Looking Back (and Ahead) at Salvage Treatment for Non‑Hodgkin Lymphoma

Drs. Hernandez-Ilizaliturri and Czuczman should be complimented on their comprehensive review of management options for patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL).[1] In addition to reviewing results of therapy with conventional chemotherapy salvage regimens and newer targeted treatments, they have also provided valuable information on the outcome of patients treated in the “post-rituximab” era. The need for more effective salvage treatments is underscored by sobering data suggesting that second-line treatments for DLBCL may be less effective in patients who received rituximab as part of their primary therapy.

The invitation to write this commentary provides us with an opportunity to look backward as well as forward. More than 20 years ago, in 1987, we wrote an article on “Salvage Therapy for Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma,” which was published in one of the first issues of this journal.[2] At that time non-Hodgkin lymphoma in this country was usually classified according to the Working Formulation, which was based on morphology.[3] This classification system did not provide information on T- or B-cell phenotype. Although there was a category of “malignant lymphoma, diffuse, large cell,” there was no “diffuse large B-cell lymphoma” entity. The most recent World Health Organization (WHO) lymphoma classification separates DLBCL into a larger number of variants than all of the 10 major types of non-Hodgkin lymphoma combined, which formed the basis of the Working Formulation.[4] These new variants are based on morphologic and clinical characteristics, and additional subgroups based on immunohistochemistry and molecular phenotype are also described.

Evolving Armamentarium

In 1987 we reviewed some of the same regimens including DHAP (dexamethasone, high-dose cytarabine [Ara-C], cisplatin [Platinol]), which had only been published in abstract form at the time. Ifosfamide was not yet approved, although we discussed several salvage regimens containing this agent. It is simultaneously ironic, disappointing, and gratifying that 22 years later a 2009 review on non-Hodgkin lymphoma salvage regimens is discussing the ongoing Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL), which is testing whether ICE (ifosfamide, carboplatin, etoposide) is superior to DHAP for relapsed and refractory DLBCL.[5] In 1987 we also mentioned agents such as methyl-GAG and gallium nitrate, which have not made a significant impact. We provided only one reference on the use of monoclonal antibodies,[6] and we are humbled by our statement that “ . . . there is no evidence that these products are useful in the management of intermediate- and high-grade lymphoma.”

In addition to the new drugs discussed in the current article, a wide variety of agents targeting other pathways are being investigated. An example of one such agent is fostamatinib which is an oral agent targeting SYK (spleen tyrosine kinase). Phase II data demonstrate activity in a variety of lymphoma histologic subtypes including DLBCL.[7] Other drugs undergoing study include dasatinib (Sprycel), as well as agents targeting Aurora kinase, polo-like kinase 1 (PLK1), and the vascular endothelial growth factor receptor (VEGFR).

It seems likely that we will see trials using combinations of these agents in the future, so that multiple pathways are inhibited, and that these agents will be combined with chemotherapy and monoclonal antibodies. Ultimately, it is likely that these agents will be incorporated into upfront chemotherapy regimens. For example, an international randomized trial is currently investigating whether bevacizumab (Avastin) added to R-CHOP (rituximab, cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) improves the progression-free survival of patients with DLBCL.

Customized Therapy

As mentioned in the article under review, our ultimate goal is to customize therapy based on tumor-associated and patient-associated characteristics. It is likely that some of the different ­DLBCL variants recognized in the updated WHO classification will require unique salvage therapy approaches. It is hoped that techniques such as gene-expression profiling and nucleotide polymorphism analyses will identify patients that require specific treatments. This approach is currently being applied to test for KRAS mutations in patients with metastatic colorectal carcinoma to determine responsiveness to anti–epidermal growth factor receptor (EGFR) antibody therapy.[8] Although similar testing is not yet dictating management decisions for patients with lymphoma, there is evidence, for example, that FCRIIIa gene polymorphisms may be associated with response to R-CHOP in diffuse large B-cell lymphoma.[9]

Other gene polymorphisms related to the host immune response and drug pharmacodynamics may play a future role in the management of patients with DLBCL. For example, investigators at the Mayo Clinic demonstrated that overall survival in patients with DLBCL was correlated with germline variations in genes associated with a proinflammatory state.[10] Sequence alterations in genes regulating drug metabolism and drug targets are important, and knowledge of these polymorphisms is essential when patients receive agents such as tamoxifen, mercaptopurine, irinotecan, trastuzumab (Herceptin), and cetuximab (Erbitux). Although this information is not yet being used to guide management, a recent report noted that gene polymorphisms associated with metabolism of the drugs in R-CHOP were correlated with the outcome of DLBCL patients.[11]

Looking Ahead

In the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry, the relative 5-year survival of patients with non-Hodgkin lymphoma increased more than 30% in the time between publication of our prior review and the publication of the Hernandez-Ilizaliturri/Czuczman review in the most recent issues of ONCOLOGY.[12] Salvage therapy options that were undreamed of in 1987 are now available for patients with diffuse large B-cell lymphoma, and these options have undoubtedly contributed to improved survival rates. Nevertheless, our ultimate goal is to improve the results of upfront treatment, although this might mean that lymphomas would be less likely to respond to treatment in the salvage setting. We are hopeful that additional progress will result in survival improvements that will be noted in future reviews.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Hernandez-Ilizaliturri FJ, Czuczman MS: Therapeutic options in relapsed or refractory diffuse large B-cell lymphoma (pts 1 and 2). Oncology (Williston Park) 23:546-553, 610-615, 2009.
2. Bierman P, Armitage JO: Salvage therapy for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Oncology (Williston Park) 1(9):11-20, 1987.
3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. The Non Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 49:2112-2135, 1982.
4. Swerdlow SH, Campos E, Harris NL, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC; Lyon, France; 2008.
5. Hagberg H, Gisselbrecht C: Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 DLBCL followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: An update of the CORAL study. Ann Oncol 17(suppl 4):iv31-iv32, 2006.
6. Miller RA, Maloney DG, Warnke R, et al: Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med 316:889-897, 1982.
7. Friedberg JW, Sharman J, Schaefer-Cutillo J, et al: Fostamatinib disodium (FosD), an oral inhibitor of Syk, is well-tolerated and has significant clinical activity in diffuse large B cell lymphoma and chronic lymphocytic leukemia (abstract 3). Blood 112(11):3-4, 2008.
8. Lièvre A, Bachet J-B, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006.
9. Kim DH, Jung HD Kim JG, et al: FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 108:2720-2725, 2006.
10. Habermann TM, Wang SS, Maurer MJ, et al: Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era. Blood 112:2694-2702, 2008.
11. Rossi D, Rasi S, Franceschetti S, et al: The pharmacogenetic background of the host is an independent predictor of outcome and toxicity in DLBCL treated with R-CHOP21 (abstract 480). Blood 112(11):183, 2008.
12. Horner MJ, Ries LAG, Krapcho M, et al (eds): SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, Md. Available at http://seer.cancer.gov/csr/1975_2006/. Based on Nov 2008 SEER data submission, posted to the SEER website, 2009.