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2009 114: 2581-2588 Prepublished online July 29, 2009; doi:10.1182/blood-2009-05-206821
Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time?
Julio Delgado, Donald W. Milligan and Peter Dreger
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Review article

Julio Delgado,1 Donald W. Milligan,2 and Peter Dreger3

1Department

of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 2Department of Hematology, Heart of England National Health Service Trust, Birmingham, United Kingdom; and 3Department of Medicine V, University of Heidelberg, Heidelberg, Germany
The development of reduced intensity conditioning regimens has increased the number of patients diagnosed with chronic lymphocytic leukemia that are referred for allogeneic hematopoietic cell transplantation (allo-HCT). However, given the toxicity of allo-HCT, it should only be offered to eligible patients whose life expectancy is signicantly reduced by the disease. Accordingly, the European Group
of Blood and Marrow Transplantation has recently identied those patients in whom allo-HCT could be a reasonable therapeutic approach. In this review, we have evaluated the outcome of chronic lymphocytic leukemia patients undergoing alloHCT, either after conventional or reduced intensity conditioning regimens, in the context of current nontransplantation strategies. We have also analyzed the
most important predisposing factors that might interfere with the procedure as well as posttransplantation complications that are particularly common in these patients. Finally, we have addressed the most relevant factors when deciding what patients should be considered for alloHCT and the timing of the procedure. (Blood. 2009;114:2581-2588)

Introduction

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that has in the past been considered a disease of the elderly and, therefore, not suitable for hematopoietic cell transplantation (HCT). Indeed, the median age at diagnosis is approximately 72 years,1 and a good proportion of patients can be managed effectively with palliative chemotherapy. However, there is a group of younger patients with poor-risk disease whose life expectancy is signicantly reduced. As a result, both autologous and allogeneic HCTs have been investigated as potentially curative procedures. Moreover, the development of reduced intensity conditioning (RIC) regimens and the greater availability of volunteer unrelated donors have increased the proportion of patients who might benet from allogeneic HCT (allo-HCT). Consequently, the number of patients allografted has increased consistently over the past 10 years (Figure 1). Ideally, the place of transplantation in the management of CLL would be established in prospective randomized trials. These have been proven difcult to do in CLL. Not a single published study has prospectively assessed the efcacy of autologous or allogeneic HCT compared with conventional chemotherapy. For this reason, the European Group for Blood and Marrow Transplantation (EBMT) recently published a set of guidelines suggesting situations where allo-HCT might be considered a therapeutic option for CLL patients. Their conclusions were that allo-HCT was reasonable for younger CLL patients refractory to udarabine, relapsing within 2 years of intensive treatment or with p53 abnormalities requiring treatment.2 Although the use of autologous HCT, which solely relies on dose intensity and does not appear to be curative in CLL, is rapidly declining with the advent of modern immunochemotherapy, alloHCT remains a unique modality because of its graft-versus-CLL effect and can be effective even in otherwise refractory disease. In this review, we therefore focus on allo-HCT, trying to answer the following key questions: (1) What denes poor-risk CLL? (2) What are the results of myeloablative and reduced intensity transplantation strategies? (3) How do these results compare with the available alternative therapies? (4) What are the specic problems of CLL patients undergoing allogeneic HCT? (5) How can we improve these results?

CRR indicates complete remission rate; FCR, udarabine, cyclophosphamide, and rituximab; OFAR, oxaliplatin, udarabine, cytarabine, and rituximab; HDMP, high-dose methylprednisolone; and NS, not stated.
BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13 ALLO-HCT FOR CLL 2583
Table 2. Results of conventional (myeloablative) allogeneic hematopoietic transplantation for CLL
Median age, y (range) 41 (21-58) 45 (26-57) 47 (29-55) 48 (32-59) 39 (29-53) 43 (26-58) Donor, % related Survival, % OS and/or PFS (y) 46 OS (3 y) 33 OS, 30 PFS (5 y) 0 NS NS (6y) 47 (5y) (6y) 50 extensive OS, 24 PFS (6 y) 39 OS, 39 PFS (5 y) 65 OS, 65 PFS 45 OS, 42 PFS (5 y) Reference (year) Michallet et al34 (1996) Pavletic et al35 (2005) Gribben et al36 (2005) Toze et al37 (2005) Esteve et al38 (2001) Khouri et al39 (2002)

N 54 38

Chemorefractory, % (26FR)

TCD, % 15 5

NRM, % 46 (3y) 38 (5y)
Grade II-IV aGVHD, % 37 45
cGVHD, % 49 (17 extensive) 85
TCD indicates T-cell depletion; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; FR, udarabine-refractory; and NS, not stated.
In conclusion, CLL patients with poor-risk features, as identied by the EBMT group, have a dismal outcome with nontransplantation strategies. Can these results be improved by allo-HCT?
What are the results of myeloablative and reduced intensity transplantation strategies?
Conventional (myeloablative) allogeneic HCT
Traditionally, conventional allo-HCT has been associated with unacceptable toxicity and mortality in CLL patients (Table 2). Results published by the EBMT together with the International Bone Marrow Transplantation Registry revealed a long-term nonrelapse mortality (NRM) and OS of 46% each.34 More recent registry data, considering recipients of unrelated donors only, showed a 38% NRM and 33% OS at 5 years.35 However, compared with autologous HCT, late relapses are uncommon in most published series, stressing the rationale for allo-HCT. Single-center studies have shown slightly better results. The Dana-Farber Cancer Institute enrolled 162 high-risk CLL patients in a study where patients with HLA-matched siblings underwent T celldepleted allo-HCT, whereas patients without sibling donors underwent autologous HCT. At 6 years, there were no signicant differences in OS between the groups (55% vs 58% for patients allografted and autografted, respectively), but PFS was superior in the autologous group (24% vs 30%, P .04).36 In Canada, 30 CLL patients were conditioned with myeloablative chemo-irradiation and received grafts from 20 and 10 HLA-matched siblings and unrelated donors, respectively. Actuarial OS and PFS were 39% at 5 years, signicantly better for sibling compared with unrelateddonor recipients (48% vs 20%, P .02).37 At Hospital Clinic, Barcelona, 12 young patients underwent conventional allo-HCT from HLA-matched sibling donors, and both OS and PFS were 65% at a median follow-up of 43 months.38 At the M. D. Anderson Cancer Center (MDACC), 28 young patients were allografted after myeloablative conditioning, 20 of them from HLA-identical siblings. The 5-year OS was 45%, signicantly worse for chemorefractory patients compared with those with chemo-sensitive disease at transplantation (78% vs 31%, P .05).39 However, taking into account that median age at CLL diagnosis is 72 years and that conventional allo-HCT is rarely performed above 50 years of age, very few patients are ever considered candidates for this procedure. Indeed, the median age at transplan-

tation ranged from 39 to 48 years in the studies previously mentioned (Table 2). Furthermore, at least 2 studies have retrospectively compared myeloablative with RIC regimens for CLL patients. The rst study by the EBMT group found a signicantly lower NRM in patients receiving RIC regimens but also a trend toward a higher relapse rate. However, these differences did not translate into a prolonged OS or PFS.40 Second, a recent retrospective analysis performed at the Fred Hutchinson Cancer Research Center (FHCRC) revealed that CLL patients with comorbidities, whether young or old, had better long-term survival after RIC compared with conventional allo-HCT. In contrast, patients without comorbidities had comparable NRM, PFS, and OS. The same study also showed that the conditioning regimen only played a minor role in terms of disease control, with very similar relapse rates for both the myeloablative and RIC groups.41 Moreover, the lack of curative activity of autologous HCT emphasizes that dose intensity may not be a crucial factor for long-term disease control in CLL. In conclusion, evidence that myeloablative conditioning is superior to RIC, even in younger or patients with fewer comorbidities, is lacking, although a potential role of conditioning intensity in patients with refractory/bulky disease or HLA-mismatched donorrecipient pairs cannot be excluded.42,43

RIC allogeneic HCT

RIC regimens were developed in the 1990s to allow allo-HCT in older patients or younger patients with comorbidities. Understandably, CLL was one of the diseases that beneted most from the implementation of RIC transplantation programs around the globe. In Europe, the total number of allogeneic transplantations for CLL patients has almost tripled in the last 7 years (Figure 1). In the past decade, multiple reports from both sides of the Atlantic have suggested that RIC allo-HCT may be a potentially curative strategy for CLL patients. This suggestion was based on circumstantial evidence of a clinically effective graft-versusleukemia effect in CLL patients undergoing RIC allo-HCT, such as achievement of long-term molecular responses,44 reduced relapse rates in patients with chronic graft-versus-host disease (GVHD),40,45 increased relapse rates associated with T celldepleted grafts,46,47 and some efcacy of donor lymphocyte infusions (DLIs).46,48,49 Multiple single-center phase 2 studies have evaluated several different RIC regimens with different myeloablative and immunoablative potential (Figure 2; Table 3).43-46,48-54

2584 DELGADO et al BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13

Delgado et al53 (2008)

Dreger et al71 (2008)

Khouri et al52 (2007)

Myeloablative
Cy + TBI (12 Gy)34-49 Flu + Mel50,53 Flu + Mel + Alem 49,53 Flu + Bu + ATG 48

Reduced Intensity

Flu + Bu51 Flu + Cy44 Flu + TBI (2 Gy)43

Survival, % OS and PFS

PFS (4 y)

PFS (5 y)

PFS (3 y)

48 OS, 44

PFS (2 y)

50 OS, 39

66 OS, 42

65 OS, 39

57 OS, 47

IMMUNOSUPPRESSION

Figure 2. The different myelosuppressive and immunosuppressive potential of most conditioning regimens mentioned in this report. Adapted from Storb et al54 with permission. Flu indicates, udarabine; Bu, busulfan; Mel, melphalan; Cy, cyclophosphamide; ATG, thymoglobulin; Alem; alemtuzumab; TBI, total body irradiation. 53 unrelated Extensive cGVHD

49 related,

72 OS, 67

54 OS, 34

The outcome of 82 patients treated at the FHCRC consortium using a nonablative conditioning regimen (udarabine and lowdose total body irradiation) was recently updated.43 Eighty-seven percent of patients had udarabine refractory disease and 9% had del(17p). At 5 years, the NRM and relapse rate were 23% and 38%, respectively, which translated into a 50% OS and 39% PFS. Patients with bulky lymphadenopathy ( 5 cm) at the time of transplantation had a particularly poor outcome, with a 5-year relapse rate and PFS of 71% and 8%, respectively. Extensive chronic GVHD was diagnosed in 50% of patients, but it resolved in most of them eventually. At the MDACC, 39 patients were conditioned with a nonablative udarabine-cyclophosphamide-rituximab regimen. NRM was 28% at 4 years. Current PFS (ie, not counting patients who relapsed after transplantation but achieved a remission with DLIs rituximab) was 44%, and OS was 48% at 4 years. Patients with mixed chimerism at 3 months or with chemorefractory disease at the time of transplantation had a signicantly increased relapse rate.52 Preliminary results from the GCLLSG CLL3X trial have been recently published. Thirty patients underwent udarabine plus cyclophosphamide-conditioned allo-HCT from 13 HLA-matched siblings and 17 HLA-matched unrelated donors. The cumulative incidence of extensive chronic GVHD was 59% at 1 year, and the NRM was 11% at 3 years. OS and PFS were 71% and 58% at 3 years, respectively. MRD eradication was achieved in more than 50% of patients and was a very strong predictor of PFS. Of note, patients with signicant comorbidities were excluded from the study, which probably contributed to the signicant reduction in NRM and improved outcomes.44 The British and Spanish Cooperative groups used a fairly similar, and slightly more intensive, RIC regimen. The Spanish group used udarabine plus melphalan,50 whereas the United Kingdom groups added alemtuzumab to the combination. In this context, alemtuzumab is used to deplete recipient and incoming donor T cells, providing sustained engraftment while reducing the incidence of GVHD.49 This reduced GVHD rate is counterbalanced by delayed immune reconstitution, increased risk of severe infections, and increased relapse rate.55 We have recently compared and updated the results from 4 institutions selected from these collaborative groups.53 NRM, relapse rate, PFS, and OS, with and without alemtuzumab, were 28% versus 34% (P .735), 32% versus 20% (P .112), 39% versus 47% (P .361), and 65% versus 57%

Grade II-IV aGVHD, %

55 related, 66

unrelated

NRM, %

23 (5 y)

28 (4 y)

23 (3 y)

34 (3 y)

Donor, % related

28 (3 y)

16 (2 y)

Prior auto-HCT, %
Table 3. Results of RIC allogeneic hematopoietic transplantation for CLL

Chemorefractory, %

24 (47 FR)

15 (43 FR)

38 (29 FR)

Median age, y (range)

53 (27-65)

57 (34-70)

56 (42-72)

52 (37-64)

54 (34-64)

RIC regimen

Flu-Mel-Alem

Flu-Cy-Ritux

Flu-Cy based

Flu-Bu-ATG

Flu-LDTBI

Flu-Mel

50 (12-63)

Flu-Bu

53 (35-67)

17 (2 y)

Brown et al51 (2006)

Sorror et al43 (2008)

Reference (year)

MYELOSUPPRESSION

aGVHD indicates acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; Flu, udarabine; LDTBI, low-dose total body irradiation; Cy, cyclophosphamide; Ritux, rituximab; ATG, thymoglobulin; Mel, melphalan; Alem, alemtuzumab; Bu, busulfan; FR, udarabine-refractory; and , not stated.

Schetelig et al48 (2003)

BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13 ALLO-HCT FOR CLL 2585
(P .629) at 3 years. Patients receiving alemtuzumab had a higher risk of mixed chimerism at 6 months, and there was a trend toward a higher viral infection rate in the same group. In contrast, the incidence of extensive chronic GVHD was signicantly higher in patients not receiving alemtuzumab (48% vs 10%, P .03). The Cooperative German Transplant Study Group analyzed the clinical outcome of 30 CLL patients conditioned with udarabine, busulfan, and thymoglobulin. At 2 years, OS and PFS were 72% and 67%, respectively. NRM was 16% at 2 years, being signicantly higher in unrelated donor compared with sibling donor recipients (28% vs 0%, P .04). GVHD was considered the underlying cause of death in all these patients.48 Finally, the Dana-Farber Cancer Institute evaluated the use of udarabine plus busulfan as an RIC regimen in 43 patients. The patients received unmanipulated grafts from 15 (33%) siblings and 31 (67%) unrelated donors. At 2 years, NRM was 17%, but the relapse rate was 48%. Median PFS was 10 months (34% at 2 years) and the 2-year OS was 54%. The most important factor associated with disease relapse and NRM was chemorefractory disease at the time of transplantation. Increased number of prior therapy lines and CLL marrow involvement were also associated with OS and PFS.51 In summary, RIC allo-HCT was associated with a 11% to 34% NRM, a 34% to 67% PFS, and a 48% to 72% OS depending on the conditioning regimen and follow-up. Long-term disease control was obtained in a substantial proportion of patients, particularly in those with chemosensitive and nonbulky disease at the time of transplantation. Extensive chronic GVHD rates can be as low as 10% when in vivo T-cell depletion is used or as high as 59% when unmanipulated grafts are infused. However, the low incidence of primary chronic GVHD after T-cell depletion may be offset by higher rates of secondary chronic GVHD induced by preemptive or therapeutic DLIs as suggested by a recent EBMT analysis.56

CLL patients undergoing allogeneic HCT have remarkably high graft rejection rates. Some initial reports using myeloablative conditioning regimens showed rejection rates approximately 18% to 20%.34,62 Indeed, a study performed in Nebraska acknowledged the fact that only 65% of all CLL allograft patients achieved sustained trilineage engraftment and transfusion independence.63 In the case of RIC regimens, the incidence of graft rejection varies from 12% to 25%, when grafts are T celldepleted in vivo or in vitro,46,49 to 5% to 6% in the case of unmanipulated grafts.44,52,64 The recent British-Spanish comparative study found a secondary rejection rate of 12% and 9% for patients conditioned with or without alemtuzumab, respectively.53 In comparison, patients with follicular lymphoma undergoing transplantation with the same conditioning regimens are reported to have a 3% to 6% rejection rate.58,60,61 A possible explanation for this phenomenon could be the signicant marrow inltration allowed in CLL patients at the time of transplantation, which would probably preclude transplantation in patients with other malignancies. As such, at least 2 studies have shown an inverse correlation between the degree of marrow involvement and outcome.51,64 Other hypotheses, such as the role played by host dendritic cells, which are seriously defective in CLL patients,53 or the effect of prior alemtuzumab therapy are still speculative at this time.
High infection rates resulting from preexisting immunosuppression
Infections account for up to 50% of all CLL-related deaths.65,66 These percentages are probably higher in patients who are refractory to udarabine and/or alemtuzumab,15,29 precisely those patients who are referred for allo-HCT. This susceptibility is both disease and therapy-related and is secondary to multiple factors, including hypogammaglobulinemia, defective T and natural killer cell function, neutropenia, and decient complement activity.67 It is not surprising, then, that CLL patients subjected to allo-HCT had a high incidence of infections, particularly, but not exclusively, when alemtuzumab was part of the conditioning regimen. Indeed, more than 60% of all nonrelapse deaths were the result of infections in the Spanish-British comparative study, most of them related to
2586 DELGADO et al BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13
GVHD.53 Other similar studies have shown similar rates (30%66% of all nonrelapse deaths) with a clear correlation between the risk of infections and the presence of GVHD.43,50,52 Comparatively, this degree of immunosuppression before HCT is rarely encountered in patients with other lymphoproliferative disorders, such as follicular lymphoma, whose main cause of death is disease progression.68 On the other hand, patients with refractory CLL also have a high risk of infections when managed using nontransplantation approaches15,16 and, perhaps, could benet from the shorter period of neutropenia provided by a functioning bone marrow.

The role of DLIs: is there any evidence of graft-versus-CLL effect?
There is strong circumstantial evidence of the existence of graftversus-CLL (GVCLL) effect in patients undergoing RIC allo-HCT. Examples are the achievement of long-term molecular responses on withdrawal of immunosuppression,44 reduced relapse rates in patients with chronic GVHD,40,45 reduced relapse rates in recipients of unrelated donor grafts compared with HLA-matched siblings,64 increased relapse rates associated with T celldepleted grafts,36,47 and the efcacy of DLIs.46,48,49 The efcacy of DLI has been specically studied in 12 patients conditioned with udarabine, busulfan, and thymoglobulin and allografted with T celldepleted HLA-matched stem cell products. No GVHD prophylaxis was given, and DLIs were anticipated in all patients. Eleven patients nally received DLI: 1 for mixed chimerism, 7 for both mixed chimerism and persistent disease, and 3 for progressive disease. In patients with progressive disease, DLI was not effective, but in the remaining 8 patients DLI achieved a CR in 5 of them, translating into a 2-year OS and PFS of 67% and 33%, respectively. Of note, the authors could detect CLL-reactive T-cell clones in patients who responded to DLI, but not in those with unresponsive disease.46 Similar results were obtained after an alemtuzumab containing a RIC regimen. DLIs were given to 18 patients for various reasons. They were effective for reverting mixed chimerism in more than 50% of patients but only achieved sustained responses in less than one-third of patients with progressive disease.49 Other studies using T cellreplete grafts have used less DLIs because of higher GVHD rates, but the results have been broadly similar, with response rates approximately 15% or less in patients with relapsed disease after HCT.48,51,64 Better results might be achieved with DLI given preemptively for persistent MRD.44 At the MDACC, 50% of patients with relapsed disease after HCT responded to DLI, but the interpretation of these results is complicated by the concomitant administration of rituximab. Interestingly, the presence of mixed chimerism was a negative predictor of response to DLI in this study.52 One explanation for the relatively poor efcacy of DLI in T-replete patients despite strong evidence for GVCLL might be the secondary GVCLL resistance phenomenon described by Ritgen et al.44

The occurrence of early and late relapses
trial, some patients showed MRD kinetics characterized by a steep decrease coincident with the onset of chronic GVHD followed by a delayed increase of MRD and clinical relapse despite ongoing GVHD (secondary GVCLL resistance).44 Several hypotheses were offered by the authors, including CLL clonal evolution, the development of tolerance,46 and the survival of tumor cells in GVCLL sanctuary sites. In this respect, there are plenty of reports in the literature of relapses up to 10 years after allo-HCT, and a signicant percentage of these late relapses occurred in lymph nodes in the absence of bone marrow or peripheral blood involvement, or even in patients with MRD status.29,36,37,39,69,70 Furthermore, the presence of bulky lymphadenopathy at the time of allo-HCT had a negative impact on PFS in the FHCRC study, further sustaining the hypothesis of the existence of GVCLL sanctuary sites.43 It is thus apparent that, at least in a fraction of patients, the GVCLL effect is inadequate to ensure complete disease eradication. Furthermore, this phenomenon emphasizes the important role of imaging studies, such as CT scans in the early detection of disease relapse after allo-HCT.
How can we improve these results?

Better patient selection

In our opinion, the EBMT guidelines are a good platform to build future trials of RIC allo-HCT for CLL. They identify a group of patients in whom available therapies are unlikely to achieve a prolonged disease-free survival. On the other hand, RIC allo-HCT is able to mitigate the adverse prognosis conferred by purine analog resistance and unfavorable genetics (How do these results compare with the available alternative therapies?). However, one of the most important aims when trying to improve the results obtained with allo-HCT should be to reduce NRM. The FHCRC analysis revealed that comorbidities were more important than CLL-related variables for predicting PFS and OS.43 Another risk factor for NRM, usually correlated with the presence of comorbidities, is refractory disease at transplantation.71 Thus, it would appear prudent, given our current knowledge, to limit allo-HCT to tter patients without evidence of refractory disease.

Better timing

If a CLL patient is eligible for RIC allo-HCT and has a donor available, he or she should proceed to transplantation as soon as EBMT criteria are met. By denition, these patients have poor-risk disease and one should not wait too long if a reasonable response is obtained with chemoimmunotherapy because the general prognosis and the outcome after allo-HCT are signicantly impaired once the disease has reached a state of complete unresponsiveness.

MRD monitoring

Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients (Table 3). Early relapses are thought to occur in patients with chemorefractory disease at the time of transplantation, for which RIC regimens are ineffective in controlling the disease before the GVCLL effect can take place. This phenomenon also occurs in other lymphoproliferative disorders. More intriguing and different from the pattern observed in follicular lymphoma are late relapses. In the GCLLSG CLL3X
Whereas MRD monitoring provides very important prognostic information after allo-HCT for CLL,44,45 it remains unproven whether MRD-based preemptive immune modulation (immunosuppression withdrawal and/or DLI) might improve the results of the procedure.71
Modulation of the GVCLL effect and maintenance therapy
Rituximab given concomitantly with RIC allo-HCT or DLI may facilitate disease control.52 This may be due, not only to direct cytotoxicity, but also to modulation of the GVCLL effect. Interestingly, rituximab has been shown to promote the cross-presentation
BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13 ALLO-HCT FOR CLL 2587
of tumor-derived peptides by antigen-presenting cells, thus enhancing the formation of cytotoxic T-cell clones and a GVCLL effect.72 A more powerful way of redirecting donor T cells to residual CLL cells could be the posttransplantation administration of bispecic antibody constructs targeting both B- and T-cell antigens, such as blinatumomab.73 In addition, maintenance therapy with monoclonal antibodies or immunomodulatory drugs with proven activity in poor-risk CLL, such as lenalidomide, could be explored in future trials to minimize the risk of relapse. In conclusion, because of the potent GVCLL effect, allogeneic HCT is a very powerful tool in the management of poor-risk CLL patients, but there is room for improvement. Patients who can expect a signicant reduction of life expectancy under alternative therapies should be promptly identied and referred for allo-HCT before the disease becomes unresponsive to salvage treatment, provided there is a related or unrelated donor available. Because of old age, frequent marrow involvement, preexisting immune suppression, and other adverse features, these patients are prone to several transplantation-related complications and should be managed with great care in experienced centers using RIC regimens. The role of more intensive myeloablative conditioning regimens in younger
patients and/or those with refractory disease remains to be settled. Novel transplantation strategies, such as MRD-based preemptive immune modulation or posttransplantation maintenance therapy, could improve the results and should be tested in the context of clinical trials. It is important that patients understand the risks and potential benets of transplantation and are able to make an informed choice. All these facts should be kept in mind if we want to make further progress.

Authorship

Contribution: J.D., D.W.M., and P.D. wrote and proofread all versions of this manuscript. Conict-of-interest disclosure: J.D. has received lecturing fees from Bayer Schering Pharma and Roche and consulting fees from Bayer Schering Pharma, Roche, and GlaxoSmithkline. D.W.M. and P.D. declare no competing nancial interests. Correspondence: Julio Delgado, Servei dHematologia, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08205, Barcelona, Spain; e-mail: jdelgadog@santpau.cat.

References

1. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer. cancer.gov/csr/1975_2005, based on November 2007 SEER data submission, posted to the SEER web site, 2008. 2. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007;21(1):12-17. 3. Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE. Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med. 2006;145(6):437-447. 4. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2): 219-234. 5. Binet JL, Leporrier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia: prognostic signicance. Cancer. 1977;40(2):855864. 6. Rozman C, Bosch F, Montserrat E. Chronic lymphocytic leukemia: a changing natural history? Leukemia. 1997;11(6):775-778. 7. Molica S, Levato D. What is changing in the natural history of chronic lymphocytic leukemia? Haematologica. 2001;86(1):8-12. 8. Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood. 1999;94(2):448-454. 9. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26): 1910-1916. 10. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulinvariable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348(18):17641775. 11. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351(9):893-901. 12. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and nonresponse to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85(6): 1580-1589. 13. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer InstituteWorking Group 1996 guidelines. Blood. 2008; 111(12):5446-5456. 14. Tam CS, OBrien S, Wierda W, et al. Long-term results of the udarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975980. 15. Keating MJ, OBrien SO, Kontoyiannis D, et al. Results of rst salvage therapy for patients refractory to a udarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002;43(9): 1755-1762. 16. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in udarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer. 2002;94(7):2033-2039. 17. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed udarabine: results of a large international study. Blood. 2002;99(10):3554-3561. 18. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in udarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27(24): 3994-4001. 19. Wierda W, OBrien S, Wen S, et al. Chemoimmunotherapy with udarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18): 4070-4078. 20. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, udarabine, cytarabine, and rituximab combination therapy in patients with Richters syndrome or udarabinerefractory chronic lymphocytic leukemia. J Clin Oncol. 2008;26(2):196-203. 21. Chanan-Khan A, Czuczman M, Padmanabhan S, et al. Clinical efcacy of lenalidomide in udarabine-refractory chronic lymphocytic leukemia patients [abstract]. Blood. 2007;110:Abstract 3108. 22. Phelps MA, Lin TS, Johnson AJ, et al. Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of avopiridol in relapsed chronic lymphocytic leukemia. Blood. 2009;113(12):2637-2645. 23. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with highdose methylprednisolone for the treatment of udarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008;22(11):2048-2053. 24. Stilgenbauer S, Zenz T, Winkler D, et al. Genomic aberrations, VH mutation status and outcome after udarabine and cyclophosphamide (FC) or FC plus rituximab (FCR) in the CLL8 Trial [abstract]. Blood. 2008;112:Abstract 781. 25. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as rst-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25(35):5616-5623. 26. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103(9):3278-3281. 27. Ferrajoli A, Keating M, Wierda W, et al. Lenalidomide is active in patients with relapsed/refractory chronic lymphocytic leukemia carrying unfavorable chromosomal abnormalities [abstract]. Blood. 2007;110:Abstract 754. 28. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukaemia after alemtuzumab is associated with prolonged survival. J Clin Oncol. 2005;23(13):2971-2979. 29. Tam CS, OBrien S, Lerner S, et al. The natural history of udarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma. 2007;48(19):1931-1939. 30. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25(7):799-804. 31. Catovsky D, Richards S, Matutes E, et al. Assessment of udarabine plus cyclophosphamide

2588 DELGADO et al BLOOD, 24 SEPTEMBER 2009 VOLUME 114, NUMBER 13
for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370(9583):230-239. 32. Hallek M, Fingerle-Rowson G, Fink AM, et al. Immunochemotherapy with udarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus udarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients with advanced chronic lymphocytic leukemia [abstract]. Blood. 2008;112:Abstract 325. 33. Bosch F, Ferrer A, Villamor N, et al. Fludarabine, mitoxantrone and cyclophosphamide as initial therapy for chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008;14(1):155-161. 34. Michallet M, Archimbaud E, Bandini G, et al. HLAIdentical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. Ann Intern Med. 1996;124(3):311-315. 35. Pavletic SZ, Khouri IF, Haagenson M, et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol. 2005;23(24):5788-5794. 36. Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005;106(13):4389-4396. 37. Toze CL, Galal A, Barnett MJ, et al. Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant. 2005;36(9):825-830. 38. Esteve J, Villamor N, Colomer D, et al. Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia. 2001;15(3):445451. 39. Khouri IF, Keating MJ, Saliba RM, Champlin RE. Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy. 2002;4(3):217-221. 40. Dreger P, Brand R, Milligan D, et al. Reducedintensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a populationmatched analysis. Leukemia. 2005;19(6):10291033. 41. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood. 2008;111(1):446452. 42. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using udarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998;16(8):2817-2824. 43. Sorror ML, Storer BE, Sandmaier BM, et al. Fiveyear follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26(30): 4912-4920. 44. Ritgen M, Bottcher S, Stilgenbauer S, et al. Quantitative MRD monitoring identies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia. 2008;22(7):1377-1386. 45. Farina L, Carniti C, Dodero A, et al. Qualitative and quantitative polymerase chain reaction moni-

toring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation. Haematologica. 2009;94(5):654-662. 46. Hoogendoorn M, Jedema I, Barge RM, et al. Characterization of graft-versus-leukemia responses in patients treated for advanced chronic lymphocytic leukemia with donor lymphocyte infusions after in vitro T-cell depleted allogeneic stem cell transplantation following reduced-intensity conditioning. Leukemia. 2007;21(12):2569-2574. 47. Schetelig J, van Biezen A, Brand R, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol. 2008; 26(31):5094-5100. 48. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003;21(14):2747-2753. 49. Delgado J, Thomson K, Russell N, et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. 2006;107(4):17241730. 50. Caballero D, Garcia-Marco JA, Martino R, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res. 2005;11(21):7757-7763. 51. Brown JR, Kim HT, Li S, et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2006;12(10):10561064. 52. Khouri IF, Saliba RM, Admirand J, et al. Graftversus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol. 2007;137(4):355-363. 53. Delgado J, Pillai S, Benjamin R, et al. The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2008;14(11):12881297. 54. Storb RF, Champlin R, Riddell SR, Murata M, Bryant S, Warren EH. Hematology (ASH Education Program Book). 2001;375-391. 55. Perez-Simon JA, Kottaridis PD, Martino R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002;100(9):3121-3127. 56. Schetelig J, Milligan D, Niederwieser D, et al. In vivo T-cell depletion in allogeneic haematopoietic cell transplantation for chronic lymphocytic leukaemia: a retrospective EBMT analysis [abstract]. Bone Marrow Transplant. 2009;43:Abstract 891. 57. Delgado J, Pillai S, Phillips N, et al. Does reduced-intensity allogeneic confer a survival advantage to patients with poor prognosis chronic lymphocytic leukaemia? A case-control retrospective analysis. Ann Oncol. 2009 July 12 [Epub ahead of print]. 58. Vigouroux S, Michallet M, Porcher R, et al. Longterm outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for lowgrade lymphoma: a survey by the French Society

of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007; 92(5):627-634. 59. Hari P, Carreras J, Zhang MJ, et al. Allogeneic transplants in follicular lymphoma: higher risk of disease progression after reduced-intensity compared to myeloablative conditioning. Biol Blood Marrow Transplant. 2008;14(2):236-245. 60. Khouri IF, McLaughlin P, Saliba RM, et al. Eightyear experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with udarabine, cyclophosphamide, and rituximab. Blood. 2008; 111(12):5530-5536. 61. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkins lymphoma. J Clin Oncol. 2008;26(2):211-217. 62. Khouri IF, Przepiorka D, van Besien K, et al. Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of udarabine on acute graft-versus-host disease. Br J Haematol. 1997;97(2):466-473. 63. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcomes of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant. 2000;25(7):717-722. 64. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23(16): 3819-3829. 65. Oscier D, Fegan C, Hillmen P, et al. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol. 2004;125(3): 294-317. 66. Francis S, Karanth M, Pratt G, et al. The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia. Cancer. 2006;107(5):1023-1033. 67. Hensel M, Kornacker M, Yammeni S, Egerer G, Ho AD. Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia. Br J Haematol. 2003;122(4):600-606. 68. Johnson PW, Rohatiner AZ, Whelan JS, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center. J Clin Oncol. 1995;13(1):140-147. 69. Moreno C, Villamor N, Colomer D, et al. Clinical signicance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood. 2006;107(11):4563-4569. 70. Malhotra P, Hogan WJ, Litzow MR, et al. Longterm outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years. Leuk Lymphoma. 2008;49(9):1724-1730. 71. Dreger P, Stilgenbauer S, Boettcher S, et al. Prognostic factors for outcome of nonmyeloablative allogeneic stem cell transplantation (NST) in poor-risk chronic lymphocytic leukemia (CLL): Final results from a prospective multicenter trial (GCLLSG CLL3X study) [abstract]. Blood. 2008; 112:Abstract 565. 72. Hsu FJ, Komarovskaya M. CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells. J Immunother. 2002;25(6):455-468. 73. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by of a T cell engaging antibody. Science. 2008;321(5891):974-977.