Advances in the Treatment of Low-grade Non-Hodgkin’s Lymphoma

Posted on March 8th, 2009 by

Advances in the Treatment of Low-grade Non-Hodgkin’s Lymphoma

Recent advances in the treatment of low-grade non-Hodgkin’s lymphoma (NHL) have led to improvements in progression-free and overall survival. Research presented at the 2008 ASH meeting highlighted further progress in this area.

Impact of Rituxan on Low-grade NHL

Rituxan® (rituximab) has made a major impact in the treatment of patients with B-cell NHL. It is estimated that the addition of Rituxan to CHOP increases the median progression-free survival in patients with advanced follicular lymphoma to 36 months. At ASH 2008 an oral session was devoted to reporting follow-up data documenting the long-term impact of Rituxan on NHL treatment.

Role of Rituxan Maintenance

Several randomized Phase III trials have shown that patients with relapsed follicular lymphoma who achieve a remission with Rituxan plus chemotherapy benefit from prolonged Rituxan maintenance compared with placebo.1 Researchers from the University of Kentucky have also reported that the administration of Rituxan maintenance to patients with follicular lymphoma in second remission is cost-effective.2

Researchers affiliated with the EORTC Lymphoma Group/HOVON reported follow-up data on Rituxan maintenance in patients with relapsed or resistant follicular lymphoma.3 The results of the EORTC/HOVOV trial were originally published in 2006 in Blood.4 This trial included 465 patients with relapsed/resistant follicular NHL who were randomly allocated to receive CHOP or R-CHOP; both groups were subsequently randomly allocated to receive or not receive Rituxan maintenance. The current follow-up of this study is now six years. As previously reported, the complete response rates were higher in patients receiving R-CHOP, and Rituxan maintenance significantly improved median progression-free survival from 2.3 years to 3.7 years. The current overall five-year survival is 74% for the Rituxan maintenance group versus 64% for the control group (p=0.07). The fact that there was not a statistically survival difference is explained by the fact that 41% of patients in the observation group received salvage Rituxan. These data also suggest that, in general, progression-free survival is a better end point than overall survival for patients with low-grade NHL.

Rituxan, Mitoxantrone, and Dexamethasone for Elderly with Follicular Lymphoma

Researchers from Italy presented data on 158 patients, age 60 to 75 years, with previously untreated advanced follicular lymphoma who received a regimen of Rituxan, mitoxantrone, and dexamethasone.5 All patients in this study received consolidation therapy with Rituxan and were randomly allocated to receive Rituxan maintenance or no further therapy. The overall response rate was 90%, with 51% having a complete response following four cycles of induction therapy. Following Rituxan consolidation the complete response rate increased to 65%.

Rituxan and Pentostatin

Previous studies have shown that pentostatin, a purine analog, can be substituted for fludarabine for the treatment of CLL and low-grade NHL with possibly less toxicity.6 7 At ASH 2008 researchers from the M. D. Anderson Cancer Center presented the results of treating 80 patients with indolent B-cell lymphomas with the combination of pentostatin, cyclophosphamide, and Rituxan (PCR).8 This study included patients with follicular lymphoma, SLL/CLL, and mucosa-associated lymphoid tissue. The overall response rate was 96%, with a complete response rate of 81%. Neutropenia was the most frequent side effect occurring in half the patients. These authors suggest that pentostatin-based therapy is effective and possibly less toxic than fludarabine-based therapy.

Rituxan and Treanda®

Treanda® (bendamustine) is a bifunctional agent with both alkylator and purine-like activity that is currently in Phase II-III testing in a variety of diseases in the United States. One advantage of Treanda is that it is not cross-resistant with other alkylating agents. Treanda has been marketed and used clinically in Germany for many years in patients with NHL, CLL, multiple myeloma, breast cancer, and other solid tumors such as lung cancer. Treanda is approved by the U.S. Food and Drug Administration (FDA) for the treatment of CLL. The study that led to FDA approval of Treanda was a multicenter trial that included 301 patients with previously untreated Binet stage B and C (RAI Stage I-IV) CLL, which showed superiority of Treanda over chlorambucil.9 Treanda has also been approved by the U.S. FDA for the treatment of relapsed or refractory NHL. The study that led to the approval for NHL involved the combination of Treanda and Rituxan.10

Researchers affiliated with the Studygroup Indolent Lymphomas (StiL) have reported that initial treatment of patients with follicular, indolent, and mantle cell NHL with Treanda plus Rituxan is at least as effective as treatment with R (Rituxan)-CHOP and has fewer side effects.11 This randomized Phase III clinical trial is still ongoing, but results were available for more than 400 patients. Study participants were randomly assigned to receive initial treatment with either R-CHOP or Treanda plus Rituxan. There was a suggestion that patients treated with Treanda had better progression-free survival than patients treated with CHOP, although this result did not meet the criteria for statistical significance. It is possible to conclude, however, that Treanda is at least as effective as CHOP. Side effects such as leucopenia and hair loss were less common among patients treated with Treanda than among patients treated with CHOP. These results suggest that Treanda is at least as effective as CHOP for patients with low-grade NHL and carries a lower risk of side effects. This study may help pave the way toward Treanda becoming a standard part of the initial treatment of patients with low-grade NHL.

Newer Agents for Low-grade Lymphoma: RO5072759 (GA101)

Researchers from France have reported that RO5072759 was effective in patients with relapsed and refractory NHL.12 RO5072759 is a humanized and glycoengineered monoclonal anti-CD20 antibody. The authors of this abstract state that “glycoengineering results in a significantly increased antibody-dependent cytotoxicity.” They treated 24 patients with relapsed or refractory NHL, with the majority having follicular lymphoma. All had previously received Rituxan. In the Phase II portion of the trial, seven of 12 patients responded to treatment with three complete responses and four partial responses and an additional patient having stable disease. This is another promising antibody for the treatment of B-cell malignancies.

Autologous Stem Cell Transplantation

Patients with low-grade lymphomas currently have a plethora of effective treatment options including: accelerated CHOP, fludarabine, Rituxan, Bexxar® (tositumomab and Iodine I 131 tositumomab), Zevalin® (ibritumomab tiuxetan), high-dose chemotherapy or chemoradiotherapy with stem cell support, and allogeneic stem cell transplants with myeloablative or non-myeloablative treatment regimens. However, it is not clear which of these therapies or combinations of therapies offer the best chance for “cure” of patients with low-grade NHL.

Researchers affiliated with the German Low Grade Lymphoma Study Group (GLSG) reported that consolidation with an autologous stem cell transplant in first complete remission may improve survival of patients with follicular lymphoma.13 These researchers looked at data from two clinical trials that compared either interferon or chemotherapy maintenance therapy to autologous stem cell transplantation for patients achieving a first complete remission. The five-year progression-free survival was 66% following stem cell transplant compared with 27% for patients receiving interferon or chemotherapy. Patients who had induction with R-CHOP versus CHOP followed by interferon had a progression-free survival of 67% compared with 79% for those receiving R-CHOP followed by stem cell transplant. These data show the importance of Rituxan in induction and suggests that new randomized trials will be necessary to fully understand the role of stem cell transplantation as consolidation therapy.

Several studies dating back more that 20 years have shown that patients with low-grade NHL benefit from a high-dose chemotherapy and autologous stem cell transplant in first relapse compared with conventional chemotherapy. However, with the development of many new therapies for the treatment of low-grade NHL, this observation needs to be re-confirmed. At ASH 2008 researchers from France and Belgium presented data on 175 patients who relapsed after initial therapy.14 Sixty-three patients in this study relapsed while on therapy for newly diagnosed disease, and 112 relapsed after completing initial therapy. One hundred fifry-four of the 175 patients received salvage therapy, and 42 received an autologous stem cell transplant. The median follow-up of this study was 31 months. Progression-free survival at three years was 50%, but this was reduced to 26% at five years. The three-year overall survival was 72% at three years and 52% at five years. The 42 patients who received an autologous stem cell transplant had significantly better overall and progression-free survivals than those who did not. Patients receiving Rituxan in the salvage regimen also fared better than those who did not, even if they had received prior Rituxan therapy. These authors concluded that “a rituximab-based chemotherapy regimen followed by autologous stem cell transplant is likely to be the standard of care for eligible relapsed/refractory FL patients.”

Researchers from Germany have 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.15 This study was initiated before Rituxan was available, and the results of this study were first published in 2005.16 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. This reflected effective salvage therapy with 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.

Allogeneic Stem Cell Transplantation

Reduced-intensity allogeneic stem cell transplants are being increasingly used as salvage therapy for patients with non-Hodgkin’s lymphoma who relapse, including those who relapse after an autologous stem cell transplant.

Researchers from Germany presented data on 36 patients with advanced indolent non-Hodgkin’s lymphoma who received a reduced-intensity allogeneic stem cell transplant with a regimen containing Zevalin® (yttrium-90-ibritumomab tiuxetan).17 This approach resulted in a one-year survival of 67%.

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.18 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).19

Researchers from Poland have reported in vitro studies to suggest that statins may reduce the effectiveness of Rituxan in treatment of NHL.20 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.21 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 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 Hiddemann W, Underhalt M R, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized trial of the German Low Grade Lymphoma Group (GLSG). Blood. 2006;108:4003-4008.

2 Hayslip JW, Simpson KN. Cost-effectiveness of extended adjuvant rituximab for US patients aged 65-70 years with follicular lymphoma in second remission. Clinical Lymphoma Myeloma. 2008;8:166-170.

3 Van Oers MHJ, van Glabbeke M, Baila L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. Blood. 2008;112:308, abstract 836.

4 Van Oers MHJ, Klasa, Marcus RE. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108:3295-3301.

5 Ladetto M, Boccomini C, Gamba E, et al. Brief chemoimmunotherapy rituximab (R)-FND with or without R maintenance as first line treatment of elderly patients with advanced follicular lymphoma (FL): Preliminary analysis of a prospective randomized phase IIL trial. Blood. 2008;112:309.

6 Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B-chronic lymphocytic leukemia. Blood 2007;109:405-411.

7 Lamanna N, Kalaycio M, Maslak P, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. Journal of Clinical Oncology. 2006;24:1575-1581.

8 Samaniego F, Fanale M Pro B, et al. Pentostatin, cyclophosphamide, and rituximab (PCR) achieve high response rates in indolent B-cell lymphoma without prolonged myelosuppression. Blood. 2008;112:309. abstract 835.

9 Knauf WU, Lissichkov T, Aldaoud A, et al. Bendamustine versus chlorambucil in treatment-naïve patients with B-cell chronic lymphocytic leukemia (B-CLL): Results of an international phase III study. Blood. 2007;110:609a, abstract 2043.

10 Robinson K, Williams M, van der Jagt R, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent b-cell and mantle cell non-Hodgkin’s lymphoma. Journal of Clinical Oncology [early online publication]. July 14, 2008. DOI: 10.1200/JCO.2008.17.0001.

11 Rummel MJ, von Gruenhagen U, Niederle N et al. Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with follicular, indolent and mantle cell lymphomas: results of a randomized phase III study of the Studygroup Indolent Lymphomas (StiL). Blood. 2008;112:900, abstract 2596.

12 Salles GA, Morschhauser F, Cartron G, et al. A phase I/II study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant disease. Blood. 2008;112:93, abstract 234.

13 Hiddemann W, Buske C, Kneba M, et al. Autologous stem cell transplantation after myeloablative therapy in first remission may be beneficial in patients with advanced stage follicular lymphoma after front-line therapy with R-CHOPl An analysis of two consecutive studies of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2008;112:286, abstract 772.

14 Le Louill S, De Guibert S, Volteau C, et al. Autologous stem cell transplantation (auto-SCT) as the treatment of choice for follicular lymphoma patients in first relapse: Final analysis of the outcome of 175 patients treated in the GELA/GOelams FL 2000 study. Blood. 2008;112:287, abstract 773.

15 Hoster E, van Hoof A, Metzner B, 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.

16 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.

17 Radioimmunotherapy with yttrium-90ibritumomab tiuxetan as part of a reduced intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced indolent non-Hodgkin lymphoma: Interim analysis of a phase II study. Blood. 2008;112:684, abstract 1959.

18 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.

19 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.

20 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.

21 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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