Malik E. Juweid

Revised Response Criteria for Malignant Lymphoma

PURPOSE Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. METHODS The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. RESULTS New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkins and Hodgkins lymphoma. Standardized definitions of end points are provided. CONCLUSION We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

Use of Positron Emission Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma

PURPOSE To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Response Assessment of Aggressive Non-Hodgkin’s Lymphoma by Integrated International Workshop Criteria and Fluorine-18–Fluorodeoxyglucose Positron Emission Tomography

PURPOSE To determine whether a response classification based on integration of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. RESULTS By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. CONCLUSION Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

Role of Positron Emission Tomography in Lymphoma

Positron emission tomography (PET) scanning, particularly using [F]fluorodeoxyglucose (FDG), has recently emerged as a powerful functional imaging tool for assessment of patients with Hodgkin’s disease and nonHodgkin’s lymphoma (NHL). Numerous investigations have been reported on its use for staging, restaging, and monitoring tumor response of lymphoma, with only a few exploring its value in predicting the tumor’s malignancy grade. In this issue of the Journal of Clinical Oncology, Schoder et al seek to determine whether the intensity of FDG uptake measured using the standardized uptake value (SUV) could differentiate between indolent and aggressive NHL. The SUV is a semiquantitative measure of the degree of FDG uptake, which may be conceptualized as the ratio between the tumoral concentration of tracer and its concentration in the entire body if the tracer were evenly distributed throughout. Because of its simplicity, this parameter is widely utilized both in the research setting and in clinical practice. In their study of 97 patients with NHL, Schoder et al concluded that the SUV is lower in indolent than in aggressive NHL, that patients with an SUV 10 have a high likelihood of aggressive NHL, and that this information may be helpful if there is discordance between biopsy and clinical behavior. These findings clearly have implications in treatment planning and prognosis. While the study by Schoder et al is the largest to date to attempt to distinguish between indolent and aggressive NHLs based on the SUV, the findings are not very different from those of previously reported smaller studies. Similar to those previous studies, a considerable overlap in the SUVs was found between indolent and aggressive NHL, with a relatively wide range of SUVs observed even within the same histologic subtype. This variability could have been even greater had the authors determined the SUVs for all well-delineated tumor lesions in each patient rather than only for the most intense lesion because of the known intrapatient variability in SUV in patients with NHL and other cancer types. Despite this overlap, two conclusions may be drawn reasonably from the data. First, an SUV 13 in the most intense lesion indicates a high likelihood of aggressive histology, while an SUV of 6 is very likely associated with indolent histology. Second, these upper and lower cutoff SUVs provide relatively high accuracy in grading NHL in only approximately 55% of patients, because only approximately 58% of patients with biopsy-proven aggressive histology had an SUV 13, and slightly less than 50% of those with indolent histology had an SUV 6. Consequently, approximately 45% of patients remain in a gray zone between the SUVs of 6 and 13, where the overlap is so pronounced that it practically precludes a justifiable degree of confidence in grading NHL. The adverse effect of this overlap becomes apparent when examining the results of the receiver operating characteristic (ROC) analysis used to determine optimum cutoff SUV that distinguishes indolent from aggressive histologies: this optimum cutoff SUV of 10, although associated with a fair balance of sensitivity and specificity, resulted in a 29% misclassification rate for aggressive NHL and a 19% misclassification rate for indolent NHL. The latter may result in overtreatment of a significant fraction of patients with indolent lymphoma. Conversely, misclassification of almost one third of patients with aggressive lymphoma may result in their undertreatment, which cannot be justified considering the potentially curable nature of their disease. The moderate sensitivity and specificity of the cutoff SUV of 10 needs to be further evaluated in light of the fact that this value was derived post hoc, potentially resulting in an overestimation of its diagnostic accuracy. However, the findings in the 22 patients in whom the biopsy was taken from a site other than that with the most intense FDG uptake could serve as an initial test for the performance of this cutoff in an independent, albeit small, cohort of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 21 JULY 2

Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study

Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

Phase I/II trial of 131I‐MN‐14 F(ab)2 anti–carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma

Monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA) have been recognized as targeting agents for medullary thyroid carcinoma (MTC). This Phase I/II study was initiated to determine the safety, maximum tolerated dose (MTD), and therapeutic potential of 131I‐MN‐14 F(ab)2 anti‐CEA MAb for patients with metastatic MTC.

Improvement of Early 18F-FDG PET Interpretation in Diffuse Large B-Cell Lymphoma: Importance of the Reference Background

This study investigated whether the reference background above which a residual mass is considered positive in the International Harmonization Project criteria should be modified for early 18F-FDG PET evaluation. Methods: In 92 patients with newly diagnosed diffuse large B-cell lymphoma, the maximal standardized uptake value (SUVmax) was measured on post–cycle 2 PET in the most intense residual mass (or, in the case of negative PET findings, in the area of most intense tumor uptake before therapy), in the mediastinal blood pool (MBP) and the liver, as potential reference background tissues. Results: With MBP as a reference (SUVmax, 2.0 ± 0.6), PET was unable to distinguish early responders from nonresponders. In contrast, with liver as a reference (SUVmax, 2.5 ± 0.7), 2-y progression-free survival was significantly different between patients with PET-negative findings (81.8% [95% confidence interval, 71%–93%]) and patients with PET-positive findings (51.8% [95% confidence interval, 35%–69%], P = 0.003). Conclusion: When assessing early response, particularly in risk-adapted therapeutic trials, it seems preferable to refer to a background tissue (liver) with a higher level of uptake than that of current international criteria (MBP) which were designed for end-of-treatment evaluation.

Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22

Abstract LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell, non-Hodgkin’s lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method (dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab′)2, Fab′], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels (i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively. Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy.

First Demonstration of Leukemia Imaging with the Proliferation Marker 18F-Fluorodeoxythymidine

Acute myeloid leukemia (AML) is a neoplasm of hematopoietic stem cells with partial or complete loss of the ability to differentiate but with preserved proliferation capacity. The aim of our study was to evaluate if the in vivo proliferation marker 3′-deoxy-3′-18F-fluorothymidine (FLT) is suitable for visualizing leukemia manifestation sites and if 18F-FLT is a surrogate marker for disease activity. Methods: In this pilot study, 10 patients with AML underwent pretherapeutic imaging with 18F-FLT PET or 18F-FLT PET/CT. The biodistribution of 18F-FLT was assessed 60 min after intravenous injection of the radiotracer. Standardized uptake values were calculated for reference segments of bone marrow, spleen, and normal organs. 18F-FLT PET in 10 patients with benign pulmonary nodules and the absence of malignant or inflammatory disease served as controls. Results: Retention of 18F-FLT was observed predominantly in bone marrow and spleen and was significantly higher in AML patients than in controls (mean 18F-FLT SUV in bone marrow, 11.5 and 6.6, P < 0.05; mean 18F-FLT SUV in spleen, 6.1 and 1.8, P < 0.05). Outside bone marrow, focal 18F-FLT uptake showed extramedullary manifestation sites of leukemia in 4 patients (meningeal disease, pericardial, abdominal, testicular, and lymph node), proven by other diagnostic procedures. Conclusion: This pilot study indicated that PET using 18F-FLT is able to visualize extramedullary manifestation sites of AML and reflects disease activity. Because 18F-FLT uptake in bone marrow is caused by a combination of both neoplastic and normal hematopoietic cells, the correlation of 18F-FLT uptake in bone marrow and leukemic blast infiltration did not reach statistical significance.

Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen.

PURPOSE This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). PATIENTS AND METHODS Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions. RESULTS The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three. CONCLUSION Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.