Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI

Aim: To demonstrate quantitative assessment of tumor response to treatment in patients with follicular lymphoma using parallel monitoring of minimal residual disease (MRD) and diffusion-weighted MRI (MRI-DWI) derived apparent diffusion coefficient (ADC). Materials and Methods: Two patients with foll...

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Datum:2015
Hauptverfasser: Meleshko, A.N., Kharuzhyk, S.A., Piatrouskaya, N.A.
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Veröffentlicht: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2015
Schriftenreihe:Experimental Oncology
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Zitieren:Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI / A.N. Meleshko, S.A. Kharuzhyk, N.A. Piatrouskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 295-297. — Бібліогр.: 17 назв. — англ.

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spelling irk-123456789-1455602019-01-24T01:23:20Z Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI Meleshko, A.N. Kharuzhyk, S.A. Piatrouskaya, N.A. Case report Aim: To demonstrate quantitative assessment of tumor response to treatment in patients with follicular lymphoma using parallel monitoring of minimal residual disease (MRD) and diffusion-weighted MRI (MRI-DWI) derived apparent diffusion coefficient (ADC). Materials and Methods: Two patients with follicular lymphoma were undergone synchronous evaluation of MRD and MRI-DWI at definite time points before, during and after chemotherapy. MRD level was calculated in diagnostic and follow up samples relative to the highest level of amplification of the target. Allele-specific primer for clonal IgH gene rearrangement was used as a target for real-time quantitative polymerase chain reaction (PCR). 1.5 Tesla scanner was used for MRI-DWI. The largest non necrotic lymph node was chosen for serial ADC measurement. Results: In first patient MRD reduced drastically in blood after chemotherapy but persisted at low level in bone marrow. Whole body MRI-DWI demonstrated regression of most of tumor lesions except one ­marginally enlarged iliac lymph node and allowed to predict tumor progression in this particular anatomical site based on low ADC value after treatment. In the second patient all three methods (MRD, ADC and radiologic evaluation) gave concordant result of complete tumor response and patient remained in a clinical remission during follow-up time. Conclusion: Quantitative PCR measurement may detect very low level of MRD in patients with follicular lymphoma which may have prognostic value. Combination of both PCR-based MRD and quantitative evaluation of MRI-DWI derived ADC provides safe added-value disease monitoring in lymphoma. Key Words: follicular lymphoma, minimal residual disease, diffusion-weighed MRI, apparent diffusion coefficient, response monitoring. 2015 Article Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI / A.N. Meleshko, S.A. Kharuzhyk, N.A. Piatrouskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 295-297. — Бібліогр.: 17 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145560 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Case report
Case report
spellingShingle Case report
Case report
Meleshko, A.N.
Kharuzhyk, S.A.
Piatrouskaya, N.A.
Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
Experimental Oncology
description Aim: To demonstrate quantitative assessment of tumor response to treatment in patients with follicular lymphoma using parallel monitoring of minimal residual disease (MRD) and diffusion-weighted MRI (MRI-DWI) derived apparent diffusion coefficient (ADC). Materials and Methods: Two patients with follicular lymphoma were undergone synchronous evaluation of MRD and MRI-DWI at definite time points before, during and after chemotherapy. MRD level was calculated in diagnostic and follow up samples relative to the highest level of amplification of the target. Allele-specific primer for clonal IgH gene rearrangement was used as a target for real-time quantitative polymerase chain reaction (PCR). 1.5 Tesla scanner was used for MRI-DWI. The largest non necrotic lymph node was chosen for serial ADC measurement. Results: In first patient MRD reduced drastically in blood after chemotherapy but persisted at low level in bone marrow. Whole body MRI-DWI demonstrated regression of most of tumor lesions except one ­marginally enlarged iliac lymph node and allowed to predict tumor progression in this particular anatomical site based on low ADC value after treatment. In the second patient all three methods (MRD, ADC and radiologic evaluation) gave concordant result of complete tumor response and patient remained in a clinical remission during follow-up time. Conclusion: Quantitative PCR measurement may detect very low level of MRD in patients with follicular lymphoma which may have prognostic value. Combination of both PCR-based MRD and quantitative evaluation of MRI-DWI derived ADC provides safe added-value disease monitoring in lymphoma. Key Words: follicular lymphoma, minimal residual disease, diffusion-weighed MRI, apparent diffusion coefficient, response monitoring.
format Article
author Meleshko, A.N.
Kharuzhyk, S.A.
Piatrouskaya, N.A.
author_facet Meleshko, A.N.
Kharuzhyk, S.A.
Piatrouskaya, N.A.
author_sort Meleshko, A.N.
title Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
title_short Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
title_full Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
title_fullStr Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
title_full_unstemmed Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI
title_sort response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted mri
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
publishDate 2015
topic_facet Case report
url http://dspace.nbuv.gov.ua/handle/123456789/145560
citation_txt Response monitoring in follicular lymphoma by synchronous evaluation of minimal residual disease and diffusion-weighted MRI / A.N. Meleshko, S.A. Kharuzhyk, N.A. Piatrouskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 295-297. — Бібліогр.: 17 назв. — англ.
series Experimental Oncology
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AT piatrouskayana responsemonitoringinfollicularlymphomabysynchronousevaluationofminimalresidualdiseaseanddiffusionweightedmri
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fulltext Experimental Oncology 37, 295–297, 2015 (December) 295 RESPONSE MONITORING IN FOLLICULAR LYMPHOMA BY SYNCHRONOUS EVALUATION OF MINIMAL RESIDUAL DISEASE AND DIFFUSION-WEIGHTED MRI A.N. Meleshko1, S.A. Kharuzhyk2, N.A. Piatrouskaya2,* 1Center for Pediatric Oncology, Hematology and Immunology, Minsk 223053, Belarus 2N.N. Alexandrov National Cancer Center of Belarus, Minsk 223040, Belarus Aim: To demonstrate quantitative assessment of tumor response to treatment in patients with follicular lymphoma using parallel monitoring of minimal residual disease (MRD) and diffusion-weighted MRI (MRI-DWI) derived apparent diffusion coefficient (ADC). Materials and Methods: Two patients with follicular lymphoma were undergone synchronous evaluation of MRD and MRI-DWI at definite time points before, during and after chemotherapy. MRD level was calculated in diagnostic and follow up samples relative to the highest level of amplification of the target. Allele-specific primer for clonal IgH gene rearrangement was used as a target for real-time quantitative polymerase chain reaction (PCR). 1.5 Tesla scanner was used for MRI-DWI. The largest non necrotic lymph node was chosen for serial ADC measurement. Results: In first patient MRD reduced drastically in blood after chemotherapy but persisted at low level in bone marrow. Whole body MRI-DWI demonstrated regression of most of tumor lesions except one marginally enlarged iliac lymph node and allowed to predict tumor progression in this particular anatomical site based on low ADC value after treatment. In the second patient all three methods (MRD, ADC and radiologic evaluation) gave concordant result of complete tumor response and patient remained in a clinical remission during follow-up time. Conclusion: Quantitative PCR measurement may detect very low level of MRD in patients with follicular lymphoma which may have prognostic value. Combination of both PCR-based MRD and quantitative evaluation of MRI-DWI derived ADC provides safe added-value disease monitoring in lymphoma. Key Words: follicular lymphoma, minimal residual disease, diffusion-weighed MRI, apparent diffusion coefficient, response monitoring. Achievements in the field of non-Hodgkin lym- phomas (NHL) molecular biology lead to progressive development of treatment personalization. At the same time they provide an option for accurate response monitoring and prognostication. A range of laboratory molecular techniques are available in lymphoma [1]. Evaluation of minimal residual disease (MRD) is used as supporting and additional data which help in re- sponse assessment fulfilled by conventional clinical and diagnostic imaging methods [2]. MRD is defined as any approach aimed at detecting and possibly quan- tifying residual tumor cells beyond the sensiti vity level of routine imaging and laboratory techniques [3]. MRD has established role in leukaemias where it is used to detect persistent leukaemic cells in bone marrow or blood. High sensitivity of the test allows detecting leukaemic cells at level down to one cell per million. It was shown that MRD level after chemotherapy for acute lymphoblastic leukaemia is closely related to the probability of relapse [4]. To lesser extent MRD was studded in patients with indolent NHL, primarily fol- licular and mantle cell lymphomas [5–7]. Computed tomography (CT) or 18F-fluorodeoxy- glucose-PET are standard methods for diagnostics, response evaluation and follow-up of patients with NHL. Before, during and after treatment numerous CT and FDG-PET exams are performed that leads to accumulation of ionizing radiation dose and increasing risk of secondary malignancy development, especially in children and young patients [8, 9]. MRI with diffu- sion-weighed imaging (MRI-DWI) is a radiation-free and highly sensitive method for detection of nodal and extranodal lesions in lymphoma [10, 11]. DWI is a MRI pulse sequence specially designed to detect microscopic water molecules movement in tissues and fluids in vivo. In solid tumors water diffusion takes place mainly in the intercellular spaces. In lymphomas diffusion in restricted because of increased cellular density and high nuclear to cytoplasm ratio allowing to characterize tumor at the cellular level. Because of high safety profile MRI-DWI may be repeated during and after treatment as many times as needed for treat- ment monitoring and follow-up. Another advantage of DWI compared to other MRI pulse sequences is a quantitative evaluation using apparent diffusion coefficient (ADC). Solid malignant tumors including lymphomas are characterized by low ADC, generally below 1–1.2•10–3 mm2/s [12, 13]. During effective cy- totoxic treatment ADC increases because of cell death mechanisms such as apoptosis and necrosis [14]. Due to quantitative nature MRD and MRI-DWI might be used in parallel to monitor tumor response in NHL. MATERIALS AND METHODS In frame of clinical projects “Idiotype DNA vaccines for B-cell NHL” and “MRI-DWI diagnostics in patients with lymphomas” synchronous evaluation of MRD and MRI-DWI derived ADC was performed in 2 patients with Submitted: December 01, 2015. *Correspondence: E-mail: savitri@tut.by Abbreviations used: ADC — apparent diffusion coefficient; CT — computed tomography; DWI — diffusion-weighted imaging; FDG — fluorodeoxyglucose; MRI — magnetic resonance imaging; MRD — minimal residual disease; NHL — non-Hodgkin lymphoma; PET — positron emission tomography; RQ-PCR — real-time quanti- tative polymerase chain reaction. Exp Oncol 2015 37, 4, 295–297 CASE REPORTS 296 Experimental Oncology 37, 295–297, 2015 (December) follicular lymphoma at the definite time points before, during and after treatment. Patients got standard diagnostic imaging tests for tumor staging, response evaluation and follow-up according to current practice in our institution. MRD detection was performed as previously de- scribed [15]. DNA from primary removed neck lymph node was used for target identification and standard curve construction. Allele-specific primer for clonal IgH gene rearrangement was used as a target for real- time quantitative polymerase chain reaction (RQ-PCR) measurement [16]. MRD level was calculated in diag- nostic and follow up samples relative to the highest level of amplification of the target. 1.5 Tesla scanner was used for MRI-DWI. Scanning technique was previously described [11]. Staging and treatment response assessment was based on whole body MRI-DWI. For serial ADC measurement the largest non necrotic lymph node (target lesion) was chosen on staging MRI-DWI. Lymph node was con- toured on three diffusion-weighted images with largest tumor dimensions using scanner software. Contours were automatically transferred to corresponding ADC maps. Mean signal intensity on ADC map corresponds to tumor ADC value. ADC values on three slices were averaged in order to get a lesion ADC. RESULTS AND DISCUSSION A 28-year-old woman (patient 1) was diagnosed with follicular B-cell NHL involving axillary, me- diastinal, mesenteric, paraaortic, iliac lymph nodes and bone marrow, Ann Arbor stage IV (Figure). Im- munohistochemistry: CD20+++, CD5−, CD3−, cyclin D1−, CD21−, CD23−, Ki-67 up to 20%. A patient was undergone to eight courses of chemotherapy FC (fludarabine, cyclophosphamide). Before and after first, before and after second, before third course and after chemotherapy (8 courses) synchronous quan- titative evaluation of MRD and ADC was performed (Table 1). During chemotherapy PCR-based MRD reduced drastically in blood but persisted at low level in bone marrow. Paraaortic lymph node measuring 6.2×4.2 cm was chosen for serial ADC evaluation. ADC value of target lesion increased gradually from 0.51 to 1.59•10–3 mm2/s corresponding to size nor- malization of most lymph nodes at restaging except right iliac one. ADC value of this lymph node was still low at the end of treatment (0.95•10–3 mm2/s) showing chemotherapy resistance. Tumor progression deve- loped in this region one month later. a b Figure. Whole body DWI of patient 1 with follicular lymphoma before treatment (a) and after 8 courses of chemotherapy (b). Inverted gray scale maximum intensity projection images are presented. Axillary, mediastinal, mesenteric, paraaortic and iliac lymph nodes were initially involved (a). After chemotherapy all lesions regressed except right iliac lymph node (arrow on b). Physiologic diffusion restriction in the brain, spinal cord, spleen, ovaries and endometrium is noted Table 1. Serial MRD, ADC and radiological evaluation in patient 1 with follicular NHL Time point MRD ADC, ×10–3 mm2/s Radiologic evaluation 1 month before treatment Tissue of lymph node 85.85% Peripheral blood 2.52% − − Staging immediately before treatment Peripheral blood 15% Bone marrow 100% Paraaortic lymph node 0.51 Right iliac lymph node 0.59 Whole body MRI-DWI: lesions of left axillary, mediastinal, mesenteric, paraaortic, iliac lymph nodes and bone marrow Immediately after FC 1 − Paraaortic lymph node 0.75 − Immediately before FC 2 Peripheral blood 0.002% Paraaortic lymph node 0.96 − Immediately after FC 2 Peripheral blood 0.008% Paraaortic lymph node 1.15 − Immediately before FC 3 Peripheral blood 0% Paraaortic lymph node 1.19 − Restaging after 8 courses of che- motherapy (partial response) Peripheral blood 0% Bone marrow 0.002% Paraaortic lymph node 1.59 Right iliac lymph node 0.95 Whole body MRI-DWI: upper diaphragm all lesions regressed, lower diaphragm — right iliac lymph nodes up to 1.3 cm Follow-up 2 months after treatment (progression) Peripheral blood 0.002% − Ultrasound: right iliac lymph node enlarged to 2.5×1.6 cm 4 months follow-up (further pro- gression) Peripheral blood 0.009% − CT scan: right iliac lymph node enlarged to 4.9×4.5 cm, all other lymph nodes are normal in size Table 2. Serial MRD, ADC and radiological evaluation in patient 2 with follicular NHL Time point MRD ADC, ×10–3 mm2/s Radiologic evaluation Staging before treatment Tissue of lymph node 100% Peripheral blood 75,67% Left iliac lymph node 0.54 Whole body MRI-DWI: lesions of cervical, supracla- vicular, infraclavicular, axillary, mediastinal, mesen- teric, paraaortic, iliac, inguinal lymph nodes, spleen and bone marrow Restaging after 8 courses of chemotherapy (complete response) Peripheral blood 0% Left iliac lymph node 1.53 Whole body MRI-DWI: all lesions regressed Follow-up 5 months after treatment (remission) Peripheral blood 0% − Abdominal and pelvic MRI-DWI: no lesions detected Experimental Oncology 37, 295–297, 2015 (December) 297 A patient 2 is a 43-year-old woman diagnosed with follicular B-cell NHL involving cervical, supraclavicular, infraclavicular, axillary, mediastinal, mesenteric, para- aortic, iliac, inguinal lymph nodes, spleen and bone marrow, Ann Arbor stage IV. Immunohistochemistry: CD20+++, bcl6+++, CD10+++, bcl2++, CD21−/+, cyclin D1−, CD5−, CD3−, Ki-67 more than 40%. A patient was un- dergone to eight courses of chemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincris- tine, prednisolon). Before and after chemotherapy (8 courses) synchronous quantitative evaluation of MRD and ADC was performed (Table 2). Left iliac lymph node was chosen as a target for ADC measurement. After end of chemotherapy MRD was not detectable in the blood any more, target lesion ADC increased to the level above 1.5•10–3 mm2/s and radiological evaluation showed complete response of all tumors. Patient remains in re- mission during 6 months of follow-up. In this report we present clinical cases of two pa- tients with follicular NHL treated with chemotherapy with serial MRD and MRI-DWI examination. Results of MRD, ADC and radiological evaluation at different time points before, during and after treatment are presented. In patient 1 whole body MRI-DWI after eight courses of chemotherapy demonstrated regres- sion of most of tumor lesions. Only iliac lymph node remained marginally enlarged measuring 1.3 cm. Such small lymph nodes might be difficult to detect and even more difficult to characterize by conventional imaging techniques such as CT, ultrasonography or MRI. DWI with ADC calculation is a functional imaging technique which allowed to predict tumor progression in this par- ticular anatomical site based on low ADC value after treatment. In the patient 2 all three methods (MRD, ADC and radiologic evaluation) gave concordant result of complete tumor response and patient remained in a clinical remission during follow-up time. In the published literature MRD was used in patients with indolent lymphomas for molecular monitoring of treatment response and as a surrogate marker for prognosis. In follicular lymphoma negative PCR-based MRD status after rituximab treatment predicted higher freedom from recurrence rate — 57% compared with 20% in patients with molecular positivity [6]. In ad- vance stage follicular lymphoma patients achieved an adequate remission with induction therapy PCR detectable disease in the bone marrow before au- tologous stem cell transplantation was the strongest predictor of decreased progression-free survival [17]. To best of our knowledge our report is the first one correlating MRD with relatively new quantitative func- tional imaging technique — diffusion-weighted MRI with ADC calculation. In conclusion, quantitative PCR measurement may detect very low level of MRD in patients with follicular lymphoma which may have prognostic value. Combi- nation of both PCR-based MRD and quantitative evalu- ation of MRI-DWI derived ADC provides added-value disease monitoring in lymphoma. REFERENCES 1. Spagnolo DV, Ellis DW, Juneja S, et al. 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Brown JR, Feng Y, Gribben JG, et al. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. Biol Blood Marrow Transplant 2007; 13: 1057–65. Copyright © Experimental Oncology, 2015