Posttransplant Consolidation Maintenance Therapy

HDC with AHCT can cure nearly half of NHL patients with chemosensitive disease and about 30% of patients with primary refractory disease. However, relapse still accounts for the majority of deaths in this patient population with most relapses occurring in sites of previous bulk disease. IFRT as adjuvant therapy posttransplantation is a strategy that can reduce this risk. Advantages for administering IFRT posttransplantation include the ability to tailor radiation dose based on residual disease volume, which may allow use of lower radiation doses and avoid delaying HDC in patients with rapidly progressive disease. The University of Chicago group transplanted 53 patients with relapsed/refractory NHL with 6 patients receiving IFRT to sites of persistent disease after transplantation.90 Although the sample size was small, the IFRT patients experienced significantly improved local control of persistent disease sites (100% vs 29%, p = 0.01) and had a lower incidence of recurrences in previously active sites. Not surprisingly, the sites at greatest risk of relapse were sites failing to achieve a CR to induction therapy regardless of subsequent response to AHCT. Vose et al. from Nebraska demonstrated that not receiving IFRT either before or after transplant was an adverse prognostic factor for OS in a series of 184 patients with NHL patients with primary refractory disease.91 The University of Rochester group provided AHCT to 136 relapsed/refractory NHL patients.92 Fifty-one patients received posttransplant IFRT. Of the 58 patients transplanted with bulky disease, the 30 patients who received IFRT had a 3-year EFS of 35% versus 16% (p = 0.04) for the 28 patients who did not receive IFRT. Bulky disease was defined as nodal or extranodal disease >2 cm in diameter or >20% of marrow involvement with lymphoma. The patients with nonbulky disease did not experience a survival advantage with IFRT as consolidation. Unfortunately, there are no comparative trials addressing the role of IFRT after transplantation but IFRT should be offered as a valuable adjunct in this setting to reduce relapse rates in sites of previous bulk disease and to confer local control in residual sites after transplantation. However, potential concerns associated with IFRT include increased incidence of pneumonitis, transient cytopenias, and an increased risk of secondary MDS/AML.93'94

Numerous other strategies that have been employed to reduce the relapse risk include cytokine therapy with IL-2, antibody-based therapies, and cellular therapies involving IL-2 activated products with natural killer cells or cytokine-induced killer cells.95-99 However, the use of the anti-CD20 monoclonal antibody, RTX, as maintenance therapy after transplantation to eliminate residual tumor cells is increasingly being explored. Given its minimal toxicity profile and non-cross-resistant mechanism with chemotherapy, RTX has currently emerged as the most appealing agent for adjuvant therapy posttransplantation for patients with indolent, aggressive, and mantle cell B-cell NHL. In a German multicenter phase II study, 20 patients with newly diagnosed FL and 10 patients with MCL received four weekly doses of RTX at a median of 2 months posttransplant.100 The addition of RTX increased both the complete clinical and molecular remission rates over time. At 6 months of follow-up, the clinical CR rate of 59% increased to 88% after 24 months of follow-up. Additionally, prior to transplantation, 22% of peripheral blood or BM samples were PCR negative. These numbers increased to 53% immediately after AHCT to 72% immediately after RTX administration and then to an impressive 100% PCR negativity at 6 months posttransplantation. These results indicated that clearance of MRD can continue for several months after RTX administration. The RTX was well tolerated with a 4% incidence of transient leukopenia and lymphocytopenia although seven patients developed pneumonia. B-cell peripheral blood counts normalized approximately 12 months after RTX consolidation therapy. Buckstein et al. administered RTX maintenance therapy to 17 patients with follicular NHL who had also received RTX prior to the mobilization regimen.101 At a median of 1 year of follow-up, all assessable patients remained in CR and all seven patients evaluable for molecular monitoring remained bcl-2 negative at 6 months. In this study, four of 12 patients who received alpha-interferon instead of RTX for maintenance relapsed at a median follow-up of 28 months. In other published reports, Magni et al. and Ladetto et al. demonstrated the safety and feasibility of incorporating RTX for the purposes of in vivo purging and post-HSCT maintenance therapy in patients with B-cell NHL including follicular NHL.44 58 A large ongoing trial in Europe conducted by the EBMT is evaluating the roles of both in vivo purging and maintenance therapy with RTX in a multicenter setting for FL patients in second or third remission. This trial involves a four-arm randomization to either in vivo purging and maintenance, purging without maintenance, maintenance without purging, or no RTX administration.

The Stanford Group administered four weekly infusions of RTX to 28 patients with NHL beginning 42 days after transplant with additional infusions given at 6 months.97 All patients had rapid depletion of B cells with no increase in infection or significant adverse events except for an isolated transient neutropenia that occurred in 54% of the patients. At a median follow-up of 30 months, the EFS and OS rates were 83% and 88%, respectively. These results compare very favorably when the subgroup of 21 patients with DLCL were compared to a historical control group of DLCL patients who underwent AHCT without RTX maintenance therapy (see Figure 64.5). The 2-year EFS and OS rates were 58% and 62%, respectively, in the control group. Longer follow-up and the results of an ongoing Intergroup randomized trial will reveal the true clinical benefit of RTX maintenance therapy, but initial data speak strongly for both the safety and efficacy in the adjuvant setting.

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