Search

Cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma, is thought to arise from mature tissue-resident memory T cells. The most common subtypes include Mycosis Fungoides and Sezary Syndrome. The role of skin microbiota remains unclear in the symptom manifestation of MF. Among 39 patients with MF, we analyzed bacteria colonizing MF lesions and non-lesional skin in the contralateral side and characterized regional changes in the skin microbiota related to MF involvement using the difference in relative abundance of each genus between lesional and contralateral non-lesional skin. We investigated the relationship between these skin microbiota alterations and symptom severity. No statistically significant difference was found in bacterial diversity and richness between lesional and non-lesional skin. Different skin microbiota signatures were associated with different symptoms. More pronounced erythema in the lesions was associated with an increase in Staphylococcus. Pain and thick skin in the lesions were associated with a decrease in Propionibacterium. The results of this pilot study suggest that the skin microbiota plays an important role in changing skin phenotypes among patients with MF. Larger skin microbiota studies are needed to confirm these findings and support the use of antibiotic treatment to mitigate CTCL symptoms.

Background Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD). Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130), including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. Methods Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m2 romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. Results Of the 32 patients (25 %) with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment). The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m2 on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. Conclusions We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. Trial registration NCT00426764

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

INTRODUCTION: Large granular lymphocyte (LGL) leukemia is associated with increased numbers of circulating NK or T-LGL cells with only 5% of these cases related to NK-cell expansion. NK-LGL leukemia is primarily characterized by chronic anemia in association with low to normal numbers of erythroid precursors in the bone marrow and chronic neutropenia. Here, we explore the mechanism of pathogenesis in the first case report of a patient with NK-LGL leukemia in association with primary pulmonary hypertension (PPH). This patient displayed a diffuse pulmonary infiltrate with sustained elevated mean pulmonary artery pressure at rest confirmed by right-sided cardiac catheterization meeting the clinical diagnostic criteria for PPH. Association between T-LGL leukemia and PPH has been reported previously suggesting a causitive link between LGL expansion and PPH pathogenesis. METHODS: Cytotoxicity of a normal pulmonary endothelial cell line (CRL-2598) was determined by 5-hr 51-Cr-release assays using NK-cells from this NK-LGL patient compared to healthy controls. Specific NK receptors were blocked by antibodies added to the effector cells for 30 min prior to the cytotoxicity assay. Production of TNFα was assessed by intracellular cytokine staining with detection by flow cytometry. To block NK receptor signals, dominant negative adaptor proteins, DAP10 and DAP12, were constructed and expressed in recombinant vaccinia viruses. These viruses were engineered to carry a single Y-A mutation at Y102 or a double mutation at both Y9 and Y102 within the YxxM activating ITAM motif of the adaptor protein. Perforin granule mobilization was determined by immunofluorescence microscopy. RESULTS: Sixty-eight % of peripheral blood and bone marrow mononuclear cells from this patient were phenotypically NK-LGLs with skewed reactivity to the anti-CD158a antibody (KIR2DS1/2DS2), which was shown by mRNA analysis to consist primarily of activating KIR2DS1. We examined the susceptibility of CRL-2598 cells to NK lysis and found that patient-derived NK-cells produced greater lysis without prior activation than healthy controls. Furthermore, NK-cells from this patient produced more TNF-α in response to paraformaldehyde-fixed CRL-2598 cells and displayed perforin granule mobilization to the contact site between effector and target cells. Addition of blocking antibodies against the activating receptors NKG2D and KIR2DS1/KIR2DL1 (anti-CD158a) produced a blockade in this process showing that these receptors were responsible for lysis. When DAP10 and DAP12 adaptor signaling steps were blocked, killing and perforin granule redistribution toward the contact site of the conjugated targets was suppressed. CONCLUSION: This study shows that the presence of activating NK-receptors and DAP10/DAP12 adaptors contibuted to lysis of normal endothelial cells in this patient. DAP10 and DAP12 are key initiators for both NK− and T−cell function suggesting that targeted disruption of these signaling events may prove beneficial for autoimmune inflammatory diseases such as PPH and LGL leukemia.