Investigators at Fred Hutchinson Cancer Research Center in Seattle recently reported the results of retrospective study of 118 patients with mantle cell lymphoma. After receiving a variety of first-line chemotherapy regimens, including R-HyperCVAD and R-CHOP, 85 patients underwent consolidation with autologous stem cell transplantation. Initially, it appeared that patients who received an aggressive induction regimen, like R-HyperCVAD, had a better outcome following stem cell transplantation. Interestingly, after controlling for other prognostic factors, like age, LDH, White Blood Cell count, and performance status, it became apparent that choice of induction chemotherapy had little effect on outcome after transplant. In other words, patients that had a better baseline prognosis were more likely to be treated with aggressive first-line regimens, which gave the appearance that the more aggressive regimens were responsible for better outcomes. Click here to read the abstract.
This study is important because it helps us to contextualize the results of many of the phase 2 studies that have been published on mantle cell lymphoma. It is possible that the results of phase 2 studies appear to be more or less impressive than standard therapies because there is no comparison group; i.e., it is the baseline prognostic factors of the patients that explain the results rather than the treatment regimen being tested. Retrospective studies, such as the study from Seattle, are also prone to bias because it is difficult to control for everything, particularly prognostic factors that we don’t yet know about. That is why randomized studies comparing at least two regimens are of critical importance. Only randomized studies can distinguish the between the good and bad effects of two or more regimens.
In fact, one randomized phase 3 trial comparing pretransplant regimens in mantle cell lymphoma was reported at the annual meeting of the American Society of Hematology in December 2010 (click here to read the abstract). In that study, investigators in Europe compared treatment with R-CHOP followed by autologous stem cell transplantation to treatment with alternating R-CHOP and R-DHAP followed by transplantation using a slightly different transplant regimen. They found that the alternating R-CHOP/R-DHAP regimen resulted in longer remissions than standard R-CHOP, although the different transplant regimens make these results a little more difficult to interpret. Based on these results, for patients that are planning to receive autologous stem cell transplant consolidation, the R-CHOP/R-DHAP regimen appears to be the regimen of choice for the moment. In the absence of phase 3 trials, the role of R-HyperCVAD prior to transplant is somewhat less clear. A randomized phase 2 study comparing R-HyperCVAD to R-bendamustine prior to transplantation is being developed by the national cooperative groups and will hopefully shed important light into the question.
In addition to the choice of front-line therapy, the investigators at Fred Hutchison also looked at whether a period of observation prior to initiation of treatment had any impact on outcome.
In 2009, my colleagues and I at Weill Cornell Medical College published data from our experience suggesting that up to one-third of patients with mantle cell lymphoma did not require urgent therapy at the time of diagnosis. On occasion, patients could be observed for several years with no apparent detriment to their overall outcome. Click here to read the abstract.
Subsequently a second group of researchers reported similar findings (click here to read).
Very few of our patients, however, underwent stem cell transplantation as consolidation following first-line therapy, making the data from Seattle particularly interesting. There, investigators also found that a period of observation of at least three months had no apparent negative effect on the outcome of their patients. Again, neither study was a randomized comparison of observation vs. early treatment (and it is not likely that such a trial will take place). Therefore, based on available data, it seems reasonable that deferred initial therapy in selected patients with mantle cell lymphoma is an acceptable management approach.