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Diffuse large B-cell lymphoma (DLBCL) is a common lymphoid malignancy among adults in the developed world and accounts for about a third of all patients newly diagnosed with non-Hodgkin lymphoma each year [1]. The prognosis of patients with DLBCL has improved over the past 10 years since the advent of chemoimmunotherapy regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) [2, 3]. However, a significant number of patients still experience disease relapse or progression after first or second line therapy, and ∼40% of patients will die within 5 years [4]. In particular, elderly patients and those ineligible for high-dose chemotherapy due to comorbidities require effective salvage treatment options with favorable toxicity profile. Several novel therapeutic approaches have been proposed for these patients including monoclonal antibodies, radioimmunotherapy, proteasome inhibitors, mTOR inhibitors, and the immunomodulatory drugs such as thalidomide and lenalidomide.

Here we report a case of an elderly female patient with relapsed DLBCL who achieved a sustained complete remission during salvage therapy with a combination of lenalidomide plus low dose dexamethasone and prophylactic G-CSF.

A 71-year-old woman was diagnosed with DLBCL (Unclassified/type 3) [5]. Based on a lymph node biopsy in 2006, the patient was Epstein-Barr virus negative, epithelial membrane antigen negative, B-cell lymphoma (Bcl)-2+, CD20+, CD10/Bcl-6+, MUM1/IRF4+, CD30−/+, CD138, CD15, and Ki-67 was expressed in 50% of cells. Further investigations established that the lymphoma was in the Ann Arbor Stage III disease classification. Examinations using a 18FDG-PET/CT scan revealed multiple metabolically active lymphadenopathy in the abdomen and thorax. No lymphoma symptoms (night sweats, weight loss, fever), or bone marrow infiltration was seen and the patient was classified as having an International Prognostic Index (IPI) score of 3 (high-intermediate risk) based on her high serum lactate dehydrogenase levels, age, and stage III disease [6]. Her past medical history was remarkable for hypertension which was managed pharmacologically.

The patient received six cycles of R-CHOP administered every 21-day and achieved a complete response after completion of the treatment course, which was confirmed by a 18FDG-PET/CT scan being negative for pathologic lesions. Subsequently, she experienced disease relapse within 8 months as shown by a diffuse18FDG-PET/CT scan positivity and lymph node biopsy. According to recent study who emphasize the role of immune status of the host at relapse in the final outcome, the Absolute lymphocyte count at relapse (ALC-R) was >1.0 × 109 /L [7]. As per routine clinical practice in our institute, the patient was treated with eight cycles of a weekly, third-generation, combination chemotherapy VNCOP-B (cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisolone) plus rituximab for four cycles. After the treatment the patient obtained a 18FDG-PET/CT scan negativity confirming the second complete remission.

After 10 months of remission, the patient had a second relapse with a 18FDG-PET/CT scan showing diffuse positive lesions (Fig. 1).

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Figure 1. 18FDG-PET/CT scan at baseline (above) and after four cycles of combination treatment with lenalidomide plus low dose dexamethasone (below). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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A rebiopsy of a lymph node confirmed the histopathologic diagnosis of DLBCL (Unclassified/type 3). Again, no lymphoma symptoms or bone marrow infiltration was present. The IPI score now was 2 (low-intermediate risk) based on the patient's age and Ann Arbour stage III and ALC-R was again >1.0 × 109 /L The patient was now considered unsuitable for further polychemotherapy and alternative treatment strategies were explored. As daily oral lenalidomide (25 mg) has demonstrated efficacy in patients with relapsed or refractory DLBCL [8], we started a treatment regimen of lenalidomide 25 mg once-daily on days 1–21 of every 28-day cycle.

A previous study in patients with multiple myeloma demonstrated that lenalidomide plus dexamethasone was more effective than either agent alone [9]. Moreover, a randomized trial in patients with multiple myeloma found that low doses of pulsed dexamethasone was better tolerated and less toxic when used in combination with lenalidomide therapy [10]. Based on these data, we added low doses of dexamethasone (20 mg weekly for 4 weeks) to single agent lenalidomide.

During the first cycle of lenalidomide plus low dose dexamethasone therapy the patient experienced significant neutropenia. Therefore, subcutaneous granulocyte colony-stimulating factor (G-CSF) was administered on days 22–26 of each 28-day cycle. Aspirin (100 mg/day) was given as prophylaxis against deep-vein thrombosis and weekly co-trimoxazole (every Saturday and Sunday) was given as prophylaxis against Pneumocystis jirovecii infections. Patient compliance was good and no tumor lysis syndrome or tumor flare reactions were seen. There was a 1-week delay in treatment as a result of neutropenia, but after the introduction of G-CSF adverse events were grade 2 fatigue and grade 1 neutropenia showing that the treatment had low toxicity. After four cycles of treatment with lenalidomide and low dose dexamethasone a 18FDG-PET/CT scan was completely negative for lesions (Fig. 1); after six cycles of treatment (about 6 months) this result was confirmed. Now, about 10 months since documented complete response, the patient remains in remission. Based on tolerance and the convenient oral administration of the drugs, the patient is currently on maintenance treatment with lenalidomide at a lower daily dose (15 mg) plus weekly dexamethasone (10 mg) and prophylactic agents against infection and thrombosis. DLBCL is incurable for patients who experience relapse after first or second line therapy, and are unsuitable for stem cell transplantation because of comorbidities or advanced age. Salvage therapy with lenalidomide has been evaluated in this aggressive non-Hodgkin lymphoma, with an overall response rate ranging from 20 to 35%, and with a low percentage of complete responses [8]. The mechanism of action of immunomodulatory drugs and, in particular, lenalidomide is currently being explored. However, it has been shown that lenalidomide induces enhanced-activity of Th1 immunity and natural killer cell mediated cytotoxicity [11, 12]. In vitro models have demonstrated that lenalidomide exerts antiproliferative activity through inhibition the Akt pathway and the upregulation of the p21 tumor suppressor gene, which leads to cell cycle arrest in the G1 phase [13–15]. Moreover, lenalidomide has been shown to inhibit T-regulatory cell function and exert antiangiogenic effects on the tumor microenvironment [16, 17]. Recently it was reported to promote immune synapse restoration through its effects on malignant B cells and the T-cell microenvironment [18]. It has been shown that the addition of dexamethasone, with its induction of apoptosis via caspase-9, enhances the pro-apoptotic effect of lenalidomide especially as lenalidomide induces apoptosis via caspase-8 [19]. Furthermore, combination lenalidomide pulsed dexamethasone may prevent tumor flare reactions, improve patient compliance, and preserve the antiproliferative effect of lenalidomide, without impairing its immunomodulatory action [20].

The quick response shown by our patient was in agreement with results obtained in a previous study of lenalidomide monotherapy in DLBCL patients in terms of the time to response (about 4 months in our study) [8]. However, the negative for lesions 18FDG-PET/Tc scan, showed that the complete response in this elderly, heavily pretreated patient was of particular interest considering the good compliance with the treatment schedule. Moreover, we can hypothesize that there was synergistic activity between lenalidomide, dexamethasone, and the G-CSF agent via the influence of the G-CSF agent in the production of interleukin (IL)-12 p40 and, in particular, reducing IL-12 p40 and IL-12 (p40/p70) levels, with IL-12 p40 being a strong antagonist of IL-12 p70 immunological activity [21]. This effect might have enhanced lenalidomide antitumor activity by stimulating antitumor immune responses.

To verify these hypothesis, we are planning a prospective, translational study with lenalidomide and low dose dexamethasone, combined with prophylactic G-CSF, in a subset of elderly, heavily pretreated patients.

Acknowledgements

We thank Celgene Italy for providing Revlimid® for compassionate use in this patient.

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Gerardo Musuraca*, Pier Paolo Fattori*, Michela Ceccolini*, Delia Cangini*, Maria Benedetta Giannini*, Sonia Ronconi*, Federica Matteucci†, Silvia Asioli‡, Dino Amadori*, * Department of Hematology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy, † Department of Nuclear Medicine, Morgagni-Pierantoni Hospital, Forli, Italy, ‡ Department of Pathologic Anatomy, Morgagni-Pierantoni Hospital, Forli, Italy.