A prospective, single-arm, open-label, nonrandomized Phase 2 study of combined fludarabine and mitoxantrone (FM) plus radioimmunotherapy was conducted to evaluate efficacy and safety in patients with untreated, indolent, nonfollicular non-Hodgkin lymphoma (NHL).
Between February 2005 and June 2006, at their institute, the authors treated 26 eligible patients with previously untreated, indolent, nonfollicular NHL (10 marginal zone lymphomas, 8 lymphoplasmacytic lymphomas, and 8 small lymphocytic lymphomas) using a novel regimen that consisted of 6 cycles of FM chemotherapy followed 6 to 10 weeks later by yttrium-90 (90Y) ibritumomab tiuxetan.
After FM chemotherapy, the overall response rate was 80.5% and included a 50% complete remission (CR) rate (13 patients) and a 30.5% partial remission (PR) rate (8 patients). Of the 20 patients (13 with CR and 7 with PR) who were evaluable (at least a PR with normal platelet counts and bone marrow infiltration <25%) for subsequent 90Y ibritumomab tiuxetan, 100% obtained a CR at the end of the entire treatment regimen. At a median follow-up of 20 months, the estimated 3-year progression-free survival rate was 89.5%, and the estimated 3-year overall survival rate was 100%. The 90Y ibritumomab tiuxetan toxicity included grade ≥3 hematologic toxicity in 16 of 20 patients; the most common grade ≥3 toxicities were neutropenia (11 patients) and thrombocytopenia (16 patients) (adverse events were graded according to the World Health Organization criteria for toxicity). Transfusions of erythrocytes and/or platelets were given to 5 patients.
Apart from extranodal mucosa-associated lymphoma tissue (MALT) lymphomas, which can be cured by surgery, local radiotherapy, or antibiotic treatment,1–3 indolent, nonfollicular non-Hodgkin lymphomas (NHL) generally are regarded as incurable. Studies from Stanford in the 1970s indicated that there was no difference in freedom from disease progression or survival between 4 different approaches to treatment—namely, single-agent, alkylating agent therapy; whole-body irradiation, combined cyclophosphamide, vincristine, and prednisolone (CVP) chemotherapy; and CVP plus total lymphoid irradiation.4, 5 The Stanford group also reported that patients with indolent, nonfollicular NHL did not necessarily need to start treatment as soon as a diagnosis was made and that a “watch-and-wait” policy in selected groups of patients did not lead to an inferior outcome for these individuals.6 This conservative approach is particularly applicable to elderly patients (the majority), who usually are less tolerant to drug toxicity.
In the last decade, fludarabine has emerged as one of the most active agents available for the treatment of indolent NHL. Although early trials using single-agent fludarabine produced overall response rates that ranged from 30% to 50% in previously treated patients,7–10 more recent efforts have focused on combining fludarabine with other agents, especially mitoxantrone,11–16 idarubicin,17–19 cyclophosphamide,20–22 and a combination of fludarabine with cyclophosphamide and mitoxantrone.23, 24 Phase 2 trials using these combination regimens have yielded reproducible overall response rates from 40% to 70%, which appear to be superior to the rates reported with single-agent fludarabine.
With regard to the role of rituximab in patients with indolent, nonfollicular NHL, to our knowledge its efficacy is not well known because there have been conflicting results. In a European trial in patients with recurrent indolent, nonfollicular NHL, the efficacy of rituximab was lower than that reported in patients with follicular NHL, with response rates ranging between 14% and 38%, depending on the histologic subtype.25 However, in untreated patients, the response rate reportedly was higher.26 In a Phase 2 study, Hainsworth et al.26 reported a 51% response rate after 4 administrations with only a 4% complete remission (CR) rate.
Radioimmunotherapy has emerged as an important treatment option for patients with B-cell NHL. Yttrium-90 (90Y) ibritumomab is a murine monoclonal immunoglobulin G1 κ antibody to CD20, which is a surface antigen that is expressed on 90% of B-cell lymphomas,27 and is conjugated to the metal chelator tiuxetan for retention of the β emitter 90Y for therapy. Thus, treatment with 90Y ibritumomab tiuxetan targets radiation to B-cell lymphomas, which inherently are sensitive to radiation.28
In the initial Phase 1/2 trial of 90Y ibritumomab tiuxetan, responses were observed in 82% of 34 patients with indolent NHL, including a CR in 26% of patietns.29 Witzig et al. compared 90Y ibritumomab tiuxetan with standard-dose rituximab in a randomized, controlled, Phase 3 study30 in patients with recurrent or refractory, indolent, follicular NHL and reported statistically significantly higher overall response and CR rates. Other investigators have reported additional data that tends to confirm the safety and activeness of 90Y ibritumomab tiuxetan in patients with follicular NHL.31, 32 In view of these findings, we decided to investigate the efficacy and safety of a novel approach combining induction chemotherapy with fludarabine and mitoxantrone (FM) chemotherapy followed by consolidation with 90Y ibritumomab tiuxetan in a Phase 2 trial for patients with previously untreated, nonfollicular NHL.
MATERIALS AND METHODS
Patients aged ≥18 years with biopsy-proven, untreated, bidimensionally measurable, stage II, III, or IV (graded according to the Ann Arbor Staging System), indolent nonfollicular (small lymphocytic, lymphoplasmacytic, and marginal zone lymphoma) NHL that expressed the CD20 antigen were eligible for this trial if they had a World Health Organization (WHO) performance status of 0 to 2. All patients were notified of the investigational nature of this study and signed a written informed-consent for that was approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the Institutional Review Board. All diagnostic biopsies were reviewed by an expert pathologist (Stefano Pileri) from our institute to confirm the diagnosis of indolent, nonfollicular lymphoma according to the WHO classification.33
All patients who entered this trial were required to undergo a full history; physical examination; complete blood cell count with leukocyte differential; platelet count; computed tomography (CT) scans of the neck, chest, abdomen, and pelvis; and bone marrow aspiration and biopsy. According to good medical practice, patients also were tested for blood chemistry (including creatinine, liver function tests, uric acid, and lactate dehydrogenase) and underwent urinalysis and electrocardiography. Patients who had a history of impaired cardiac status were assessed by echocardiograph and were eligible only if their cardiac ejection fraction was normal.
Patients received standard FM chemotherapy every 28 days for 6 cycles with dosages of 25 mg/m2 of fludarabine on Days 1 through 3 and 10 mg/m2 of mitoxantrone on Day 1 (both drugs were administered intravenously). Allopurinol (300 mg orally) was recommended as adjunctive therapy for patients with bulky disease. If patients had a granulocyte count <1500/μL or a platelet count <100,000/μL by the start of the next cycle, then treatment was delayed for 1 week, and counts were repeated. If counts had not recovered after 2 weeks, then the patient received at 75% of the last dose of cyclophosphamide and doxorubicin received. Re-escalation was at the discretion of the treating physician. Growth-stimulating factors were not administered to prevent neutropenia, but patients who experienced grade 3 or 4 neutropenia or who developed neutropenic fever between cycles of chemotherapy were allowed to receive growth factors for subsequent cycles of therapy at the discretion of the treating physician.
Patients were restaged from 4 to 6 weeks after they completed the sixth cycle of FM chemotherapy by physical examination, blood testing, CT scans, and bone marrow aspiration and biopsy. Patients who achieved at least a partial response after 6 cycles of FM were eligible for consolidation with 90Y ibritumomab tiuxetan provided their granulocyte count was >1500/μL granulocytes, their platelet count was >100,000/μL, and their bone marrow examination at the completion of FM chemotherapy had ≤25% involvement with lymphoma.
Six to 10 weeks after completing the sixth cycle of FM chemotherapy, eligible patients received 1 course of 90Y ibritumomab tiuxetan (Fig. 1), which consisted of an initial infusion of rituximab at a dose of 250 mg/m2 on Day 1 and another on Day 7, 8, or 9; a second infusion of rituximab at a dose of 250 mg/m2 was followed by a weight-based dose of 90Y ibritumomab tiuxetan (Schering AG, Berlin, Germany) given as a slow intravenous push over 10 minutes. The dose of 90Y ibritumomab tiuxetan was 11.1 megabecquerels (MBq)/kg (0.3 mCi/kg) in patients with pretreatment platelet counts from 100,000 to 149,000/μL and 14.8 MBq/kg (0.4 mCi/kg) in patients with pretreatment platelet counts ≥150,000/μL. In all patients, the maximum total dose was 1184 MBq (32 mCi). 90Y ibritumomab tiuxetan was administered routinely on an outpatient basis because of the lack of γ emissions.
Disease status was evaluated with a physical examination; a bone marrow biopsy; and CT scans of the neck, chest, abdomen, and pelvis along with other clinically relevant tests. This assessment was repeated 3 months after 90Y ibritumomab tiuxetan infusion.
Safety and tolerability were assessed by monitoring the incidence, severity, and type of any adverse event. Adverse events were graded according to the WHO criteria for toxicity. Responses were classified according to the International Working Group Response Criteria.34
Sample size estimation was performed by using the Fleming single-stage procedure.35, 36 Previous experience has demonstrated that the response rate (adjusted for the response criteria as par) is 50%. By defining π0 as the proportion of responses below which treatment does not warrant further investigation and defining πa as the proportion of responses beyond which a Phase 3 trial should be performed, we set π0 = 0.5 and πa = 0.8. According to this calculation, the number of patients required is 18 given a type I error (α) of .05 (2-sided) and a power of 1-β = 80%, and the number of successes (responses) required is 13. If, by the end of the trial, at least 13 responses (successes) are observed, then the treatment will be accepted for a Phase 3 trial.37 Overall survival (OS) and progression-free survival (PFS) curves were plotted by using the Kaplan-Meier method.38 PFS was defined as the time from registration to the first observation of progressive disease or death from any cause.
Twenty-six patients were registered on the current trial between February 2005 and June 2006, when the study reached completion and was closed. The patients' characteristics are listed in Table 1. The median age of the patients was 61 years (range, 45–82 years). Thirteen patients (50%) were men, and 13 patients (50%) were women. Four patients had stage III disease, 22 patients had stage IV disease (22 patients had bone marrow involvement), and 2 patients (8%) had bulky disease.
Table 1. Patient Characteristics (n = 26)
No. of patients (%)
Bulky disease was defined as disease that measured ≥6 cm in greatest dimension.
At the evaluation after 6 cycles of FM chemotherapy, the overall response rate was 80.5%: Thirteen patients (50%) were in CR, 8 patients (30.5%) were in PR, and the remaining 5 patients were considered nonresponders. According to histology, the 5 nonresponders had 2 small lymphocytic leukemia, 2patients had lymphoplasmacytic lymphoma, and 1 patient had marginal zone lymphoma.
Twenty of 26 patients were evaluable for 90Y ibritumomab tiuxetan treatment, including all patients who achieved CR and 7 patients who achieved PR (the remaining patient who achieved PR had a small lymphocytic lymphoma and was excluded from the second part of the therapy program because of bone marrow infiltration >25%). There is no record of any patient receiving a reduced dose of 90Y ibritumomab tiuxetan because of persisting thrombocytopenia after FM. The median time from the initiation of Course 6 of chemotherapy to the initiation of radioimmunotherapy was 8 weeks.
The overall response rate of the 20 patients who completed the entire treatment regimen (FM plus 90Y ibritumomab tiuxetan) was 100%, and the CR rate was 100%. Therapy with 90Y ibritumomab tiuxetan improved the CR rate substantially (Table 2). In all 7 patients (100%) who initially achieved PR on the FM regimen alone, the addition of 90Y ibritumomab tiuxetan improved the overall best response (from PR to CR). With a median follow-up of 20 months (range, 12–39 months), 2 eligible patients experienced disease progression, resulting in an estimated 3-year PFS rate of 89.5% (Fig. 2). One patient died because of lymphoma progression; the 3-year OS estimate was 100% (Fig. 2).
Table 2. Response to Therapy
No. of patients (%)
After FM, n = 26
After FM and 90Y ibritumomab tiuxetan, n = 20
FM indicates fludarabine plus mitoxantrone.
There were no treatment-related deaths. The FM regimen was tolerated well by most patients. Reversible hematologic toxicities constituted most of the adverse events, including grade 4 hematologic toxicity in 5 patients (19%) and grade 3 hematologic toxicity in 13 patients (50%). We observed that all of these patients presented with neutropenia. Only 1 patient (4%) developed febrile neutropenia.
With regard to 90Y ibritumomab tiuxetan, there were no infusion-related reactions. Adverse events after 90Y ibritumomab tiuxetan treatment were primarily hematologic and transient; and no patient discontinued treatment because of an adverse event.
The duration of hematologic toxicity is listed in Table 3. Grade 3 and 4 thrombocytopenia occurred in 16 of 20 patients (61.5%), grade 3 and 4 neutropenia occurred in 11 of 20 patients (42%), and grade 3 and 4 anemia occurred in 7 of 20 patients (27%). In terms of the median duration (in days) of nadir with grade 3 and 4 hematologic toxicity, the data indicated that anemia and thrombocytopenia were longer lasting than what is observed normally in patients with aggressive lymphoma. Four patients (15%) received granulocyte colony-stimulating factors, 3 patients (11.5%) received platelet transfusions, and 5 patients (19%) received erythrocyte transfusions. Only 1 patient (4%) experienced febrile neutropenia requiring hospitalization. No patients developed elevated thyroid-stimulating hormone levels or any secondary malignancies.
Table 3. Hematologic Toxicity After 90Y Ibritumomab Tiuxetan
Time from baseline to nadir, d
Median duration for patients with grade 3 or 4 nadir (Range), d*
ANC indicates absolute neutrophil count.
Graded according to World Health Organization criteria for toxicity.
In this study, we established the feasibility, tolerability, and efficacy of sequential treatment with 6 cycles of FM chemotherapy followed by 90Y ibritumomab tiuxetan as front-line therapy for patients with untreated, indolent, nonfollicular NHL. In particular, to our knowledge, the data represent the first demonstration in the literature of the real role of 90Y ibritumomab tiuxetan in the treatment of indolent nonfollicular NHL.
The clinical evaluation of immunotherapy based on anti-CD20 monoclonal antibodies has affected the treatment approach markedly for patients with indolent nonfollicular NHL.25, 26 At the same time, the fluorinated nucleotide analog fludarabine is a potent inhibitor of DNA synthesis and has demonstrated activity in indolent NHL both as a single agent and in combination with other agents.11, 39 In parallel, radioimmunotherapy with 90Y ibritumomab tiuxetan has been developed and has been proven to be among the most active agents in lymphoma therapy. Its toxicity is manageable and consists primarily of transient myelosuppression in addition to typical antibody-associated infusion reactions. Clinical trials with this agent have demonstrated significant activity in indolent NHL,29, 30, 32 including disease that is resistant to chemotherapy or rituximab.31 The data have demonstrated that a substantial proportion of patients can have durable remissions, extending in some patients >5 years. On the basis of these data, further investigations have monitored radioimmunotherapy as consolidation after initial treatment with chemotherapy40, 41 in patients with follicular NHL. Initial reports from those indicate acceptable toxicity with promising antilymphoma activity, and randomized studies are in progress in indolent, follicular NHL. The principal challenge when it comes to applying these radiolabeled immunotherapies is how to integrate them into the treatment approach in the most effective manner. The finding that radioimmunotherapy has demonstrated the highest response rate of any “single-agent” approach in lymphoma therapy highlights the potential importance of this therapeutic modality.
The reason we decided to conduct this sequential treatment trial using conventional chemotherapy followed by radioimmunotherapy (90Y ibritumomab tiuxetan) was to test its degree of activity and its safety in this particular subset of patients with indolent, nonfollicular NHL in which conventional chemotherapy and/or rituximab are significantly less active than in indolent, follicular NHL. By the end of sequential combined treatment, 20 patients (100%) had achieved CR. It is even more noteworthy that, of the 7 patients who achieved PR with FM, all improved their remission status after treatment with 90Y ibritumomab tiuxetan, and the 3-year PFS rate was 89.5%. However, of course, a longer follow-up will be required to really comment on these data in terms of the duration of response.
The toxicities we observed generally were mild without any aspect of cumulative toxicity. Hematologic toxicity was moderate with 90Y ibritumomab tiuxetan after 6 cycles of FM and rarely led to infection or required transfusion support. Conversely, nonhematologic toxicity practically was absent with 90Y ibritumomab tiuxetan.
In particular, the current results have demonstrated the possibility of using FM, a regimen that contains fludarabine (an important immunosuppressor agent), sequentially with 90Y ibritumomab tiuxetan in this histologic subtype and producing a complete hematologic recovery. Because this novel sequential treatment appears to be promising compared with results reported in the literature for the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone/CVP/fludarabine-containing regimens plus rituximab, we believe that the current Phase 2 trial represents an important first step and positive new angle in therapy to combat indolent, nonfollicular NHL.