Sequential Therapy Combining Clofarabine and HLA-Haploidentical Hematopoietic Stem Cell Transplantation In The Treatment Of Refractory and Advanced Lymphoma: Feasibility, Toxicity and Early Outcome

Allogeneic hematopoietic stem cell transplantation (HSCT) is a valuable treatment option for patients with relapsed or refractory lymphoma including patients with relapse after a first autologous HSCT. However, outcome in non-remission patients is still poor. Here we report the feasibility and efficacy of a protocol using the concept of sequential therapy with clofarabine induction chemotherapy followed by a HLA-haploidentical HSCT in the treatment of patients with advanced non-remission lymphoma.

16 adults (11 male, median age: 53 years, median comorbidity index: 3) with MCL (n=7), CLL (n=1), AITL (n=2), secondary DLBCL (n=2), DLBCL (n=2), follicular lymphoma (n=1), B- lymphoblastic lymphoma (n=1) were treated between September 2010 and February 2013. After induction-chemotherapy with clofarabine (5x30 mg/m² IV), followed by 3 days of rest, a reduced intensity conditioning (RIC) consisting of fludarabine/cyclophosphamide plus melphalan 110 mg/m² IV was performed prior to a T-cell replete HLA-haploidentical HSCT. High dose cyclophosphamide (Cy) was administered for post-grafting immuno-suppression followed by mycophenolate mofetil and tacrolimus.

The median number of immuno-chemotherapy attempts prior to haploidentical HSCT was 4 including 8 autologous HSCT. None of the patients were in complete remission (CR) prior to haploidentical HSCT. After salvage therapy and prior to haploidentical HSCT, progressive disease (PD) was documented in 9 patients with one patient being primarily refractory, while in 7 patients a partial remission (PR) was observed.

Neutrophil engraftment was achieved in 16 patients (100%) within a median of 21 days (range 14-36) and platelet engraftment in 14 patients (88%) within a median of 30 days (range 18-115). No primary graft rejection occured. By day +30 CR was achieved in 4 patients (25%) and PR in 11 patients (69%), whereas 1 patient (6%) showed PD. Full donor chimerism on day +30 was detected in all 16 patients. By day +100, 8 of the 14 evaluated 14 patients (57%) achieved CR, 4 (29%) PR, and only 2 (14%) had relapsed. Full donor chimerism was detected in 13 (93%) patients. The rate of acute GvHD grade II-IV was 31%, while chronic GvHD occurred in 3 of 14 (21%) evaluable patients (21%). Non hematologic regimen-related grade III-IV toxicity was observed in 9 patients (56%), and included most commonly transient elevation of liver enzymes (38%), mucositis (19%), and nausea and vomiting (19%). Creatinine elevation (6%), hand-foot syndrome (6%) and haemorrhagic cystitis (6%) were rare. After a median follow up of 14.5 months (range 5.7-35) 4 patients had relapsed, and 4 patients had died, while death was lymphoma-associated only in one patient. Causes of non-relapse mortality (NRM) were haemorrhagic cerebral bleeding in one patient (day +101), and toxicity/infection in 2 patients (day +141; day +156). Cumulative incidence of NRM was 0% on day +100 and increased up to 20% (7-50) on day +360. Estimated one-year overall survival and progression-free survival were 75% (95 CI 46-90) and 56% (95 CI 30-76), respectively.

Sequential therapy combining cloforabine induction-chemotherapy and HLA-haploidentical HSCT using RIC, a T-cell replete graft and high dose Cy post-transplant is feasible, shows a favourable toxicity profile and furthermore achieves significant anti-lymphoid activity in patients with advanced non-remission lymphoma. These early results are promising, but longer follow up is needed.