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1
Department of Radiology and Medical Imaging, UCL 10/2942, Saint Luc University
Hospital, Université Catholique de Louvain,
Hippocrate Ave., 10, B1200 Brussels, Belgium
2
Department of Hematology, Saint Luc University Hospital,
Université Catholique de Louvain, Brussels,
Belgium.
Received May 30, 2000;
accepted after revision June 30, 2000.
Supported by Fonds National de la Recherche Scientifique-Televie (Brussels,
Belgium), grant
FNRS-Télévie
No7.4555.95; and by Association
Européenne pour l'Enseignement et la Recherche
en Radiologie (Bordeaux, France).
Abstract
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SUBJECTS AND METHODS. MR images (T1-weighted images before and after injection of gadolinium and T2*-weighted images) of the spine and pelvis were obtained 1 month before and 1 month after marrow transplantation in 25 consecutive patients with stage III myeloma. Pre- and posttreatment MR imaging patterns of marrow involvement (normal, focal, diffuse), number of focal lesions, and a "marrow evolution index" (0-8 on the basis of comparison of the lesions [number, size, contrast enhancement] and of the surrounding marrow background on pre- and posttreatment MR images) were determined. Hematologic and MR imaging parameters were correlated with the quality of response to treatment (complete versus partial remission) and with relapse-free and overall survival.
RESULTS. Response quality did not differ among categories of patients determined on the basis of MR images. Individual MR imaging parameters did not correlate with response duration and survival. Patients with a low marrow evolution index had significantly longer relapse-free (p < 10-3) and overall survival (p = 0.005) than patients with a high index.
CONCLUSION. Individual MR imaging parameters before and after treatment had no prognostic significance in our series of myeloma patients treated with marrow transplantation. Comparison of MR images before and after treatment using a marrow evolution index may help predict response duration and survival.
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We undertook this prospective study in a homogeneous series of myeloma patients treated with high-dose cytotoxic chemotherapy and bone marrow transplantation to assess the prognostic value of MR imaging of the bone marrow before and after treatment.
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Five patients received allogenic human leukocyte antigen—identical
sibling transplants, and 20 patients received an autologous peripheral blood
stem cell transplant. Five patients had primary unresponsive disease, four
patients had resistant relapse, and 16 patients had achieved remission after
the initial treatment. Before the high-dose cytotoxic chemotherapy and bone
marrow transplantation, all patients had undergone at least four to six cycles
of standard first-line chemotherapy: vincristine, doxorubicin, and
dexamethasone. The bone marrow transplantation conditioning regimens consisted
of the IV administration of high-dose melphalan (140 mg/m2) in all
patients, with total body irradiation in 18 patients. Maintenance therapy of
interferon-
was started after hematologic reconstitution in 12
patients.
Assessment of Response to Treatment and Patient Follow-Up
Response to therapy was determined using the criteria of the Eastern
Cooperative Oncology Group
[13]. Partial response was
defined as a 50% or more decrease of the monoclonal protein in serum or urine
or more than 50% reduction of bone marrow infiltration (in non-secretory
myeloma). Complete response was defined as no monoclonal protein measurable in
serum, 10 times concentrated urine by immunofixation analysis, and less than
5% plasma cells with no abnormal morphology in bone marrow smears. These
plasma cells had to be polyclonal on immunofluorescence staining.
According to these criteria, 14 patients achieved a complete remission and 11 achieved a partial remission. After transplantation, patients were followed up monthly at our hematology unit. In patients with complete remission, "relapse" was defined on the basis of the reappearance of detectable monoclonal protein, the appearance of other symptoms of myeloma, or the appearance of new lytic lesions or progression of existing lesions on radiographic skeletal surveys. In patients with partial remission, relapse was defined as an increase of more than 25% of the monoclonal peak. The median relapse-free survival was 502 days (range, 77-1379 days). The median overall survival was 879 days (range, 153-2164 days). By the time of this study, 15 patients had relapsed and six had died. All deaths were considered related to the disease.
Bone Marrow MR Imaging
All patients underwent prospective MR imaging studies of the spine and
pelvis at a median of 4 weeks (range, 3-6 weeks) before and 5 weeks (range,
4-8 weeks) after marrow transplantation. MR imaging was performed on a 0.5-T
unit (Gyroscan NT; Philips Medical Systems, Best, The Netherlands).
T1-weighted spin-echo MR images were obtained of both the cervicothoracic and lumbosacral spine in the sagittal plane using a dedicated phased array coil in the receive-only mode (TR/TE, 400/20; 384 x 512 matrix; four signals acquired; 5-mm-thick sections; 0.5-mm interslice gap; and 400-mm field of view). T2*-weighted gradient-echo MR images were also obtained (540/27; flip angle, 30°). In the pelvis, T1-weighted spin-echo and T2*-weighted gradient-echo MR images were obtained in the coronal plane using a body coil (192 x 256 matrix; four signals averaged; 6-mm-thick sections; 0.6-mm interslice gap; and 400-mm field of view).
In patients with bone marrow abnormalities, T1-weighted spin-echo MR images of the thoracic and lumbar spine and pelvis were repeated immediately after the IV administration of 0.1 mmol/kg of gadoterate meglumine (Dotarem; Guerbet, Aulnay-sous-Bois, France). Patients with unequivocal normal bone marrow status on MR images did not receive a contrast material injection.
MR Image Analysis
All MR images of the spine and pelvis were reviewed by two radiologists.
The patients were classified into three categories according to the MR imaging
patterns of spinal bone marrow involvement. The three patterns were the normal
pattern, characterized by an intermediate to high marrow signal intensity on
T1-weighted images and a normal intermediate signal intensity on
T2*-weighted images; the focal pattern, characterized by the
presence of nodular lesions of at least 5-mm in diameter and of low signal
intensity on T1-weighted images and high signal intensity on
T2*-weighted images in an otherwise normal-appearing bone marrow;
and the diffuse pattern, characterized on T1-weighted images by a diffuse
lowering of the marrow signal intensity, which becomes identical to or lower
than the signal of the intervertebral disks, and on T2*-weighted
images by diffusely or focally increased signal intensity. In patients with
the focal pattern, the sizes (maximal diameters) of the spinal and pelvic
lesions were measured, and the mean and median of these values were noted.
Enhancement of the lesion signal intensity was assessed after contrast
material injection and was categorized as either diffuse homogeneous, only
peripheral, or absent. The surrounding "background" marrow was
further studied without taking into account the focal lesions and was
qualified as being either normal-appearing or diffusely altered if it showed
high signal intensity or abnormally decreased signal intensity, respectively,
on T1-weighted MR images.
Four MR imaging parameters were evaluated to assess bone marrow changes on MR images before and after marrow transplantation: lesion number, size, contrast enhancement, and appearance of the bone marrow background, independently of focal lesions (Figs. 1A,1B,1C,1D,2A,2B,3A,3B). A score of 0, 1, or 2 was given if the number of focal lesions decreased, remained unchanged, or increased, respectively, on MR studies before and after transplantation. A score of 0, 1, or 2 was given if the mean lesion size decreased, remained stable, or increased, respectively. A score of 0, 1, or 2 was given if the number of lesions showing diffuse contrast enhancement decreased, remained stable, or increased, respectively, compared with the number of lesions showing lack of enhancement or only peripheral rim enhancement. A score of 0, 1, or 2 was given if the marrow background showed evolution from diffuse alteration to normal appearance, remained stable, or showed evolution from normal appearance to diffuse alteration, respectively.
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A "marrow evolution index" ranging from 0 to 8 was determined for each patient after summation of these four values.
Statistical Analysis
The chi-square test was used to compare complete and partial remission
rates among the various subgroups. Relapse-free and overall survival were
estimated using the Kaplan-Meier method. The influence of MR imaging findings
and of hematologic parameters on survival was analyzed using the log-rank
test.
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Correlation with the Quality of Response
After treatment, 14 patients achieved complete remission and 11 patients
achieved partial remission. The proportion of patients presenting either
complete or partial response did not differ according to the pre- and
posttransplantation MR imaging appearances of the bone marrow, number and size
of focal lesions, and changes in marrow appearance on MR images before and
after transplantation (Table
2). No correlation was observed between biologic data (serum
levels of ß2-microglobulin, C-reactive protein, calcium,
hemoglobin, and monoclonal protein) before transplantation and quality of
response.
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Correlation with the Relapse-Free and Overall Survival
Table 3 illustrates
univariate analysis of the prognostic influence of MR imaging and clinical and
therapeutic parameters on response duration and overall survival. Individual
MR imaging parameters before and after treatment had no prognostic value.
Changes in lesion size, number, and contrast enhancement, and changes in the
MR imaging appearance of the marrow background, had no prognostic value.
Patients with a marrow evolution index of less than 4 had a significantly
longer response duration (p < 10-3) and overall
survival (p = 0.005) than did those with an index greater than or
equal to 4 (Figs. 4 and
5).
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Patients with ß2-microglobulin levels less than 3 mg/dL had significantly longer response duration (p = 0.004) and a trend toward a longer survival (p = 0.06) than those with ß2-microglobulin levels greater than or equal to 3 mg/dL (Fig. 6). Achievement of complete remission was also associated with a trend toward longer response duration (p = 0.06).
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The MR imaging appearance of the bone marrow and its prognostic significance have been evaluated in multiple myeloma patients treated with conventional chemotherapy [16,17,18]. Little has been written about the evaluation of bone marrow using MR imaging in the setting of bone marrow transplantation in myeloma patients. Agren et al. [19] obtained MR images of the bone marrow in 20 patients before and after (in 13 cases) bone marrow transplantation, but a large variety in sequences, in contrast material injection, in studied anatomic areas, and in time intervals with respect to the bone marrow transplantation precluded any definitive analysis of the predictive value of MR images in these patients. Our study of the potential prognostic value of bone marrow MR imaging in a homogeneous series of patients undergoing high-dose cytotoxic chemotherapy and bone marrow transplantation has two main results. First, it shows that individual MR imaging parameters before and after treatment do not have significant prognostic value. Second, careful comparison of MR images before and after treatment yielded information relevant to the duration of response and overall survival.
In our study, none of the MR imaging parameters before and after treatment had individual prognostic value. The MR imaging patterns before transplantation did not correlate with survival. Our results also show that residual marrow abnormalities may be observed on MR images after bone marrow transplantation and the administration of high-dose myeloablative chemotherapy, in the same way that they occur after conventional chemotherapy regimens [16, 17, 20]. The clinical relevance of these residual abnormalities after transplantation may be questioned, because patients with these abnormalities did not appear to have a poorer outcome than those with normal posttransplantation MR imaging findings.
The originality of our work relies on careful comparison of precisely scheduled pre- and posttreatment MR imaging studies, with characterization of the evolution of four different MR imaging parameters. Indeed, conversion of a diffuse to a focal or normal MR imaging pattern of marrow involvement, reduction in lesion size and number, absent or only peripheral lesion enhancement on contrast-enhanced MR images have been shown in association with a response to standard chemotherapy [17, 20]. None of these changes on MR images before and after transplantation have prognostic value if isolated. The novel finding is that an index combining the various changes in marrow and lesion appearance on the MR images before and after treatment provides valuable prognostic information. A future step should aim at determining the respective contribution to prognosis of each of the four MR imaging features.
One limitation of our study is that, given the limited number of patients and limited follow-up, multivariate analysis of the prognostic value of clinical, biologic, cytogenetic, and MR imaging findings could not be performed. Whether MR imaging parameters will add original information to the many existing prognostic variables requires further evaluation in an ongoing long-term study. The serum ß2-microglobulin levels before treatment have prognostic significance in our study. This finding to some extent validates our study population because ß2-microglobulin—an excellent indicator of tumor burden and one of the most important prognostic factors in myeloma patients treated with standard therapy—has been repeatedly shown to be a strong independent prognostic factor for relapse-free and overall survival after bone marrow transplantation [9, 21, 22].
The choice of T2*-weighted gradient-echo MR imaging must be discussed. The sensitivity of this sequence for myeloma lesion detection has been repeatedly emphasized, especially on medium-field-strength MR imaging scanners [18, 23, 24]. At higher field strengths, focal field inhomogeneities caused by trabecular bone will lead to signal intensity loss, and other sequences might be recommended, such as fat-suppressed T2-weighted spin-echo and short inversion time inversion recovery MR images [25].
In conclusion, this study shows that individual MR imaging parameters before or after treatment do not have prognostic value in patients treated with high-dose cytotoxic chemotherapy and marrow transplantation. Residual marrow abnormalities may be observed on MR images after treatment, and these abnormalities do not negatively affect survival. Determining and comparing the four parameters on MR images before and after treatment provide a simple index that can help predict response duration and survival. Conversely, this noninvasive approach could help recognize patients at a high risk for early relapse.
Acknowledgments
We thank Francoise Martin and Martine Milecan for secretarial assistance,
Ben Dehon for artwork, and Patrick Schmitz for his incomparable technical
skills.
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4).
