Page 1456 - Hematology_ Basic Principles and Practice ( PDFDrive )

1296 Part VII Hematologic Malignancies

are refractory to or relapse early after use with rituximab containing ASCT in patients with FL, which the investigators conclude, should
regimens and showed improved outcome in the Gallium study be reserved for relapsed patients. A meta-analysis concluded that
comparing obinutuzumab plus chemotherapy head-to-head with high-dose therapy and ASCT does not improve overall survival in
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rituximab plus chemotherapy (NCT01332968). FL. In view of these results, ASCT should be used in first remission
only in the setting of clinical trials.
Conjugated Radio-Labeled Monoclonal Antibody
Therapy TREATMENT OF RELAPSED INDOLENT LYMPHOMA

Complexing a radioisotope to a monoclonal antibody (radioimmu- The treatment options after relapse remain the same as for first-line
noconjugate) might be expected to improve efficacy over antibody therapy (see Table 80.6), and relapsed patients should ideally be
therapy alone. Tositumomab complexes 131 Iodine to the anti-B1 treated in clinical trials. Agents approved for rituximab refractory
antibody and has been studied extensively in the treatment of heavily disease include idelalisib and obinutuzumab. Relapsed asymptomatic
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pretreated, untreated, and for retreatment of indolent lympho- disease is not necessarily an indication for treatment and patients can
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mas. Best responses are seen in previously untreated patients with again be managed expectantly. A number of factors must be taken
FL treated with a single treatment course with tositumomab in whom into account in planning therapy and it is not possible to define
there was a 95% OR, 75% CR, and 80% of assessable patients treatment at relapse without considering the goal of therapy (pallia-
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achieved eradication of PCR detectable MRD patients. Median PFS tive versus potentially curative) performance status, previous therapy,
was 6.1 years, with 40 patients remaining in remission for 4.3–7.7 response, and duration of response. Single-agent rituximab is
years and no cases of myelodysplastic syndrome were observed. A approved for relapsed lymphoma and is widely used in this setting.
SWOG study investigated chemoimmunotherapy with six cycles of A multicenter randomized trial in relapsed patients has demonstrated
CHOP chemotherapy followed 4–8 weeks later by tositumomab in a survival advantage for chemoimmunotherapy with CHOP-R or
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90 patients with previously untreated, advanced-stage FL. The OR CHOP followed by rituximab compared with CHOP alone, and a
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was 91%, including 69% CR and at median follow-up time of 5.1 further benefit for rituximab maintenance therapy. For younger
years, the estimated 5-year OS was 87%, and PFS 67%, 23% better patients who are suitable candidates for either ASCT or reduced
than CHOP alone on previous SWOG protocols. Ibritumomab intensity conditioning (RIC) allogeneic transplantation, referral to a
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Tiuxetan is a Y-labeled anti-CD20 antibody and produced OR of transplant center should be considered early to discuss the potential
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74% and 15% CR in 57 FL patients refractory to rituximab. Toxic- role and timing of transplantation. Best results are seen when trans-
ity is primarily hematologic, with nadir counts occurring at 7–9 plantation is considered sufficiently early in the course of disease that
weeks and lasting approximately 1–4 weeks. The risk of hematologic patients have not already become chemorefractory. High-dose therapy
toxicity increased with dose delivered and with degree of baseline BM and ASCT remains an effective treatment approach for younger
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lymphoma involvement. An acceptable safety profile was observed patients with chemoresponsive relapsed disease, SCT approaches
in relapsed patients with less than 25% lymphoma marrow involve- must be considered in the context of the improving results that are
ment, adequate marrow reserve, platelets greater than 100,000 being seen with novel salvage therapies.
cells/µL, and neutrophils greater than 1500 cells/µL.
The Role of Transplant in Relapsed Indolent
High Dose Therapy as Consolidation of First Remission Lymphomas
The role of high dose therapy and ASCT in patients with FL Unlike aggressive lymphomas, the use of high-dose chemotherapy
during first remission was explored in phase II trials, 90,91 and in with ASCT in the treatment of FL has not yet been fully established.
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three phase III randomized trials. 35,87,92 The GLSG trial recruited The rationale for considering transplantation is that the disease is
307 previously untreated patients up to 60 years of age and patients incurable using standard approaches, young patients with FL will die
who responded after induction chemotherapy with two cycles of of their disease, and promising results have been observed in a number
CHOP or mitoxantrone-chlorambucil-prednisone (MCP) and were of phase II studies. 94–96 Detection of MRD has been a useful surrogate
randomized to ASCT or IFN-α maintenance. Among 240 evaluable marker for tracking long-term PFS in patients examining the autolo-
patients, the 5-year PFS was 64.7% for ASCT, and 33.3% in the gous stem cells or serial samples after transplantation. 96–100 A major
IFN-α arm (p < .0001). Acute toxicity was higher in the ASCT concern relates to the risk of development of secondary myelodysplasia/
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group, but early mortality was below 2.5% in both study arms. acute myeloid leukemia. The European Bone Marrow Transplant
Longer follow-up is necessary to determine the effect of ASCT on Registry (EBMTR) sponsored CUP (conventional chemotherapy,
OS. In the Groupe Ouest-Est des Leucémies Aigües et des Maladies unpurged, purged autograft) study is the only prospective random-
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du Sang study, 172 patients newly diagnosed with advanced FL were ized trial to assess the role of ASCT in patients with relapsed FL.
randomized either to cyclophosphamide, doxorubicin, teniposide, The results of the study suggest a PFS and OS advantage of ASCT
prednisone (CHVP), and IFN-α or to high-dose therapy followed over conventional chemotherapy, with 4-year OS of 46% for the
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by purged ASCT. Patients treated with high-dose therapy had a chemotherapy arm, versus 71% for the unpurged and 77% for the
higher response rate than patients who received chemotherapy and purged ASCT arms. The study was closed early because of slow
IFN-α (81% versus 69%, p = .045) and a longer median PFS (not accrual with 140 of the planned 250 patients accrued and only 89
reached versus 45 months), but this did not translate into a better OS randomized.
because of an excess of secondary malignancies after transplantation.
A subgroup of patients with a significantly higher event-free survival
rate ASCT could be identified using the FLIPI. The GELF94 study Novel Agents
enrolled 401 previously untreated patients with advanced-stage FL
who were randomized to receive CHVP plus IFN-α compared There are a large number of novel approaches that are being studied
with four courses of CHOP followed by HDT with total body in patients with FL. Recently approved agents for FL include idelal-
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irradiation (TBI) and ASCT and overall response (OR) rates were isib and obinutuzumab, the first type II glycoengineered and
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similar in both groups (79% and 78% respectively) and 87% of humanized monoclonal anti-CD20 antibody. Other agents under
eligible patients underwent ASCT. Intent-to-treat analysis after a investigation include novel monoclonal antibodies, immunomodula-
median follow up of 7.5 years showed no difference between the tory agents, and novel kinase inhibitors. Combinations of monoclonal
two arms for OS (p = .53) or PFS (p = .11). Long-term follow up antibodies are being explored, such as combining anti-CD20 with
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demonstrated no statistically significant benefit in favor of first-line anti-CD22 antibodies. Kinases involved in the B-cell receptor