Noninvasive phosphorus magnetic resonance spectroscopic imaging predicts outcome to first-line chemotherapy in newly diagnosed patients with diffuse large B-cell lymphoma

Abstract

Rationale and objectives: Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy.

Experimental design: The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine.

Results: On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001).

Conclusions: The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

Keywords: In vivo; MR spectroscopy; lymphoma; metabolic imaging; prediction of therapy outcome.

Figure 1. Example of the noninvasive 3D-localized ³¹P MRS exam from a target tumor mass of a DLBCL patient

Top, T₁-weighted Spin-Echo MR images acquired in the three orthogonal orientations from the right inguinal area of a newly diagnosed DLBCL patient are shown. In the images a tumor mass of approximately 32–35 millimeters in each diameter is shown (white arrows). Each image is overlaid with a grid representing the projection of the 3-dimensional acquisition matrix of voxels where ³¹P spectral signals were localized. Shaded in grey are the 2D projections of a voxel that was included in the tumor mass. Bottom, The ³¹P spectrum of the voxel highlighted in the images is shown with corresponding peak assignments (PE, phosphoethanolamine; PC, phosphocreatine; Pi, inorganic phosphate; PDE, the phosphodiester region; PCr, location of the phosphocreatine signal [not present in the tumor spectrum but prominent in the spectra of surrounding muscle; and NTP, the α, β, and γ phosphates of nucleoside triphosphates). The sum of the phosphomonoester (PME) signals phosphoethanolamine (PE) and phosphocholine (PC) and the triplet of the Pβ of NTP (highlighted in red in the spectrum) were integrated to obtain the tumor PME/NTP value.

FIGURE 2. Kaplan-Meier curves modeling the Time to Treatment Failure (TTF) of DLBCL patients segregated by the pretreatment PME/NTP tumor value obtained noninvasively by ³¹P MR spectroscopy

Survival curves of the DLBCL patients set apart by the PME/NTP cutoff that maximized the comparative relative risk to fail treatment (cutoff at 2.2). The blue survival curve belongs to the group below the cutoff while the green survival curve belongs to the group above it with circles corresponding to censor points in both curves. The statistical difference of the survival function curves determined by the Tarone-Ware was highly significant (p < 0.00001) with a comparative relative risk to fail treatment of 8.66.