Page 1672 - Williams Hematology ( PDFDrive )

1646 Part XI: Malignant Lymphoid Diseases Chapter 99: Follicular Lymphoma 1647

been reported for the addition of rituximab to other regimens for both lymphomas because (1) many high-quality antibodies are available tar-
frontline therapy and relapsed FL. 41,47,49,50 The selection of the “opti- geting pan–B-cell antigens expressed at high levels on lymphoma cells,
mal” chemotherapy regimen to combine with rituximab remains hotly (2) lymphomas are exquisitely sensitive to radiotherapy, and (3) cross-
contentious. Two recent large international phase III randomized fire radiotherapy from β particles emitted by decaying radionuclides on
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studies compared the efficacy and toxicity of R-CVP, R-CHOP, and rit- targeted lymphoma cells can kill neighboring antigen-negative tumor
uximab-fludarabine–based therapy, which until recently were the three cells (or inaccessible cells deep in tumor clumps), which would escape
most commonly employed regimens for frontline therapy of FL. Both killing by nonradioactive antibodies. Several trials have demonstrated
trials demonstrated superior PFS for patients treated with R-CHOP or ORRs of 50 to 80 percent and CR rates of 15 to 40 percent in patients
rituximab-fludarabine regimens than with R-CVP, although OS did not with relapsed or refractory indolent lymphoma treated with either
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differ. Both studies also concluded that regimens with fludarabine and 131 iodine-tositumomab or yttrium-ibritumomab tiuxetan. 57,59,60 In a
rituximab had significantly more hematologic toxicity and a higher risk randomized study comparing treatment of patients with relapsed FL
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of secondary malignancies than either R-CVP or R-CHOP, making flu- with either Y-ibritumomab tiuxetan or rituximab, the ORR (86 per-
darabine-based regimens less desirable. The investigators conducting cent vs. 55 percent) and the CR rate (30 percent vs. 15 percent) were
these trials concluded that R-CHOP was the preferred regimen for FL, both statistically superior in the group treated with the radioimmuno-
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although some oncologists are hesitant to routinely employ R-CHOP conjugate. Similarly, I-tositumomab was compared with unlabeled
in patients with indolent lymphomas because of its greater toxicity, tositumomab in a randomized trial of relapsed indolent lymphoma and
including a 1 to 2 percent risk of cardiomyopathy, and the absence of both the ORR (55 percent vs. 19 percent) and the CR rate (33 percent vs.
a demonstrated OS advantage. These risks may be particularly justifi- 8 percent) were higher in patients receiving the radiolabeled antibody. 61
able, however, for patients with grade 3 FL, as many authorities believe Six phase II studies have studied frontline RIT for patients with
anthracycline-based regimens may be curable for high-grade FL, which newly diagnosed FL, either as a single agent or in combination with
National Comprehensive Cancer Network (NCCN) guidelines advise various chemotherapy regimens, including CVP, CHOP, and fludara-
treated identically to diffuse large B-cell lymphoma. To further amplify bine. In all six studies, outstanding ORR rates (90 to 100 percent) and
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the controversy, two recent randomized trials comparing bendamustine CR rates (50 to 96 percent) were observed with first-line RIT, with
plus rituximab (BR) with R-CHOP show similar efficacy for the two median PFSs in excess of 5 years in several of the studies. 62–64 A phase III
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regimens, and less toxicity for BR. 52,53 Although these studies have been randomized study evaluated the utility of consolidation therapy with
criticized for methodologic flaws, they have been highly influential and Y-ibritumomab tiuxetan for patients with FL in remission after frontline
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have catapulted BR to prominence as the most popular frontline induc- chemotherapy. In this trial, 414 patients in either partial or complete
tion regimen for FL, with approximately 65 to 70 percent of FL patients remission after a variety of chemotherapy induction regimens (chlo-
in the United States and Europe currently receiving this regimen for rambucil, CVP, CHOP, fludarabine or rituximab combinations) were
frontline therapy. randomized to either consolidation with RIT or to no consolidation.
RIT dramatically improved the median PFS in the total patient pop-
Maintenance Rituximab ulation (36.5 months vs. 13.3 months, p <0.0001), and this advantage
Despite the ability to induce long-lasting remissions in the majority of was observed regardless of whether patients were in partial remission
FL patients treated with chemoimmunotherapy regimens as outlined (PR; 29.3 months vs. 6.2 months, p <0.0001) or CR (53.9 months vs.
above, most patients will eventually relapse. Several strategies have 29.5 months, p = 0.015) at the time of consolidation. Furthermore, RIT
emerged to prolong the remission durations and to delay lymphoma consolidation converted 77 percent of patients who were in PR after
recurrence. The most popular approach is to administer extended induction chemotherapy to CR following RIT. However, a recent study
courses of rituximab, also known as rituximab “maintenance” to fore- comparing six cycles of R-CHOP with six cycles of CHOP (without rit-
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stall reappearance of FL. The PRIMA trial randomized 1217 patients uximab) followed by a single dose of I-tositumomab (CHOP-RIT)
2
with FL to either maintenance rituximab (375 mg/m every 2 months demonstrated similar outcomes in both treatment arms. 17
for 2 years) or no maintenance therapy, following frontline induc- The major toxicity of RIT is myelosuppression, with cytopenic
tion therapy with R-CVP, R-CHOP, or rituximab, fludarabine, cyclo- nadirs occurring 4 to 7 weeks after treatment and requiring 2 to
phosphamide, and mitoxantrone (R-FCM). This study convincingly 4 weeks for recovery. Growth factor administration and transfusions
42
demonstrated the superiority of 2 years of maintenance rituximab (PFS are required in approximately 20 percent of patients. Human antimouse
74.9 percent) compared to observation alone after induction (PFS, antibodies (HAMA) may develop in the serum of approximately
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57.6 percent, p <0.0001), regardless of which induction chemotherapy 1 percent of patients treated with Y-labeled ibritumomab and in 10
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regimen is used. Despite the marked improvement in PFS afforded by percent of patients treated with I-labeled tositumomab. A potential
maintenance rituximab in PRIMA, however, there was no significant long-term concern with both radiolabeled antibody formulations is the
difference in OS between the rituximab maintenance and observation potential development of myelodysplasia and acute leukemia as late
arms. Similar improvements in PFS but not OS have also been demon- complications. Hypothyroidism may also occur as a delayed toxicity of
strated for maintenance rituximab given for 2 years following rituximab 131 I-labeled tositumomab in approximately 10 percent of patients.
monotherapy in the frontline setting and following CHOP or R-CHOP
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induction in the relapsed setting. 54 Interferon-α 2
Interferon (IFN)-α has been studied in 10 large phase III studies eval-
2
Radioimmunotherapy uating its utility in both the induction phase of treatment and for main-
Radiolabeled monoclonal antibodies targeting lymphoma-associated tenance therapy. A meta-analysis of 1922 newly diagnosed patients with
cell surface antigens, including idiotypic immunoglobulin, CD20, CD22, FL treated in these trials concluded that the addition of IFN-α to induc-
2
and HLA-DR, have emerged as effective and safe therapeutic agents for tion chemotherapy did not significantly influence response rates, but did
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patients with FL. 55,56 Two radioimmunoconjugates targeting the CD20 show a significant difference in favor of IFN-α with regard to survival.
2
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antigen, iodine-tositumomab (Bexxar) and yttrium-ibritumomab tiux- Results differed greatly from trial to trial and further analyses were car-
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etan (Zevalin), have been extensively tested in indolent lymphomas. 57–59 ried out to define the circumstances in which IFN-α prolonged OS. The
2
Radioimmunotherapy (RIT) is an attractive therapeutic option for survival advantage was seen when IFN-α was given (1) in conjunction
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