Hematological Oncology Hematol Oncol 2009; 27: 53–60 Published online 8 April 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hon.884

Review Article

The role of stem cell transplantation in the management of chronic lymphocytic leukaemia Constantine S. Tam1 and Issa Khouri2* 1

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2

*Correspondence to: Issa Khouri, Department of Stem Cell Transplantation and Cellular Therapy, Unit 423, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. E-mail: [email protected] Received: 21 October 2008 Revised: 28 October 2008 Accepted: 28 October 2008

Abstract The majority of patients diagnosed with chronic lymphocytic leukaemia (CLL) will ultimately die of their disease. Stem cell transplantation (SCT) remains the only treatment modality capable of cure, but has traditionally been associated with very high morbidity and mortality. We review the results of myeloablative autologous and allogeneic SCT in CLL, discuss the evolution of the new non-myeloablative approaches, and make recommendations for when SCT should be considered in patients with CLL. Copyright # 2009 John Wiley & Sons, Ltd. Keywords: bone marrow transplantation; reduced intensity conditioning; rituximab; alemtuzumab

It’s indolent—so why consider stem cell transplantation (SCT)? Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the Western World [1] and has long been considered an indolent disease affecting elderly patients, worthy only of palliation. The reality is that a substantial proportion of patients with CLL are diagnosed prior to the age of 60, and that 70% of patients diagnosed with CLL will die either directly or indirectly of their disease [2]. Recent advances in the understanding of CLL biology have allowed us to identify select subgroups of patients with adverse characteristics such as chromosomal abnormalities [3], unmutated IgVH genes [4,5] and aberrant ZAP-70 expression [6,7], some of whom have projected survival as short as 3 years. Among patients with progressive CLL who require treatment, those who eventually develop disease resistance to currently available drugs have a dismal survival of less than 12 months [8,9]. As SCT is the only treatment modality capable of cure in CLL, it is likely that a discussion regarding its use will arise at some point during the disease course in a majority of patients. In this review, we will discuss the history and evolution of SCT in CLL, and make recommendations regarding when clinicians should consider its use in the care of their patients with CLL.

The rise and fall of autologous SCT Autologous SCT permit the escalation of cytotoxic treatment to doses beyond the threshold for spontaneous marrow recovery, and is an important treatment modality in the treatment of other lymphoid malignancies including follicular lymphoma [10] and diffuse large cell lymphoma Copyright ß 2009 John Wiley & Sons, Ltd.

[11]. Autologous SCT was studied in CLL in two settings: as salvage therapy for patients who have failed conventional treatment, and as an attempt to eradicate leukaemia in younger patients with early stage disease. The results of autologous transplantation as salvage treatment in patients with multiply relapsed and/or refractory CLL were disappointing, mainly because the majority of patients were proceeding to transplantation with active, chemorefractory disease. Investigators from the University of Texas MD Anderson Cancer Center (MDACC) reported the outcome of autologous SCT in 11 patients, 7 of whom had in vitro purging of the stem cell product [12]. The median age was 59 years (maximum, 66 years), and patients were heavily pretreated, having received up to six previous lines of chemotherapy. Five (45%) patients had disease refractory to fludarabine, alkylating agent or both, and six (54%) patients had active CLL at the time of transplantation. Although autologous transplantation was successful in achieving either a complete or nodular partial response in 10 of 11 (91%) patients, the responses were not durable, with 3 (30%) relapsing with Richter’s transformation at 4–8 months and 2 (20%) relapsing with CLL at 12–15 months. Two (20%) other patients died in ongoing remission of suspected or proven infection. These results suggested that autologous SCT in the setting of advanced, chemorefractory disease was not capable of long-term disease control, a finding that was echoed by results reported other groups [13,14]. A number of studies evaluated the feasibilty of tumour eradication in younger patients by the early application of autologous SCT, at a time of minimal disease burden. Rabinowe reported the Dana Farber Cancer Institute (DFCI) experience with autologous SCT in 12 patients aged 27–54 years (median 45 years) who were debulked to a state of low disease burden (
2 cm nodes, no

54

organomegaly,
20% bone marrow infiltration) prior to transplantation [15]. The conditioning regimen was high dose cyclophosphamide and total body irradiation (CyTBI), and all stem cell products were purged using a combination of antibodies. The initial paper had insufficient follow-up for assessment of long-term disease control, which was addressed by a subsequent report from the same group 12 years later [16]. In total, 137 patients aged 19–66 (median 51 years) received autologous SCT after being first treated to a state of low disease burden using conventional chemotherapy. Following protocol amendment in 1994, patients were permitted to receive autologous SCT after only one line of chemotherapy, and 58% of patients in this study received transplantation during their first remission. Conditioning was with CyTBI, and all marrow products underwent in vitro purging prior to re-infusion. Stable engraftment was achieved in 97%, and transplant-related mortality (TRM) was acceptable at 4% at day 100, rising to 17% at 2 years. Disappointingly, despite the application of autologous SCT at a time most conducive to leukaemia eradication—early in disease course, low tumour burden, chemosensitive disease and purged product—no cure fraction was evident on the progression curve, with a continuous pattern of relapse. At 6 years, rates of overall survival and progression free survival (PFS) were 58 and 51%, respectively. Similar results were reported by other investigators pursuing a curative strategy with autologous transplantation. Milligan et al. [17] reported the outcome of 65 patients aged 27–60 (median 49 years) who underwent autologous SCT using cytokine mobilized peripheral blood stem cell products. These patients had previously untreated disease, and were entered onto an induction strategy of fludarabine as initial chemotherapy, followed by autologous SCT consolidation in first remission. Following conditioning with Cy-TBI (75%), BEAM (17%) or other myeloablative regimens, the rate of complete remission (CR) improved from 19% after fludarabine therapy to 74% after transplantation. day 100 TRM was 2%. A continuous pattern of relapse was seen with no evidence of a cured fraction: after 3 years, 20% of patients have relapsed, and 48% of patients have died or relapsed by 5 years. Esteve et al. [18] reported the Spanish experience in 14 patients aged 29–61 (median 47 years) receiving predominantly Cy-TBI (86%) autologous transplantation, three of which also underwent in vitro purging. No TRM was encountered, but patients relapsed in a continuous pattern after a median remission of 3 years. Investigators from Germany reported the experience in 58 patients aged 29–64 (median 50 years) conditioned with Cy-TBI and rescued with purged stem cell products [19]. Seventy-nine per cent of patients were transplanted in first remission as part of a planned induction strategy. After 2 years, the risk of relapse was significantly higher among patients with unmutated IgVH (19%) as compared with patients with mutated IgVH (0%, p < 0.001), and relapses continued to occur in both groups with no evidence of a cured fraction. In aggregate, these studies showed that although autologous transplantation in the setting of minimal disease Copyright ß 2009 John Wiley & Sons, Ltd.

C. S. Tam et al

burden could produce prolonged remissions, complete disease eradication was not achieved. The response kinetics were highlighted by minimal residual disease (MRD) studies in several reports showing suppression of leukaemia immediately following transplantation, followed by inevitable CLL regeneration which was detectable as MRD prior to actual clinical relapse [17–19]. A large EBMT series of 193 CLL patients undergoing autologous SCT essentially confirmed the results of the single centre studies discussed above [20]. Why has autologous transplantation fallen so far out of favour? After all, even if cure is not achieved, remission durations of 5–6 years are still worthwhile outcomes, and a non-randomized comparison suggested that CLL patients treated with autologous transplantation may have better survival than chemotherapy treated patients [21]. The reasons are threefold. Firstly, autologous SCT is not able to overcome the adverse prognostic effects of biological markers, particularly in patients with unmutated IgVH [19,22]. Secondly, the outcomes of chemotherapy has improved significantly over the past two decades, such that CR rates of >70% and remission durations of >6 years are now achievable using chemotherapy alone [23]. Lastly, concerns regarding late toxicity, in particular the risk of myelodysplasia, remain unresolved. In the DFCI and the UK multicentre studies, late myelodysplasia or secondary leukaemia occurred in 9 and 8% of autotransplanted patients, respectively [16,17], a rate substantially higher than the 2.7% reported with chemotherapy alone [23].

Myeloablative allogeneic SCT in CLL Although myeloablative allogeneic SCT is an intensive procedure applicable only in younger patients, it has several theoretical advantages over autologous SCT. Firstly, any potential concern for tumour contamination of the stem cell product is eliminated (although new data are emerging about the potential for unrecognized familial CLL to be transmitted from a related donor—see discussion later). Secondly, there is the potential for the graft versus leukaemia (GVL) effect to eliminate chemotherapy-resistant leukaemia cells by immune mechanisms. Indeed, the demonstration of dramatic responses following donor lymphocyte infusions (DLI) in patients with CLL [24] and follicular lymphoma [25] established the low grade lymphoid malignancies as being among the cancers most susceptible to immune clearance. The enthusiasm for myeloablative allogeneic SCT in CLL, using either related or unrelated donors, is however tempered by registry reports showing very high TRM rates of 38–50% [20,26,27]. In contradistinction with the results of autologous SCT, however, plateaus in the survival curves emerge 1–2 years following allogeneic transplantation. Currently, published registry data indicate that approximately two-thirds of allotransplanted CLL patients will succumb either to TRM or to recurrent disease, and approximately one-third will be cured of their disease [20,26,27]. Patients with chemosensitive disease have significantly better outcomes than patients with refractory Hematol Oncol 2009; 27: 53–60 DOI: 10.1002/hon

Role of SCT in the management of CLL

disease [26,27], suggesting that an earlier application of allogeneic SCT may further improve transplantation outcomes. The results of myeloablative allogeneic SCT from individual transplantation centres have generally been more favourable than that of the registry studies. Investigators from the DFCI reported the results of CyTBI based sibling allotransplantation in 25 patients early in their disease course (median one previous line of therapy, 56% transplanted during their first remission) [15,16]. Median age was 47, with the oldest patient being 55 years old. All patients had chemosensitive disease and were debulked to a state of low disease burden prior to allotransplantation. Graft versus host prophylaxis included the universal application of in vitro stem cell T-cell depletion (TCD). All patients engrafted successfully, and day 100 TRM was acceptable at 4%, rising to 24% at 2 years. Unfortunately, no plateau in the survival curve was evident, with 68% of patients progressing by 6 years in a continuous pattern of relapse. Overall survival at 6 years was 55%. The toxicity and disease control of allotransplantation were not significantly different from that of a larger group of patients undergoing autotransplantation at the same institution [16], and the authors speculated that the universal application of TCD may have contributed to the lack of GVL effect. Indeed, when DLI were given to seven patients who progressed in this study, six (86%) demonstrated an objective response. Several transplantation centres have published results of myeloablative SCT in advanced, multiply relapsed patients. Khouri et al. [28] reported the long-term MDACC experience with Cy-TBI (96%) or BEAM (4%) conditioned allogeneic transplantation in 28 patients using either sibling (75%) or alternative (25%) donors. Median age was 43, with the oldest patient being 58 years old. Patients had undergone a median of three previous lines of therapy and only 21% had chemosensitive disease at the time of transplantation. The majority of patients had >50% bone marrow infiltration by leukaemia. day 100 TRM was 11%, and 49% of patients developed acute GVHD, although this was severe (grade 3) in only one patient. Sixty-four per cent of patients developed chronic GVHD. Overall survival was 45% at 5 years. Consistent with the data from the registry studies, PFS was significantly superior in patients with chemosensitive disease (78% at 5 years) than in patients with refractory disease (26% at 5 years, p ¼ 0.03). The outcome of chemosensitive patients in the MDACC study was in line with results from the Barcelona group, who reported a 5-year PFS of 71% in a population of less heavily pretreated patients [18,22]. An important observation from the latter study was that in contradistinction with the results of autologous transplantation, the risk of disease relapse following allogeneic SCT was similar irrespective of the patient’s IgVH status, suggesting that the GVL effect may be able to overcome the adverse prognostic impact of an unmutated IgVH. The Barcelona group also compared the results of patients receiving autologous and allogeneic transplantation in a non-randomized manner [18]. Unlike the DFCI study, where universal TCD may have negated some of the Copyright ß 2009 John Wiley & Sons, Ltd.

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GVL effect, in the Barcelona report there was a clear difference in outcomes between autotransplanted and allotransplanted patients, with a disease plateau emerging after 6 months in allogeneic SCT patients, compared with a continuous pattern of relapse in autologous SCT patients. In addition, the assessment of MRD kinetics showed that the elimination of disease following allogeneic transplantation was gradual and continued to occur well after the effects of conditioning had worn off, consistent with the presence of an ongoing GVL effect. An interesting consideration in allogeneic transplantation using related donors is the possibility of leukaemia transfer from a donor with unrecognized CLL. CLL shows a clear familial predisposition, and a recent study showed that a subclinical CLL clone was detectable in 13.5% of first degree relatives of CLL patients [29]. Indeed, in the DFCI report, seven-related donors were excluded due to the discovery of a lymphoproliferative disorder during routine work-up [16]. Pavletic et al. [30] reported a series of 19 patients with CLL undergoing myeloablative transplantation from genetically identical twins. In this study, one patient relapsed 6 years after transplantation with a CLL clone that was subsequently shown to be derived from his brother, who in turn was diagnosed with CLL after he had completed stem cell donation. Therefore, the work-up of any potential-related donor for a patient with CLL must include multi-parameter flow cytometry to exclude the possibly of subclinical CLL in the donor.

Non-myeloablative SCT: GVL with reduced toxicity There are compelling reasons to support the exploration of non-myeloablative SCT (NST) in CLL. Unlike myeloablative allogeneic transplantation, the preparative regimen in most NST regimens is substantially less toxic, making the procedure feasible in older and/or less medically robust patients. As epithelial damage from cytotoxic conditioning and the resultant cytokine storm are at least partly contributory to the development of acute GVHD, nonmyeloablative regimens have the potential to reduce early morbidity and mortality by reduction in both direct tissue damage and acute GVHD. The flip side of the equation is that the therapeutic burden in NST shifts entirely to GVL, with minimal contribution from the conditioning regimen itself. As CLL is highly susceptible to the GVL effect [16,24], and as most patients requiring allogeneic SCT for CLL are 55 years or older, this therapeutic trade-off appears reasonable for the majority of patients. Investigators from the MDACC first reported the feasibility of NST in indolent lymphoid diseases in 1998 [31]. Six years later, the early results of NST in 17 CLL patients receiving sibling grafts were reported (Table 1) [24]. Median age was 54 years, and 23% of patients were 60 years or older. This was a heavily pretreated cohort who had failed a median three lines of previous therapy, and less than half had chemosensitive disease at the time of NST. The conditioning regimen was a true non-myeloablative regimen of fludarabine 30 mg/m2 and cyclophosphamide Hematol Oncol 2009; 27: 53–60 DOI: 10.1002/hon

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C. S. Tam et al

Table 1. Outcomes of non-myeloablative allogeneic transplantation in CLL Report

N Conditioning regimen

Median age %Chemosensitive %CR (range) disease

Khouri (2004)

17 FC or FCR

54 (44–73)

47

71

57 (34–70) 50 (12–63) 56 (44–69)

72 50 47

71 40 50

Caballero (2005) 30 Various 53 (35–67) Brown (2006) 46 Flu/Bu 53 (35–67) Delgado (2006) 41 Flu/Melphalan/Alemtuzumab 54 (37–67)

80 43 83

78 — —

Dreger (2003)

65

69

Khouri (2007) 39 FCR Schetelig (2003) 30 Flu/Bu/ATG Sorror (2005) 64 TBI  Flu

77 Various

54 (30–66)

0 22 3 15 11 22 20 2 5 26 18

%TRM

%Progression

%Survival

(3 (2 (3 (2 (3 (2 (6 (3 (3 (2 (1

20 (2 years)

80 (2 years)

months) years) months) years) months) years) years) months) months) years) year)

22 (2 years)a 48 (4 years) 17 (2 years) 72 (2 years) 26 (2 years) 60 (2 years) 7 (5 years) 48 (2 years) 29 (2 years)

70 (6 years) 54 (2 years) 51 (2 years)

31 (2 years)

72 (2 years)

Flu, fludarabine; FC, fludarabine and cyclophosphamide; FCR, FC and rituximab; Bu, busulfan; ATG, anti-thymocyte globulin; TBI, total body irradiation; CR, complete remission; TRM, transplant-related mortality. a Patients with chemosensitive disease.

750 mg/m2 (FC) on days -5 to -3 of their transplant; in addition, 10 (59%) patients also received high-dose rituximab (FCR, Figure 1). Graft versus host prophylaxis was with three doses of intravenous methotrexate and 6 months of tacrolimus. Patients who did not respond to the transplantation regimen, or who progressed following transplantation, underwent immunomanipulation in order to augment the GVL effect. This was accomplished by the tapering of immunosuppression, followed by dose-escalated DLI titrated to the degree of leukaemia response and GVHD encountered. Following the observation of dramatic augmentation of the GVL effect following rituximab administration in one patient, high-dose rituximab (375 mg/m2, followed by 1 g/m2 weekly) was added to the immunomanipulation regimen. In this heavily pretreated population, NST with or without immunomanipulation achieved a final CR of 71%. All patients engrafted, with the median period of

neutrophil 95%, p ¼ 0.02). Four-year PFS and overall survival were 44 and 48%, respectively. An important observation from this study was that patients who were ZAP-70 positive had similar outcomes as those who were ZAP-70 negative, confirming that the GVL effect was able to overcome the adverse prognostic impact of select biological factors. Other investigators had reported similarly favourable outcomes with NST, and confirmed the kinetics of tumour clearance following non-myeloablative conditioning. In a large survey of EBMT centres, Dreger et al. [35] reported a 69% conversion to CR, 1-year TRM rate of 11% and 2-year progression rate of 31% in a similar group of older patients with heavily pretreated disease. Forty per cent of patients in this series received TCD, which may have adversely impacted the control of leukaemia: although the rates of progression were similar in the first year after transplantation, no relapses occurred in the non-TCD group after the first year, compared with a continuous pattern of relapse in the TCD group ( p ¼ 0.02 based on a 12-month landmark). In addition, the occurrence of chronic GVHD was associated with a significantly higher chance of achieving CR, and the occurrence of acute GVHD was associated with a significantly lower risk of late disease progression. Investigators from Germany transplanted 30 patients with advanced disease using a more intensive regimen of fludarabine, busulfan and ATG, half of whom received their stem cells from an unrelated donor [36]. Although acute GVHD (56%, grade 3þ 20%) and chronic GVHD (75%, extensive 21%) rates were high, 2-year TRM was acceptable at 15%, and the 2-year risk of progression low at 17%. Investigators from the DFCI also tested the regimen of fludarabine and busulfan in 46 patients, 67% of whom had an unrelated donor [37]. Two-year progression was substantially higher at 48% in the DFCI study, which may be related to the heavily pretreated state of the patients (median five lines of previous therapy). Copyright ß 2009 John Wiley & Sons, Ltd.

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The Seattle group reported results in 64 patients with advanced disease conditioned with TBI with (17%) or without (83%) fludarabine [38]. Thirty-one per cent were transplanted from an unrelated donor. Rates of acute GVHD (55%), chronic extensive GVHD (50%), 2-year TRM (22%) and 2-year progression risk (26%) were similar to the German experience. Consistent with an augmented GVL effect, patients receiving unrelated grafts had higher CR rate, lower relapse rate and faster clearance of leukaemia (as assessed by flow cytometry). Further evidence of the GVL effect in CLL patients receiving NST was provided by the results of 30 Spanish patients who received sibling transplants with excellent outcome (7% progression at 5 years for responders), in whom MRD studies by flow cytometry demonstrated the clearance of residual leukaemia shortly after the onset of GVHD in several patients [39]. An important observation from the Seattle study was the importance of pre-transplantaton comorbidities (as assessed by an adapted form of the Charlson comorbidity index) in influencing transplantation outcome [38]. Two studies have compared the outcome of NST against autologous SCT [40] or myeloablative allogeneic SCT [41]. In a German multicentre study, Ritgen et al. [40] showed that the treatment outcome of NST was superior to that of autologous transplantation in patients known to have an unmutated IgVH status. In a large EBMT study of patients receiving myeloablative allografts (n ¼ 82) or NST (n ¼ 73), NST was associated with a significantly lower risk of TRM but a higher risk of disease progression, resulting in comparable overall survival [41]. Although these data may be interpreted as not showing any substantive advantage for the new, non-myeloablative approach, one must remember that the median age of the NST group was in fact significantly older than that of the myeloablative group (53 vs. 45 years, respectively, p < 0.0001). Furthermore, nearly half of NST patients in the EBMT survey received a T-cell depleted graft, which could have diluted the impact of the GVL effect. A final issue regarding NST is the potential role of alemtuzumab in conditioning. Alemtuzumab has significant single-agent activity against CLL [42], and may be effective in preventing GVHD [43]. However, in a nonrandomized comparison of NST with or without alemtuzumab, alemtuzumab use may be associated with a trend to increased disease relapse, presumably by impairing donor T-cell engraftment [44]. Indeed, in the United Kingdom multicentre study of an alemtuzumab containing NST protocol in CLL patients, problems with primary engraftment and secondary graft loss were encountered, and only two-thirds of patients achieved full chimerism 6 months after transplantation [45]. All patients with incomplete chimerism by 6 months in this study were scheduled to receive DLI by study protocol, which may have accounted for why the progression rate (29% at 2 years) was not as high as one would expect based on the results from other centres. Two-year overall survival and PFS were 51 and 45%, respectively. In both of these studies, the total dose of alemtuzumab was relatively high at 100 mg. It is not known if lower doses of alemtuzumab may be effective in Hematol Oncol 2009; 27: 53–60 DOI: 10.1002/hon

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Table 2. Indications for consideration of potential allogeneic transplantation in CLL Indications for consideration of potential allogeneic transplantation in CLL

Frontline setting Relapsed/refractory setting

Partial response due to residual disease, or no response, following FCR or equivalent therapy. De novo 17p deletion patients. De novo Richter transformation. Relapse from FCR or equivalent therapy. Disease refractory to fludarabine and alemtuzumab. Patients with 17p deletion who have failed previous chemotherapy. Patients with Richter transformation.

FCR, fludarabine, cyclophosphamide and rituximab.

improving disease control and preventing GVHD, without impairing donor T-cell engraftment.

CLL: when should we consider transplantation? The remarkable advances made in SCT for CLL over the past 20 years have made it a viable procedure in patients up to 70 years of age. A key lesson learnt from studies of myeloablative and non-myeloablative allogeneic transplantation is that these procedures achieve their best outcomes if they are performed at a stage when the leukaemia is still chemosensitive [34,35,37,38,41], particularly if the leukaemia can be debulked to a low disease burden prior to transplantation [35,37,38,41]. The latter point in particularly important in NST, where the eradication of leukaemia typically occurs over a period of weeks to months [34,35,37–39,41]. With the advent of modern chemotherapy, the majority of patients (including those with unmutated IgVH and ZAP-70 positivity) can achieve a durable first remission without the need for early transplantation [23,46]. Longterm results from the fludarabine, cyclophosphamide and rituximab regimen showed that the median remission duration for complete responders was 85 months, being somewhat shorter in patients with detectable marrow MRD (median 49 months for flow cytometry positive, and 40 months for PCR positive) [23]. In contrast, patients achieving partial response only had disappointing median remission duration and survival of 19 and 34 months, respectively, and should be considered for allogeneic transplantation (Table 2). Other frontline patients who may be allogeneic transplantation candidates include those with genomic deletions of chromosome 17p [47,48]. The EBMT consensus recommendations currently consider patients with chromosome 17p to be a high-risk group for which allogeneic SCT is a reasonable treatment option, and a recent retrospective series had confirmed that allogeneic SCT is capable of exerting durable disease control in patients with multiply relapsed, 17p-deleted CLL [49,50]. Patients who have progressive disease which had failed conventional therapy should be referred for transplantation. Any patient who develop Richter transformation at any stage of disease should also be considered for transplantation [51]. Copyright ß 2009 John Wiley & Sons, Ltd.

Patients who relapse following first-line treatment with modern chemoimmunotherapy have a median survival of less than 3 years from the time of relapse, and those patients with the most favourable survival were those who eventually underwent allogeneic SCT [52]. As the process of initiating sibling typing and/or unrelated donor search may take a considerable period of time, we recommend that a discussion regarding the potential need for transplantation be conducted at the time of first relapse from frontline therapy with FCR or equivalent regimen.

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