Potential role of rituximab in metastatic castrate-resistant prostate cancer

Abstract

Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.

Keywords

Castrate resistant prostate cancer Rituximab

Introduction

Men who are treated with androgen deprivation therapy (ADT) for locally invasive or metastatic prostate cancer eventually develop resistance to hormone-directed therapy and disease progression. The overall median survival of metastatic castrate-resistant prostate cancer is between 17 and 30 months.¹ For a long time, there were limited therapeutic options for castrate-resistance prostate cancer with docetaxel as the preferred chemotherapeutic agent.² Docetaxel only improved survival by two to three months when compared to other therapies which improved quality of life in these men without affecting survival.^2–4 Approval of enzalutamide and abiraterone led to prolonged overall survival in patients with metastatic castrate-resistant prostate cancer but was limited by inevitable development of resistance to therapy.^5,6

Recognition of immune infiltration as a mediator of progression of prostate cancer has set in motion a new era of therapeutics for advanced prostate cancer.⁷ Pro-inflammatory marker-mediated B-cell infiltration has been proposed as a potential mechanism for development of castrate-resistant disease.^8,9 Targeting B cells using a monoclonal antibody against CD20 may play a role in delaying disease progression and improving progression-free survival.

We present a patient with progressive, metastatic castrate-resistant prostate cancer who had a sustained prostate-specific antigen (PSA) response after receiving rituximab and bendamustine for concurrent development of follicular lymphoma.

Case presentation

A 79-year-old male diagnosed with prostate cancer in 1999 was treated with prostatectomy and ADT with leuprolide acetate. In 2015, the patient had biochemical progression with sudden elevation of prostate specific antigen (PSA). Bicalutamide was initiated. As he continued to have biochemical and radiographic progression, this was changed to abiraterone acetate and prednisone. Monthly denosumab was added to prevent skeletal-related events. The patient had a biochemical PSA response to abiraterone acetate, yet he developed significant transaminitis six months later, attributed to abiraterone acetate. Transaminitis persisted despite appropriate dose reductions, thus his therapy was changed to enzalutamide (Figure 1).

During this time, he also developed left eye discomfort and swelling. Imaging studies showed a soft tissue mass in the left orbit, which was biopsied. Pathology revealed extra-nodal follicular lymphoma with translocation (14:18). Bone marrow aspirate showed normocellular bone marrow with maturing tri-lineage hematopoiesis and partial involvement by B cell non-Hodgkin lymphoma. FISH analysis was positive for IGH/BCL2 rearrangement in 10.5% cells, which was consistent with follicular lymphoma.

He was initiated on bendamustine and rituximab therapy with intrathecal methotrexate for orbital involvement. After completion of six cycles of therapy, the patient underwent a PET-CT scan which showed resolution of fludeoxyglucose (FDG) activity in the left orbit, left cervical lymph nodes, left prepectoral lymph nodes, and bilateral pulmonary nodules. Additionally, complete resolution of activity in a left para-aortic retroperitoneal lymph node was noted. The osteoblastic skeletal lesions demonstrated increased sclerosis compared to prior study, indicating healing metastases. PSA level normalized and remained <4 ng/mL on surveillance after 12 months of completion of bendamustine and rituximab for stage IV follicular lymphoma.

Discussion

The mechanism of development of castrate-resistant prostate cancer is poorly understood. A mouse model of prostate cancer has shown that ADT leads to hypoxia and death of tumor cells, which release pro-inflammatory factors. These factors promote CXCL13-mediated infiltration of B-lymphocytes into the regressing androgen-dependent tumors.^8,9 The tumor infiltrating B cells produce lymphotoxin B (LTB) that activates IkB kinase alpha (IKK alpha) nuclear translocation and signal transducer and activator of transcription 3 (STAT3) activation, which promote androgen-free survival of the tumor cells.¹⁰ STAT3 which is a regulator of procarcinogenic inflammation, and hypoxia-inducible factor-1 (HIF-1) were targeted in combination in an investigation which demonstrated significant reduction in the tumor growth in nude mice bearing both murine and human prostate cancer cells.¹¹ Ammirante and colleagues ⁹ further demonstrated that the mice with B-cell specific deficiency in lymphotoxin B (LTB) had delayed growth of castrate-resistant prostate cancer, but those mice with T-cell deficiency in LTB did not. B cell reduction by using a CD20 antibody or an LTB decoy receptor also delayed growth of castrate-resistant prostate cancer when compared to controls in these mice.

Tumor-infiltrating B cells were identified not only in mice prostate cancer, but also in human prostate cancer samples.⁹ Immunohistochemical staining for the B-cell marker, CD-20 in the radical prostatectomy samples of 53 patients showed higher B cell infiltration in the intra-tumoral prostate cancer cells as compared to extra-tumoral benign prostate cells.¹² This suggests that B cell-specific LTB may also be involved in the pathogenesis of human castrate-resistant prostate cancer. B cell depletion and LTB inhibition with currently approved biological agents can delay progression and potentially improve survival in human subjects.

In 2014, Dalgleish and colleagues also reported a case in which rituximab elicited a significant biochemical response in a patient who had advanced prostate cancer and generalized lymphadenopathy.¹³ Furthermore, a recent report of a patient with concomitant metastatic prostate cancer and B-cell non Hodgkin’s lymphoma with R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) and goserelin hormonal therapy produced encouraging results.¹⁴ A clinical trial evaluating the efficacy of neoadjuvant rituximab therapy in patients with prostate cancer prior to prostatectomy is currently underway.¹⁵

Complementing existing ADT and chemotherapy regimens with these biological agents may also induce remission in advanced, metastatic disease as demonstrated in our patient after treatment with bendamustine and rituximab. This case underlines the need to evaluate the role of rituximab in advanced castrate-resistant prostate cancer.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Halabi

Lin

Kelly

et al.

Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2014; 32: 671–677.

Berthold

Pond

Soban

et al.

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 26: 242–245.

Tannock

de Wit

Berry

et al.

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New Engl J Med 2004; 351: 1502–1512.

Petrylak

Tangen

Hussain

et al.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New Engl J Med 2004; 351: 1513–1520.

De Bono

Logothetis

Molina

et al.

Abiraterone and increased survival in metastatic prostate cancer. New Engl J Med 2011; 364: 1995–2005.

Scher

Fizazi

Saad

et al.

Increased survival with enzalutamide in prostate cancer after chemotherapy. New Engl J Med 2012; 367: 1187–1197.

Strasner

Karin

. Immune infiltration and prostate cancer. Frontier Oncol 2015; 5: 128–128.

Ammirante

Shalapour

Kang

et al.

Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci 2014; 111: 14776–14781.

Ammirante

Luo

Grivennikov

et al.

B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 2010; 464: 302–302.

10.

Ammirante

Kuraishy

Shalapour

et al.

An IKKα–E2F1–BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Develop 2013; 27: 1435–1440.

11.

Reddy

Guan

Qin

et al.

Combined treatment targeting HIF-1α and Stat3 is a potent strategy for prostate cancer therapy. Prostate 2011; 71: 1796–1809.

12.

Woo

Liss

Muldong

et al.

Tumor infiltrating B-cells are increased in prostate cancer tissue. J Translat Med 2014; 12: 30–30.

13.

Dalgleish

Featherstone

Vlassov

et al.

Rituximab for treating CD20+ prostate cancer with generalized lymphadenopathy: a case report and review of the literature. Investigat New Drugs 2014; 32: 1048–1052.

14.

Hanna F, Prakash A, Allan E, et al. Successful treatment of concomitant metastatic prostate cancer and B-cell non-Hodgkin’s lymphoma with R-EPOCH chemotherapy regimen and antiandrogen therapy. BMJ Case Rep. Published Online First: doi:10.1136/bcr-2017-223637.

15.

Stephen H. Rituximab neoadjuvant therapy in patients with prostate cancer scheduled to undergo radical prostatectomy. Bethesda, MD: National Library of Medicine (US), 2000, https://clinicaltrials.gov/ct2/show/NCT01804712 (accessed 8 April 2018).