Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma (2009)

Most Hodgkin Lymphoma (HL) patients can be cured with chemotherapy, radiotherapy or combined modality treatment. However, current treatment is associated with toxicities, such as infertility, cardiovascular damage and secondary malignancies (Fuchs et al, 2006). Moreover, about 10% of all HL patients have refractory disease despite high dose chemotherapy and autologous or allogeneic stem cell transplantation (Cashen & Bartlett, 2008; Laport, 2008; Sureda et al, 2008). Lenalidomide (Revlimid), a thalidomide-derivate, belongs to a novel class of immunomodulatory drugs (IMIDs) approved for the treatment of Multiple Myeloma and Myelodysplastic Syndrome with deletion (-q5) (Chanan-Khan & Cheson, 2008). Lenalidomide has multiple modes of action, including direct induction of apoptosis in tumour cells, antiangiogenic effects and the activation of immune cells, such as Natural Killer cells and T-cells (Marriott et al, 2001; Bartlett et al, 2004). Apoptosis resistance, increased neoangiogenesis and impaired immunity critically contribute to HL (Re et al, 2005; Enblad et al, 2007). We therefore hypothesized that single agent lenalidomide might be active in HL patients who have failed conventional chemotherapy. Lenalidomide was provided by Celgene (Munich, Germany) for each individual patient within a named patient program. Between February 2007 and November 2008, 12 patients with relapsed or refractory HL were included in this program in four German centres (Table I). Participants gave written informed consent, had no curative treatment options, an Eastern Cooperative Oncology Group performance status ≤2 and normal organ functions including peripheral blood counts within the normal range. Patients received oral Lenalidomide 25 mg/d for 21 d of a 28-day cycle. Patients were staged and restaged with computed tomography (CT) of the initially involved sites; the use of PET was optional. Response was defined according to the National Cancer institute Sponsored International Working Group criteria (Cheson et al, 1999) and evaluated after two cycles and every other cycle thereafter. Treatment was continued until disease progression or intolerable toxicity occurred. Concomitant anti-thrombotic prophylaxis with oral acetylsalicylic acid 100 mg/d was mandatory. Patients with a history of thrombosis or thrombembolic events received low molecular heparin. All patients were informed regarding the teratogenic risks of lenalidomide and agreed to use effective contraception at least during treatment and 4 weeks afterwards. Toxicities were assessed at each study visit according to National Cancer Institute Common Terminology Criteria (CTC) for Adverse Events version 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). Twelve adult patients (median age 34·5 years, range 20–64 years) with relapsed (Patients 4 and 8) or refractory HL (all other patients) were treated with single-agent lenalidomide. Two patients had lymphocyte predominant HL, all other patients had classical HL; nodular sclerosis was the most frequent histological subtype. All patients had relapsed after at least four chemotherapies (mean 6, range 4–9 previous therapies) and 10 of the 12 patients had advanced-stage disease. All but two patients had previously undergone high-dose chemotherapy and autologous stem cell transplantation; one patient had relapsed after allogeneic stem cell transplantation. Most patients (10 of 12) had not responded to the previous treatment. One patient discontinued lenalidomide because of asymptomatic pulmonary embolism, which was detected on a routine CT scan. One patient withdrew consent after two cycles of lenalidomide. All other patients completed a minimum of four treatment cycles. None of the patients received concomitant medication other than anticoagulation. Four patients continued the treatment after the first four cycles and three patients are currently still on treatment. The mean number of cycles applied to date was 7 (range 2–25). Overall toxicity was very low with no toxicity occurring with a CTC grade above 2. Non-haematological toxicities observed were one CTC grade-2 pulmonary embolism in a patient who discontinued the treatment and CTC grade-1 constipation and CTC grade-1 dyspnea in two other patients. One patient experienced an episode of CTC grade-2 diarrhoea with positive testing for Norovirus-RNA, and another patient developed a non-squamous, spontaneously resolving CTC grade-2 rash. Haematological toxicity included CTC grade-2 leucopenia in two patients and CTC grade-2 thrombocytopenia in another patient. All patients continued on the same dose level and recovered without further intervention. For two patients (No 7 and 9) the dose of lenalidomide was increased to 25 mg/d continuously after the sixth cycle due to the decision of the treating physician. None of the 12 patients showed radiological evidence of progression after two cycles of lenalidomide. Overall, six of the heavily pretreated patients responded to lenalidomide (overall response rate: 50%). Six patients had stable disease and five patients achieved partial remission after two cycles. The best response was observed in one patient, who had relapsed stage IIA disease with nodal involvement at iliacal, paraaortic and inguinal location. The patient had relapsed after six previous therapies including high-dose chemotherapy, and achieved partial remission after two cycles, and complete remission after four cycles of lenalidomide. The patient is currently still on lenalidomide treatment without signs of relapse after 24 months. The duration of response is ongoing. Figure 1C shows the maximum cumulative change in tumour size (volume of the six largest lesions) compared to baseline tumour volume. Clinical signs of response were observed in two patients: one patient experienced a complete alleviation of a persistent HL-related pruritus, and in another patient, night sweats ceased after two cycles of lenalidomide. The response measured by CT scan correlated with a decrease in fluorodeoxyglucose uptake at the tumour sites (representative example shown in Fig 1). Interestingly, all patients but one achieved their best response to lenalidomide after the first two cycles. However, two of the four responding patients had evidence of progression after 2 or 4 months. (A) and (B) Fluorodeoxyglucose-positron emission tomography of Patient 7 before (A) and after two cycles (B) of lenalidomide. PET was performed according to the recommendations published by the international harmonization project on malignant lymphoma. (C) Cumulative change in tumour size for each patient. Bars indicate tumour volume after treatment with lenalidomide as percentage of baseline tumour volume measured by CT scan. In conclusion, Lenalidomide was very well tolerated in patients with refractory or multiple relapsed HL. Even in two patients receiving lenalidomide 25 mg/d continuously, we did not observe any toxicity higher than CTC grade-2. All patients treated with lenalidomide in this named patient program had clinical benefit of lenalidomide treatment in terms of disease stabilization. Half of the patients responded to single-agent lenalidomide, including one patient with an ongoing complete remission. As a consequence of our observations, an international phase II study of single agent lenalidomide in relapsed HL patients is planned. Moreover, an international phase I/II study of lenalidomide combined with conventional chemotherapy (AVD-Rev) for elderly HL patients has been initiated. BB analysed date and wrote the manuscript. PB, MT, MH, KSR, AE and RN coordinated the research, collected and analysed data and contributed in writing the paper. The authors report no competing financial interests.