Introduction

Recently, the use of radioimmunotherapy (RIT) was suggested in patients with first relapse of follicular lymphoma (FL) after rituximab containing chemotherapy, even prior to autologous stem cell transplantation [1]. Based on the currently available data, this national consensus reevaluates a therapeutic algorithm for patients with advanced FL (Fig. 1).

Fig. 1
figure 1

Therapeutic algorithm for FL (consensus workshop 04 May 2005)

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Principles of therapy for FL

Patients with FL have a median age of 60 years. About 80% is in the advanced stage of the disease (stage III/IV) and have no curative treatment option. The median overall survival is about 10 years. During the last 30 years, numerous modifications either of chemotherapy schemes or in radiotherapy have not led to a substantial prolongation in overall survival. Therefore, especially in elderly patients, selection of applied regimens is markedly influenced by the tolerability of therapy and the patient’s quality of life, respectively.

In asymptomatic patients with advanced FL, “watchful waiting” with initiation of therapy only in symptomatic cases or rapidly progressing disease is still the standard approach, as no advantage in overall survival was shown for an immediate start of therapy [2–6]. A conventional chemotherapy is indicated for symptomatic patients with FL requiring treatment. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard option for younger patients with FL, encompassing the option of high dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) at a later phase of the disease.

In contrast, in elderly patients, it might be reasonable to choose a less toxic therapy, accepting a slightly lower efficacy in favor of a higher quality of life. Accordingly, there is no generally accepted international standard treatment for elderly patients. In Western Europe, including France and Germany, CHOP remains the preferred treatment option also for elderly patients as long as clinically relevant comorbidities do not preclude, e.g., the application of anthracyclins.

In FL patients requiring treatment dose escalations, the use of very aggressive chemotherapies, e.g., the “alternating triple therapy,” has not shown any major improvement in overall survival [7]. Similarly, patients achieve only a modest benefit in overall survival by the addition of interferon alpha maintenance after initial chemotherapy induction [8]. Myeloablative consolidation with subsequent ASCT is a superior therapeutic option in relapse patients with FL and showed a significant advantage over conventional salvage therapy in terms of progression-free and overall survival [9]. However, first-line treatment with HD consolidation followed by ASCT should only be performed within clinical studies as no improvement in overall survival has been proven so far [10].

Only the monoclonal anti-CD20 antibody rituximab was shown to achieve a substantial and long-lasting improvement in the treatment of FL. In the pivotal trial, approximately half of the patients with FL responded to rituximab. However, the median relapse-free survival (13 months) was relatively short [11], which might be overcome by a prolonged antibody therapy. In a study by Ghielmini et al. [12], an extended schedule (eight applications over 9 months) resulted in a doubling of remission duration in comparison with the standard four times a week regime (23 vs 12 months; p = 0.024). Rituximab maintenance after rituximab containing chemotherapy was recently confirmed to achieve an even higher benefit in two independent studies.

Irrespective of the type of chemotherapy [CHOP, MCP (mitoxantrone, chlorambucile, and predisolone), and CVP (cyclophosphamide, vincristine, and prednisolone] that rituximab is combined with, statistically significant advantages of combined immunochemotherapy were proven. The rate of objective remission and the median relapse-free and event-free time almost doubled. The combination of MCP and rituximab compared to MCP alone also demonstrated a significant advantage in median overall survival [14]. However, differences in efficacy of various regimes remain apparent even in combination with the antibody. Thus, results of CHOP chemotherapy are not only inferior to the rituximab and CVP combination, recent updates have also suggested a benefit of combined immunochemotherapy in overall survival [13–15].

In another multicenter phase III trial, relapse patients with FL also profited from a rituximab-containing chemotherapy. After rituximab and FCM (fludarabine, cyclophosphamide, and mitoxantrone), the rate of complete remissions (CR) was doubled compared to FCM alone (40 vs 23%, p = 0.106), which led to a significantly higher overall response rate (94 vs 70%, p = 0.011) and a significantly longer progression-free survival (p = 0.0288) [16]. Further follow-up also indicates an advantage in overall survival [17].

RIT: early use of a selective principle of efficacy

In view of the urgent need to further optimize the treatment of FL, RIT is a new and interesting perspective. In a number of clinical studies, the selective mode of action was proven to be efficacious. Of particular interest is the excellent tolerability of RIT due to its specific mechanism of action—the antibody selectively binds to the CD20 antigen on the lymphoma cells. The radioisotope 90Yttrium (90Y)—a pure beta emitter—is linked to the monoclonal anti-CD20 antibody ibritumomab by the chelator tiuxetan. The range of the beta rays of 90Y of about 5 mm is sufficient not only to destroy the bound cell, but also to eliminate unmarked cells in the direct neighborhood (“cross-fire effect”). However, a clinically relevant third party radiation exposition does not exist. Therefore, RIT can be applied in an outpatient setting, as long as legal regulations for radiation protection are followed [18]. The main side effect of RIT is a reversible and predictable hematotoxicity, which is clinically manageable in most cases. However, it is of particular note that the nadir is delayed and appears about 4–8 weeks after treatment [19]. Severe nonhematological toxicities have not been generally observed. Finally, this short-term treatment modality of only 2 days achieves long remission duration almost comparable to conventional treatment in a subgroup of patients.

Consensus: therapeutic algorithm for FL

RIT monotherapy with 90Y-ibritumomab is a valid therapeutic option in low-risk patients with the primary focus of control of symptoms and a high quality of life. In this classic palliative setting, RIT may be preferred due to its excellent tolerability paired with high efficacy. Besides these medical considerations, the therapeutic decision of classic palliative treatment should always consider the patient’s individual premises and goals of life:

  • RIT is an established treatment option for second and higher relapses.

  • In patients with first relapse, the use of RIT depends on the individual risk profile of the patient, such as clinical or cellular proliferation and age.

  • First-line treatment with RIT appears to be justified for patients with a contraindication against chemotherapy.

RIT in relapsed disease

Applying RIT, the well-known curative approach of radiotherapy in early stages can be transferred to the treatment of advanced stages of disease. In a randomized comparison with rituximab, RIT with 90Y-ibritumomab led to statistically significant higher response rates (80 vs 56%; p = 0.002) and particularly higher rates of CR (30 vs 16%, p = 0.040) [20]. Progression-free survival was comparable in both study arms; however, a subgroup analysis of patients achieving a CR/unconfirmed remission (CRu) after RIT demonstrated a remarkably longer progression-free survival (Fig. 2) [21].

Fig. 2
figure 2

Patients in CR/CRu after RIT with 90Y-ibritumomab achieve long-lasting remissions [21]

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In subsequent clinical trials, the CR rate post-RIT has proven to be a valid surrogate marker for a long progression-free survival. In a phase I/II study in relapse or refractory patients with indolent lymphoma the CR patients remained in remission for a median of 28.3 months (median duration of remission 27.5 months) [22].

Therefore, it should be the primary goal of RIT to achieve a CR in most patients. A pooled data analysis of the long-term responders of four registration studies with 90Y-ibritumomab demonstrated an increasing CR rate with decreasing numbers of prior therapies [23]. Patients with only one previous therapy achieved a higher response rate after RIT than the ones with two or more prior treatments, and the rate of CR was especially significantly higher in those patients receiving RIT at first relapse (49 vs 28%; p = 0.004). In the subgroup of patients with FL, over 90% achieved an objective response when 90Y-ibritumomab was applied in first relapse and CR rate almost doubled (55 vs 30%, p = 0.004). The higher response rates and better remission quality resulted in a significantly longer duration of remission and prolonged progression-free survival (Table 1).

Table 1 Efficacy of RIT with 90Y ibritumomab tiuxetan is increasing with lower number of prior therapies [23]
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A subsequent evaluation based on the data of the same four registration studies underlined these findings [24, 25]. Sixty-five percent of all long-term responders had a CR and remained progression-free for a median of 31 months. Over 80% of the long-term responders were alive after a median of 50 months. It is interesting to note that elderly and younger patients equally profit from RIT. About half of the patients of this analysis were above the age of 60, with 25% even above the age of 70 years. The latest update of this trial [25] demonstrates that elderly patients—even those above 70 years of age—respond to RIT as well as the younger ones (Table 2). The tolerability is comparable and durable remissions were obtained in all age groups.

Table 2 RIT shows similar efficacy in elderly and younger patients [25]
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Recently, these results were confirmed by an analysis of more than 1,100 FL patients treated with 131I-tositumomab [26]. Based on these results, an early use of RIT after initial immunochemotherapy may be more efficient, and in contrast to ASCT, RIT bears the advantage of high efficacy paired with a superior tolerability, being less burdening to the patient.

In relapsed disease, high-risk patients with either large tumor masses (bulky disease), accelerated progression, a marked increase in LDH suggesting secondary transformation to high malignancy or refractory disease after chemotherapy/immunotherapy carry a high risk of treatment failure, and thus require an initial effective debulking of the tumor:

  • In younger patients, RIT may be used for myeloablative consolidation in combination with HD chemotherapy before ASCT within clinical trials.

  • In elderly patients, a conventional dosed RIT consolidation after a reinduction with a rituximab-containing chemotherapy may potentially improve quality of response by eliminating residual tumor masses or minimal residual disease (MRD) and prolong the patient’s relapse-free interval.

  • In low-risk patients, RIT induction with 90Y-ibritumomab may be considered at first relapse.

Rationale for first-line RIT

Promising results of studies on first-line RIT suggest that the early use of RIT further increases the rate of the prognostically relevant CR, and may justify first-line RIT in patients with contraindications against chemotherapy.

In an American phase II study, 95% of previously untreated patients with advanced FL achieved an objective response after 131I-tositumomab RIT; the CR rate was 75%. After 5 years of follow-up 59% of all patients were still progression-free and 89% was still alive, and none of the patients developed myelodysplasia [27]. First results with 90Y-ibritumomab as a first-line treatment followed by rituximab maintenance demonstrated an objective response in all eight eligible patients with stage III/IV FL, among them five were in CR (62%). The treatment was tolerated well [28]. However, this clinical benefit is mostly referred to the CR patients and additional studies indicate that patients with a high risk of relapse—large tumor mass (> 5 cm), bone marrow infiltration, high LDH, and fast cell proliferation—should not receive RIT as a single-agent treatment [29–31]. One option for these patients could be the additional RIT consolidation after a primary immunochemotherapy to improve or consolidate the treatment success of the induction therapy. Recent results of a number of phase II studies support this hypothesis.

In 90 patients with advanced FL, the Southwest Oncology Group extended the treatment after six cycles of CHOP by adding 131I-tositumomab [32]. A total of 81 patients (89%) achieved an objective remission, among them 60 patients with a CR/CRu (67%). In 27 non-CR patients after CHOP the response status further improved after RIT. After a median follow-up of 2.3 years the 2-year overall survival is estimated at 97% with 81% of patients still in ongoing remission.

In another phase II trial, Shipley et al. [33] treated 22 patients with advanced FL (stage II/IV) after rituximab-containing first-line therapy with 90Y-ibritumomab consolidation. Ten patients in partial remission after initial chemotherapy achieved a CR after RIT, resulting in a CR of 19 out of 22 patients (86%) after completion of RIT consolidation. The most recent update of this trial demonstrates a relapse-free survival of 77% (32 out of 42 patients) after a median follow-up of 2 years. Accordingly, 90Y-ibritumomab consolidation increased the CR rate from 28% after chemotherapy to 67% [34].

The therapeutic concept of RIT consolidation after chemotherapy induction is going to be validated in further clinical studies. In Europe and Canada, the recruitment of a phase III study with more than 400 patients with newly diagnosed advanced B cell NHL (stage III/IV) was completed (first analysis pending). After initial chemotherapy induction, patients were randomized to receive either 90Y-ibritumomab or no further treatment.

In a similar current intergroup trial coordinated by the German Low-Grade Lymphoma Study Group (GLSG), patients with relapsed FL receive an abbreviated immunochemotherapy (e.g., four cycles rituximab and FC) and responding patients are subsequently randomized between 90Y-ibritumomab consolidation followed by rituximab maintenance vs antibody maintenance only (RitZ trial).

Efficacy of therapies subsequent to RIT

An important prerequisite for the early use of RIT is that the feasibility of subsequent therapies, such as chemotherapy, external beam radiation, immunotherapy, or transplantation are not negatively influenced [35–37]. To date, there is no evidence that RIT is limiting the potential of subsequent stem cell mobilization. In the survey of Ansell et al. [36], 56% of patients responded to salvage therapies and among them all patients who received transplantation after 90Y-ibritumomab RIT. Seventy percent received an external beam radiation, 5% received immunotherapy, and 45% received chemotherapy (Fig. 3).

Fig. 3
figure 3

Efficacy of subsequent therapies is not limited after RIT [35]

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Future perspectives of RIT

Further areas for RIT in patients with FL emerge in the field of HD chemotherapy as a targeted conditioning regimen prior to ASCT. Thus, RIT may serve as a superior alternative to total body irradiation (TBI).

In a phase I/II study, 31 patients, 9 with FL, received a HD RIT with 90Y-ibritumomab (40–100 mCi; day −14) with a maximum target dose of 1,000 cGy for normal organ tissue followed by HD chemotherapy with etoposide/cyclophosphamide and subsequent ASCT. All patients engrafted. Nine patients with active disease at the time of transplant achieved a CR. Besides an excellent tolerability, 90% of the patients remained disease-free after 24 months [38].

Phase I/II trials also confirm RIT as an efficacious and well-tolerated conditioning regimen in combination with BEAM (carmustine, etoposide, cytarabine, and melphalan) in extensively pretreated or elderly patients [39, 40]. After a median follow up of 13 months, 94% of patients were alive with 74% in continuous remission [40]. Various studies are currently testing the dose escalation of 90Y-ibritumomab within conditioning regimens, e.g., in the GLSG trial, TBI is substituted by 90Y-ibritumomab in a dose range of 0.4–0.8 mCi/kg body weight. The primary aim of these studies is a substantial prolongation of progression-free survival.

Currently, there are no valid data available for the use of RIT in other CD20-positive indolent lymphoma. Therefore, corresponding clinical trials are highly recommended, especially in patients with marginal zone or mantle cell lymphoma (MCL). Recent study results in MCL reveal the use of RIT preferably as consolidation after rituximab-containing reinduction chemotherapy [41].

RIT in the view of the private based oncologist

In Germany two thirds of the patients with FL are treated by private-based hematologists or oncologists. Due to the close relationship between the physician and the patient, the individual situation of the patient’s life strongly influences the therapeutic decisions. Due to its tolerability RIT is an important option for the treatment in the private-based office and strongly complies with the patients’ needs. Organ toxicities generally do not occur. The hematotoxicity is predictable and relatively easy to handle. Further advantages are the short treatment period of only 2 days, the possibility of outpatient application and the prolonged time to next lymphoma treatment. An interesting scientific concept may be the application of RIT consolidation to eradicate MRD.

RIT in the view of the patient

Representatives of patient organizations confirm the high acceptance of RIT among the patients. This is primarily based on the high efficacy paired with an excellent tolerability. Patients favor the short treatment period and good quality of life. Thus, the interest of patients in additional information about RIT is high. An often discussed point of criticism is the restrictive approval practice of the European authorities and resulting obstacles in “off-label situations”; patient advocates therefore support the demand for corresponding investigator-sponsored studies.

Summary

Patients and oncologists perceive RIT as an efficacious and well-tolerated therapy for FL. However, its potential should be used in an optimized manner, providing a highly efficacious treatment paired with good quality of life.