The addition of rituximab to CHOP therapy alters the prognostic significance of CD44 expression
- Xiaolei Wei†1,
- Meng Xu†1,
- Yongqiang Wei1,
- Fen Huang1,
- Tong Zhao2,
- Xiangzhao Li2,
- Ru Feng1Email author and
- B Hilda Ye3Email author
© Wei et al.; licensee BioMed Central Ltd. 2014
Received: 21 February 2014
Accepted: 24 March 2014
Published: 16 April 2014
Expression of CD44 splice isoforms has been previously reported to correlate with inferior outcomes in DLBCL patients treated with CHOP therapy. However, it is unclear whether this observation remains valid in the R-CHOP era. In this study, we correlated CD44H and CD44v6 status with survival outcomes among DLBCL patients with an emphasis on the comparison between CHOP- and R-CHOP-treated subgroups. Our results suggest that rituximab has significantly decreased the prognostic value of CD44H. We also observed that the therapeutic benefit of rituximab is largely restricted to CD44H-positive cases in this cohort.
To the Editor
Although incorporation of rituximab into CHOP (R-CHOP) has dramatically improved the outcome of DLBCL [1–5], approximately 40% of patients still succumb to the disease . One of the prognostic markers studied in the CHOP era is CD44, a transmembrane glycoprotein with many alternative splicing isoforms . Variations in its extracellular domain lead to isoform-specific activities of CD44 in cell adhesion, lymphocyte homing, and cell signaling . In general, CD44 plays a positive role in cell survival and invasiveness, and it is implicated in cancer stem cell maintenance in certain solid tumors . The objective of the current study is to compare the prognostic significance of CD44 isoforms in the CHOP and R-CHOP treatment groups.
This study enrolled 117 de novo DLBCL patients among whom 53 were treated with CHOP and 64 were treated with R-CHOP (Additional file 1; Additional file 2: Table S1). As expected, the incorporation of rituximab markedly improved the overall survival (OS) and event-free survival (EFS) rates (not shown). We used immunohistochemistry (IHC) to examine the expression of CD44H (the standard isoform) and CD44v6 (isoforms containing the variant exon 6) in diagnostic specimens (Additional file 3: Figure S1). Expression of CD44H and CD44v6 was detected in 65.0% and 34.2% of patients, respectively, with strong correlation to each other (Spearman’s correlation, r = 0.423, p < 0.001). The baseline clinical features were not significantly different between the CD44H+ and CD44H- patients. The CD44v6+ and CD44v6- cases were also very comparable (Additional file 2: Table S2).
Possibly due to the use of different antibodies and different IHC staining/scoring methods, there have been some controversial observations on the prognostic importance of CD44 in CHOP-treated DLBCL patients. In agreement with the majority of published studies [9–11], we have observed a negative survival impact of CD44H and CD44v6 expression in our entire study cohort (Figure 1 and Additional file 2: Table S3) as well as the CHOP treatment group (Figure 1E and F), although there were differences between these two markers. As the first study aimed to examine CD44 isoform expression in the R-CHOP era, our data suggest that rituximab has decreased the prognostic significance of CD44H, while the impact of rituximab on CD44v6 awaits future studies of larger cohorts. We also observed that the rituximab-associated survival benefit was profound among CD44H-positive cases but fairly limited among the CD44H-negative subgroup.
This work was supported by the National Natural Science Foundation of China (Grant No. 81028013), the Science and Technology Project of Guangdong Province of China (Grant No. 2010B050700020), the Science and Technology Project of Guangzhou City (Grant No. 12C22121553), and a pilot grant from CFAR, the Center for AIDS Research at the Albert Einstein College of Medicine.
- Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002, 346 (4): 235-242. 10.1056/NEJMoa011795.View ArticlePubMedGoogle Scholar
- Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol: Official J Am Soc Clin Oncol. 2006, 24 (19): 3121-3127. 10.1200/JCO.2005.05.1003.View ArticleGoogle Scholar
- Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M, German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL): Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008, 9 (2): 105-116. 10.1016/S1470-2045(08)70002-0.View ArticlePubMedGoogle Scholar
- Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M, MabThera International Trial Group: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006, 7 (5): 379-391. 10.1016/S1470-2045(06)70664-7.View ArticlePubMedGoogle Scholar
- Cang S, Mukhi N, Wang K, Liu D: Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012, 5: 64-10.1186/1756-8722-5-64.PubMed CentralView ArticlePubMedGoogle Scholar
- Sehn LH: Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2012, 2012: 402-409.PubMedGoogle Scholar
- Ponta H, Sherman L, Herrlich PA: CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003, 4 (1): 33-45. 10.1038/nrm1004.View ArticlePubMedGoogle Scholar
- Guo W, Frenette PS: Alternative CD44 splicing in intestinal stem cells and tumorigenesis. Oncogene. 2013Google Scholar
- Horst E, Meijer CJ, Radaszkiewicz T, Ossekoppele GJ, Van Krieken JH, Pals ST: Adhesion molecules in the prognosis of diffuse large-cell lymphoma: expression of a lymphocyte homing receptor (CD44), LFA-1 (CD11a/18), and ICAM-1 (CD54). Leukemia. 1990, 4 (8): 595-599.PubMedGoogle Scholar
- Inagaki H, Banno S, Wakita A, Ueda R, Eimoto T: Prognostic significance of CD44v6 in diffuse large B-cell lymphoma. Mod Pathol. 1999, 12 (5): 546-552.PubMedGoogle Scholar
- Drillenburg P, Wielenga VJ, Kramer MH, van Krieken JH, Kluin-Nelemans HC, Hermans J, Heisterkamp S, Noordijk EM, Kluin PM, Pals ST: CD44 expression predicts disease outcome in localized large B cell lymphoma. Leukemia. 1999, 13 (9): 1448-1455. 10.1038/sj.leu.2401490.View ArticlePubMedGoogle Scholar
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