We explored the feasibility of high-dose cyclophosphamide and rituximab in-vivo B-cell purging without stem cell rescue as an alternative to conventional autoSCT in patients with low grade B-cell lymphomas. After documenting universal hematopoietic recovery, this study was expanded from a safety trial to an exploratory efficacy trial in two cohorts: low-grade B cell lymphomas and mantle cell lymphoma.
A potential advantage of this approach is the ability to avoid reinfusion of lymphoma cells with the autologous stem cell graft. The concern for autograft graft contamination is not just theoretic: tumor cells can be found circulating in the blood of most patients with lymphoid malignancies as well as in autologous stem cell grafts.[11
] Moreover, autograft contamination as a contributor to relapse may explain the lower relapse rates observed in syngeneic and purged autologous SCT as compared to unmanipulated autologous SCT.[2
The therapy was well tolerated with no unexpected adverse events. All patients achieved rapid and full hematologic recovery, similar to that seen with autologous transplantation and the toxicities of stem cell mobilization were avoided.[16
] Moreover, adverse events were mild: fewer than a third of patients developed febrile neutropenia, fewer than half required hospitalization, nearly a fifth did not require platelet transfusion support and no deaths occurred.
Despite the lack of a myeloablative preparative regimen, these results are similar to previous autoSCT reports for low grade lymphoma. Patients with low-grade, non-MCL histologies exhibited a 5 year EFS and OS of 40% and 72%, respectively. Comparatively, in 693 follicular lymphoma patients (43% with ex-vivo
manipulation) Montoto et al, reported a 5 year PFS and OS of 44% and 64% after autoSCT.[5
] Similarly, Bierman et al, reported a 5 year PFS and OS of 46% and 62%, in 160 patients who received a purged autoSCT and a 5 year PFS and OS of 37% and 50%, in 427 patients who received an unpurged autoSCT for low grade NHL.[2
The 5 year EFS and OS was 39% and 62%, respectively, in our 39 mantle cell patients. While our current study was neither powered nor designed to be compared to other reports, contemporary approaches to MCL requires comment. No consensus exists on the optimal treatment paradigm for MCL. In fact, dichotomous recommendations from deferring initial therapy to high-dose induction therapy followed by autologous hematopoietic progenitor cell transplantation (HSCT) in first remission have been published in 2009.[18
] However, a single institutional report generated at the MD Anderson Cancer Center supports early intensive treatment. In their a non-randomized experience, fifty patients who underwent an autologous HSCT in first remission had a median progression free survival of 42 months and overall survival of 93 months.[18
] The Nordic Lymphoma group, reported in 2008, a 6-year EFS and OS of 56% and 70% with a non-relapse mortality rate of 5% in 160 consecutive, untreated MCL patients younger than 66 years treated with Maxi-RCHOP-21 ×3 alternating with rituximab high-dose cytarabine x3 followed by rituximab in-vivo
purged autologous transplant.[20
] Both of these trials suggest that a more aggressive pre-transplant treatment than CHOP, as used in our patients, is critical to the improved results with autoSCT.[18
] While these results argue for immediate and aggressive intervention, Martin et al, reported on 31 patients with MCL who had a median pre-treatment observation time of 12 months (range: 4 to 128 months), concluding some patients can be observed and even suggested these patients may have an improved overall survival compared with those who receive early treatment.[19
] As a whole, these results suggest patient selection and lead-time bias can greatly affect treatment result interpretation in mantle cell lymphoma.
Our data suggest high-dose cyclophosphamide with in-vivo rituximab purging may have a role as an alternative to autoSCT in multiple subtypes of low grade B-cell lymphoma. Compared to autoSCT, this treatment is simpler, less labor-intensive, and avoids the costs and risks of stem cell mobilization and processing. Furthermore, the treatment was well tolerated by older individuals: neither mortality nor unexpected or excessive toxicities were observed in the 17 patients who were 65 years or older, suggesting this approach may also be especially well suited for individuals not candidates for intensive cytoreduction followed by autoSCT. Moreover, this treatment approach does not preclude relapsed patients from salvage allogeneic transplant, as occurred in 19 patients of whom 10 remain disease-free. HDC with in-vivo rituximab purging is a well tolerated consolidative therapy that can provide a platform for the integration of novel molecularly targeted compounds.