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Current Treatment Approaches for Mantle-Cell Lymphoma Thomas E. Witzig From the Mayo Clinic College of Medicine and Mayo Foundation Rochester, MN. Submitted March 15, 2005; accepted July 7, 2005. Supported in part by Grants No. CA97274 and CA25224 from the National Institutes of Health and the National Cancer Institute. Author’s disclosures of potential conflicts of interest are found at the end of this article.

Address reprint requests to Thomas E. Witzig, MD, Mayo Clinic, Stabile 628, 200 First St SW, Rochester, MN 55905; e-mail: [email protected].  2005 by American Society of Clinical Oncology 0732-183X/05/2326-6409/$20.00 DOI: 10.1200/JCO.2005.55.017

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Mantle-cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell non-Hodgkin’s lymphoma. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The cells are characterized as CD20⫹ CD5⫹ CD23⫺ with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. Response to chemotherapy usually results in a tumor response but unmaintained remissions are short and the median survival is 3 to 4 years. The treatment approach to newly diagnosed patients with MCL depends on the patient’s eligibility for stem cell transplantation (SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by SCT or rituximab-HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) followed by observation. The purine nucleoside analogues also have activity as single agents and with rituximab. Unfortunately none of these approaches can definitively cure patients with MCL, and new agents are needed. Recent studies in patients with relapsed MCL have shown substantial antitumor activity of single-agent bortezomib, single-agent temsirolimus, and the combination of thalidomide and rituximab. Studies integrating these novel agents earlier in the disease course or in combination with each other will hopefully produce more durable responses with less toxicity. J Clin Oncol 23:6409-6414.  2005 by American Society of Clinical Oncology INTRODUCTION

Mantle-cell lymphoma (MCL) is a distinct clinical type of B-cell non-Hodgkin’s lymphoma that accounts for approximately 8% of all lymphoma diagnoses. This disorder tends to occur in older adults with a higher incidence in males.1 The immunophenotype of the malignant cells in MCL is typically CD20⫹, CD5⫹, CD10⫺, CD23⫺, light chain restricted, and BCL-1⫹ (B-cell lymphoma 1, also known as cyclin-D1 or CCND1).2,3 Cyclin-D1 overexpression occurs as a result of a translocation of the cyclin-D1 gene on 11q13 to the promoter of the immunoglobulin heavy chain locus on 14q32.4 This translocation can be detected in the tumor cells by classical cytogenetics or fluorescence in situ hybridization (FISH; Fig 1).5-9 Additional genetic and proteomic abnormalities have been de-

scribed10-12 and are discussed in this issue by Pasqual et al. The initial diagnostic evaluation includes computed tomography scans of the chest, abdomen, and pelvis; a CBC; blood chemistries for renal and liver function; and an aspiration and biopsy of the bone marrow. Many patients have circulating lymphoma cells that are detectable by a peripheral blood smear or by flow cytometry.13,14 An excisional lymph node biopsy should be evaluated by an expert hematopathologist with immunophenotyping and cyclin-D1 staining. In routine clinical practice, cytogenetic analysis (classical or FISH) is necessary only in cases in which the cyclin D1 stain is equivocal or the histology or immunophenotype are difficult to interpret, as can occur when the diagnostic tissue is from the blood or a bone 6409

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Fig 1. Results of fluorescence in situ hybridization (FISH). (A) Healthy cell showing two signals each for CCND1 on chromosome 11 (orange) and the IgH gene on chromosome 14 (green). (B) Tumor cells from a patient with mantle-cell lymphoma demonstrating the yellow signal that results from the 11;14 translocation that is characteristic of MCL. (Photograph courtesy of G. Dewald, PhD).

marrow aspirate. Staging tests usually demonstrate advanced stage (III or IV), and involvement of extranodal sites such as the intestinal tract, kidney, bone marrow, and peripheral blood is common. Routine upper and lower endoscopy is not necessary unless the patient has symptoms such as gastrointestinal hemorrhage or pain suggestive of involvement.15 The clinical course of MCL is characterized by a very high overall response rate (ORR) to induction treatment with a relatively short time to progression and a poor overall survival (OS) of approximately 3 to 4 years.1,16-19 There is currently no standard therapy for newly diagnosed or relapsed MCL. Patients with massive splenomegaly often benefit from splenectomy to relieve symptoms and improve blood counts.20,21 Many regimens have been demonstrated to be highly active in producing tumor responses, but relapse typically occurs and patients usually die of their disease. New agents and approaches to MCL are needed and indeed are becoming reality as discussed below. This brief review will discuss each major treatment modality and suggest a treatment strategy based on current data. RITUXIMAB

The anti-CD20 antibody rituximab (R-) has been tested as a single agent for both previously untreated and relapsed MCL. In the study by Ghielmini et al,22 88 patients received four standard doses of rituximab and the response rate at week 12 was 27% with 2% complete responses. Among the 34 patients who were previously untreated, the response rate was 27% with 3% complete response rate.22 Others have demonstrated a somewhat higher response rate for MCL patients of about 33-38%.23,24 Rituximab is generally not adequate as a single-agent for MCL but it is in common use in combination with standard chemotherapy regimens. CHEMOTHERAPY

Although there are many potential induction regimens for MCL, they can be separated into three general catego6410

ries: (1) standard doxorubicin-containing regimens such as R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); (2) intensive combination chemotherapy regimens, including anti-metabolites such as R-HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate); and (3) purine analog–based regimens such as R-FCM (fludarabine, cyclophosphamide, mitoxantrone). Each of these regimens typically produces response rates in the 80% to 95% range. A single-arm phase II study by Howard et al25 treated 40 new MCL patients with R-CHOP and reported a 96% overall and 48% complete response rates. The benefit of R-CHOP was confirmed in a randomized trial in which 122 patients with stage III/IV MCL were randomly assigned to CHOP (n Z 60) or R-CHOP (n Z 62).26 The response rate was 94% versus 75% and the complete response rate 34% versus 7% for R-CHOP and CHOP, respectively. Patients treated with R-CHOP had a longer time to progression, but there was no survival advantage and the majority of patients relapsed within 2 years, such that R-CHOP cannot be considered curative therapy. Romaguera et al27 reported the results of 100 untreated MCL patients treated with R-hyperCVAD. Patients received three cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with 3 cycles of rituximab/methotrexate/cytarabine without transplantation or maintenance. Ninety-seven patients were assessable and 87% went into complete remission. The median follow-up was 40 months and the 3-year failure free survival and OS were 67% and 81%, respectively. Age, beta-2 microglobulin, and gastrointestinal involvement were adverse prognostic factors. For example, if the patient was ⬍ 65 years of age, 78% were free of disease at 3 years compared with 46% if the patient’s age was ⬎ 65. There were 5% toxic deaths, and four additional patients have developed myelodysplastic syndrome (MDS) or acute leukemia after treatment. The purine nucleoside analogs also have single-agent activity in MCL. Studies with fludarabine have shown a 33% to 41% response rate as a single agent28,29 and 63% when combined with cyclophosphamide.30 A recent randomized study demonstrated that rituximab combined with fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) was superior to FCM alone for patients with relapsed MCL.31 2-Chlorodeoxyadenosine (2-CDA) has also shown an 81% response rate as a single agent32 and 100% response rate with a median duration of response of 24 months when combined with mitoxantrone.33 A study of 2-CDA and rituximab for patients with untreated MCL who are not candidates for stem cell transplantation is ongoing in the North Central Cancer Treatment Group. Patients with relapsed MCL had a 54% response rate and 21% complete response rate to 2-CDA with a median time to progression of 5.4 months.34 JOURNAL

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RADIOIMMUNOTHERAPY

There have been limited studies using single-agent radioimmunotherapy (RIT) for patients with relapsed MCL. In a phase I trial of 90Yttrium-ibritumomab tiuxetan, there were 3 patients with relapsed MCL and none responded.35 A trial devoted specifically to patients with relapsed MCL demonstrated a 33% (five of 15) response rate to 90 Yttrium-ibritumomab tiuxetan.36 The reported response to RIT (90Y-ibritumomab or 131I-tositumomab) as single agents is similar to rituximab. Current approaches are now combining RIT with chemotherapy at the time of induction. For example, the Eastern Cooperative Oncology Group recently completed a phase II trial that delivered R-CHOP ⫻ 4 cycles followed by a standard dose of 90 Yttrium-ibritumomab tiuxetan in the first remission. Another strategy is using 131Iodine-tositumomab as initial treatment followed by R-CHOP.36a These approaches of combining RIT and chemotherapy seem to be safe; whether they will produce a longer time to progression or survival than observed with R-CHOP alone is yet to be determined. TRANSPLANTATION

High-dose therapy with stem cell transplantation (SCT) has been studied extensively in MCL.37-45 These studies fall into several categories: standard autologous or allogeneic SCT, autologous SCT with rituximab used as part of the SCT conditioning, autologous SCT with RIT as part of the preparative regimen, and reduced-intensity allogeneic SCT. There has been only one trial that randomly assigned patients who had responded with a complete or partial remission after induction chemotherapy to autologous SCT or interferon maintenance.43 Two hundred sixty-nine patients were enrolled, but only 122 were assessable. In patients receiving SCT, the median progression-free survival rate was 39 months compared with 17 months in the interferon arm, with 3-year progressionfree survival rates of 54% and 25% for the SCT and interferon arms, respectively (P Z .01). In subset analysis, patients who underwent transplantation in complete remission received greater relative benefit from the transplant maneuver. At a median follow-up of 34 months, the 2-year survival probability with SCT was 86% compared with 82% with interferon (P Z NS). The survival curves did not show a plateau for either treatment arm. Other trials using SCT generally have been small and retrospective, but they do provide data useful in making decisions about patient management. Lefrere et al39 recently reported a median survival of more than 6 years with a median progression-free survival of 51 months in patients receiving autologous SCT for MCL in first complete remission. Approaches to improve the preparative regimen for autologous SCT include adding rituximab

or a radioimmunoconjugate. Mangel et al41 treated 20 patients with new MCL with CHOP followed by stem cell mobilization with rituximab. Patients then underwent standard autologous SCT with chemotherapy conditioning followed by rituximab maintenance (rituximab ⫻ 4 doses at 8 and 24 weeks post-SCT). The progressionfree survival at 3 years was 89% for SCT compared with 29% for matched historical controls; OS at 3 years was 88% and 65%, respectively. Gianni et al46 also used rituximab as part of the preparative regimen for autologous stem cell collection, but did not use rituximab maintenance. They treated 28 patients, and 24 remain in complete remission with a median follow-up of 35 months. These results were superior to a matched control group. Another approach is to use RIT as part of the preparative regimen. This approach was pioneered for MCL by Gopal et al44 using high-dose 131I-tositumomab, etoposide, cyclophosphamide with stem cell support in 16 patients with relapsed MCL. The response rate was 100% with 91% complete responses; 93% survival at 3 years and 61% of patients remain progression free at 3 years. There have been no treatment-related deaths. Other studies using 90Yttrium-ibritumomab tiuxetan with chemotherapy and SCT are in progress.47,48 Several reports have included a mix of patients treated with either autologous or allogeneic transplantation. Kasamon et al38 recently reported on 58 MCL patients who had undergone SCT (19 allogeneic and 39 autologous). The estimated median progression-free survival was 43 months for the entire cohort and the actuarial 3-year progression-free survival was 51%. Sixty-four patients underwent transplantation in first complete remission and these patients had a statistically significant, longer progression-free survival than if the transplant were performed at relapse. There was no difference in the progression-free survival between patients who received an allogeneic versus an autologous SCT. Patients failing to benefit from an autologous SCT underwent successful salvage treatment with allogeneic SCT using reduced-intensity conditioning with fludarabine and total-body irradiation.42 NEW AGENTS FOR MCL

Recent studies have identified new treatment approaches for relapsed MCL. Three groups of agents have shown activity: proteosome inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and thalidomide. Bortezomib is an inhibitor of the intracellular protein degradation pathway known as the proteosome and is United States Food and Drug Administration approved for relapsed multiple myeloma. Studies of bortezomib for relapsed MCL have shown antitumor activity. Goy et al49 treated 33 patients with bortezomib 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. 6411

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Twenty-nine patients were assessable for response and 12 (41%) responded, six with complete response. The median time to progression was not reached with a median follow-up of 9.3 months. O’Connor et al50 used the same schedule of bortezomib in 11 patients with relapsed MCL. Patients were required to have received no more then three prior chemotherapy regimens and to be 3 or more months beyond prior rituximab treatment. Five (50%) of 10 assessable patients responded (one complete remission) with a duration of response ranging from 6 to 19 months. Thalidomide, another agent used predominantly for the treatment of multiple myeloma, has been evaluated in MCL alone and in combination. Kaufmann et al51 recently reported on a study of 16 patients who were treated with rituximab 375 mg/m2 once weekly for four weeks together with thalidomide 200 mg/day orally with a dose escalation to 400 mg/day on day 15. The rationale for this combination was to target the tumor cells with rituximab and the microenvironment with thalidomide. The median time from MCL diagnosis to protocol treatment was 21 months. All patients had previously received CHOP chemotherapy and three had had a prior transplant. However, only three had received rituximab previously, and 50% (8 of 16) had received only one prior therapy. The rituximab/ thalidomide combination produced a high ORR of 81% (13/16) with five complete and eight partial responses. The median time to progression was 20 months, and eight of the 13 responders subsequently relapsed. There were two thromboembolic events. The mTOR kinase regulates mRNA translation by phosphorylation of two critical substrates—eukaryotic initiation factor 4E binding protein and p70S6 kinase. These phosphorylation events enhance translation of cyclin-D1 mRNA into cyclin-D1 protein. Activity of mTOR can be inhibited by rapamycin analogs such as temsirolimus (also known as CCI-779). A recent trial of temsirolimus utilized 250 mg as a flat dose intravenously weekly for a maximum of 12 months.52 Thirty-five patients were accrued of whom 38% responded (one complete and 12 partial remissions). The median time to progression was 6.8 months. The dose-limiting adverse effect in this study population was reversible thrombocytopenia. Ongoing trials are testing lower doses of temsirolimus (25 mg weekly) to learn if these will be better tolerated while maintaining response. It is clear that inhibiting this signal transduction pathway can produce substantial tumor responses in patients with heavily pretreated MCL. CURRENT TREATMENT APPROACHES

On the basis of the generally less-than-satisfactory outcomes with current cytotoxic approaches, consideration should be given to a quality clinical trial as the initial treatment for MCL as well as at relapse. For those who do not wish to participate or for whom a suitable trial is not available, the pre6412

ceding discussion of therapeutic agents provides a framework to recommend a treatment strategy for patients with MCL as of 2005 (Fig 2). Before choosing which regimen to use, the treating physician must take into account the patient’s age, performance status, and other comorbidities and decide whether the patient will ever be a candidate for high-dose therapy with stem cell rescue. If the patient is ⬍ 75 years old and in excellent physical condition, then autologous SCT can be considered a potential option. This influences the initial treatment approach because if stem cell harvest is anticipated, then the use of a purine nucleoside analog as induction should be avoided or limited in the number of cycles. The most commonly used regimens are R-CHOP induction followed by stem cell harvest and SCT in first remission or R-hyperCVAD without transplantation if the patient achieves a complete response. As noted earlier, the results with R-CHOP and autologous SCT in first complete remission are similar to that reported with R-HyperCVAD without SCT. Both approaches can be considered ‘‘aggressive’’ because they are associated with similar treatment-related mortality and risk of MDS. If R-CHOP ⫹ SCT is chosen, one should consider using an investigational preparative regimen for the SCT that includes in vivo purging with rituximab or a radioimmunotherapy agent because these approaches may add efficacy without added toxicity. If the patient is elderly and not a SCT candidate, the use of a rituximab-containing chemotherapy regimen is appropriate. Purine nucleoside analogs with rituximab may be especially useful in the elderly patient population or those who cannot tolerate anthracyclines. Those patients who relapse after these induction regimens should be considered for novel treatment programs or, if the patient had a long time to progression from the New untreated mantle cell lymphoma

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Fig 2. Outline of treatment approaches for patients with mantle-cell lymphoma. Eligible patients should be encouraged to participate in clinical trials at each phase of the disease. R-hyperCVAD, rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete remission; mTOR, mammalian target of rapamycin.

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initial regimen, re-treated with the previously successful therapy. The success of bortezomib, temsirolimus, and thalidomide provides a rationale for combination with conventional therapies in a variety of designs. Indeed, it

is truly an exciting time for MCL research and it is likely that the outcome for this non-Hodgkin’s lymphoma subtype will improve. - - -

Author’s Disclosures of Potential Conflicts of Interest The following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Author Name

Employment

Leadership

Thomas E. Witzig

Consultant

Stock

Honoraria

Research Fund

Testimony

Other

Wyeth Pharmaceuticals (A) Dollar Amount codes:

REFERENCES 1. Andersen NS, Jensen MK, de Nully Brown P, et al: A Danish population-based analysis of 105 mantle cell lymphoma patients: Incidences, clinical features, response, survival and prognostic factors. Eur J Cancer 38:401-408, 2002 2. Kurtin PJ: Mantle cell lymphoma. Adv Anat Pathol 5:376-398, 1998 3. Kurtin PJ, Hobday KS, Ziesmer S, et al: Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol 112: 319-329, 1999 4. Bertoni F, Zucca E, Cotter FE: Molecular basis of mantle cell lymphoma. Br J Haematol 124:130-140, 2004 5. Siebert R, Matthiesen P, Harder S, et al: Application of interphase cytogenetics for the detection of t(11;14)(q13;q32) in mantle cell lymphomas. Ann Oncol 9:519-526, 1998 6. Caraway NP, Gu J, Lin P, et al: The utility of interphase fluorescence in situ hybridization for the detection of the translocation t(11;14) (q13;q32) in the diagnosis of mantle cell lymphoma on fine-needle aspiration specimens. Cancer 105:110-118, 2005 7. Remstein ED, Kurtin PJ, Buno I, et al: Diagnostic utility of fluorescence in situ hybridization in mantle-cell lymphoma. Br J Haematol 110:856-862, 2000 8. Au WY, Gascoyne RD, Viswanatha DS, et al: Cytogenetic analysis in mantle cell lymphoma: A review of 214 cases. Leuk Lymphoma 43:783-791, 2002 9. Bentz JS, Rowe LR, Anderson SR, et al: Rapid detection of the t(11;14) translocation in mantle cell lymphoma by interphase fluorescence in situ hybridization on archival cytopathologic material. Cancer 102:124-131, 2004 10. Rubio-Moscardo F, Climent J, Siebert R, et al: Mantle cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 105:4445-4454, 2005 11. Ghobrial IM, McCormick DJ, Kaufmann SH, et al: Proteomic analysis of mantle cell lymphoma by protein microarray. Blood 105: 3722-3730, 2005

(A) ⬍ $10,000

(B) $10,000-99,999

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12. Schraders M, Pfundt R, Straatman HM, et al: Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide arraybased comparative genomic hybridization. Blood 105:1686-1693, 2005 13. Hanson CA, Kurtin PJ, Katzmann JA, et al: Immunophenotypic analysis of peripheral blood and bone marrow in the staging of B-cell malignant lymphoma. Blood 94:3889-3896, 1999 14. Cohen PL, Kurtin PJ, Donovan KA, et al: Bone marrow and peripheral blood involvement in mantle cell lymphoma. Br J Haematol 101: 302-310, 1998 15. Romaguera JE, Medeiros LJ, Hagemeister FB, et al: Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer 97:586-591, 2003 16. Zucca E, Roggero E, Pinotti G, et al: Patterns of survival in mantle cell lymphoma. Ann Oncol 6:257-262, 1995 17. Bosch F, Lopez-Guillermo A, Campo E, et al: Mantle cell lymphoma: Presenting features, response to therapy, and prognostic factors. Cancer 82:567-575, 1998 18. Fisher RI, Dahlberg S, Nathwani BN, et al: A clinical analysis of two indolent lymphoma entities: Mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): A Southwest Oncology Group study. Blood 85:1075-1082, 1995 19. Samaha H, Dumontet C, Ketterer N, et al: Mantle cell lymphoma: A retrospective study of 121 cases. Leukemia 12:1281-1287, 1998 20. Matutes E, Parry-Jones N, Brito-Babapulle V, et al: The leukemic presentation of mantle-cell lymphoma: Disease features and prognostic factors in 58 patients. Leuk Lymphoma 45: 2007-2015, 2004 21. Yoong Y, Kurtin PJ, Allmer C, et al: Efficacy of splenectomy for patients with mantle cell non-Hodgkin’s lymphoma. Leuk Lymphoma 42: 1235-1241, 2001 22. Ghielmini M, Schmitz S-FH, Cogliatti S, et al: Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: A study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 23:705-711, 2005

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23. 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 24. 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 18:317324, 2000 25. Howard OM, Gribben JG, Neuberg DS, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:12881294, 2002 26. Lenz G, Dreyling M, Hoster E, et al: Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23:1984-1992, 2005 27. Romaguera JE, Fayad L, Rodriguez MA, et al: Rituximab plus hyperCVAD (R-HCVAD) alternating with rituximab plus high-dose methotrexate-cytarabine (R-M/A) in untreated mantle cell lymphoma (MCL): Prolonged follow-up confirms high rates of failure-free survival (FFS) and overall survival (OS). Blood 104, 2004 (abstr 128) 28. Decaudin D, Bosq J, Tertian G, et al: Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas. J Clin Oncol 16: 579-583, 1998 29. Foran JM, Rohatiner AZ, Coiffier B, et al: Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom’s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 17:546-553, 1999 30. Cohen BJ, Moskowitz C, Straus D, et al: Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma 42:1015-1022, 2001

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31. Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064-3071, 2004 32. Inwards D, Brown D, Fonseca R, et al: NCCTG phase II trial of 2-chlorodeoxyadenosine (2-CDA) as initial therapy for mantle cell lymphoma: A well-tolerated treatment with promising activity. Blood 94:660a, 1999 (suppl 1) 33. Rummel MJ, Chow KU, Karakas T, et al: Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin’s lymphoma. Eur J Cancer 38:1739-1746, 2002 34. Inwards DJ, Fonseca R, Kurtin PJ, et al: NCCTG phase II trial of 2-chlorodeoxyadenosine (2-CDA) as therapy for previously treated mantle cell lymphoma: Promising single agent activity limited by brief response duration. Blood 96: 140a, 2000 35. 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 36. Oki Y, Pro B, Delpassand E, et al: A phase II study of Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin) for treatment of patients with relapsed and refractory mantle cell lymphoma (MCL). Blood 104, 2004 (abstr 2632) 36a. Zelenetz AD, Donnelly G, Halaas J, et al: Initial treatment of mantle cell lymphoma with sequential radioimmunotherapy with tositumomab/iodine I131 I-tositumomab followed by CHOP chemotherapy results in a high complete remission rate. Blood 102, 2003 (abstr 1477) 37. Nachbaur D, Greinix HT, Koller E, et al: Long-term results of autologous stem cell transplantation for Hodgkin’s disease (HD) and low-/

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