Management Of Malignant Lymphoma Research Articles

Targeted therapies in the management of malignant lymphoma - is the end of conventional chemotherapy near?

Advances in the understanding of the biology of malignant lymphoma has facilitated the development of numerous molecularly targeted therapies. The incorporation of these precision therapeutics has produced more effective and often less-toxic treatment regimens leading to a significant improvement of treatment outcomes for individuals with lymphoid malignancies.In relapsed diseases, molecularly targeted therapeutic approaches have demonstrated superior outcomes compared to conventional chemotherapy, leading to a growing number of patients being treated entirely chemotherapy-free. This review outlines the current landscape of targeted therapies for both B-cell (B-NHL) and T-cell non-Hodgkin lymphomas (T-NHL) and provides an overview of targeted agents currently approved for the treatment of malignant lymphoma.

FDG-PET Imaging for Hodgkin and Diffuse Large B-Cell Lymphoma-An Updated Overview.

Since the mid-1990s, 18F-fluorodeoxglucose (FDG)-positron emission tomography (PET) in combination with computed tomography has come to play a prominent role in the management of malignant lymphomas. One of the first PET applications in oncology was the detection of lymphoma manifestations at staging, where it has shown high sensitivity. Nowadays, this imaging modality is also used during treatment to evaluate the individual chemosensitivity and adapt further therapy accordingly. If the end-of-treatment PET is negative, irradiation in advanced-stage Hodgkin lymphoma patients can be safely omitted after highly effective chemotherapy. Thus far, lymphoma response assessment has mainly been performed using visual criteria, such as the Deauville five-point scale, which became the international standard in 2014. However, novel measures such as metabolic tumor volume or total lesion glycolysis have recently been recognized by several working groups and may further increase the diagnostic and prognostic value of FDG-PET in the future.

ISY9-1 - Interim PET-CT-adapted treatment for malignant lymphoma

Positron emission tomography-computed tomography (PET-CT) is widely used in the management of malignant lymphoma especially in staging and response assessment at the end of treatment. PET-CT provides more accurate information than conventional imaging studies including computed tomography (CT) and has been incorporated into essential imaging study for staging and response assessment in the recently published criteria (Lugano classification). In patients with advanced stage classic Hodgkin lymphoma (HL), results of interim PET-CT after 1-3 cycles of standard chemotherapy including ABVD have been shown to be predictive for prognosis when the patient continues the same regimen regardless of the result of interim PET-CT. Thus, it would be a reasonable approach to switch therapy to more intensive regimen such as escalated BEACOPP in patients with a positive interim PET-CT or less intensive regimen in patients with a negative result. Clinical trials to evaluate such an interim PET-CT-adapted approach have been conducted for advanced stage HL (SWOG S0816, UK RATHL, GITIL-FIL HD 0607). Results of these studies suggests that interim PET-CT-adapted intensified treatment may improve prognosis of patients with positive interim PET-CT. Moreover, in interim PET-CT-negative patients, omitting bleomycin, potentially pulmonary toxic agent, might be possible without jeopardizing prognosis. There are several challenges in incorporating interim PET-CT-adapted treatment in clinical practice in Japan. For instance, interpretation of PET-CT based on 5-point scale has not been widely accepted among PET-CT specialists. Japan Clinical Oncology Group is conducting a clinical trial (JCOG1305) to confirm the utility of PET-guided treatment strategy for previously untreated advanced stage HL.

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2．悪性リンパ腫診療の進歩：リンパ腫学のすすめ

2．悪性リンパ腫診療の進歩：リンパ腫学のすすめ

2．悪性リンパ腫診療の進歩：リンパ腫学のすすめ

PET/CT in malignant lymphoma: basic information, clinical application, and proposal

Coregistered fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) provides functional and morphologic data useful for the management of lymphoma. PET/CT is a promising tool in initial staging/re-staging, monitoring post-treatment recurrence/exacerbation, and evaluating prognosis at mid-treatment use [interim PET/CT (iPET/CT)]. Many multicenter studies are currently underway to investigate the effectiveness and safety of stratified treatment protocols using iPET/CT. Thus, the establishment of a system focusing on standardization of image quality through established protocols for scanning or quality control (QC) of the acquired data and organization of a core laboratory facility to promote standardization would be beneficial. Uniformity of image quality across multiple institutions can be guaranteed through optimization of imaging conditions and appropriate QC of PET/CT scanners to ensure standardization. Further research is required to ensure the standardization of PET/CT protocols used in the management of malignant lymphoma.

Guest editorial: Management of malignant lymphoma is continuously improving

This issue of IJH contains four ‘‘Progress in Hematology(PIH)’’ review articles describing the management ofmalignant lymphoma, with a focus on recent clinical trials.Malignant lymphoma, characterized by its marked hetero-geneity, is the most frequent hematologic malignancy inthe world. Among the various subtypes of malignantlymphoma, the following three are clinically important:Hodgkin lymphoma, follicular lymphoma (FL), and diffuselarge B cell lymphoma (DLBCL). The current and futuremanagement of these three major subtypes are discussed byinternationally distinguished lymphoma experts who havecontributed to the establishment of the current standardmanagement of each subtype. In addition, the current andfuture management of NK/T cell lymphoma is discussed byDr. Yamaguchi, based on clinical trials recently publishedby her group.Current issues to be addressed in the management ofmalignant lymphoma differ somewhat from disease todisease. In Hodgkin lymphoma, continuous efforts toestablish more effective chemotherapy with or withoutradiotherapy have yielded high cure rates in patients withlocalized and advanced diseases. Drs. Eichenauer andEngert of the German Hodgkin Study Group (GHSG)prepared a comprehensive review article regarding thecurrent standard management, based mainly on clinicaltrials conducted by GHSG. Treatment strategies forHodgkin lymphoma are scientifically discussed, andupdated information, including that on ongoing clinicaltrials, should help readers to better understand the mostsuccessful history of using non-surgical treatment modali-ties in clinical oncology.In FL, which remains incurable in most patients, theissues are somewhat different from those in Hodgkinlymphoma. Anti-CD20 monoclonal antibodies, such asrituximab, and radioimmunotherapy have markedly pro-longed survival. In the second PIH article, Drs. Salles andGhesquie`res of Groupe d’Etudes des Lymphomes del’Adulte (GELA), which has recently been renamed theLymphoma Study Association (LYSA), summarize recentadvances in the management of patients with FL, based onthe results of recent clinical trials including the PRIMAStudy, which revealed the efficacy of maintenance use ofrituximab [1]. Considering the marked heterogeneity of FL,the prolonged median survival time probably exceeding15 years under the current treatment modalities, and theemergence of several less toxic but highly effective agents,personalized approaches will be more important in thetreatment of FL in the future.Since the establishment of rituximab plus CHOP as astandard therapy for DLBCL [2], progress has been lessremarkable. In the third PIH article in this issue,Drs. Roschewski, Dunleavy, and Wilson of the NationalCancer Institute in the United States present an excellentreview of further progress in the treatment of DLBCL. Animproved understanding of the biology of DLBCL hasrevealed a number of oncogenic driver mutations and sig-naling pathways essential for growth of the lymphoma cell.As many of these signaling pathways can be targeted bysmall molecule inhibitors, treatment of DLBCL may be instore for a paradigm shift.Finally, Dr. Yamaguchi in Japan summarizes newlydevelopedtreatmentstrategiesforNK/Tcelllymphoma,basedon the results of multicenter clinical trials. NK/T cell lym-phoma is a distinct disease subtype with dismal prognosis

Whole-Body Diffusion-Weighted Imaging: The Added Value to Whole-Body MRI at Initial Diagnosis of Lymphoma

The objective of our study was to evaluate the diagnostic performance of conventional whole-body MRI without and with diffusion-weighted imaging (DWI) in the detection of known (18)F-FDG-avid lymphomas. The conventional whole-body MRI protocol consisted of a T2-weighted sequence and a T2-weighted spectral attenuated inversion recovery (SPAIR) sequence with frequency-selective fat suppression. The second protocol used the same sequences as the first protocol but also included DWI. Seventeen patients with pathologically confirmed, newly diagnosed, untreated lymphoma were recruited. T2-weighted and T2-weighted SPAIR images were evaluated first, separate from the DW images, and then were evaluated with the DW images. We used (18)F-FDG PET/CT as the standard of reference. True-positive, false-positive, and false-negative values were evaluated on a per-lesion basis. Tumor staging based on T2-weighted and T2-weighted SPAIR imaging without DWI and then with DWI was compared using the Ann Arbor staging system. True-positive lesions were increased from 89% to 97%, false-positive lesions were increased from 3% to 6%, and false-negative lesions were decreased from 11% to 3% by the addition of DWI. Diagnostic sensitivity was significantly increased (p = 0.002) by adding DWI. Lesions detected on DWI but not on T2-weighted and T2-weighted SPAIR imaging were located in renal (n = 1), paraaortic (n = 6), and pelvic (n = 3) lymph nodes. On DWI, 47% of the lesions (n = 55) were more conspicuous than on T2-weighted and T2-weighted SPAIR imaging; most of these lesions (58%, n = 32) were from lymph nodes in the pelvic or abdominal regions and bone marrow. No difference was found between T2-weighted and T2-weighted SPAIR imaging without DWI and T2-weighted and T2-weighted SPAIR imaging with DWI in lymphoma staging, being consistent with PET/CT in 88% of the patients (n = 15). The addition of DWI to conventional whole-body MRI sequences enhanced lesion conspicuity and improved diagnostic accuracy for lymphomas. With technical optimization, whole-body MRI with DWI, as a nonionizing imaging modality, may potentially be useful as an alternative method to PET/CT in the management of malignant lymphoma.

FDG-PET in T-cell and NK-cell neoplasms

A growing number of studies demonstrate the utility of (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T-cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. T/NK-cell neoplasms incorporated in this study were generally FDG-avid except for cutaneous lesions and bone marrow involvement.

Value of ultrasound‐guided core biopsy in the diagnosis of malignant lymphoma

Ultrasound-guided core needle biopsy for the diagnosis and management of malignant lymphomas is controversial and has not been accepted as an alternative to surgical biopsy. We investigate the clinical usefulness of this procedure in a large series of patients. Over a 5-year period (2000-2004), ultrasound-guided core needle biopsies were performed in 102 malignant lymphomas. Five diagnostic categories were considered: large B-cell lymphomas (LBCL), small B-cell lymphomas (SBCL), Hodgkin's disease (HD), T cell lymphomas, and miscellaneous. Surgical excisional biopsy of the node was performed in 47 cases (46.1%) for diagnostic confirmation. The overall diagnostic accuracy of ultrasound-guided core needle biopsy was 88.2% (90/102). SBCL (39), LBCL (36), HD (15), T cell lymphomas (5), and miscellaneous (7) [including T cell-rich B cell (2), natural killer cell (1), Burkitt's lymphoma (1), and non-Hodgkin's lymphoma of the B cell type, NOS (3)] were correctly diagnosed. Three HDs, 1 natural killer cell lymphoma, 1 follicular lymphoma, and 1 LBCL were not correctly diagnosed. The core needle biopsy did not yield tumor tissue in 6 cases. Ultrasound-guided core needle biopsy is effective in the diagnosis of malignant lymphomas and can be used as the first diagnostic approach in selected clinical situations.

The Value of CT Scan in Diagnosis and Management of Malignant Lymphoma: A Clinical Practice‐Oriented Overview

SummaryThe impact of computed tomography (CT) scanning on the accurate diagnosis of malignant lymphoma (ML) and the assessment of the course of disease has rapidly improved over the last years. This is mainly due to the development of multi‐slice CT (MSCT) with its unique utility to perform high‐resolution full‐body scans within a very short period of time. Its standardized sectional views permit excellent comparability to previously performed images with high inter‐observer agreement. MSCT is the method of choice for the chest, abdominal and urinary tract regions which is also true with some restrictions to the head and neck region. In the musculoskeletal system the accuracy is lower when compared with magnetic resonance imaging. Among the variety of imaging technologies MSCT plays a central role for staging and restaging of ML with a major impact on therapeutic decisions.

FDG PET in the Evaluation of Treatment for Lymphoma: Clinical Usefulness and Pitfalls

Positron emission tomography (PET) with 2-[fluorine-18] fluoro-2-deoxy-d-glucose (FDG) may play an important role in the evaluation and management of malignant lymphoma. FDG uptake is predictive of therapeutic response during the course of treatment. After completion of chemotherapy, residual abnormalities representing either residual tumor or necrotic or fibrotic tissue are not uncommon, and FDG PET may be more accurate than computed tomography (CT) or magnetic resonance imaging in assessing residual disease and identifying patients who require more intense treatment. However, posttreatment FDG PET does not help exclude the presence of minimal residual disease, which may lead to disease relapse. Furthermore, FDG is not a tumor-specific substance, and increased accumulation may be seen in a variety of benign entities and scenarios (eg, infection, drug toxicity, granulocyte colony-stimulating factor therapy, radiation therapy, physiologic activity, postoperative or postbiopsy changes, fracture, degenerative change, injection leakage), which may yield false-positive findings. Nevertheless, recognition of these entities and correlation of FDG PET findings with clinical and other radiologic findings-especially those at combined PET and CT or PET-CT fusion imaging-allows improved diagnostic accuracy. If the interpretation of positive findings is exceptionally difficult, short-term follow-up may be helpful.

Radioimmunotherapy in non-Hodgkin lymphoma.

Targeted therapy using monoclonal antibodies against a tumor-specific antigen is now an established mode of therapy in the management of malignant lymphomas. Radioimmunotherapy, a novel way of delivering systemic radiotherapy concurrently with immunotherapy, has finally appeared on the horizon, with promising results. Recent clinical trials have demonstrated the safety and efficacy of radioimmunoconjugates. Durable antitumor responses have been achieved, even in heavily pretreated patients. The optimal position that these novel agents should take in the algorithm of lymphoma therapy remains to be defined.

Current trends in the management of malignant lymphoma: new WHO classification, guidelines for high-dose therapy with HSCT, and new response criteria

Several reports on the management of non-Hodgkin’s lymphoma (NHL) have recently been published, with a new classification of lymphoma being proposed. The first World Health Organization (WHO) classification of leukemia and lymphoma was published in 1976. Since that time, multiple classifications have been proposed through analyses of the immunological and clinical aspects of lymphoma. The Working Formulation (WF) for NHL was developed to resolve the classification controversies. The WF classified NHL based on clinical outcomes; however, pathologists did not agree with the disease definitions or with the terminology used. The Revised European-American Classification of Lymphoid Neoplasms (REAL classification), based on the cell of origin, was proposed subsequently. The new WHO classification adopts the REAL classification, with minor modifications and with a reassessment of the provisional categories. The first International Consensus Conference on Intensive Chemotherapy plus Hematopoietic Stem Cell Transplantation (HSCT) in Malignancies was held in 1993. At that time, the data were insufficient for a consensus to be reached. At the second conference, held in 1998, there were discussions on when and how to perform HSCT in aggressive NHL, with the task of evaluating available data. It was regarded as essential to standardize response criteria for NHL to compare recent randomized trials. The international effort to establish new response criteria was welcomed. Here, the trends and the questions that have arisen in recent developments in the management of NHL are reviewed.

Management of malignant lymphoma in two siblings with Bloom's syndrome

Treatment of the malignant neoplasms which develop in patients with chromosome fragile syndrome, such as Bloom's syndrome (BS), requires extremely careful planning of the chemotherapy regime because of the excessive chemosensitivity of patients with such syndromes. Two siblings with BS developed B cell-type non-Hodgkin's lymphoma in the third decade of their lives. In both cases a 3-bp homozygous deletion of the BLM gene was detected. Since the lymphoma of the older brother was nasopharyngeal in origin, he was administrated radiation therapy as the primary treatment. However, hepatic metastasis was detected and this was the cause of his death. A 9-bp deletion in exon 7 of the p53 gene was detected in the metastatic lymphoma. His younger sister developed a lymphoma of abdominal lymph node in origin. She received a half dose of the drugs used in the acute lymphoblastic leukemia treatment without radiation, and twenty months after the diagnosis of her lymphoma she continues to be in complete remission and free of treatment complications. The p53 gene mutation was not detected in her lymphoma. These results suggest that radiation therapy and the radiation dose for the treatment for lymphoma in patients with BS should be carefully considered.

Positron emission tomography (PET) in diagnosis and therapy planning of malignant lymphoma

The management of patients who have malignant lymphomas requires functional methods to differentiate residual soft tissue masses. Positron emission tomography (PET) was performed in patients with histologically proven malignant lymphomas prior to the onset of second-line chemotherapy to examine tumor viability. Twenty patients (68 malignant lesions and 3 benign lesions) with Hodgkin lymphomas (HL) as well as 26 patients (46 malignant lesions and 1 benign lesion) with non-Hodgkin lymphomas (NHL) were studied with fluorine-18-deoxyglucose (FDG). Oxygen-15-labelled water was used in addition in 14 patients with 25 lesions to obtain information on the tissue perfusion. PET with FDG is highly sensitive for the detection of viable tumor tissue, all malignant lesions being correctly classified in this study. We noted no statistically significant difference in FDG metabolism for Hodgkin and non-Hodgkin lymphomas. Even normal-sized lymph-node metastases (< 1 cm) were detected with PET and FDG. The possible limitations are inflammatory processes, which may obscure tumor detection because of the increased FDG uptake, as well as malignant lesions with low FDG uptake as a result of reduced perfusion. Comparison of tumor perfusion and FDG uptake showed a significant nonlinear correlation of r = 0.78 between the two parameters. Two patients with scar tissue and no evidence of malignancy were excluded from blood stem-cell support therapy as a result of the PET study. The data demonstrate that PET is a useful tool for making a diagnosis and deciding on therapy for malignant lymphomas.

Venous Access in the Management of Malignant Lymphoma

There have been rapid advances in the therapy of children with cancer. The use of tunnelled right atrial catheters has simplified the management of these cancers. Placement techniques, choice of device, management, and complications are outlined. Emphasis is also placed on the timing of insertion and the absolute neutrophil count.

Diagnostic imaging of mediastinal masses in children.

Mediastinal masses are the most common thoracic masses in children. The encyclopedic list of diagnostic considerations can be distilled into a concise and practical differential diagnosis based on the location of the mass and the established prevalence of various tumors and pseudotumors in the mediastinal compartments. Malignant lymphoma, benign thymic enlargement, teratomas, foregut cysts, and neurogenic tumors make up 80% of mediastinal masses in children. Continuing advances in imaging technology have altered traditional approaches to the evaluation and diagnosis of mediastinal masses in children. Plain chest radiography remains the basic imaging examination to define location and morphology. Cross-sectional imaging subsequently clarifies the morphology and extent of the mass. In general, CT is the primary cross-sectional imaging procedure in the evaluation of most mediastinal masses in children. Exceptions to this rule include MR in children with posterior mediastinal masses or suspected vascular lesions: in such cases, MR imaging is the preferred initial postradiographic examination. Sonographic examination may be diagnostic in foregut cysts and some other mediastinal masses. Gallium-67 scintigraphy has an emerging role in management of malignant lymphoma.

The evolving role of etoposide in the management of lymphomas and hodgkin's disease

Etoposide, a derivative of epipodophyllotoxin, is one of the most important new drugs that was introduced into the management of the malignant lymphomas during the past decade. A growing number of specific protocols include this useful agent in the management of malignant lymphoma, both at the time of primary treatment and at relapse. The broad activity of etoposide across several histologic subtypes of malignant lymphoma and Hodgkin's disease indicates a potential that is only now being fully exploited. Used according to optimal doses and schedules, etoposide has single-agent activity that rivals earlier drugs such as the alkylating agents and doxorubicin. Functioning as a protein synthesis and topoisomerase II inhibitor, it offers the potential for non-cross-resistant cytotoxicity. After a brief comment on the single-agent activity of etoposide, this report will focus on the integration of etoposide into multiagent protocols used in the primary treatment of malignant lymphoma and Hodgkin's disease. The specific findings from protocols such as prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide-cytarabine, bleomycin, vincristine, and methotrexate (Pro-MACE-CytaBOM) (US National Cancer Institute [NCI]) and etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) (Vancouver) for the primary treatment of malignant lymphoma, and vinblastine, etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, and prednisone (VECABOP) (Vancouver) for the treatment of previously untreated patients with advanced Hodgkin's disease will be discussed.

Role of fine needle aspiration-cytology in the management of lymphoma

Fine needle aspiration (FNA) is a recognised technique in the diagnosis and management of malignancy. Its application has been used less in the management of non-Hodgkin's malignant lymphomas (NHML) than other malignancies. The reasons for this are difficulty in distinguishing benign hyperplasias from malignant lymphomas, inability to use Rappaport Classification on smears, associated fibrosis causing poor cell yield and less experience due to the less frequent occurrence of lymphoma compared to epithelial malignancy. Using FNA sufficient numbers of cells can be obtained to perform tumour markers, T and B lymphocyte markers and Electron Microscopy studies. During a two year period 72 Fine Needle Aspirates were performed on patients with a previous diagnosis of malignant lymphoma or clinical findings suggesting malignant lymphoma. 26(36%) were benign 9(12%) suspicious and 37(51%) malignant and 8 unsatisfactory. One benign case was diagnosed as aspergillus. 13(18%) of the cytologically benign cases and 8(10%) unsatisfactory were histologically diagnosed as malignant. The false negative rate was 29%. There was no false positive diagnosis. Cytological diagnoses on the 37 malignant cases were 20 large cell lymphoma, 6 mixed large and small cleaved cell lymphoma, 6 myeloma, 6 lymphoma cell type not classifiable and 1 small cell lymphoma. The results indicate Fine Needle Aspiration is a reliable diagnostic technique in the management of malignant lymphoma, it is safe, decreases time for diagnosis and cost effective.