5 months 10. This agent is now being tested in a wide variety of lymphomas, and is being combined with rituximab in some studies.Other small molecules may also have a future in therapy of lymphomas: a histone deacetylase inhibitor, vorinostat has already been approved by the Food and Drug Administration for therapy of cutaneousT-cell lymphomas, and others, including depsipeptide and LBH589, are being evaluated 11, 12, 13, 14. Tifarnib, a methylquinolone derivative that inhibits farnesyl transferase, and forodesine, a purine nucleoside phosphorylase inhibitor, have also entered phase I and II trials 15, 16. These drugs all have the potential for inclusion in therapy for sensitive malignancies, and only clinical trials can determine their value.
Pralatrexate: A new “super methotrexate?”
Investigators at Memorial-Sloan Kettering Cancer Center have recently developed a novel 10-deazaminopterin, pralatrexate, which has a high affinity for the reduced folate carrier, RFC-1 17. This drug is more easily internalized into the cell than are other aminopterin derivatives, and is therefore has bioavailability for susceptible malignancies. Its target, RFC-1, is an oncofetal protein that is preferentially overexpressed on fetal and malignant cells, and is upregulated by a variety of oncogenes, including c-myc and H-ras.
In a recent phase I-II study that treated a variety of relapsed and chemotherapy-resistant lymphomas, the maximally tolerated dose was 30 mg/m2 given weekly 16. Doses were administered for six weeks, with one week of rest. Forty-two of 54 patients were evaluable in a presentation at ASH, 2006: 6 patients had CR, and 6 had PR, for an OR rate of 28%. Patients with T-cell and B-cell responded: although only 2 with B-cell lymphomas responded with a PR, the OR rate for those with T-cell lymphomas was 45%. Twenty-two of the 30 patients with T-cell disease were evaluable, and CR was obtained in 6 (27%): 4 others had PR, and 3 of these became PET scan negative. Responses were observed in patients with NK-T cell lymphomas and in patients with resistant disease. This drug is being moved into phase II trials in combination with other drugs, and may become a particularly important treatment for T-cell lymphomas.
Bortezomib: An important drug for mantle cell and other lymphomas
The proteosome is an important group of enzymes that degrade proteins targeted for disposal by cellular mechanisms specific for their target. The drug bortezomib is the first inhibitor of the proteosome to be developed, and is the first of its class to be made available for treatment of cancer. In four independent phase II studies, the drug was found active in treatment of lymphomas, especially follicular and mantle cell lymphomas, and investigators have recently confirmed its activity in MCL in a multi-center trial that included 155 patients with relapsed disease who received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 on 21-day cycles. One hundred and forty-one patients were evaluable for response: the OR rate was 47%, with 8% entering CR and 26% PR. At a median follow-up of 13.4 months, the duration of response for those in response was 9.2 months, and the median time to progression was 6.2 months. Seventeen percent experienced grade 4-5 adverse events, 13% grade 3-4 neuropathy and 11% grade 3-4 thrombocytopenia. Although the OR and time to progression rates were lower in those who had undergone prior stem cell transplant, 27% of these patients had a response and their median duration of response was 9.2 months. This study prompted approval of the drug for commercial use in therapy of relapsed MCL, and investigators are currently investigating the drug in combination with other chemotherapy- and antibody-based regimens for a variety of lymphomas, including R-CHOP for aggressive lymphomas, R-cyclophosphamide-prednisone for indolent lymphomas, and multiple different combinations for MCL.
For treatment of relapsed indolent lymphomas, the drug was combined with rituximab, and studied in two different treatment schedules: in one, the drug was given twice weekly at 1.3 mg/m2 for two weeks, with a week’s rest between cycles, and in the other, the dose was 1.6 mg/m2, given 4 weeks in a row, with a week’s rest between cycles. Response rates were the same in the two arms (57 and 53%, respectively), but the drug was surprizingly tolerated much better in the higher-dose schedule, with less thrombocytopenia and neuropathy, when given less frequently, but at the higher dosing schedule 19. Investigators have also combined the drug in escalating doses with R-CHOP as initial therapy for 20 patients with aggressive B-cell lymphomas, with the maximum dose of bortezomib being 1.3 mg/m2 given on days 1 and 4 of a standard R-CHOP cycle every 21 days 20. They have reported OR and CR rates of 95 and 85%, respectively, with grade 3 peripheral neuropathy in only 5%, and no grade 4 non-hematologic toxicities. In this group of patients, 35% had grade 4 thrombocytopenia or leucopenia, with the former being the dose-limiting factor. The drug is now being studied in combination with R-HyperCVAD at M D Anderson Cancer for MCL and is being investigated as therapy in combination with rituximab and dexamethasone for Waldenstrom’s Macroglobulinemia, among other regimens for other T- and B-cell lymphomas.
Other “new” drugs for therapy of lymphomas
Three other drugs are now being evaluated in the treatment of lymphomas: one of these, bendamustine, has been studied for years in Europe, and is now being combined with other drugs in studies in the United States 21. This drug has both alkylating agent and purine moieties, and is an active agent in a variety of lymphomas, with myelosuppression being the main dose limiting factor. In combination with rituximab, the drug produced an OR rate of 94% in treatment of patients with relapsed indolent B-cell and mantle cell lymphomas, with 41% and 42% CR rates, respectively. Thalidomide, a drug approved for therapy of relapsed myeloma, has been used in combination with rituximab for therapy of relapsed MCL, and a derivative of thalidomide, lenalidomide, also recently approved to treat myeloma, has been reported to induce an 11% CR rate in patients with relapsed CLL: the latter drug is now being explored in therapy of both indolent and aggressive lymphomas 22,23. Finally, vincristine has been incorporated into sphingosomes, and in 29 patients with relapsed Hodgkin’s lymphoma induced an OR rate of 30%: 6 of the 8 responders had had prior stem cell transplant, and the drug was given at 2 mg/m2 with no capping and minimal neuropathy, an advantage that it has over unencapsulated vincristine 24. In a second study that included 119 patients with relapsed or refractory aggressive lymphomas, the drug induced 6% CR and 25% OR rates: response rates were higher (48%) for those with chemotherapy-sensitive disease than they were for those with previously resistant disease 25. In combination with rituximab, the drug induced 23% CR and 56% OR rates, respectively, in patients with relapsed diffuse large B-cell lymphomas, and as initial therapy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for 69 patients with aggressive lymphomas induced CR and OR rates of 97% and 100% 26, 27. In the last of these studies, results were unaffected by age, thrombocytopenia was the dose-limiting factor, and significant sensory neuropathy occurred in only 7% of patients. Although these results are encouraging, further studies are warranted to determine how valuable these drugs and combinations including them will be in comparison with standard therapies.
Conclusion:
With the development of new technologies, investigators now have a wide variety of drugs to study that may ultimately be very important in therapy of lymphomas. Development of antibodies remains an important area of research and development, and investigators hope to improve results with a variety of lymphomas by adding these relatively non-toxic drugs to standard treatments. “Small molecules” that target important pathways in the development or proliferation of malignant cells are being vigorously explored, and investigators hope for rapid approval of the most successful of these. Other agents have been approved by the FDA to treat patients with relatively rare malignancies, including cutaneous T-cell lymphomas and MCL; however, with broader experience, investigators may prove that these drugs can be useful in the front-line setting for a wider variety of lymphomas. Finally, older drugs or their variants have been “rediscovered,” and may become valuable in either the relapsed or front-line setting.
References
1 Friedberg JW, Leonard JP, Younes A, et al. Updated Results from a Phase II Study of Galiximab (Anti-CD80) in Combination with Rituximab for Relapsed or Refractory, Follicular NHL. Blood. 2005;106:685a. Abstract # 2435.
2 Leonard JP, Coleman M, Ketas J, et al. Combination Antibody Therapy With Epratuzumab and Rituximab in Relapsed or Refractory Non-Hodgkin's Lymphoma. J Clin Oncol. 2005; 23:5044-5051.
3 Micallef IN, Kahl BS, Maurer MJ, et al. A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. Cancer. 2006; 107:2826-2832.
4 Advani R, Forero-Torres A, Furman RR, et al. SGN-40 (Anti-huCD40 mAb) Monotherapy Induces Durable Objective Responses in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma: Evidence of Antitumor Activity from a Phase I Study. Blood. 2006;108: Abstratct # 695.
5 Duvic M, Kim Y, Reddy S, et al. Phase II Preliminary Results of SGN-30 (Anti-CD30 mAb) in Patients with CD30+ Lymphoproliferative Disorders. Blood. 2006;108: Abstratct # 2733.
6 Advani A, Giné A, Gisselbrecht C, et al. Preliminary Report of a Phase 1 Study of CMC-544, an Antibody-Targeted Chemotherapy Agent, in Patients with B-Cell Non-Hodgkin’s Lymphoma (NHL). . Blood. 2005; 106:70a. Abstract # 230.
7 Younes A, Vose JM, Zelenetz AD, et al. Results of a Phase 2 Trial of HGS-ETR1 (Agonistic Human Monoclonal Antibody to TRAIL Receptor 1) in Subjects with Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL). Blood. 2005;106:46a. Abstract # 489.
8 d’Amore F, Relander T, Jerkeman M, et al. Zanolimumab, a Fully Human Monoclonal Antibody: Preliminary Results of an Ongoing Clinical Trial in CD4+ Peripheral T-Cell Lymphomas (PTCL). Blood. 2006;108: Abstract # 2723.
9 Witzig TE, Geyer SM, Ghobrial I, et al. Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma. J Clin Oncol. 2005; 23:5347-5356.
10 Ansell SM, Geyer SM, Kurtin PJ, et al. Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group. Proc ASCO. 2006; 24: Abstract # 7532.
11 Duvic M, Kim YH, Kuzel TM, et al. Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Clinical Benefit to Advanced Cutaneous T-Cell Lymphoma Patients: Updated Results of the Phase IIb Multicenter Clinical Trial. . Blood. 2006;108:122a. Abstract # 399.
12 Lerner A, Demierre MF, Whittaker S, et al. Romidepsin (Depsipeptide, FK228) Induces Clinically Significant Responses in Treatment-Refractory CTCL: Interim Report of a Phase II Multicenter Study. Blood. 2006; 108:699a. Abstract # 2468.
13 Piekarz RL, Frye R, Turner M, et al. Phase II Trial of Romidepsin, FK228, in Cutaneous and Peripheral T-Cell Lymphoma: Clinical Activity and Molecular Markers. . Blood. 2006; 108:699a. Abstract # 2469.
14 Prince M, George DJ, Johnstone R, et al. LBH589, a Novel Deacetylase Inhibitor (DACi), Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL). Skin Gene Expression Profiles in the First 24 Hours Related to Clinical Response Following Therapy. Blood. 2006; 108: Abstract # 2715.
15 Witzig TE, Maurer MJ, Johnston PB, et al. Oral Tipifarnib (R115777) Has Single Agent Anti-Tumor Activity in Patients with Relapsed Aggressive Non-Hodgkin Lymphoma (NHL): Results of a Phase II Trial in the University of Iowa/Mayo Clinic Lymphoma SPORE (CA97274). Blood. 2006;108: Abstract # 530.
16 Duvic M, Forero-Torres A, Foss F, et al. Oral Forodesine (Bcx-1777) Is Clinically Active in Refractory Cutaneous T-Cell Lymphoma: Results of a Phase I/II Study. Blood. 2006; 108: Abstract # 2467.
17 O’Connor OA, Hamlin PA, J. Gerecitano, et al. Pralatrexate (PDX) Produces Durable Complete Remissions in Patients with Chemotherapy Resistant Precursor and Peripheral T-Cell Lymphomas: Results of the MSKCC Phase I/II Experience. Blood. 2006; 108: Abstract # 400.
18 Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol. 2006; 24:4867.
19 De Vos J, Haferlach T, Mills K, et al. An international multi-center study to assess the clinical accuracy of the molecular subclassification of leukemia by gene expression profiling. J Clin Oncol. 2006; 24: Abstract # 6522.
20 Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated Chemotherapy With Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab for Untreated Follicular Lymphoma. J Clin Oncol. 2005; 23:5696-5704.
21 Williams ME, Cohen P, Tulpule A, et al. A phase II, multicenter study of bendamustine HCl plus rituximab in relapsed indolent B-cell and mantle-cell non-Hodgkin’s lymphoma (NHL). Proc ASCO. 2006; 24: Abstract # 7528.
22 Kaufmann H, Raderer M, Wöhrer S, et al. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood. 2004;104: 2269.
23 Chanan-Khan AA, Miller KC, DiMiceli L, et al. Results of Phase II Study of Lenalidomide (L) {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). Blood. 2005; 106:135a. Abstract # 447.
24 Fayad L, Romaguera J, Hart S, et al. Report of a phase II study of sphingosomal vincristine (SV) in patients with relapsed or refractory Hodgkin’s disease. J Clin Oncol. 2005; 23: Abstract # 6624.
25 Winter JN. Multiply Relapsed Diffuse, Aggressive Non-Hodgkin s Lymphoma (NHL) Patients Respond to Single Agent Sphingosomal Vincristine. Session Type: Poster Session 524-II. Blood. 2003; 102:638a. Abstract # 2353.
26 Ashcroft AJ, Kaplan LD, Damon LE, Morgan JG, et al. Sphingosomal Vincristine Plus Rituximab for Treatment of Large B-Cell Lymphoma. Session Type: Poster Session 566-I. Blood. 2003; 102:402a. Abstract # 1454.
27 Rodriguez MA, Sarris A, East K, et al. A Phase II Study of Liposomal Vincristine in CHOP with Rituximab for Patients with Untreated Aggressive B-Cell Non-Hodgkin’s Lymphoma (NHL): A Safe and Effective Combination. Blood. 2002; 100:92a. Abstract # 338.
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