LETTER TO THE EDITOR

Can survivin expression predict the response to bortezomibin cases with mantle cell lymphoma?

SEMRA PAYDAS

Cukurova University Faculty of Medicine, Department of Oncology, Balcali, Adana, Turkey

(Received 25 April 2006; accepted 10 May 2006)

I read with great interest the paper concerning

targeting the proteasome in mantle cell lymphoma

by Bogner et al. [1]. The most important and

clinically useful lesson from their paper is the

excellent overview of the use of bortezomib in non-

Hodgkin’s lymphoma (NHL) and the fact that there

is an excellent response to this agent in mantle cell

lymphoma (MCL), with long-term responses even in

relapsed and/or refractory cases. The results of two

studies presented in their review are particularly

important. In one study by Goy et al. [2], 29 cases

with MCL were evaluated and, among them, six

achieved complete response (CR) and six achieved a

partial response (PR) with an overall response rate

(ORR) of 41%, whereas only four of 21 non-MCL

responded (ORR 19%). In the second study by

O’Connor et al. [3], 24 cases were evaluated for

response to bortezomib and five of the 10 MCL cases

showed major responses, whereas no cases with small

lymphocytic lymphomas responded. Interestingly,

one case with MCL in leukemic phase showed a

dramatic reduction of the leukemic burden [2,3]. To

date, bortezomib has been used in many patients

with NHL and has only proved useful in MCL and

some cases with adult T cell leukemia (ATL) [4 – 7].

It is known that NFkB has a central role in the

induction of several genes contributing to the

malignant phenotype. These genes promote cell

proliferation, cytokine release, surface adhesion

molecules and also anti-apoptotic molecules [8].

Survivin is a 16.5-kDa protein and belongs to the

family of inhibitors of apoptosis. Its expression is

dependent on the cell cycle and has a dual function:

(i) promoter of cell division and (ii) inhibition of

apoptosis. Survivin suppresses caspase activity and

protects the cells from apoptosis induced by a variety

of drugs [9]. Survivin expression is generally a bad

prognostic indicator in tumors: shorter overall

survival (OS) and/or disease-free survival with lower

response rate to therapy [10]. An association between

NFkB and survivin has been reported, most recently

in a microarray study [11], where survivin expression

was associated with cell proliferation, contributing to

the aggressive phenotype and poor prognosis in

lymphomas. The two important findings of the study

were: (i) a higher BIRC5/survivin expression in

Burkitt’s and diffuse large B-cell lymphoma (63%

and 48%, respectively) and the absence of survivin in

small lymphocytic lymphoma and (ii) NFkB inhibi-

tion caused a decrease in BIRC5/survivin expression

in cell lines. When we examined the survivin

expression in NHLs, it was found in 60% and 68%

of the cases with diffuse large B-cell and anaplastic

large-cell lymphomas, respectively, and in all of the

Burkitt’s lymphoma cell lines, as well as in ATL

[10,12 – 14]. In these studies, a lower response rate

to conventional chemotherapy and shorter OS was

noted in cases showing survivin expression. In

another study, survivin mRNA has been explored

in 80 MCL samples and survivin mRNA was detec-

ted in all cases, with MCL ranging from 5 – 95%

(highest levels in blastoid variants) with shortest OS

in cases with the highest survivin mRNA [15]. The

response rate is lower in cases with MCL and ATL

that show the highest survivin expression among the

lymphomas.

These findings suggest that there is a correlation

between NFkB and survivin and that inhibition of

Correspondence: Semra Paydas, Cukurova University Faculty of Medicine, Department of Oncology 01330, Balcali, Adana, Turkey. E-mail: sepay@cu.edu.tr

Leukemia & Lymphoma, November 2006; 47(11): 2412 – 2413

ISSN 1042-8194 print/ISSN 1029-2403 online � 2006 Informa UK Ltd.

DOI: 10.1080/10428190600807079

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NFkB causes survivin down-regulation. With this

analogy, it is possible to explore the survivin

expression in all cases with MCL and other NHLs,

and it is possible that results may be related to

survivin expression in responders and non-

responders. For this aim, immunohistochemistry

may be used to provide a simple and relevant method

for detecting survivin expression in archival tissues. A

study of this nature may help us understand whether

survivin expression can predict the response to

bortezomib, and whether survivin levels can predict

the response to bortezomib. This may lead to the use

of bortezomib alone or in combination with other

cytotoxic and/or biological agents in cases with high

survivin expression.

In conclusion, if there is a link between survivin

expression and the response to bortezomib, it may be

possible to predict the response to bortezomib or at

least the safe use of bortezomib in cases with high

survivin expression. Similarly, survivin expression

could be explored in cases with multiple myeloma

where there already is much data regarding the

response to bortezomib. This information may prove

important for the safe use of bortezomib in the future

regarding both the cost and toxicity of this drug in

clinical practice.

References

1. Bogner C, Peschel C, Decker T. Targeting the proteasome in

mantle cell lymphoma: a promising therapeutic approach.

Leuk Lymphoma 2006;47:195 – 205.

2. Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE,

Hagemeister F, et al. Phase II study of proteasome inhibitor

bortezomib in relapsed or refarctory B cell lymphoma. J Clin

Oncol 2005;23:667 – 675.

3. O’Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-

Cortelli B, Stubblefield M, et al. Phase II clinical experience

with the novel proteasome inhibitor Bortezomib in patients

with indolent non-Hodgkin’s lymphoma and mantle cell

lymphoma. J Clin Oncol 2005;23:676 – 684.

4. Fisher RI, Miller TP, O’Connor OA. Diffuse aggressive

lymphoma. In: Broudy VC, Berliner N, Larson RA, Leung

LL, editors. American Society of Hematology Educational

Program Book. Washington DC: 2004. pp 221 – 236.

5. Richardson PG, Mitsiades C, Hideshima T, Anderson KC.

Proteasome inhibition in the treatment of cancer. Cell Cycle

2005;4:290 – 296.

6. Goy A, Gilles F. Update on the proteasome inhibitor

bertezomib in hematologic malignancies. Clin Lymphoma

2004;4:230 – 237.

7. Tan C, Waldman TA. Proteasome inhibitor PS-341, a

potential therapeutic agent for adult T cell leukemia. Cancer

Res 2002;62:1083 – 1086.

8. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The

ubiquitin-proteasome pathway is required for processing the

NF-KB1 precurcor protein and the activation of NF-KB. Cell

1994;78:773 – 785.

9. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis

gene, survivin, expressed in cancer and lymphoma. Nat Med

1997;3:917 – 921.

10. Nakayama K, Kamihira S. Survivin an important determinant

for prognosis in adult T-cell leukemia: a novel biomarker in

practical Hemato-oncology. Leuk Lymphoma 2002;43:2249 –

2255.

11. Tracey L, Perez-Rosado A, Artiga MJ, Carnacho FI,

RodriGuez A, Martinez N, et al. Expression of the NF-KB

targets BCL2 and BIRC5/Survivin characterizes small B-cell

and aggressive B-cell lymphomas, respectively. J Clin Pathol

2005;206:123 – 134.

12. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J,

et al. Prognostic significance of survivin expression in diffuse

large B-cell lymphomas. Blood 2000;96:1921 – 1925.

13. Schlette EJ, Meleinos LJ, Goy A, Lai R, Rasidakis GZ.

Survivin expression predicts poorer prognosis in anaplastic

large cell lymphoma. J Clin Oncol 2004;22:1682 – 1688.

14. Doucet JP, Hussain A, Al-Rasheed M, Gaidano G,

Gutierrez MI, Magrath I, et al. Differences in the expression

of apoptotic proteins in Burkitt’s lymphoma cell lines:

potential models for screening apoptosis-inducing agents.

Leuk Lymphoma 2004;45:357 – 362.

15. Martinez A, Bellesilo B, Bosch F, Ferrer A, Marce S,

Villamor N, et al. Nuclear survivin expression in mantle cell

lymphoma is associated with cell proliferation and survival.

Am J Pathol 2004;164:501 – 510.

Letter to the Editor 2413

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