Athena Kritharis

Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities.

Lenalidomide is an immunomodulatory drug (IMiD) with activity in lymphoid malignancies occurring primarily through immune modulation (eg, T-cell immune synapse enhancement and NK-cell/T-cell effector augmentation) and antiproliferative effects. Food and Drug Administration-approved for bortezomib-resistant, relapsed/refractory mantle-cell lymphoma, lenalidomide has demonstrated efficacy in several additional lymphoma subtypes. There are many ongoing clinical trials examining the use of lenalidomide alone or in combinatorial therapy. It will be important in these studies to delineate reliable, predictive biomarkers to optimally integrate lenalidomide into lymphoma treatment paradigms.

Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B‐cell lymphoma: Characteristics, outcomes, and prognostication among a large multicenter cohort

Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B‐cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty‐three percent of patients presented with MGZL, whereas 57% had non‐MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide‐doxorubicin‐vincristine‐prednisone +/− rituximab (CHOP+/−R) 46%, doxorubicin‐bleomycin‐vinblastine‐dacarbazine +/− rituximab (ABVD+/−R) 30%, and dose‐adjusted etoposide‐doxorubicin‐cyclophosphamide‐vincristine‐prednisone‐rituximab (DA‐EPOCH‐R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31‐month median follow‐up, 2‐year progression‐free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/−R had markedly inferior 2‐year PFS (22% versus 52%, P = 0.03) compared with DLBCL‐directed therapy (CHOP+/−R and DA‐EPOCH‐R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03–3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18–0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab‐based, DLBCL‐specific regimen. Am. J. Hematol. 90:778–783, 2015.

Current Therapeutic Strategies and New Treatment Paradigms for Follicular Lymphoma

Follicular lymphoma (FL) is an indolent non-Hodgkins lymphoma that remains an incurable disease for most patients. It is responsive to a variety of different treatments, however it follows a pattern of relapsing and remitting disease. Traditional therapeutic options for patients with untreated FL include expectant observation for asymptomatic and low tumor burden and multiagent cytotoxic chemotherapy for symptomatic and/or high tumor burden. Biologics have become an integral part of therapy with agents that target B lymphocytes, including monoclonal anti-CD20 antibodies and radiolabeled anti-CD20 antibodies. Treatment response to cytotoxic and biologic therapy is high initially; however, with subsequent treatments, response rate and remission duration typically decline and cumulative toxicities increase. The identification of novel targeted agents, use of stem cell transplantation, and new treatment combinations provide the opportunity to enhance patient outcomes. In this review, we critically examine standard treatment strategies for patients with newly diagnosed and relapsed or refractory FL and discuss established and emerging novel therapeutic approaches.

How I manage patients with grey zone lymphoma

Since grey zone lymphoma (GZL) was originally included in the 2008 World Health Organization classification as a B‐cell lymphoma unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL), new biological and clinical knowledge have been learned. It is important to highlight that diagnosis of this entity is complex and involvement by haematopathologists with expertise in this disease is recommended. It is recognized now that patients with GZL may present clinically with primary mediastinal localization or systemic disease without mediastinal involvement. Regardless of clinical presentation, patients with GZL have relatively high relapse rates, especially compared with primary mediastinal DLBCL or cHL. Interestingly, relapsed/refractory GZL patients appear to be salvaged fairly successfully, especially with haematopoietic stem cell transplantation (HSCT). Off of a clinical trial, we recommend R‐CHOP (rituximab, cyclophosphamide, doxorubicin, oncovin, prednisolone) or dose‐adjusted EPOCH‐R (etoposide, prednisolone, oncovin, cyclophosphamide, doxorubicin, rituximab) for frontline treatment of GZL. Additionally, we advocate use of consolidative radiotherapy for localized and/or bulky disease. For patients with relapsed/refractory GZL, salvage chemotherapy followed by consolidative autologous HSCT should be considered. Finally, continued biological and pathologic examination of this unique disease entity is warranted as well as exploration towards the integration of targeted therapeutic agents (e.g., brentuximab vedotin, programmed cell death 1inhibitors, B‐cell receptor inhibitors, proteasome inhibitors, etc.) into the treatment paradigm of GZL.

Comparative oncology DNA sequencing of canine T cell lymphoma via human hotspot panel

T-cell lymphoma (TCL) is an uncommon and aggressive form of human cancer. Lymphoma is the most common hematopoietic tumor in canines (companion animals), with TCL representing approximately 30% of diagnoses. Collectively, the canine is an appealing model for cancer research given the spontaneous occurrence of cancer, intact immune system, and phytogenetic proximity to humans. We sought to establish mutational congruence of the canine with known human TCL mutations in order to identify potential actionable oncogenic pathways. Following pathologic confirmation, DNA was sequenced in 16 canine TCL (cTCL) cases using a custom Human Cancer Hotspot Panel of 68 genes commonly mutated in human TCL. Sequencing identified 4,527,638 total reads with average length of 229 bases containing 346 unique variants and 1,474 total variants; each sample had an average of 92 variants. Among these, there were 258 germline and 32 somatic variants. Among the 32 somatic variants there were 8 missense variants, 1 splice junction variant and the remaining were intron or synonymous variants. A frequency of 4 somatic mutations per sample were noted with >7 mutations detected in MET, KDR, STK11 and BRAF. Expression of these associated proteins were also detected via Western blot analyses. In addition, Sanger sequencing confirmed three variants of high quality (MYC, MET, and TP53 missense mutation). Taken together, the mutational spectrum and protein analyses showed mutations in signaling pathways similar to human TCL and also identified novel mutations that may serve as drug targets as well as potential biomarkers.

Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DLBCL and classical HL

Gray zone lymphoma (GZL) is described as sharing features with classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). However, there remains complexity in establishing diagnosis, delineating prognosis, and determining optimum therapy. Sixty-eight cases diagnosed as GZL across 15 North American academic centers were evaluated by central pathology review to achieve consensus. Of these, only 26 (38%) were confirmed as GZL. Morphology was critical to GZL consensus diagnosis (eg, tumor cell richness); immunohistochemistry showed universal B-cell derivation, frequent CD30 expression, and rare Epstein-Barr virus (EBV) positivity (CD20+, 83%; PAX5+, 100%; BCL6+, 20%; MUM1+, 100%; CD30+, 92%; EBV+, 4%). Forty-two cases were reclassified: nodular sclerosis (NS) cHL, n = 27 (including n = 10 NS grade 2); lymphocyte predominant HL, n = 4; DLBCL, n = 4; EBV+ DLBCL, n = 3; primary mediastinal large BCL n = 2; lymphocyte-rich cHL and BCL-not otherwise specified, n = 1 each. GZL consensus-confirmed vs reclassified cases, respectively, more often had mediastinal disease (69% vs 41%; P = .038) and less likely more than 1 extranodal site (0% vs 25%; P = .019). With a 44-month median follow-up, 3-year progression-free survival (PFS) and overall survival for patients with confirmed GZL were 39% and 95%, respectively, vs 58% and 85%, respectively, for reclassified cases (P = .19 and P = .15, respectively). Interestingly, NS grade 2 reclassified patients had similar PFS as GZL consensus-confirmed cases. For prognostication of GZL cases, hypoalbuminemia was a negative factor (3-year PFS, 12% vs 64%; P = .01), whereas frontline cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab (CHOP±R) was associated with improved 3-year PFS (70% vs 20%; P = .03); both factors remained significant on multivariate analysis. Altogether, accurate diagnosis of GZL remains challenging, and improved therapeutic strategies are needed.

Gray Zone Lymphoma: Current Diagnosis and Treatment Options

The morphology of gray zone lymphoma (GZL) is variable with tumor cells spanning the spectrum of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma. The immunophenotype is frequently discordant. Clinically, the initial case descriptions of GZL were primarily with mediastinal presentation; however, a nonmediastinal (systemic) clinical subtype is now recognized. Patients with GZL have high relapse rates. Recommended treatment of GZL is with a DLBCL-directed regimen with consideration for consolidative radiotherapy for bulk disease. Continued biologic examination of this entity is needed and there should be exploration toward integration of novel targeted therapeutic agents into the treatment paradigm of GZL.

Paraneoplastic pyoderma gangrenosum with posttransplant lymphoproliferative disorder

Dear Editor, Pyoderma gangrenosum (PG) is an uncommon and serious ulcerating disease seen most often in females aged 20-50 years.[1] It is associated with malignancy in approximately 7% of cases. These are most commonly hematologic malignancies of which acute myelogenous leukemia is the most common.[2] To the best of our knowledge, there have been no prior reported cases of PG occurring during solid organ transplant (SOT)-related post-transplant lymphoproliferative disorder (PTLD). A 62 year-old female with history of a liver transplant for severe non-alcoholic steatohepatitis presented 3 months following SOT with repetitive neutropenic fever and pancytopenia. The absolute neutrophil count was 900 cells/mm3, hemoglobin 9.8 gram/dL, and platelets of 92,000 cells/mm3. Early in clinical course, the patient developed significant, non-healing ulcers in the left inguinal region (Figure 1A). Figure 1 PTLD-related pyoderma gangrenosum. Multiple large, deep necrotic ulcers were noted in the patients left inguinal region prior to treatment in panel A). Panel B) shows the same lesions 8 weeks thereafter (4 weeks following 4 doses of weekly rituximab. ... Biopsy of the inguinal cutaneous lesion showed ulceration with extensive tissue necrosis without lymphocytic infiltrate; special stains and tissue cultures were negative. The findings were most consistent with PG. An 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed a 3.1 cm hypermetabolic lymph node in the porta hepatis. Needle biopsy showed large lymphoid B-cells staining positive by immunohistochemistry for CD10 and CD20; Ki67 was 60%; Epstein Barr Virus (EBV) by EBV-encoded RNA in situ hybridization was negative. Clonal rearrangements of immunoglobin heavy chain gene and kappa light chain gene were detected. Altogether, the diagnosis was consistent with B-cell PTLD, monomorphic subtype, EBV-negative. The patient’s immunosuppression was decreased by approximately 75%. In addition, she received weekly single-agent rituximab. After four doses/weeks, restaging FDG-PET documented that the patient was in complete remission and her pancytopenia resolved. Furthermore, the patients PG began to improve (Figure 1B). She was treated with a total of 8 induction doses/weeks of rituximab and subsequently received maintenance rituximab every 3 months for 1 year. During this time, her PG progressively improved and ultimately resolved (Figures 1C-D). She has remained in complete remission 2 years following diagnosis. There is no standardized approach to the treatment of PTLD. This in part relates to significant patient and disease heterogeneity as well as an absence of randomized studies. Reduction/cessation of immunosuppression still remains a mainstay of treatment and rituximab has been shown to have a significant impact on the disease.[3, 4] Further, single-agent rituximab (in combination with reduced immunosuppression) may result in in long-term disease-free survival, including for polymorphic and monomorphic B-cell PTLD. Treatment of PG is challenging in part as there are no available randomized prospective trials. Therapy may include systemic steroids, cytotoxic drugs, and immunosuppressants.[2] The etiology of PG has not been fully elucidated, but it is linked in part to aberrant neutrophil activity.[2] There is a paucity of data regarding use of rituximab for treatment of PG. Two case reports of patients with granulomatosis with polyangiitis both associated with PG were successfully treated with infliximab followed by rituximab maintenance therapy[5] and rituximab alone, respectively, have been reported.[6] In summary, PG may occur as a paraneoplastic manifestation of PTLD. Furthermore, therapy with single-agent rituximab and reduced immunosuppression may be an effective therapeutic strategy.

Correction: Comparative oncology DNA sequencing of canine T cell lymphoma via human hotspot panel

[This corrects the article DOI: 10.18632/oncotarget.25209.].

Managing Lymphoma During Pregnancy

Lymphoma is one of the most common cancers that occurs during pregnancy. Primarily due to its usual peak onset in reproductive years, Hodgkin lymphoma (HL) occurs slightly more often during pregnancy than non-Hodgkin lymphoma (NHL). Prompt diagnosis to determine the exact lymphoma subtype is important, and specific staging studies are recommended for lymphoma occurring during pregnancy. NHLs are typically an aggressive subtype, commonly occur later in gestation, diagnosed at a more advanced stage, and often involve the reproductive organs. Treatment recommendations are based in part on the clinical scenario and patient/family wishes. Overarching goals for the treatment of pregnant mothers with lymphoma should be to concurrently optimize maternal survival and minimize treatment-related fetal toxicity and prematurity. This is maximized by close collaboration with high-risk maternal–fetal medicine and also with a goal of continuing pregnancy to full term (i.e., beyond 37 weeks). The decision to administer chemotherapy, radiation, and/or other therapeutic agents during gestation is individualized with the risk of antenatal therapy weighed against the potential adverse effects of delaying curative therapy. Overall, there should be consideration to delay anti-lymphoma treatment until after the first trimester and in select scenarios after delivery (e.g., asymptomatic indolent lymphomas, diagnosis in late third trimester, etc.), while antenatal therapy during the second and third trimesters is tenable in many cases (i.e., beyond 12 weeks). This detailed review describes available data on disease presentation and patient characteristics, gestational data, treatment (including targeted therapeutics), maternal and fetal complications, and additional considerations for patients diagnosed with NHL and HL during pregnancy.