Baseline circulating tumour DNA and interim PET predict response in relapsed/refractory classical Hodgkin lymphoma.

Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non-haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [18 F]-FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non-invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials.

Primary central nervous system marginal zone lymphoma.

Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.

Dose-adjusted EPOCH and rituximab for the treatment of double expressor and double-hit diffuse large B-cell lymphoma: impact of TP53 mutations on clinical outcome.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic stem-cell transplantation. Posttransplantation cyclophosphamide (PT/CY) has become standard prophylaxis of GVHD in T-replete haploidentical transplantation. The question is whether adding antithymocyte globulin (ATG) to PT/CY may further reduce the incidence of GVHD compared to PT/CY only. PATIENTS AND METHODS: We retrospectively studied 268 patients undergoing myeloablative haploidentical transplantation with thiotepa, busulfan, and fludarabine (TBF) conditioning. Sixty-nine patients (26%) received ATG. RESULTS: In the ATG group, 3% died due to GVHD versus 8% in the no ATG group. The 100-day and 1-year nonrelapse mortality (NRM) was 0% and 19%, respectively, in the whole cohort. On univariate analysis, the 1-year NRM was 8% versus 23% in patients receiving ATG and no ATG, respectively (P = .005). The no ATG group had a higher incidence of acute GVHD at 12 months compared to the ATG group (22% vs. 12%, respectively, P = .029). The ATG group had better overall survival at 12 months compared to the no ATG group (79% vs. 69%, P = .029). On multivariate analysis, adding ATG to PT/CY had no significant impact on any of the outcomes. A low disease risk index was associated with better overall survival and lower NRM, while Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥ 3 was associated with higher NRM. CONCLUSION: ATG can be safely used as part of the pretransplantation conditioning and does not increase the incidence of relapse or complications after transplantation.

Pretransplant active disease status and HLA class II mismatching are associated with increased incidence and severity of cytokine release syndrome after haploidentical transplantation with posttransplant cyclophosphamide.

Cytokine release syndrome (CRS) represents a life-threatening side effect after haploidentical stem cell transplantation (Haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo-SCT with PT-Cy. The two cohorts were similar in main patients' characteristics besides disease type (P = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High-grade fever (39°-41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P = .0005; 87% vs 71%, P = .009; 20% vs 7%, P = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1-year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% (P = .002) and 40% vs 8% (P = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P = .002), HLA-DRB1 mismatching (57% vs 14%, P = .007), and PBSC graft (P = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P = .005) and HLA-DRB1 mismatching (HR: 17.19, P = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo-SCT with PT-Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA-DRB1 mismatching.