Non Hodgkin's Lymphoma
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Information Patients and the Public (16 links)


Information for Health Professionals / Researchers (11 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Dunleavy K, Pittaluga S, Maeda LS, et al.
Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.
N Engl J Med. 2013; 368(15):1408-16 [PubMed]
BACKGROUND: Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.
METHODS: We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.
RESULTS: The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.
CONCLUSIONS: Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).


Sarantopoulos GP, Palla B, Said J, et al.
Mimics of cutaneous lymphoma: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.
Am J Clin Pathol. 2013; 139(4):536-51 [PubMed]
The Society for Hematopathology and European Association for Haematopathology workshop, from October 27 to 29, 2011, in Los Angeles, CA, exhibited many exemplary skin biopsy specimens with interesting inflammatory changes mimicking features of cutaneous lymphoma. This article reviews features observed in cutaneous lymphoid hyperplasia, cutaneous drug reactions, lupus-associated panniculitis, pityriasis lichenoides, hypereosinophilic syndrome, histiocytic necrotizing lymphadenitis, traumatic ulcerative granuloma with stromal eosinophils, and pigmented purpuric dermatosis, as well as a brief review of the pertinent literature and discussion of submitted conference cases. For the pathologist, it is important to be aware of diagnostic pitfalls as well as the limitations of ancillary testing (eg, clonality studies). Finally, correlation with total clinical information, good communication with clinical colleagues, close clinical follow-up with rebiopsy, and prudent use of laboratory studies are vital and will likely offer the best path toward a correct diagnosis.


Swerdlow SH, Quintanilla-Martinez L, Willemze R, Kinney MC
Cutaneous B-cell lymphoproliferative disorders: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.
Am J Clin Pathol. 2013; 139(4):515-35 [PubMed]
The diagnosis and classification of the cutaneous B-cell lymphomas can be quite a challenge, with a definitive diagnosis sometimes being elusive, even when an extensive workup has been performed. Distinction of benign from neoplastic disorders can be difficult, with some hyperplasias mimicking lymphomas and vice versa. There are only a limited number of skin-specific B-cell lymphomas, including primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous marginal zone lymphomas have distinctive features but are classified with the other mucosa-associated lymphoid tissue lymphomas. It is important, however, to also remember that many other B-cell lymphomas/ plasma cell neoplasms can primarily, or more often secondarily, involve the skin. Some may mimic one of the skin-specific lymphomas but have very different clinical implications. Iatrogenic and senescent immunodeficiency-associated lymphoproliferative disorders that are often Epstein-Barr virus (EBV) positive can also primarily involve the skin, including cases also known as EBV-positive mucocutaneous ulcer.


Quintanilla-Martinez L, Jansen PM, Kinney MC, et al.
Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.
Am J Clin Pathol. 2013; 139(4):491-514 [PubMed]
Primary cutaneous T-cell lymphomas (CTCL) excluding mycosis fungoides (MF) were discussed in 2 sessions of the 2011 Society for Hematopathology/ European Association of Haematopathology Workshop, Los Angeles, CA. Session 2 focused on primary cutaneous CD30+ T-cell lymphoproliferative disorders and their differential diagnosis, including systemic CD30+ T-cell lymphoma secondarily infiltrating the skin. Interesting features like special morphologic variants and atypical phenotypes were presented. In addition, the possibility of rare ALK+ primary cutaneous lymphomas was discussed. Session 3 examined other more uncommon non-MF CTCLs, including subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and rare subtypes of primary cutaneous peripheral T-cell lymphoma, not otherwise specified. In addition, systemic T-cell lymphomas involving the skin secondarily, such as angioimmunoblastic T-cell lymphoma, were included in this session. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be highlighted. The necessity to integrate histologic, immunophenotypical, genetic, and in particular, clinical data to arrive at the correct diagnosis, and subsequently provide adequate treatment, is emphasized.


Song SX, Willemze R, Swerdlow SH, et al.
Mycosis fungoides: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.
Am J Clin Pathol. 2013; 139(4):466-90 [PubMed]
Session 1 of the 2011 Workshop of the Society for Hematopathology and European Association for Haematopathology focused on mycosis fungoides (MF), the most common cutaneous lymphoma. The 62 cases in this case group demonstrated a wide spectrum of clinicopathologic features, including those seen in typical cases as well as those, by contrast, with atypical clinical history, morphology, immunophenotype, and/or genotype. Of the 62 cases, 27 (44%) were presented at the workshop and highlighted diagnostic challenges plus related issues. This report summarizes the approach recommended for making a confident diagnosis of MF and its clinically significant variants; emphasizes pitfalls in evaluating early MF, assessing nodal involvement, and diagnosing transformed MF; and discusses the relationship between MF and primary cutaneous CD30+ T-cell lymphoproliferative disorders. Last, Sézary syndrome is discussed, with concentration on those features distinct from MF.


Khan AA, Garg A, Dhawan S, et al.
T cell non-Hodgkin's lymphoma with colesional mucormycosis presenting as palatal perforation: a case report.
J Indian Med Assoc. 2012; 110(7):499-500 [PubMed]
Non-Hodgkin's lymphoma (NHL) is predominantly a disease of lymph nodes, but extranodal involvement is not very uncommon. Palatal involvement by NHL is rare. Mucormycosis is a devastating fungal infection commonly seen in immunocompromised individuals, including those with NHL, but it is affecting the same region has been reported very rarely. Simultaneous infiltration of hard palate by NHL and mucormycosis is extremely unusual. Herein we describe a patient who presented with palatal hole with histopathological examination revealing presence of lymphoma with colesional mucormycosis. The identification of mucor was vital because chemotherapy alone in the absence of antifungals would have had devastating consequences as the mortality of untreated mucormycosis is high.


Paugam A, Lebuisson A, Lortholary O, et al.
Peripheral blood and bone marrow cells cultivated in Novy-Mcneal-Nicolle medium for visceral leishmaniosis diagnosis revealed Rhodotorula fungemia in an AIDS patient with lymphoma.
Clin Lab. 2013; 59(1-2):215-6 [PubMed]
Rhodotorula is a ubiquitous yeast that can infect immunocompromised patients. Here, we present the case of a 45-year-old patient with AIDS who developed a Rhodotorula mucilaginosa fungemia. The patient had a past history of visceral leishmaniasis (VL) and was hospitalised to receive chemotherapy for a B-cell lymphoma of the sinonasal cavities. The patient had no fever and no signs of VL. A systematic research for Leishmania by blood and bone marrow cultures was made and he received liposomal amphtotericin B (3 mg/kg in a single dose) to prevent a VL relapse. Rhodotorula fungemia was accidentally detected after 17 days of blood culture using a specific medium for leishmaniasis diagnosis. This long culture incubation time was probably facilitated by amphotericin B treatment. Rhodotorula is an emerging pathogen that may escape detection due its slow growth in culture.


Pacilli A, Calienni M, Margarucci S, et al.
Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis.
J Natl Cancer Inst. 2013; 105(7):489-98 [PubMed]
BACKGROUND: The metabolic alterations of cancer cells represent an opportunity for developing selective antineoplastic treatments. We investigated the therapeutic potential of ST1326, an inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid (FA) import into mitochondria.
METHODS: ST1326 was tested on in vitro and in vivo models of Burkitt's lymphoma, in which c-myc, which drives cellular demand for FA metabolism, is highly overexpressed. We performed assays to evaluate the effect of ST1326 on proliferation, FA oxidation, and FA mitochondrial channeling in Raji cells. The therapeutic efficacy of ST1326 was tested by treating Eµ-myc mice (control: n = 29; treatment: n = 24 per group), an established model of c-myc-mediated lymphomagenesis. Experiments were performed on spleen-derived c-myc-overexpressing B cells to clarify the role of c-myc in conferring sensitivity to ST1326. Survival was evaluated with Kaplan-Meier analyses. All statistical tests were two-sided.
RESULTS: ST1326 blocked both long- and short-chain FA oxidation and showed a strong cytotoxic effect on Burkitt's lymphoma cells (on Raji cells at 72 hours: half maximal inhibitory concentration = 8.6 μM). ST1326 treatment induced massive cytoplasmic lipid accumulation, impairment of proper mitochondrial FA channeling, and reduced availability of cytosolic acetyl coenzyme A, a fundamental substrate for de novo lipogenesis. Moreover, treatment with ST1326 in Eµ-myc transgenic mice prevented tumor formation (P = .01), by selectively impairing the growth of spleen-derived primary B cells overexpressing c-myc (wild-type cells + ST1326 vs. Eµ-myc cells + ST1326: 99.75% vs. 57.5%, difference = 42.25, 95% confidence interval of difference = 14% to 70%; P = .01).
CONCLUSIONS: Our data indicate that it is possible to tackle c-myc-driven tumorigenesis by altering lipid metabolism and exploiting the neoplastic cell addiction to FA oxidation.


Cao HY, Zou P, Zhou H
Genetic association of interleukin-10 promoter polymorphisms and susceptibility to diffuse large B-cell lymphoma: a meta-analysis.
Gene. 2013; 519(2):288-94 [PubMed]
Published data on the association between interleukin-10 (IL-10) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed, focusing on four major IL-10 gene variants in the promoter region: -3575T/A, -1082A/G, -819C/T and -592C/A. We applied the false discovery rate (FDR) method to adjust for multiple testing. A significant association between IL-10 -3575T/A polymorphism and the risk of DLBCL was observed in the pooled 10 case-control studies (A vs. T: OR=1.16, 95% CI=1.08-1.25, P<0.0001; AA+TA vs. TT: OR=1.20, 95% CI=1.08-1.33, P=0.0009; AA vs. TA+TT: OR=1.25, 95% CI=1.09-1.44, P=0.001). The results indicated that carriers of -1082G allele (-1082GG/GA genotypes) had a nearly 30% increased risk of DLBCL, as compared with carriers of -1082AA genotype (GG+GA vs. AA: OR=1.30, 95% CI=1.08-1.57, P=0.005). When P-values were not adjusted for multiple testing, the risk was significantly decreased among people with -592AA genotype (AA vs. AC+CC: OR=0.63, 95% CI=0.43-0.94, P=0.02), while carriers with -819TT genotype also modestly weakened the DLBCL susceptibility at a marginal level of significance (TT vs. CT+CC: OR=0.59, 95% CI=0.35-0.99, P=0.05). However, these associations were not significant after correction for multiple testing. This meta-analysis suggests that IL-10 -3575A allele confers a greater risk to DLBCL susceptibility, while -1082A/G polymorphism also has significant association with DLBCL risk. These results may help to further clarify the malignancy-risk gene signature of DLBCL, and thus have prognostic and predictive value especially for early-stage DLBCL.


Metcalf RA, Bashey S, Wysong A, et al.
Intravascular ALK-negative anaplastic large cell lymphoma with localized cutaneous involvement and an indolent clinical course: toward recognition of a distinct clinicopathologic entity.
Am J Surg Pathol. 2013; 37(4):617-23 [PubMed]
Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.


Hiramoto N, Kobayashi Y, Nomoto J, et al.
Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.
Jpn J Clin Oncol. 2013; 43(4):417-21 [PubMed]
We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer.


Mweempwa A, Prasad J, Islam S
A rare neoplasm of the thyroid gland.
N Z Med J. 2013; 126(1369):75-8 [PubMed]
Burkitt's lymphoma of the thyroid gland is a rare malignancy. We present a case of a 58-year-old female who developed a rapid enlargement of her thyroid gland. Core biopsy confirmed the diagnosis of Burkitt's lymphoma. The tumour resolved after three cycles of chemotherapy. This case report emphasises the importance of considering lymphoma when dealing with thyroid nodules and goitres, as its management is different from that of other thyroid pathologies and delaying treatment has an impact on prognosis.


Keane C, Gill D, Vari F, et al.
CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy.
Am J Hematol. 2013; 88(4):273-6 [PubMed]
Despite the Revised International Prognostic Index's (R-IPI) undoubted utility in diffuse large B-cell lymphoma (DLBCL), significant clinical heterogeneity within R-IPI categories persists. Emerging evidence indicates that circulating host immunity is a robust and R-IPI independent prognosticator, most likely reflecting the immune status of the intratumoral microenvironment. We hypothesized that direct quantification of immunity within lymphomatous tissue would better permit stratification within R-IPI categories. We analyzed 122 newly diagnosed consecutive DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemo-immunotherapy. Median follow-up was 4 years. As expected, the R-IPI was a significant predictor of outcome with 5-year overall survival (OS) 87% for very good, 87% for good, and 51% for poor-risk R-IPI scores (P < 0.001). Consistent with previous reports, systemic immunity also predicted outcome (86% OS for high lymphocyte to monocyte ratio [LMR], versus 63% with low LMR, P = 0.01). Multivariate analysis confirmed LMR as independently prognostic. Flow cytometry on fresh diagnostic lymphoma tissue, identified CD4(+) T-cell infiltration as the most significant predictor of outcome with ≥23% infiltration dividing the cohort into high and low risk groups with regard to event-free survival (EFS, P = 0.007) and OS (P = 0.003). EFS and OS were independent of the R-IPI and LMR. Importantly, within very good/good R-IPI patients, CD4(+) T-cells still distinguished patients with different 5 year OS (high 96% versus low 63%, P = 0.02). These results illustrate the importance of circulating and local intratumoral immunity in DLBCL treated with R-CHOP.


Hagtvedt T, Aaløkken TM, Smith HJ, et al.
Enhancement characteristics of retroperitoneal lymphomatous lymph nodes.
Acta Radiol. 2013; 54(3):333-9 [PubMed]
BACKGROUND: Previous studies of CT enhancement of lymphomatous lymph nodes (LLN) of the neck and the mediastinum showed that the LLN had lower enhancement values than normal lymph nodes.
PURPOSE: To elucidate the contrast medium enhancement curves of LLN in the retroperitoneum by comparing the curves of LLN with those of normal lymph nodes, to test whether differences between these curves could be of diagnostic value, and to compare the present enhancement curves of LLN of the retroperitoneum with the curves of LLN of the neck and the mediastinum from previous similar investigations.
MATERIAL AND METHODS: Twenty-eight consecutive patients with LLN of the retroperitoneum (three with Hodgkin's lymphoma [HL]) and 21 control patients with sarcomas and thus presumably normal retroperitoneal nodes underwent dynamic CT examinations. The previous, similar investigation of lymph nodes of the neck comprised 28 patients with LLN and the investigation of mediastinal lymph nodes comprised 24 patients with LLN.
RESULTS: The enhancement curves of the retroperitoneal LLN had significantly lower attenuation than those of the retroperitoneal control nodes. A combination of peak contrast value and time to peak adjusted to total body weight yielded a diagnostic accuracy which at the best showed a sensitivity of 90.5% with a specificity of 82.6%. The LLN of the retroperitoneum had higher attenuation values than corresponding nodes of the mediastinum but no significant difference was found between LLN of the retroperitoneum and LLN of the neck in previous similar investigations.
CONCLUSION: The comparison of enhancement curves of retroperitoneal LLN with retroperitoneal control nodes showed a marked similarity with and substantiates our previous findings in lymph nodes of the neck and of the mediastinum. The best diagnostic accuracy was achieved by combining the parameters peak contrast value and time to peak and adjusting these values to the body weight. Peak enhancement of the retroperitoneal LLN was higher and arrived earlier than that of the mediastinal nodes from the previous investigation.


Wang SA, Hutchinson L, Tang G, et al.
Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components.
Am J Hematol. 2013; 88(3):219-24 [PubMed]
Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.


Muramatsu T, Tanaka Y, Higure R, et al.
Thymic and pulmonary mucosa-associated lymphoid tissue lymphomas.
Ann Thorac Surg. 2013; 95(3):e69-70 [PubMed]
A 52-year-old woman with no history of autoimmune disease was found to have a mediastinal tumor and focal airspace opacity in the right lung. Tissue diagnosis was obtained by resection of the mediastinal tumor and open fine needle aspiration of the right pulmonary tissue through a median sternotomy. Histopathologic examination and immunohistochemistry of the thymus tumor and cytologic analysis of the pulmonary tissue were both consistent with mucosa-associated lymphoid tissue (MALT) lymphoma. This case suggests that multiorgan MALT lymphoma can also develop in the absence of an autoimmune disease such as Sjogren's syndrome.


Taylor WS, Vaughan P, Trotter S, Rajesh PB
A rare association of pulmonary carcinoid, lymphoma, and sjögren syndrome.
Ann Thorac Surg. 2013; 95(3):1086-7 [PubMed]
Pulmonary carcinoid and pulmonary lymphoma are both rare cancers and are seldom seen together. Cases have been reported of their coexistence in the gastrointestinal tract, but our literature searches only found a single case of their coexistence in the lung. We discuss our case as well as the literature to try to find a connection and explanation for this occurrence.


Rummel MJ, Niederle N, Maschmeyer G, et al.
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.
Lancet. 2013; 381(9873):1203-10 [PubMed]
BACKGROUND: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.
FUNDING: Roche Pharma AG, Ribosepharm/Mundipharma GmbH.


Seto M
Cyclin D1-negative mantle cell lymphoma.
Blood. 2013; 121(8):1249-50 [PubMed]
In this issue of Blood, Salaverria et al report that more than half of Cyclin D1- (CCND1) negative SOX11-positive mantle cell lymphoma (MCL) had CCND2 gene rearrangement predominantly with immunoglobulin (IG) light chain genes.(1)


Maeshima AM, Taniguchi H, Fukuhara S, et al.
Follow-up data of 10 patients with B-cell non-Hodgkin lymphoma with a CD20-negative phenotypic change after rituximab-containing therapy.
Am J Surg Pathol. 2013; 37(4):563-70 [PubMed]
Recently, a CD20-negative phenotypic change in CD20-positive B-cell non-Hodgkin lymphoma (B-NHL) after rituximab therapy was described. We report the follow-up data of 10 B-NHL patients showing this change after rituximab therapy. Ten patients (4 men and 6 women; median age, 57 y) with B-NHL who were initially CD20 positive and became CD20 negative after rituximab therapy were analyzed. Clinicopathologic features, including clinical course, CD20 expression, and histopathology, were examined. CD20 expression in lymphoma cells was evaluated using immunohistochemistry and/or flow cytometry. Histopathologically, diagnosis at initial presentation was follicular lymphoma (FL) in 7 patients; diffuse large B-cell lymphoma in 1; and chronic lymphocytic leukemia in 2. Six patients (60%, 3 FL, 1 diffuse large B-cell lymphoma, and 2 chronic lymphocytic leukemia patients) showed continuous CD20 negativity until 24 months after the phenotypic change. Three patients (30%) with FL regained CD20 expression within 1 to 7 months after detection of the CD20 change. Two patients (20%) with FL, including 1 who regained CD20 expression, showed heterogenous CD20 expression with a CD20-negative low-grade component and a CD20-positive large cell component. The overall response rate to therapy before the CD20-negative change was 70%. We reported the follow-up data of 10 B-NHL patients with a CD20-negative phenotypic change associated with rituximab-containing therapy. The most common histologic phenotypes were continuous CD20 negativity, recovery of CD20 expression within 7 months, and heterogenous CD20 expression. As the changes in morphology and CD20 expression after rituximab therapy vary widely, careful follow-up and rebiopsy are recommended.


Zangari P, Santilli V, Cotugno N, et al.
Raising awareness of non-Hodgkin lymphoma in HIV-infected adolescents: report of 2 cases in the HAART era.
J Pediatr Hematol Oncol. 2013; 35(3):e134-7 [PubMed]
Human immunodeficiency virus (HIV) chronically infected patients are at increased risk of developing non-Hodgkin lymphoma compared with the general population. Highly active antiretroviral therapy has had a dramatic effect on the natural history of HIV infection, reducing the incidence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma and improving overall survival. However, problems related to adherence to treatment, frequently experienced during adolescence, may increase the risk of acquired immunodeficiency syndrome-related cancers. Optimizing highly active antiretroviral therapy and monitoring noncompliant patients with persisting HIV replication should be considered by physicians who take care of these patients. We herein report 2 cases of relapsed/progressive Burkitt lymphoma in HIV vertically infected adolescents.


Gabali A, Ross CW, Edwards PC, et al.
Pediatric extranodal marginal zone B-cell lymphoma presenting as amyloidosis in minor salivary glands: a case report and review of the literature.
J Pediatr Hematol Oncol. 2013; 35(3):e130-3 [PubMed]
We report an unusual case of an extranodal marginal zone B-cell lymphoma (EMZL) arising in the labial minor salivary gland in an immunocompetent 11-year-old boy. The initial histopathologic review favored localized amyloidosis. However, further evaluation supported the diagnosis of low-grade B-cell lymphoma with plasmacytic differentiation, surrounded by deposits of AL κ-type amyloid. Clinical management consisted of excision with no recurrence at 1-year follow-up. This case demonstrates that a diagnosis of lymphoma must be considered in cases of amyloidosis associated with minor salivary gland involvement, even in children. In addition, we provide a literature review of extranodal marginal zone B-cell lymphoma arising in salivary glands.


Jain P, O'Brien S
Richter's transformation in chronic lymphocytic leukemia.
Oncology (Williston Park). 2012; 26(12):1146-52 [PubMed]
Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). "Richter's transformation" refers to the development of aggressive lymphoma during the course of CLL. Diffuse large B-cell lymphoma occurs in the majority of cases of Richter's transformation. Clinically, patients with Richter's transformation present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. Specific risk factors for the development of Richter's transformation in a patient with CLL have yet to be identified; however, TP53 disruption, c-MYCabnormalities, unmutated immunoglobulin heavy chain (IGHV) < 2%, non-del13q cytogenetics, CD38 gene polymorphisms, stereotypy, and VH4-39 gene usage may predispose to Richter's transformation. The prognosis is generally poor, with a median survival of about 10 months. Development of rituximab (Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg, R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone] or OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C]) have improved response rates but have not clearly affected long-term outcomes. Allogeneic stem-cell transplantation may offer a chance for prolonged survival.


Khandanpour C, Phelan JD, Vassen L, et al.
Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia.
Cancer Cell. 2013; 23(2):200-14 [PubMed] Article available free on PMC after 11/02/2014
Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of proapoptotic p53 targets such as Bax, Noxa (Pmaip1), and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias.


Yao Y, Mark LA
Woringer-Kolopp disease mimicking foot dermatitis.
Cutis. 2012; 90(6):307-9, 316 [PubMed]
Woringer-Kolopp disease, also known as localized pagetoid reticulosis, is a rare cutaneous lymphoproliferative disorder classified as a solitary variant of mycosis fungoides (MF). Despite the indolent and benign nature of the disease, misdiagnosis and inappropriate treatment may result in years of debilitating symptoms and even loss of function. We present the case of a patient with long-standing Woringer-Kolopp disease that mimicked foot dermatitis. Histopathologic examination demonstrated epidermotropic infiltration of atypical lymphocytes that were CD3+ CD4- CD8-. The patient was successfully treated with topical keratolytics and bexarotene gel 1% with minimal residual lesions after 8 years of follow-up. We discuss the characteristics of this rare disease in contrast with localized MF as well as more aggressive forms of epidermotropic T-cell lymphoma.


Bouabdallah K, Ribrag V, Terriou L, et al.
Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects.
Curr Opin Oncol. 2013; 25 Suppl 2:S1-12 [PubMed]
PURPOSE OF REVIEW: Temsirolimus (Torisel) is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The recommended dosage in this indication (175 mg once weekly for 3 weeks and then 75 mg once weekly as maintenance) is higher than that for renal cell carcinoma; thus, the safety profile is quite different in the two indications. The aim of this review is to examine safety data for temsirolimus in MCL and provide guidance on the incidence and management of adverse events. Medline and EMBASE searches using the search terms 'temsirolimus' and 'mantle cell lymphoma'.
FINDINGS: Four main published phase II-III clinical studies of temsirolimus in MCL were identified. Many adverse events are class-effect toxicities of mTOR inhibitors but, for others, often an accurate relationship with temsirolimus is difficult to assess with certainty. Haematological adverse events are the most frequently reported, but these are generally successfully managed by dose reductions or treatment delay. Gastrointestinal toxicity, especially diarrhoea, is a frequent and common adverse effect, but the incidence of grade 3-4 events is low. Other non-haematological toxicities include stomatological/dermatological and endocrinological adverse events. Incidence of these adverse events can be reduced by careful management and/or prevention. Grade 3 or higher pneumonitis, a known mTOR inhibitor-associated toxicity, was rarely reported in this indication, but the incidence was higher when temsirolimus was administered in combination with rituximab. Other adverse events include fatigue/asthenia, infection, hypersensitivity and extravasation. Sexual disorders, foetal malformations and psychiatric disorders are rarely reported.
SUMMARY: Most temsirolimus-associated adverse events in patients with relapsed/refractory MCL are manageable, often without impacting administration of temsirolimus.


Villa D, Crump M, Panzarella T, et al.
Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group.
J Clin Oncol. 2013; 31(9):1164-71 [PubMed]
PURPOSE: To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone.
PATIENTS AND METHODS: This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation.
RESULTS: One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT.
CONCLUSION: Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.


Li YJ, Li ZM, Xia XY, et al.
Prognostic value of interim and posttherapy 18F-FDG PET/CT in patients with mature T-cell and natural killer cell lymphomas.
J Nucl Med. 2013; 54(4):507-15 [PubMed]
UNLABELLED: The prognostic value of interim PET or PET/CT performed after 1-4 cycles of chemotherapy has been widely confirmed in Hodgkin lymphoma and diffuse large B-cell lymphoma but remains unknown in T-cell and natural killer (T/NK) cell lymphomas. Therefore, our aim was to investigate the prognostic value of interim and posttherapy PET/CT in T/NK-cell lymphomas.
METHODS: A retrospective analysis was conducted on data from 88 patients with newly diagnosed T/NK-cell lymphoma who underwent interim (after 1-4 cycles of chemotherapy, n = 62) or posttherapy PET/CT (after the completion of first-line therapy, n = 47). Interim and posttherapy PET/CT status (positive vs. negative) was visually interpreted according to criteria of the International Harmonization Project, and PET/CT status was assessed for its ability to predict progression-free survival (PFS) and overall survival (OS).
RESULTS: Interim PET/CT results were negative in 17 of 62 (27.4%) cases, and posttherapy PET/CT results were negative in 29 of 47 (61.7%) cases. The 2-y PFS and OS rates were 71.9% and 80.2%, respectively, in patients with negative results at interim PET/CT versus 20.5% and 46.9%, respectively, in patients with positive results (P < 0.001 and P = 0.022, respectively). The 2-y PFS and OS rates were 57.8% and 78.0%, respectively, in patients with negative results on posttherapy PET/CT versus 0% and 20.4%, respectively, in patients with positive results (P < 0.001 and P = 0.003, respectively). Bivariate analysis showed that interim PET/CT status and posttherapy PET/CT status remain independent predictors of PFS and OS after controlling for the score on the Prognostic Index for Peripheral T-Cell Lymphoma, Unspecified.
CONCLUSION: Both interim PET/CT status and posttherapy PET/CT status are independent predictors of PFS and OS in T/NK-cell lymphomas.


Mbulaiteye SM, Clarke CA, Morton LM, et al.
Burkitt lymphoma risk in U.S. solid organ transplant recipients.
Am J Hematol. 2013; 88(4):245-50 [PubMed] Article available free on PMC after 01/04/2014
Case reports of Burkitt lymphoma (BL) in transplant recipients suggest that the risk is markedly elevated. Therefore, we investigated the incidence of BL in 203,557 solid organ recipients in the U.S. Transplant Cancer Match Study (1987-2009) and compared it with the general population using standardized incidence ratios. We also assessed associations with demographic and clinical characteristics, and treatments used to induce therapeutic immunosuppression. BL incidence was 10.8 per 100,000 person-years, representing 23-fold (95% confidence interval (CI) 19-28) greater risk than in the general population, and it peaked 3-8 years after the time of transplantation. In adjusted analyses, BL incidence was higher in recipients transplanted when <18 vs. ≥35 years (incidence rate ratio [IRR] 3.49, 95% CI 2.08-5.68) and in those transplanted with a liver (IRR 2.91, 95% CI 1.68-5.09) or heart (IRR 2.39, 95% CI 1.30-4.31) compared with kidney. BL incidence was lower in females than males (IRR 0.45, 95% CI 0.28-0.71), in blacks than whites (IRR 0.33, 95% CI 0.12-0.74), in those with a baseline Epstein-Barr virus (EBV)-seropositive versus EBV-seronegative status (IRR 0.34, 95% CI 0.13-0.93), and in those treated with azathioprine (IRR 0.56, 95% CI 0.34-0.89) or corticosteroids (IRR 0.48, 95% CI 0.29-0.82). Tumors were EBV-positive in 69% of 32 cases with results. EBV positivity was 90% in those aged <18 years and 59% in those aged 18+ years. In conclusion, BL risk is markedly elevated in transplant recipients, and it is associated with certain demographic and clinical features. EBV was positive in most but not all BL cases with results.


Wilcox RA
Cutaneous B-cell lymphomas: 2013 update on diagnosis, risk-stratification, and management.
Am J Hematol. 2013; 88(1):73-6 [PubMed]
UNLABELLED: DISEASE OVERVIEW: Approximately one-fourth of cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle-center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT).
DIAGNOSIS: Diagnosis and disease classification is based on histologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histology remains the most important prognostic determinant. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with an excellent long-term prognosis. In contrast, PCLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: PCFCL and PCMZL patients with solitary or relatively few skin lesions may be affectively managed with local radiation therapy. Although single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCLBCL, LT is comparable to the management of patients with systemic DLBCL.


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