Whereas several controversies were addressed at the ASH meeting, it is not clear that they were resolved.
The recently published PRIMA study provided the most compelling support for rituximab maintenance in patients with follicular non-Hodgkin's lymphoma (NHL).1 In this trial, a response to immunochemotherapy was followed by randomization to either maintenance or observation. The primary endpoint of a prolongation of PFS was met; however, there was no evidence yet for a survival advantage, and no data yet on any impact on the efficacy of subsequent therapy.
At ASH 2010, Ardeshna et al2 showed that, in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma, whereas early treatment with rituximab induction and maintenance was associated with a longer time to next treatment than watchful waiting—again there was no survival benefit. At ASH 2011, Kahl and his ECOG colleagues3 presented the first analysis of the long-awaited RESORT (Rituximab Extended Schedule or Retreatment) in which 384 patients with low-tumor burden follicular lymphoma were randomized to either four weekly doses of rituximab and retreatment upon progression, or four weekly doses followed by a single dose of maintenance every three months until an event.
“One of the most effective agents for the treatment of Hodgkin lymphoma appears to be brentuximab vedotin, a drug antibody conjugate consisting of an anti-CD30 monoclonal antibody tightly linked to the toxin methyl malonyl auristatin, a tubulin poison.”
Time to treatment failure was similar between the arms, and the conclusion was that the retreatment approach was preferable as it was associated with a median of 4.5 doses rather than 15.3 doses of rituximab. It would seem that, based on these results, there is less support for maintenance in follicular NHL.
“Whereas several controversies were addressed at the ASH meeting, it is not clear that they were resolved.”
Newer Monoclonal Antibodies
Given the success of rituximab, numerous companies have developed second- and third-generation anti-CD20s. However, to replace rituximab, an antibody should either be effective in rituximab-resistant patients, or be more active than rituximab. At ASH, several abstracts provided data on a type II, glycosylated anti-CD20, GA-101 (obinutuzumab).
GA-101 appears to be active as monotherapy not only in follicular but in diffuse large B-cell and mantle cell NHL4 However, in a direct comparison with rituximab, despite a modestly increased overall and complete response rate, there were greater infusion reactions but no difference in progression-free survival5 A study of bendamustine with or without GA-101 in rituximab-refractory follicular lymphoma is underway.
RIT is possibly the most active, least used treatment for FL. Response rates of 60-80% have been reported in relapsed or refractory disease.6,7 At ASH several studies were presented with Y90-ibritumomab tiuxetan demonstrating a high level of activity in previously untreated patients. Illidge et al reported a 100% rate of CR/CRu rate using fractionated Y90-ibritumomab tiuxetan with a PFS of 67% at 1.5 years.8
In the previously reported FIT trial, consolidation of a response to induction therapy, generally without rituximab, lead to a prolongation of PFS, but without a survival advantage, yet resulted in FDA approval for this indication.9 However, data from a SWOG-led intergroup trial were presented by Press and coworkers at ASH in which patients were randomized to R-CHOP or CHOP followed by I-131 tositumomab. The progression-free survival rates were similar between the arms.10 Whether the results would have been different with R-CHOP followed by RIT cannot be determined. However, these results will certainly not encourage the use of RIT in this setting.
Access the hyperlinks (shown in blue) in this article and throughout the issue by reading it on OT's free iPad app.
The role of radiation therapy in the management of limited stage Hodgkin lymphoma represents another controversy. In a study reported in 2005 by the National Cancer Institute of Canada-led North American intergroup, two cycles of ABVD followed by subtotal nodal irradiation appeared to be associated with a prolonged time to progression compared with four cycles of ABVD (93% vs 87%).11 At ASH, Meyer et al reported the final analysis of this study with 11.3 years of follow-up.12 The results demonstrated a significantly inferior survival for the irradiated patients as a result of secondary malignancies and cardiac events.
“Radioimmunotherapy is possibly the most active, least used treatment for follicular lymphoma.”
However, the argument could be made that the radiation used in this study was more extensive than the involved field or involved nodal fields used today. Nevertheless, while the controversy will likely continue, such data provide support for the ongoing risk-adapted trials in the US in limited stage disease and limited stage-bulky disease. In both, patients receive two cycles of ABVD followed by a PET scan. Those with a positive study undergo escalated BEACOPP therapy. Whereas those with limited disease and a negative scan continue with two more cycles, those with bulky disease complete six cycles of ABVD. The goal is to limit treatment to reduce the likelihood of late therapy-related complications.
One of the most effective agents for the treatment of Hodgkin lymphoma appears to be brentuximab vedotin. This drug antibody conjugate consists of an anti-CD30 monoclonal antibody tightly linked to the toxin MMAE (methyl malonyl auristatin E), a tubulin poison. In patients with relapsed and refractory disease following autologous stem cell transplantation, this agent achieves a 76% response rate.13 At ASH, the results with this agent incorporated into front-line therapy were presented.14
When combined with ABVD, there was an unacceptable 40% risk of pulmonary toxicity, which might have been predicted by previous data from the CALGB with SGN-30, the backbone of this DAC, with the drug combination of liposomal doxorubicin, vinorelbine, and gemcitabine in which life-threatening and fatal pulmonary toxicity resulted in early closure of the study.15 However, brentuximab combined with AVD induced a PET-confirmed complete remission in almost all patients and was well-tolerated. A study of ABVD vs A(BV)VD is underway and others are in development incorporating BV into initial treatment strategies.
“Whether any of these studies will alter practice in the near future remains to be seen. However, the results will engender considerable discussion and debate until ASH 2012. Moreover, the shift from non-specific cytotoxic therapy to a focus on novel targeted agents bespeaks for a major change in treatment strategies in the foreseeable future to more effective and less toxic therapies for patients with lymphoma.”
The outcome for most histologies of peripheral T-cell NHL remains poor, with the exception of ALK-positive anaplastic large cell NHL. Whereas CHOP remains the standard regimen, it clearly needs to be replaced. In recent years several new agents have demonstrated activity in patients with relapsed and refractory disease, notably the antifolate pralatrexate16 and the histone deacetylase inhibitor romidepsin,17 as well as brentuximab vedotin in those with CD30-positive anaplastic large cell lymphoma.
At ASH, Friedberg and coworkers presented the first data with alisertib, an aurora A kinase inhibitor, which demonstrated a high level of activity in a small number of patients with T-NHL (5/8), with an acceptable toxicity profile, including neutropenia, thrombocytopenia, and stomatitis.18 These data have led to a confirmatory trial in the US cooperative groups, and a randomized phase III company-sponsored study. Strategies incorporating one or more of these drugs may eventually replace CHOP for the initial treatment of these patients.
Whether any of these studies will alter practice in the near future remains to be seen. However, the results will engender considerable discussion and debate until ASH 2012. Moreover, the shift from non-specific cytotoxic therapy to a focus on novel targeted agents bespeaks for a major change in treatment strategies in the foreseeable future to more effective and less toxic therapies for patients with lymphoma.
1. Salles G, Seymour JF, Offner F, et al. Rituximab manitenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42–51
2. Ardeshna KM, Smith P, Qian W, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patiens with stage II, III, IV asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A preliminary analysis. Blood. 2010;116:5 (abstract #4)
3. Kahl BS, Hong F, Williams ME, et al. Results of the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosiong strategies for low tumor burden follicular lymphoma. Blood. 2011;118:LBA-6
4. Salles GA, Morschhauser F, Thieblemont C, et al. Efficacy and safety of obinutuzumab (GA101) monotherapy in relapsed/refractory indolent non-Hodgkin's lymphoma: results from a phase I/II study (BO20999). Blood. 2011;118:123–124 (abstract #268)
5. Sehn LH, Goy A, Offner F, et al. Randomized phase II trial comparing GA101 (Obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. Blood. 2011;118:124 (abstract #269)
6. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002;20:3262–3269
7. Horning SJ, Younes A, Jain V, et al. Efficacy and safety of tositumomab and iodine-131 toxitumomab (Bexxar) in B-cell lymphoma progressive after rituximab. J Clin Oncol. 2005;23:712–719
8. Illidge TM, Pettengell R, Bayne M, et al. Fractionated 90y-ibritumomab tiuxetan (ZevalinTM) radioimmunotherapy as an initial therapy of follicular lymphoma - first results from a phase Ii study in patients requiring treatment according to GELG/BNLI criteria. Blood. 2011;118:49–50 (abstract #102)
9. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26:5156–5164
10. Press OW, Unger J, Rimza LM, et al. A phase III randomized intergroup trial (SWOG S0016) of CHOP chemotherapy plus rituximab vs. CHOP chemotherapy plus Iodine-131-tositumomab for the treatment of newly diagnosed follicul non-Hodgkin's lymphoma. Blood. 2011;118:48 (abstract 98)
11. Meyer RM, Gospodarowicz MK, Connors JM, et al. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23:4634–4642
12. Meyer RM, Gospodarowicz M, Connors JM, et al. Final analysis of a randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy (RT) in patients with limited-stage Hodgkin lymphoma (HL): NCIC CTG/ECOG HD.6. Blood. 2011;118:271–272 (abstract #590)
13. Younes A, Bartlett NL, Kennedy DA, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. New Engl J Med. 2010;363:1812–1821
14. Younes A, Connors JM, Park SI, et al. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. Blood. 2011;118:436–437 (abstract 955)
15. Blum KA, Jung SH, Johnson JL, et al. Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with FcgammaRIIIa-158 V/F polymorphism. Ann Oncol. 2010;21:2246–2254
16. O'Connor O, Pro B, Pinter-Brown L, et al. PROPEL: Results of the pivotal, multicenter, phase II study of pralatrexate in aptients with relapsed or refractory peripheral T-cell lymphoma (PTCL). J Clin Oncol. 2009;27:449s (abstract 8561)
17. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27:5410–5417
18. Friedberg J, Mahadevan D, Jung J, et al. Phase 2 trial of alisertib (MLN237), an investigational, potent inhibitor of aurora A kinase (AAK), in patients (pts) with aggressive B- and T-cell non-Hodgkin lymphoma (NHL). Blood. 2011;118:46 (abstract #95)