Lenalidomide and Temozolomide Combination in a Very Elderly Patient with CNS Relapse of Diffuse Large B-Cell Lymphoma
1 Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
2 University of Siena, Siena, Italy.
3 Unit of Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Università Senese, "Santa Maria alle Scotte" University and NHS Hospital, Siena, Italy.
Received: March 13, 2017
Accepted: May 10, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017040 DOI 10.4084/MJHID.2017.040
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nervous system (CNS) relapse is an infrequent but severe complication
for DLBCL patients, associated with poor prognosis. Intravenous
prophylaxis with high-dose methotrexate has shown promising results but
is rarely feasible in elderly and/or nephropathic patients.
Overall, very few agents pass through blood brain barrier (BBB), such as temozolomide, but long-term remissions in primary CNS lymphoma are seldom observed with this drug.
Lenalidomide has a pleiotropic effect and has been widely used in relapsed DLBCL; there are some interesting reports about its efficacy in CNS relapse and its capacity to cross BBB.[8-11]
According to this background, we would like to report our experience in a case of CNS relapse in an elderly patient.
Immunochemotherapy with etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisone, and bleomycin (VNCOP-B) was administered, in association with rituximab.[13,14] The patient received chemotherapy weekly and rituximab every 2 weeks for 12 weeks, as previously published. The regimen was completed without dose delays or dose reductions; total body CT scan showed a complete remission (CR). Treatment toxicity was mild with only grade 1 peripheral neuropathy that disappeared after treatment completion; thank primary prophylaxis with filgrastim no neutropenia occurred.
The patient maintained CR for 6 months when she came to the emergency department because of a headache and cognitive impairment. Brain CT scan showed CNS relapse with a right frontal mass that extended to the ipsilateral frontal-basal areas, a wide ipsilateral vasogenic edema with ventricular compression and initial trans-falcial herniation. The patient was defined ineligible for radiotherapy (RT) because of age, wide vasogenic edema and high risk of neurotoxicity and started intramuscular dexamethasone 8mg daily and oral temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle; total body CT scan (Figure 1 A) showed a further increase of the right frontal mass (diameter 7cm) without other disease localizations.
Given the promising data of lenalidomide use for CNS lymphoma and the lack of other treatment options, we decided to administer lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement in general and cognitive conditions after the 1st cycle, headache disappeared, both Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) improved. We decided to continue this association; Gadolinium-enhanced brain MRI (Figure 1 B) was performed after the 2nd cycle and showed a wide reduction of neoplastic tissue (diameter 37 mm), vasogenic edema, and mass effect. In accordance with these promising results, the patients received other 4 cycles. Therapy was well tolerated, grade 2 neutropenia without infections and grade 2 thrombocytopenia that recovered after one-week dose delay were observed; no extra-hematological toxicity was observed, and no hospitalization was needed.
The patients maintained good clinical conditions until the end of the 6th cycle when a headache recurred. Gadolinium-enhanced brain MRI (Figure 1 C) showed disease progression. Clinical conditions rapidly worsened, the patient came to the hospital, we tried to administer steroid therapy, mannitol, and oral procarbazine, but the patient did not respond to treatment and died.
Procarbazine, lomustine, and vincristine (PCV) was administered to 8 recurrent CNS lymphoma patients (age 36-72 years old) and showed an overall response rate (ORR) of 50% with a median progression-free survival (PFS) of 7 months. Temozolomide, an alkylating agent that can penetrate into the brain, demonstrated promising results both as first-line treatment and for recurrent primary CNS lymphoma. In a retrospective series of 17 elderly patients CR rate was 47%, median PFS and overall survival (OS) were 5 and 21 months, respectively.
The possibility for lenalidomide to accumulate in the cerebrospinal fluid was reported in a case of blastoid mantle cell lymphoma. Lenalidomide as salvage therapy for recurrent primary CNS lymphoma was administered to 6 elderly patients (median age 73.5 years, range 64-78), 2/6 patients achieved CR and 1/6 achieved partial remission (PR). Salati and colleagues showed a leptomeningeal relapse in a patient with DLBCL successfully treated with lenalidomide monotherapy. The patient was elderly, had an early relapse after first-line chemoimmunotherapy of a double-hit DLBCL and received high-dose MTX and cytarabine as salvage treatment, alternating with bi-weekly liposomal cytarabine. MRI showed a significant reduction of leptomeningeal contrast enhancement, the patient refused RT and was successfully consolidated with lenalidomide 15mg daily for 21 every 28 days, achieving a complete and durable response (month+9).
Moreover, an interesting phase I study of lenalidomide was presented at last International Conference on Malignant Lymphoma (ICML) meeting, 6 out of 8 patients achieved at least PR, in 2 patients a duration of response of more than 1 year was reported.
Lenalidomide in combination has shown an unexpected toxicity, and a dose of 5 mg has been suggested.[18,19] It is important to note that in our case the combination with temozolomide of lenalidomide daily dose of 15 mg was well tolerated.
- A, Orfao A; Spanish Lymphoma Group (GELTAMO).
Guidelines for diagnosis, prevention and management of central nervous
system involvement in diffuse large B-cell lymphoma patients by the
Spanish Lymphoma Group (GELTAMO). Haematologica, 2017; 102: 235-245
N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B,
Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler
M, Savage KJ. CNS International Prognostic Index: A Risk Model for CNS
Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With
R-CHOP. J Clin Oncol, 2016; 34: 3150-3156 PMID:27382100 https://doi.org/10.1200/JCO.2015.65.6520
CY, Seymour JF. Central nervous system prophylaxis in non-Hodgkin
lymphoma: who, what, and when? Curr Oncol Rep, 2015; 17: 25
H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A,
Walewski J, André M, Johnson PW, Pfreundschuh M, Ladetto M; ESMO
Guidelines Committee. Diffuse large B-cell lymphoma (DLBCL): ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol, 2015; 26: v116-125 PMID:26314773 https://doi.org/10.1093/annonc/mdv304
AJ, Bruno-Ventre M, Donadoni G, Ponzoni M, Citterio G, Foppoli M,
Vignati A, Scarfò L, Sassone M, Govi S, Caligaris-Cappio F.
Risk-tailored CNS prophylaxis in a mono-institutional series of 200
patients with diffuse large B-cell lymphoma treated in the rituximab
era. Br J Haematol, 2015; 168: 654-662 PMID:25312994 https://doi.org/10.1111/bjh.13194
D, Glas M, Roth P, Weimann E, Lohner H, Waha A, Schabet M, Reifenberger
G, Weller M, Herrlinger U. Primary CNS lymphoma in the elderly:
temozolomide therapy and MGMT status. J Neurooncol, 2010; 97: 389-392
TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA,
Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes
AL, Czuczman MS. An international phase II trial of single-agent
lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's
lymphoma. Ann Oncol, 2011; 22: 1622-1627 doi: 10.1093/annonc/mdq626.
C, Choquet S, Touitou V, Martin-Duverneuil N, Navarro S, Mokhtari K,
Soussain C, Hoang-Xuan K. Lenalidomide monotherapy as salvage treatment
for recurrent primary CNS lymphoma. Neurology, 2015; 84: 325-326
MC, Mannino G, Lionetto L, Naso V, Simmaco M, Spiriti MA. Lenalidomide
for aggressive B-cell lymphoma involving the central nervous system? Am
J Hematol, 2011; 86: 957 doi: 10.1002/ajh.22148. No abstract available.
JL, Treseler PA, Stewart PJ. Regression of refractory intraocular large
B-cell lymphoma with lenalidomide monotherapy. J Clin Oncol, 2011; 29:
595-597 PMID:21519022 https://doi.org/10.1200/JCO.2011.34.7252
M, Tarantino V, Maiorana A, Bettelli S, Luminari S. Durable remission
in a patient with leptomeningeal relapse of a MYC/BCL6-positive
double-hit DLBCL treated with lenalidomide monotherapy. Hematol Oncol
2016 [Epub ahead of print] PMID:27301994 https://doi.org/10.1002/hon.2315
N, Held G, Ziepert M, Kempf B, Viardot A, Hänel M, Witzens-Harig M,
Mahlberg R, Rübe C, Fleckenstein J, Zwick C, Glass B, Schmitz N,
Zeynalova S, Pfreundschuh M. The role of radiotherapy and intrathecal
CNS prophylaxis in extralymphatic craniofacial aggressive B-cell
lymphomas. Blood, 2014; 124: 720-728 https://doi.org/10.112/bl8ood-2013-10-535021 PMID:24939657
M, Tani M, Stefoni V, Musuraca G, Marchi E, Pellegrini C, Alinari L,
Derenzini E, Bacci F, Pileri S, Baccarani M, Zinzani PL. VNCOP-B plus
rituximab in the treatment of diffuse large B-cell lymphoma in the
elderly. Leuk Lymphoma, 2007; 48: 2167-2171. PMID:17990178 https://doi.org/10.1080/10428190701642102 PMid:17990178
K, Urase F, Nagare Y, Kimura H, Manabe M, Yagi T, Teshima H, Hayashi K,
Shibano M, Tsukaguchi M, Katsurada T, Mugitani A, Kitayama H, Nomura
S.VNCOP- B plus rituximab therapy in elderly patients with aggressive
B-cell non-Hodkin lymphoma: A multicenter experience. Arch Gerontol
Geriatr, 2010; 51:209-215. https://doi.org/10.1016/j.archger.2009.10 PMID:19926148
B, Loeffler J, Illerhaus G, Ferreri AJ, Rubenstein J, Batchelor TT. The
role of whole brain radiation in primary CNS lymphoma. Blood, 2016;
128: 32-66 PMID:27207798 https://doi.org/10.1182/blood-2016-01-650101
YJ, Choe JH, Park JH, Hong YK. Efficacy of Procarbazine, Lomustine, and
Vincristine Chemotherapy for Recurrent Primary Central Nervous System
Lymphomas. Brain Tumor Res Treat, 2015; 3: 75-80 PMID:26605261 https://doi.org/10.14791/btrt.2015.3.2.75
JL, Formaker P, Wang X, Chen N, Fraser E, Munster P, Damato B.
Lenalidomide is highly active in recurrent CNS lymphomas: phase I
investigation of lenalidomide plus rituximab and outcomes of
lenalidomide as maintenance monotherapy. Hematol Oncol (ICML abstracts)
2015; 33 :175.
H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock
Martín A, Redondo AM, Dlouhy I, Salar A, González-Barca E, Canales M,
Montes-Moreno S, Ocio EM, López-Guillermo A, Caballero D; Spanish Group
for Lymphomas and Autologous Bone Marrow (GELTAMO).. Lenalidomide in
combination with R-ESHAP in patients with relapsed or refractory
diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group. Br
J Haematol. 2016 Apr;173(2):245-52. https://doi.org/10.1111/bjh.13945
Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S,
Link E,Swern A, Cowan L, Dimopoulos MA, Miles Prince H. Upfront lower
dose lenalidomide is less toxic and does not compromise efficacy for
vulnerable patients with relapsed refractory multiple myeloma: final
analysis of the phase II RevLitestudy. Br J Haematol. 2017
May;177(3):441-448. Epub 2017 Feb 15. PubMed PMID: 28197996 https://doi.org/10.1111/bjh.14562 .