Autologous 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 clinically 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 on 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. Autologous HCT may result in prolonged remissions 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 autologous HCT in FL is reviewed below. The use of allogeneic HCT in FL and comparison with other treatment options are presented separately.

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

●(See "Initial treatment of stage II to IV follicular lymphoma".)

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

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

TIMING OF TRANSPLANT — Outside of a clinical trial, autologous HCT is reserved for patients with relapsed or refractory FL and for those with histologic transformation to a more aggressive histology. Novel cellular therapies, such as chimeric antigen receptor T cells, may replace autologous HCT for this population in the future. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Chimeric antigen receptor T cells'.)

Interpretation of the trials that have investigated the relative value of autologous HCT versus combination chemotherapy alone for patients with FL is complicated by subsequent changes in the standard care of FL. Importantly, the routine incorporation of anti-CD20 monoclonal antibodies into the standard treatment of FL has improved survival rates among patients who do not undergo autologous HCT. Survival advantages seen in some early trials of autologous HCT may not have been evident had the combination chemotherapy treatment arms included anti-CD20 monoclonal antibodies. Conversely, a lack of survival advantage seen in other early trials may have been because the patients did not receive sufficient chemotherapy immediately before transplantation, leading to incomplete disease control and/or infusion of occult lymphoma cells contaminating the stem cell infusate.

Relapsed disease — FL is a heterogeneous disease and approximately 20 percent of patients have an aggressive disease course with short remission durations, frequent relapses, and shortened survival. We recognize such patients as having early treatment failure defined as progression within 24 months of immunochemotherapy or within 12 months of single-agent rituximab.

Small retrospective studies suggest that autologous HCT may improve progression-free survival (PFS) and overall survival (OS) in patients with early treatment failure if they are in complete remission or have minimal disease at the time of HCT. Larger studies are needed to confirm a benefit. Since the efficacy of autologous HCT depends on the response to chemotherapy, autologous HCT is not appropriate for chemotherapy-resistant disease. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Early treatment failure'.)

Treatment options for relapsed or refractory FL and strategies for choosing among them are presented separately. (See "Treatment of relapsed or refractory follicular lymphoma".)

Data regarding the use of autologous HCT for FL come from several retrospective analyses and a single randomized trial performed prior to the development of immunotherapy (eg, rituximab):

A European phase III randomized trial (the CUP trial) compared high dose therapy (cyclophosphamide plus total body irradiation) followed by autologous HCT versus combination chemotherapy alone in 89 patients with relapsed or progressive FL [1]. At a median follow-up of 69 months, patients treated with high dose therapy followed by autologous HCT had the following significant outcomes:

●Higher PFS rates at two years (55 to 58 versus 26 percent)

●Higher four-year OS rates (71 to 77 versus 46 percent)

The above study was performed before rituximab was available for the treatment of FL and during an era when the median survival of patients with newly diagnosed FL was much shorter than it is with modern therapy. This study has been criticized for the small number of patients in each arm of the trial. The tremendous responses seen with rituximab treatment have made clinicians question whether the benefit of autologous HCT still holds true in the rituximab era.

The efficacy of autologous HCT likely differs according to the aggressiveness of disease:

●Patients with early treatment failure – Initial reports suggest that autologous HCT may have the greatest benefit for patients with early treatment failure. Patients with progression within 24 months of immunochemotherapy or within 12 months of single-agent rituximab have an aggressive disease course with short remission durations, frequent relapses, and shortened survival [2-4]. Several retrospective analyses focusing on this population suggest that autologous HCT improves survival when compared with chemoimmunotherapy alone [5-9].

As an example, a retrospective analysis used data from the National LymphoCare Study and the Center for International Blood and Marrow Transplant Research to report the outcomes of 349 patients who progressed within two years or did not respond to initial chemoimmunotherapy [6]. When the population was analyzed as a whole, OS was similar whether or not autologous HCT was performed. However, in a planned subset analysis, when compared with those who didn't undergo HCT, the 123 patients receiving autologous HCT within one year of treatment failure had superior OS at five years (73 versus 60 percent). A mortality benefit for early autologous HCT was maintained when the analysis was matched for age and other known risk factors. These results suggest that early autologous HCT may benefit this high-risk population. Further studies of HCT in this population are described separately. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Autologous transplant for eligible patients'.)

●Patients with late relapse – Retrospective analyses comparing autologous HCT versus chemoimmunotherapy for the larger population of patients with relapsed FL in the rituximab era have had mixed results [10-15]. As an example, in a retrospective analysis of 254 patients with relapsed FL, patients treated with high dose therapy followed by autologous HCT had higher rates of five-year event-free survival (EFS; 51 versus 24 percent) and OS (70 versus 42 percent) when compared with patients who did not receive HCT [10]. However, when this analysis was limited to patients who received rituximab as part of their salvage regimen, the benefit from HCT lost its statistical significance for both outcomes.

Several mature single-institution and registry studies have reported on the long-term follow-up of autologous HCT for FL [12,16-21]. Across those studies, the 10-year PFS is consistently in the 30 to 50 percent range. There is a plateau in the survival curves between 10 and 15 years after autologous HCT, suggesting that this procedure may be curative for one-quarter to one-third of transplanted patients.

Following histologic transformation — Patients with FL develop transformation to a more aggressive histology at a rate of approximately 1 to 3 percent per year. Histologic transformation from an indolent to an aggressive histology has been associated with a poor prognosis. The use of autologous HCT or allogeneic HCT in patients with transformed FL is controversial and depends on both tumor and patient characteristics. This is discussed in more detail separately. (See "Histologic transformation of follicular lymphoma".)

Previously untreated disease — Several prospective randomized trials examined the use of high dose chemotherapy followed by autologous HCT in the treatment of newly diagnosed FL. While some have demonstrated improvements in PFS, none has shown an OS benefit. These trials are presented in more detail separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Is there a role for transplant?'.)

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 general, age is not considered to be a strict inclusion or exclusion criterion for high dose chemotherapy and autologous HCT (rescue). In most centers in the United States, patients with one or more of the following factors are not considered eligible for autologous HCT:

●Direct bilirubin >2.0 mg/dL (34.2 micromol/liter)

●Serum creatinine >2.5 mg/dL (221 micromol/liter) unless on chronic stable dialysis

●Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain (table 1)

●New York Heart Association functional status Class III or IV (table 2)

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

COLLECTION AND STORAGE OF STEM CELLS — Peripheral blood progenitor cells (PBPCs) are preferred over bone marrow harvested grafts for autologous HCT by most groups due to quicker engraftment and a potential for less contamination with tumor cells. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Hematopoietic stem cells are mobilized using granulocyte colony-stimulating factor (G-CSF) with or without plerixafor. The method used is mainly dependent on institutional preference and experience. Often, G-CSF is used as a single agent initially. Plerixafor is then added for those who fail to mobilize adequate numbers of CD34+ cells with G-CSF alone. Apheresis is used to collect the PBPCs, which are cryopreserved until the day of infusion. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

PREPARATIVE REGIMEN — A preparative (conditioning) regimen, consisting of chemotherapy with or without radiation therapy, is given to eradicate malignant cells prior to rescue of the hematopoietic system with a PBPC infusion. Selection of the preparative regimen is individualized and informed by institutional preference and physician experience. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Choice of regimen'.)

A choice among preparative regimens must take into account the center's experience, the short- and long-term toxicities of the regimen, and the patient's comorbidities. Historically, many of the trials that incorporated autologous HCT into the treatment of FL used preparative regimens with total body irradiation (TBI). A possible association between TBI and subsequent treatment-related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) has led many centers to switch to chemotherapy-only preparative regimens (table 3). (See "Preparative regimens for hematopoietic cell transplantation", section on 'Chemotherapy without RT'.)

However, an increased risk of second malignancies with TBI in this setting has not been confirmed and data are conflicting. A retrospective study from the European Group for Blood and Marrow Transplantation evaluated the outcomes of 2233 patients with FL undergoing autologous HCT following conditioning with either a TBI-containing regimen or with carmustine (BCNU), etoposide, cytosine arabinoside, and melphalan (BEAM) between 1995 and 2007 [22]. After a median follow-up of 73 months, the preparative regimen did not appear to impact the estimated rates of nonrelapse mortality at 5 (6 percent) and 10 (10 percent) years. Treatment-related MDS/AML was observed in 3.4 and 2.8 percent of patients receiving TBI and BEAM, respectively, at a median time to MDS/AML of 50 months.

Attempts to purge the autologous graft of remaining tumor cells by using rituximab in the transplant setting have not demonstrated a benefit [23]. In contrast, maintenance rituximab appeared to improve progression-free survival. (See 'Maintenance' below.)

CARE DURING THE TRANSPLANTATION — Autologous HCT has been performed in both inpatient and outpatient settings. Approximately 24 hours after completion of the preparative chemotherapy, peripheral blood progenitor cells are reinfused. A period of pancytopenia follows. Red blood cell and platelet transfusions are administered as necessary while hematopoietic colony-stimulating factors (ie, G-CSF) are used to speed neutrophil engraftment. Neutrophil engraftment usually occurs by day 12 and platelet counts are expected to recover to greater than 20,000 by day 16 [24]. Red blood cell transfusion requirements during autologous HCT are usually minimal. (See "Hematopoietic support after hematopoietic cell transplantation".)

Patients who undergo autologous 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 thoroughly investigated. 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)".)

MAINTENANCE — Maintenance therapy refers to the prolonged administration of agents with low toxicity profiles in an attempt to prevent progression of disease. In patients without rituximab resistance, maintenance rituximab improves progression-free survival (PFS). Toxicities are increased and the effect on overall survival (OS) is not clear. Maintenance using other agents should be limited to clinical trials.

We suggest maintenance rituximab rather than observation for patients with relapsed or refractory FL without evidence of rituximab resistance. Rituximab resistance is assumed if a patient has relapse or progression of FL while on or within six months of receiving an anti-CD20 monoclonal antibody, either as a single agent or in combination. Rituximab maintenance is not expected to benefit patients with rituximab resistance.

Even though maintenance therapy is designed to have a low toxicity profile, a decision regarding the use of maintenance therapy in an individual patient must take into consideration both the potential benefit from attaining a deeper response and the likelihood that this patient will tolerate the prolonged therapy. Maintenance rituximab is associated with a higher rate of late neutropenia, infections, the reactivation of viral infections (eg, hepatitis), and blunted responsiveness to vaccination (eg, influenza vaccination).

When administering maintenance rituximab, it is important to use one of the established regimens, such as rituximab every two months for a total of two years [25]. Trials that have used longer courses of maintenance (eg, four years) have noted increased toxicity towards the end of maintenance [26,27]; as such, rituximab maintenance should not exceed two years.

Our approach is in general agreement with consensus recommendations from the American Society of Blood and Marrow Transplantation (ASBMT, now American Society for Transplantation and Cellular Therapy), Center for International Blood and Marrow Transplant Research (CIBMTR), and Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) [28].

Support for the use of maintenance rituximab in this setting comes from a single randomized trial and extrapolation of data from its use after initial chemoimmunotherapy, which demonstrate improved PFS, but not OS. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Use of maintenance'.)

The multicenter phase III trial of 280 rituximab-naïve patients with relapsed FL who achieved a complete response or very good partial remission to induction chemotherapy randomly assigned treatment in a 2x2 fashion to autologous HCT with or without in vivo rituximab purging, each with or without rituximab maintenance therapy (administered every two months for a total of four infusions) [23]. At a median follow-up of 8.3 years, when compared with observation, rituximab maintenance resulted in superior estimated PFS at 10 years (54 versus 37 percent), which did not translate into an improvement in OS (73 versus 68 percent). In vivo purging did not improve PFS or OS.

FOLLOW-UP — Patients are seen at periodic intervals to monitor for treatment complications and 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'.)

Transplant recipients are at risk of developing therapy-related complications that may present years after treatment. 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".)

Patients who relapse after autologous HCT should be strongly considered for nonmyeloablative allogeneic HCT or enrollment on a clinical trial. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Multiply relapsed disease'.)

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.)

●Basics topics (see "Patient education: Autologous 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 AND RECOMMENDATIONS

●Indications – The use of hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) is controversial. HCT should be performed as part of a clinical trial whenever possible.

High dose chemotherapy and autologous HCT (rescue) is generally reserved for patients with relapsed or refractory FL (algorithm 1), or for those with histologic transformation to a more aggressive histology (algorithm 2), each in the setting of chemotherapy-sensitive disease. Novel cellular therapies, such as chimeric antigen receptor T cells, may replace HCT for this population in the future. (See 'Timing of transplant' above and "Treatment of relapsed or refractory follicular lymphoma", section on 'Chimeric antigen receptor T cells'.)

●Eligibility – To be eligible for autologous HCT, the patient must have normal cardiac, liver, and renal function, and have a good performance status. In general, age is not considered to be a strict exclusion criterion. (See 'Determining transplant eligibility' above.)

The decision of whether to proceed with autologous HCT should be based on the patient's preference, condition, and the expected disease course. For the latter, there is no definitive score or metric. Among patients with relapsed FL, we consider autologous HCT for patients with early treatment failure (eg, progression within 24 months of immunochemotherapy or within 12 months of single-agent rituximab). (See 'Relapsed disease' above and "Treatment of relapsed or refractory follicular lymphoma", section on 'Autologous transplant for eligible patients'.)

Autologous HCT has been associated with a treatment-related mortality rate of less than 10 percent and a potential cure rate of up to 25 to 40 percent. As with other malignancies, peripheral blood progenitor cells are preferred over bone marrow harvested grafts. (See 'Relapsed disease' above.)

●Role of maintenance rituximab – For patients with relapsed or refractory FL without evidence of rituximab resistance, we suggest maintenance rituximab following autologous HCT rather than observation (Grade 2C). Rituximab resistance is assumed if a patient has relapse or progression of FL while on or within six months of receiving an anti-CD20 monoclonal antibody, either as a single agent or in combination. Maintenance rituximab improves progression-free survival. Toxicities are increased and the effect on overall survival is not clear. (See 'Maintenance' above.)