Follicular helper T cell: Emerging roles in lymphomagenesis.

Follicular helper T cells (Tfh) are a subset of CD4+ T cells that are fundamental to forming germinal centers, which are the primary sites of antibody affinity maturation and the proliferation of activated B cells. Tfh cells have been extensively studied over the past 10 years, especially regarding their roles in cancer genesis. This review describes the characteristics of normal Tfh cells and focuses on the emerging link between Tfh cells and lymphomagenesis. Advances in lymphoma genetics have substantially expanded our understanding of the role of Tfh cells in lymphomagenesis. Moreover, we detail a range of agents and new therapies, with a major focus on chimeric antigen receptor T-cell therapy; these novel approaches may offer new treatment opportunities for patients with lymphomas.

Novel cellular immunotherapies for hematological malignancies: recent updates from the 2021 ASH annual meeting.

Cellular immunotherapy, including the chimeric antigen receptor T (CAR-T) cell therapy and CAR- natural killer (CAR-NK) cell therapy, has undergone extensive clinical investigation and development in recent years. CAR-T cell therapy is now emerging as a powerful cancer therapy with enormous potential, demonstrating impressive anti-tumor activity in the treatment of hematological malignancies. At the 2021 ASH annual meeting, numerous breakthroughs were reported concerning acute lymphocytic leukemia (ALL), lymphoma, acute myeloid leukemia (AML), and multiple myeloma (MM). Universal CAR-T cell and CAR-NK cell therapy, as well as induced pluripotent stem cell (iPSC)-derived immunotherapy, offer great "off-the-shelf" benefits. Major development and updates of cellular immunotherapy for hematological malignancies reported at the 2021 ASH annual meeting are summarized in this review.

Phase 2 study of oral thalidomide-cyclophosphamide-dexamethasone for recurrent/refractory adult Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm with various clinical manifestations and heterogeneous prognoses. No standard therapy is available for recurrent/refractory LCH patients. This single-center, single-arm, phase 2 study enrolled 32 patients diagnosed with recurrent/refractory LCH. The TCD regimen (thalidomide 100 mg daily, cyclophosphamide 300 mg/m2 Day 1, 8, 15, and dexamethasone 40 mg Day 1, 8, 15, 22 every 4 weeks) was administered for 12 cycles and thalidomide alone as maintenance for 12 months. The primary endpoint was event-free survival (EFS). Events were defined as progression during or after TCD therapy or death from any cause. After a median follow-up of 22 months (range 5-24 months), no patient died of all causes. The overall response rate was 87.5%, including 18 patients (56.3%) achieving complete remission and 10 patients (31.3%) as partial remission. The estimated 24-month EFS was 64.0%. Patients with risk organ involvement had similar EFS compared to patients without risk organ involvement (P = 0.38). The common toxicities of TCD regimen include grade 1-2 neutropenia (18.8%), grade 1-2 constipation (12.5%), grade 1-2 tiredness (9.4%) and grade 2 peripheral neuropathy (12.5%). Oral thalidomide, cyclophosphamide and dexamethasone are effective and safe regimen for recurrent/refractory LCH patients, particularly for patients with risk organ involvement.

Effective treatment of progressive nodular histiocytosis by intermediate-dose cytarabine: a case report and literature review.

BACKGROUND: Progressive nodular histiocytosis (PNH) is a rare, clinically distinct non-Langerhans cell histiocytic neoplasm affecting the skin and mucous membranes with no signs of spontaneous regression of the lesions. Patients typically have hundreds of lesions of superficial xanthomatous papules to nodules and deep larger fibrous nodules, which can be life-threatening if laryngeal mucosa was involved. So far, few cases of PNH have been reported and no effective treatment has been shown to reverse the progressive clinical course. CASE PRESENTATION: Here we describe a case of PNH presenting as diffuse, progressively enlarging papules, nodules and even leonine appearance in a young woman. The diagnosis was confirmed by histological and immunohistochemical findings. Next-generation sequencing (NGS) showed identical missense mutation in XIAP Y404C and in-frame deletion in MAPK1 A2[6>5]. Since ERK inhibitor has not been on the market yet, the patient received chemotherapy instead. Traditional chemotherapy with intermediate-dose of cytarabine (500 mg/m2 cytarabine by 3-hour infusion every 12 hours for 3 days every 5 weeks) achieved favorable therapeutic effect as confirmed by clinical symptoms and PET/CT imaging. CONCLUSIONS: PNH is a rare, proliferative disorder with disfiguring lesions and deteriorative quality of life. Mutations in MAPK1, XIAP may play crucial roles in the pathogenesis of PNH. Intermediate-dose cytarabine can be considered as a promising treatment option for PNH patients.

Pulmonary manifestations of Erdheim-Chester disease: clinical characteristics, outcomes and comparison with Langerhans cell histiocytosis.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis that typically affects many organs, including the lung and pleura. However, there are few studies concerning pulmonary involvement in ECD patients, as well as the difference of pulmonary involvement between ECD and Langerhans cell histiocytosis (LCH). We performed a retrospective study of 54 ECD patients, and compared the pulmonary manifestations with those of adult LCH patients in our centre. The median age of diagnosis of the 54 ECD patients was 48 years (range 9-66 years). Chest computed tomography (CT) scans revealed lung involvement in 49 (91%) patients and pleural involvement in 34 (63%). Thirty-three (61%) patients had interstitial lung disease (ILD) with varying degrees of interlobular septal thickening, micronodules, and ground-glass opacities. ECD and LCH patients with pulmonary involvement showed significant differences in smoking status (P < 0·001), respiratory symptoms (P = 0·001) such as cough and pneumothorax (P < 0·001), and radiological findings, including cysts (P < 0·001), opacities (P < 0·001), and pleural thickening (P < 0·001). With a median follow-up duration of 24 months (range, 1-84 months), the estimated three-year overall survival (OS) of this entire ECD cohort was 90·2%. Patients with ILD tended to have worse progression-free survival (PFS) than those with no ILD (P = 0·29).

Early or deferred treatment of smoldering multiple myeloma: a meta-analysis on randomized controlled studies.

PURPOSE: Smoldering multiple myeloma (SMM) is a rare asymptomatic plasma cell disorder. Even with emerging therapeutic approaches and risk stratification, the optimal time to treat SMM remains controversial. This meta-analysis aimed to compare early treatment with deferred treatment of SMM, especially high-risk SMM. METHODS: Early treatment was defined as treatment immediately after diagnosis. Deferred treatment was initiated after progression. The primary outcome was progression. Secondary outcomes were mortality, response, and safety. PubMed, EMBASE, Medline, Cochrane, and ClinicalTrials.gov databases were searched from January 1990 to March 2019. Randomized controlled trials (RCTs) comparing early treatment with deferred treatment in SMM patients were eligible. Risk ratios (RRs) with 95% confidence interval (CI) were pooled. RESULTS: Eight RCTs covering 885 SMM patients were included. Considering all the different treatment approaches, early treatment significantly decreased progression of SMM (RR=0.53, 95% CI 0.33-0.87, P=0.01). In subgroup analysis, melphalan plus prednisone (RR=0.22, 95% CI 0.08-0.64, P=0.005) and immuno-modulatory drugs (RR=0.43, 95% CI 0.31-0.59, P<0.00001) significantly reduced progression. However, neither mortality nor response rate was significantly affected by early treatment. In terms of high-risk SMM patients, early treatment significantly decreased both progression (RR=0.51, 95% CI 0.37-0.70, P=0.0001) and mortality (RR=0.53, 95% CI 0.29-0.96, P=0.04). Frequently seen adverse events were infection, constipation, asthenia, and second primary malignancy. A remarkably elevated risk of constipation was associated with early treatment using immuno-modulatory agents (RR=4.43, 95% CI 2.14-9.12, P<0.0001). Second primary malignancy was significantly increased with early treatment (RR=4.13, 95% CI 1.07-15.97, P=0.04). No significant difference was identified in infection or asthenia. CONCLUSION: These findings suggest that early treatment could decrease progression and mortality of high-risk SMM patients with a tolerable safety profile.

Increased activated regulatory T cell subsets and aging Treg-like cells in multiple myeloma and monoclonal gammopathy of undetermined significance: a case control study.

BACKGROUND: Accumulating evidence have indicated that regulatory T cells (Tregs) play an essential role in T cell-mediated immune response and development of multiple myeloma (MM). CD4+FoxP3+ T cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA+FoxP3lo resting Tregs (rTregs), CD45RA-FoxP3hi activated Tregs (aTregs) and CD45RA-FoxP3lo non-suppressive T cells (non-Tregs). We aimed to clarify the frequency and function of these three subpopulations in newly diagnosed multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) patients. In addition, CD28-CD4+FoxP3+ Treg-like cell is a senescent regulatory T cell subset with partial suppressive function, which could be impaired during myelomagenesis. METHODS: we examined 20 patients with MGUS, 26 patients with newly diagnosed MM and 18 healthy volunteers. Flow cytometric analysis in peripheral blood and bone marrow was performed for frequency study. The immunosuppressive function of Treg subsets was assessed by their ability to suppress the proliferation of responder cells in co-culture. Concentration of cytokine from the culture supernatants of proliferation assay was measured using ELISA. RESULTS: The proportion of activated Tregs in CD4+ T cells was significantly higher in MGUS and MM patients than healthy controls (P = 0.01, P < 0.001) in both PB and BM; while the proportion of rTregs in MGUS, MM patients was significantly lower than that of controls (P = 0.02, P < 0.01) only in BM. There was no significant difference in frequencies of non-Tregs from MGUS to MM patients with normal controls (P = 0.14, P = 0.88). Significant increase in PB and BM Treg-like cells was observed in MGUS and MM cohort compared with healthy controls (P < 0.01, P < 0.01). Treg-like cells in MM patients were significantly higher than those in MGUS patients (P < 0.01). The inhibition rate of aTreg in bone marrow of MM patients was significantly higher than that of rTreg (P < 0.01), while the inhibition rate of non-Treg was significantly lower than that of rTreg cells (P < 0.01). Functional assays revealed the suppressive and secretory abilities of three Treg subsets were intact in MM patients. CONCLUSIONS: In summary, aTregs and aging Treg-like cells were quantitatively altered in MGUS and MM patients, which might be associated with disease progression and prognosis.