Aims
Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage.
Methods and results
This ...prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision‐making regarding therapy. Over the 12‐year study period, among the 233 patients included, 133 were NYHA III‐IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT‐proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut‐off values for Stage 1: hsTnT ≤ 107 ng/L and NT‐proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT‐proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT‐proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI 2–24. At 1 year, 102 (44%) patients died and the Kaplan–Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI 11–18) and stage 3, 6.6 months (95% CI 1–13). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2.
Conclusions
The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.
The causal protein of amyloid light‐chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several ...manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme‐linked immunosorbent assay (ELISA) (Sebia) with N‐Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non‐AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free‐light chain difference (dFLC) were lower than N‐Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N‐Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases.
Chronic CD8(+) T-cell expansions can result in parotid gland swelling and other organ infiltration in HIV-infected patients, or in persistent cytopenias. We report 14 patients with a CD8+ T-cell ...expansion to better characterize the clinical spectrum of this ill-defined entity. Patients (9 women/5 men) were 65 year-old (range, 25-74). Six patients had ≥ 1 symptomatic organ infiltration, and 9 had ≥ 1 cytopenia with a CD8(+) (>50% of total lymphocyte count) and/or a CD8(+)/CD57(+) (>30% of total lymphocyte count) T-cell expansion for at least 3 months. One patient had both manifestations. A STAT3 mutation, consistent with the diagnosis of large granular lymphocyte leukemia, was found in 2 patients with cytopenia. Organ infiltration involved lymph nodes, the liver, the colon, the kidneys, the skin and the central nervous system. Three patients had a HIV infection for 8 years (range, 0.5-20 years). Two non-HIV patients with hypogammaglobulinemia had been treated with a B-cell depleting monoclonal antibody (rituximab) for a lymphoma. One patient had a myelodysplastic syndrome with colon infiltration and agranulocytosis. The outcome was favorable with efficient antiretroviral therapy and steroids in HIV-infected patients and intravenous immunoglobulins in 2/3 non-HIV patients. Six patients had an agranulocytosis of favorable outcome with granulocyte-colony stimulating factor only (3 cases), cyclophosphamide, methotrexate and cyclosporine A, or no treatment (1 case each). Three patients had a pure red cell aplasia, of favorable outcome in 2 cases with methotrexate and cyclosporine A; one patient was unresponsive. Chronic CD8(+) T-cell expansions with organ infiltration in immunocompromised patients may involve other organs than parotid glands; they are non clonal and of favorable outcome after correction of the immune deficiency and/or steroids. In patients with bone marrow infiltration and unexplained cytopenia, CD8(+) T-cell expansions can be clonal or not; their identification suggests that cytopenias are immune-mediated. Our results extend the clinical spectrum of chronic CD8(+) T-cell expansions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this ...study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic ...tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.
•Early identification of ultra-risk DLBCL patients is needed to aid stratification to alternative treatment approaches.•High baseline TMTV (±ECOG) was a strong prognosticator of inferior PFS and OS in REMARC patients post-R-CHOP, irrespective of maintenance.
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Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence ...demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
•End of treatment HD-MTX did not increase risk of CNS relapse compared with intercalated delivery and caused fewer delays to R-CHOP therapy.•CNS relapse rates in this large analysis of HD-MTX-treated patients were similar to published cohorts receiving minimal CNS prophylaxis.
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COVID-19 patients affected by haematological malignancies have a more severe course of the disease and higher mortality, prompting for effective prophylaxis. The present study aims to evaluate the ...humoral response after mRNA vaccination as well as the impact of a third vaccine dose in patients with lymphoid malignancies.
We conducted a single-centre study, evaluating the serological responses of mRNA vaccination amongst a cohort of 200 patients affected by lymphoid malignancies after two or three doses using an industrial SARS-CoV-2 serology assay for anti-receptor binding domain (RBD) Spike IgG detection and quantification.
Among patients with plasma cell disorders, 59 of 96 (61%) had seroconversion (anti-RBD >50 AU/mL), and recent anti-CD38 therapies were associated with lower serological anti-RBD IgG concentrations (median IgG concentration 137 (IQR 0–512) AU/mL vs. 543 (IQR 35–3496) AU/mL; p < 0.001). Patients with B-cell malignancies had a lower seroconversion rate (20/84, 24%) mainly due to the broad usage of anti-CD20 monoclonal antibodies; only 2 of 53 (4%) patients treated by anti-CD20 antibodies during the last 12 months experienced a seroconversion. A total of 78 patients (44 with plasma cell disorders, 27 with B-cell malignancies, and 7 with other lymphomas) received a third dose of vaccine. The seroconversion rate and antibody concentrations increased significantly, especially in patients with plasma cell disorders, where an increment of anti-RBD IgG concentrations was observed in 31 of 44 (70%) patients, with an anti-RBD concentration median-fold increase of 10.6 (IQR 2.4–25.5). Its benefit in B-cell malignancies is uncertain, with only 2 of 25 (8%) patients having seroconverted after the vaccine booster, without increased median antibody concentration.
A third mRNA vaccine dose significantly improved humoral responses among patients with plasma cell disorders, whereas the effect was limited among patients with B-cell malignancies.
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Background Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS ...patients is usually very poor with short survival (typically <1 year) due to chemoresistance. Indeed, chemoimmunotherapy regimens used in de novo DLBCL failed to induce a significant complete remission rate (CRR) (R-CHOP, 7%; ofatumumab-CHOP, 27%) (Langerbeins et al., AJH 2014; Eyre et al., BJH 2016). CD19-targeted chimeric antigenic receptor (CAR) T-cell therapy such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have been transformative for patients with relapsed/refractory DLBCL. Here, we aimed to investigate the efficacy and safety profile of CD19-CAR T-cell therapy for patients with RS.Methods In this Lymphoma Study Association/ Lymphoma Academic Research Organization (LYSA/LYSARC) study, we conducted an analysis of the DESCAR-T registry which collects real-life data of patients treated with approved CD19-directed CAR T-cell therapies (axi-cel and tisa-cel) since July 1st, 2018 in France. We selected patients with biopsy-proven RS of DLBCL histology, treated by tisa-cel or axi-cel in either the frontline or relapse setting. Data regarding prior CLL history were collected in addition to the DESCAR-T registry data. The data cut-off was April 29th, 2022. The primary endpoint was best CRR according to Cheson IWG 2014 (Lugano Classification) after CAR-T cell infusion. Secondary endpoints were overall response rate (ORR), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (ASTCT Consensus) as well as hematological toxicity (NCI CTCAE v5.0).Results CD19-directed CAR T-cell therapy was planned for 14 patients from January 6th, 2020 to March 2nd, 2022, 12 were infused and subsequently included in the present analysis (1 patient refused the infusion and 1 was not infused due to disease progression). Median age was 60 years (range, 42-76) and sex ratio M/F was 2. CLL cytogenetic features at baseline (when available) were as follows: 2/8 (25%) patients had 17p deletion, 6/8 (75%) 11q deletion and 3/6 (50%) complex karyotype. TP53 mutations were seen in 4/7 (57%) patients. 4/6 (67%) patients harbored unmutated IGHV. Median number of prior therapeutic lines for CLL before RS was 2 (range, 0-9). Of the 12 patients who were infused, 3 (25%) did not receive any prior therapy for CLL. Seven (58%) patients received chemo-immunotherapy, 7 (58%) had been exposed to ibrutinib including 5 (42%) to both ibrutinib and venetoclax. Median time from CLL diagnosis to RS was 7 years (range, 3-22). Ten (83%) patients received ≥ 1 prior lines of therapy for RS (median 3, range 0-3) and bridging therapy was administered to all but one patient. Evaluation for disease status prior CAR T-cell infusion revealed progression for 7 (58%) patients, complete response in 1 (8.3%), partial response in 2 (16.7%) and stable disease in 1 (8.3%) (1 patient non-evaluated).Following CAR T-cell infusion with axi-cel (5 patients) or tisa-cel (7 patients), best CRR was 42% and best ORR was 50%. Ten (83%) patients presented with CRS, 3 (25%) with grade > 2. Tocilizumab was administered to 9 (75%) patients. Five (42%) patients had ICANS, 3 (25%) with grade > 3. Regarding hematotoxicity, 6 (50%) patients presented with grade > 2 thrombocytopenia, 5 (42%) with grade > 2 anemia, and 7 with (58%) grade > 2 neutropenia. One case of macrophage activation syndrome was reported. Three patients were admitted to intensive care. A total of 5 (42%) patients had infections. After a median follow-up of 1.6 months (range, 0-23), 8 (67%) patients were alive, 4 (33%) patients died (2 from CRS and 2 from disease progression).Conclusions CD19-directed CAR T-cell therapy showed high response rates in our series of heavily pretreated RS patients. Frequency of CAR T-cell-specific adverse events was in the range of what is observed in de novo DLBCL while severity appeared higher (Schuster et al., NEJM 2019; Neelapu et al., NEJM 2017). Larger cohort with longer follow-up and prospective trials are warranted to confirm these observations.
Introduction Post-transplant lymphoproliferative disorders (PTLD) are rare and severe complications of organ or allogeneic stem cell transplants (AST), often linked to EBV. The recommended first-line ...management of systemic PTLD, in addition to lowering immunosuppression, currently consists of response-tailored treatment (RTT): monotherapy with rituximab (R) and, in case of CR, a continuation of rituximab as monotherapy (RM), otherwise 4 courses of R-CHOP. The data in the literature are limited to a few very rare prospective studies and limited series, generally monocentric. Patients and methods The French national K-virogref database, supported by the French Institute against Cancer (INCa), started in September 2013, gathers data from PTLDs confirmed by biopsy and re-reading in the Lymphopath network. Data from 10 years of this registry have been analyzed. Results A total of 525 adult patients are analyzed, the median age of transplant is 44 years, that of diagnosis of PTLD 58 years, 63% are men. Transplants are 61% kidneys, 17% livers, 6% lungs, 6% hearts, 8% stem cells. The median time from transplant to diagnosis of PTLD is 97 months, with 16% of diagnosis within the first year. The histology is of early lesion type in 4.6%, polymorphic in 12% and of lymphoma type in 83.3%, 46.7% are linked to EBV. Of the total 435 are systemic and 90 (17%) are localized to the central nervous system (CNS); predictors of CNS PTLD are later age at transplant (52 years vs 43 years), male gender ( p=1.10-3), a kidney transplant (69% vs 60%), CNS PTLDs are more often late after the transplant, more often of the lymphoma type and almost always linked to EBV (97.8%). The EBV status of the recipient at the time of transplantation was known in 242 cases, of which 50 were EBV negative; the negative EBV status is linked to an earlier age at diagnosis (43 years vs 58 years), a shorter time between transplant and diagnosis (11.5 months vs 66.5), more often early forms, more frequent localization in the graft (24% vs 9%), better survival. The median overall survival (OS) of all patients is 2700 days, tumor EBV status has no influence on OS, progression-free survival (PFS) is 1500 days. Median survivals are 2600 days for AST, 4600 for hearts, 5400 for lungs and not reached (NR) for livers and kidneys. Among the classic prognostic criteria, the IPI is not discriminating between 0 and 2, whereas the personal status is clearly discriminating (cf figure). Of the patients CD20+ without CNS localization nor Burkitt, treatment data were known for 274 patients: 27% received only immuno-chemotherapy (IC), 38% had RM and 35% R then R-CHOP. Survival is identical between IC and R then R-CHOP, with less chemotherapy in the sequential treatment, and is significantly higher (p=0.011) for RM, the RTT has a trend to a better OS than IC (p=0.062). In the event of chemotherapy, the use of an anthracycline has a better OS (median NR vs 750 days). Conclusion To our knowledge, this is the largest series of PTLD presented to date. The results of OS are similar to those presented in the prospective studies with selected patients and our data confirm the interest of RTT, with in case of chemotherapy, the need to use an anthracycline. The most discriminating and simplest prognostic criterion is PS. However, this very large series only concerns adult patients and cannot describe real-life pediatric PTLD.
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