Transplantation in Chronic Lymphocytic Leukemia: Timing and Expectations

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1 CLL Leukemia 2008 Proceedings Transplantation in Chronic Lymphocytic Leukemia: Timing and Expectations Simon Hallam, John G. Gribben Abstract Stem cell transplantation in chronic lymphocytic leukemia (CLL) is an evolving field. Younger patients with high-risk disease might derive the greatest benefit from this approach and the availability of reduced-intensity conditioning regimens has made allogeneic stem cell transplantation more relevant to patients with CLL. Patient selection, timing of transplantation, and method of conditioning, stem cell delivery and immunosuppression appear to influence outcomes. We collect and review the available data to assist clinical decision-making in this field. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S186-S193, 2009; DOI: /CLM.2009.s.010 Keywords: Allogeneic transplantation, Autologous transplantation, Donor lymphocyte infusion, Myeloablative, Reduced-intensity conditioning Introduction In most patients with chronic lymphocytic leukemia (CLL) the disease follows an indolent course for which aggressive therapies are not warranted. However, a significant minority of patients with rapidly progressive CLL exists who are very likely to die of this disease even with conventional chemo-immunotherapy. It is possible to identify patients with poor-risk features at diagnosis, or early in their disease course, so that alternative strategies incorporating stem cell transplantation (SCT) can be considered. Despite widespread enthusiasm for this approach, there have been no randomized trials comparing the outcome of SCT with standard chemotherapy for patients with CLL. Recruitment of appropriate patients into well-designed clinical trials is vital in evaluating the role of SCT in CLL, particularly in light of promising results with novel chemoimmunotherapy combinations alone. Phase II studies of autologous stem cell transplantation have demonstrated feasibility but disease relapse appears inevitable. The optimal strategy for allogeneic SCT in CLL is not clear. A graftversus-leukemia (GVL) effect in CLL has been demonstrated, with encouraging responses seen to reduced-intensity conditioning SCT and to donor lymphocyte infusions. Myeloablative conditioning results in very high transplantation-related mortality (TRM) and is inappropriate for many patients with CLL. In the absence of any Institute of Cancer, Bart s and the London School of Medicine, Charterhouse Square, London, UK Submitted: May 8, 2009; Revised: Jul 2, 2009; Accepted: Jul 29, 2009 Address for correspondence: John G. Gribben, MD, DSc, FRCP, Institute of Cancer, Bart s and the London School of Medicine, Charterhouse Square, London, EC1M 6BQ, UK Fax: ; john.gribben@cancer.org.uk other treatment modalities currently capable of improving survival, the treatment of choice for younger patients with poor-risk CLL may well be allogeneic SCT. Management Strategies in Chronic Lymphocytic Leukemia Evidence of a survival benefit from treatment is available only for patients with advanced-stage CLL (Rai III and IV or Binet B and C). The decision to treat is also guided by the presence of symptoms and the disease activity. Initiating treatment for early-stage CLL is only justified by the presence of disease-associated morbidity such as troublesome lymphadenopathy or constitutional symptoms. Traditionally, treatment was based on alkylating agents such as chlorambucil alone, cyclophosphamide, doxorubicin, and prednisone (CAP), or cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Three large randomized trials have demonstrated that monotherapy with the purine analogue fludarabine produces superior overall response, higher response rates, and longer duration of response compared with alkylating agent based therapy. 1-3 However, this has not translated into a survival advantage because of the relatively high response rates to salvage therapy with purine analogues for patients treated initially with alkylating agents. The combination of fludarabine with cyclophosphamide (FC) has been shown in randomized trials to result in increased response rates and produce a longer duration of response than fludarabine alone. 4, As a single agent the anti-cd20 monoclonal antibody rituximab has less activity in CLL than in follicular lymphoma. However, the addition of rituximab (R) to chemotherapy appears to improve response rates and duration of responses compared with fludarabine, 6 or fludarabine and cyclophosphamide using the FCR regimen. 7 This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN # , provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA USA S186 Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009

2 Table 1 Phase II Study Outcomes Following Autologous Stem Cell Transplantation for CLL Study Numbers of Patients Numbers With TRM Numbers in Ongoing CR Median Follow-up, Months Gribben et al Early 13 MDS/AML 1 other cancer Jantunen et al Milligan et al Early MDS/AML 4 36 Pavletic et al Dreger et al Khouri et al Sutton et al Enrolled; 12 stem cells collected 0 36 Itala et al Abbreviations: AML = acute myelogenous leukemia; CLL = chronic lymphocytic leukemia; CR = complete remission; MDS = myelodysplastic syndromes; TRM = transplantation-related mortality The management of relapsed CLL is an evolving field that currently defies a clear consensus. Combination chemo-immunotherapy produces the best response rates, 2,8 yet the optimal regimen should be tailored for individual circumstances. The aims and selection of treatment are dependent upon several clinical factors. Age, performance status, previous treatments, the extent and duration of response to such treatments, and time from last treatment appear critical. In addition, the goal of therapy, whether aggressive or palliative, should be established. There is no evidence to date that any available chemo-immunotherapy combination is curative and patients invariably relapse again and subsequently develop resistance to chemotherapy, often with the loss of function of p3. 9 When refractory to purine analogues the median survival has been reported as < 1 year. 10 The humanized anti-cd2 monoclonal antibody alemtuzumab is approved for treating fludarabine-refractory CLL. In the pivotal study of alemtuzumab in 93 such patients, the overall response rate was 33%, though only 2% of patients achieved complete response (CR). 11 The median time to progression for responders was 9. months and there was an improvement in survival in responding patients at 32 months, compared with 16 months for all patients. Of note, alemtuzumab appears to have activity against cases that are unresponsive to chemotherapy because of the presence of p3 mutations. 12,13 Despite often affecting hematologic responses, alemtuzumab has relatively poor activity against bulky lymphadenopathy. Alemtuzumab has shown benefit when used in combination with fludarabine. 14,1 Studies are also examining the role of alemtuzumab treatment after chemotherapy to clear residual disease, 16 and this may be an effective way to obtain autologous peripheral blood stem cells free of contamination with CLL. 17 Role of Transplantation in Chronic Lymphocytic Leukemia Several studies have attempted to ascertain whether SCT might offer the potential of cure or reversal of chemotherapy resistance in CLL. Largely a disease of later life, with a median age of presentation between 6 and 70 years, most patients with CLL are insufficiently robust to consider such an approach with its attendant morbidity and mortality. However, 40% of patients with CLL are aged under 60 years and 12% under 0 years at the time of diagnosis. Younger patients do not have a worse prognosis than older patients and have similar prognostic factors. Unlike older patients, who often die of comorbidity not associated with the CLL, more than 90% of younger patients die because of CLL itself. 18 As such, this group might gain the most benefit and suffer the least morbidity and mortality from more aggressive approaches incorporating SCT. The various strategies for using SCT in CLL are explored herein. Autologous Stem Cell Transplantation There has been no prospective study directly comparing the outcome after conventional therapy compared with that obtained after autologous SCT, although a retrospective matched-pair analysis suggested a survival advantage for autologous SCT. 19 A number of phase II studies have reported the outcome following autologous SCT for CLL (Table 1) The approach is feasible in CLL with a transplantation-related mortality of between 2% and 10%. 2,26 Encouraging early results were reported in patients with chemosensitive disease, 20 whereas patients transplanted in relapse or with chemoresistant disease had poor outcome. 21 Poor results with a high relapse rate after autologous SCT in CLL were also observed in a study of 16 patients. At a median follow-up of 41 months, 8 had relapsed and 6 had died (3 from progressive CLL). 24 Other groups have observed better results. In 18 patients with CLL including early-stage disease, transplantation was performed in 13 patients, only one of whom had relapsed at the time of publication. 23 Eight heavily pretreated patients received autologous SCT with partially purged CD34+ peripheral blood stem cells and though 4 patients remained in CR, the median follow-up was only 9 months. 22 The experience in Finland has been updated recently for 72 patients autografted in centers between 199 and The median age was 7 years (range, years) with a median time from diagnosis of 32 months (range, months). The median number of previous therapies was 1. The most commonly used conditioning regimen was total body irradiation (TBI) Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009 S187

3 Transplantation in CLL and cyclophosphamide (Cy; n = 38, 3%). There were no early TRMs. Thirty-seven percent had relapsed or progressed after a median follow-up of 28 months. The projected median progression-free survival (PFS) and overall survival (OS) was 48 months and 9 months, respectively. A pilot study from the Medical Research Council (MRC) enrolled previously untreated patients and followed them prospectively to assess the feasibility of performing autologous SCTs. 2 Only 6 of 11 patients (6%) entered into the study were able to proceed to autologous SCT following remission induction with fludarabine. However, only 1 patient died of early transplantation-related complications and the CR rate after transplantation was 74% (48 of 6). The -year OS was 77.% and -year PFS was 1.%. None of the variables examined at study entry were predictive of either OS or PFS. Sixteen of 20 patients available for analysis achieved a molecular CR in the first 6 months after transplantation. Detectable molecular disease by polymerase chain reaction (PCR) was highly predictive of disease recurrence. Of concern, of 6 (8%) patients developed posttransplantation acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). This equates to a -year actuarial risk of developing MDS/AML post autologous SCT of 12.4% (9% CI 2.%-24%). No potential risk factor analyzed was predictive. The group postulates that potential causative factors might be fludarabine, low cell dose, and use of TBI in the conditioning regimen. This finding has been supported by the long-term outcome reported in a series from the Dana-Farber Cancer Institute, which reported an actuarial incidence of MDS/ AML in CLL patients postautograft of 12% at 8 years. 26 Although the early TRM is low after autologous SCT, there is a high incidence of opportunistic infections in patients with CLL compared with other patient populations. Whether this is due to disease-related immune defects in patients with CLL, or is secondary to the immune-suppressive effects of treatment is unknown. Patients have a better outcome when they are treated early in the course of the disease and when they have less tumor burden. By extrapolation of this principle, it might be considered beneficial to transplant selected high-risk patients in first complete or partial remission, though data sufficient to support this is lacking. One difficulty in selecting high-risk patients is that these patients might also have an adverse outcome even after SCT. The immunoglobulin gene mutation status maintains its poor prognostic significance after autologous transplantation 28 though it appears that this can be overcome using allogeneic SCT. 29,30 A randomized trial proposed by the European Bone Marrow Transplant Group should help to address this issue. The timing of the harvesting of the cells and whether they should be harvested in first remission and kept until later in the treatment course also needs to be further investigated. It is not always possible to collect enough CD34+ cells, especially in heavily pretreated patients 31 and an interval of at least 3 months should be allowed between the last dose of fludarabine and stem cell collection. 32 The major problem after autologous SCT remains relapse of disease, and patients continue to relapse years later. 33 A number of methods including multiparameter flow cytometry analysis 34 and PCR 3 are being used to investigate whether persistence of minimal residual disease will predict which patients will relapse following transplantation in CLL. Molecular remissions can be achieved in more than two thirds of patients but these are not durable 2,3-37 and most patients who achieve CR postautologous SCT will eventually relapse. Detectable molecular disease post transplantation is, however, highly predictive of clinical recurrence. 2 One of the major concerns in autologous transplantation is that reinfusion of tumor cells may theoretically contribute to the risk of relapse. Numerous groups have attempted to improve outcome by purging the graft. The techniques most frequently employed use either negative selection using B-cell monoclonal antibodies to deplete tumor cells from the graft or positive selection of stem cells using CD34 antibodies. Unfortunately these methods remain inefficient at removing CLL cells. 3 Purging also results in stem cell loss. If there has been difficulty in obtaining a sufficiently large harvest, as seen in 0% of cases in the MRC Pilot Study, purging cannot be performed. This problem could be addressed by attempting in vivo purging using alemtuzumab or rituximab as part of the conditioning regimen. In this way, high-dose alemtuzumab was used in one arm of the CLL3 trial from the German CLL Study Group, with unexpected consequences. 38 Sixteen patients were treated in this arm and received a median dose of alemtuzumab of 103 mg. A high incidence of initially unexplained skin rashes led to further analysis. Twelve of 16 patients (87%) developed a skin rash between 43 and 601 days post autologous SCT, in 7 of whom a diagnosis of graftversus-host disease (GVHD) could be made compared with no cases in the TBI/Cy only conditioned patients. Autologous GVHD is an autoimmune syndrome initiated by autologous effector T cells that recognize self MHC Class II antigens and is usually self-limiting. In this case, however, all cases required immunosuppression and the median duration was 17 days (range, days). The trial was discontinued because of the high nonrelapse mortality. However, of note, the addition of alemtuzumab led to improved disease control at the molecular level. It is interesting that the use of alemtuzumab in combination with other immunosuppressants before allogeneic SCT results in effective prevention of GVHD. In this situation it was postulated that the markedly immunosuppressive regimen depleted regulatory CD4 and CD8 T cells and natural killer cells, allowing subsequent development of autoimmune disease. The patients receiving alemtuzumab/tbi/cy had a severe CD8 lymphopenia in the first year after SCT. The authors recommend that future trials investigating in vivo purging with alemtuzumab should use a less immunosuppressive conditioning regimen such as BEAM, and avoid the use of TBI. The concept of using alemtuzumab for in vivo purging should perhaps not yet be discarded. When used at a modification from the standard doses (10 mg subcutaneously 3 times per week for 6 weeks) in 34 patients who had had a clinical response to a fludarabine-based regimen the CR rate improved from 3% to 79.% with 6% achieving eradication of MRD. 39 Peripheral blood stem cell (PBSC) collection was subsequently successfully performed in 92%. Eighteen patients underwent autologous SCT with 17 remaining in CR at a median follow-up of 14. months post-sct. As induction regimens have evolved, it would now be useful to look at the new chemo-immunotherapeutic regimens in direct comparison with autologous SCT. S188 Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009

4 Simon Hallam, John G. Gribben Table 2 Long-Term Disease Control in Patients Who Survive Myeloablative Allogeneic Transplantation For CLL (Data Refer to Absolute Numbers) Study Numbers of Patients Numbers With TRM Severe GVHD Ongoing CR Median Follow-up, Months Michallet et al Gribben et al Early Late 13 8 after DLI 78 Doney et al Pavletic et al Khouri et al Abbreviations: CLL = chronic lymphocytic leukemia; CR = complete remission; GVHD = graft-versus-host disease; DLI = donor lymphocyte infusion; TRM = transplantation-related mortality Myeloablative Allogeneic Stem Cell Transplantation Myeloablative allogeneic SCT attempts to supplement the dose intensification effect of autologous SCT with alloreactive immune mechanisms to generate a GVL effect. This introduces the potential for better disease control, and possibly cure, but at the price of greater toxicity. The morbidity and mortality of allogeneic SCT mostly relate to organ failure caused by both the toxicities of the conditioning regimen, and acute GVHD (agvhd) and chronic GVHD (cgvhd). The risk of life-threatening infection is increased by both GVHD itself and the immune-suppressive treatment used to control GVHD. The feasibility of allogeneic SCT in CLL was first demonstrated in 1988 in 8 patients, of whom were alive in CR after a median follow-up of 27 months post-sct. 40 The high TRM rate was apparent from registry data with rates of 46%-0% reported. 41 Despite the high TRM, patients who survive can have long-term disease control (Table 2). 20,41-44 Among 2 patients with CLL who underwent allogeneic SCT at the Fred Hutchinson Cancer Center, developed grades 2-4 agvhd and 10 developed extensive cgvhd. Nonrelapse mortality at day 100 was unacceptably high at 7% for the 7 patients conditioned with busulphan and cyclophosphamide and 17% for the 18 patients conditioned with TBI-containing regimens. Actuarial survival at years for the 2 patients was 32%. All patients who received busulphan and cyclophosphamide died within 3 years of transplantation. For the 14 patients who underwent transplantation since 1992 and who received TBI, actuarial -year OS is 6%, suggesting that long-term disease-free survival might be achieved in this disease. However, there are no data from randomized trials demonstrating improved outcome with dose intensification. Indeed, the major advantage of the use of allogeneic SCT appears to be the potential for a GVL effect. A strong GVL effect was noted with those developing acute or chronic GVHD having near complete protection from relapse. 4 This effect can be exploited by infusion of donor lymphocytes following allografting, 26,46 or after cessation of immunosuppressive therapy. 47 Studies are under way addressing the issue of the number of lymphocytes required and the optimal timing of donor lymphocyte infusions after allogeneic SCT in this and other hematologic malignancies. As HLA-matched sibling allogeneic transplantations are only possible in a quarter of all potential recipients, the use of unrelated donor stem cells has been investigated. Among 38 heavily pretreated patients, 11 were alive and disease free at a median of 6 years. 48 The -year overall survival rate was 33%, TRM was 38%, and disease-progression rate was 32%. Of note, 4% developed grade 2-4 agvhd and 8% had cgvhd. The authors concluded that lasting remissions could be achieved but that the high TRM illustrated that HLA-mismatched unrelated donors should be avoided. Comparison of Autologous Versus Allogeneic Stem Cell Transplantation Registry data has suggested that though durable responses were being achieved after allogeneic SCT, survival was worse than after autologous SCT with 3-year probability of survival reported as 4% for allogeneic SCT and 87% for autologous SCT. 49 Studies from the M. D. Anderson Cancer Center, however, have suggested improved outcome after allogeneic compared with autologous transplantation. 21 In 1 patients with CLL refractory to or relapsed after chemotherapy with fludarabine, 13 (87%) achieved a CR posttransplantation. At the time of reporting, 9 patients (3%) remained alive and in CR with a median follow-up of 36 months, 0 suggesting that allogeneic hematopoietic transplantation can induce durable remission even in patients with CLL refractory to fludarabine. There are no studies directly comparing the outcome of autologous compared with allogeneic SCT. In a phase II study at Dana-Farber Cancer Institute, 162 patients with high-risk CLL were enrolled in a study between 1989 and 1999 in which 2 patients with an HLA-matched sibling donor underwent T-cell depleted allogeneic transplantation and 137 with no sibling donor underwent B-cell purged autologous transplantation. 26 The 100-day mortality was 4% in both autologous and allogeneic SCT groups, though later TRM had a major effect on outcome. With a median follow-up of 6. years there was no difference in OS of 8% after auto and % after allogeneic SCT. Progressionfree survival was significantly longer following autologous SCT than T-cell depleted allogeneic SCT, but no significant differences were observed in disease recurrence or deaths without recurrence according to type of transplantation. Reduced-Intensity Conditioned Allogeneic Stem Cell Transplantation The rationale of reduced-intensity conditioning (RIC) allogeneic SCT is to exploit the GVL effect while avoiding the significant Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009 S189

5 Transplantation in CLL Table 3 Outcomes Following Reduced-Intensity Conditioned Allogeneic Stem Cell Transplantation for CLL Study No. of Patients Age, Years (Range) Previous Regimens (Range) Chemotherapy Refractory Donor (Includes Mismatch) TRM GVHD Acute Grade 2-4 Chronic Extensive Survival Schetelig et al (12-63) 3 (0-8) 47% 0% Related 0% Unrelated 13% Overall 6% 21% OS, 72% at 2 years PFS, 67% Dreger et al (30-66) 3 (0-8) 33% 10 Previous auto-sct 81% Related 18% at 12 months 34% 8% OS, 72% at 2 years PFS, 6% Sorror et al (44-69) 4 3% 69% Related 31% Unrelated 11% at 100 days 22% Overall 61% 0% OS, 48% at years PFS, 38% Khouri et al (34-70) 3 (2-8) Not stated 87% active disease 90% Related 10% Unrelated 2% at 100 days 4% 8% OS, 48% at 4 years PFS, 44% Brown et al (3-67) (1-10) 7% 10 Previous auto-sct 33% Related 67% Unrelated 17% Overall 34% 43% OS, 4% at 2 years PFS, 34% Delgado et al (37-67) 3 (1-8) 27% 11 Previous auto-sct 8% Related 42% Unrelated % at 100 days 26% Overall 10% (Grade 3-4) 33% a OS, 1 at 2 years PFS, 4% a After DLI. Abbreviations: CLL = chronic lymphocytic leukemia; DLI = donor lymphocyte infusion; GVHD = graft-versus-host disease; OS = overall survival; PFS = progression-free survival; TRM = transplantation-related mortality morbidity and mortality associated with myeloablative conditioning. Indeed, study data indicates that RIC regimens do appear to be associated with a decreased mortality, and allow transplantation in older patients, making this approach more applicable to increased numbers of patients with CLL. 1-7 Patients in these studies were often heavily pretreated and refractory to therapy. Despite this the majority demonstrated donor engraftment with a high CR rate. Survival was improved in patients who underwent transplantation while they still had chemosensitive disease. These studies provide strong evidence for a clinically significant GVL effect in CLL. A major focus of ongoing research is the amount of pretransplantation and posttransplantation immunosuppression required to establish stable mixed chimerism and eventual full donor chimerism following RIC allogeneic SCT. The optimal patient selection, timing, and conditioning regimen for such RIC approaches to SCT remain to be elucidated, and these procedures continue to be investigational in nature. Although the acute morbidity and mortality appears significantly lower compared with high-dose conditioning regimens with allogeneic transplantation, the longer-term results are awaited. Benefit could potentially be gained by separating the beneficial GVL effects of allogeneic SCT from the detrimental ones of GVHD. One such approach would be to target tumor-specific antigens, and exvivo expansion of FACS-sorted donor-derived T-lymphocytes has allowed the infusion of peptide-specific cells with the potential to target CLL cells directly. Such experimental approaches hold great interest when considering future allogeneic SCT strategies. To examine whether RIC decreases treatment-related mortality after allogeneic SCT for CLL, the outcome of 73 patients treated with RIC was compared with that of 82 matched patients from the European Bone Marrow Transplant Registry (EBMTR) database who had undergone standard myeloablative conditioning for CLL during the same time period. 8 Patients undergoing RIC had a significant reduction of TRM, but a higher incidence of relapse. There was no significant difference in OS or event-free survival between the two groups. Outcomes have been reported after RIC allogeneic SCT for 64 patients with advanced CLL using the Fred Hutchinson Cancer Research Center multi-institutional protocol using related (n = 44) or unrelated donors (n = 20). 9 As shown in Table 3, the median age was 6 years (range, years). The majority of patients were fludarabine refractory. TRM at 100 days was 11%, and 22% by 2 years, with significant GVHD. At a median follow-up of years, 28 patients were alive, 21 in CR. Five-year OS was 48% and disease-free survival was 38%. Though complications were higher in the patients with unrelated donors, there were higher CR and lower relapse rates than with related SCT, suggesting more effective GVL activity from the unrelated donors. A similar high rate of GVHD was seen in a smaller group of Australian patients. 60 Clinical trials indicate that the incidence of GVHD can be reduced by the use of alemtuzumab. Unfortunately, it also delays post-sct immune reconstitution, increases the risk of infective complications and potentially impairs the GVL effect. This impaired antitumor response might necessitate the early use of donor lymphocyte infusions post-sct. 61 A study by the British Society of Bone Marrow Transplantation (BSBMT) used alemtuzumab with fludarabine and melphalan as the conditioning regimen. 62 Fortyone consecutive patients were treated; 24 had HLA-matched sibling donors and 17 had unrelated volunteer donors (4 mismatched). The conditioning regimen had significant antitumor effects with 100% of patients with chemosensitive disease and 86% with chemorefractory disease attaining CR or partial response. The TRM rate was 26%, OS was 1%, and relapse risk 29% at 2 years. GVHD S190 Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009

6 Simon Hallam, John G. Gribben rates were relatively low with agvhd occurring in 17 (41%) and cgvhd in 13 (33%). The unexpectedly high TRM rate was due to a high incidence of fungal and viral infections. What emerged from this study was the clear adverse prognostic factor of fludarabine refractoriness. This group of patients had a 2-year OS of only 31%. It has been demonstrated that patients with unmutated CLL who have undergone autologous SCT have a poor outcome. 19,28 This adverse event can be overcome with the use of allogeneic SCT. 30 Among 0 patients who underwent SCT, 34 had unmutated immunoglobulin variable heavy chain genes (IgVH; 14 allogeneic SCT and 20 autologous SCT) and 16 had mutated IgVH genes (9 allogeneic SCT and 7 autologous SCT). There was no difference in CR rate between mode of transplantation and IgVH mutational status. After a median follow-up of years, autologous SCT resulted in a significantly higher relapse rate than allogeneic SCT in both mutational groups. Thus the GVL effect of allogeneic SCT might overcome the negative effect on outcome of unmutated VH gene status on outcome. Myeloablative conditioning may not be required for this effect. In 30 patients with poor prognosis CLL (as defined by mutational status of VH genes and cytogenetic abnormalities 11q-, 17p-) who underwent RIC allogeneic SCT, OS, and event-free survival for the poor-prognosis group were 90% and 92%, respectively, and was not significantly different to that seen in the good-prognosis group. 63 Conclusion No clear guidelines exist describing which patients are candidates for autologous SCT. Autologous SCT offers a chance of lasting remissions with low TRM rates, yet it appears to not be curative, and all patients eventually relapse. Whether this still results in improvement in survival, as has been observed in randomized trials in other diseases such as multiple myeloma, remains to be determined. Furthermore, it is currently unclear if autologous SCT offers a superior survival advantage over the newer chemo-immunotherapeutic regimens. Autologous transplantation appears to not overcome the poor prognosis conferred by unmutated VH genes or poor-risk cytogenetic abnormalities. Allogeneic SCT should be considered in these patients. Myeloablative regimens currently offer no survival advantage over autologous procedures and therefore a RIC regimen might be the optimal approach to management. In this regard, European Bone Marrow Transplant (EBMT) guidelines have been established outlining indications for allogeneic SCT in CLL. 64 The guidelines conclude that there is an evidence basis supporting the efficacy of allogeneic SCT in CLL and that this approach is indicated for selected high-risk patients. Precisely what factors are defined as high risk is not clearly stated, but patients with p3 deletions or mutations are considered candidates in first remission, and ongoing studies are assessing the effect of biomarkers including IgVH mutational status and cytogenetic abnormalities to identify patients at sufficiently high risk to merit consideration for transplantation in first remission. The consensus of the EBMT working group was that allogeneic SCT was recommended early in the disease course for young patients with CLL who fail to achieve CR or who progress within 12 months after purine analogues, and those who relapse within 24 months after having achieved a response with purine analogue based combination therapy or autologous transplantation. It is clear that neither of these Table 4 Autologous SCT The Role of Transplantation in CLL Treatment Myeloablative Allogeneic SCT RIC Allogeneic SCT Role No defined role Clinical trial only Chemo-refractory disease in young patients Partial response or less to first-line chemo-immunotherapy Short duration of response after purine analogue containing regimens Richter s transformation p3 mutation at first treatment Other high-risk in clinical trials Abbreviations: CLL = chronic lymphocytic leukemia; RIC = reduced-intensity conditioned; SCT = stem cell transplantation categories requires assessment of biologic risk factors. There is consensus that patients requiring treatment who have p3 abnormalities have sufficiently poor prognosis to merit transplantation in first response. Ongoing prospective clinical studies are required to determine the additional risk factors that identify patients at sufficiently high risk to merit use of allogeneic SCT in first CR. Myeloablative allogeneic SCT is associated with increased morbidity and mortality and should be restricted to selected patients with very poor prognosis. Although no direct comparisons of myeloablative and RIC allogeneic SCT have been performed, given the older age of patients with CLL, it seems most reasonable to consider RIC transplantations as the approach of choice for the majority of patients with CLL being evaluated for allogeneic SCT. This should be considered early in the disease course to avoid development of refractory disease. The indications for these approaches are shown in Table 4. However, the high risk of GVHD needs to be taken into account. The optimal immunosuppressive conditioning regimen that minimizes GVHD while maximizing GVL remains to be defined. Questions remain regarding appropriate patient selection for SCT, when to proceed, the use of autologous versus allogeneic SCT, use of nonmyeloablative regimens, and how to optimize the GVL effect. Despite encouraging initial results, we are still in the position where the follow-up of most clinical trials is too short to assess whether SCT can cure CLL. Future approaches to the management of this disease must take into account the balance between the increased morbidity and mortality of SCT in CLL with the curative potential that these approaches may offer. In the absence of any other treatment modalities currently capable of improving survival, the treatment of choice for younger patients with poorrisk CLL may indeed be allogeneic or autologous SCT. Continued enrollment of appropriate patients into well-designed clinical trials is vital for further progress. Disclosures Dr. Gribben has received Honoraria from Bayer Pharmaceuticals Corporation, Bioden Idec, Celgene Corporation, and Roche Pharmaceuticals. Dr. Hallam has no relevant relationships to disclose. Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009 S191

7 Transplantation in CLL References 1. Johnson S, Smith AG, Loffler H, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 1996; 347: Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343: Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 2001; 98: Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107: 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; 2: Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB Blood 200; 10: Keating MJ, O Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 200; 23: Wierda W, O Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 200; 23: Dohner H, Fischer K, Bentz M, et al. p3 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 199; 8: Keating MJ, O Brien S, Kontoyiannis D, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma 2002; 43: Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath- 1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99: Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p3 gene mutation and resistance to chemotherapy. N Engl J Med 2002; 347: Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p3 mutations and deletions. Blood 2004; 103: Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood 2002; 99: Elter T, Borchmann P, Schulz H, et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol 200; 23: Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia 2004; 18: Montillo M, Tedeschi A, Rossi V, et al. Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H. Leukemia 2004; 18: Montserrat E, Gomis F, Vallespi T, et al. Presenting features and prognosis of chronic lymphocytic leukemia in younger adults. Blood 1991; 78: Dreger P, Stilgenbauer S, Benner A, et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood 2004; 103: Rabinowe SN, Soiffer RJ, Gribben JG, et al. Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 1993; 82: Khouri IF, Keating MJ, Vriesendorp HM, et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 1994; 12: Itala M, Pelliniemi TT, Rajamaki A, et al. Autologous blood cell transplantation in B-CLL: response to chemotherapy prior to mobilization predicts the stem cell yield. Bone Marrow Transplant 1997; 19: Dreger P, von Neuhoff N, Kuse R, et al. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure? Br J Cancer 1998; 77: Pavletic ZS, Bierman PJ, Vose JM, et al. High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 1998; 9: Milligan DW, Fernandes S, Dasgupta R, et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 200; 10: Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic stem cell transplantation for poor risk chronic lymphocytic leukemia. Blood 200; 106: Jantunen E, Itala M, Siitonen T, et al. Autologous stem cell transplantation in patients with chronic lymphocytic leukaemia: the Finnish experience. Bone Marrow Transplant 2006; 37: Ritgen M, Lange A, Stilgenbauer S, et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2003; 101: Ritgen M, Stilgenbauer S, von Neuhoff N, et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104: Moreno C, Villamor N, Colomer D, et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 200; 23: Sala R, Mauro FR, Bellucci R, et al. Evaluation of marrow and blood haemopoietic progenitors in chronic lymphocytic leukaemia before and after chemotherapy. Eur J Haematol 1998; 61: Michallet M, Thiebaut A, Dreger P, et al. Peripheral blood stem cell (PBSC) mobilization and transplantation after fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic Leukaemias Working Party (CLWP). Br J Haematol 2000; 108: Dreger P, Montserrat E. Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 2002; 16: Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98: Provan D, Bartlett-Pandite L, Zwicky C, et al. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 1996; 88: Schey S, Ahsan G, Jones R. Dose intensification and molecular responses in patients with chronic lymphocytic leukaemia: a phase II single centre study. Bone Marrow Transplant 1999; 24: Schultze JL, Donovan JW, Gribben JG. Minimal residual disease detection after myeloablative chemotherapy in chronic lymphatic leukemia. J Mol Med 1999; 77: Zenz T, Ritgen M, Dreger P, et al. Autologous graft-versus-host disease-like syndrome after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2006; 108: Montillo M, Tedeschi A, Miqueleiz S, et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24: Michallet M, Corront B, Hollard D, et al. Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: report from the European Cooperative Group for bone marrow transplantation (8 cases). Nouv Rev Fr Hematol 1988; 30: Michallet M, Archimbaud E, Bandini G, et al. HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for blood and marrow transplantation and the International bone marrow transplant registry. Ann Intern Med 1996; 124: Khouri I, Champlin R. Allogenic bone marrow transplantation in chronic lymphocytic leukemia. Ann Intern Med 1996; 12: Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 2: Doney KC, Chauncey T, Appelbaum FR. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 2002; 29: 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 200; 36: Rondon G, Giralt S, Huh Y, et al. Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 1996; 18: demagalhaes-silverman M, Donnenberg A, Hammert L, et al. Induction of graft-versus-leukemia effect in a patient with chronic lymphocytic leukemia. Bone Marrow Transplant 1997; 20: 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 200; 23: Horowitz M, Montserrat E, Sobocinski K, et al. Haemopoietic stem cell transplantation for chronic lymphocytic leukaemia. Blood 2000; 96(suppl 1): (Abstract 224). 0. 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 fludarabine on acute graft-versus-host disease. Br J Haematol 1997; 97: Schetelig J, Thiede C, Bornhauser M, et al. Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia. Ann Hematol 2002; 81(suppl 2):S Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and S192 Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009

8 Simon Hallam, John G. Gribben allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21: Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98: Dreger P, Brand R, Hansz J, et al. Treatment-related mortality and graft-versusleukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 2003; 17: Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 200; 23: 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: Dreger P, Brand R, Milligan D, et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 200; 19: Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 2008; 26: Hertzberg M, Grigg A, Gottlieb D, et al. Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders. Bone Marrow Transplant 2006; 37: Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-hodgkin lymphoma. Blood 2004; 104: Delgado J, Thomson K, Russell N, et al. Results of alemtuzumab-based reducedintensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood 2006; 107: 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 200; 11: 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: Sutton L, Maloum K, Gonzalez H, et al. Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia. Leukemia 1998; 12: Khouri IF. Reduced-intensity regimens in allogeneic stem-cell transplantation for non-hodgkin lymphoma and chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2006; Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009 S193