High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.

Complete hematologic response after belinostat treatment and allogeneic stem cell transplantation for multiple relapsed/refractory angioimmunoblastic T-cell lymphoma: A case report.

Key Clinical Message: This case report highlights the potential of belinostat for the treatment of relapsed/refractory peripheral T-cell lymphomas, for which effective therapies are still scarce. Abstract: Peripheral T-cell lymphomas have an aggressive disease course associated with poor outcomes. We report a young patient with highly pretreated relapsed/refractory nodal follicular helper T-cell lymphoma (angioimmunoblastic-type [nTFHL-AI]), who successfully received an allogeneic stem cell transplantation following belinostat therapy. The complete hematologic response achieved has lasted more than 2 years.

Comparison of bone marrow trephine sample quality between a drill-powered system and a manual needle system.

CONTEXT: Bone marrow biopsy (BMB) is a common procedure in haematology used for the diagnosis and evaluation of response treatment. Because the procedure is difficult for haematologists to perform, patients often experience pain and stress. On Control, a system device, was introduced in the 2000s and uses a drill-powered needle to perform BMB. OBJECTIVE: The aim of this study was to compare the quality of BMB, based on the length of the trephine, the number of interosseous spaces and the interpretability of the examination, obtained from manual BMB vs. drill-powered BMB. The secondary objectives were to evaluate the patient's pain and anxiety, and the haematologist's perceived difficulty in performing BMB. DESIGN: This was a retrospective study conducted between June 2016 and June 2017 in the Henri Becquerel Cancer Centre in Rouen, France. RESULTS: A total of 439 patients were included in the study; the sex ratio (M:F) was 1.34 and 70.2% underwent a drill-powered BMB. A significant difference was observed concerning trephine length (14.30 ± 5.58 mm with the drill-powered system vs. 11.18 ± 4.43 mm with manual BMB, p < 0.0001) and the number of interosseous spaces (9.49 ± 5.35 vs. 7.93 ± 4.01, respectively, p = 0.01). The interpretability of the examination did not differ between the two procedures (p = 0.9). CONCLUSIONS: On Control, the drill-powered system for BMB, is widely distributed in North America and Europe, but this procedure is not yet generally applied. Although this procedure is costly, the ongoing development of this technique, because of its performance, is beneficial especially to obese patients.

Circulating tumor DNA in primary mediastinal large B-cell lymphoma versus classical Hodgkin lymphoma: a retrospective study.

Few data exist concerning circulating tumor DNA (ctDNA) relevance in primary mediastinal B-cell lymphoma (PMBL). To explore this topic, we applied a 9-gene next-generation sequencing pipeline to samples from forty-four PMBL patients (median age 36.5 years). The primary endpoint was a similarity between paired biopsy/plasma mutational profiles. We detected at least one variant in 32 plasma samples (80%). The similarity between the biopsy and ctDNA genetic profiles for the 30 patients with paired mutated biopsy/plasma samples was greater than or equal to 80% in 19 patients (63.3%). We then compared PMBL ctDNA features with those of a cohort of Hodgkin lymphoma patients (n = 60). The top three mutated genes were SOCS1, TNFAIP3, and B2M in both lymphoma types. PMBL displayed more alterations in TNFAIP3 (71.9% vs. 46.3%, p = 0.029) and GNA13 (46.9% vs. 17.1%, p = 0.013) than cHL. Our 9-gene set may delineate tumor genotypes using ctDNA samples from both lymphoma types.

Kidney Transplant T Cell-Mediated Rejection Occurring After Anti-CD19 CAR T-Cell Therapy for Refractory Aggressive Burkitt-like Lymphoma With 11q Aberration: A Case Report.

Post-transplant lymphoproliferative disorder is a growing complication of kidney transplantation and is associated with a poor prognosis. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an important new treatment option modifying the outcome of refractory hematological cancers. Here, we report the case of a 40-year-old kidney transplant recipient who developed a Burkitt-like lymphoma with 11q aberration 5 years after transplantation. After 3 unsuccessful lines of chemotherapy, it was decided to treat the patient with anti-CD19 CAR T cells as a salvage therapy. Three months after CAR T-cell infusion, she experienced a grade IIB T cell-mediated rejection with severe tubulitis (T3), slight interstitial inflammation (I1), and severe intimal arteritis (V2) with blood suffusion. Among T cells infiltrating the graft, some of them expressed the anti-CD19 CAR. CAR T cells within the graft and in blood samples were also detected by droplet digital polymerase chain reaction. Function of the kidney transplant improved after corticosteroid treatment and remained stable. However, lymphoma progressed, with a massive pulmonary mass leading to the patient's death 10 months after CAR T-cell infusion.

Successful treatment of T/myeloid mixed-phenotype acute leukemia with the translocation (10;11)(p13;q14) PICALM/AF10 with 3 + 7 myeloid standard treatment: A case report.

The translocation PICALM/AF10 is described in multilineage diseases. We report a patient with PICALM/AF10 T/myeloid mixed-phenotype acute leukemia who achieved durable complete remission after AML-like treatment suggesting a myeloid origin.

Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: a prospective study.

The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients] were assessed in this non-interventional study. Median age of the patients was 33.5 years (range 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype are correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, NA=6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). Mean of DeltaSUVmax after C2 was -78.8%. We analyzed ctDNA after C2 for 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.

Light chain lambda myeloma with fatal AL cardiac amyloidosis in a 21-year-old patient: A case report and review.

Multi-organ AL amyloidosis is a therapeutic challenge because of light chain deposits severely damaging the function of concerned organs. Cardiac involvement, which leads to concentric hypertrophy of both ventricles, is particularly severe and leads to poor prognosis regardless of combination chemotherapy. This case pinpoints the relevance of combining clinical, histological, and echocardiographic information in the management of this complex and life-threatening disease.

Non-invasive detection of somatic mutations using next-generation sequencing in primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphomas (PCNSL) have recurrent genomic alterations. The main objective of our study was to demonstrate that targeted sequencing of circulating cell-free DNA (cfDNA) released by PCNSL at the time of diagnosis could identify somatic mutations by next-generation sequencing (NGS). PATIENTS AND METHODS: PlasmacfDNA and matched tumor DNA (tDNA) from 25 PCNSL patients were sequenced using an Ion Torrent Personal Genome Machine (Life Technologies®). First, patient-specific targeted sequencing of identified somatic mutations in tDNA was performed. Then, a second sequencing targeting MYD88 c.T778C was performed and compared to plasma samples from 25 age-matched control patients suffering from other types of cancer. RESULTS: According to the patient-specific targeted sequencing, eight patients (32% [95% CI 15-54%]) had detectable somatic mutations in cfDNA. Considering MYD88 sequencing, six patients had the specific c.T778C alteration detected in plasma. Using a control group, the sensitivity was 24% [9-45%] and the specificity was 100%. Tumor volume or deep brain structure involvement did not influence the detection of somatic mutations in plasma. CONCLUSION: This pilot study provided evidence that somatic mutations can be detected by NGS in the cfDNA of a subset of patients suffering from PCNSL.

Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: implications for targeted EZH2 inhibitor therapy?

Enhancer of Zeste Homolog 2 (EZH2) plays an essential epigenetic role in Diffuse Large B Cell Lymphoma (DLBCL) development. Recurrent somatic heterozygous gain-of-function mutations of EZH2 have been identified in DLBCL, most notably affecting tyrosine 641 (Y641), inducing hyper-trimethylation of H3K27 (H3K27me3). Novel EZH2 inhibitors are being tested in phase 1 and 2 clinical trials but no study has examined which patients would most benefit from this treatment. We evaluated the immunohistochemical (IHC) methylation profiles of 82 patients with DLBCL, as well as the mutational profiles of 32 patients with DLBCL using NGS analysis of a panel of 34 genes involved in lymphomagenesis. A novel IHC score based on H3K27me2 and H3K27me3 expression was developed, capable of distinguishing patients with wild-type (WT) EZH2 and patients with EZH2 Y641 mutations (p = 10-5). NGS analysis revealed a subclonal EZH2 mutation pattern in EZH2 mutant patients with WT-like IHC methylation profiles, while associated mutations capable of upregulating EZH2 were detected in WT EZH2 patients with mutant-like IHC methylation profiles. IHC and mutational profiles highlight in vivo hyper-H3K27me3 and hypo-H3K27me2 status, pinpoint associated activating mutations and determine EZH2 mutation clonality, maximizing EZH2 inhibitor potential by identifying patients most likely to benefit from treatment.