Hematopoietic cell transplantation in chronic lymphocytic leukemia

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm) characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.

CLL is considered to be identical (ie, one disease at different stages) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), a clinically indolent non-Hodgkin lymphoma. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.

The natural history of CLL/SLL is extremely variable. While many cases follow an indolent course that is well controlled with standard therapy, others progress rapidly and die from complications or causes directly related to CLL/SLL.

Hematopoietic cell transplantation (HCT) is performed in a minority of patients with relapsed or refractory CLL/SLL. Allogeneic HCT may cure a percentage of patients with CLL/SLL; it is reserved for relapsed and/or refractory CLL/SLL given the risk of treatment-related morbidity and mortality, and availability of alternative therapies. In contrast, autologous HCT is not curative and is rarely used given the efficacy of non-HCT therapies.

The term "hematopoietic cell transplantation (HCT)" will be used throughout this review as a general term to cover transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, cord blood). Otherwise, the source of such cells will be specified (eg, autologous peripheral blood progenitor cell transplantation). (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

The use of HCT in CLL/SLL will be reviewed here. The clinical manifestations, diagnosis, staging, prognosis, and non-HCT therapies are presented separately.

●(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●(See "Staging and prognosis of chronic lymphocytic leukemia".)

●(See "Overview of the complications of chronic lymphocytic leukemia".)

●(See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

●(See "Overview of the complications of chronic lymphocytic leukemia".)

DETERMINING TRANSPLANT ELIGIBILITY — Most patients with CLL/SLL are older adults and, due to the relatively benign course of the disease and efficacy of targeted therapies in the majority of patients, only a selected subset is considered for HCT. Transplant eligibility is determined based on a risk-benefit assessment and the needs and wishes of the patient. Eligibility for HCT varies across countries and institutions and depends on the type of transplantation (ie, allogeneic versus autologous), the conditioning regimen (eg, myeloablative versus nonmyeloablative), and compatibility between donor and recipient cells.

While all types of transplant have been studied in CLL/SLL, nonmyeloablative or reduced intensity allogeneic HCT is the preferred type used by most centers.

In most centers in the United States, patients meeting all of the following criteria may be eligible for nonmyeloablative or reduced intensity allogeneic HCT (see "Determining eligibility for allogeneic hematopoietic cell transplantation"):

●Age <75 years

●Normal cardiac, liver, and renal function

●Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (table 1)

For myeloablative allogeneic transplantation, eligibility is more restrictive in that patients should typically be less than 55 to 60 years of age.

TIMING OF TRANSPLANT — HCT is reserved for young, fit patients with relapsed and/or refractory CLL/SLL who have high-risk disease and ideally performed in the context of a clinical trial. Such trials are most appropriate for patients with clinically aggressive relapsed or refractory disease, including those with high-risk genetic factors (eg, deletion 17p13 and TP53 mutations). HCT may also be considered for patients with histologic transformation to a more aggressive histology. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'HCT'.)

The following sections describe the use of HCT at different times in the disease course. Interpretation of trials comparing HCT versus non-HCT therapies alone is complicated by changes in the standard care of CLL/SLL. Since these trials were performed, the availability of agents targeting the B cell receptor pathway and BCL2 have improved survival rates among patients who do not undergo HCT, therefore, HCT is less commonly used in this disease. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Relapsed or refractory disease — Nonmyeloablative or reduced intensity allogeneic HCT is a potentially curative treatment option for young, fit patients with clinically aggressive relapsed or refractory CLL/SLL. The decision to use HCT in this setting is individualized based on the aggressiveness of disease and available non-HCT therapies.

While relapsed disease is typically sensitive to additional non-HCT therapies, the duration of remission becomes shorter with each subsequent regimen. The selection of therapy for relapsed or refractory CLL/SLL, including the incorporation of HCT, is discussed in detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Choice of therapy' and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Hematopoietic cell transplantation'.)

The following principles apply to the use of HCT for relapsed or refractory CLL/SLL:

●Assessing disease aggressiveness – While limited, our best measure of disease aggressiveness is the length and quality of initial (and subsequent) remission(s). Patients with refractory disease or an initial remission duration significantly less than the median progression-free survival for an individual treatment regimen are more likely to have a short subsequent remission duration. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Evaluate exposure to prior therapies and response'.)

Certain genomic features are associated with more aggressive disease biology. While targeted agents have improved outcomes in these populations, patients with 17p deletion and/or TP53 mutation treated with targeted agents have inferior outcomes when compared with other patients treated with these same agents. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'Del(17p) or TP53 mutations'.)

●Achieving a response prior to HCT – Observational studies suggest that patients in complete response at the time of HCT will have a better prognosis [1-3]. As such, even patients who plan to undergo HCT should be treated with non-HCT therapies at the time of relapse to achieve a remission prior to transplant. (See 'Nonmyeloablative HCT' below.)

●Limitations of the evidence – Autologous HCT, myeloablative HCT, and nonmyeloablative or reduced intensity HCT have not been directly compared for the treatment of relapsed CLL/SLL in a randomized fashion. As such, judgement of these treatment modalities must keep in mind selection biases that limit comparisons of retrospective analyses and uncontrolled prospective case series. The use of each of these modalities is described in more detail below. (See 'Type of transplantation' below.)

Following histologic transformation — A minority of CLL/SLL tumors transform to a more aggressive histology. Histologic transformation is associated with a poor prognosis. The use of allogeneic HCT for patients with treatment-sensitive transformed CLL/SLL is supported by small retrospective analyses, as discussed in more detail separately. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'HCT'.)

Previously untreated disease — Modern regimens for the initial treatment of CLL/SLL are well tolerated and produce prolonged responses in most patients. Allogeneic HCT is not recommended in this setting due to its higher morbidity and mortality rates. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Several retrospective analyses and a single multicenter prospective randomized trial have examined the use of high dose chemotherapy followed by autologous HCT in the treatment of newly diagnosed CLL/SLL. While some studies have demonstrated improvements in progression-free survival, none has shown an overall survival benefit. As such, management without HCT remains the standard therapy for patients with previously untreated CLL/SLL. (See 'Autologous HCT' below.)

TYPE OF TRANSPLANTATION — The role of HCT in CLL/SLL is changing with advances in targeted therapies and our knowledge of who might respond to these therapies. When HCT is performed, most experts offer a nonmyeloablative or reduced intensity allogeneic HCT, ideally in the context of a clinical trial.

●Reduced intensity and nonmyeloablative allogeneic HCT have a treatment-related mortality of approximately 5 to 25 percent, and a three year overall survival (OS) of approximately 60 percent, with a significant proportion of patients achieving durable responses [1,4-11]. Side effects are much less than those of myeloablative regimens, and these approaches are better tolerated in older individuals. (See 'Nonmyeloablative HCT' below and "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

●Myeloablative allogeneic HCT is rarely performed due to less toxic alternatives. It has a treatment-related mortality rate that approaches 30 to 50 percent [10,12-14], but it may be curative in a highly selected cohort of patients. Side effects include graft-versus-host disease (GVHD), secondary malignancies, chronic immunosuppression, and cardiac and pulmonary toxicity. (See "Preparative regimens for hematopoietic cell transplantation" and "Preparative regimens for hematopoietic cell transplantation", section on 'Myeloablative regimens'.)

●Autologous HCT is rarely performed. It has a low treatment-related mortality rate and may prolong progression-free survival (PFS), but not OS, in a subset of patients who are in complete response (CR) or have minimal disease at the time of HCT. Patients who undergo autologous HCT appear to have an increased risk of developing myelodysplastic syndrome, perhaps as a result of chemotherapy and/or radiation therapy administered before or during the preparative regimen. (See 'Autologous HCT' below.)

Myeloablative HCT has not been directly compared with nonmyeloablative/reduced intensity or autologous HCT or with non-HCT therapies in a prospective manner, and it is unlikely that such trials will be attempted due to the advanced age of most patients with CLL/SLL. Nonrandomized comparisons of myeloablative versus nonmyeloablative approaches, and single-arm studies of each approach are discussed in the sections below. (See 'Nonmyeloablative versus myeloablative HCT' below.)

Allogeneic HCT

Graft-versus-leukemia effect — Allogeneic HCT is the only treatment option for patients with CLL/SLL with the potential for cure. This appears to be largely due to the graft-versus-leukemia (GVL) effect, which relies on graft immune cells to recognize and lyse the leukemia cells.

A GVL effect in CLL is supported by the following observations:

●Donor lymphocyte infusions are sometimes effective in the treatment of relapse after allogeneic HCT [15-17].

●Dose reduction of immunosuppressive agents following HCT may decrease tumor burden [18].

●Nonmyeloablative allogeneic HCT, which relies primarily on a GVL effect, has resulted in long-term remissions. (See 'Nonmyeloablative HCT' below.)

CLL/SLL appears to be an excellent target for alloimmune effects, which characterize the GVL effect. Basic principles underlying graft-versus-tumor effects following HCT across diseases are discussed separately. (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

A major complication with both myeloablative and nonmyeloablative allogeneic HCT is the induction of GVHD. Efforts are underway to dissociate GVL from GVHD. This is discussed in more detail separately. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)

Nonmyeloablative versus myeloablative HCT — When HCT is performed in CLL/SLL, most experts offer a nonmyeloablative or reduced intensity allogeneic HCT, ideally in the context of a clinical trial [19]. The use of myeloablative conditioning regimens is limited by high treatment-related mortality. Nonmyeloablative approaches have been better tolerated in this patient population that tends to be older and often has other comorbid medical conditions.

Uncontrolled studies have evaluated the efficacy of both myeloablative and nonmyeloablative allogeneic HCT in CLL/SLL. Interpretation is limited by differences in patient selection, since variable criteria have been used to determine appropriate candidates for HCT. Eligibility criteria for myeloablative HCT are stricter; as such, patients who have undergone myeloablative HCT are likely to be younger and more clinically fit than those who have undergone nonmyeloablative HCT.

Nonmyeloablative and reduced intensity conditioning regimens are less toxic and may improve OS when compared with myeloablative regimens. The following are the largest studies that have compared these two approaches:

●In a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of patients undergoing allogeneic HCT for CLL/SLL in 2001 to 2011, estimated three-year survival rates were higher among the 912 patients who received a reduced intensity conditioning regimen when compared with the 426 patients who received a myeloablative conditioning regimen (58 +/- 2 versus 50 +/- 3 percent) [20].

●A meta-analysis of 48 studies published prior to 2014 that included 1903 patients with CLL/SLL who underwent allogeneic transplant reported the following pooled rates following nonmyeloablative or reduced intensity conditioning (NMA/RIC) versus myeloablative conditioning (MAC) [11]:

•OS – 60 percent (95% CI 56 to 65 percent) NMA/RIC; 51 percent (95% CI 42 to 61 percent) MAC; there was substantial heterogeneity within and between the groups, especially among those undergoing MAC.

•Event-free survival or PFS – 46 percent NMA/RIC; 41 percent MAC

•Nonrelapse mortality – 23 percent NMA/RIC; 32 percent MAC

•Grade 2 to 4 acute GVHD – 46 percent NMA/RIC; 46 percent MAC

•Chronic GVHD – 55 percent RIC; 59 percent MAC

●A single center retrospective analysis of transplants performed between 1996 and 2006 reported higher OS following reduced intensity conditioning (21 patients, OS 63 percent at five years) versus myeloablative conditioning (29 patients, OS 18 percent at five years), despite older age and greater use of unrelated donors in the reduced intensity conditioning group [21].

●Studies evaluating conditioning regimens across different diseases illustrate that myeloablative conditioning regimens are associated with greater morbidity and higher rates of treatment-related mortality [10,22]. Patients undergoing myeloablative conditioning experience more toxicity in multiple systems, including hematologic, gastrointestinal, hepatic, hemorrhagic, infectious, metabolic, and pulmonary toxicity [22]. Treatment-related mortality rates approach 30 to 50 percent [10,12-14].

Nonmyeloablative HCT — Reduced intensity and nonmyeloablative allogeneic HCT are treatment options for younger, fit patients with relapsed or refractory CLL/SLL who are willing to undergo the risks of this aggressive therapy as part of a clinical trial.

Initial studies suggest that prior targeted agents (eg, ibrutinib, venetoclax) do not impact the safety or efficacy of allogeneic HCT, and HCT is largely reserved for patients already exposed to these agents [23-25]. Observational studies also suggest that patients in CR at the time of HCT will have a better prognosis. As such, additional treatment should be used at the time of relapse to achieve a remission prior to HCT. Prognostic factors that predict for poor outcomes with standard therapy include a short duration of first remission, certain genetic risk factors (eg, deletion 17p, TP53 mutations), and unmutated immunoglobulin heavy chain variable (IGHV) genes.

Reduced intensity conditioning or nonmyeloablative conditioning followed by matched-related or matched-unrelated allogeneic HCT offers the potential benefit of decreased treatment-related mortality when compared with myeloablative HCT, while still maintaining a GVL effect [17,26]. The reported rates of OS after nonmyeloablative allogeneic HCT vary, but they are approximately 50 to 60 percent at five years and do not differ by cytogenetic risk group. Specific regimens used for reduced intensity and nonmyeloablative allogeneic HCT are discussed in detail separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

Several studies have suggested a potential benefit to reduced intensity or nonmyeloablative HCT in CLL/SLL [1,4-9,27]:

●The largest prospective trial of nonmyeloablative HCT with the longest follow-up evaluated a regimen combining low dose total body irradiation (200 cGy) with or without fludarabine used to treat 82 patients with advanced, fludarabine-refractory CLL/SLL with related (n = 52) or unrelated (n = 30) donors [4,5]. Patients had the following outcomes:

•Overall response and CR rates were 70 and 55 percent, respectively; all patients achieving a morphologic CR achieved a molecular remission.

•Patients who received grafts from unrelated donors had a higher rate of CR at five years (67 versus 48 percent), perhaps due to a more effective GVL effect.

•Cumulative rates of five-year OS, PFS, and nonrelapse mortality were 48, 38, and 25 percent, respectively.

•Chronic extensive GVHD developed in approximately 50 percent of patients requiring a median duration of treatment for GVHD of 25 months.

●Another prospective trial evaluated fludarabine/cyclophosphamide-based conditioning followed by allogeneic HCT in 90 patients with poor-risk CLL/SLL as defined by primary refractory disease, initial relapse within 12 months, relapse after autologous HCT, or progressive disease in the presence of unfavorable genetic features [1-3]. After a median follow-up of 9.7 years, the estimated rates of nonrelapse mortality, relapse incidence, and OS at 10 years were 20, 46, and 51 percent, respectively. Relapse rates were lower among the 27 patients who attained measurable residual disease negativity after HCT (25 versus 80 percent) and higher among those with uncontrolled disease at the time of HCT. The 32 patients who were alive at six years had a low rate of late relapse (18 percent), low nonrelapse mortality (3 percent), and high PFS (79 percent). HCT outcomes did not differ based on the presence of high-risk genetic features (eg, mutations in TP53, SFB1, or NOTCH1).

●A retrospective case-control study from two institutions (data from 1999 to 2007) compared outcomes in 37 patients with CLL/SLL who underwent nonmyeloablative HCT with 43 patients (controls) from the same institutions who were candidates for HCT but did not have a suitable donor or refused the procedure and were treated with conventional therapy only [6]. Median OS for the HCT and control subjects was 113 versus 85 months, respectively, when calculated from the time of diagnosis, and 103 versus 67 months, respectively, when calculated from the time of first treatment. It is not clear that the patients were cured by the reduced intensity conditioning regimen despite the longer survival.

Myeloablative HCT — Given the high rate of treatment-related morbidity and mortality, myeloablative HCT cannot be recommended outside of a clinical trial for the treatment of CLL/SLL [19]. Allogeneic HCT takes advantage of the GVL effect to eradicate remaining disease and may cure a subset of patients with untransformed CLL/SLL. Several nonrandomized prospective trials and retrospective analyses have demonstrated the potential efficacy of myeloablative allogeneic HCT in CLL/SLL [1,4,5,12,15,28-32]. This approach has been associated with treatment-related mortality rates of 30 to 50 percent.

Autologous HCT — Autologous HCT is rarely performed for CLL/SLL. Although it may delay progression in a subset of patients, it does not improve OS and impairs quality of life (QOL). Non-HCT strategies are the preferred initial therapy for CLL/SLL. Targeted agents are also the main treatment modality used for relapsed or refractory CLL/SLL, either alone or in combination with allogeneic HCT. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Hematopoietic cell transplantation' and "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma".)

While initial retrospective studies suggested benefit from autologous HCT, especially in patients with high-risk disease [15,33-35], an OS benefit has not been confirmed. Further, many of these studies were performed prior to the development of more active, targeted agents for the treatment of CLL/SLL. The best data regarding the use of autologous HCT come from two randomized trials performed prior to the incorporation of immunotherapy (eg, rituximab) and targeted agents (eg, ibrutinib, venetoclax) into the initial treatment of CLL/SLL [36-38]. High dose chemotherapy followed by autologous HCT can delay progression in a subset of patients who are in CR or have minimal disease at the time of HCT, but it is not curative and impairs QOL. The lack of a survival benefit likely reflects the efficacy of second- and third-line therapies in patients relapsing after standard initial therapy. In addition, impaired stem cell collection may limit autologous HCT in patients with prior exposure to fludarabine.

TREATMENT OF RELAPSE AFTER HCT — Treatment options for CLL/SLL relapsed after allogeneic HCT include reduction of immunosuppression and donor lymphocyte infusion (DLI) in addition to other therapies used for relapsed or refractory CLL/SLL. Reduction of immunosuppression and DLI should be incorporated into the initial management of all patients with relapse unless concerns regarding graft-versus-host disease (GVHD) or myelosuppression make this approach unfeasible.

There is a paucity of data regarding the efficacy of these treatment options. Small case reports suggest that DLI and reduction of immunosuppression are effective [16,39-41]. In one report, reduction of immunosuppression and DLI, with or without rituximab therapy, resulted in a complete response in 7 of 10 patients with relapsed or refractory CLL/SLL after nonmyeloablative HCT [40]. A prospective multicenter trial reported high rates of undetectable minimal residual disease (MRD) at 12 months after using MRD levels to guide reduction of immunosuppression and use of DLI [41]. DLI is discussed in more detail separately. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

Patients who do not respond to or are not candidates for reduction of immunosuppression and DLI can be treated with other therapies used for relapsed CLL/SLL. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)" and "Patient education: Chronic lymphocytic leukemia (CLL) (The Basics)" and "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Transplant eligibility – Hematopoietic cell transplantation (HCT) is performed in a minority of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most patients with CLL/SLL are older adults and, due to the relatively benign course of the disease in the majority of patients, only a small fraction of selected patients are considered for HCT.

Eligibility for HCT varies across countries and institutions and depends on the type of transplant and the conditioning regimen. While many types of transplant have been studied in CLL/SLL, nonmyeloablative or reduced intensity allogeneic HCT is usually preferred. In most centers in the United States, eligibility criteria include age <75 years; normal cardiac, liver, and renal function; and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (table 1). (See 'Determining transplant eligibility' above.)

●Timing and pretreatment – HCT is reserved for patients with relapsed and/or refractory CLL/SLL, ideally performed in the context of a clinical trial. Such trials may be appropriate for young, fit patients with clinically aggressive disease, including those with high-risk genetic factors (eg, deletion 17p13 and TP53 mutations). HCT may also be considered for tumors with transformation to a more aggressive histology. (See 'Timing of transplant' above.)

At the time of relapse, patients are treated with non-HCT therapies with the aim of achieving a complete or partial response. Observational studies suggest better outcomes in patients in complete response at the time of HCT. Following response, nonmyeloablative allogeneic HCT is a reasonable option for young patients with high-risk disease, as long as they have a good performance status and few comorbidities. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia" and 'Relapsed or refractory disease' above.)

The treatment of relapsed or refractory CLL/SLL is discussed in more detail separately. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

●Type of transplant and outcomes – For most patients undergoing allogeneic HCT for CLL/SLL, we suggest nonmyeloablative or reduced intensity conditioning rather than myeloablative conditioning (Grade 2C). Data comparing these approaches is limited to observational studies and interpretation is limited by differences in patient selection. Nonmyeloablative and reduced intensity conditioning regimens are less toxic and may improve overall survival when compared with myeloablative regimens. (See 'Nonmyeloablative versus myeloablative HCT' above.)

Nonmyeloablative or reduced intensity allogeneic HCT can achieve a durable response in a significant proportion of patients. Side effects are much less than those of myeloablative regimens, and these approaches are better tolerated in older individuals. Reported treatment-related mortality ranges from 5 to 25 percent. The reported rates of overall survival are approximately 50 to 60 percent at five years and do not differ by cytogenetic risk group. Approximately half of patients will experience chronic extensive graft-versus-host disease.