Allogeneic hematopoietic cell transplantation in follicular lymphoma

INTRODUCTION — Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of hematopoietic neoplasms".)

The initial treatment of FL depends upon the stage of disease at presentation. Patients with early stage disease may be cured with radiation therapy, while patients with advanced stage disease are initially managed with an immunotherapy-based regimen (eg, rituximab plus chemotherapy). The use of either autologous or allogeneic hematopoietic cell transplantation (HCT) in FL is controversial. When applied to a highly selected patient population, autologous HCT results in a disease-free survival at 10 years of approximately 40 percent and has a low treatment-related mortality rate. In comparison, allogeneic HCT may cure a higher percentage of patients with advanced stage FL, but is associated with substantial treatment-related mortality.

The use of allogeneic HCT, however, is limited since even ideal candidates who undergo allogeneic HCT have a high rate of treatment-related mortality, its efficacy compared with autologous HCT is not fully established, and non-transplant treatment options have expanded over recent decades. In addition, chimeric antigen receptor modified T cell therapy is being studied in patients with FL and may replace allogeneic HCT for a subset of patients.

The use of allogeneic HCT in FL is reviewed below. The use of autologous HCT in FL and comparison with other treatment options are presented separately.

●(See "Autologous hematopoietic cell transplantation in follicular lymphoma".)

●(See "Initial treatment of stage I follicular lymphoma".)

●(See "Treatment of relapsed or refractory follicular lymphoma".)

●(See "Primary cutaneous follicle center lymphoma".)

TIMING OF TRANSPLANT — The ideal timing of HCT in FL is unknown and controversial. Ideally, allogeneic HCT should be performed within the context of a clinical trial. However, attempts to conduct randomized trials in this setting have failed. Outside of a clinical trial, HCT is reserved for patients with relapsed or refractory FL or for those with histologic transformation to a more aggressive histology. This is discussed in more detail separately. (See "Histologic transformation of follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma", section on 'Autologous transplant for eligible patients'.)

DETERMINING TRANSPLANT ELIGIBILITY — The determination of transplant eligibility should be made 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) and the conditioning regimen (eg, myeloablative versus nonmyeloablative).

In most centers in the United States, patients are considered eligible for nonmyeloablative allogeneic HCT if they are less than 70 years of age, with normal cardiac, liver, and renal function, and have a good performance status (ECOG performance status 0 or 1). For myeloablative allogeneic transplantation, eligibility is more restrictive in that patients should typically be less than 55 years of age.

A more detailed discussion of transplant eligibility is presented separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

DONOR SELECTION — The preferred donor for patients undergoing allogeneic HCT for FL is an HLA-matched sibling or matched unrelated donor (MUD). However, fewer than 25 percent of patients in the transplantable age group have an HLA-matched sibling donor. Allogeneic HCT using a partially matched family member donor or umbilical cord blood may be considered for patients who do not have an HLA-identical matched donor. (See "Donor selection for hematopoietic cell transplantation" and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

PREPARATIVE REGIMEN

Regimen intensity definitions — Preparative regimens are generally divided into three categories: myeloablative, nonmyeloablative, and reduced-intensity regimens. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Definitions'.)

●Myeloablative regimens – A myeloablative regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow, and results in profound pancytopenia within one to three weeks from the time of administration. The resulting pancytopenia is long-lasting, usually irreversible, and in most instances fatal unless hematopoiesis is restored by infusion of hematopoietic stem cells.

●Nonmyeloablative regimens – A nonmyeloablative regimen is one that will cause minimal cytopenia (but significant lymphopenia) by itself and does not require stem cell support. However, the transplant, when given in this setting, usually becomes myeloablative because the engrafting donor T cells will eventually eliminate host hematopoietic cells, allowing the establishment of donor hematopoiesis.

●Reduced intensity regimens – Reduced intensity regimens are an intermediate category of regimens that do not fit the definition of myeloablative or nonmyeloablative. Such regimens cause cytopenias, which may be prolonged and result in significant morbidity and mortality, and require hematopoietic stem cell support.

Nonmyeloablative and reduced intensity preparative regimens rely more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease.

Choice of regimen — A nonmyeloablative or reduced intensity preparative regimen is used for most patients with FL undergoing allogeneic HCT [1]. The choice of regimen for an individual patient must take into account the patient's age and comorbidities, the behavior of the disease, and the depth of response at the time of transplant.

Nonmyeloablative, reduced intensity, and myeloablative regimens all appear to have a survival benefit for the treatment of relapsed FL, but differing risks. Nonrandomized comparisons suggest that, when compared with myeloablative regimens, nonmyeloablative and reduced intensity regimens are associated with lower treatment-related mortality and a higher risk of relapse [1-5]. However, a comparison of nonrandomized trials of these different procedures is limited by the use of different patient selection criteria for the different regimens [6]. Unfortunately, a randomized trial is difficult to perform in this circumstance.

Nonmyeloablative and reduced intensity regimens are preferred for most patients, especially older patients and those with comorbidities, those who are in complete remission at the time of transplant, and those who relapse after autologous HCT. Myeloablative allogeneic HCT is associated with greater treatment-related mortality and most patients will not be candidates for this approach [7-10]. Myeloablative regimens are typically reserved for young, highly motivated patients with highly aggressive FL.

EFFICACY AND TOXICITY

Allogeneic transplant overall — When compared with autologous HCT, allogeneic HCT is associated with a higher treatment-related mortality, but also with a lower relapse rate and greater potential for cure. Allogeneic HCT is associated with mortality from both short-term (eg, graft-versus-host disease [GVHD], infection) and long-term (eg, myelodysplastic syndrome, acute myeloid leukemia, other secondary malignancies) transplant-related complications.

Even with nonmyeloablative or reduced intensity allogeneic HCT, the treatment-related mortality at two to three years ranges from 15 to 25 percent and largely reflects deaths from GVHD and infectious complications [2,11]. Moreover, the cumulative incidence of GVHD (especially chronic GVHD) is consistently above 50 percent [2,11-13]. Despite this toxicity, single-institution series and registry studies have reported progression-free survival rates at three to five years of 45 to 85 percent [2,11-15].

A combined analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Society for Blood and Marrow Transplantation (EBMT) evaluated the outcomes of 1567 patients with relapsed or refractory FL who underwent allogeneic HCT from 2001 to 2011 with an HLA-matched related or unrelated donor [1]. Patients with transformed FL and those undergoing a planned tandem HCT were excluded. A nonmyeloablative or reduced intensity preparative regimen was used in 77 percent. After a median follow-up of 55 months, the following estimated five-year outcomes were reported:

●Overall survival – 61 percent

●Progression-free survival – 52 percent

●Relapse or progression – 19 percent

●Treatment-related mortality – 29 percent

●Acute GVHD grade 2 to 4 – 20 percent at day 100

●Chronic GVHD – 45 percent at one year

Predictors of worse outcome included older age, >3 prior lines of therapy, chemotherapy-resistant disease, and impaired performance status.

Nonmyeloablative and reduced intensity HCT — A nonmyeloablative or reduced intensity preparative regimen is used for most patients with FL undergoing allogeneic HCT [1]. Nonmyeloablative allogeneic HCT and reduced intensity HCT are associated with lower rates of treatment-related toxicity and treatment-related mortality, but higher rates of relapse compared with rates previously seen with myeloablative allogeneic transplantation.

Nonmyeloablative and reduced intensity conditioning regimens have extended the eligibility of allogeneic HCT to older patients and those with comorbidities [16-23]. Even for patients who have relapsed after autologous HCT, nonmyeloablative or reduced intensity conditioning allogeneic HCT affords the possibility of prolonged disease-free survival. The reported rates of progression-free survival after nonmyeloablative allogeneic HCT vary, but are reliably above 40 percent (and mostly around 60 percent) at two to three years [1,12,17,22-26]. In these series, there is also convincing evidence for a plateau in the progression-free survival curves suggesting that nonmyeloablative allogeneic HCT has curative potential. Specific regimens used for nonmyeloablative allogeneic HCT are discussed in detail separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

The following is a survey of studies that have reported on the use of nonmyeloablative allogeneic HCT in patients with FL:

●The longest experience is from a prospective trial of nonmyeloablative HCT in 47 patients with chemotherapy-sensitive relapsed FL given a preparative regimen of fludarabine, cyclophosphamide, and rituximab [11]. The two patients with a matched unrelated donor were also given equine antithymocyte globulin prior to the graft infusion. GVHD prophylaxis consisted of tacrolimus and methotrexate. Acute GVHD was seen in 11 percent of patients. At a median follow-up of 107 months, the estimated rates of overall and progression-free survival at 11 years were 78 and 72 percent, respectively [27].

●In another prospective trial, the same investigators treated 26 patients with relapsed or refractory (10 patients) FL with fludarabine, cyclophosphamide, and ⁹⁰Y-ibritumomab tiuxetan followed by allogeneic HCT from a 5 or 6 of 6 HLA-matched donor [27]. At a median follow-up of 33 months, the estimated rates of progression-free and overall survival at three years were 85 and 88 percent, respectively. Similar outcomes were seen in patients with chemotherapy-sensitive and chemotherapy-refractory disease at the time of enrollment. The three-year cumulative incidence of chronic GVHD was 39 percent (24 percent extensive).

●Another study of nonmyeloablative allogeneic HCT involved 188 patients, including 52 previously treated patients with indolent non-Hodgkin lymphoma (NHL), 85 percent of whom had chemosensitive disease; 29 percent had received a prior autologous HCT [18]. Nonmyeloablative allogeneic HCT yielded a 100-day treatment-related mortality of 11 percent, and an estimated two-year overall survival rate of 65 percent. Predictors for an adverse outcome included chemotherapy-resistant disease and age >50 years.

●A retrospective review of total body irradiation with or without fludarabine followed by allogeneic HCT in 62 patients with chemotherapy-refractory indolent (75 percent) or transformed NHL reported three-year estimated overall and progression-free survival rates of 52 and 43 percent, respectively [12]. Patients with indolent disease and related donors had even higher overall and progression-free survival rates of 67 and 54 percent, respectively. Treatment was well tolerated. Long-term complications were limited. Survivors had a median Karnofsky performance status rating of 85 percent (table 1). Approximately half of patients suffered from extensive chronic GVHD.

Myeloablative HCT — Myeloablative preparative regimens are used in a minority of patients undergoing allogeneic HCT for FL. They are generally reserved for young, highly motivated patients with highly aggressive FL. When compared with autologous HCT, myeloablative allogeneic HCT results in lower relapse rates but a higher treatment-related mortality of approximately 30 percent [15,28-30]. These differences were highlighted in a report from the International Bone Marrow Transplant Registry [29]:

●In 176 patients with FL, 67 percent of whom had chemotherapy-sensitive disease at the time of HCT, estimated treatment-related mortality, recurrence rates, and overall survival at five years following allogeneic HCT were 30, 21, and 51 percent, respectively.

●During this same period of time, 597 patients with FL received unpurged autologous HCT; 82 percent were chemotherapy sensitive at the time of transplant. Estimated treatment-related mortality, recurrence rates, and overall survival at five years following unpurged autologous HCT were 8, 58, and 55 percent, respectively.

CARE DURING THE TRANSPLANTATION — Allogeneic HCT is largely reserved for the inpatient setting. Engraftment takes longer than it does for autologous HCT, and infections are more common. Virtually all patients require blood product support in the form of red blood cell and platelet transfusions until the transplanted marrow cells engraft sufficiently to support hematopoiesis. (See "Hematopoietic support after hematopoietic cell transplantation".)

Patients who undergo HCT are at risk for bacterial, viral, and fungal infections, the time course of which varies in the post-transplant period, according to the degree of immune deficiency and cytopenia induced by the transplantation procedure (figure 1). Prophylactic therapies to prevent infection, including antiviral and antifungal drugs, are recommended during a period of increased risk. In addition, all markers of potential infection must be investigated thoroughly. These issues are discussed in detail separately. (See "Overview of infections following hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

FOLLOW-UP — Patients are seen at periodic intervals to assess for progression. Our approach parallels that which we use after initial treatment. This is presented in detail separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Surveillance for relapse'.)

Allogeneic transplant recipients are at risk of developing therapy-related complications that may present years after treatment. These complications have surfaced as significant causes of increased mortality. Our approach to the ongoing evaluation of the long-term HCT survivor is presented separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

TREATMENT OF RELAPSE AFTER HCT — Treatment options for relapsed FL after an allogeneic HCT include reduction of immunosuppression, donor lymphocyte infusion (DLI), and treatment with salvage chemotherapy. (See "Treatment of relapsed or refractory follicular lymphoma".)

Both withdrawal of immunosuppression and DLI harness the graft-versus-tumor effect and have demonstrated clinical benefit in many patients with FL relapsing after allogeneic HCT [31-33]. Predictive factors for response to DLI are remission before HCT and the occurrence of acute or chronic graft-versus-host disease. DLI has been complicated by graft-versus-host disease in a substantial percentage of patients and in some instances graft failure. Thus, the optimal dose and schedule of DLI continue to be explored. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of follicular lymphoma".)

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 info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

●Role in therapy – The use of hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) is controversial.

HCT is generally reserved for patients with relapsed or refractory FL or for those with histologic transformation to a more aggressive histology, each in the setting of chemotherapy-sensitive disease. While allogeneic HCT may rescue some patients with chemotherapy-refractory disease, the outcomes are clearly inferior in this setting. (See 'Timing of transplant' above.)

●Determining HCT eligibility – To be eligible for HCT, the patient must have normal cardiac, liver, and renal function, and have a good performance status. In most centers in the United States, patients are considered eligible for nonmyeloablative allogeneic HCT if they are less than 70 years of age. For myeloablative allogeneic transplantation, patients should typically be less than 55 years of age. (See "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Determining transplant eligibility'.)

●Comparison with other therapies – The decision of whether to proceed with transplantation should be based on the patient's preference, condition, and the expected disease course. For the latter, there is no definitive score or metric. A choice among therapies for patients with relapsed FL is discussed separately. (See "Treatment of relapsed or refractory follicular lymphoma".)

The use of allogeneic HCT is limited since even ideal candidates who undergo allogeneic HCT have a high rate of treatment-related mortality and nontransplant treatment options have expanded over recent decades. In addition, chimeric antigen receptor modified T cell therapy is an option for patients with FL after two or more lines of therapy and may replace allogeneic HCT for a subset of patients.

When compared with autologous HCT, allogeneic HCT is associated with a higher treatment-related mortality rate (15 to 25 percent), but a higher potential rate of cure (50 to 60 percent). A nonmyeloablative or reduced intensity preparative regimen is used for most patients with FL undergoing allogeneic HCT. (See 'Nonmyeloablative and reduced intensity HCT' above.)

●Relapse after HCT – Treatment options for relapsed FL after an allogeneic HCT include reduction of immunosuppression, donor lymphocyte infusion, and treatment with salvage chemotherapy. (See 'Treatment of relapse after HCT' above.)