Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy. In the wake of novel treatment approaches that offer high efficacy and highly durable responses with little toxicity, our approach to HSCT in CLL needs to be re-evaluated. While we wait for data on the long-term efficacy of novel therapies to inform the choice of HSCT or alternative treatment, strategies must be assessed individually for every patient, and treatment must be conducted in the setting of randomized clinical trials whenever possible.
Introduction
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Its hallmark is the accumulation of mature B lymphocytes within the bone marrow, blood, and secondary lymphoid organs.[1,2] In most patients with CLL in whom it can be used, first-line immunochemotherapy results in high overall response rates (ORRs) and long-term progression-free survival (PFS).[3,4] However, because this approach is suitable for only a few patients and yields poor results in those with high-risk features,[5] allogeneic hematopoietic stem cell transplantation (HSCT) is a promising treatment option for a selected subgroup of patients with CLL.[6] This, however, must always be considered in view of newer and potentially less toxic therapies, which have only recently become available for the treatment of CLL. These include several new agents and cellular therapies, which demonstrate impressive and durable responses in patients who might previously have been candidates for allogeneic stem cell transplantation.[7,8] As a result, HSCT in the setting of CLL is facing a number of challenges:
• To identify those patients who will benefit most from HSCT and in whom novel approaches are unlikely to have long-term curative potential.
• To recognize the appropriate time when HSCT should be offered.
• To determine whether the full potential of HSCT can be capitalized on through the use of intelligent combination approaches.
The aim of this review is to summarize the current knowledge on HSCT in CLL and to discuss critically its role in the age of novel treatment strategies.
Immunochemotherapy in Standard-Risk and High-Risk CLL
Immunochemotherapy approaches in CLL
CLL is mostly an indolent disease and does not warrant treatment unless overt clinical signs of the disease have developed or disease progression is staggering.[9] Over the past decade, a wide range of treatment options for patients in need of therapy have been developed. In elderly patients not deemed fit enough to tolerate more aggressive treatment approaches, combinations of anti-CD20 antibodies with chlorambucil (Clb) or bendamustine have been found to be beneficial.[5,10] In young patients without significant comorbidities, immunochemotherapy with fludarabine, cyclophosphamide, and the anti-CD20 monoclonal antibody rituximab (FCR) has been established as the first-line standard treatment.[4] While this approach leads to high ORRs and prolongs PFS, it yields only poor results in patients who have high-risk features, who are refractory to standard purine analog–based immunochemotherapy, or who relapse shortly after initial therapy. These subgroups have repeatedly been identified as having a poor long-term response to standard immunochemotherapy, and their clinical management has therefore been extremely challenging.[11]
Definition of ‘high-risk’ CLL
The definition of high-risk CLL largely reflects current CLL guidelines. According to the 2008 International Workshop on CLL guidelines, patients with disease that is refractory to purine analog–based therapy or to autologous HSCT, those with a short time to progression after therapy, and those with deletion of the chromosome region 17p13.1 [del(17p)] should be considered as being at high risk.[9]
Fluorescence in situ hybridization is used to detect del(17p). This deletion occurs in 5% of previously untreated patients with CLL but in up to 30% of those with relapsed and refractory disease. Patients with del(17p) typically require therapy within 1 year of diagnosis and have a median overall survival (OS) of just 32 months. In clinical trials of immunochemotherapy, del(17p) was the strongest negative predictive factor for response to therapy and survival, and the clinical responses that were achieved in patients with del(17p) were not durable.[12]
This lack of chemosensitivity is caused by the malfunction of the tumor suppressor protein TP53. The TP53 gene locus is located on the short arm of chromosome 17, and deletion of 17p leads to inactivation of the TP53 gene. This is often accompanied by inactivating mutations of the second TP53 allele, which results in a complete loss of function. TP53 mutations even in the absence of del(17p) are associated with an equally poor prognosis.[13]
Based on the predicted effectiveness of conventional immunochemotherapy, the consideration of specific subgroups as “highest-risk” patients has also been proposed. Features that define “highest risk” include TP53 loss/mutation, refractoriness to purine analogs, relapse within 24 months after FCR (or FCR-like) treatment, and failure to achieve complete response after FCR.[11]
Another group of patients who are very difficult to treat but who are not included in these definitions are those who have undergone Richter transformation, or Richter syndrome (RS). RS is the development of an aggressive lymphoma-usually diffuse large B-cell lymphoma-and occurs in up to 10% of patients with CLL. Risk factors include advanced stage and poor prognostic markers, such as CD38 and ZAP-70 expression and del(17p) and del(11q), as well as other genetic mutations, but the exact pathomechanisms are still poorly understood. Because patients with RS have dismal response rates and survival, there is an urgent need to identify those at risk for transformation early in the course of their disease.[14]
Efficacy, Adverse Events, and Risks of HSCT in CLL
HSCT in CLL: evidence of efficacy
The first myeloablative treatment–based transplant strategies in CLL were developed more than 30 years ago. Although they demonstrated potent disease control, they were unsuitable for the majority of patients because of their substantial morbidity and mortality.[15,16] However, it was soon recognized that toxicities could be reduced by nonmyeloablative reduced-intensity conditioning (RIC) strategies without compromising engraftment and antitumor activity. This has made HSCT accessible to a larger cohort of CLL patients.
Indeed, CLL is currently the most frequent indication for HSCT among lymphomas. Several large prospective studies have been conducted, some of which have now reached a median follow-up of up to 6 years. These long-term results indicate that RIC HSCT provides long-term disease control in about 40% of patients and also overcomes the negative prognostic effect of TP53 abnormalities and fludarabine refractoriness, as well as other recently identified adverse mutations, such as SF3B1 and NOTCH1. The results from the largest reported prospective studies are summarized in Table 1.[17-21] The efficacy of HSCT in CLL is largely a result of the graft-vs-leukemia (GvL) effect, which continuously mounts an antitumor immune response, likely directed at minor host antigenic variations or CLL-associated antigens.
Adverse events and risks of HSCT in CLL
Because of substantial improvements in supportive and anti-infective treatments and the availability of dedicated transplant units, acute adverse effects-such as nausea, mucositis, and infections-are considerably easier to manage nowadays than in the era of myeloablative HSCT. This is also reflected in very low early mortality rates in the first 100 days after HSCT.
GvL activity in CLL itself seems to be closely correlated to graft-vs-host disease (GvHD), as patients with chronic GvHD (cGvHD) have a reduced risk of relapse and prolonged OS.[17,22] Accordingly, an increased relapse rate was observed in several studies when donor T cells were depleted.[23-25]
Despite its clear clinical advantages, cGvHD remains a significant clinical problem as well and is often only minimally tractable. Across published large prospective studies, cGvHD affects almost 60% of patients and is the major cause of increased nonrelapse mortality rates. In addition, it is the major determinant of quality of life after HSCT.
Markers Predictive of Successful HSCT in CLL
Remission state, EBMT score, and outcome
HSCT seems particularly active in patients with complete or partial disease remission at the time of transplant (ie, in patients with chemosensitive disease). In such patients, the 5-year OS can be increased by up to 80%.[25,26] Achieving a good remission state is, however, quite challenging, especially in patients with TP53 abnormalities and RS. Dose-intensified immunochemotherapy and CD52 monoclonal antibody–based regimens might help prepare patients for successful HSCT by improving their pretransplant remission stage, but at the cost of significant and potentially dose-limiting toxicities.[27-40] Other pretransplant characteristics predictive of OS can be modeled by specific risk scores, such as the European Society for Blood and Marrow Transplantation (EBMT) score, which includes age, time from diagnosis to transplant, donor type (ie, matched unrelated donors vs human leukocyte antigen–matched sibling donors), and donor-recipient gender combination.[31]
MRD monitoring after HSCT
For CLL, minimal residual disease (MRD) is defined as a contamination of five CLL cells or fewer per nanoliter of peripheral blood in the absence of clinical signs or symptoms of the disease. Patients who have fewer than one CLL cell in 10,000 leukocytes in peripheral blood or bone marrow are considered to be MRD-negative. MRD levels are an independent predictor of PFS and OS after immunochemotherapy and add significantly to the prognostic power of known pretreatment parameters. After transplant, MRD kinetics rather than levels seem to identify patients who are at risk for clinical relapse. Patients who are able to clear MRD by defined landmarks 6 to 12 months after allogeneic HSCT have a significantly lower risk of relapse than those who fail to become MRD-negative by these time points. Sustained MRD negativity and clinical remission are most likely mediated by ongoing GvL activity of donor T lymphocytes and their continuous antileukemic activity, which is highly sensitive to immunomodulation by tapering of immune suppression or donor lymphocyte infusions (DLIs).[20,32-34]
Management of Relapse After HSCT
As mentioned earlier, patients who fail to clear MRD by the predefined time points or even show increasing MRD levels are at increased risk for relapse. In these patients and in those who demonstrate overt relapse after HSCT, the GvL effect can be enhanced with DLIs.[34-36]
To date, no standard treatment or guidelines exist for patients who relapse after HSCT and are unresponsive to post-HSCT immunomodulation by DLI. However, post-HSCT relapses are sensitive to salvage therapy: 2- and 5-year PFS rates are nearly 70% and 40%, respectively. Commonly used salvage regimens are anti-CD20 monoclonal antibody– and alemtuzumab-based immunochemotherapy, as well as treatment with novel agents, such as thalidomide, lenalidomide, and ibrutinib.[37]
Autologous Stem Cell Transplantation and CLL
Several prospective trials have demonstrated that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) can prolong event-free survival and PFS if used as part of early front-line treatment. However, autoSCT fails to improve OS and lacks the potential to overcome the negative impact of biomarkers that are associated with resistance to chemotherapy or that indicate a risk of early relapse. In addition, autoSCT is associated with an increased risk of late adverse events, such as secondary malignancies.[23,38-40] Therefore, autoSCT does not currently play a role in the treatment of CLL, and patients who have benefited from this approach in the past are also those who are most likely to respond to conventional immunochemotherapy.
Alternative Immunochemotherapy-Based Treatment Options for Patients With TP53 Abnormalities
The only immunochemotherapy-based treatment option that appears to overcome the negative prognostic value of TP53 abnormalities is the anti-CD52 monoclonal antibody alemtuzumab and its combination with Clb, high-dose corticosteroids, rituximab, and FCR. Although effective, these regimens are associated with a high rate of hematologic and nonhematologic toxicities and severe infectious complications.[41-46] Identifying new strategies for patients with del(17p) and TP53-mutated CLL remains urgent. In patients with relapsed CLL (with and without TP53 abnormalities), FCR and combinations with high-dose corticosteroids, alemtuzumab, or alternative regimens consisting of rituximab, oxaliplatin, cytarabine, and fludarabine have only limited and short-term efficacy and are associated with high toxicity.[27,46-51] They might, however, serve as suitable (and in some instances the only available) strategies to prepare patients for transplant.
Novel Treatment Options in CLL
The availability of novel treatments is dramatically changing the standard of care in CLL.[7] These approaches include:
• Monoclonal antibodies, such as new anti-CD20 monoclonal antibodies, and monoclonal antibodies against receptor tyrosine kinase–like orphan receptor 1 (ROR1) or CD44.
• B-cell receptor signaling pathway inhibitors, such as the Bruton tyrosine kinase inhibitor ibrutinib and the phosphoinositide 3-kinase regulatory subunit p110δ inhibitor idelalisib.
• B-cell lymphoma 2 (BCL-2) antagonists, such as venetoclax (ABT-199), which mainly work by triggering apoptosis via modulation of mitochondrial stability.
• Chimeric antigen receptor (CAR) technology, which allows specific targeting of malignant cells with precisely engineered T cells.
Monoclonal antibodies
Monoclonal antibodies against CD20, such as rituximab and ofatumumab, are now integral components of CLL therapy.[4,52-55] Obinutuzumab is a novel antibody against CD20 that causes more direct cell killing and confers enhanced antibody-dependent cellular cytotoxicity. Obinutuzumab has shown enhanced efficacy in killing CLL cells in vitro compared with rituximab and ofatumumab, and early clinical data demonstrated very rapid clearance of B cells from peripheral blood. In a phase III study that compared Clb alone, Clb with rituximab (R-Clb), and Clb with obinutuzumab (G-Clb) in previously untreated patients with comorbidities, both R-Clb and G-Clb resulted in statistically significant improvements in ORR and PFS compared with Clb alone, as well as in complete remissions. PFS was 16.3 months with R-Clb vs 11.1 months with Clb alone (hazard ratio [HR], 0.44; P < .001) and 26.7 months with G-Clb vs 11.1 months with Clb alone (HR, 0.18; P < .001). Updated data from the G-Clb arm in comparison with Clb alone also demonstrated an OS benefit that favored G-Clb (9% deaths for G-Clb vs 20% deaths for Clb [HR, 0.41; P = .002]). The safety of obinutuzumab was largely similar to that of rituximab, with the exception of an increased rate of infusion reactions during the first dose.[52,53] Several other new monoclonal antibodies, including those against ROR1 and CD44, are currently being tested for efficacy in CLL.[56,57]
B-cell receptor signaling inhibitors
Agents that inhibit B-cell receptor signaling are well tolerated and very active. In a phase I/II study in 85 heavily pretreated patients, the ORR of single-agent ibrutinib was 71%, with a PFS rate of 75% and an OS rate of 83% at 26 months. These responses were independent of the presence of del(17p). Treatment was very well tolerated; toxicities included grade 1/2 transient diarrhea, fatigue, and upper respiratory tract infection. After a median follow-up of 3 years, improved response qualities and durable responses in both treatment-naive patients and those with relapsed/refractory CLL were reported, and higher-grade adverse events diminished.[57] In a single-arm phase II study of single-agent ibrutinib in patients with TP53 aberrations, both the activity and safety profile supported consideration of the drug as a treatment option for patients with high-risk CLL in both first- and second-line settings.[58] In combination with rituximab, ibrutinib is well tolerated and active in patients with high-risk CLL.[58]
Compared with ofatumumab monotherapy, ibrutinib significantly improved ORR, PFS, and OS, and overcame the adverse effect of del(17p) in patients with relapsed/refractory CLL. However, disease progression occurs primarily in patients with del(17p), which indicates that the natural dismal course associated with this cytogenetic alteration is not altered but simply prolonged.[59] Ibrutinib also increased PFS and OS compared with Clb in previously untreated patients with CLL.[60]
Idelalisib produced an ORR of 72% in a phase I study of 54 heavily pretreated patients with relapsed/refractory CLL, including patients with del(17p).[61] A randomized trial that compared idelalisib in combination with rituximab against rituximab plus placebo was interrupted after the first interim analysis because of overwhelming improvement in efficacy in the idelalisib arm. However, higher-grade adverse events were frequent and included pneumonia, neutropenic fever, diarrhea, rash, and transaminitis.[61]
BCL-2 antagonists
BCL-2 antagonists, such as navitoclax (previously ABT-263) and venetoclax (ABT-199), are able to trigger CLL-cell apoptosis via modulation of mitochondrial stability. In a phase I study of 29 patients with relapsed/refractory CLL treated with navitoclax, lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis, and a partial response or stabilization of disease was achieved in almost half of the patients, including those with del(17p) CLL.[62] The major dose-limiting toxicity for BCL-2 antagonists is thrombocytopenia, but newer agents such as ABT-199 are more specific for BCL-2 and lack platelet-depleting activity.[63]
Limitations of novel agents
Although novel agents are effective in the majority of patients, existing data are not yet mature enough to allow any conclusions regarding their long-term efficacy. In addition, patients who previously responded can become resistant because of mutations of drug-binding sites within the B-cell receptor pathway or because of microenvironmental signals. Recent studies indicate that about 25% of patients who receive ibrutinib have to discontinue treatment, mostly because of disease transformation, progressive CLL, and adverse events. Rescuing or re-treating these patients has proved to be extremely difficult, and median OS is currently just a few months.[64] Several clinical trials exploring whether this can be overcome by intelligent combinations of conventional and novel substances are ongoing. Of note, all currently available novel agents are associated with substantial individual out-of-pocket and societal costs.
CAR T cells
CAR technology uses the single-chain variable fragment from an antibody molecule fused with an internal T-cell signaling domain to form a CAR, which is then transduced into T cells.[7,65] A major advantage of this approach is that it eliminates major histocompatibility complex restriction, and several clinical trials have reported impressive results with anti-CD19 CARs.[66-68] However, CAR T-cell therapy can be associated with very severe and potentially lethal complications, such as cytokine release syndrome and persistent normal B-cell depletion.[69] The long-term efficacy of CAR T-cell therapy is potentially hampered by increased expression of inhibitory immune receptors, such as programmed death 1, and the ongoing presence of an immune-suppressive tumor microenvironment.[8]
The success of CAR therapy depends on the inclusion of lymphocyte-reducing conditioning chemotherapy and the choice of CAR design, both of which are being evaluated in ongoing large-scale research efforts. Because CAR T-cell therapy requires sophisticated and complex manufacturing and treatment facilities, it is generally available only in a few specialized CAR centers and is mostly reserved for patients who lack other therapeutic options.
TO PUT THAT INTO CONTEXT
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Brian T. Hill, MD, PhD
Taussig Cancer Institute
The Cleveland Clinic, Cleveland, OhioWhat Are the Limitations of Targeted Treatments for CLL?Targeted treatment for chronic lymphocytic leukemia (CLL) is advancing at a tremendous pace, with four novel agents recently approved by the US Food and Drug Administration, including B-cell pathway and BCL-2 inhibitors. However, the rapid introduction of targeted therapy has greatly outpaced our ability to fully study the optimal sequencing and combination of these agents. And while the conventional chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab (FCR) may produce long-term remissions in a minority of patients, current data suggest that despite excellent response rates, the new targeted agents do not achieve minimal residual disease–negative complete remission for most patients with relapsed or high-risk CLL. For this reason, it is reasonable to expect that many patients will eventually fail treatment with the currently available CLL armamentarium.When Should Stem Cell Transplant Be Seriously Considered?In particular, for younger patients with relapsed/refractory CLL and a human leukocyte antigen–matched donor, reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (HSCT) remains a treatment option with curative potential. Here, Dr. Schwarzbich and colleagues provide a comprehensive review of the published literature addressing the safety and efficacy of RIC allogeneic HSCT for relapsed/refractory CLL, as well as the above-mentioned targeted agents and innovative new treatment strategies, including adoptive cellular therapy using chimeric antigen receptor (CAR) T cells. The authors recommend withholding HSCT in high-risk patients in first remission but considering transplant after response to novel therapies, depending on patient preferences, age, comorbidities, and the availability of a well-matched stem cell donor.What Question Do CLL Researchers Now Need to Address?Given the absence of prospective data comparing transplant to continued management with targeted agents, the crucial issue going forward will be when to proceed with transplant. The decision point is difficult and clearly highly patient-specific. The authors’ review of this topic represents a timely and welcome guideline to frame this discussion.Financial Disclosure: Dr. Hill serves on advisory boards for Gilead and Pharmacyclics, and receives research support from AbbVie.
Is HSCT Still a Valid Option in the Age of Novel Treatments?
In contrast to novel agents, long-term follow-up from large prospective trials of HSCT has reached almost a decade in a few centers. This vast body of experience demonstrates the following:
• HSCT is effective and has curative potential in about half of patients.
• HSCT has been conducted primarily in high-risk patients, as recommended by internationally accepted guidelines, and this approach appears to overcome the negative impact of high-risk constellations known to confer an adverse prognosis. There are currently no prospective data on whether HSCT can change the natural biologic course of high-risk CLL, but some retrospective data indicate that OS is significantly improved in patients who have a donor, as compared with those who lack a donor.[70]
• HSCT can be conducted only in selected groups of patients, however, and is associated with cGvHD and reduction of quality of life-both of which can significantly affect long-term mortality and morbidity.
• While relapse after HSCT is generally considered difficult to treat, and no standard approach exists, patients can be successfully rescued and respond to immunochemotherapy.
The advantages and disadvantages of novel substances and HSCT are shown in Table 2.
Which Patients Should Be Offered HSCT in the Era of Novel Agents?
Because there are no direct comparisons between HSCT and novel agents, and their combinations with each other have not yet been tested in clinical trials, general evidence-based recommendations are very difficult to make. It is therefore essential to understand the limitations of each approach and to carefully weigh their potential benefits and risks on a case-by-case basis. According to recently published updated recommendations from the EBMT and the European Research Initiative on CLL (ERIC)[71]:
• It is feasible to withhold HSCT in high-risk patients in first remission, but the lack of curative potential of novel agents in this subgroup must always be considered. This is particularly important in high-risk patients with relapsed/refractory CLL and in patients whose disease progresses with novel therapies.[26,71]
• HSCT should be considered after a response to novel therapies because its success is highly dependent on the remission state at the time of transplant.
• Individual treatment histories and patient characteristics and preferences must always be carefully considered, along with the availability of investigational protocols.
These recommendations are summarized in the Figure. Ideally, biomarkers will be developed to help identify patients in whom novel agents are likely to fail and those who are the most suitable candidates for HSCT.
Summary
Standard immunochemotherapy is unsuitable and yields only poor results in patients with TP53 abnormalities and those who relapse shortly after initial therapy. These patients are considered “high/highest risk” and require alternative treatment strategies. AutoSCT is not an adequate CLL treatment. Allogeneic HSCT offers the only potentially curative approach for high-risk patients with CLL but is suitable for only a minority of them because of the comorbidities and advanced age seen in most CLL patients.
Remission status at the time of transplant and pretransplant characteristics are predictive of HSCT outcome. MRD kinetics aid in the assessment of response and indicate the level of ongoing GvL-mediated immunotherapeutic activity after HSCT. Allogeneic stem cell transplantation is associated with significant treatment-related mortality and morbidity. Therefore, it must always be considered in view of other, potentially less toxic therapies.
Several new agents demonstrate impressive and durable responses in high-risk patients who might be candidates for transplant, but these agents probably lack curative potential in such patients.[26,71] HSCT can therefore be withheld in high-risk patients in first remission; however, the lack of curative potential of novel agents in this subgroup must always be kept in mind. HSCT should be considered after a response to novel therapies to consolidate remission. The choice of HSCT vs a novel agent must be gauged on a patient-by-patient basis, and individual treatment histories and patient characteristics and preferences must always be carefully considered. Until mature data are available, patients should be treated in clinical trials whenever possible.
Irrespective of the findings summarized here, the number of patients currently undergoing HSCT for CLL is markedly decreased. Determining whether this represents a change in practice or simply a deferment of HSCT until later in the treatment course will require longer follow-up.
Financial Disclosure: Dr. Gribben has received honoraria from AbbVie, Acerta, Janssen, Pharmacyclics, and Roche/Genentech. Dr. Schwarzbich and Dr. McClanahan have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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