Is there a place for allogeneic stem cell transplantation in chronic lymphocytic leukaemia in the era of the new molecules?

185 Is there a place for allogeneic stem cell transplantation in chronic lymphocytic leukaemia in the era of the new molecules? D. Selleslag, MD SUMMARY Allogeneic stem cell transplantation can cure about 40% of patients with chronic lymphocytic leukaemia. The early transplant related mortality with reduced intensity conditioning is low, but the late non relapse mortality is around 20% due to the high incidence of chronic graft versus host disease. The graft versus leukaemia effect is crucial for cure of chronic lymphocytic leukaemia after allogeneic stem cell transplantation and can be obtained by immune interventions. The place of allogeneic stem cell transplantation needs to be redefined in the era of novel targeted treatments (BCR pathway inhibitors and BCL2 inhibitors). Taking into consideration the promising results of BCR pathway inhibitors in genetically high-risk chronic lymphocytic leukaemia (with 17p deletion/tp53 mutation or complex karyotype) and fludarabine resistant chronic lymphocytic leukaemia, the current recommendation is to proceed with allogeneic stem cell transplantation in chronic lymphocytic leukaemia patients failing a BCR pathway inhibitor. The question when to proceed with allogeneic stem cell transplantation in responding patients remains unanswered. In the absence of randomised or prospective observational studies comparing novel agents to allogeneic stem cell transplantation the decision should be individualised and depend on the estimated transplantation risks and the patient s desires. (BELG J HEMATOL 2017;8(5):185-91) INTRODUCTION Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western hemisphere. While emergence of novel targeted therapies has significantly improved the outcome of CLL and has completely altered the therapeutic landscape in recent years the disease remains only curable by allogeneic stem cell transplantation (allosct). In 2014, about 2% (total number 353) of all allosct reported to the European Group of Blood and Marrow Transplantation (EBMT) were performed for CLL. Since 2000, the number of allosct for CLL is constantly increasing while autologous transplantation for CLL has almost completely disappeared (only nineteen autosct performed in 2014). 1 In 2007, EBMT defined consensus recommendations for allosct in CLL. AlloSCT candidates were considered those patients with high-risk CLL defined by the following criteria: not achieving a response or relapsing within twelve months after purine analogue therapy (fludarabine resistant CLL); relapsing within 24 months after intensive treatment (purine analogue containing combination chemotherapy, autologous SCT); presence of p53 mutation or 17p deletion and requiring therapy. 2 The 2007 recommendations were based on the poor outcome of these patients with conventional therapies. The long-term results of first salvage therapy in patients relapsing after Fludarabine-Cyclophosphamide-Rituximab (FCR) therapy demonstrate that patients with a first remission Department of Haematology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium. Please send all correspondence to: D. Selleslag, MD, AZ Sint-Jan Brugge-Oostende, Department of Haematology, Ruddershove 10, 8000 Brugge, Belgium, tel: +32 050 45 23 21, email: Dominik.selleslag@azsintjan.be. Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest. Keywords: allogeneic stem cell transplantation, chronic lymphocytic leukaemia, ibrutinib, idelalisib, venetoclax.

REVIEW HEMATOLOGY 186 TABLE 1. Results of RIC allosct for CLL in largest recent studies. Fred Hutchinson Cancer Centre German CLL Study Group MD Anderson Cancer Centre Dana Farber Cancer Institute Sorror 2008 Dreger 2010 Khouri 2011 Brown 2013 Number of patients 82 90 86 76 Conditioning regimen Flu/low dose TBI FluCy +/- ATG FluCy +/- RTX FluBu Donors, % (Sib vs MUD) 63/37 41/59 50/50 37/63 Median follow-up (months) 60 72 37 61 Early mortality, % (<100 days) <10 <3 <3 <3 NRM (%) 23 23 17 16 Acute GVHD, grade 3-4, % 20 14 7 17 Severe chronic GVHD, % 53 55 56 48 PFS, % 39 (5 years) 38 (6 years) 36 (6 years) 43 (6 years) Overall survival, % 50 (5 years) 58 (6 years) 51 (6 years) 63 (6 years) Abbreviations: RIC: reduced intensity conditioning; sib: sibling; MUD: matched unrelated donor; GVHD: graft versus host disease; PFS: progression free survival; Flu: fludarabine; TBI: total body irradiation; FluCy: fludarabine cyclophosphamide; FluBu: fludarabine busulfan; ATG: anti-thymoglobulin; RTX: rituximab. duration of <1 year after FCR had a median overall survival of only thirteen months and those with a remission duration of one to three years had a median overall survival of 27 months. 3 The long-term results of alemtuzumab-dexamethasone treatment in patients with del17p (first-line and relapse) have been presented by Stilgenbauer at ASH 2014. Progression free survival at three years improved significantly from 20 to 50% with allosct versus alemtuzumab-dexamethasone maintenance. Several randomised trials and a meta-analysis have shown that high dose chemotherapy and autologous SCT does not offer a survival advantage in CLL compared to conventional chemotherapy and immunochemotherapy. Autologous SCT has been abandoned from current treatment algorithms for CLL and previous autologous SCT is no longer a prerequisite for allosct. 4 The effectiveness of targeted treatments has challenged the appropriateness of the 2007 EBMT consensus recommendations. Targeted treatments of CLL include inhibitors of the BCR pathway (ibrutininb, idelalisib) and BCL2 inhibitors (venetoclax). The place of allosct in the era of these novel targeted treatments will be the focus of this manuscript. RESULTS OF ALLOSCT IN CLL There are no randomised studies comparing reduced intensity conditioning (RIC) with myeloablative conditioning as preparative regimen for allosct in CLL. The Centre for International Blood and Marrow Transplant Research (CIBMTR) reported in a retrospective study the outcomes of matched sibling donor SCT in CLL with RIC versus myeloablative conditioning. Transplants performed after 2000 with RIC conditioning had a significantly superior survival and progression free survival as compared to myeloablative transplants. 5 The current practice is to offer a RIC conditioning to nearly all transplant candidates with CLL. Table 1 shows the results of the largest series of CLL patients undergoing RIC transplants. From this table it is evident that the cure rate with RIC allosct is around 40% with a low early mortality rate of <10% and a late non relapse mortality rate of around 20% due to a 50% incidence of severe chronic graft versus host disease (GVHD). 6 There are no prospective randomised controlled trials comparing allosct with other non-transplant strategies. Three recently published non-randomised studies comparing allosct versus non-transplant strategies provide evidence favouring 5

187 the option of allosct for relapsed or refractory CLL. 7,8,9 A Markov decision analysis from Moffitt Cancer Centre demonstrated a better overall life expectancy for allosct (35 months versus 25 months). 7 Similarly, a retrospective comparative analysis of donor versus no-donor from Heidelberg, once again in the RIC context, showed a 2-year overall survival advantage that favoured allosct (88% versus 38%, p<0.0001) for poor risk CLL as defined by 2007 EBMT criteria. 8 A third retrospective comparative analysis from the MD Anderson Cancer Centre using a consult-transplant versus consult-do not transplant design, limited to patients with del17p, also showed a 2-year overall survival advantage that favoured allosct (64% versus 25%, p=0.001). 9 These studies are not generalisable beyond the use of RIC regimens for allografting and preceded the approval of novel targeted therapies. GRAFT VERSUS LEUKAEMIA EFFECT IS CRUCIAL FOR CURING CLL AFTER ALLOSCT The basis for allosct in CLL is graft-versus-leukaemia (GVL) activity. Efficacy of GVL in CLL is supported by the lower relapse risk after chronic GVHD and the higher relapse risk associated with T-cell depletion. The strongest proof of the GVL principle in CLL comes from studies that analyse minimal residual disease (MRD). MRD kinetics studies after HSCT for high-risk CLL demonstrate that MRD clearance often occurs late after allosct in the context of chronic GVHD or immune interventions, such as tapering of immunosuppression or donor lymphocyte infusions (DLI). A study from Heidelberg demonstrated that long-term disease control in CLL is dependent on the GVL pattern: patients achieving immediate MRD negativity after allosct had a higher relapse risk beyond twelve months than patients achieving MRD negativity with immunomodulation such as tapering of immunosuppression or DLI. This finding emphasises the importance of GVL for the cure of CLL. 10 A study from the German CLL study group has shown that CLL patients with MRD positivity at twelve months after allosct have a much higher risk of clinical relapse during later follow-up. 11 The current recommendation is to start MRD monitoring between day 30 and day 90 after allosct. 12 UPDATED RECOMMENDATIONS FOR ALLOSCT IN CLL IN THE ERA OF NOVEL AGENTS HIGH-RISK CLL WITH UNFAVOURABLE GENETIC FEATURES The outcome of treatment-naive and relapsing CLL patients with del 17p or TP53 mutation has significantly improved with novel targeted therapies. Treatment outcomes achieved with these drugs are the best ever reported in patients with del(17p)/tp53 mutations. In a phase II study 51 high-risk CLL patients (del17p, TP53 mutations) of whom 35 (69%) were treatment-naïve, received ibrutinib. The response rate in the treatment-naïve patients was 97% and the estimated 2-year survival was 84%. In patients with relapsed/refractory CLL, the response rate was 80% and 2-year survival was 74%. Progression rate at two years was 9% for previously untreated and 20% for relapsed/refractory CLL. 13 In another study, older treatment-naïve CLL patients with del 17p or TP53 mutations had a progression free survival of 100% at two years with idelalisib and rituximab. 14 More mature results are now available for ibrutinib in relapsed CLL with del17p/tp53 mutations showing a progression free survival of 48% and a survival rate of 65% at 30 months. 15 Venetoclax produced an overall response rate of 79% and a one year progression free survival of 72% in patients with relapsed/ refractory CLL with del(17p). Based on these results a recent international consensus panel of predominantly American CLL experts does not recommend offering allosct in the front-line consolidation for CLL patients with del17p/tp53 mutations. This is a paradigm shift from the 2007 EBMT consensus criteria. The panel recommends offering allosct to CLL with del17p/ TP53 mutations relapsing after conventional first-line therapy and responding to BCR-inhibitors or BCL-2 inhibitors. Also patients refractory to these agents should be offered allosct. 12 Complex karyotype is an even stronger predictor than del17p for inferior outcome in relapsed and refractory CLL treated with ibrutinib. 16 In the international consensus recommendations CLL with complex karyotype is considered as high-risk CLL and should be offered allosct in the same way as CLL with del17p/tp53 mutations. 12 It should be emphasised that CLL with complex karyotype continues to have an inferior outcome after allosct as compared to CLL without complex karyotype. 17 Patients with TP53 mutated CLL have a similar outcome after allosct as patients without TP53 mutations. 18 OTHER HIGH RISK PATIENTS CLL that is refractory to or relapsing within 12-24 months after initial fludarabine based therapy is still considered as high-risk disease. Even with ibrutinib the outcome of fludarabine resistant CLL is still inferior as compared to fludarabine sensitive CLL. 16 The consensus panel did not consider fludarabine resistance as an indication for immediate allosct. The avoidance of immediate allosct is a major shift from the previous 2007 EBMT consensus recommendations that results from the emergence of promising novel

REVIEW HEMATOLOGY 188 FIGURE 1. Allo SCT in patients with high risk CLL responding to targeted drugs: balancing pros and cons. therapies for high-risk CLL. Initial overall response rates of 71% are obtained with ibrutinib even in heavily pre-treated CLL patients (who had received prior fludarabine therapy) and rise over time to 90% with a 30-month progression free survival of 69%. 14 Similar encouraging findings were reported for idelalisib combined with rituximab in previously treated CLL who had failed fludarabine in over 50% of cases. 19 Patients with documented Richter transformation who demonstrate an objective response to treatment with anthracycline based chemotherapy should be offered allosct. Responses to combination chemotherapy are generally shortlived with a median progression free survival of only ten months. Limited experience with allosct in Richter transformation shows an overall survival for patients allografted in complete or partial remission of 41-75% at three years. 20 STANDARD RISK CLL Standard risk CLL is defined as CLL with absence of del17p and P53 mutations and without complex karyotype. The international consensus panel recommends offering an allosct only when there is lack of response or evidence of progression after BCR inhibitors. Concerns remain about the difficulty of re-inducing remission after relapse or progression on BCR inhibitors. No randomised data exists, to date, which compares allosct versus non-transplant strategies in patients who do not respond or progress on BCR inhibitors. Several mechanisms of resistance to ibrutinib have been reported predominantly in subjects with high-risk features who develop a cysteine-to-serine mutation in Bruton s Tyrosine Kinase (BTK) at the binding site of ibrutinib and/or activating mutations in PLCγ2, which is directly downstream of BTK. 21 Investigators have shown a median OS of only 3.1 months after discontinuation of ibrutinib for various reasons, emphasising the urgency in identifying these cases and initiating a search for an HLA identical donor as soon as possible. 22 Madocks et al. reported a cumulative incidence of Richter transformation of 4.5% at twelve months during ibrutinib treatment for CLL. 23 While the incidence of Richter transformation appears to be relatively low, early identification of these cases and prompt referral to transplant centres is important considering the short-lived responses and the aggressive biology of this disease. There are no established guidelines about the optimal timeframe to offer allosct for CLL with del 11q. The comparative efficacy of therapies such as ibrutinib or chemoimmunotherapy in patients with del11q as compared to non-del11q suggests that del11q patients may be more appropriately incorporated within standard-risk treatment algorithms, unless they show evidence of clonal progression with del17p or complex karyotype or Richter transformation. 15 5

189 FIGURE 2. Factors affecting the balance between immediate and delayed allosct. CAN NOVEL TARGETED MOLECULES IM- PROVE THE OUTCOME OF ALLOSCT IN CLL? Several studies have demonstrated that the outcome of CLL after allosct is superior in patients allografted in complete or partial remission as compared to patients with stable or progressive disease. 24,25 An effective salvage remission induction regimen for fludarabine refractory CLL is R-DHAP (rituximab, dexamethasone, high dose Ara-C and cisplatin) immunochemotherapy enabling the majority of patients to proceed to allosct. 26 This regimen can be given to patients who have no access or do not respond to targeted therapies. To date, there is virtually no published experience on the outcome of allosct in patients who have been exposed to BCR inhibitors, and also data on the use of these drugs after allosct is scarce. However, some theoretical considerations on the interaction between BCR inhibitors and allosct can be made: 1. How will pre-transplant exposure to BCR inhibitors affect the outcome of subsequent allosct? Given the pronounced capacity of ibrutinib and idelalisib of clearing bulky lymph nodes by redistributing CLL cells to the circulation, it is tempting to speculate that these agents could be particularly suitable to optimise the remission status prior to allosct. However, preliminary experience indicates that responses achieved with BCR inhibitors in high-risk CLL may be less stable after cessation of the drug (tumour flare) than those achieved with chemoimmunotherapy, implying that BCR inhibitor-mediated remissions could not be durable enough for allowing the GVL activity to become effective. Thus, it remains to be seen whether BCR inhibitors increase the quality of response before transplant. In this context, the EBMT is currently running a registry study aimed at collecting feasibility and efficacy data on allosct after BCR/BCL2 inhibitor exposure in patients with high-risk CLL. 2. Will allosct outcomes be improved by giving BCR/BCL2 inhibitors post transplant? Post transplant BCR/BCL2 inhibitor administration might be considered as preventive, pre-emptive (MRD-triggered), or therapeutic upon clinical relapse. To date, only anecdotal information is available on the use of ibrutinib for treatment of CLL relapsing after allosct. In a murine model ibrutinib ameliorated chronic GVHD by inhibition of interleukin-2-inducible kinase (ITK). 27 Preliminary clinical results suggest that ibrutinib treatment might indeed improve the outcome of clinical CLL relapse after allosct without risk of eliciting GVHD. 28 In conclusion, the introduction of BCR/BCL2 inhibitors could improve the outcome of transplant approaches in highrisk CLL, but their actual effect remains largely speculative with limited evidence available to date.

REVIEW HEMATOLOGY 190 KEY MESSAGES FOR CLINICAL PRACTICE 1 Allogeneic stem cell transplantation (allosct) can cure 40% of patients with CLL. 2 Early transplant related mortality with reduced intensity conditioning is low. 3 Late non relapse mortality is around 20% due to the high incidence of chronic graft versus host disease. 4 Graft versus leukaemia effect is crucial for curing CLL after allosct and can be obtained by immune interventions (DLI, tapering immunosuppression). 5 The promising results of BCR pathway inhibitors in genetically high-risk CLL (with 17p deletion/tp53 mutation or complex karyotype) and fludarabine resistant CLL led to the current recommendation to proceed with allosct in CLL patients failing a BCR pathway inhibitor. 6 The question when to proceed with allosct in patients responding to a BCR pathway inhibitor remains unanswered. Randomised or prospective observational studies comparing novel agents to allosct are lacking. At this time the decision should be individualised and depends on the estimated transplantation risks and the patient s desires. 7 Patients with documented Richter transformation who demonstrate an objective response to treatment with anthracycline based chemotherapy should be offered allosct. 8 Knowledge on the optimal use of BCR/BCL2 inhibitors pre- or post transplant is limited and is a field of active investigation. BALANCING PROS AND CONS OF ALLOSCT IN HIGH-RISK CLL RESPONDING TO NOVEL DRUGS (Figure 1) Compared to allosct, BCR/BCL2 inhibitors have the advantage of much less procedure-related mortality and morbidity. On the other hand, disadvantages of these novel agents are the absence of curative potential, the uncertainty of durability of response after salvage therapy with alternative BCR/BCL2 inhibitors in case of disease progression, and less efficacy in del17p/tp53 mutated CLL. In contrast, allosct has curative potential even in genetically very unfavourable disease with effective salvage options such as DLI for patients relapsing after transplant. Downsides of allosct are limitations related to age, comorbidity, and donor availability. Taking these points into consideration, the European Research Initiative on CLL (ERIC) and the EBMT have proposed a rational approach to counselling patients with high-risk CLL about the optimal treatment strategy including the transplant option. 29 CONCLUSION HOW TO COUNSEL THE CLL PATIENT IN THE ERA OF NOVEL AGENTS ON IMMEDIATE VERSUS DELAYED ALLOSCT? If possible, every patient with high-risk CLL should be offered one of the new drugs to induce remission. Once maximum response is achieved, there are two options to maintain it: either performing a consolidating allosct or continuing on BCR/BCL2 inhibitors until progression, thereby postponing allohsct until failure to novel drugs is observed. In the absence of controlled studies, in the relapsed/refractory setting, available evidence does not suggest a superiority of one of these two choices over the other, survival being comparable with both options during the first 24 months. Thereafter, survival of patients allografted in a sensitive disease status is well documented, whereas the information on prognosis with continued treatment with BCR/BCL2 inhibitors is still limited. An abstract presented at ASH 2016 described 5-year follow-up with ibrutininb in relapsed refractory CLL: estimated progression free survival at 5-years was 43% and median progression free survival was 52 months. Although these figures are comparable to the outcome of allosct, median follow-up with ibrutinib was still shorter (39 versus >60 months). 30 Decision for immediate or delayed allosct has to be taken after careful discussion of risks and chances of the two options, taking into account the individual situation. Factors affecting the balance between immediate versus delayed allosct are listed in Figure 2. If ever possible, the two options should be compared within a clinical trial or, alternatively, within the framework of an observational study. 5

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