Assessment Of Molecular Response And Minimal Residual Disease

In contrast to studies of functional imaging, the use of molecular response as an endpoint has been addressed mostly in the context of FLs. Standard clinical and pathologic techniques including routine light microscopy and immunohistochemistry are capable of detecting tumor cells to the level of approximately 1 in 100 normal cells. Lower levels of disease, detected by molecular techniques, are designated as minimal residual disease (MRD). Molecular techniques can detect tumor cells to the level of 1 in

1,000,000 normal cells. Clearing of disease at the molecular level is termed molecular remission (MR). The relationship between MR and clinical outcome is unclear at present, and MR is therefore being incorporated into study endpoints in many clinical trials in FL.

Two targets for monitoring of MRD have been evaluated in FL. The t(14;18) (q32:q21) translocation is detectable in most cases of FL. It can be detected by fluorescence in situ hybridization (FISH) techniques, or by polymerase chain reaction (PCR). In the uncommon case of FL without a detectable t(14;18), the IgH gene rearrangement unique to the malignant clone, also detectable by PCR, has been used for MRD detection. Most studies exploring the role of MRD have assessed this either in peripheral blood, bone marrow, or both.

There is increasing evidence that treatment regimens which result in molecular remissions in FL are associated with prolonged clinical remissions. In a study from MD Anderson Cancer Center, 194 patients with low-grade follicular NHL and a detectable bcl-2 gene rearrangement were treated with one of three chemotherapy regimens.8 Most patients also received interferon a as maintenance therapy. Although a correlation was observed between molecular and clinical CR rates, one-third of patients achieving clinical CRs were not in MR at the completion of therapy and one-third of patients in PR after 3-5 months eventually achieved MR. Patients achieving MR during the first year following treatment had significantly longer failure-free survival rates than those not in MR (4 year failure-free survival = 76% vs 38%; p < 0.001). MR was independently predictive of outcome in multivariate analysis and was also predictive within the group of patients in clinical CR. In this study, there was a concordance rate of approximately 70% between results in the peripheral blood and bone marrow, indicating that the tissue used for evaluation of MRD is an important variable. This study demonstrated that conventional dose chemotherapy regimens produce a significance MR rate in FL, a fact which has subsequently been confirmed in many other studies, especially those in which rituximab has been used as a component of first-line therapy in combination with chemotherapy.9-11 This study also demonstrated that the achievement of both clinical CR and MR improved with time over the first 20 months of follow-up from completion of therapy, indicating that the timing of response assessment may influence the correlation between these parameters and outcome. Additionally, despite the strong correlation between achievement of MR and failure-free survival, most patients eventually progressed, indicating that MR does not equate with cure.

Several studies have now demonstrated a similar relationship between the attainment of MR and prolonged failure-free survival, and have also confirmed that the re-emergence of PCR detectable disease (or an increase in the level using quantitative PCR techniques) is correlated with subsequent clinical relapse.12-14

The use of MR has also been investigated in the context of patients with FL undergoing high-dose therapy and ASCT. Most of these studies have demonstrated a correlation between PCR negativity in the blood and bone marrow and subsequent disease-free survival after ASCT.12-14 Freedman et al. reported experience in 153 patients undergoing high-dose therapy and ASCT for relapsed FL.12 All of these patients were treated with cyclophosphamide and total body irradiation (TBI), and all had in vitro manipulation of the stem cell product with monoclonal antibodies prior to reinfusion. In this series, continued PCR negativity in the peripheral blood and marrow after ASCT correlated with continued clinical CR, an observation made in several other smaller post ASCT studies.

In summary, there are accumulating data which suggest that the achievement of MR in FL is a meaningful endpoint which correlates with clinical outcome. At present, molecular endpoints have not been incorporated into the IWC, although this is likely to change. In the meantime, the use of molecular endpoints in FL trials is essential to obtain further information on the predictive value of molecular response.

Despite encouraging data, there are several limitations to the use of molecular endpoints. The bcl-2 rearrangement can be detected in the blood of 5-10% of normal individuals (although using quantitative techniques, it is usually present at much lower levels than in the FL population).1516 Optimal timing for the evaluation of MR is uncertain at the moment, since PCR-detectable disease can continue to diminish and eventually disappear several months after completion of therapy.817 Monoclonal antibodies such as ritux-imab have been shown to clear PCR-detectable disease from the blood and bone marrow more effectively than from lymph nodes, indicating that the specific therapy and the site of evaluation for MRD can both influence the molecular response.1819

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