Development of a novel Indium-111 radiolabeled mogamulizumab targeting CCR4 for imaging adult T-cell leukemia/lymphoma in vivo.

OBJECTIVE: Adult T-cell leukemia/lymphoma (ATL), caused by human T-cell lymphotropic virus type I (HTLV-1) infection, is among the most aggressive categories and has the worst prognosis among T-cell lymphomas. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR 4), has been shown to be effective in the treatment of ATL; however, some ATL cases are often resistant, particularly the lymphoma-type ATL. To evaluate drug delivery in vivo and identify the distribution of CCR4-positive cells in the body, we developed a novel mogamulizumab tracer labeled with Indium-111 (111In) via diethylenetriaminepentaacetic acid (DTPA) for single-photon emission computerized tomography (SPECT), named [111In]In-DTPA-mogamulizumab, and evaluated its potential for visualizing CCR4 expression in vivo. METHODS: [111In]In-DTPA-mogamulizumab was added to HCT116/CCR4 or HCT116/empty vector (EV) cells, and their radioactivity was measured 1 h after administration. A blocking study was additionally performed by treating HCT116/CCR4 cells with excess mogamulizumab in addition to [111In]In-DTPA-mogamulizumab. The biodistribution and SPECT imaging of [111In]In-DTPA-mogamulizumab in HCT116/CCR4 and HCT116/EV dual-xenografted BALB/c-nu mice were evaluated for 72 h after intravenous injection. RESULTS: [111In]In-DTPA-mogamulizumab was acquired with a radiochemical purity > 95%. The cellular uptake level of [111In]In-DTPA-mogamulizumab by HCT116/CCR4 cells was significantly higher than that by HCT116/EV cells (HCT116/CCR4: 0.951 ± 0.069, HCT116/EV: 0.006 ± 0.001%dose/mg protein, p < 0.01), and the uptake was significantly suppressed by co-incubation with excess mogamulizumab (0.013 ± 0.003%dose/mg protein, p < 0.01). In the in vivo study, the radioactivity of the HCT116/CCR4 tumor tissue was significantly higher than that of the HCT116/EV tumor tissue at 72 h after the administration of [111In]In-DTPA-mogamulizumab (HCT116/CCR4: 20.5 ± 5.4, HCT116/EV: 5.7 ± 1.0%ID/g), and HCT116/CCR4 tumors were clearly and specifically visualized on SPECT imaging. CONCLUSIONS: We have successfully developed a novel SPECT imaging tracer targeting CCR4, [111In]In-DTPA-mogamulizumab, which showed good specificity and pharmacokinetics, indicating potential in visualizing CCR4 expression in vivo.

Event-free survival at 24 months is a robust surrogate endpoint for long-term survival in pediatric, adolescent, and adult T cell lymphoblastic lymphoma.

T cell lymphoblastic lymphoma (T-LBL) has an aggressive clinical behavior. To date, powerful and consistent prognostic factors have not been established for T-LBL. In this study, we first evaluated the association of event-free survival (EFS) at 24 months (EFS24) with overall survival (OS) in T-LBL patients. Besides, we sought to identify clinical factors of prognostic importance in this rare entity. Between January 2006 and December 2017, ninety-one patients with newly diagnosed T-LBL were retrospectively analyzed. EFS was defined as the time from diagnosis to relapse or progression, unplanned retreatment, death from any cause, or to the last follow-up. In total, 91 patients with a median age of 24 years were enrolled. At a median follow-up of 40.4 months (range, 1.4 to 163.3 months), the 5-year OS and EFS was 47.9% and 43.2%, respectively. Of all patients, 45 (49.5%) achieved EFS24 and 46 (50.5%) did not. Patients who achieved EFS24 showed a markedly superior outcome, compared with those who failed to achieve EFS24 (5-year OS, 90.5% vs 3%, P < 0.001). Univariate analysis indicated bone marrow involvement, response to induction treatment, and stem cell transplantation (SCT) consolidation to be prognostic factors for EFS and OS. In addition, compared with the patients receiving non-Hodgkin's lymphoma (NHL)-like treatment protocols, patients treated with hyper-CVAD showed significantly improved EFS and OS. Such survival advantage in terms of EFS and OS was also observed of BMF-90 regimens over NHL-like therapy, despite that the difference in EFS did not reach statistical significance (P = 0.056). Multivariate analysis demonstrated that achievement of complete remission (CR) after induction therapy and SCT consolidation were independent prognostic indicators for both EFS and OS. We confirm that EFS24 is a strong surrogate endpoint for long-term survival in T-LBL, which is clinically useful for individualized risk reassessment, future clinical trial design, and biomarker discovery validation. Further validation in the context of directed prospective clinical trials is warranted.

Human T cell lymphotropic virus type-1 associated lymphoma presenting as an intramuscular mass of the calf.

Adult T cell leukemia/lymphoma (ATLL) is a mature T cell neoplasm caused by the human oncogenic retrovirus human T lymphotropic virus type-1 (HTLV-1). While several musculoskeletal manifestations have been described in ATLL, skeletal muscle involvement is unusual, with only four cases reported in the English-language literature. We present a rare case of ATLL manifesting as an intra-muscular calf mass in a 58-year-old man who immigrated to the USA from West Africa. While skeletal muscle involvement by lymphoma is uncommon, it remains important to consider within the differential diagnosis when there are suggestive imaging findings because it entails important technical biopsy considerations as well as treatment implications. This case report also raises awareness of ATLL presenting outside of typical HTLV-1 endemic areas, related to current population migration patterns. ATLL should therefore be considered in patients with appropriate risk factors.

Orbital Adult T-Cell Leukemia/lymphoma With Skin Involvement Demonstrated on FDG PET/CT.

An 85-year-old woman presented with decreased visual acuity. MRI of the brain revealed bilateral orbital masses, and FDG-PET/CT demonstrated moderate to intense uptake in the orbital tumors and thickened skin on the left lower leg. Biopsies of the orbital and cutaneous lesions revealed infiltration by T-cell lymphoma, and the presence of human T-cell lymphotropic virus type 1 antigens confirmed the diagnosis of adult T-cell leukemia/lymphoma (ATLL). Although orbital ATLL is rare, the skin is a common site of extranodal involvement of T-cell lymphomas, including ATLL, and FDG uptake by a cutaneous lesion can facilitate early diagnosis.

Thoracic manifestations of adult T-cell leukemia/lymphoma on chest CT: difference between clinical subtypes.

PURPOSE: We aimed to evaluate thoracic computed tomography (CT) findings in adult T-cell leukemia/lymphoma (ATL) and their differences among clinical subtypes. METHODS: Thoracic CT scans of 49 ATL patients were retrospectively reviewed. On CT scans, the presence of lung parenchymal abnormalities (10 patterns), enlarged lymph nodes, pleural and pericardial effusions, and subcutaneous nodules was evaluated by two radiologists in cooperation. According to the Shimoyama criteria, the patients were divided into aggressive ATL group (n=28, acute and lymphoma types) and indolent ATL group (n=21, chronic and smoldering types). Differences in the prevalence of the CT findings between the two groups were examined. In the indolent ATL group, CT scans of 10 patients who eventually underwent transformation to aggressive ATL were also evaluated. RESULTS: In aggressive ATL, enlarged lymph nodes (68%) was the most frequently observed finding. Several patterns of lung abnormalities were observed, such as ground-glass attenuation (36%), bronchial wall thickening (32%), nodules (29%), and centrilobular opacities (29%). In indolent ATL, enlarged lymph nodules (24%) and bronchiectasis (24%) were relatively frequently detected. Overall, the incidence of abnormal findings was higher in aggressive than in indolent ATL, except for bronchiectasis. Patients with transformation to aggressive ATL frequently demonstrated enlarged lymph nodes (80%). CONCLUSION: On thoracic CT, enlarged lymph nodes and various lung and airway abnormalities, such as ground-glass attenuation and bronchial wall thickening, were observed in ATL patients, particularly those with aggressive ATL. Bronchiectasis was similarly found in patients with indolent ATL and aggressive ATL.

Human T-lymphotropic virus 1 associated with adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon neoplasm of mature T lymphocytes associated with infection by human T-lymphotropic virus 1 (HTLV-1), which is increasing in incidence in areas of the United States with large immigrant populations. Human T-lymphotrophic virus 1 infection is asymptomatic in most patients and has been associated with ATLL as well as tropical spastic paraparesis. Because there is considerable histologic overlap with other cutaneous T-cell lymphomas, high suspicion and clinical features must be present to make the diagnosis of ATLL.

Diagnostic challenges of adult T-cell leukemia/lymphoma in North America - a clinical, histological, and immunophenotypic correlation with a workflow proposal.

Adult T-cell leukemia-lymphoma (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1) and little is known about ATLL endemic to the Caribbean basin and Latin America, designated as western ATLL (W-ATLL). Due to extensive systemic involvement and nonspecific clinical presentation, the initial diagnosis in this cohort can be very challenging. We have diagnosed 60 patients with W-ATLL over a 14-year period. ATLL involves the peripheral blood, bone marrow, and cerebrospinal fluid (CSF) in 98, 87, and 52% cases, respectively; while lymphadenopathy, pulmonary infiltrates, splenomegaly, and hepatomegaly was present in 90, 82, 48, and 45% patients, respectively. While 87% patients developed hypercalcemia only 28% had lytic bone lesions. We propose that any diagnosis of a peripheral T-lymphoproliferative disorder should result in a comprehensive review of the patient's endemic, laboratory information, HTLV-1 testing for proper diagnosis, and identification due to the varied manifestations of this disease.

Clinical usefulness of FDG-PET/CT for the evaluation of various types of adult T-cell leukemia.

PURPOSE: The aim was to explore undefined useful indices for clinically grading adult T-cell leukemia (ATL) using [18F] 2-fluoro-2-deoxyglucose (FDG) - positron emission tomography/computed tomography (PET/CT). METHODS: A total of 28 patients with ATL (indolent, 9; aggressive, 19) were enrolled; all patients with aggressive ATL underwent FDG-PET/CT before chemotherapy. Patients with indolent ATL underwent FDG-PET/CT at the time of suspected disease progression and/or transformation; some received lymph node biopsy. The quantitative parameters maximum standardized uptake values (SUVmax), and mean and peak SUV, metabolic tumor volume (MTV), and volume-based total lesion glycolysis were calculated with the margin threshold as 25%, and 50% of the SUVmax for all lesions. RESULTS: All parameters except for MTV-25% showed significant differences (P ≤ 0.05) in differentiating the aggressive type from the indolent type of ATL. Areas under the curve for receiver-operating characteristic (ROC) analysis regarding the series of parameters investigated ranged from 0.75 to 0.92; this indicated relatively high accuracy in distinguishing the aggressive type from the indolent type. No malignant findings were detected in lymph node biopsies in indolent ATL patients with lymphadenopathy. DISCUSSION: We performed evaluation of a line of parameters of FDG-PET, thereby demonstrating their significantly high accuracy for grading malignancy in ATL patients. In particular, low accumulation of FDG in indolent ATL patients with lymphadenopathy might predict that it is not a sign of disease transformation, but rather a reactive manifestation. CONCLUSION: FDG-PET/CT findings could be useful for clinically grading ATL.

Primary Cardiac T-Cell Lymphoma Localized in the Mitral Valve.

Primary cardiac lymphoma is a rare cardiac tumor, and usually originates from B cells and involves the right side of the heart. We present an extremely rare case of primary cardiac T-cell lymphoma involving the mitral valve alone. A 58-year-old woman who was positive for human T-cell leukemia virus 1 underwent mitral valve replacement because of severe mitral regurgitation. The postoperative pathologic diagnosis of the mitral valve was T-cell lymphoma. Further evaluation revealed no malignancy, except for the mitral valve. To the best of our knowledge, this is the first case of primary cardiac T-cell lymphoma localized in the mitral valve.

Ultrasonography and magnetic resonance imaging findings of rheumatoid arthritis-like arthritis in a patient with adult T-cell leukemia.

A 43-year-old Japanese woman with adult T-cell leukemia (ATL) developed rheumatoid arthritis-like polyarthritis with dermatitis and skin erosion. Her rheumatoid factor and C-reactive protein results were positive. Musculoskeletal ultrasonography showed intra-articular and peritendinous power Doppler signal-positive synovitis. Plain magnetic resonance imaging showed synovitis of the above lesion and remarkable bone marrow edema/osteitis. She was diagnosed as having ATL-associated arthritis based on the invasion of ATL cells by skin biopsy at the arthritis lesion.

Hand osteolysis in patients with adult T-cell leukemia-lymphoma: radiographic characteristics.

Adult T-cell leukemia-lymphoma (ATLL) is caused by human T-cell lymphotrophic virus I (HTLV-I) infection. Among ATLL cases, 70% of patients present with leukemia and the remaining patients present with lymphoma. Hand osteolysis in the patients with ATLL is considered as paraneoplastic syndrome and caused by parathyroid hormone-related peptide (PTHrP) released from tumor cells. Radiographic features are similar to hyperparathyroidism, but the distribution of osteolysis in hands appears to be slightly different with the authors' experiences. The objective of this study was to identify radiographic characteristics of hand osteolysis associated with ATLL. We included six ATLL patients (5 men and 1 woman; age range, 45-71 years). All the patients presented with acute leukemia, and three were associated with hypercalcemia and pain in various locations including hands. Patterns of osteolysis on hand radiographs were evaluated and recorded independently by three musculoskeletal radiologists. We analyzed the distribution of the bone resorption in the ray distribution of the hand, finger predilection, and the difference between the ulnar and radial sides. The bone resorption was characterized by frequent involvement of the distal and proximal phalanges, predilection of ring fingers and prominent involvement on the ulnar side, compared with frequent involvement of proximal and middle phalanges, index and middle fingers, and on the radial side in the bone resorption of typical hyperparathyroidism. Such distribution may be a characteristic feature of hand osteolysis in patients with ATLL. The present findings are helpful for physicians to differentiate PTHrP-mediated osteolysis in ATLL from parathyroid hormone-mediated hyperparathyroidism.

Chest HRCT findings in acute transformation of adult T-cell lymphoma/leukemia.

OBJECTIVES: To assess chest high-resolution computed tomography (HRCT) findings in patients with acute transformation of adult T cell leukaemia/lymphoma (ATLL). METHODS: We retrospectively identified 72 consecutive patients at our institution with ATLL between October 2000 and March 2014. The cases included acute type (n = 20), lymphoma type (n = 21), smouldering type (n = 24) and chronic type (n = 7). Sixteen (7 men, 9 women; aged 36-85 years, mean 63.3 years) of 31 patients (24 with smouldering and seven with chronic type; 51.6 %) developed acute transformation of ATLL, and had undergone chest HRCT examinations. Parenchymal abnormalities, enlarged lymph nodes, pericardial effusion, pleural effusion and skin lesions were evaluated on HRCT. RESULTS: Chest HRCT of 15 of the 16 patients showed abnormal findings, including ground-glass opacity (GGO) (n = 8), consolidation (n = 5), interlobular septal thickening (n = 5) and nodules (n = 5). Pleural effusion was found in five patients, lymph node enlargement in 10 patients and multiple skin thickening in two patients. CONCLUSIONS: Almost all patients with acute transformation of ATLL had abnormal findings on chest HRCT, which consisted mainly of lymph node enlargement, GGO, interlobular septal thickening, nodules and bilateral pleural effusions. KEY POINTS: • The recognition of CT findings of acute transformation is important • Almost all patients with acute transformation have abnormal findings on HRCT • Characteristic CT features are present in acute transformation of indolent ATLL.

Hypermetabolic pulmonary and bone marrow lesions in a patient with chronic adult T-cell leukemia.

A 69 years old woman with adult T-cell leukemia (ATL) (chronic type) was referred for a fluorine-18 fluorodeoxyglucose positron emission computed tomography ((18)F-FDG PET/CT). Multiple hypermetabolic pulmonary and bone lesions were evidence. The patient underwent chemotherapy, but did not respond, and she died approximately 8 months from the onset of symptoms. Autopsy showed ATL cells infiltrating the lung parenchyma and the pulmonary hilum. In conclusion, we present a case of hypermetabolic pulmonary lesions associated with thoracic CT findings on a (18)F-FDG PET/CT scan in a patient with a chronic adult T-cell leukemia.

[Composite lymphoma consisting of adult T-cell leukemia-lymphoma and diffuse large B-cell lymphoma].

A 68-year-old man was admitted to our hospital because of left back pain and systemic lymphadenopathy with hypercalcemia. Serum anti-HTLV-1 antibody was positive. Left cervical lymph node (LN) biopsy revealed proliferation of medium-sized to large CD4-positive atypical cells with modest infiltration of CD20 and Epstein-Barr virus (EBV)-encoded RNA dual-positive atypical large cells. Monoclonal integration of HTLV-1 proviral DNA, plus clonal rearrangement of the T-cell receptor chain gene and the immunoglobulin heavy chain gene, were detected in the same LN specimen. Composite lymphoma consisting of adult T-cell leukemia/lymphoma (ATL) and EBV positive diffuse large B-cell lymphoma (DLBCL) was diagnosed. He was successfully treated with aggressive chemotherapy including rituximab and attained remission. However, eight months later, he developed right shoulder pain due to multiple bone invasions with bilateral cervical lymphadenopathy. Biopsies of a bone lesion and cervical LN revealed recurrence of ATL alone. The patient died despite salvage chemoradiotherapy. These findings suggest that ATL-related immunodeficiency might induce EBV-associated DLBCL.

CT scans of the chest in carriers of human T-cell lymphotropic virus type 1: presence of interstitial pneumonia.

RATIONALE AND OBJECTIVES: To evaluate pulmonary findings on computed tomography (CT) scans in carriers of human T-lymphotropic virus type 1 (HTLV-1). MATERIALS AND METHODS: This retrospective study was approved by the Institutional Review Board at each institution, and informed consent was waived. Patients who were diagnosed with adult T-cell lymphoma/leukemia or collagen vascular disease were excluded from the study. Chest CT of 106 HTLV-1 carriers (54 females and 52 males; age range 44-94 years) were initially evaluated by two chest radiologists. Assessed CT findings included centrilobular nodules, thickening of bronchovascular bundles, ground-glass opacity, bronchiectasis, interlobular septal thickening, consolidation, honeycombing, crazy-paving appearance, enlarged lymph nodes, pleural effusion, and pericardial effusion. Three chest radiologists secondarily evaluated the CT scans with the abnormal findings to judge the presence of interstitial pneumonia patterns or a bronchiolitis/bronchitis pattern. RESULTS: Abnormal CT findings were found in 65 (61.3%) patients, including ground-glass opacity (n = 33), bronchiectasis (n = 28), centrilobular nodules (n = 25), and interlobular septal thickening (n = 19). Honeycombing (n = 5) and crazy-paving appearance (n = 3) were also observed. Based on the CT findings, 10 subjects were diagnosed with interstitial pneumonia (usual interstitial pneumonia pattern, n = 3; nonspecific interstitial pneumonia pattern, n = 5; organizing pneumonia pattern, n = 2; respectively). Twenty subjects were diagnosed with the bronchitis/bronchiolitis pattern. CONCLUSION: Although the bronchiolitis/bronchitis pattern is predominant on chest CT in HTLV-1 carriers, the HTLV-1 infection is associated with various interstitial pneumonias.

[Adult T-cell leukemia/lymphoma in a patient on hemodialysis-resistance to CHOP, but unexpected effect and remission achieved by sobuzoxane alone].

A 66-year-old man, on thrice-weekly hemodialysis for 7 years, was referred to Chiba Cancer Center Hospital in August 2006 because of a left axillary tumor. Computed tomography revealed several enlarged lymph nodes assembling at the left axilla. The serum soluble IL-2 receptor was 47,500 U/mL, and HTLV-1 antibody was positive. His parents came from Kyushu. The pathological diagnosis was peripheral T-cell lymphoma, CD4(+). He was clinically diagnosed as having an adult T-cell leukemia/lymphoma, lymphoma type, and clinical stage II. Two courses of CHOP therapy were given to the patient, without any response. Because the patient had to undergo hemodialysis consistently, we preferred mild salvage therapy to more intensive treatment. Then, sobuzoxane (SBZ), 1,600 mg/day in two divided doses, was administered orally for 5 days. Soon thereafter, unexpectedly, the axillary tumor rapidly became small, resulting in disappearance four months later. SBZ therapy, 800 mg/day x 3 days, was continued at intervals of 7 to 8 weeks until October 2008. At the time of reporting, May 2009, the patient was well without recurrence of ATLL, and the remission has lasted 26 months or more. The reason why CHOP-resistant ATLL responded dramatically to SBZ alone is not clear, but the plasma concentration of the metabolite of SBZ was possibly very high because of renal failure. Another possibility is that hemodialysis removed the growth factor(s) or anti-apoptotic factor(s) derived from ATLL cells.

Localized ground glass opacities with multiple pulmonary small cysts in adult T-cell leukemia or lymphoma: an "alloy wheel" appearance.

We herein report a case of adult T-cell leukemia or lymphoma showing multiple lung cysts within a localized ground glass opacity (GGO) on computed tomography scan. The patterns of multiple localized GGOs having multiple small cysts were varied, including a large air space in the center of the localized GGO with surrounding small cysts, a solid part in the center of the localized GGO with peripheral small cysts, and clustered small cysts. These findings were considered to simulate the appearance of an "alloy wheel." Some of the central large air spaces had thickened walls. On the basis of the histopathologic findings, the pathogenesis of multiple cyst formation was considered to be a combination of 2 main mechanisms as follows: a check valve mechanism due to stenosis or an obstruction by the tumor cells' infiltration along the bronchioles, traction bronchiolectasis and ectatic alveoli by fibrosis.