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REVIEW Current status and future perspectives for -90 (90Y)- in transplantation for non-Hodgkin’s

C Gisselbrecht1, W Bethge2, RF Duarte3, AM Gianni4, B Glass5, C Haioun6, G Martinelli7, A Nagler8, R Pettengell9, A Sureda10, H Tilly11 and K Wilson12

1Institut d’He´matologie, Hoˆpital Saint-Louis, Paris, France; 2Medizinische Universita¨tsklinik II Hematology/Oncology, Tu¨bingen, Germany; 3Institut Catala` d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain; 4Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; 5University Hospital Go¨ttingen, Go¨ttingen, Germany; 6Service d’He´matologie Clinique, Hoˆpital Henri Mondor, Cre´teil, France; 7European Institute of Oncology, Milan, Italy; 8Chaim Sheba Medical Center, Tel-Hashomer, Israel; 9St George’s Hospital, University of London, London, UK; 10Hospital de la Santa Creu i Sant Pau, Universidad Autonoma de Barcelona, Barcelona, Spain; 11Department of Hematology, Centre Henri Becquerel, Rouen, France and 12School of Medicine, Cardiff University, Wales, UK

Haematopoietic SCT is currently considered a therapeutic Keywords: non-Hodgkin’s lymphoma; yttrium-90 ibritu- option mainly in relapsed or refractory non-Hodgkin’s momab tiuxetan; radiolabelled immunotherapy; stem cell lymphoma (NHL) owing to high post-transplant- transplantation; autologous; allogeneic ation relapse rates and significant toxicity of conventional myeloablative conditioning for allogeneic SCT. Radio- labelled immunotherapy combines the benefits of mono- clonal targeting with therapeutic doses of radiation, and is a promising advance in the treat- Introduction ment of malignant . It is now under investiga- tion as a component of conditioning prior to SCT, with In non-Hodgkin’s lymphoma (NHL), haematopoietic SCT the aim of improving outcomes following SCT without is primarily considered as a therapeutic option for relapsed increasing the toxicity of high-dose pre- or refractory patients, who have a poor prognosis with transplant conditioning. An expert panel met at a conventional salvage chemotherapy. It is also occasionally European workshop in November 2006 to review the used as an initial treatment in some younger high-risk latest data on radiolabelled immunotherapy in the patients, although there are controversies over the clinical transplant setting, and its potential future directions, with evidence indicating that outcomes are better versus a focus on 90Y-ibritumomab tiuxetan. They reviewed data conventional chemotherapy. A variety of conditioning on the combination of standard/high/escalating dose 90Y- regimens, which aim to eliminate or reduce cancer cells ibritumomab tiuxetan with high-dose chemotherapy, and prior to transplant, have been investigated. Myeloablative high/escalating dose 90Y-ibritumomab tiuxetan as the sole conditioning traditionally comprises high-dose chemother- myeloablative agent, prior to autologous SCT, and also apy (HDC) with or without TBI but is associated with 90Y-ibritumomab tiuxetan as a component of reduced toxicity, which limits its use in certain patient groups such intensity conditioning prior to allogeneic SCT. The as the elderly. Moreover, there is still a significant relapse preliminary data are highly promising in terms of rate post-transplantation, indicating that eradication of conditioning tolerability and patient outcomes following tumour cells is incomplete or that there is a lack of transplant; further phase II studies are now needed to GvL effect after allograft. The combination of consolidate these data and to investigate specific patient immunotherapy with conventional chemotherapy regimens populations and NHL subtypes. led to improvements in response rates in NHL, and now Bone Marrow Transplantation (2007) 40, 1007–1017; radiolabelled immunotherapy, which combines the benefits doi:10.1038/sj.bmt.1705868; published online 8 October 2007 of targeting with therapeutic doses of radiation, is promising to be a major step forward in the treatment of malignant lymphomas. The improved toler- ability of radiolabelled immunotherapy plus HDC com- pared with TBI plus HDC may allow transplantation in a wider patient group in the future than was previously Correspondence: Professor C Gisselbrecht, Institut d’He´ matologie, feasible. This article reviews the latest data on yttrium-90 Hoˆ pital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10, (90Y)-ibritumomab tiuxetan (Zevalin, Schering France. E-mail: [email protected] Pharma AG, Berlin, Germany) in both autologous and Received 30 May 2007; revised 20 August 2007; accepted 20 August 2007; allogeneic SCT for NHL, and summarizes the outcomes published online 8 October 2007 of a European workshop held to discuss the potential 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1008 future role for 90Y-ibritumomab tiuxetan in transplantation younger patients5–8 with the exception of cardiac toxicity conditioning regimens. and renal impairment, which may be higher in elderly patients;9 however, it should be noted that transplant is only possible in selected patients over the age of 65 years, Current concepts in SCT in NHL that is, those fulfilling all of the eligibility criteria for transplant. Transplant-related mortality (TRM) is low for 10 The treatment of NHL and the role of SCT autologous SCT, with rates below 5%. However, auto- Non-Hodgkin’s lymphoma is a heterogeneous group of logous transplantation has only limited success when lymphoid malignancies that most commonly occur in performed in the refractory or progressive stages of individuals over the age of 60 years. Aggressive (high- lymphoma and in heavily pre-treated or multiply relapsed grade) subtypes progress rapidly but are potentially patients. curable, whereas indolent (low-grade) subtypes are slower Allogeneic transplantation has the advantage of provid- growing but usually relapse after conventional treatment. ing a tumour-free graft and the additional benefit of a The introduction of immunotherapy, and its combination potent GvL anti-tumour effect, allowing potential cure with chemotherapy, greatly improved remission rates even in low-grade and advanced lymphoma patients, albeit compared with chemotherapy alone in NHL, and more at the cost of higher morbidity and mortality derived from recently, the combination of immunotherapy plus 90Yor the development of GvHD. It is generally considered for iodine-131 (131I) radiation has shown much greater efficacy younger patients for whom there is a suitable donor, and than immunotherapy alone and may improve overall may also offer an alternative in patients not suitable for, or survival (OS). having relapsed after, autologous SCT. Retrospective The greatest challenge in NHL is keeping patients in multi-centre studies suggest that relapse rates and PFS remission once they respond to . Following induc- are better following allogeneic transplant compared to tion therapy, options for consolidation therapy include autologous SCT in NHL, with cure rates of around 11–13 chemotherapy and SCT, with or without maintenance 20–40%, although prospective, randomized trials are therapy; SCT permits higher doses of chemotherapy to needed to confirm this. Conventional high-dose myelo- be used. ablative conditioning (cyclophosphamide plus TBI or busulphan) is associated with high toxicity and TRM rates of up to 40%.10 However, TRM associated with allogeneic Outcomes of SCT in NHL SCT is steadily being reduced, particularly with the High-dose chemotherapy conditioning and autologous introduction of reduced-intensity conditioning (RIC) regi- SCT now have an established role in patients in first mens.12 RIC regimens use lower doses of chemotherapy chemosensitive relapse of aggressive NHL, resulting in and radiation, allowing engraftment of donor cells with estimated 5-year -free survival rates of 40–50%,1 reduced toxicity compared to myeloablative regimens. and significantly higher survival rates versus chemotherapy Most are fludarabine-based and include TBI or other alone.2 There is still controversy over the use of HDC and agents such as melphalan.4,14–17 RIC regimens shift the SCT as consolidation first-line in poor-prognosis aggressive burden of tumour-killing from chemotherapy to the GvL lymphoma. Several phase III studies prior to the rituximab effect mediated by donor T cells; therefore, efficacy is era suggested an improvement in event-free survival (EFS) dependant on the immune response to the donor cells and a in poor-prognosis (FL). In a recent longer time may be required to achieve remission. phase III trial comparing the efficacy of rituximab plus Allogeneic SCT after RIC is therefore more suitable for standard chemotherapy (R-CHOP) with rituximab plus indolent lymphomas. Aggressive lymphomas often progress HDC and autologous SCT (R-HDC-SCT) as first-line or relapse before the anti-lymphoma effect develops and therapy in poor-risk FL patients, preliminary data indi- are therefore better suited to conventional high-dose cated better EFS and progression-free survival (PFS) in the myeloablative conditioning. RIC is generally carried out R-HDC-SCT arm. No differences were observed in terms in patients already in remission; as the conditioning is not of OS at that time, although the trial was not designed to myeloablative, the risk of relapse is high if the patient has assess this.3 A clinical study evaluating rituximab admin- not achieved a CR or very good PR before SCT.18 The istration after autologous (n ¼ 16) or allogeneic (n ¼ 12) reduced toxicity and better tolerability of RIC regimens SCT in patients at high risk for post-transplant relapse also allow SCT in older patients and in those with indicated that rituximab may be effective in reducing the comorbidities or contraindications to conventional regi- relapse rate and improving outcome in high-risk aggressive mens. To date there are no randomized comparisons of lymphoma. Of 24 patients receiving rituximab starting at a conventional and RIC regimens and further data are median of 47days post-transplant, 9 patients converted to awaited to confirm the best conditioning regimen in a CR. Onset of GvHD was observed in three patients. At a different patient groups. median follow-up of 12 months the estimated 2-year OS rate was 95%, the disease-free survival rate was 64% and the relapse rate was 35%.4 Autologous and allogeneic SCT in Europe Autologous SCT was previously not carried out in Data from the European Group for Blood and Marrow elderly patients owing to their expected inability to tolerate Transplantation (EBMT) lymphoma registry show that in myeloablative conditioning regimens. Some studies have B-cell NHL, the total number of SCTs carried out from shown no differences in outcome between older and January 2001 to December 2005 totalled 15 636, of which

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1009 88% were autologous (Lymphoma Working Party of the phase II to phase III clinical trials with single-agent EBMT, 2006). Of the autologous transplants performed, 90Y-ibritumomab tiuxetan have been previously reviewed 33% were in patients with refractory, relapsed or progres- in detail.19–21,23 sive disease, and 24% in patients in their first CR. Recent Radiolabelled immunotherapy agents such as 90Y-ibritu- figures show that TBI was used in the conditioning regimen momab tiuxetan are likely to play an increasingly for only 8% of autologous transplants. The use of TBI in significant role in SCT by improving the tolerability and conditioning regimens in FL has fallen over the past 15 increasing the efficacy of the conditioning regimen, thereby years; in 1992 it was used in over 50% transplants but in reducing the relapse risk. Owing to its good tolerability 2005 in only 15%; a similar decrease has been seen for profile, the use of 90Y-ibritumomab tiuxetan at high dose as diffuse large B-cell lymphoma (DLBCL) from 28% in 1990 the sole conditioning agent in place of HDC is also showing to just 2% in 2005. promise, and may allow transplantation in patients who cannot tolerate the more aggressive conditioning regimens, Rationale for using 90Y-ibritumomab tiuxetan in SCT such as the elderly or those with comorbidities, especially Lymphomas are inherently radiosensitive, providing a cardiovascular disease. The dose-limiting toxicity of rationale for using radiation to treat NHL, and the radiolabelled immunotherapy is haematotoxicity; SCT targeted delivery of radiation directly to tumour sites is eliminates this toxicity and may allow even further dose better tolerated and more efficient than TBI. The principles escalation. The following sections review the key studies 90 of radiolabelled immunotherapy, which allows targeted investigating the use of Y-ibritumomab tiuxetan in delivery of a therapeutic dose of radiation not only to the conditioning regimens prior to autologous and allogeneic surface of tumour cells at multiple sites but also to SCT. neighbouring deeper cells, have been reviewed extensively in recent publications.19–22 The only radiolabelled immuno- conjugates currently approved for the treatment of 90Y-ibritumomab tiuxetan in autologous SCT NHL are 90Y-ibritumomab tiuxetan and 131I- (Bexxar, GlaxoSmithKline, USA; only approved in the Standard-dose 90Y-ibritumomab tiuxetan plus United States), both of which are directed against the CD20 chemotherapy cell surface . 90Y-ibritumomab tiuxetan comprises Shimoni and colleagues4,24 have investigated the inclusion the anti-CD20 monoclonal antibody, ibritumomab, con- of standard-dose 90Y-ibritumomab tiuxetan in the con- jugated via the tiuxetan chelator to the pure b-emitting ditioning regimen prior to autologous SCT in refractory, radioisotope yttrium-90 (90Y). It is currently approved for aggressive NHL expected to have poor outcome with the treatment of adult patients with rituximab relapsed or standard conditioning (Table 1). In this study, reduced cell refractory CD20-positive follicular B-cell NHL, and is the counts and extensive bone marrow involvement were not only therapy approved for use after rituximab failure. A exclusion criteria. Presence of active disease was deter- review of the latest 90Y-ibritumomab tiuxetan data in NHL mined using positron emission tomography and computed outside the transplant setting is in preparation. Adverse tomography (PET-CT) scanning. Overall, 11 patients had events (AEs) with 90Y-ibritumomab tiuxetan are predict- primary refractory disease, 12 had refractory relapsed able and manageable, with the primary toxicity being disease and 14 had bulky disease at transplant. Patients transient, reversible haematotoxicity. Safety data from received the Z-BEAM conditioning regimen, comprising

Table 1 Selected ongoing phase I/II studies of standard-dose radiolabelled immunotherapy plus high-dose BEAM prior to autologous SCT

Study n Patient population Conditioning regimen Results

Shimoni et al., Israel24 23 DLBCL (n ¼ 15) Z-BEAM Projected 2-year OS 67% (95% CI, Transformed low grade 46–87%) (n ¼ 7) 2-year cumulative relapse 32% MCL (n ¼ 1) (95% CI 17–60%) Estimated 1-year OS 59% Estimated 1-year PFS 49% Gisselbrecht et al., GELA, 77 Low-grade refractory/ Z-BEAM (n ¼ 29) Median recovery: France relapsed FL or MZL (3%) Neutrophils 40.5 g/l 11 days (range, 9–31) Neutrophils 41 g/l 12 days (range, 9–35) 420 g/l 12 days (range, 5–42) Krishnan and colleagues, 33 DLBCL, FL grade I–III, Z-BEAM 2-year OS 88% USA25–28 transformed, MCL 2-year PFS 72% Khouri et al., USA29 26 Relapsed FL, DLBCL, Z-BEAM Estimated 2-year OS 92% MCL Estimated 2-year PFS 83% Vose et al., USA30 23 Induction failed/relapsed/ B-BEAM At median follow-up of 38 months: resistant DLBCL, FL grade OS 55% III, MCL PFS 39%

Abbreviations: B ¼ 131I-tositumomab (Bexxar); BEAM ¼ BCNU, etoposide, ara-C, melphalan; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; GELA ¼ Groupe d’E´ tude des Lymphomes de l’Adulte; MCL ¼ ; MZL ¼ marginal zone lymphoma; PFS ¼ progression- free survival; OS ¼ overall survival; R ¼ rituximab; Z ¼ 90Y-ibritumomab tiuxetan (Zevalin).

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1010 rituximab 250 mg/m2 and 90Y-ibritumomab tiuxetan following SCT, time to engraftment was rapid (independent 0.4 mCi/kg (Z) on day À14 followed by BCNU, etoposide, of transfusion), with a better, sustained haematological ara-C, melphalan (BEAM) starting on day 6. All patients reconstitution at day 100 compared with a matched control engrafted rapidly, in a median of 10 days (range, 10–22), group of low-grade lymphoma patients receiving TBI in a indicating that 90Y-ibritumomab tiuxetan had no impact on conditioning regimen prior to autologous SCT. At day 100 engraftment kinetics. Overall 16 of 21 evaluable patients post-transplant WBC was 4700/mm3 in the 90Y-ibritumo- achieved a CR (76%): 11 achieved a CR, 9 achieved a PR, mab tiuxetan group versus 2950/mm3 in the TBI group of whom 5 converted to CR with additional radiation (P ¼ 0.04), platelets were 136 000 versus 85 000/mm3, therapy to eliminate residual disease. After a median respectively, and Hb 14 versus 11.25 g/dl (P ¼ 0.0023), follow-up of 17months (range, 6–27months) 16 of 23 respectively. In terms of toxicity, 83% of patients patients were alive. A total of seven patients relapsed or did experienced grade III–IV infections and 48% mucositis. not respond and, as expected with refractory disease, all There were no toxicity-related deaths. These preliminary relapses occurred within 6 months of SCT. The cumulative results suggest that Z-BEAM is a well-tolerated and incidence of relapse was relatively low for patients with effective regimen for older patients with poor-risk NHL refractory disease, and the OS and PFS rates compared undergoing autologous SCT. very favourably with the expected rates (o20%) for Two further studies of standard-dose 90Y-ibritumomab standard autologous SCT in this patient group. Non- tiuxetan in the conditioning regimen prior to autologous relapse mortality at day 100 in these heavily pre-treated SCT are ongoing, and are described in Table 1.25–29 Studies refractory patients was 9% (95% confidence interval (CI), investigating 131I-tositumomab as a component of con- 2–33). The median first day of neutropenia was day 2 ditioning have also been carried out30 (Table 1); a larger, (range, À3 to 4); however, nine patients became neutro- phase III study (n ¼ 224) with 131I-tositumomab investigat- penic prior to or on the day of SCT, which is an uncommon ing rituximab plus BEAM versus 131I-tositumomab plus occurrence with standard BEAM. Two patients with very BEAM in relapsed DLBCL is now ongoing. large abdominal masses died of multi-organ toxicities early after transplant. The only NCI grade IIIÀIV toxicities were massive gastrointestinal bleeding (n ¼ 1) and severe gastritis High-dose and escalated-dose 90Y-ibritumomab tiuxetan (n ¼ 1). Both patients had extensive lymphomatous infiltra- plus chemotherapy tion of the stomach at the time of SCT but recovered Dosimetry studies in NHL patients undergoing standard- completely. In addition, one patient died of septic shock 4 dose 90Y-ibritumomab tiuxetan treatment (0.4 mCi/kg) months after SCT and one of bronchiolitis obliterans have shown that the estimated dose of radiation absorbed (probably infection-related) 5 months after SCT. There was by non-lymphoma tissues and organs is minimal and well no apparent additional toxicity related to the use of 90Y- below accepted tissue dose limits.31 These findings have ibritumomab tiuxetan and the investigators concluded that prompted studies using higher 90Y-ibritumomab tiuxetan its inclusion in this conditioning regimen was relatively radiation doses in SCT conditioning regimens. safe and improved outcomes in patients with refractory Nademanee and colleagues27,32 conducted a phase I/II lymphoma. trial of high-dose 90Y-ibritumomab tiuxetan conditioning The Groupe d’E´ tude des Lymphomes de l’Adulte (median 71.6 mCi) for autologous SCT in combination with (GELA) in France also investigated Z-BEAM conditioning high-dose etoposide and cyclophosphamide in 31 patients prior to autologous SCT in patients with relapsing low- with CD20-positive NHL. Patients underwent dosimetry grade NHL (unpublished data). Patients had to have followed 1 week later by 90Y-ibritumomab tiuxetan to experienced a relapse after CR, stable disease (SD) or PR deliver a target dose of 1000 cGy to normal organs. This with no more than three prior chemotherapy treatments conditioning regimen appeared to be well tolerated, with with or without rituximab, and be chemosensitive to the most common treatment-related toxicities being muco- salvage therapy. The study protocol is shown in Figure 1. sitis (100%), neutropenic fever (96%) and rash (90%). The interim safety analysis is presented here. After the last Engraftment of transplanted cells was rapid, and OS and pre-transplant salvage treatment the response rates of these PFS rates were high (Table 2). The investigators concluded patients were nine CR (31%), thirteen CRu (unconfirmed that high-dose 90Y-ibritumomab tiuxetan could be safely CR; 45%) and seven PR (24%). The median dose of combined with high-dose etoposide and cyclophosphamide 90Y-ibritumomab tiuxetan administered was 27.8 mCi without any increase in transplant-related toxicity or any (range, 19.2–34.9 mCi). Preliminary results show that delay in engraftment.

R 250 mg/m2 R 250 mg/m2 90Y ibritumomab 111 tiuxetan 0.4 mCi/Kg Stem In ibritumomab EEEE tiuxetan 5 mCi (15 MBq/kg)* cells BAAAAM d-21 d-14d-6 d-5 d-4 d-3 d-2 d-1 d0

Figure 1 Z-BEAM protocol used in the GELA study. *Maximum 32 mCi or 1200 MBq. Abbreviations: A ¼ ara-C; B ¼ BCNU (carmustine); E ¼ etoposide; M ¼ melphalan; R ¼ rituximab.

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1011 Table 2 Selected ongoing phase I/II studies of dose-escalated radiolabelled immunotherapy plus high-dose chemotherapy prior to autologous SCT

Study n Patient population Conditioning regimen Results

Nademanee and 31 Relapsed FL (n ¼ 12) Escalating Median time to: colleagues, USA27,32 DLBCL (n ¼ 14) Z+E+CY ANC 4500/ml: 10 days MCL (n ¼ 5) Platelets 420 000/ml: 12 days Estimated 2-year OS 92% Estimated 2-year PFS 78% Winter and 28 Relapsed/refractory Escalating Z-BEAM Median time to: colleagues, USA33–35 MCL (n ¼ 5) Granulocytes 500/ml 10 days (range, 8–18) FL (n ¼ 5) Platelets 20 000/ml 21 days (range, 13–40) DLBCL (n ¼ 13) At median follow-up of 1 year: Transformed FL 3-year OS 60% (n ¼ 5) 3-year PFS 50% Press et al., USA36 52 Relapsed FL, High-dose At 2 years: DLBCL, MCL CY+E+B OS 83% PFS 68% Gopal et al., USA37 16 Relapsed MCL High-dose Estimated 3-year: CY+E+B OS 93% PFS 61%

Abbreviations: B ¼ 131I-tositumomab (Bexxar); BEAM ¼ BCNU, etoposide, ara-C, melphalan; CY ¼ cyclophosphamide; DLBCL ¼ diffuse large B-cell lymphoma; E ¼ etoposide; FL ¼ follicular lymphoma; MCL ¼ mantle cell lymphoma; PFS ¼ progression-free survival; OS ¼ overall survival; R ¼ rituximab; Z ¼ 90Y-ibritumomab tiuxetan (Zevalin).

Escalating-dose 90Y-ibritumomab tiuxetan (0.3–1.2 mCi/ 0.8 mCi/kg (n ¼ 13) or 1.2 mCi/kg (n ¼ 16) followed by kg) plus high-dose BEAM was investigated in a phase I tandem autografting of peripheral blood stem cells on days trial of relapsed or refractory CD20-positive NHL.33–35 þ 7and þ 14. Re-infusion was performed in the presence Based on dosimetry results, patient-specific doses of of potentially myelotoxic radioactivity at day 7after 90Y-ibritumomab tiuxetan calculated to deliver escalating radiolabelled immunotherapy to induce an immediate, radiation doses (300–2100 cGy) to critical organs (liver, albeit transient, haematopoietic recovery; another infusion lung or kidney) were administered. The median age of the was performed on day 14 when the radiation-absorbed dose patients was 54 years (range, 25–72 years) and most had to the stem cells was estimated to be o5 cGy, thus ensuring received three or more treatment regimens, including a long-lasting haematopoietic recovery. rituximab. The toxicity profile of the 90Y-ibritumomab Toxicity was as expected, but notably, there was an tiuxetan-containing conditioning regimen was similar to absence of the most frequent severe complications normally that seen with high-dose BEAM alone. The most common seen with conventional HDC. Grade IV neutropenia was grade III/IV toxicities were infection, fever, stomatitis, observed in 13 patients (45%), and only lasted a median of nausea, vomiting, diarrhoea, haemorrhage and oedema. 4 days (range, 1–14 days). Grade IV thrombocytopenia Engraftment was rapid and 3-year OS and PFS rates were occurred in 19 patients (65%) for a median duration of 5 good (Table 2). days (range, 1–14 days). Fifteen patients (52%) required Studies investigating high-dose 131I-tositumomab have transfusions and fourteen patients (48%) under- also been published (Table 2).36,37 went one red blood cell transfusion each. No extra- haematologic toxicity was observed except for mild nausea in 17% of the patients, and all but three patients were cared High-dose and escalated-dose 90Y-ibritumomab tiuxetan for as outpatients. Two-year OS and PFS rates were high monotherapy (Table 3). These positive results suggest that high-dose 90Y-labelled immunotherapy alone as a conditioning regi- 90Y-ibritumomab tiuxetan with tandem SCT would be a men may be a therapeutic option for elderly patients who valuable conditioning regimen in a pre-treated and elderly are unable to tolerate HDC conditioning prior to SCT, patient population as it showed minimal toxicity, with the patients with chemoresistant disease and patients relapsing added advantage that it can be used in an outpatient after conventional autologous SCT. setting. Efficacy remains to be defined in comparison to A pilot study was undertaken by Devizzi and collea- conventional HDC and standard-dose 90Y-ibritumomab gues38,39 to evaluate the feasibility and toxicity of myelo- tiuxetan (0.4 mCi/kg). ablative 90Y-ibritumomab tiuxetan doses with tandem stem High-dose 90Y-ibritumomab tiuxetan monotherapy plus cell support in a prospective cohort of 29 refractory or peripheral blood stem cell support has also been investi- relapsed NHL patients. Prior to 90Y-ibritumomab tiuxetan, gated by Vanazzi and colleagues40–42 in a phase I/II study all patients received three cycles of standard-dose salvage of refractory or chemoresistant NHL patients. Following chemotherapy followed by one cycle of high-dose cyclopho- dosimetry, patients received 0.8, 1.2 or 1.5 mCi/kg 90Y- sphamide plus rituximab, and one cycle of high-dose ibritumomab tiuxetan. Dosimetry showed acceptable cytarabine plus rituximab, at patient-adapted doses. 90Y- radiation-absorbed doses to critical normal organs in all ibritumomab tiuxetan was administered at a dose of cases. All but one patient engrafted promptly, defined as an

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1012 Table 3 Selected ongoing phase I/II studies of dose-escalated radiolabelled immunotherapy as sole myeloablation prior to autologous SCT

Study n Patient population Conditioning regimen Results

Devizzi and colleagues, 29 Relapsed/refractory 3 Â DHAP/CHOP At median follow-up of 12 months Italy38,39 DLBCL (n ¼ 11) 1 Â CY+R (indolent/aggressive): FL (n ¼ 10) Zevalin 2-year OS 87/85% MCL (n ¼ 3) PFS 55/77% Small lymphocytic (n ¼ 4) Richter syndrome (n ¼ 1) Vanazzi and colleagues, 18 Relapsed Zevalin 7CR Italy40–42 DLBCL (n ¼ 11) 4PR MCL (n ¼ 4) 1SD FL (n ¼ 2) 6PD Transformed MZL (n ¼ 1) Flinn and colleagues, 16 Relapsed/refractory low- Zevalin At Day 60 post-SCT: USA43,44 grade MCL, DLBCL 10 CR, 3 PR, 2 PD Press and colleagues, 29 Relapsed B-cell NHL Bexxar CR 79% USA45–47 At median follow-up of 42 months estimated: OS 68% PFS 42% Behr et al., USA48 7Relapsed/refractory Bexxar All re-engrafted at 7–10 days after re-infusion MCL after autologous 6 CR, 1 PR SCT 6 patients alive at 43 years Hohloch et al., 16 Relapsed/refractory R-Dexa-BEAM, 5/6 CR Germany49 transformed FL, MCL, BEAM then high-dose 1PR DLBCL, MZL Bexxar 4/6 alive at 22–31 months Gopal et al., USA50 24 Relapsed B-cell NHL Bexxar Median time for recovery: X60 years Platelets X20 000 ¼ 9 days Neutrophils 4500 ¼ 15 days At median follow-up of 2.9 years, estimated 3-year: OS 59% PFS 51%

Abbreviations: BEAM ¼ BCNU, etoposide, ara-C, melphalan; CHOP ¼ cyclophosphamide, doxorubicin, vincristine, prednisolone; CR ¼ complete response; CY ¼ cyclophosphamide; DHAP ¼ dexamethasone, Ara-C, cisplatin; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; MCL ¼ mantle cell lymphoma; MZL ¼ marginal zone lymphoma; NHL ¼ non-Hodgkin’s lymphoma; PD ¼ progressive disease; PFS ¼ progression-free survival; PR ¼ partial response; OS ¼ overall survival; R ¼ rituximab; SD ¼ stable disease.

absolute neutrophil count 41.0 Â 109 per litre or platelet Tolerability count 420 Â 109 per litre on day 28 after SCT. Non- These preliminary data indicate that 90Y-ibritumomab haematologic toxicity was as expected and relatively mild, tiuxetan at standard and high/escalating doses was well with no pulmonary, renal or cardiac toxicity observed. tolerated as a component of transplant conditioning Responses were seen in 60% patients (Table 3), demon- regimens. Toxicity profiles were similar to those seen with strating that 90Y-ibritumomab tiuxetan at myeloablative other high-dose regimens such as TBI, etoposide and doses is a feasible treatment with peripheral blood stem cell cyclophosphamide, with no additional toxicity and no AEs support, and may be suitable for elderly and heavily pre- or allergic reactions specifically attributed to 90Y-ibritumo- treated patients, including those who have previously mab tiuxetan. AEs observed following 90Y-ibritumomab received HDC. The investigators suggest an activity of tiuxetan plus HDC and transplant were as expected and 1.5 mCi/kg is suitable for those patients with normal included skin rashes, nausea/vomiting, mucositis, infection, platelet counts, while 1.2 mCi/kg could be considered for cardiac, pulmonary and hepatic toxicity. In studies where patients with a platelet count o150 Â 109. 90Y-ibritumomab tiuxetan was the sole myeloablative Further support for the use of 90Y-ibritumomab tiuxetan agent, AEs were as expected for monotherapy (neutro- monotherapy and autologous SCT has been provided by a penia, infections) and were relatively mild, and the most study by Flinn and colleagues.43,44 They found that frequent, severe complications normally seen with conven- significant dose escalation could be achieved, with a range tional HDC conditioning were not observed. Tolerability of doses (20–143 mCi) being given in outpatient setting. findings were similar in 131I-tositumomab studies; abnormal Autologous SCT was performed when the estimated levels of thyroid-stimulating hormone were also frequently radiation dose to the bone marrow was o1 cGy per hour. observed following 131I-tositumomab-based conditioning. All patients engrafted rapidly and at day 60 post-SCT the Conventional chemotherapy for NHL, such as alkylating overall response rate was 81% (Table 3). agents, is associated with an increased risk of myelodys- A number of studies investigating 131I-tositumomab plastic syndrome (MDS) and acute myelogenous leukaemia monotherapy for conditioning prior to SCT have also been (AML). They usually develop within 10 years of treatment carried out, and are described in Table 3.45–50 exposure and are associated with a poor prognosis. One

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1013 analysis estimated the risk of MDS/AML in NHL patients before making the decision to move on to randomized receiving either conventional dose chemotherapy or high- studies in poor-prognosis NHL patients. dose therapy and autologous SCT to be 10%,51 although it is probably lower with modern treatment approaches. Analysis of 90Y-ibritumomab tiuxetan clinical data indi- The role of radiolabelled immunotherapy in allogeneic SCT cated that 17of 746patients developed treatment-related MDS or AML (2.3%), with an annualized rate of 0.7% Experience with 90Y-ibritumomab tiuxetan in RIC regimens from the time of treatment, indicating that there is no for allogeneic SCT increase in risk compared with conventional chemother- Fietz et al.55 reported encouraging results with two apy.52,53 Most 90Y-ibritumomab tiuxetan-treated patients relapsed lymphoma patients (one transformed marginal had already received prior conventional chemotherapy as zone lymphoma (MZL) and one mantle cell lymphoma well. No cases of MDS/AML have developed in a group of (MCL)) who underwent allogeneic SCT from HLA- 76 patients receiving 131I tositumomab as single-agent first- matched donors. The conditioning regimen consisted of line therapy with a median follow-up of almost 5 years.54 rituximab (250 mg/m2) on days À21 and À14, 90Y- ibritumomab tiuxetan 0.4 mCi/kg on day À14 and fludar- abine (30 mg/m2) plus cyclophosphamide (500 mg/m2)on Current and future directions for the use of days À7to À3. The data demonstrated that engraftment 90Y-ibritumomab tiuxetan in autologous SCT was fast with leucocytes reaching 41 Â 109 per litre on day There is still a substantial need to further improve 12 and platelets 450 Â 109 per litre on day 10. conditioning regimens in SCT through a safe treatment In an ongoing, multi-centre phase I/II study, Bethge et al. modality. The high relapse rates observed after autologous are investigating 90Y-ibritumomab tiuxetan in an RIC SCT suggest that most conditioning regimens are inade- conditioning regimen for allogeneic SCT from HLA- quate and therefore more effective options are needed. identical donors in patients with advanced NHL who have Radiolabelled immunotherapy, in particular 90Y-ibritumo- relapsed after 42 including rituximab or mab tiuxetan, has shown great promise as part of after autologous SCT (unpublished data). The study conditioning regimens both as high-dose monotherapy, protocol is shown in Figure 2. and at standard and escalated doses alongside HDC, and Of 21 patients enrolled so far, 16 are evaluable for appears to offer an effective and well-tolerated alternative engraftment and have a median age of 55 years. The to TBI. Future research to evaluate the role of 90Y- median follow-up is 136 days (range, 50–210 days). ibritumomab tiuxetan alone with peripheral blood stem cell Preliminary results show no added toxicity with the support should take a stepwise approach, focusing initially inclusion of 90Y-ibritumomab tiuxetan in the conditioning on phase II studies in patients with different histological regimen and no graft rejections. Engraftment results are NHL subtypes, but including clear eligibility criteria to shown in Table 4. The TRM rate is two patients so far and define an homogenous population of lymphoma patients; GvHD grade II–IV occurred in 43% of patients. Ten those with a poor prognosis, and also as first-line therapy patients achieved a CR and three achieved a PR. Thirteen and following relapse. Subsequently, these results can be of sixteen evaluable patients are alive and well. These compared with standard regimens in historical controls findings suggest that radiolabelled immunotherapy as part

R R 250 mg/m2 250 mg/m2 Arm A: 90 indolent 111 In Y NHL ibritumomab ibritumomab tiuxetan tiuxetan m SCT 185 MBq* 15 MBq/kg TBI FFF 2 Gy

d -21 d -14 d-8 d-7 d-6 d-5 d-4 d-3 d-2 d0

F F F F F Cam# Cam# 111In 90Y ibritumomab ibritumomab M SCT Arm B: tiuxetan tiuxetan aggressive 185 MBq 22/30 MBq/kgm NHL R R 250 mg/m2 250 mg/m2

Figure 2 Protocol for study of 90Y-ibritumomab tiuxetan in an RIC conditioning regimen prior to HLA-identical related/unrelated allogeneic SCT in patients with advanced indolent and aggressive relapsed CD20 þ non-Hodgkin’s lymphoma (NHL) after X2 prior (including rituximab) or autologous SCT. *Only in first five patients; ydose corrected for patients 480 kg; #related/unrelated donors. Abbreviations: Cam ¼ 20/30 mg; F ¼ fludarabine 30 mg/m2;M¼ melphalan 140 mg/m2;R¼ rituximab.

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1014 Table 4 Ongoing studies of radiolabelled immunotherapy in RIC prior to allogeneic SCT

Study n Patient population Conditioning regimen Results

Bethge et al., Germany 60 Arm A (indolent): Indolent: Median time to neutrophil planned FL (n ¼ 8) Z/Flud/TBI engraftment MCL (n ¼ 4) Aggressive: Z/Alem/Flud/Mel Arm A: 14 days (0–69) CLL (n ¼ 3) Arm B: 18 days (13–21) Arm B (aggressive): Median time to platelet DLBCL (n ¼ 4) engraftment MCL (n ¼ 1) Arm A: 4 (0–69) Richter (n ¼ 1) Arm B: 20 (10–29) Shimoni and colleagues, Israel56,57 12 DLBCL (n ¼ 3) Z/Flud/BU or Z/Flud/Mel Projected 1-year PFS 34% (95% Transformed low-grade CI, 0–68%) (n ¼ 2) 1-year cumulative relapse MCL (n ¼ 2) incidence 20% (95% CI, 6–70%) Gopal et al.,USA58 14 Relapsed chemoresistant Z/Flud/TBI At median follow-up of 6 MCL (n ¼ 5) months: DLBCL (n ¼ 4) 9 (64%) alive FL (n ¼ 3) 7(50%) alive and progression Small lymphocytic (n ¼ 1) free Hairy cell (n ¼ 1)

Abbreviations: Alem ¼ alemtuzumab; BU ¼ busulphan; CLL ¼ chronic lymphocytic leukaemia; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; Flud ¼ fludarabine; MCL ¼ mantle cell lymphoma; Mel ¼ melphalan; PFS ¼ progression-free survival; Z ¼ 90Y-ibritumomab tiuxetan (Zevalin).

of an RIC regimen is feasible, engraftment is fast and there probably related to the planned early withdrawal of is no added toxicity. in patients with active disease and Shimoni and colleagues56,57 have also investigated 90Y- expected poor prognosis. The investigators suggested that ibritumomab tiuxetan as part of an RIC regimen using better results might be achieved in patients transplanted either fludarabine/melphalan or fludarabine/busulphan earlier in the disease course and with a longer duration of prior to allogeneic SCT in patients with chemorefractory immune suppression. This study confirms that the inclusion aggressive NHL (Table 4). Patients were eligible for of 90Y-ibritumomab tiuxetan in RIC prior to allogeneic inclusion if they did not achieve a CR with prior SCT is feasible with no impairment in engraftment and chemotherapy (either as initial treatment or after relapse) relatively low organ toxicity in heavily pre-treated patients and had active lymphoma by PET-CT scan, or if they had with refractory NHL. relapsed after a prior autologous SCT. Median age was 54 Gopal et al.58 undertook a phase II trial enrolling years (range, 37–62 years) and median time from diagnosis relapsed or refractory NHL patients who were not eligible was 38 months (range, 9–96 months). The median number for a traditional myeloablative transplant but had lympho- of prior therapies was 4 (range, 2–6) and four patients had a ma that was too high risk for a routine non-ablative prior autologous SCT. One patient had primary refractory transplant. The median number of prior regimens was 6 disease and eleven had relapsed refractory disease. Allo- and five patients had previous autologous transplant. 90Y- geneic SCT was performed using an HLA-matched sibling ibritumomab tiuxetan on day À14 was combined with an donor in seven patients, a one-antigen mismatched related RIC regimen using fludarabine and 2 Gy TBI. Cyclosporin donor in one patient and a matched unrelated donor in four and mycophenolate mofetil were administered as GvHD patients. Prophylaxis against GvHD was given using prophylaxis. There were no non-relapse-related deaths in cyclosporin from day À1, 15 mg/m2 on day the first 100 days, no graft rejections or failures, and all 1 and 10 mg/m2 on days 3 and 6. Immunosuppression was patients achieved 480% donor chimerism by 28 days after withdrawn early (before 3 months) in patients who did not transplant. Three patients achieved a CR and four achieved show signs of GvHD. All patients engrafted in a median of a PR, including one CR, six PR and three SD by 1 month 14 days (range, 10À22) and 90Y-ibritumomab tiuxetan had after transplant. Outcomes are shown in Table 4. no impact on engraftment kinetics. Of the nine patients evaluable for response, five achieved a CR and four a PR. After a median follow-up of 9 months (range, 1–27 months), six patients were alive, and six had died (one Current and future directions for the use of early death due to multi-organ toxicity). The 1-year 90Y-ibritumomab tiuxetan in allogeneic SCT cumulative incidence of relapse was relatively low for patients with refractory disease, suggesting that this regi- Reduced-intensity conditioning regimens used prior to men has an additional anti-lymphoma effect. Two patients allogeneic SCT may not be intensive enough to control relapsed, but as expected from refractory disease, these the tumour during the period while the immune response is occurred within a very short time after transplantation. The being established. It is likely that radiolabelled immuno- cumulative incidence of acute GvHD grade III–IV was therapy will have a role to play in boosting the anti-tumour 60% (95% CI, 36–100%) and due to this high incidence of effect during RIC with acceptable toxicity. Phase II studies severe acute GvHD the rate of non-relapse mortality was to evaluate 90Y-ibritumomab tiuxetan in this setting are relatively high at 46% (95% CI, 21–100%). This was now warranted.

Bone Marrow Transplantation 90Y-ibritumomab tiuxetan in stem cell transplant C Gisselbrecht et al 1015 Conclusions lymphoma (FL) at diagnosis: results from a multicenter randomized GITMO trial. Blood 2005; 106, abstract 675. Monoclonal have now become established 4 Shimoni A, Hardan I, Avigdor A, Yeshurun M, Raanani P, components of therapeutic regimens to combat haemato- Ben Bassat I et al. Rituximab reduces relapse risk after logical malignancies due to their targeted efficacy. The allogeneic and autologous stem cell transplantation in patients Br J development of radiolabelled immunotherapies such as with high-risk aggressive non-Hodgkin’s lymphoma. 90 Haematol 2003; 122: 457–464. Y-ibritumomab tiuxetan has capitalized on this targeted 5 Bitran JD, Klein L, Link D, Kosirog-Glowacki J, Stewart C, approach with the added power of delivering therapeutic Raack D et al. High-dose myeloablative therapy and doses of radiation to disseminated tumour sites. In a autologous peripheral blood progenitor cell transplantation number of independent studies in the transplant setting, for elderly patients (greater than 65 years of age) with relapsed 90Y-ibritumomab tiuxetan has been shown to have a large cell lymphoma. Biol Blood Marrow Transplant 2003; 9: promising role as a component of conditioning regimens, 383–388. not only to augment standard chemotherapy regimens 6 Villela L, Sureda A, Canals C, Sanz Jr MA, Martino R, (immunotherapy-enhanced conditioning), but also as the Valcarcel D et al. Low transplant related mortality in sole conditioning agent, extending the option of transplant- older patients with hematologic malignancies undergoing Haematologica ation to a wider range of patients. In autologous SCT, the autologous stem cell transplantation. 2003; 90 88: 300–305. use of Y-ibritumomab tiuxetan in combination with HDC 7Buadi FK, Micallef IN, Ansell SM, Porrata LF, Dispenzieri A, has no effect on the speed of engraftment and has a toxicity Elliot MA et al. Autologous hematopoietic stem cell trans- profile similar to conventional conditioning regimens. As a plantation for older patients with relapsed non-Hodgkin’s monotherapy conditioning regimen, high-dose 90Y-ibritu- lymphoma. Bone Marrow Transplant 2006; 37: 1017–1022. momab tiuxetan is effective, with minimal toxicity. Further 8 Gopal AK, Gooley TA, Golden JB, Maloney DG, Bensinger phase II, and subsequent phase III, studies are now needed WI, Petersdorf SH et al. Efficacy of high-dose therapy and to evaluate the role of 90Y-ibritumomab tiuxetan in autologous hematopoietic stem cell transplantation for non- combination with HDC (for example, Z-BEAM versus Hodgkin’s lymphoma in adults 60 years of age and older. Bone BEAM) or alone prior to autologous SCT. These studies Marrow Transplant 2001; 27: 593–599. should investigate different patient subgroups, such as 9 Mileshkin LR, Seymour JF, Wolf MM, Gates P, Januszewicz EH, Joyce P et al. Cardiovascular toxicity is increased, elderly patients, or according to histology. In allogeneic but manageable, during high-dose chemotherapy and SCT, phase II studies are warranted to determine the place autologous peripheral blood stem cell transplantation for 90 of Y-ibritumomab tiuxetan as part of RIC regimens to patients aged 60 years and older. Leuk Lymphoma 2005; 46: augment disease control and engraftment, to build upon 1575–1579. the promising preliminary data. 10 Khouri IF. Reduced-intensity regimens in allogeneic stem-cell transplantation for non-Hodgkin lymphoma and chronic lymphocytic . Hematology Am Soc Hematol Educ Program 2006, 390–397. Acknowledgements 11 Peniket AJ, Ruiz de Elvira MC, Taghipour G, Cordonnier C, Gluckman E, de Witte T et al. 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