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Bendamustine and stem-cell mobilization: not so bad!

Recent studies have shown the alkylating agent bendamustine to be effective salvage chemotherapy for relapsed and refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL).[1–4] Furthermore, autologous stemcell transplant (SCT) after salvage chemotherapy is currently standard of care for relapsed/refractory lymphomas.[5,6] However, little is known about what effects bendamustine may have on the process of mobilization of peripheral blood stem cells. Other alkylating agents may impair peripheral stem-cell mobilization.[7,8] In addition, the purine analog, fludarabine negatively impacts stem cell mobilization.[9,10] Bendamustine, though considered an alkylating agent, has secondary biochemical properties similar to purine analogs and this raises further questions about its effects on stem-cell mobilization.[11] Recently, two publications in Leukemia and Lymphoma have examined this issue. Gac et al. conducted a retrospective analysis of 23 cases of HL and NHL treated with bendamustine prior to stem cell mobilization.[12] Seventeen underwent stem cell mobilization immediately after receiving bendamustine, while another six patients underwent mobilization after completion of bendamustine-containing chemotherapy regimens, with a median 115 days between completion of therapy and stem-cell mobilization. Bendamustine was a poor mobilizing agent with only 16% (10/12) of patients achieving successful mobilization when bendamustine was used in conjunction with G-CSF. Higher rates of successful stem-cell mobilization were ultimately achieved with the concurrent use of GCSF and plerixafor after bendamustine (67% (6/9)); 2/4 after remobilization, 4/5 after initial mobilization). Yields were equivalent for patients who required remobilization with other chemotherapy or G-CSF (67%; (4/ 6)). The six patients who underwent delayed mobilization with plerixafor a long time after receiving bendamustine had the best mobilization yields (83%; (5/6)), suggesting that use of bendamustine does not permanently impair mobilization and that the delay in mobilization allowed some time for marrow recovery and thus improved mobilization results. While bendamustine may be a poor mobilization agent, its use did not appear to affect long-term management, as all patients were ultimately able proceed to transplant and achieved successful engraftment. A second study by Iliff et al. from the University of Kansas explores this same question in patients with relapsed NHL.[13] They describe 18 patients with either relapsed follicular lymphoma or diffuse large B-cell lymphoma who received the combination of bendamustine plus rituximab as salvage chemotherapy. Only 10 patients, all with follicular lymphoma, were ultimately selected to undergo autologous SCT. Similar to the first paper, all patients selected for transplant were able to complete successful large volume stem-cell mobilization despite prior exposure to bendamustine, and all patients ultimately engrafted with appropriate hematopoietic reconstitution. Of note, the use of plerixafor was substantially lower in these patients (2 of 10). It is unclear what factors accounted for the better efficiency of stem-cell mobilization in this study. What can we conclude from these studies? Together they appear to show that use of bendamustine in salvage therapy does not appear to prevent the ability to perform successful stem cell harvesting, nor does it appear to negatively affect engraftment after transplant. It is, however, important to recognize that these studies are limited by the small number of patients, differing methodologies and by the heterogeneity of patient diagnoses. They also demonstrate significant variability in the efficiency of peripheral blood stem-cell mobilization, independent of the use of bendamustine. Lastly, both studies lack long-term outcome data that could provide additional insights into whether there might be discernible differences in