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Improving survival in patients with transformed B cell non Hodgkin lymphoma: consolidation with 90 Yttrium ibritumomab tiuxetan‐BEAM and autologous stem cell transplantation

2012; Wiley; Volume: 157; Issue: 3 Linguagem: Inglês

10.1111/j.1365-2141.2011.08991.x

1365-2141

Mariëlle J. Wondergem, Josée M. Zijlstra, Madelon de Rooij, Otto Visser, Peter C. Huijgens, Sonja Zweegman,

Chronic Lymphocytic Leukemia Research

Recently, Eide et al (2011) suggested an important role for high dose chemotherapy followed by autologous stem cell transplantation (AuSCT) in patients with histologically transformed B cell non-Hodgkin lymphoma (NHL). However, this prospective study was conducted in the pre-rituximab era, therefore the results cannot be translated to patients who would currently be treated with rituximab-containing chemotherapy regimens prior to AuSCT. Since 2006, a cohort of 32 patients with transformed B cell NHL has uniformly been treated with rituximab-containing reinduction therapy at our centre. Of these 32 patients, 25% did not reach at least partial remission (PR, defined as a decrease in tumour diameter of at least 50% on a computerized tomography scan). We hereby present the results of the 24 patients who proceeded to AuSCT following conditioning with 90Yttrium-ibritumomab tiuxetan-BEAM and AuSCT (Z-BEAM: 90Yttrium-ibritumomab tiuxetan=Zevalin® dose 14·8 MBq/kg (maximum 1184 MBq) on day −15, carmustine 300 mg/m2 on day −6, etoposide 100 mg/m2 every 12 h and cytarabine 200 mg/m2 once daily on days −5 to −2 and melphalan 140 mg/m2 on day −1). Histological confirmation of transformation was defined as a diagnosis of diffuse large B cell lymphoma (DLBCL) in patients with either a previous (n = 19) or simultaneous (n = 5) histological diagnosis of follicular lymphoma (FL) according to the World Health Organization classification (Harris et al, 1994). Importantly, patients with DLBCL with indolent lymphoma in the bone marrow only were excluded as a superior outcome has been reported in these patients (Robertson et al, 1991). Similar to the series reported by Eide et al (2011), patients were eligible for AuSCT at the time of first diagnosis of transformation (n = 15) or after subsequent relapse (n = 9). Unlike the Eide series (Eide et al (2011), all of our 24 patients were treated with rituximab during the re-induction regimen. Eleven patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and 13 with R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin). However, unexpectedly, the addition of rituximab to chemotherapy did not result in an improved response rate before AuSCT as compared to that reported by Eide et al (2011) (75% in our series versus 72% in Eide's series). A possible explanation might be that pre-treatment with rituximab leads to rituximab resistance, as 15/24 patients had been treated with rituximab prior to re-induction therapy. Moreover, it can be hypothesized that histological transformation itself confers rituximab resistance. Several mechanisms of rituximab resistance in lymphoma have been suggested, such as downregulation of CD20 expression and polymorphisms of FcR or complement components leading to diminished antibody-mediated cellular cytotoxicity or complement-dependent cytotoxicity response. Lastly, up-regulation of signalling pathways and anti-apoptotic proteins has been implicated in causing rituximab resistance. Unfortunately, specific mechanisms conferring resistance in transformed lymphoma are presently unknown (Stolz & Schuler, 2009) Currently, the median follow up of all patients undergoing AuSCT after conditioning with Z-BEAM is 20 months (range 6–56). Five patients relapsed after 6, 10, 11, 23 and 23 months, respectively. None of the patients who were rituximab-naïve before re-induction therapy have relapsed. Progression-free survival (PFS) at 2 years was 80% and overall survival is 100% to date. Radioimmunotherapy did not lead to additional toxicity as compared to our previous experience with BEAM conditioning: treatment-related mortality was 0%, median time until neutrophil recovery (>0·5 × 109/l) and platelet recovery (>20 × 109/l) was 15 d (platelet recovery >50 × 109/l: 24 d). Patients who experienced relapse following AuSCT had sufficient bone marrow capacity to undergo salvage treatment. They were rescued with either an allogeneic transplantation (n = 2, 1 for relapse of DLBCL, 1 for relapse of FL) or chemoimmunotherapy (n = 2, 1 for relapse of DLBCL, 1 for relapse of FL). One patient with relapsed FL has not required treatment yet. We supplemented AuSCT conditioning with radioimmunotherapy because the latter treatment adds a new therapeutic modality in an inherently radiosensitive disease and allows escalation of radiation dose to tumour sites without additional toxicity to uninvolved organs. Indeed, the addition of 90Yttrium-ibritumomab tiuxetan (Zevalin®) and 131Iodine tositumomab (Bexxar®) to high dose conditioning regimens for AuSCT has lead to promising results [estimated 2-year overall survival (OS) of 65–85%] in high risk NHL patients. However, these studies included only a total of 15 transformed lymphoma patients (Vose et al, 2005; Shimoni et al, 2007; Krishnan et al, 2008). Our series is the largest consisting of transformed lymphoma patients only, who were uniformly treated with Z-BEAM and AuSCT. The follow-up is still short, but importantly, the survival rate of 100% at 2 years compares favourably to the 2-year OS of 73% reported by Eide et al (2011) who performed AuSCT without the addition of radioimmunotherapy. While it is still unclear whether patients who respond well to (re)induction with chemoimmunotherapy benefit from upfront consolidation with AuSCT, both the study reported by Eide et al (2011) and our results strongly suggests an additive effect of consolidation with AuSCT on survival in this patient group. Moreover, we have obtained an impressive outcome by the addition of radioimmunotherapy with 90Yttrium-ibritumomab tiuxetan, reaching a 2-year PFS of 80% (cf. 50% reported by Eide et al, 2011) and a 2-year OS of 100% (cf. 73% reported by Eide et al, 2011) Unfortunately, the superiority of consolidation with Z-BEAM and AuSCT over consolidation with BEAM and AuSCT or rituximab-based chemotherapy only is unlikely to ever be substantiated by a randomized controlled trial, considering the low incidence of transformed B cell NHL. However, it is important to realize that the outcome we describe in patients treated with Z-BEAM compares favourably with the 5-year OS of 57% in a study that used rituximab-based chemotherapy only (Abdulwahab et al, 2007), especially when taking into account that these patients were all rituximab-naïve and that PFS and OS were 100% at last follow-up in our rituximab-naïve patients. In addition, when comparing our data to Eide et al (2011), the addition of rituximab to induction chemotherapy did not increase the response rate, highlighting the need for radioimmunotherapy. Although not directly comparable with the cohort reported by Eide et al (2011), our data strongly support the incorporation of radioimmunotherapy in the treatment of patients with transformed B cell NHL. All authors contributed to collection of patient data and MR and MJW performed data analyses. MJW and SZ wrote the manuscript. All authors critically reviewed and approved the manuscript.