A Phase II Clinical Trial of Fludarabine and Cyclophosphamide Followed by Thalidomide for Angioimmunoblastic Lymphoma (AITL), an NCRI Clinical Trial. CRUK C17050/A5671

Angioimmunoblastic T-cell lymphoma (AITL) is a rare disease accounting for 1–2% of all non-Hodgkin's lymphomas. It characteristically has an aggressive course with poor prognosis and a median overall survival (OS) in the order of 3 years. The median age at presentation is 65–70 years and most patients present with advanced stage disease. Due to its low incidence, few prospective clinical trials have been performed and the optimal treatment is not known. There is evidence that purine analogues are efficacious in AITL and the combination of fludarabine and cyclophosphamide (FluCy) has a high level of efficacy in other lymphoproliferative disorders. There are also good theoretical reasons and preliminary evidence to support the use of thalidomide in AITL. This multi-centre, phase II trial was designed to assess the efficacy and tolerability of FluCy chemotherapy and incremental response to consolidation with 6 months of thalidomide treatment.

Using a Bayesian 2-stage design, it was planned to recruit 15 patients with a further 22 patients recruited to a second stage if a complete remission (CR) rate of >33% was achieved. Inclusion criteria were previously untreated AITL with measurable disease, performance status <3, age >18 years, and valid consent. The primary endpoint was response rate to FluCy. Secondary endpoints were response rate to thalidomide, toxicity, progression free survival (PFS), and OS. Treatment consisted of fludarabine 40mg/m² and cyclophosphamide 250mg/m² orally on days 1–3 of each 28 day cycle. Four cycles of FluCy were given prior to restaging. Patients progressing on FluCy came off study. Those with stable disease or responses had the option of 2 further cycles of FluCy prior to commencing thalidomide maintenance. Thalidomide 100mg once daily was given as continuous therapy starting 4 weeks after the final cycle of FluCy, with dose increases every 4 weeks to 300mg if tolerated.

15 patients were recruited from 6 centres over 3 years from February 2009 to March 2012. The median age was 68 years (range 52–91) with more female than male patients (67% vs. 33%). 87% of patients had advanced stage disease. Four or more cycles of FluCy were administered in 53% of patients. Responses (CR, CRu, PR) were achieved in 9 patients (60%) with CR in 5 (33%). Reasons for early cessation of treatment were hematological toxicity (n=2), death (n=2) and failure to respond (n=3). Grade 3 or 4 hematological toxicity occurred in 8 (53%) patients, grade 3 or 4 non-hematological toxicity was experienced in 9 (60%) patients. Grade 1–2 peripheral neuropathy was reported in 2 patients. Guillain-Barré syndrome was reported in 2 patients in the thalidomide maintenance phase but resolved in both cases. Of the 9 patients with at least stable disease after FluCy, 7 received thalidomide, 2 patients did not receive thalidomide due to hematological toxicity and progression respectively. Remission status did not improve in any patients receiving thalidomide maintenance (6 patients progressed or have died and remission status was unchanged in the remaining patient). At a median follow-up of 14.9 months, 8 patients (53%) are alive. The estimated median OS is 18.2 months and median PFS is 7.9 months. Of the patients still alive, 4 have progressed, 2 (13%) are alive without progression, and 2 are not assessable for response due to early termination of treatment. The causes of death in the 7 deceased patients were lymphoma (5), infection (1), and Crohn's disease (1).

AITL is an aggressive lymphoma with poor outcome. The overall response rate in this trial of 60% (CR rate of 33%) was promising but remissions were short lived with a PFS of only 7.9 months. Only 2 patients are alive without progression at a median follow-up of 14.9 months. Thalidomide maintenance did not consolidate remission in any patients. The trial did not proceed to the 2^nd stage of recruitment and demonstrates the difficulties in conducting prospective clinical trials in rare disorders such as AITL. The CR rate and duration of remission observed with FluCy are inferior to those reported with CHOP-type regimens. On the basis of these results, we recommend considering FluCy as first line treatment for AITL only when CHOP is contraindicated. Also, we found no evidence to support the use of thalidomide in this disease.

Off Label Use: Thalidomide is used off licence in the trial for the treatment of AITL.