Advances in the Treatment of Aggressive Non-Hodgkin’s Lymphoma

<Title_en>Advances in the Treatment of Aggressive Non-Hodgkin’s Lymphoma<Body_en>

A Report from the 2008 Meeting of the American Society of Hematology

Rituxan and Intensive HyperCVAD Chemotherapy for Mantle Cell Lymphoma

Mantle cell lymphoma is a subset of non-Hodgkin’s lymphoma that is characterized by diffuse lymph node involvement, advanced stage of cancer at diagnosis, bone marrow involvement, and lymphoma cancer cells in the blood. More than half of patients with mantle cell lymphoma will respond to initial treatment, but the responses are typically short and patients have an average survival of less than three years from diagnosis. Recent research has focused on intensive treatments including stem cell transplantation.

Researchers from the M. D. Anderson Cancer Center have reported that R (Rituxan® [rituximab])-HyperCVAD alternated with R-MA (methotrexate/cytarabine) improves failure-free survival in patients with newly diagnosed mantle cell lymphoma.1 This study was first reported in the February 1, 2005 issue of the Journal of Clinical Oncology.2 This study involved 79 patients with newly diagnosed mantle cell lymphoma. Patients were treated with Rituxan plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with Rituxan plus high-dose methotrexate-cytarabine. A total of six to eight cycles were administered at 21-day intervals. The median follow-up in 2005 was 40 months. The complete response rate was 87%, and 10% achieved a partial response. The overall three-year survival was 82%, and the three-year failure-free survival was 64%. For patients younger than 65 years, the three-year failure-free survival was 73%. Five patients died of acute toxicity, and four patients developed myelodysplasia/acute myeloid leukemia. The overall treatment-related mortality was 8%. At ASH 2008 the median follow-up of this study was 84 months. The overall survival at seven years was 60%, and the failure-free survival was 43%.

  • Among patients 65 years or younger, the overall survival was 68% and failure-free survival was 52%.
  • Age over 65 years, an elevated serum B2 microglobulin and an elevated LDH were adverse prognostic variables.

The lead investigator of the study, Dr. Jorge Romaguera, noted that survival in this study was generally similar to survival following stem cell transplantation. He went on to say, “There is some disagreement about whether these younger patients should receive a bone marrow transplant as frontline therapy rather than chemotherapy. Our results with chemotherapy are as good as any transplant data. We don’t believe a transplant is necessary as a first treatment in newly diagnosed mantle cell lymphoma.”

The results of this study suggest that intensive chemotherapy effectively delays recurrence in patients with mantle cell lymphoma. The question of stem cell transplantation versus intensive chemotherapy can only be answered in a randomized controlled trial. There are now many effective up-front regimens for mantle cell lymphoma, with and without stem cell support; the optimal approach remains to be determined.

VcR-CVAD for Untreated Mantle Cell Lymphoma

Researchers from the University of Wisconsin treated 30 patients with mantle cell lymphoma with a modified HyperCVAD regimen.3 These authors have previously reported good results with treatment of mantle cell lymphoma with a regimen that omits methotrexate and cytarabine from the HyperCVAD regimen.4 This new regimen adds Velcade® (bortezomib) to the modified R-HyperCVAD regimen with Neupogen® (filgrastim) support followed by Rituxan maintenance. The complete response rate was 77%, with 13% having a partial response. The addition of Velcade appeared to increase the complete response rate from 64% in historical controls to 77% in the current study.

Autologous Stem Cell Transplantation for Mantle Cell Lymphoma

The role of autologous stem cell transplantation in first remission of mantle cell lymphoma has been explored. A recent study compared interferon maintenance to high-dose chemotherapy with an autologous stem cell transplant in patients with mantle cell lymphoma achieving a partial or complete remission to induction therapy.5 This study showed a clear improvement in progression-free survival following autologous stem cell transplants as consolidation therapy. However, overall survival was not improved at a median of 25 months follow-up. This reflects effective salvage therapy with stem cell transplants and probably other newer agents. Thus, it still is not clear if transplants should be used up-front or for salvage therapy for mantle cell lymphoma.

French researchers have also reported that the addition of Rituxan to induction chemotherapy followed by autologous stem cell transplantation improved overall survival of patients with mantle cell lymphoma without added toxicity.6 At ASH 2008 French researchers reported outcomes of 60 patients with mantle cell lymphoma; 49 of these patients received an autograft.7 They observed that R-DHAP (Rituxan, dexamethasone, cytarabine, and cisplatin) was more effective than R-CHOP in producing remissions prior to transplantation. R-CHOP produced complete remissions in 12% of patients compared with 61% for R-DHAP. Forty-seven of the 49 patients who received an autologous transplant were in complete remission. Most transplanted patients received a total body irradiation regimen. The median follow-up of this study was 67 months. The median event-free survival was 83 months and median survival has not been reached. The five-year overall survival was 75%. Retrospective comparison demonstrated that Rituxan improved outcomes. There were no treatment-related deaths in this study. This study suggests that a cytarabine/Rituxan regimen may be better than CHOP for induction in patients with mantle cell lymphoma.

Researchers from Germany have also reported a long-term follow-up of a randomized trial of autologous stem cell transplantation in first remission versus interferon maintenance therapy for patients with newly diagnosed mantle cell lymphoma.8 This study was initiated before Rituxan was available; results were first published in 2005.9 This study showed a clear improvement in progression-free survival following autologous stem cell transplants as consolidation therapy for mantle cell lymphoma. However, overall survival was not improved at a median of 25 months’ follow-up. As in the French trial, this reflected effective salvage therapy with stem cell transplants and probably other newer agents. The median follow-up of this study is now over six years. The median progression-free survival was 3.7 years for the transplant group and 1.6 years for the interferon group. Patients who were in complete remission at the time of transplant had a median response duration of 4.5 years compared with 1.6 years for the interferon group. Median survival after autologous stem cell transplantation was 7.5 years compared with 5.4 years for the interferon group. These authors concluded that dose intensified therapy was warranted for younger patients with mantle cell lymphoma. This study demonstrates the curative potential of high-dose therapy even in the pre-Rituxan era.

Researchers from the M. D. Anderson Cancer Center reported that the use of Rituxan in autologous stem cell transplant regimens for patients in first remission improved outcomes of patients with mantle cell lymphoma compared with historical controls who did not receive Rituxan.10 However, they found no improvement when Rituxan was added to the regimen of patients who had relapsed. Patients who had an upfront transplant in the pre-Rituxan era and those who had transplants with Rituxan had similar two-year progression-free survival rates of approximately 60%. However, there was a plateau of approximately 60% in patients receiving Rituxan while the non-Rituxan group continued to relapse. These authors concluded that Rituxan may be curative for patients transplanted in first remission.

Allogeneic Stem Cell Transplantation for Mantle Cell Lymphoma

There has been significant interest in the use of reduced-intensity allogeneic stem cell transplants for the treatment of patients with mantle cell lymphoma. Researchers from M. D. Anderson Cancer Center previously reported an 82% progression-free survival for 18 patients with relapsed mantle cell lymphoma following a reduced conditioning regimen and an allogeneic stem transplant.11 A study from Johns Hopkins reviewed the outcomes of 19 patients with mantle cell lymphoma undergoing allogeneic stem cell transplants and 38 undergoing an autologous stem cell transplant.12 Event-free survival at three years was 51% for the entire group with no difference between auto or allo transplants. The three-year event-free survival for patients transplanted in first remission was 70%. Researchers from the University of Minnesota also reported that autologous or allogeneic stem cell transplantation can result in five-year survivals of 40-50% in patients with mantle cell lymphoma.13

At ASH 2008 researchers affiliated with a Fred Hutchinson Cancer Research Center multi-institutional study reported that reduced-intensity allogeneic stem cell transplantation was potentially curative for patients with mantle cell lymphoma.14 They treated 53 patients with relapsed mantle cell lymphoma, including 40% who had failed an autologous stem cell transplant. The five-year progression-free survival was 50% for recipients of related or unrelated stem cells. They also pointed out that chronic graft-versus host disease usually resolved after five years.

Researchers affiliated with the EBMT registry reported the outcomes of 279 patients with mantle cell lymphoma receiving reduced intensity allogeneic stem cell transplants.15 These authors reported a three-year survival rate of 43%. Adverse risk factors were refractory disease, transplantation before 2002, and poor performance status.

Researchers from Stanford University reported outcomes of 36 patients with mantle cell lymphoma or chronic lymphocytic leukemia who received Rituxan after a reduced intensity allogeneic stem cell transplant.16 The relapse rate was 18%, and the two-year survival was 73%. These authors suggest that post-transplant Rituxan depletes B-cells and lowers the incidence of GVHD without decreasing the graft-versus lymphoma effect. These researchers utilized a novel conditioning regimen of total nodal lymphoid irradiation and anti-thymocyte globulin.17

Autologous Stem Cell Transplantation for Diffuse Large B-cell Lymphoma (DLBCL)

Previous studies have suggested that patients with diffuse DLBCL benefit from an autologous stem cell transplant after first relapse. The efficacy of transplantation as consolidation therapy in first remission, however, remains more controversial than salvage transplants.

Researchers from France reported on extended follow-up data from the GOELAMS072 trial, which was originally published in the March 25, 2004 issue of The New England Journal of Medicine.18 This study demonstrated that high-dose chemotherapy with autologous stem cell support was superior to CHOP for treatment of patients with aggressive NHL. This study was a randomized trial where one group received four cycles of CHOP; responders in this group received an additional four cycles of CHOP and the non-responders went off study. The experimental arm of this study received two cycles of cyclophosphamide, epirubicin, vindesine, and methylprednisolone (CEEP) followed by collection of peripheral blood stem cells, usually after the second cycle. Non-responders in the experimental study also went off-study, while the responders received a single cycle of high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan). These authors reported that 84% of patients had a PR or CR following four cycles of CHOP compared with 86% for the two cycles of CEEP in the high-dose arm. At the end of treatment, 57% of patients in the CHOP arm and 79% in the high-dose arm achieved a CR. Further analysis showed that conventional CHOP followed by salvage therapies including upfront stem cell transplants result in similar survival to up-front stem cell transplants for low and low-intermediate risk patients. However, for high-intermediate risk patients there appeared to be a clear survival advantage with upfront transplants. This study now has a median follow-up of 9.8 years.19 All patients in this analysis had aggressive lymphomas. Event-free survival was 46% for the transplant group and 27% for the CHOP arm. Overall survival was 55% for the transplant arm and 33% for the CHOP arm. These data suggest that a subgroup of patients with aggressive NHL may be cured by autologous stem cell transplantation even when treated in the pre-Rituxan era. This study will have to be repeated with the use of R-CHOP.

Researchers from France reported that high-dose chemotherapy and autologous stem cell transplantation as consolidation in first remission may benefit patients with DLBCL with poor-risk features.20 This study evaluated a regimen of Rituxan, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in 209 patients with poor-risk DLBCL. Induction chemotherapy was delivered in four cycles at 15-day intervals. One hundred seventy-six patients (84%) responded, 61% had a complete response, and 155 (75%) received an autologous stem cell transplant. The median follow-up was 37 months. The complete response rate following transplantation was 72%, the progression-free survival was 85%, and overall survival was 90%. Treatment-related deaths occurred in 4% of patients during induction, and there were four deaths during the transplant procedure (<2%). These authors suggest that the addition of Rituxan to this regimen improved outcomes compared with previous studies and suggested that consolidation with stem cell transplantation also improved outcomes.

Researchers affiliated with the Lymphoma Working Party of the EBMT have reported that autologous stem cell transplantation is effective treatment for patients with diffuse large B-cell lymphoma (DLBCL) after first relapse who received Rituxan in the induction regimen.21 Patients in this study were induced into second remission after first relapse and then received an autologous stem cell transplant. Using the duration of first remission as a control, they concluded that the duration of second remission was usually longer than that of the first remission. During the initial phase of the disease, 72% relapsed within two years compared with 32% who relapsed within two years of an autologous transplant in second remission. When they compared the benefit of transplant between those who had or had not received Rituxan they found no difference. The concluded that the use of Rituxan did not decrease the beneficial effects of salvage stem cell transplant. However, the duration of first remission remains an important prognostic parameter for outcome of transplantation.

Radiation Therapy for Diffuse Large B-cell Lymphoma

Researchers from Germany reported that radiotherapy for elderly patients with diffuse large B-cell lymphoma (DLBCL) with bulky disease did not add to the effectiveness of Rituxan-based therapy.22 These same researchers have previously reported that six cycles of R-CHOP-14 is the optimal treatment of elderly patients with DLBCL.23 The current study looked at the outcomes of 166 elderly patients with bulky DLBCL who were treated with six cycles of R-CHOP without radiotherapy. They compared outcomes with 306 patients from previous trials who had received radiotherapy for bulky disease. These authors reported that patients who achieved a complete remission with six cycles of R-CHOP did not benefit from radiation therapy to areas of bulky disease. However, patients who were not in remission after six cycles appeared to benefit from radiation therapy to areas of bulky disease.

Treatment of Primary CNS Lymphoma

Primary central nervous system lymphoma (PCNSL) is a relatively uncommon form of lymphoma that has been increasing in incidence over the past three decades. Unlike the progress made in the general treatment of NHL, there has been little progress in the treatment of PCNSL. The standard treatment is high-dose methotrexate and whole-brain radiotherapy, which has improved outcomes. However, treatment-related neurotoxicity is common, especially in the elderly who often have poor renal function. One study has suggested that Rituxan and Temodar® (temozolomide) is an effective treatment regimen for patients with PCNSL.24 Researchers from Germany have also reported that a high-dose regimen of carmustine and thiotepa appeared to improve outcomes of patients with PCNSL when followed by whole-brain radiation therapy.25

At ASH 2008 Italian researchers presented the largest study to date of treatment of PCNSL.26 This study compared the effectiveness of high-dose methotrexate with or without high-dose cytarabine in 79 patients with PCNSL. The complete response rate to combination therapy was 46% compared with 18% for high-dose methotrexate alone. The three-year event-free survival was 38% for combination therapy and 18% for high-dose methotrexate alone. Thus, combination therapy should be the standard by which other therapies are judged.

Treatment of T-cell Lymphomas

T-cell lymphomas are a relatively uncommon form of NHL that generally do not respond as well to treatment as B-cell NHL. Though patients with B-cell NHL benefited significantly from Rituxan therapy over the past decade, there is no comparable T-cell antibody for treatment of T-cell lymphomas. High-dose chemotherapy with autologous stem cell transplants has been used with some success for the treatment of patients with T-cell lymphoma. However, even after ASCT the probability of recurrent disease is high. Allogeneic stem cell transplantation offers a more curative approach, but transplant-related mortality is high. The optimal approach to the treatment of T-cell lymphomas remains uncertain, and the prognosis for many patients is poor, especially those with peripheral T-cell lymphomas (PTCL).

At ASH 2008 researchers affiliated with the European Bone Marrow Transplant (EBMT) program reported the outcomes of 424 patients with mature T-cell lymphoma from the EBMT registry who received high-dose chemotherapy followed by autologous stem cell infusion between 2000 and 2005.27 This study excluded patients with cutaneous T-cell lymphoma but included 176 patients with PTCL. The median age of this group was 51 years with the oldest being 74 years. Ninety-seven percent of patients in this study had a good performance status. Non-relapse mortality was 7.4%, and the relapse rate was 43%. Patients with PTCL had a significantly worse prognosis than other types of T-cell lymphoma. Advanced disease and chemo-refractory disease were also adverse prognostic factors. These authors concluded that patients with poor performance status or resistant disease did not benefit from transplantation. These data should help determine which patients benefit from an autologous transplant and which should receive an allogeneic stem cell transplant or some alternative innovative regimen.

Effects of Statins in Patients with NHL

Researchers from Europe have previously reported that individuals who regularly use statins may have a decreased risk of developing lymphoma.28 Researchers from the Mayo Clinic have also reported that the use of statins may reduce the risk of developing NHL, especially diffuse large B-cell lymphoma (DLBCL).29

Researchers from Poland have reported in vitro studies to suggest that statins may reduce the effectiveness of Rituxan in treatment of NHL.30 These researchers found that statins alter the shape of CD20 antigens, reducing the ability of Rituxan to bind to B-cells. These results suggested that statins could interfere with the diagnosis of CD20-positive NHL as well as decreasing the effectiveness of Rituxan.

At ASH 2008 researchers from the Mayo Clinic reported that statin use in fact improved the outcomes of patients with follicular lymphoma but had no impact on patients with DLBCL.31 This study included 293 patients with newly diagnosed follicular lymphoma and 228 patients with DLBCL. All patients received Rituxan-based therapy. Statin use at diagnosis was associated with an improvement in event-free survival in patients with follicular lymphoma (HR=0.57) but had no statistically significant effect on patients with DLBCL (HR=0.67). Statin use during therapy was also associated with an improved event-free survival, but these data did not reach statistical significance. These results are reassuring, as they demonstrate that statins do not adversely affect treatment of NHL with Rituxan.

Summary

There were a large number of important studies in NHL presented at ASH 2008. The oral sessions were dominated by the long-term impact of Rituxan and the role of intensive therapy including autologous stem cell transplantation in attempts to cure patients with NHL. Collectively, the data in follicular lymphoma and mantle cell lymphoma suggest that high-dose therapies with stem cell support may be curing a significant fraction of patients. There is also no doubt that intensive therapies have improved the outcomes of patients with aggressive lymphomas.

References


1 Romaguera J, Fayad L, Rodriguez A et al. Rituximab (R) + Hypercvad alternating with R-methotrexate/cytarabine after 9 years: continued high rate of failure-free survival in untreated mantle cell lymphoma (MCL). Blood. 2008;112:309, Abstract 833.

2 Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. Journal of Clinical Oncology. 2005;23:7013-7023.

3 Kahl B, Chang J, Eickhoff J, et al. VcRCVAD produces a high complete response rate in untreated mantle cell lymphoma: A phase II study from the Wisconsin Oncology Network. Blood. 2008;112:105, abstract 265.

4 Kahl BS, Longl WC, Eickhoff JC, et al. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Annals of Oncology. 2006;17:1419-1423.

5 Thieblemont C, Antal D, Lacotte-Thierry L, et al. Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma. Cancer. 2005;104:1434-1341.

6 Thieblemont C, Antal D, Lacotte-Thierry L, et al. Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma. Cancer. 2005;104:1434-1341

7 Delarue R, Haioun C, Ribrag V, et al. RCHOP and RDHAP followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): Final results of a Phase II study from GELA. Blood. 2008;112:218, abstract 581.

8 Dreyling MH, Hoster E, van Hoof A, et al. Early consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission of mantle cell lymphoma: Long term follow up of a randomized trial. Blood. 2008;112:285, abstract 769.

9 Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677-2684.

10 Tam CS, Bassett R, Ledesma C, et al. Rituximab containing autologous stem cell transplantation may be curative in mantle cell lymphoma for patients in first remisson, but not for patients with reccurrent disease. Blood. 2008;112:417, abstract 1142.

11 Khouri IF, Lee M-S, Saliba RM, et al. Nonablative Allogeneic Stem-Cell Transplantation for Advanced/Recurrent Mantle-Cell Lymphoma. Journal of Clinical Oncology. 2003;21:4407-4412.

12 Kasamon YL, Jones RJ, Diehl LF, et al. Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma. Biology of Blood and Marrow Transplantation. 2005;11:39-46.

13 Laudi N, Arora M, Burns L, et al. Efficacy of high-dose therapy and hematopoietic stem cell transplantation for mantle cell lymphoma. American Journal of Hematology. 2006;81:519-424.

14 Sorror ML, Storer B, Sandmaier BM, et al. Sustained graft-versus lymphoma effect among patients (PTS) with mantle cell lymphoma (MCL) given non-myeloablative allogeneic hematopoietic cell transplantation (HCT). Blood. 2008;112:747, abstract 2147.

15 Robinson SP, Sureda A, Canals Sr C, et al. Identification of prognostic factors predicting the outcome of reduced intensity allogeneic stem cell transplantation in mantle cell lymphoma. An analysis from the Lymphoma Working Party of the EBMT. Blood. 2008;112:174, abstract 457.

16 Aral S, Sahaf B, Jones C, et al. Prophylactic rituximab after reduced intensity conditioning transplantation results in lower chronic Gvhd. Blood. 2008;112:178, abstract 466.

17 Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. New England Journal of Medicine 2005;353:1321-1331

18 Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of Aggressive Lymphoma with High-Dose Chemotherapy with Autologous Stem-Cell Support. The New England Journal of Medicine. 2004;350:1287-1295.

19 Gastine T, Damaj G, Lamy T, et al. High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) versus CHOP regimen in patients with untreated aggressive non-Hodgkin’s lymphoma: An update of the Goelams 772 trial with a median follow-up of 9.8 years. Blood. 2008;112:286, abstract 770.

20 Gisselbrecht C, Fitoussi O, Belhadj K, et al. Survival impact of rituximab combined to ACVBP (R-ACVBP) in 209 poor risk diffuse large B0cell lymphoma (DLBCL patients treated with upfront high-dose consolidative autotransplantation (HDC): A GELA phase II study. Blood. 2008;112:286, abstract 771.

21 Sureda A, Canals C, Mounier N, et al. High dose therapy and autologous stem cell transplantation still improves progresson free survival in first relapse for DLBCK in the rituximab era: A study using patients as their own controls. Blood. 2008;112:764, abstract 2191.

22 Ziepert M, Reiser M, Poeschel V, et al. The role of radiotherapy to bulky disease in the rituximab era: Results of two prospective trials of the German High-Grade Non-Hodgkin-Lymphoma Study Group (DSHNHL) for elderly patients with DLBCL. Blood. 2008;112:219, abstract 584.

23 Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomized controlled trial (RICOVER-60). The Lancet Oncology. 2008;9:105-116.

24 Spadaro P, Pitini V, Arrigo C. et al. Immunochemotherapy with temozolomide and rituximab for central nervous system lymphomas in the elderly populations. Proceedings from the annual meeting of the American Society of Clinical Oncology. Orlando FL. 2005; Abstract 6673.

25 Illerhaus G, Marks R, Ihorst G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. Journal of Clinical Oncology. 2006;24:3865-3870.

26 Ferreri AJM, Reni M, Foppoli M, et al. Randomized phase II trial on primary chemotherapy with high-dose methotrexate alone or associated with high-dose cytarabine for patients with primary CNS lymphoma (IELSG #20 Trial):Tolerability, activity and event-free survival. Blood. 2008;112:218, abstract 580.

27 Nickelsen M, Canals C, Schmitz N, et al. Patients with mature T-cell lymphoma show high relapse rates after high dose therapy and autologous stem cell transplantation. Blood. 2008;112:287, abstract 774.

28 Fortuny J, de Sanjose S, Becker N, et al. Statin Use and Risk of Lymphoid Neoplasms: Results from the European Case-Control Study EPILYMPH. Cancer Epidemiology Biomarkers and Prevention. 2006; 15: 921-925.

29 Cerhan J, Zachary S, Fredericksen ML, et al. Statin use and risk of non-Hodgkin Lymphoma (NHL): Preliminary results from the Mayo Clinic case-control study. Blood. 110;770a. Abstract 2615.

30 Winiarska M, Bil J, Wilczek E, et al. (2008) Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med. 2008;5:e64 http://dx.doi.org/10.1371/journal.pmed.0050064.

31 Nowakaowski GS, Mauer M, Habermann TM, Statin use and prognosis in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Blood. 2008;112:219, abstract 583.

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