Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus

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1 (2007) 21, & 2007 Nature Publishing Group All rights reserved /07 $ LEADING ARTICLE Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus P Dreger 1, P Corradini 2, E Kimby 3, M Michallet 4, D Milligan 5, J Schetelig 6, W Wiktor-Jedrzejczak 7, D Niederwieser 8, M Hallek 9 and E Montserrat 10, on behalf of the Chronic Working Party of the EBMT 1 Department of Medicine V, University of Heidelberg, Heidelberg, Germany; 2 Department of Hematology, Istituto Nazionale dei Tumori, University of Milano, Milano, Italy; 3 Hematology Center, Karolinska University Hospital, Huddinge, Sweden; 4 Unite de Greffe de Cellules Souches Hématopoïétiques, Hôpital Edouard Herriot, Lyon, France; 5 Department of Haematology, Heartlands Hospital, Birmingham, UK; 6 Department of Medicine I, University of Dresden, Dresden, Germany; 7 Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland; 8 Department of Hematology and Medical Oncology, University of Leipzig, Leipzig, Germany; 9 Department of Medicine I, University of Cologne, Cologne, Germany and 10 Hematology Department, Institute of Hematology and Oncology, IDIBAPS. Hospital Clínic, University of Barcelona, Barcelona, Spain The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-sct) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MED- LINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-sct is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of poor-risk CLL requires further investigation, allo-sct is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purineanalogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-sct in CLL. Nevertheless, whenever possible, allo-sct should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL. (2007) 21, doi: /sj.leu ; published online 16 November 2006 Keywords: CLL; salvage treatment; allogeneic stem cell transplantation; practice guidelines Introduction The availability of reduced-intensity conditioning (RIC) has resulted in increased use of allogeneic stem cell transplantation (allo-sct) in B-cell chronic lymphocytic leukemia (CLL). A vast majority of these transplants are being performed outside of disease-specific clinical trials. Although there is clear evidence that allo-sct can provide long-term disease control even in patients with otherwise very poor prognosis, indications for allo- SCT in CLL are still undefined. The purpose of this project was to Correspondence: Dr P Dreger, Department of Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany. peter.dreger@med.uni-heidelberg.de Received 22 July 2006; revised 1 September 2006; accepted 14 September 2006; published online 16 November 2006 identify situations where allo-sct might be considered as a reasonable treatment option for patients with CLL. Approach In order to establish a consensus on allo-sct in CLL, a panel of international experts (PD, PC, EK, MM, DM, JS, WW, DN, EM) was nominated by the European Group for Blood and Marrow Transplantation (EBMT) CLL subcommittee. A first panel meeting (Lyon, January 2005) defined the rationale and the aim of the project and elected two members (PD, EM) to set up a draft proposal, taking into account recent developments in diagnosis, treatment and transplantation methodology in CLL. In particular, focus was on the following issues, which were considered to be essential in this context: Does graft-versus-leukemia (GVL) activity in CLL exist? If yes, is it effective in high-risk CLL? What is the success rate of SCT? Which prognostic risk level justifies SCT? A review of available information on allo-sct in CLL was based on a MEDLINE search. Other sources included meeting abstracts and unpublished investigator-derived data. The draft was subsequently further developed and approved upon final discussion and revision by a second panel meeting (Stockholm, June 2005). The approved consensus was presented and discussed at the XI International Workshop on CLL (New York, September 2005). Does GVL activity in CLL exist, and is it effective in high-risk disease? Evidence for an ongoing GVL effect in CLL was derived from the observation that even in patients with poorest risk disease, longterm clinical remissions can be observed after allo-sct but not with any other treatment modality. The reason for the long-term superiority of T-cell-replete allo-sct over conventional treatment is largely due to the fact that in contrast to autologous SCT or other intensive therapies the relapse incidence seems to decrease over time. This phenomenon is observed with traditional myeloablative conditioning 1 3 (Esteve et al. Blood 2001; 98: 482a, abstract; Michallet et al. Blood 2003; 102: 474a, abstract), and even more convincing in this

2 context with RIC 4 6 (Dreger et al. Ann Oncol 2005; 16 (Suppl 5): v43 v44, abstract; Brown et al. Blood 2005; 106: 166a 167a, abstract) (Tables 1 and 2). In addition, there is ample circumstantial evidence that GVL is effective in CLL. This includes findings that long-term molecular responses can be obtained with allo-sct but not with auto-sct, 7,8 a reduced relapse risk in the presence of chronic graft-versus-host disease (GVHD), 9 an increased relapse risk associated with the use of T-cell-depleted allografts 10 and anecdotal reports on the efficacy of donor lymphocyte infusion (DLI). 4,10,11 13 Table 1 Studies on unmanipulated allogeneic SCT with myeloablative conditioning in CLL Trial IBMTR 3,a Int. project b NMDP 40 Omaha 1 Barcelona 43 Design Registry analysis Registry analysis Registry analysis Single center Single center n Age (years) 41 (28 57) 43 (28 60) 45 (26 57) 46 (29 60) 49 (29 62) Alternative donors c 0% 0% 100% 13% 0% Conditioning regimen Various myeloablative Various myeloablative Various myeloablative TBI/CY TBI/CY TRM 44% (10 years) 31% (3 months) 38% (5 years) 30% (5 years) 17% (5 years) Relapse rate 15% (10 years) 23% (6 years) 32% (5 years) 5% (5 years) 12% (5 years) Late relapses (42 years) EFS 37% (10 years) 42% (6 years) 30% (5 years) 65% (5 years) 71% (5 years) OS 41% (10 years) 56% (6 years) 33% (5 years) 62% (5 years) 76% (5 years) Follow-up (months) 120 (60 192) 35 (11 176) 72 (36 108) 26 (9 115) 62 (17 215) Abbreviations: EFS, event-free survival; IBMTR, International Bone Marrow Transplant Registry; NMDP, National Marrow Donor Program; OS, overall survival; TBI/CY, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg; TRM, treatment-related mortality. a Michallet et al. Conventional HLA-identical sibling bone marrow transplantation is able to cure chronic lymphocytic leukemia. Blood 2003; 102: 474a, abstract. b Esteve et al. Stem cell transplantation for CLL: outcome and prognostic factors after autologous and allogeneic transplants. Blood 2001; 98: 482a, abstract. c Matched unrelated donors or mismatched related donors. Table 2 Studies on unmanipulated allogeneic SCT with reduced-intensity conditioning in CLL Study EBMT 9 Spain 6 Boston a Seattle 5 GCTSG 4,b GCLLSG b,c Design Registry data, retrospective Multicenter, retrospective Single center, prospective phase II Multicenter, prospective phase II Multicenter, prospective phase II Multicenter, prospective phase II n Age (years) 53 (30 66) 53 (35 67) 53 (35 67) 56 (44 69) 50 (12 63) 53 (27 63) Median number of pretreatment lines Fludarabinerefractory 82% 37% NA 86% 90% 33% 51% Unfavorable NA 19/23 (82%) NA NA NA 36/37 (97%) genetics d Alternative donors e 19% 0% 67% 100% 0% 57% 48% Conditioning Various RIC Various RIC FluBu6.4 FluTBI2 FluBu8 FluCy regimen TRM 19% (2 years) 22% (5 years) 17% 22% 20% (2 years) 15% (5 years) 7% (3 years) Early death o100 7% NA NA 8% 18% 6% 2% days f Relapse rate 28% (2 years) 7% (5 years) 48% (2 years) 34% 5% (2 years) 30% (4 years) 33% (3 years) Late relapses (42 years) EFS 58% (2 years) 70% (5 years) 34% (2 years) 44% 75% (2 years) 58% (4 years) 62% (3 years) OS 70% (2 years) 72% (5 years) 54% (2 years) 56% 75% (2 years) 69% (4 years) 79% (3 years) Follow-up (months) 22 (2 60) 47 (12 75) 20 (6 48) 24 (3 63) 44 (25 67) 29 (5 81) Abbreviations: EBMT, The European Group for Blood and Marrow Transplantation; EFS, event-free survival; FluBu6.4, fludarabine 120 mg/ m 2 +busulfex 6.4 mg/kg; FluBu8, fludarabine 150 ng/m 2 +busulfan 8 mg/kg; FluCy, fludarabine 150 mg/m 2 +cyclophosphamide 2.5 g/m 2 ; FluTBI2, fludarabine 90 mg/m 2 +total body irradiation 2 Gy; GCLLSG, German CLL Study Group; GCTSG, German Cooperative Transplant Study Group; NA, not available; OS, overall survival; RIC, reduced-intensity conditioning; TRM, treatment-related mortality. a Brown et al. High levels of donor chimerism and treatment-responsive disease predict improved progression-free survival following nonmyeloablative transplantation for advanced CLL. Blood 2005; 106:166a 167a, abstract. b Unpublished data. c Dreger et al. Long-term disease control of poor-risk chronic lymphocytic leukemia by allogeneic stem cell transplantation with nonmyeloablative conditioning: interim results of a prospective study. Ann Oncol 2005; 16 (Suppl 5): v43 v44, abstract. d VH unmutated, del 17p13, del 11q22 or a combination of these. e Matched unrelated donors or mismatched related donors. f TRM and CLL-related deaths.

3 14 The most compelling proof of the existence and the immunotherapeutic capacity of the GVL principle in CLL comes from a study analyzing the kinetics of minimal residual disease (MRD) by quantitative IgH real-time PCR (RQ-PCR) in patients with poor-risk CLL who were allografted after non-myeloablative conditioning. Durable MRD negativity occurred only after establishing chronic GVHD or after DLI, whereas the influence of the conditioning regimen on the tumor cell load was very limited. The dynamic pattern of this process and its close correlation with immune-relevant events strongly suggested that GVL activity was responsible for tumor control. 12 Delayed MRD clearance has also been observed after myeloablative allo- SCT. 7,13 Moreover, persistent low-level MRD without subsequent clinical relapse can occur after allo-sct, whereas in autologous transplants, MRD detection invariably heralds clinical relapse. 13 Taken together, these data indicate disease control by GVL activity. Besides clinical stages, there are a number of biological markers (e.g., cytogenetic abnormalities, VH mutational status, ZAP-70 expression) that are gaining importance in assessing prognosis in patients with CLL and also in predicting response to therapy. Although the efficacy of chemotherapy and antibodies as well as of autologous SCT is significantly impaired in the presence of unfavorable prognostic factors, correlations between risk factors and outcome after allo-sct have not been fully investigated. There are data, however, showing that longterm remissions can be observed after allo-sct in patients with fludarabine-refractory CLL 4 6 (Dreger et al. Ann Oncol 2005; 16 (Suppl 5): v43 v44, abstract) and those with unfavorable genetic markers. 17 In other words, current evidence indicates that allo- SCT is the only modality that is highly effective in both good-risk and poor-risk disease as defined by clinical and biological criteria. In summary, there appears to be sound evidence that GVL activity is effective and represents the main contributor to durable disease control after allo-sct even in poor-risk CLL. Clinical success rate of allo-sct in CLL The clinical success of a certain procedure for treatment of a malignant disease is essentially determined by the following end points: treatment-related mortality (TRM) for toxicity, relapse incidence for disease control, and event-free survival (EFS) and overall survival (OS), or the combination of both. The risks of allo-sct in patients with CLL are mostly the general risks of allogeneic SCT and are basically due to GVHD. Published information on TRM of allo-sct in CLL is summarized in Tables 1 and 2. Toxicity and mortality seem to be strongly influenced by the type of conditioning regimen employed. 9 As pointed out in the previous section, long-term disease control owing to the low rate of late recurrences has been observed in all published series (excluding those employing in vivo or ex vivo T-cell depletion), irrespective of donor source and conditioning regimens used. Accordingly, a considerable proportion of patients survive leukemia-free after allo-sct, as illustrated by 5-year EFS and OS rates ranging from 30 to 70% (Tables 1 and 2). In summary, long-term disease-free survival and possibly cure seem to be possible in one-third to two-thirds of patients undergoing allo-sct for poor-risk CLL. Which prognostic risk level justifies allo-sct? Given the toxicity of allo-sct, this procedure should be restricted to eligible patients who can expect a significant reduction of life expectancy under alternative therapies ( poorrisk CLL ). Poor-risk CLL shows an aggressive course with strongly reduced survival. In contrast to low-risk CLL, which is characterized by good responsiveness to standard agents even in relapsed disease, the hallmark of poor-risk CLL is pre-existing or rapidly developing resistance to conventional chemotherapy, including fludarabine-based regimens. 14,16,18 20 Possible salvage treatment modalities comprise combinations of fludarabine with alkylators (cyclophosphamide) and/or monoclonal antibodies, and the monoclonal antibody alemtuzumab in fludarabine-refractory disease. Although response rates in some series were up to 40%, remission duration is generally short, resulting in median overall survival of less than 1 2 years and a 4-year overall survival of less than 20% 14,18,21 23 (Stilgenbauer et al. Blood 2004; 104: 140a, Abstract). Main causes of death are disease progression not responding to conventional therapy, infections, bone marrow failure and disease transformation (Richter s syndrome). Whereas resistance to purine analogues clearly reveals aggressive disease, the identification of poor-risk CLL upon diagnosis or once treatment is needed is still difficult. The following clinical and biological parameters have been shown to be of predictive value for an individual patient s prognosis. Apart from fludarabine resistance, clinical indicators of an aggressive course are short time (o12 months) from diagnosis to first need for cytoreductive treatment; 24 incomplete response to fludarabine-containing combination therapy Biological predictors of an aggressive course are genomic aberrations defined by fluorescent in situ hybridization karyotyping, such as del 11q22 23 and mutations/ deletion of 17p13 (p53) high degree of homology (498%) of the IgH VH gene of the tumor clone with the respective germ-line sequence; 14,30 33 high ZAP-70 expression as detected by cytofluorometry or Western blot analysis; 31,34,35 high CD38 expression of leukemic cells. 32,36 38 However, to date, the prognostic impact of these variables generally has not been prospectively confirmed for patients receiving standard therapy. Therefore, their use as the sole basis for therapeutic decisions is still not considered appropriate. 39 The only plausible exception is abnormalities of 17p13 (p53), which are highly predictive of fludarabine resistance and convey a very poor prognosis as confirmed by numerous retrospective 16,28 (Bosch et al. Blood 2005; 106: 213a, abstract) and also prospective studies (Stilgenbauer et al. Blood 2005; 106: 212a, abstract; Oscier et al. Blood 2005; 106: 594a, abstract). Thus, this genetic marker identifies patients in whom allo-sct early during the course of the disease seems reasonable. The prognostic impact of all other biological prognostic factors needs to be confirmed in prospective studies before accepting them as the sole criteria for upfront intensive therapies and, particularly, allo-sct. Unless such confirmation is available, an adverse prognosis suggested by biological risk factors must be substantiated by an unfavorable clinical course, as

4 indicated by limited disease control after intensive treatment to justify allo-sct. In this regard, an analysis of 1323 autologous SCT for CLL registered in the EBMT database identified early progression (within 2 years) post-transplant as a highly significant predictor of an adverse prognosis with a median survival of less than 27 months (Dreger P, Brand R. Bone Marrow Transplant 2006; 37 (Suppl 1): S43, abstract). Similar correlations between time-to-time progression and outcome can be anticipated for intensive regimens of equivalent efficacy, such as purine analogue combinations with alkylating agents or antibodies, although this has not been formally proven. When comparing alternative salvage regimens including auto-sct to allo-sct in fludarabine-refractory CLL, the following points can be made: No regimen has been validated by a prospective phase-iii comparison. No regimen except allo-sct has shown curative potential. All regimens have a high early-death rate (410% within the first 3 months) 18,21,22 (Stilgenbauer et al. Blood 2004; 104: 140a, abstract). In summary, allo-sct seems to be a reasonable treatment option for younger patients with non-response or early relapse after purine analogues; with p53 abnormalities and treatment indication; or with relapse within 24 months after having achieved a response with intensive therapy, including autologous transplantation. Allo-SCT and quality of life Quality of life (QoL) after allo-sct depends on its success. If disease control is achieved in the absence of symptomatic chronic GVHD, QoL should markedly exceed that observed with palliative salvage treatment. The systematic investigation of QoL after allo-sct remains an important research question. Timing of allo-sct Although conclusive evidence for CLL is still lacking, experience from other entities suggests that the success rate of allo-sct can decrease as the number of cytotoxic pretreatment lines grows. This implies that it might be advisable to consider allo-sct in eligible patients as soon as criteria for poor-risk CLL are fulfilled. However, the available body of evidence does not allow sound recommendations on this issue. Stem cell sources Retrospective analyses have not shown a significant influence of the source of stem cells on the outcome of allo-sct for CLL 9 (Michallet et al. Blood 2001; 98: 859a, abstract). Thus, both bone marrow and mobilized peripheral blood stem cells are suitable as stem cell source, although following the general trend in transplantation procedures, peripheral blood is more frequently used than bone marrow. Conditioning regimens There is no doubt that the crucial therapeutic principle of allo- SCT is GVL activity. All published information suggests that reduction of conditioning regimen intensity can help to reduce TRM after SCT in CLL without affecting GVL effectiveness. However, impaired disease control associated with RIC cannot be ruled out. 9 Thus, according to the individual situation, the optimum choice of conditioning regimens may vary: whereas in the presence of comorbidity and sensitive disease, reducedintensity regimens appear to be more appropriate, high-intensity regimens might be preferable in younger patients with good performance status but poorly controlled disease. 16 Prospective clinical trials should help to precisely guide the choice of conditioning intensity. Nevertheless, the available body of evidence is robust enough to state that RIC allo-sct is an effective treatment for poor-risk CLL per se irrespective of its comparison to traditional allo-sct. Moreover, considering that in comparison to studies with myeloablative conditioning RIC studies generally contained larger numbers of patients, have mostly been performed in a prospective multicenter fashion and use more sophisticated methods for risk stratification and/or MRD monitoring, it appears that the more convincing evidence supporting allo-sct in CLL comes from RIC studies rather than from trials with traditional myeloablative allo-sct. In summary, GVL-mediated long-term disease control can be achieved with a broad range of conditioning intensities. Current evidence is not sufficient to identify a generally superior conditioning regimen. If a prospective clinical trial is not available, the choice of conditioning might be performed on an individual base using the criteria outlined above. Donors A retrospective analysis from the National Marrow Donor Program has demonstrated with a mature follow-up that allo- SCT from matched unrelated donors in CLL is basically feasible and effective. 40 As donor choice is a matter of availability, randomized comparisons between sibling and unrelated donors seem neither possible nor useful. Nevertheless, from those prospective studies including both donor sources, major outcome differences did not become evident, if any (Table 2). In conclusion, the evidence available does not indicate inferiority of matched unrelated donor transplants compared to sibling transplants in CLL. Allo-SCT in related diseases Although preliminary data suggest efficacy of allo-sct in transformed CLL (Richter s syndrome), 41 allografting cannot be regarded as standard treatment for this condition and should be performed preferably within clinical protocols. Similar conclusions apply for prolymphocytic leukemia of B- or T-cell type. 42 Summary of recommendations Allo-SCT is a reasonable treatment option for eligible patients with previously treated, poor-risk CLL (criteria for poor-risk disease: non-response or early relapse (within 12 months) after purine analogue-containing therapy; relapse (within 24 months) after purine analogue combination therapy or treatment of similar efficacy (i.e., autologous SCT); p53 deletion/mutation (del 17p13) requiring treatment). These patients should be discussed with a transplant center as early as possible to avoid extensive cytotoxic pretreatment or disease transformation. Whereas the immunotherapeutic approach of allogeneic transplantation can principally be regarded as procedure with evidence-based efficacy in poor-risk CLL, the optimum 15

5 16 transplant strategy (conditioning, donor source, GVHD prophylaxis) may vary according to distinct clinical situations and should be defined in prospective clinical protocols. Consideration of allo-sct in less well-defined risk situations may be justified but should be performed within clinical protocols. Acknowledgements This proposal has been adopted for the German CLL Study Group (GCLLSG; Chairman: Professor Dr M Hallek, Cologne) by the GCLLSG general assembly on November 4, PD, PC, EK, MM, DM, JS, WW, DN and EM participated in designing the project; all authors reviewed and interpreted available data; PD and EM wrote the paper; and all authors checked the final version of the manuscript. This work was presented in preliminary version in abstract form at the XI International Workshop on CLL, New York, September References 1 Pavletic ZS, Arrowsmith ER, Bierman PJ, Goodman SA, Vose JM, Tarantolo SR et al. 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