Hepatitis B virus-associated polyarteritis nodosa (HBV-PAN) is a typical form of classic PAN whose pathogenesis has been attributed to immune-complex deposition with antigen excess. We conducted the ...current study to 1) analyze the frequency of HBV infection in patients with PAN, in light of the classification systems described since 1990; 2) describe the clinical characteristics of HBV-PAN; 3) compare the evolution according to conventional or antiviral treatment; and 4) evaluate long-term outcome. One hundred fifteen patients were included in therapeutic trials organized by the French Vasculitis Study Group and/or referred to our department for HBV-PAN between 1972 and 2002. To determine the frequency of HBV-PAN during the 30-year period, we analyzed a control group of patients with PAN without HBV infection, followed during the same period and diagnosed on the same bases. Depending on the year of diagnosis, different treatments were prescribed. Before the antiviral strategy was established, some patients were given corticosteroids (CS) with or without cyclophosphamide (CY). Since 1983, treatment for patients with HBV markers has combined 2 weeks of CS followed by an antiviral agent (successively, vidarabine, interferon-alpha, and lamivudine) combined with plasma exchanges (PE).Ninety-three (80.9%) patients entered remission during this period and 9 (9.7%) of them relapsed; 41 (35.7%) patients died. For the 80 patients given the antiviral strategy as intention-to-treat, 4 (5%) relapsed and 24 (30%) died vs 5 (14.3%) relapses (not significant NS) and 17 (48.6%) deaths (NS) among the 35 patients treated with CS alone or with CY or PE. HBe-anti-HBe seroconversion rates for the 2 groups, respectively, were: 49.3% vs 14.7% (p < 0.001). Patients who seroconverted obtained complete remission and did not relapse.Thus, HBV-PAN, a typical form of classic PAN, can be characterized as follows: when renal involvement is present, so is renal vasculitis; glomerulonephritis due to vasculitis is never found; antineutrophil cytoplasmic antibodies (ANCA) are not detected; relapses are rare, and never occur once viral replication has stopped and seroconversion has been obtained. Combining an antiviral drug with PE facilitates seroconversion and prevents the development of long-term hepatic complications of HBV infection. The major cause of death is gastrointestinal tract involvement. Importantly, the frequency of HBV-PAN has decreased in relation to improved blood safety and vaccination campaigns.
The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky ...limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval CI, 0.3-1.2; P = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (P = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.
•For early-stage DLBCL, R-CHOP alone is not inferior to R-CHOP followed by RT.
In most patients with nonsevere systemic necrotizing vasculitides (SNVs), remission is achieved with glucocorticoids alone, but one-third experience a relapse within 2 years. This study was ...undertaken to determine whether the addition of azathioprine (AZA) to glucocorticoids could achieve a higher sustained remission rate of newly diagnosed nonsevere eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), microscopic polyangiitis (MPA), or polyarteritis nodosa (PAN).
All patients included in this double-blind trial received glucocorticoids, gradually tapered over 12 months, and were randomized to receive AZA or placebo for 12 months, with stratification according to SNV (EGPA or MPA/PAN). The primary end point was the combined rate of remission induction failures and minor or major relapses at month 24.
Ninety-five patients (51 with EGPA, 25 with MPA, and 19 with PAN) met the inclusion criteria, were randomized, and received at least 1 dose of AZA (n = 46) or placebo (n = 49). At month 24, 47.8% of the patients receiving AZA versus 49% of the patients receiving placebo had remission induction failures or relapses (P = 0.86). Secondary end points were comparable between the AZA and placebo arms. These included initial remission rate (95.7% versus 87.8%), total relapse rate (44.2% versus 40.5%), and glucocorticoid use. Two patients in the placebo arm died; 22 patients in the AZA arm (47.8%) and 23 patients in the placebo arm (46.9%) experienced ≥1 severe adverse event. For EGPA patients, the primary end point (48% in the AZA arm versus 46.2% in the placebo arm) and the percent of patients who experienced asthma/rhinosinusitis exacerbations (24% in the AZA arm versus 19.2% in the placebo arm) were comparable between treatment arms.
Addition of AZA to glucocorticoids for the induction of remission of nonsevere SNVs does not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.
The aim of this study was to describe the presentation and outcomes of patients with granulomatosis with polyangiitis (GPA) presenting with CNS involvement.
Patients were included in this nationwide ...retrospective study if they had GPA according to ACR criteria and/or the European Medicines Agency algorithm and CNS involvement.
Thirty-five patients were included in the study. CNS involvement was observed in 51% of patients at GPA diagnosis. Headache (66%) was the main symptom, followed by sensory (43%) and motor impairment (31%). CNS involvement was characterized by pachymeningitis in 20, cerebral ischaemic lesions in 15 and haemorrhagic lesions in 2, with hypophyseal involvement in 2 patients. According to the clinical-radiological presentation, we distinguished granulomatous (G-CNS) and vasculitic (V-CNS) phenotypes. G-CNS patients more frequently had headaches, while V-CNS patients more frequently had motor impairment and renal involvement. Induction therapy produced clinical responses in 86% of patients. Baseline modified Rankin scale was higher for V-CNS than G-CNS patients (3 vs 2, P = 0.002). Initial spinal cord pachymeningitis was significantly associated with the need for a new induction regimen for relapsing/refractory disease (P = 0.01). Long-term neurological sequelae were noted in 51% of patients, including 35% with G-CNS and 69% with V-CNS (P = 0.08). Neurological sequelae were mainly noted in cases of spinal cord pachymeningitis (100%) and ischaemic or haemorrhagic lesions (73%).
The clinical-radiological phenotype distinguished different long-term outcomes in patients with GPA and CNS involvement. Long-term neurological sequelae persisted in half of patients, mainly those with spinal cord pachymeningitis and vasculitic lesions.
Purpose: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment ...related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (NCT03757221).
Methods: Fifty Ixa-Dara naïve RRMM patients (1-2 prior therapy) were planned to receive oral Ixa (4 mg: days 1, 8, 15), IV Dara (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Dara (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled if frailty score was ≥2 by IMWG score and FIRST proxy score (Facon T et al, Leukemia, 2020). The primary endpoint was ≥very good partial response rate at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5.0.
Results: Among 52 patients screened during this ongoing trial, 44 were included between 03/2018 and 05/2021. Patient were at first (n=28) or second relapse (n=16). Thirty -eight patients (86%) were previously exposed to bortezomib and 8 (18%) were previously refractory to lenalidomide. Median age was 82 (80-84). All patients had a frailty score ≥2. In 22 patients ISS was stage I (n=5), II (n=10) or III (n=7). Eleven (32%) patients harbored high-risk cytogenetic, including t(4;14) (n=3) or del17p (n=8). The median duration of Tx among 23 pts with ongoing Tx was 6 months 0-27 at data cutoff (July 19). The median duration of Tx among 21 pts who stopped Tx was 7 months 0-21: 13 had progressive disease. Six patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); progressive disease (C2 & C4), sepsis (C1 & C2). Regarding toxicity, 28 ≥grade 3 AE occurred amongst 24 pts (54%). The most common grade 3-4 toxicities were thrombocytopenia (n=5), other cytopenias (n=4), infection (n=4) and gastrointestinal disorders (n=2). Fourteen out of 28 were SAE including 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % in pts with ongoing treatment and 71% in pts who stopped Tx; ≥VGPR rate was 33% and 6% respectively.
Conclusions: These preliminary results show a favorable safety profile of ixazomib and daratumumab combination, without dexamethasone, in this specific population of very elderly frail patients with RRMM and high risk cytogenetic for almost one third of them. Efficacy results will be analyzed when the 50 patients will be enrolled in the study and evaluable for the primary endpoint.
Macro: GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vincent: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support.
Ixazomib and Daratumumab association is not approved in NDMM or in RRMM
8054
Background: Frailty is associated with inferior outcome in older myeloma patients, especially in the relapse setting.
1,2
This adverse prognosis is mainly related to a high discontinuation rate ...for treatment (Tx) related adverse events (AE). Dexamethasone is responsible of a high rate of infections and metabolic AE. We present here the updated results from the phase 2 study I-Dara evaluating efficacy and tolerability of Ixazomib-Daratumumab without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-five patients (64%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 23 (42 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx (DOT) in 14 pts with ongoing Tx was 22 mos min-max: 16-40 at data cutoff (January, 19). The median DOT in 41 pts who stopped Tx was 10 mos min-max: 0-31: 28 had progressive disease (PD). Fourteen patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2), sepsis (n = 3), pneumonia (n = 2), PD (n = 7). Regarding toxicity, 31 pts had a ≥grade 3 AE (55%). The most common grade 3-4 AE were thrombocytopenia (n = 10), other cytopenias (n = 5), anemia (n = 3), infection (n = 6), gastrointestinal disorders (n = 5) and hypertension (n = 3). The ≥VGPR rate is 32 % @ 1 year (34 % overall) with an ORR of 70% @ 1 year (74 % overall). In Len refractory patients the ≥VGPR rate is 40% @ 1 y and the ORR 70 %, in HR patients the ≥VGPR rate is 60 % and ORR 80%. With a median follow-up of 23.0 mos median PFS is 18.5 mos and median OS NR (75% OS estimated at 27.9 mos). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Late benefit is consistent with one third of patients still on treatment. Clinical trial information: NCT03757221 .
Objective
Temporal arteritis (TA) is a typical manifestation of giant cell arteritis (GCA). Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs) are rarely revealed by TA ...manifestations, leading to a risk of misdiagnosis of GCA and inappropriate treatments. This study was undertaken to describe the clinical, biologic, and histologic presentations and outcomes in cases of TA revealing AAV (TA‐AAV) compared to controls with classic GCA.
Methods
In this retrospective case–control study, the characteristics of patients with TA‐AAV were compared to those of control subjects with classic GCA. Log‐rank test, with hazard ratios (HRs) and 95% confidence intervals (95% CIs), was used to assess the risk of treatment failure.
Results
Fifty patients with TA‐AAV (median age 70 years) were included. Thirty‐three patients (66%) presented with atypical symptoms of GCA (ear, nose, and throat involvement in 32% of patients, and renal, pulmonary, and neurologic involvement in 26%, 20%, and 16% of patients, respectively). Blood samples were screened for ANCAs at the time of disease onset in 33 patients, and results were positive in 88%, leading to a diagnosis of early TA‐AAV in 20 patients. The diagnosis of AAV was delayed a median interval of 15 months in 30 patients. Compared to controls with GCA, patients with TA‐AAV were younger (median age 70 years versus 74 years), were more frequently men (48% versus 30%), and had high frequencies of atypical manifestations and higher C‐reactive protein levels (median 10.8 mg/dl versus 7.0 mg/dl). In patients with TA‐AAV, temporal artery biopsy (TAB) showed fibrinoid necrosis and small branch vasculitis in 23% of patients each, whereas neither of these characteristics was evident in controls with GCA. Treatment failure–free survival was comparable between early TA‐AAV cases and GCA controls, whereas those with delayed TA‐AAV had a significantly higher risk of treatment failure compared to controls (HR 3.85, 95% CI 1.97–7.51; P < 0.0001).
Conclusion
TA‐AAV should be considered diagnostically in cases of atypical manifestations of GCA, refractoriness to glucocorticoid treatment, or early relapse. Analysis of TAB specimens for the detection of small branch vasculitis and/or fibrinoid necrosis could be useful. Detection of ANCAs should be performed in cases of suspected GCA with atypical clinical features and/or evidence of temporal artery abnormalities on TAB.
Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and ...subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.
7501 Background: CD38 targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in NDMM TI and considered the current standard of care (SOC). The best treatment ...combinations are important in NDMM TI, as outcomes worsen with successive line of therapy. To improve current SOC, we evaluated the added value of prolonged use of bortezomib for 18 months with reduced intensity weekly schedule to IsaRd, with the intent to demonstrate the impact of a PI in a quadruplet regimen to improve depth of response. In BENEFIT/IFM2020-05 study (NCT04751877), we investigated efficacy and safety of IsaRd vs Isa-VRd in NDMM TI. Methods: BENEFIT is a prospective, multicenter, randomized, parallel trial. Patients aged 65-79, non-frail, with NDMM TI were randomized 1:1 and stratified by age, high-risk cytogenetic and center. Isa-VRd arm received V (1.3 mg/m 2 SC weekly up to c12 (c), bimonthly up to c18); both arms received Isa (10 mg/kg IV weekly and bimonthly up to c12, then monthly), R (25 mg), and d (20 mg up to c12). The primary endpoint was minimal residual disease (MRD) 10 -5 negative rate (NGS) at 18 months from treatment start analyzed in ITT. Key secondary endpoints included survival times (OS, PFS, EFS, TTNT), response rates and durations, MRD endpoints, and safety (using NCI CTCAE v5.0). Results: At data cutoff date (02 Feb 2024), 270 patients (135 per arm) were recruited. Patients baseline characteristics were well balanced across arms, overall median age was 73.2 years IQR. 71;76, 90 patients (33%) were >75 years, 23 (9%) had high-risk cytogenetic (IFM score >1), 181 (76%) had R-ISS2+3, and 47 (17%) had impaired renal function (eGFR <60 mL/min). MRD negativity rates at 10 -5 at 18 months were significantly higher in Isa-VRd arm compared to IsaRd arm (47% vs 24%, OR for negative MRD =2.96 95%CI. 1.73 – 5.07, p<0.001. The MRD benefit was consistent across subgroups. At 21.2 months median follow-up, 33 (12%) patients had relapsed and 20 (7%) had died, and no significant difference were observed across arms, yet. The addition of weekly “light” schedule of bortezomib did not significantly affect relative dose intensity of IsaRd. Forty-four (33%) patients presented with neurological adverse events grade ≥2 in the Isa-VRd vs 27 (20%) in IsaRd arm. Conclusions: Isa-VRd significantly deepened responses including a significant increase of the MRD negative rate at 10 -5 vs IsaRd. The safety profile is consistent with addition of bortezomib. This study supports Isa-VRd as a new standard of care for NDMM TI non-frail patients. Clinical trial information: NCT04751877 . Table: see text
8000
Background: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to ...treatment (Tx) related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-three patients (60%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 20 (36 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx among 28 pts with ongoing Tx was 10 months 5-32 at data cutoff (February, 2). The median duration of Tx among 27 pts who stopped Tx was 6 months 0-18: 18 had progressive disease. Nine patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); sepsis (n = 4), progressive disease (n = 3). Regarding toxicity, 27 pts had a ≥grade 3 AE (49%). The most common grade 3-4 toxicities were thrombocytopenia (n = 9), other cytopenias (n = 4), infection (n = 8), hypertension (n = 3) and gastrointestinal disorders (n = 3). Fourteen out of 28 were SAE including 5 infections, 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % with a ≥VGPR rate of 32 % in the whole group. In Len refractory patients the ORR was 82 % and ≥VGPR 41%, in HR cytogenetic patients ORR was 85 % and ≥VGPR 46%. With a median follow-up of 11.6 months median PFS is 16 months and median OS NR (76% estimated at one year). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Clinical trial information: NCT03757221.
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