Combined systemic and ocular chemotherapy for anterior segment metastasis of systemic mantle cell lymphoma
© Agarwal et al. 2015
Received: 22 May 2015
Accepted: 21 September 2015
Published: 8 October 2015
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma that rarely metastasizes to the iris and the anterior segment. Blastic/pleomorphic morphology is thought to have an adverse effect on prognosis in MCL. MCL is resistant to conventional chemotherapeutic regimens with a tendency for multiple relapses. Management of anterior segment metastasis of systemic MCL has not been described in literature.
A 58-year-old male presented with an aggressive, relapsing, metastatic, systemic blastic variant of MCL with ocular involvement. At the time of initial presentation, large tumor cells were visible in the anterior chamber (AC) along with hypopyon and fibrin. The AC cells stained positively for CD20. The iris was thickened and coated with lymphoma cells. Iris neovascularization was present. Given extensive systemic and ocular involvement, the patient was given combination chemotherapy with systemic ibrutinib and intravitreal injections of methotrexate and rituximab. The disease response was monitored using multimodal imaging, including anterior segment optical coherence tomography and ultrasound biomicroscopy. Following combination of systemic and intraocular chemotherapy, there was a marked decrease in the ocular tumor load and the systemic disease.
Combination therapy with intravitreal injections of chemotherapeutic agents targeting monoclonal B-cell population and novel systemic agents may help to achieve remission in anterior segment metastasis of aggressive subtypes of NHL such as blastic variant of MCL. Multimodal imaging may assist in the management of these cases.
KeywordsMantle cell lymphoma Iris Ibrutinib Rituximab Methotrexate Metastasis Uveitis Ultrasound biomicroscopy
Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin’s lymphoma (NHL) accounting for 6–7 % of all NHL cases. Blastic/pleomorphic morphology is thought to have an adverse effect on prognosis in MCL. MCL is an aggressive form of NHL with poor response to conventional therapy and risk of multiple relapses [1, 2]. Systemic MCL can affect various organs such as lymph nodes, bone marrow, spleen, and bowel resulting in a poor median survival of 3–6 years after diagnosis . However, systemic metastases of NHL to the eye are rare with most cases confined to the orbit and adnexa . Intraocular involvement is even rarer, and it usually affects the choroid . Thus, reports of iris and anterior segment involvement due to metastasis of systemic MCL have been limited to a few case reports [6–8].
While radiation therapy has been used for the management of orbit and adnexal involvement , intravitreal injections of chemotherapeutic agents such as methotrexate (MTX) and rituximab (anti-CD20) have been used for patients with vitreoretinal NHL [10, 11]. The treatment for iris metastasis has not been well described in literature. Ibrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor recently introduced for the treatment of relapsed systemic MCL . In this index case report, multimodal imaging analysis of a patient with anterior segment metastasis of relapsed systemic MCL is described. Treatment outcome using combination chemotherapy with systemic ibrutinib and intravitreal injections of MTX and rituximab is also discussed.
A 58-year-old Caucasian man was diagnosed with systemic MCL, blastic variant, in August 2010. He received six cycles of rituximab hyper-CVAD chemotherapy consisting of alternating combinations of drugs (course A and course B). Course A included cyclophosphamide, vincristine, doxorubicin, and dexamethasone; course B consisted of MTX and cytarabine . Subsequently, the patient received autologous stem cell transplantation (ASCT) with BEAM chemotherapy [bis-chloroethylnitrosourea (carmustine), etoposide, cytarabine, and melphalan] in January 2012 . Following ASCT, the disease was in remission.
A routine restaging positron emission tomography (PET) scan in January 2013 demonstrated relapse of the disease with new, enlarged mediastinal lymph nodes. Biopsy of a gluteal mass revealed metastatic MCL in March 2013. The patient received six cycles of bendamustine plus rituximab salvage . A repeat PET scan in January 2014 did not show any disease activity.
In April 2014, the patient complained of redness, pain, and milky white deposits in the right eye (OD). He was diagnosed with anterior uveitis and elevated intraocular pressure (IOP) and was started on topical prednisone acetate 1 % (four times a day) along with pilocarpine 2 % three times a day. He underwent trabeculectomy and anterior chamber (AC) paracentesis in August 2014. The paracentesis sample was positive for CD20+ lymphoma cells. PET scan demonstrated several areas of nodal and extranodal disease (scalp mass and mediastinal nodes). Cerebrospinal fluid (CSF) and bone marrow biopsy, however, did not reveal lymphoma cells.
At 1-week follow-up, BCVA improved to 20/50 in OD. The hypopyon and iris neovascularization markedly decreased. Evaluation of the posterior segment with fluorescein angiography did not demonstrate any abnormality. During the next 3 months, the patient received two additional injections of intravitreal rituximab at 6-week intervals and one additional injection of MTX and ranibizumab 6 weeks after presentation with interval improvement. AS-OCT demonstrated marked decrease in the AC cells (Fig. 2c). The iris thickening reduced following the combination chemotherapy (Fig. 4c–f). Systemic lymphoma demonstrated stabilization followed by improvement. Ibrutinib therapy was tapered to 420 mg/day due to the concern of secondary myelodysplastic syndrome and an episode of neutropenic fever.
To the best of our knowledge, uveal metastasis of MCL has been reported in only five cases in literature thus far [6–8, 16, 17]. Among these cases, isolated involvement of the anterior segment and iris was observed in two cases [6, 7]. In a report by Economou et al. , bilateral involvement of the iris was noted in a 71-year-old male with large, reddish tumor-like masses, anterior chamber inflammation, and hyphema. Reid et al.  reported unilateral granulomatous anterior chamber inflammation along with localized undulations of the iris and presence of aberrant-appearing vasculature in an elderly male with systemic MCL. The diagnosis of intraocular MCL was confirmed using cytopathology in only one case by Economou et al. . In all these case reports, the management of secondary iris lymphoma was limited to frequent topical steroids, systemic chemotherapy, or external beam radiation. Since the description of these cases, numerous systemic and local ocular chemotherapeutic strategies have evolved in the management of aggressive relapsing tumors with secondary ocular metastasis. The use of intravitreal chemotherapy along with systemic anti-cancer agents has not been described for the treatment of iris metastasis of MCL or other types of NHL.
Concurrent treatment with intravitreal MTX and rituximab has been successfully employed in the management of vitreoretinal NHL with few adverse events and remission achieved in more than two third of cases . Similarly, for systemic therapy in NHL, rituximab is often combined with other chemotherapeutic agents given its anti-CD20 activity. In this case, we used intravitreal injections of both MTX and rituximab due to the extensive tumor load.
Ibrutinib has been approved by the United States Food and Drug Administration (US-FDA) for the treatment of MCL in patients who have received at least one prior therapy . In our patient, chemotherapy with ibrutinib resulted in marked decrease in the systemic metastatic foci of MCL. However, the exact role of ibrutinib in reducing the ocular tumor load remains unclear.
UBM and AS-OCT complement each other in the diagnosis and management of non-pigmented iris tumors . These techniques produce high-resolution images of the iris tumors resulting in excellent visualization of the tumor anatomy and measurement of tumor dimensions. Careful evaluation of morphological features of the iris on UBM and AS-OCT enabled effective monitoring of the treatment response in our patient (Figs. 2 and 4). To the best of our knowledge, the appearance of lymphoma cells on AS-OCT has not been characterized (Fig. 2). In this case, multimodal imaging allowed an objective assessment of reduction in the tumor load.
The index case describes successful initial management of anterior segment ocular metastasis in MCL with combined systemic and local ocular chemotherapeutic agents. The treatment regimen may be individualized; results on flow cytometry may guide the selection of appropriate pharmacologic agents after AC paracentesis. Iris metastasis can be well visualized using both UBM and AS-OCT, enabling serial objective assessments of the response to chemotherapy.
Consent to publish
The consent to publish has been obtained from the participant to report individual patient data.
autologous stem cell transplant
anterior segment optical coherence tomography
best-corrected visual acuity
Bruton’s tyrosine kinase
mantle cell lymphoma
magnetic resonance imaging
positron emission tomography
Financial support/Proprietary interests
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript. This study is supported in part by an unrestricted grant from Research to Prevent Blindness (RPB) to the Truhlsen Eye Institute at the University of Nebraska Medical Center.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Cortelazzo S, Ponzoni M, Ferreri AJ, Dreyling M (2012) Mantle cell lymphoma. Crit Rev Oncol Hematol 82(1):78–101. doi:10.1016/j.critrevonc.2011.05.001 View ArticlePubMedGoogle Scholar
- Campo E, Rule S (2015) Mantle cell lymphoma: evolving management strategies. Blood 125(1):48–55. doi:10.1182/blood-2014-05-521898 View ArticlePubMedGoogle Scholar
- Vose JM (2013) Mantle cell lymphoma: 2013 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 88(12):1082–1088. doi:10.1002/ajh.23615 View ArticlePubMedGoogle Scholar
- Rasmussen P, Sjo LD, Prause JU, Ralfkiaer E, Heegaard S (2009) Mantle cell lymphoma in the orbital and adnexal region. Br J Ophthalmol 93(8):1047–1051. doi:10.1136/bjo.2008.146910 View ArticlePubMedGoogle Scholar
- Mashayekhi A, Shields CL, Shields JA (2013) Iris involvement by lymphoma: a review of 13 cases. Clin Experiment Ophthalmol 41(1):19–26. doi:10.1111/j.1442-9071.2012.02811.x View ArticlePubMedGoogle Scholar
- Economou MA, Kopp ED, All-Ericsson C, Seregard S (2007) Mantle cell lymphoma of the iris. Acta Ophthalmol Scand 85(3):341–343. doi:10.1111/j.1600-0420.2006.00845.x View ArticlePubMedGoogle Scholar
- Reid JP, Puglis CL, Slagle WS (2014) Intraocular mantle cell lymphoma of the iris. Optom Vis Sci 91(4 Suppl 1):S25–29. doi:10.1097/opx.0000000000000218 View ArticlePubMedGoogle Scholar
- Chappelow AV, Singh AD, Perez VL, Lichtin A, Pohlman B, Macklis R (2008) Bilateral panocular involvement with mantle-cell lymphoma. J Clin Oncol 26(7):1167. doi:10.1200/jco.2007.14.2620 View ArticlePubMedGoogle Scholar
- Franco P, Filippi AR, Ricca I, Raucci C, Ricardi U (2009) Eyelid localization in mantle cell lymphoma: long-lasting complete remission after surface brachytherapy. Tumori 95(3):385–388PubMedGoogle Scholar
- Larkin KL, Saboo US, Comer GM, Forooghian F, Mackensen F, Merrill P, Sen HN, Singh A, Essex RW, Lake S, Lim LL, Vasconcelos-Santos DV, Foster CS, Wilson DJ, Smith JR (2014) Use of intravitreal rituximab for treatment of vitreoretinal lymphoma. Br J Ophthalmol 98(1):99–103. doi:10.1136/bjophthalmol-2013-304043 View ArticlePubMedGoogle Scholar
- Frenkel S, Hendler K, Siegal T, Shalom E, Pe'er J (2008) Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol 92(3):383–388. doi:10.1136/bjo.2007.127928 View ArticlePubMedGoogle Scholar
- Herrera AF, Jacobsen ED (2014) Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res 20(21):5365–5371. doi:10.1158/1078-0432.ccr-14-0010 View ArticlePubMedGoogle Scholar
- Ritchie DS, Seymour JF, Grigg AP, Roberts AW, Hoyt R, Thompson S, Szer J, Prince HM (2007) The hyper-CVAD-rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma. Ann Hematol 86(2):101–105. doi:10.1007/s00277-006-0193-2 View ArticlePubMedGoogle Scholar
- Martin N, Borchiellini D, Coso D, Gastaud L, Boscagli A, Saudes L, Re D, Gutnecht J, Garnier G, Petit E, Barriere J, Naman H, Rossignol B, Thyss A, Peyrade F (2015) High-dose chemotherapy with full BEAM followed by autologous stem cell transplantation is an effective treatment for elderly patients with poor-prognosis lymphoma. Leukemia & lymphoma:1–26. doi:10.3109/10428194.2014.1001987
- Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Durk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W (2013) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381(9873):1203–1210. doi:10.1016/s0140-6736(12)61763-2 View ArticlePubMedGoogle Scholar
- Ahn ES, Singh AD, Smith SD (2010) Mantle cell lymphoma with uveal metastasis. Leuk Lymphoma 51(7):1354–1355. doi:10.3109/10428194.2010.486093 View ArticlePubMedGoogle Scholar
- Rowley SA, Fahy GT, Brown LJ (2000) Mantle cell lymphoma presenting as a choroidal mass: part of the spectrum of uveal lymphoid infiltration. Eye (Lond) 14(Pt 2):241–244. doi:10.1038/eye.2000.63 View ArticleGoogle Scholar
- Krema H, Santiago RA, Gonzalez JE, Pavlin CJ (2013) Spectral-domain optical coherence tomography versus ultrasound biomicroscopy for imaging of nonpigmented iris tumors. Am J Ophthalmol 156(4):806–812. doi:10.1016/j.ajo.2013.05.025 View ArticlePubMedGoogle Scholar