Area Abbonati
doi   10.1700/1377.15326
Tumori 2013;99(5):e251-e256

Salvage lenalidomide in four rare oncological diseases
Petr Szturz1, Zdenek Adam1, Zdenek Rehak2, Renata Koukalova2, Leos Kren3,
Mojmír Moulis3, Marta Krejcí1, and Jiri Mayer1
1Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, School of Medicine, Brno; 2Department of Nuclear Medicine, PET Center at the Masaryk Memorial Cancer Institute, Brno; 3Department of Pathology, University Hospital Brno and Masaryk University, School of Medicine, Brno, Czech Republic

Key words: Langerhans cell histiocytosis, Erdheim-Chester disease, angiomatosis, Castleman disease.

Acknowledgment: This work was supported in part by institutional resources for supporting the research organization provided by the Ministry of Health of the Czech Republic to the Masaryk Memorial Cancer Institute; MH CZ-DRO (FNBr, 65269705); research project of the Ministry of Education, Youth and Sports: MSM0021622434; IGA grants of the Ministry of Health: NT12215-4/2011, NT13190-3/2012 and project MUNI/A/0723/2012.

Correspondence to: Petr Szturz, MD, PhD, Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Jihlavská 20, 625 00 Brno, Czech Republic.
Tel +420-5-32232934;
fax +420-5-32233603;

Received November 20, 2012;
accepted March 15, 2013.

In rare disorders, there are often no standard therapy recommendations. Patients with refractory disease may require novel experimental approaches. Applied as second- up to fourth-line treatment, lenalidomide (10-25 mg perorally on days 1-21 in a 28-day cycle) was used in our cohort of four adult patients with aggressive, multisystem and relapsing diseases. Complete and long-lasting remissions (more than 1 year, no maintenance therapy) were achieved in patients with Langerhans cell histiocytosis (11 cycles, combination with dexamethasone and etoposide, consolidated by allogeneic blood stem cell transplant) and plasma-cell Castleman disease (15 cycles, monotherapy). Mixed response with complete disappearance of brain infiltrates was reached in Erdheim-Chester disease (6 cycles, monotherapy) and gastrointestinal bleeding was well controlled in multiple angiomatosis (9 cycles, combination with thalidomide). For disease activity evaluation each patient underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography scan imaging, which was complemented by clinical and laboratory investigations.
Not only is it the low prevalence that bonds the 4 entities described here, but there is also diversity in their clinical picture, nearly escalating to an artful, chameleon-like camouflage. Pathological Langerhans cells as well as foamy histiocytes of Erdheim-Chester disease may proliferate and accumulate in virtually any tissue. An analogous situation arises in multiple angiomatosis with widespread invasion of histologically benign vascular tumors. Sometimes presenting a diagnostic challenge requiring repeated surgical biopsies, multicentric Castleman disease manifests with extensive lymphadenopathy, nonspecific general symptoms and laboratory abnormalities.
The malignant potential of the said disorders does not apply to their histopathological characteristics but to their unpredictable, life-threatening courses, justifying the need for a systemic therapeutic approach. Applied as the second- up to fourth-line treatment in our cohort of 4 patients, lenalidomide was used in multisystem, relapsing cases.
Case reports
During a 23-year period from November 1, 1989, to March 1, 2013, 24 patients with adult Langerhans cell histiocytosis, 2 with Erdheim-Chester disease, 3 with multiple angiomatosis and 7 with multicentric Castleman disease were followed up at our department. Four cases demonstrated refractory disease, making them potential candidates for experimental treatment. We received lenalidomide for our patients after enrollment in the Celgene’s Compassionate Use Program (Celgene Corporation, Summit, New Jersey, USA). Based on our experience, we chose a dosing scheme used in multiple myeloma, i.e. 10-25 mg perorally on days 1-21 in a 28-day cycle. Antithrombotic prophylaxis with low-molecular-weight heparin was implemented in all patients but Case 3.
The first patient, a male born in 1973 (Case 1), was diagnosed with multisystem Langerhans cell histiocytosis affecting the lymph nodes, skin and lungs at the age of 35. The initial manifestation was reminiscent of a lymphoma with expressed B symptoms (night sweats, fever, weight loss, fatigue) and generalized lymphadenopathy. Early after the first-line treatment, the disease relapsed with dissemination into the bones and even an aggressive regimen completed by autologous peripheral blood stem cell transplant did not prevent a second relapse (Figure 1A). The patient was then started on lenalidomide monotherapy, which was later enhanced with dexamethasone and etoposide to boost a slower, though convincing response to single-agent therapy. The achieved nearly complete remission (Figure 1B) was consolidated by allogeneic blood stem cell transplant following reduced-intensity conditioning. During follow-up, positron emission tomography/computed tomography (PET/CT) showed complete disease remission at 3 months (Figure 1C) and 17 months (Figure 1D) after transplant. In March 2013, clinical and laboratory examinations confirmed a sustained disease-free status.

In the second case, a male born in 1965 (Case 2), it took more than 4 years to reveal the etiology behind pituitary stalk infiltration as Erdheim-Chester disease manifesting with diabetes insipidus. Moreover, osteosclerosis of the long bones, laboratory signs of a proinflammatory state (C-reactive protein 72.6 mg/L, fibrinogen 5.9 g/L), neurological symptoms (dysarthria) and pathological fatigue were present. Although magnetic resonance imaging (MRI) revealed partial regression of multiple brain lesions after initial systemic therapy, progressive metabolic activity in the long bones was documented on PET. In March 2010, the patient was started on lenalidomide monotherapy leading to complete resolution on MRI but showing further progression on PET after 6 cycles. Nevertheless, the patient had remained clinically stable until March 2011, when he commenced receiving anakinra as third-line therapy.
Back and abdominal pain, hematemesis, sideropenic anemia and hypoproteinemia were the presenting symptoms in a male patient born in 1977 (Case 3). In May 2005, following 2 years of inconclusive diagnostic investigations, pathological findings in a biopsied specimen during exploratory laparotomy was consistent with multiple angiomatosis affecting the visceral organs, mediastinum and skeletal system. The next 5 years we were adapting the applied antiangiogenic treatment, comprising various combinations of interferon-alpha and thalidomide, to a fragile balance between disease activity on the one hand and adverse drug reactions on the other (fatigue and depression with interferon, neuropathy with thalidomide). Based on radiological and radionuclide evaluation of the vascular tumors (PET, CT and MRI), serum levels of D-dimers and fibrinogen, ethanol gelification test results, hemoglobin levels and thrombocyte counts, the disease activity was assessed. In May 2010, forced by the exhausted applicability of thalidomide and interferon alpha, we decided on lenalidomide administration (9 cycles in total). Due to a mild increase in D-dimers (from 10.8 to 17.4 µg/mL) and a decrease in hemoglobin (from 135 to 117 g/L) after the first 2 months, lenalidomide monotherapy, facilitating substantial relief of neuropathy, was abandoned and enhanced by thalidomide later on. The combination regimen managed to stabilize the disease for 6 months, until an acute hemoglobin decrease appeared in April 2011, which made the patient eligible for further treatment options (propranolol, sunitinib, paclitaxel, bevacizumab, octreotide).
Multicentric plasma-cell Castleman disease, manifesting with generalized lymphadenopathy, sple­no­me­ga­ly, vasculitis and increased serum markers of inflammation (C-reactive protein 35.4 mg/L, fibrinogen 4.7 g/L), was diagnosed in a male patient born in 1961 (Case 4). PET/CT in September 2008 revealed a large pelvic mass located dorsally from the left common iliac vessels (Figure 2A). The resulting compression of adjacent structures was an indication for systemic therapy. After first-line chemotherapy failure, we opted for less aggressive treatment with thalidomide, leading to a 50% reduction in tumor size. The thalidomide-based regimen was interrupted once by a short period of tocilizumab applications which, however, could not keep the disease in remission. In October 2010, due to progressive adverse effects of thalidomide (neuropathy) and glucocorticoids (Cushing syndrome), the treatment was switched to lenalidomide monotherapy, resulting in metabolic remission (SUVmax from 6.15 to 2.70) as well as size regression (diameter from 29 to 19 mm) as documented in Figures 2B and 2C. According to restaging PET/CT in July 2012 (Figure 2D) and clinical and laboratory investigations in March 2013, the achieved remission has been maintained.
An overview of the applied regimens and their effects is shown in Table 1, while the histopathological findings are reviewed in Figure 3. In all 4 cases, the overall tolerance of lenalidomide was excellent; hematological treatment-related toxicities, a major concern with lenalidomide, were mostly mild, which could be explained by the absence of bone marrow involvement in the patients (Table 2). Available separately are detailed reports depicting the disease courses in Cases 1 and 4 until August 20111,2. Here we present the previously unpublished final data including a 1-year disease-free follow-up without any maintenance therapy.

Exhibiting potent antiinflammatory, antiangiogenic and immunomodulatory effects, lenalidomide is a functional and structural analog of thalidomide with reduced neurotoxic adverse events. Triggered by the first successful treatment in 19873, thalidomide gained popularity in managing low-risk mucocutaneous and/or bone forms of Langerhans cell histiocytosis. A phase II trial of thalidomide in repeatedly relapsing cases was published in 20074. Of 7 evaluable patients with low-risk organ involvement (i.e., skin, bone, lymph node or pituitary), 4 and 3 achieved complete and partial responses, respectively. Conversely, in the high-risk group (i.e., involving lung, liver, spleen or bone marrow) the mortality reached 100%. Reviewing the available literature, we have found only 1 report of an overall favorable response in a patient with high-risk organ involvement (lungs). However, the treatment was complicated by fatal sepsis 5. In Erdheim-Chester disease, a related non-Langerhans cell histiocytosis, no similar articles have been published so far.
Encouraged by the antiangiogenic activity of thalidomide in vascular dysplasias, hemangiomas and teleangiectasias, the first experimental applications of lenalidomide in this area included multifocal epithelioid hemangioendothelioma with disease stabilization after 6 years of lenalidomide administration6 and hereditary hemorrhagic telangiectasia, where lenalidomide proved superior to thalidomide in the prevention of gastrointestinal bleeding7.
Thalidomide is well established in the management of multicentric Castleman disease. Several case reports documented its efficacy as monotherapy8 or in combination with prednisone and cyclophosphamide9. Excellent results of 91% complete remissions were achieved with a multiagent regimen with rituximab in 11 mostly human immunodeficiency virus-positive patients10.
Complete and long-lasting disease remissions were obtained with lenalidomide in Cases 1 and 4 of our cohort, which had previously demonstrated refractory disease that was difficult to manage. A mixed response with complete disappearance of brain infiltrates was obtained in Case 2 and gastrointestinal bleeding was well controlled in Case 3. A March 2013 MEDLINE search of the English medical literature did not retrieve any relevant reports of lenalidomide therapy in other patients diagnosed with these disorders.
Substantially mediated via cytokine modulations, the mechanisms of action of thalidomide and its more potent derivative lenalidomide are complex. These drugs downregulate the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF- ) and interleukin-6 (IL-6), as well as vascular endothelial growth factor (VEGF), which promotes angiogenesis11. Increased expression of TNF- was demonstrated in lesional cells of Langerhans cell histiocytosis and also Erdheim-Chester disease12,13. Consequently, targeted anti-TNF therapies using etanercept and infliximab, respectively, proved effective in both entities14,15. Analogously, anti-IL-6 agents (tocilizumab, siltuximab) and anti-VEGF antibody (bevacizumab) were successfully applied in multicentric Castleman disease characterized by IL-6 overproduction and multiple angiomatosis defined by VEGF dysregulation, respectively16,17. These translational findings of molecular-targeted therapies together with additional immunoregulatory effects and direct antitumor properties substantiate the novel treatment strategy with lenalidomide in the discussed diagnoses.
In conclusion, we propose lenalidomide as a standard component in the treatment of Langerhans cell histiocytosis and multicentric Castleman disease, even as frontline therapy. In cases of Erdheim-Chester disease and multiple angiomatosis it is an attractive alternative agent whose efficacy needs to be further investigated to delineate its exact indication range. Obviously, clinical studies confirming these preliminary data are required. In the setting of rare diseases, however, innovative trial designs (i.e., adaptive trials or using Bayesian statistics) and stable economic resources (e.g., drug funding) should be thoughtfully considered 18. To address these challenging new issues, an ongoing campaign, “Rare Cancers Europe” (, has been established by the European Society of Medical Oncology.
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