B-CLL is the most prevalent chronic lymphoproliferative disease and follows a typically indolent course, however 2-15% of patients [
1-
3] transform to an invariably aggressive, chemo-resistant high-grade non-Hodgkin’s lymphoma (NHL) [
4]. This high-grade transformation of CLL was first recognised in 1928 by Maurice Richter who described an aggressive, life-threatening presentation of rapidly fatal generalized lymphadenopathy and hepatosplenomegaly [
4] that he called a “reticular cell sarcoma” arising in a patient with B-CLL. Whereas all subtypes of NHL taken together represent the fifth most common cancer type in the world and its incidence continues to increase [
5], Richter’s syndrome (RS) is rare and characterised by disproportionate weight loss, rapidly growing and/or asymmetrical lymphadenopathy or extranodal fluorodeoxyglucose ([
18F] FDG) positron-emission-tomography (PET) CT-avid masses, new B symptoms, a rapidly rising lactate dehydrogenase (LDH), or new hypercalcaemia in a patient with known B-CLL. The vast majority of RS represent transformations to an activated B-cell type (ABC) diffuse large B-cell lymphoma (DLBCL) (90-95%) with a small proportion transforming to Hodgkin’s lymphoma [
6]. The prognosis of
de novo DLBCL has much improved over the last 15 years with the introduction of the anti-CD20 monoclonal antibody rituximab to an anthracycline based regimen, typically CHOP (cyclophosphamide, doxorubicin, oncovin (vincristine), prednisolone) such that the long term survival in those fit for anthracycline-based therapy is approaching 70% [
7]. Unfortunately, the same cannot be said for DLBCL-Richter’s syndrome. RS can present in either heavily pre-treated, immunosuppressed or in untreated B-CLL patients [
8]. Patients typically present with a deteriorating performance status. The median age of B-CLL diagnosis is 72 years [
9], and therefore patients often possess dose-limiting co-morbidities. Given its rarity, no multicentre randomised controlled trials have been performed. Alkylator, anthracycline, platinum and purine analogue chemotherapy have formed the backbone of a number of regimens trialled in RS. R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab) [
7], R-hyper-CVXD-MA [
10] (fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and alternating with methotrexate and cytarabine with rituximab), hyper-CVXD alone [
11], FACPGM (fludarabine, cytarabine, cyclophosphamide, cisplatin and GM-CSF) [
12], OFAR1 [
13] and OFAR2 [
14] (oxaliplatin, fludarabine, cytarabine, rituximab and pegfilgrastim) [
2] treatment regimens have been used. The best response rates are 41% with hyper-CVXD and R-hyper-CVXD-MA and 50% with OFAR1, although responses are short-lived. Moreover, these regimens are toxic and inappropriate for many patients with RS. The median survival of 8–10 months [
2] from diagnosis has generally not been bettered in the literature. Recent published data using R-CHOP in 15 patients with Richter’s Syndrome showed an overall response rate of 67% but the progression free survival (10 months) and overall survival (21 months), although an improvement, was still short and the study number was very small [
15]. Autologous and allogeneic bone marrow transplantation are reserved for younger patients with good performance status [
8].
Ofatumumab is a fully humanised monoclonal IgG anti-CD20 antibody. It specifically and powerfully targets a unique CD20 epitope on B cells. When compared with rituximab, it binds with increased affinity and has a longer dissociation time, both of which improves its complement-mediated cellular cytotoxicity [
16,
17]. As a result, ofatumumab has a greater potential to induce B cell apoptosis independently of p53 than rituximab, and has been shown to be efficacious and non-toxic in relapsed B-CLL refractory to fludarabine and alemtuzumab; a group that commonly possess TP53 mutations and/or deletions [
18]. Given the high incidence of TP53 disruption in patients with DLBCL-RS [
19] and that patients characteristically relapse early after initial response to induction, it was felt that ofatumumab as induction (alongside CHOP) and maintenance therapy would represent both a pragmatic and biologically-sound treatment for patients with RS within this phase II clinical trial. As many clinicians treat DLBCL-RS with R-CHOP outside of a clinical trial, the National Cancer Research Institute (NCRI) UK-based “CHOP-OR” single arm, multicentre study was therefore designed to investigate whether DLBCL-RS treated with six cycles of CHOP-O followed by maintenance ofatumumab every eight weeks for 48 weeks in responding patients was feasible and improved clinical efficacy over and above R-CHOP.