The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high ...response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval CI 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.
Myelodysplastic neoplasms (MDS) are characterized by clonal evolution starting from the compartment of hematopoietic stem and progenitors cells (HSPCs), leading in some cases to leukemic ...transformation. We hypothesized that deciphering the diversity of the HSPCs compartment may allow for the early detection of an emergent sub-clone that drives disease progression. Deep analysis of HSPCs repartition by multiparametric flow cytometry revealed a strong disorder of the hematopoietic branching system in most patients at diagnosis with different phenotypic signatures closely related to specific MDS features. In two independent cohorts of 131 and 584 MDS, the HSPCs heterogeneity quantified through entropy calculation was decreased in 47% and 46% of cases, reflecting a more advanced state of the disease with deeper cytopenias, higher IPSS-R risk and accumulation of somatic mutations. We demonstrated that patients with lower-risk MDS and low CD34 + CD38+HSPCs entropy had an adverse outcome and that this parameter is as an independent predictive biomarker for progression free survival, leukemia free survival and overall survival. Analysis of HSPCs repartition at diagnosis represents therefore a very powerful tool to identify lower-risk MDS patients with a worse outcome and valuable for clinical decision-making, which could be fully integrated in the MDS diagnostic workflow.
Background EMA has recently approved Luspatercept (LUSPA) for the treatment of anemia in adult patients with RBC transfusion-dependent (TD) very low- to intermediate- risk MDS-RS or MDS/MPN with ...ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T) having failed an ESA. We designed a French observational registry of patients treated with LUSPA according to this label. In case of primary/secondary failure to LUSPA, we also investigated the effect of adding an ESA to LUSPA. The basis of this combination followed a GFM trial showing that, in non-del 5q lower risk MDS failing an ESA, Lenalidomide + ESA gave better results than Lenalidomide alone (Toma A et al. Leukemia. 2016 Apr;30(4):897-905). In a phase I study (GFM Combola trial), we found no unexpected side effects in the LUSPA -ESA combination (unpublished). Patients and treatment This French multicenter prospective observational registry started when the drug became available (July 2022), with a starting dose of 1 mg/kg SC every 3 weeks (2 infusions) and, in the absence of erythroid response increase to 1.33mg/kg (2 injections) and to 1.75 mg/kg (3 injections). In the absence of response after those 7 infusions, the addition of ESA (30 KU /week during 1 month and, if no response, 60 KU/week during 3 months) was recommended. Results Between July 2022 and January 2023, 108 patients (median age 70 years, 47% males) were included. Median time from diagnosis to LUSPA treatment was 64 months (IQR 40-99). According to WHO 2016, 86% of the patients had MDS-RS, 9% MDS-RS-T, and 5% MDS-EB1 or MDS-MLD (but with > 15% ringed cells and/or SF3B1 mutation). IPSS-R was very low, low, int in 96%, and high in 4%, IPSS-M very low/low/moderate low in 82%. Sixty-six of the 73 (90%) patients tested molecularly had SF3B1 mutation. All patients had received an ESA and 44 (41%) other treatments (1 to 6, median 1). The median duration of LUSPA exposure was 6.5 months (range 0.5-11), and 94% of patients had received at least 2 months of treatment. Erythroid response (HI-E, according to IWG 2018 criteria) to LUSPA alone was currently evaluable in 83 patients; 76 of them were RBC-TD before LUSPA (23 low TB (LTB) (1-5 units /8 weeks) and 53 high TB (HTB) (≥ 6 units /8 weeks)), and 30 (39%) of these achieved RBC-TI with no relapse after a median of 6.5 months (range 4.4-11). All 9 non-TD patients obtained HI-E and were still responders after a median of 8 (range 6.5-9) months. Of the 85 patients evaluable for response to LUSPA alone, 34% and 48% required a dose increase once or twice, respectively. The prognostic value of IPSS-R karyotype, IPSS-R, number of somatic mutations, LTB, HTB, number of treatments before LUSPA, previous lenalidomide exposure, and iron chelation was analyzed for their prognostic value on HI-E. In multivariate analysis, HTB was the only variable statistically associated with lower HI-E (OR 0.19 95%CI: 0.03-0.91, p=0.047 independently of IPSS-R and number of somatic mutations. At least 1 adverse event (AE) was seen in 38/103(37%) of the patients who received at least 2 doses of LUSPA, and 12 patients presented at least one severe AE (grade 3-4 according to CTCAE 5.0): including dizziness (in 5 patients), asthenia (n=4), peripheral and axial arthralgia (n= 4), headache (n=2), described by the patients as different from those they experienced with anemia. With a median follow-up of 6 months (IQR 5-8), 20 patients (18.5%) had discontinued LUSPA before 6 months of exposure due to severe AE (n=8, 7.4%, asthenia, arthralgia, dizziness, headache), lack of HI-E (n=3), disease progression (n=3), infection (n=3), death from intercurrent disease (n=2), acute coronary syndrome (n=1). After LUSPA failure, 26 patients (24.1%) received a combination of LUSPA and ESA and are currently followed. Efficacy and safety will be presented at the meeting. We also tried to correlate gene expression and GDF-11 levels with response. Results will be available at the meeting. Conclusions In this real-life study, we confirmed the results of LUSPA in MDS-RS reported in the MEDALIST study. We observed a significant number of adverse events attributed to LUSPA, some of which led to treatment discontinuation. The importance of RBC transfusion burden was the only prognostic factor of erythroid response.
•ITP women do not increase their risk of severe bleeding during pregnancy.•NITP is associated with NITP history and the severity of maternal ITP during pregnancy.
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The risk of immune ...thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years 95% confidence interval {CI}, 40.8-69.9 vs 37.1 95% CI, 27.5-50.0; hazard ratio {HR}, 1.35 95% CI, 0.89-2.03, P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 95% CI, 1.41-5.23, P = .003; HR, 2.01 95% CI, 1.14-3.57, P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 95% CI, 1.72-17.89, P = .004 and 4.07 95% CI, 1.41-11.73, P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.
There have been no prospective studies to establish the risk of pregnancy for patients with immune thrombocytopenia (ITP). In this Plenary Paper, Guillet and colleagues report on a prospective, multicenter observational cohort study comparing ITP outcomes in 131 pregnant vs 131 nonpregnant women with a history of ITP. Neonatal thrombocytopenia occurred in 14%, similar to previous reports. However, pregnancy did not increase bleeding or the degree of thrombocytopenia over nonpregnant patients, providing some reassurance to patients with ITP contemplating pregnancy.
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